JP4194539B2 - Azolotriazines and Azolopyrimidines - Google Patents

Description

  The present invention relates to certain [1,5-a] -pyrazolo-1,3,5-triazines, [1,5-a] -1,2,3-triazolo-1,3,5-triazines. , [1,5-a] -pyrazolo-pyrimidines and [1,5-a] -1,2,3-triazolo-pyrimidines, major depression, anxiety related diseases, post-traumatic stress disorder Treatment of psychiatric and neurological disorders, including supranuclear palsy and eating disorders, as well as treatment of immunological, cardiovascular or heart disease, and psychopathological disorders and stress-related colonic hypersensitivity About.

  Adrenocorticotropic hormone-releasing factor (hereinafter referred to as CRF) is a peptide consisting of 41 amino acids and is a major physiological regulator of peptide secretion derived from pro-opiomelanocortin (POMC) from the anterior pituitary gland ( Non-Patent Documents 1 and 2: J. Rivier et al., Proc. Nat. Acad. Sci. (USA), 80, 4851, 1983; W. Vale et al., Science, 213, 1394, 1981). In addition to the endocrine role in the pituitary gland, the immunohistochemical localization of CRF revealed that this hormone is widely distributed outside the hypothalamus of the central nervous system and is a neurotransmitter or neuromodulator in the brain Is to produce a wide range of autonomy, electrophysiological and behavioral effects in harmony with the role of (Non-Patent Documents 3, 4 and 5: W. Vale et al., Rec. Prog. Horm. Res. 39, 245, 1983; GF Koob, Persp. Behav. Med. 2, 39, 1985; EB De Souza et al., J. Neurosci. 5, 3189, 1985). There is also evidence that CRF plays an important role in integrating immune system responses to physiological, psychological and immunological stressors (Non-Patent Documents 6 and 7: JE Blalock, Physiological Reviews, Vol. 69, 1). Page, 1989; JE Morley, Life Sci. 41, 527, 1987).

  Clinical data provides evidence that CRF has a role in psychiatric and neurological disorders, including depression, anxiety-related diseases and eating disorders. CRF also plays a role in the etiology and pathophysiology of diseases related to CRF neuron dysfunction in the central nervous system such as Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis. (See Non-Patent Document 8: EB De Souza, Hosp. Practice, Vol. 23, p. 59, 1988).

  In affective disorder or major depression, the concentration of CRF in cerebrospinal fluid (CSF) of patients not receiving drugs is markedly increased (Non-Patent Documents 9 to 12: CB Nemeroff et al., Science, Vol. 226, page 1342, 1984; CM Banki et al., Am. J. Psychiatry, 144, 873, 1987; RD France et al., Biol. Psychiatry, 28, 86, 1988; M. Arato et al., Biol Psychiatry, 25, 355 pages, 1989). Furthermore, the CRF receptor density in the frontal cortex of suicides is also significantly reduced, which is consistent with CRF hypersecretion (Non-Patent Document 13: CB Nemeroff et al., Arch. Gen. Psychiatry, 45, 577, 1988). In depression patients, slowing of the response of corticotropin (ACTH) to CRF (intravenously administered) has been observed (Non-Patent Documents 14-16: PW Gold et al., Am. J. Psychiatry, 141 Vol., 619, 1984; F. Holsboer et al., Psychoneuroendocrinology, 9, 147, 1984; PW Gold et al., New Eng. J. Med., 314, 1129, 1986). Preclinical studies in rats and non-human primates also provide results that further support the hypothesis that CRF hypersecretion is involved in the symptoms seen in human depression (Non-Patent Document 17: RM). Sapolsky, Arch. Gen. Psychiatry, 46, 1047, 1989). There is also preliminary evidence that tricyclic antidepressants alter CRF concentrations and modulate multiple CRF receptors in the brain (Non-patent Document 18: Grigoriadis et al., Neuropsychopharmacology, Vol. 2, p. 53, 1989. Year).

  The role of CRF has also been postulated in the etiology of anxiety-related diseases. CRF produces an anxiogenic action in animals, and the interaction between benzodiazepine / non-benzodiazepine anxiolytics and CRF has been demonstrated in various behavioral anxiety models (Non-Patent Documents 19, 20: DR). Britton et al., Life Sci. 31, 363, 1982; CW Berridge and AJ Dunn Regul. Peptides, 16, 83, 1986). Preliminary studies in various behavioral cases using α-helical sheep CRF (9-41), which is presumed to be a CRF receptor antagonist, have shown that the antagonist is “anxiolytic-like” that is homogeneous with benzodiazepines. It is clarified that the action is produced (Non-patent Documents 21 and 22: CW Berridge and AJ Dunn Horm. Behav. 21, 393, 1987, Brain Research Reviews, 15, 71, 1990). Neurochemical, endocrine and receptor binding studies all revealed an interaction between CRF and benzodiazepine anxiolytics and provided more evidence than ever before of CRF involvement in these diseases. Chlordiazepoxide is a rat conflict test (Non-Patent Document 23, 24: KT Britton et al., Psychopharmacology, 86, 170, 1985; KT Britton et al., Psychopharmacology, 94, 306, 1988) and In any of the acoustic startle tests (Non-Patent Document 25: NR Swerdlow et al., Psychopharmacology, 88, 147, 1986), the “anxiety production” action of CRF is weakened. A benzodiazepine receptor antagonist (Ro15-1788), which lacks behavioral activity only in the operant conflict test, reverses CRF action in a dose-dependent manner, whereas a benzodiazepine agonist (FG7142) enhances CRF action (Non-Patent Document 26: KT Britton et al., Psychopharmacology, 94, 306, 1988).

The mechanism and site of action for normal anxiolytics and antidepressants to produce a therapeutic effect remains out of estimation. However, it has been hypothesized that these drugs are involved in the suppression of CRF hypersecretion observed in the disease. Of particular interest is a preliminary study investigating the effects of a CRF receptor antagonist (α-helical sheep CRF _9-41 ) in various behavioral cases, where the CRF antagonist is a “anti-anxiety drug that is homogeneous with benzodiazepines. (Non-patent Document 27: GF Koob and KT Britton, Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, edited by EBDe Souza and CB Nemeroff, CRC Press, 221 Page, 1990).

  Several publications describe corticotropin releasing factor antagonist compounds and their use in the treatment of psychiatric disorders and neurological disorders. Such publications include, for example, DuPont Merck PCT application US94 / 11050 (Patent Document 1), Pfizer WO95 / 33750 (Patent Document 2), Pfizer WO95 / 34563 (Patent Document 3), Pfizer WO95 / 33727 (Patent Document). 4) and Pfizer EP 0778 277 A1 (Patent Document 5).

  To the best of our knowledge, [1,5-a] -pyrazolo-1,3,5-triazines, [1,5-a] -1,2,3-triazolo-1,3,5-triazines, [1 , 5-a] -pyrazolo-pyrimidines and [1,5-a] -1,2,3-triazolo-pyrimidines are useful for the treatment of adrenocorticotropic hormone releasing factor for the treatment of psychiatric and neurological disorders It has never been reported as a drug compound in the past. However, there have been publications teaching the use of some of these compounds for other applications.

  For example, EP 0 269 859 (Otsuka, 1988) (Patent Document 6) is expressed by the following equation:

Disclosed are pyrazolotriazine compounds in which R ¹ is OH or alkanoyl, R ² is H, OH, or SH and R ³ is an unsaturated heterocyclic group, naphthyl or substituted phenyl. States that it has xanthine oxidase inhibitory activity and is useful in the treatment of gout.

  EP 0 594 149 (Otsuka, 1994) (Patent Document 7) is expressed by the following equation:

Pyrazolotriazine and pyrazolopyrimidine compounds in which A is CH or N, R ⁰ and R ³ are H or alkyl, R ¹ and R ² are H, alkyl, alkoxyl, alkylthio, nitro, etc. are disclosed States that the compounds inhibit male hormones and are useful in the treatment of benign prostatic hypertrophy and prostate cancer.

  U.S. Pat. No. 3,910,907 (ICI, 1975) (Patent Document 8) is represented by the following formula:

Wherein R ¹ is CH ₃ , C ₂ H ₅ or C ₆ H ₅ , X is H, C ₆ H ₅ , m-CH ₃ C ₆ H ₄ , CN, COOEt, Cl, I or Br, Y is _{H, C 6 H 5, o} -CH 3 C 6 H 4 or _{p-CH 3 C 6 H 4} , Z is _{OH, H, CH 3, C} 2 H 5, C 6 H 5, n-C 3, Disclosed are pyrazolotriazines that are H ₇ , i-C ₃ H ₇ , SH, SCH ₃ , NHC ₄ H ₉ , or N (C ₂ H ₅ ) ₂ , which compounds are useful as bronchodilators. -Stated to be an AMP phosphodiesterase inhibitor.

  U.S. Pat. No. 3,995,039 (Patent Document 9) is represented by the following formula:

Pyrazolotriazines wherein R ¹ is H or alkyl, R ² is H or alkyl, R ³ is H, alkyl, alkanoyl, carbamoyl, or lower alkylcarbamoyl and R is pyridyl, pyrimidinyl, or pyrazinyl Disclosed and states that the compounds are useful as bronchodilators.

  US Pat. No. 5,137,887 (Patent Document 10) is represented by the following formula:

  Pyrazolotriazines, wherein R is lower alkoxy, are disclosed and teach that these compounds are xanthine oxidase inhibitors and are useful in the treatment of gout.

  U.S. Pat. No. 4,892,576 (Patent Document 11) is represented by the following formula:

Pyrazolotriazines wherein X is O or S, Ar is phenyl, naphthyl, pyridyl or thienyl group, R _{6 to} R ₈ are H, alkyl, etc., and R ₉ is H, alkyl, phenyl, etc. is doing. This patent states that the compounds are useful as herbicides and plant growth regulators.

  U.S. Pat. No. 5,484,760 (Patent Document 12) and WO 92/10098 (Patent Document 13) are represented by the following equations:

Wherein A is N, B is CR ₃ , R ₃ is phenyl or substituted phenyl, and R is —N (R ₄ ) SO ₂ R ₅ or —SO ₂ N (R ₆ ) R ₇ And R ₁ and R ₂ are taken together,

を形成することもあり、

May form,

  Here, a herbicidal composition is disclosed that contains a herbicidal compound in which X, Y, and Z are H, alkyl, acyl, etc., and D is O or S in other materials.

  US Pat. No. 3,910,907 (Patent Document 8) and Senga et al. (Non-Patent Document 28: J. Med. Chem. 25, 243-249, 1982) are represented by the following formulas:

In the above formula, Z is _{H, OH, CH 3, C} 2 H 5, C 6 H 5, n-C 3 H 7, iso-C 3 H 7, SH, SCH 3, NH (n-C 4 H 9 ), Or N (C ₂ H ₅ ) ₂ , where R is H or CH ₃ and R ₁ is CH ₃ or C ₂ H ₅ , discloses triazolotriazines cAMP phosphodiesterase inhibitors. This reference lists eight therapeutic areas: asthma, diabetes mellitus, female fertility regulation, male infertility, psoriasis, thrombosis, anxiety and hypertension where cAMP phosphodiesterase inhibitors are considered effective.

  WO 95/35298 (Otsuka, 1995) (Patent Document 14) discloses pyrazolopyrimidines and states that these compounds are useful as analgesics. The compound is represented by the following formula:

Wherein Q is carbonyl or sulfonyl, n is 0 or 1, A is a single bond, alkylene or alkenylene, R ¹ is H, alkyl, etc., R ² is naphthyl, cycloalkyl, heteroaryl, substituted phenyl or phenoxy, R ³ is H, alkyl or phenyl, R ⁴ is H, alkyl, alkoxycarbonyl, phenylalkyl, phenyl optionally substituted with phenylthio, or halogen, R ⁵ and R ⁶ are H or alkyl.

  EP 0 591 528 (Otsuka, 1991) (Patent Document 15) is represented by the following equation:

Wherein R ₁ , R ₂ , R ₃ and R ₄ are H, carboxyl, alkoxycarbonyl, optionally substituted alkyl, cycloalkyl, or phenyl, R ₅ is SR ₆ or NR ₇ R ₈ , R ₆ is Pyrazolopyrimidines are disclosed for use as anti-inflammatory agents where pyridyl or optionally substituted phenyl, R ₇ and R ₈ are H or optionally substituted phenyl.

  Springer et al. (Non-Patent Document 29: J. Med. Chem. 19: 2, 291-296, 1976) and Springer US Pat. Nos. 4,021,556 (Patent Document 16) and 3,920, No. 652 (Patent Document 17) is represented by the following formula:

  Based on the above formula, pyrazolopyrimidines where R is phenyl, substituted phenyl or pyridyl, and their use to treat gout based on their ability to inhibit xanthine oxidase is disclosed.

  Joshi et al. (Non-Patent Document 30: J. Prakt. Chemie, 321 (2), 341-344, 1979) is represented by the following formula:

Disclosed are compounds wherein R ¹ is CF ₃ , C ₂ F ₅ , or C ₆ H ₄ F and R ² is CH ₃ , C ₂ H ₅ , CF ₃ , or C ₆ H ₄ F Yes.

  Maquestiau et al. (Non-Patent Document 31: Bull. Soc. Belg. 101, 2, 131-136, 1992) discloses pyrazolo [1,5-a] pyrimidines of the formula:

  Ibrahim et al. (Non-Patent Document 32: Arch. Pharm. (Weinheim), 320, 487-491, 1987) is represented by the following formula:

Pyrazolo [1,5-a] pyrimidines are disclosed wherein R is NH ₂ or OH and Ar is 4-phenyl-3-cyano-2-aminopyrid-2-yl.

  Other references disclosing azolopyrimidines include EP 0 511 528 (Otsuka, 1992) (Patent Document 18), US Pat. No. 4,997,940 (Dow, 1991) (Patent Document 19). ), EP 0 374 448 (Nissan, 1990) (Patent Document 20), US Pat. No. 4,621,556 (ICN, 1997) (Patent Document 21), EP 0 531 901 (Fujisawa, 1993) ( US Pat. No. 4,567,263 (BASF, 1986) (Patent Document 23), EP 0 662 477 (Isagro, 1995) (Patent Document 24), DE 4 243 279 (Bayer, 1994). (Patent Document 25), US Pat. No. 5,397,774 (Upjohn, 1995) (Patent Document 26), EP 0 521 622 (Upjohn, 1993) (Patent Document 27), WO 94/109017 (Patent Document 27). Upjohn, 1994) Patent Document 28), J. Med. Chem. 24, 610-613, 1981 (Non-Patent Document 33) and J. Het. Chem. 22, Volume 601, 1985 (Non-Patent Document 34), It was included.

PCT application US94 / 11050 WO95 / 33750 pamphlet WO95 / 34563 pamphlet International Publication No. 95/33727 Pamphlet European Patent Application No. 0 778 277 A1 European Patent Application Publication No. 0 269 859 European Patent Application No. 0 594 149 US Pat. No. 3,910,907 US Pat. No. 3,995,039 US Pat. No. 5,137,887 US Pat. No. 4,892,576 US Pat. No. 5,484,760 International Publication No. 92/10098 Pamphlet WO95 / 35298 pamphlet European Patent Application Publication No. 0 591 528 U.S. Pat. No. 4,021,556 US Pat. No. 3,920,652 European Patent Application Publication No. 0 511 528 US Pat. No. 4,997,940 European Patent Application No. 0 374 448 US Pat. No. 4,621,556 European Patent Application Publication No. 0 531 901 US Pat. No. 4,567,263 European Patent Application Publication No. 0 662 477 German Patent Application Publication No. 4 243 279 US Pat. No. 5,397,774 European Patent Application Publication No. 0 521 622 International Publication No. 94/109017 Pamphlet J. Rivier et al., Proc. Nat. Acad. Sci. (USA), 80, 4851, 1983 W. Vale et al., Science, 213, 1394, 1981 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 J.E.Blalock, Physiological Reviews, 69, 1 page, 1989 J.E.Morley, Life Sci. 41, 527, 1987 E.B.De Souza, Hosp. Practice, 23, 59, 1988 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., Biol Psychiatry, 25, 355, 1989 C.B. Nemeroff et al., Arch. Gen. Psychiatry, 45, 577, 1988 P.W.Gold et al., Am.J.Psychiatry, 141, 619, 1984 F. Holsboer et al., Psychoneuroendocrinology, 9, 147, 1984 P.W.Gold et al., New Eng. J. Med.314, 1129, 1986 R.M.Sapolsky, Arch.Gen.Psychiatry, 46, 1047, 1989 Grigoriadis et al., Neuropsychopharmacology, 2, 53, 1989 D.R.Britton et al., Life Sci. 31, 363, 1982 C.W.Berridge and A.J.Dunnn Regul.Peptides, 16, 83, 1986 C.W.Berridge and A.J.Dunnn Horm.Behav.21, 393, 1987 C.W.Berridge and A.J.Dunn Brain Research Reviews, 15, 71, 1990 K.T.Britton et al., Psychopharmacology, 86, 170, 1985 K.T.Britton et al., Psychopharmacology, 94, 306, 1988 N.R.Swerdlow et al., Psychopharmacology, 88, 147, 1986 K.T.Britton et al., Psychopharmacology, 94, 306, 1988 G.F.Koob and K.T.Britton, Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, edited by E.B.De Souza and C.B. Nemeroff, CRC Press, 221 pages, 1990 Senga et al., J. Med. Chem. 25, 243-249, 1982 Springer et al., J. Med. Chem. 19 (2), 291-296, 1976 Joshi et al., J. Prakt. Chemie, 321, 2 (341-344), 1979 Maquestiau et al., Bull. Soc. Belg. 101, 2, 131-136, 1992 Ibrahim et al., Arch. Pharm. (Weinheim), 320, 487-491, 1987 J. Med. Chem. 24, 610-613, 1981 J. Het. Chem. 22 (601), 1985 Greene and Wuts "Protective Groups in Organic Synthesis", John Wiley & Sons, New York, 1991 Greene and Wuts "Peptides: Analysis, Synthesis, Biology", Volume 3, Academic Press, New York, 1981 "Remington's Pharmaceutical Sciences", 17th edition, Mack Publishing Company, Easton, PA, p. 1418, 1985 Uemura, S., "Oxidation of Sulfur, Selenium and Tellurium", Comprehensive Organic Synthesis, Trost, BM, (Elmsford, NY: Pergamon Press, 1991) 7, 762-769 pages Imamoto, T., “Organocerium Reagents”, Comprehensive Organic Synthesis, Trost, B.M. (Elmsford, NY: Pergamon Press, 1991), Volume 1, pages 231-250 Knochel, P., "Organic zinc, organocadmium, and organomercury reagents (Organozinc, Organocadmium, and Organomercury Reagents)", Comprehensive Organic Synthesis, Trost, BM, (Elmsford, NY: Pergamon Press, 1991), 1 Volume, pages 211-230 Knight, DW, “Coupling Reactions between sp2 Carbon Centers”, Comprehensive Organic Synthesis, Trost, BM, (Elmsford, NY: Pergamon Press, 1991), Volume 3, 481- 520 pages D. Perrin and W.L.F. Armarego, Purification of Laboratory Chemicals, 3rd edition, (New York: Pergamon Press, 1988) P. J. Munson and D. Rodbard, Anal. Biochem. 107: 220 (1980) Synapse 1: 572 (1987) by G. Battaglia et al. C. W. Berridge and A. J. Dunn, Brain Research Reviews 15:71 (1990) Remington Pharmaceutical Sciences, A. Osol

  In one aspect of the invention, novel compounds, pharmaceutical compositions and affective disorders, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear paralysis, immunosuppression, Alzheimer's disease, gastrointestinal disorders, anorexia nervosa Or treatment of other eating disorders, drug or alcohol withdrawal symptoms, drug addiction, inflammatory diseases, fertility problems, etc., treatment of the disorder is achieved or facilitated by antagonism of CRF, induced or promoted by CRF Disorders, including but not limited to, or diseases selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety related diseases; Obsessive-compulsive disorder; post-traumatic stress disorder; stress sleep disorder; pain perception such as fibromyalgia; depression, including major depression, single seizure depression, Mood disorders such as onset depression, abused child depression, and postpartum depression; mood modulation; bipolar disorders; circulating temperament; fatigue syndrome; stress headache; cancer, human immunodeficiency virus (HIV) ) Infectious diseases; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; postoperative ileus and colon associated with ulcers, irritable bowel syndrome, Crohn's disease, colonic cramps, diarrhea, and psychopathological disorders or stress Hypersensitivity; eating disorders such as anorexia nervosa or bulimia nervosa; bleeding stress; stress psychotic episodes; sinus syndrome with normal thyroid function; antidiuretic hormone (ADH) incompatibility syndrome; obesity; Head injury; spinal cord injury; ischemic neuronal damage (eg, cerebral ischemia such as cerebral hippocampal ischemia); Toxic neuronal damage; epilepsy; cardiovascular and cardiac disorders including hypertension, tachycardia and congestive heart failure; stroke; immune dysfunction including stress immune dysfunction (eg, stress fever, swine stress syndrome, cattle Fever fever, equine paroxysmal fibrillation, and chicken claustration-induced dysfunction, sheep shaving or canine human-animal interaction stress); muscle spasm; urinary incontinence; Alzheimer-type senile dementia; Infarct dementia; amyotrophic lateral sclerosis; chemical dependence or chemical addiction (eg, alcohol, cocaine, heroin, benzodiazepines, or other drugs); drugs or alcohol withdrawal symptoms; osteoporosis; society Methods are provided that can be used to treat in mammals with psychological dwarfism and hypoglycemia.

  The present invention provides novel compounds that alter the anxiety-producing effects of CRF secretion by binding to corticotropin releasing factor receptors. The compounds of the present invention comprise psychiatric disorders and neurological diseases, anxiety-related diseases, post-traumatic stress disorders, supranuclear paralysis and eating disorders and immunological, cardiovascular or heart diseases, and psychopathological disorders and Useful in the treatment of stress-related colonic hypersensitivity in mammals.

  Another aspect of the present invention provides novel compounds of formulas (1) and (2) (discussed below) useful as antagonists of corticotropin releasing factor. The compounds of the present invention show activity as antagonists of adrenocorticotropic hormone releasing factor and appear to suppress CRF hypersecretion. The present invention also includes pharmaceutical compositions containing the compounds of formulas (1) and (2) and methods of using the compounds for the suppression of CRF hypersecretion and / or the treatment of anxiety-producing diseases.

  In another aspect of the present invention, the compounds provided by the present invention (and particularly the labeled compounds of the present invention) are also useful as standards and reagents in measuring the ability of potential drugs to bind to CRF receptors. is there.

  [1] The present invention relates to affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear paralysis, immunosuppression, Alzheimer's disease, gastrointestinal disorder, anorexia nervosa or other eating Disorder, drug addiction, drug or alcohol withdrawal, inflammatory disease, cardiovascular disease or heart disease, fertility problem, human immunodeficiency virus (HIV) infection, hemorrhagic stress, obesity, infertility, head and spinal cord Including trauma, epilepsy, stroke, ulcer, amyotrophic lateral sclerosis, hypoglycemia, or disorders induced or promoted by CRF antagonism, which are achieved or facilitated by antagonism of CRF A method of treatment in mammals such as, but not limited to, a compound of formula (1) and (2),

And administering to a mammal a therapeutically effective amount of the isomer, its stereoisomer, or a mixture of its stereoisomers, and a pharmaceutically acceptable salt or prodrug thereof,
Where
A is N or CR;
Z is N or CR ²
Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4 Selected from -dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R ⁴ groups, each Ar bound to an unsaturated carbon atom;
R is independently, _H in each _case, C 1 -C _{4 alkyl,} C 2 -C _{4 alkenyl,} C 2 -C _{4 alkynyl,} C 3 -C _{6 cycloalkyl,} C 4 -C ₇ cycloalkylalkyl, halo, _CN, selected from C 1 -C ₄ haloalkyl,
R ¹ is independently in each case H, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, halo, CN, C ₁ -C ₄ haloalkyl, C ₁ -C _{12 hydroxyalkyl,} C 2 _{-C 12 alkoxyalkyl,} C 2 _{-C 10 cyanoalkyl,} C 3 -C _{6 cycloalkyl,} C 4 _{-C 10 ^{cycloalkylalkyl, NR 9 R 10, C 1}} -C 4 alkyl -NR ⁹ Selected from R ¹⁰ , NR ⁹ COR ¹⁰ , OR ¹¹ , SH or S (O) _n R ¹² ;
R ² is H, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₁₀ cycloalkyl alkyl, C ₁ -C ₄ hydroxy Alkyl, halo, CN, —NR ⁶ R ⁷ , NR ⁹ COR ¹⁰ , —NR ⁶ S (O) _n R ⁷ , S (O) _n NR ⁶ R ⁷ , C ₁ -C ₄ haloalkyl, —OR ⁷ , SH Or selected from —S (O) _n R ¹² ,
R ³ is
_{^{-H, OR 7, SH, S}} (O) n R 13, COR 7, CO 2 R 7, OC (O) R 13, NR 8 COR 7, N (COR 7) 2, NR 8 CONR 6 R 7, NR ⁸ CO ₂ R ¹³ , NR ⁶ R ⁷ , NR ^6a R ^7a , N (OR ⁷ ) R ⁶ , CONR ⁶ R ⁷ , aryl, heteroaryl and heterocyclic groups,
Or -C ₁ -C _{10 alkyl,} C 2 _{-C 10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 -C _{8 cycloalkyl,} C 5 -C _{8 cycloalkenyl,} C 4 _{-C 12} cycloalkylalkyl or _{C 6} -C ₁₀ cycloalkenylalkyl (each group, _C 1 -C ₆ alkyl, independently in each _case, C 3 -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, ^cyano, OR 15, SH, S (O) _n R ¹³ , COR ¹⁵ , CO ₂ R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ₂ , NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹³ , NR Optionally substituted with 1 to 3 substituents selected from ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclic groups Is selected from)
R ⁴ is independently in each case C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₁₂ cycloalkylalkyl, NO _2, halo, _CN, C 1 -C ₄ ^{haloalkyl, NR 6 R 7, NR 8} COR 7, NR 8 CO 2 R 7, COR 7, OR 7, CONR 6 R 7, CO (NOR 9) R 7, CO ₂ R ^7, or _{^{S (O) n R 7 (}} C 1 -C 10 _alkyl, C 2 _{-C 10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 -C ₆ cycloalkyl and _C 4 _{-C 12} cycloalkylalkyl, each independently _C 1 -C ₄ alkyl in each case, NO _2, ^{halo, CN, NR 6 R 7,} NR 8 COR 7, NR 8 CO 2 R 7, CO ^{7, OR 7, CONR 6 R} 7, CO 2 R 7, CO (NOR 9) R 7 or S, _(O) is optionally substituted with 1 to 3 substituents selected from the n ^{R 7)} Selected from
R ⁶ and R ⁷ , R ^6a and R ^7a are independently in each case
-H,
-C ₁ -C _{10 alkyl,} C 3 _{-C 10 alkenyl,} C 3 _{-C 10} alkynyl, halogen atoms 1-10 _C 1 _{-C 10 haloalkyl,} C 2 -C _{8 alkoxyalkyl,} C 3 -C ₆ Cycloalkyl, C ₄ -C ₁₂ cycloalkylalkyl, C ₅ -C ₁₀ cycloalkenyl, or C ₆ -C ₁₄ cycloalkenylalkyl (each group is independently in each case C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, _{^{cyano, OR 15, SH, S (}} O) n R 13, COR 15, CO 2 R 15, OC (O) R 13, NR 8 COR 15 _{^{, N (COR 15) 2,}} NR 8 CONR 16 R 15, NR 8 CO 2 R 13, NR 16 R 15, CONR 16 R 15, A Lumpur, is optionally substituted with 1 to 3 substituents selected from heteroaryl and heterocyclic group),
- aryl, aryl _(C 1 -C ₄ alkyl), heteroaryl, heteroaryl _(C 1 -C ₄ alkyl), or is selected from a heterocyclic group or a heterocyclic _(C 1 -C ₄ alkyl),
Alternatively, NR ⁶ R ⁷ and NR ^6a R ^7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine (each group is optionally selected from _{1 to} 3 C ₁ -C ₄ alkyl groups Is replaced with
R ⁸ is independently selected in each case from H or C ₁ -C ₄ alkyl;
R ⁹ and R ¹⁰ are independently selected in each case from H, C ₁ -C ₄ alkyl, or C ₃ -C ₆ cycloalkyl;
R ¹¹ is selected from H, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or C ₃ -C ₆ cycloalkyl;
R ¹² is C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl;
R ¹³ is C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₈ alkoxyalkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₁₂ cycloalkylalkyl, aryl, aryl (C ₁ -C ₄ alkyl)-, heteroaryl, heteroaryl (C ₁ -C ₄ alkyl)-
R ¹⁴ is C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ alkenyl, C ₃ -C ₁₀ alkynyl, C ₃ -C ₈ cycloalkyl, or C ₄ -C ₁₂ cycloalkyl alkyl (each group is Independently, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halo, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) _n R ¹⁵ , COR ¹⁵ , CO ₂ R ¹⁵ , OC (O) R ¹⁵ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ₂ , NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹⁵ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , and C ₁ -C Optionally substituted with 1 to 3 substituents selected from ₆ alkylthio, C ₁ -C ₆ alkylsulfinyl and C ₁ -C ₆ alkylsulfonyl )
R ¹⁵ and R ¹⁶ are independently in each case H, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₁₆ cycloalkylalkyl (in the case of S (O) _n R ¹⁵ , R ¹⁵ is not H)
Aryl is phenyl or naphthyl (each group independently in each case C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halo, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) _n R ¹⁵ , COR ¹⁵ , CO ₂ R ¹⁵ , OC (O) R ¹⁵ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ₂ , NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹⁵ , NR ¹⁶ R ¹⁵ , and optionally substituted with 1 to 5 substituents selected from CONR ¹⁶ R ¹⁵ )
Heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2 , 3-dihydrobenzofuranyl (each group independently in each case C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halo, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH , S (O) _n R ¹⁵ , —COR ¹⁵ , CO ₂ R ¹⁵ , OC (O) R ¹⁵ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ₂ , NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹⁵ , ^NR 16 ^{R 15,} Oyo Optionally is selected from is substituted) with 1 to 5 substituents selected from CONR ¹⁶ R ^15,
Heterocyclic groups are saturated or partially saturated heteroaryl (each group is independently in each case C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halo, C ₁ -C ₄ haloalkyl, _{^{cyano, OR 15, SH, S (}} O) n R 15, COR 15, CO 2 R 15, OC (O) R 15, NR 8 COR 15, n (COR 15) 2, NR 8 CONR 16 R ¹⁵ , optionally substituted with 1 to 5 substituents selected from NR ⁸ CO ₂ R ¹⁵ , NR ¹⁵ R ¹⁶ , and CONR ¹⁶ R ¹⁵ ),
n is independently 0, 1 or 2 in each case.

[2] A preferred method of the present invention is represented by formula (1) or (2), wherein Ar is phenyl, pyridyl, or 2,3-dihydrobenzofuranyl (each having 1 to 4 R ⁴ substituents) Wherein the compound is optionally substituted).

[3] A more preferred method of the invention is represented by the formula (1) or (2), wherein A is N, Z is CR ² , Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4 , 6-trimethylphenyl, the method of treatment with a compound wherein R ¹ and R ² are methyl and R ³ is NR ^6a R ^7a .

  [4] The present invention provides compounds of formulas (1) and (2),

And its isomers, its stereoisomers, or mixtures of its stereoisomers, and pharmaceutically acceptable salts or prodrugs thereof,
Where
A is N or CR;
Z is N or CR ²
Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4 Selected from -dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R ⁴ groups, each Ar bound to an unsaturated carbon atom;
R is independently, _H in each _case, C 1 -C _{4 alkyl,} C 2 -C _{4 alkenyl,} C 2 -C _{4 alkynyl,} C 3 -C _{6 cycloalkyl,} C 4 -C ₇ cycloalkylalkyl, halo, _CN, selected from C 1 -C ₄ haloalkyl,
R ¹ is independently in each case H, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, halo, CN, C ₁ -C ₄ haloalkyl, C ₁ -C _{12 hydroxyalkyl,} C 2 _{-C 12 alkoxyalkyl,} C 2 _{-C 10 cyanoalkyl,} C 3 -C _{6 cycloalkyl,} C 4 _{-C 10 ^{cycloalkylalkyl, NR 9 R 10, C 1}} -C 4 alkyl -NR ⁹ Selected from R ¹⁰ , NR ⁹ COR ¹⁰ , OR ¹¹ , SH or S (O) _n R ¹² ;
R ² is H, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₁₀ cycloalkyl alkyl, C ₁ -C ₄ hydroxy Alkyl, halo, CN, —NR ⁶ R ⁷ , NR ⁹ COR ¹⁰ , —NR ⁶ S (O) _n R ⁷ , S (O) _n NR ⁶ R ⁷ , C ₁ -C ₄ haloalkyl, —OR ⁷ , SH Or selected from —S (O) _n R ¹² ,
R ³ is
_{^{-H, OR 7, SH, S}} (O) n R 13, COR 7, CO 2 R 7, OC (O) R 13, NR 8 COR 7, N (COR 7) 2, NR 8 CONR 6 R 7, NR ⁸ CO ₂ R ¹³ , NR ⁶ R ⁷ , NR ^6a R ^7a , N (OR ⁷ ) R ⁶ , CONR ⁶ R ⁷ , aryl, heteroaryl and heterocyclic groups, or —C ₁ -C ₁₀ alkyl, C ₂ -C _{10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 -C _{8 cycloalkyl,} C 5 -C _{8 cycloalkenyl,} C 4 _{-C 12} cycloalkylalkyl or _C 6 _{-C 10} cycloalkenylalkyl (each group is independently in each _C 1 -C _{6 alkyl,} C 3 -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, ^cyano, OR 15, SH, S _{^{O) n R 13, COR 15}} , CO 2 R 15, OC (O) R 13, NR 8 COR 15, N (COR 15) 2, NR 8 CONR 16 R 15, NR 8 CO 2 R 13, NR 16 R ¹⁵ , CONR ¹⁶ R ¹⁵ , optionally substituted with 1 to 3 substituents selected from aryl, heteroaryl and heterocyclic groups),
R ⁴ is independently C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₁₂ cycloalkylalkyl, NO ₂ , halo, _CN, C 1 -C ₄ ^{haloalkyl, NR 6 R 7, NR 8} COR 7, NR 8 CO 2 R 7, COR 7, OR 7, CONR 6 R 7, CO (NOR 9) R 7, CO 2 R 7, Or S (O) _n R ⁷ (C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₆ cycloalkyl and C ₄ -C ₁₂ cycloalkylalkyl, respectively, _C 1 -C ₄ alkyl case independently, NO _2, ^{halo, CN, NR 6 R 7,} NR 8 COR 7, NR 8 CO 2 R 7, COR 7, OR 7, C Is selected from _{^{NR 6 R 7, CO 2 R}} 7, CO (NOR 9) R 7 is optionally substituted or by one to three substituents selected from ^{_{S (O) n R 7,}} ),
R ⁶ and R ⁷ , R ^6a and R ^7a are independently in each case
-H,
-C ₁ -C _{10 alkyl,} C 3 _{-C 10 alkenyl,} C 3 _{-C 10} alkynyl, _C 1 _{-C 10} haloalkyl having 1 to 10 halogen _atoms, C 2 -C _{8 alkoxyalkyl,} C 3 -C ₆ cycloalkyl Alkyl, C ₄ -C ₁₂ cycloalkylalkyl, C ₅ -C ₁₀ cycloalkenyl, or C ₆ -C ₁₄ cycloalkenylalkyl (each group is independently C ₁ -C ₆ alkyl, C _{3 in} each case) -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, _{^{cyano, OR 15, SH, S (}} O) n R 13, COR 15, CO 2 R 15, OC (O) R 13, NR 8 COR 15, _{^{N (COR 15) 2, NR}} 8 CONR 16 R 15, NR 8 CO 2 R 13, NR 16 R 15, CONR 16 R 15, Ali Le is optionally substituted with 1-3 substituents selected from heteroaryl and heterocyclic group),
- aryl, aryl _(C 1 -C ₄ alkyl), heteroaryl, heteroaryl _(C 1 -C ₄ alkyl), or is selected from a heterocyclic group or a heterocyclic _(C 1 -C ₄ alkyl),
Alternatively, NR ⁶ R ⁷ and NR ^6a R ^7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine (each group is optionally selected from _{1 to} 3 C ₁ -C ₄ alkyl groups Is replaced with
R ⁸ is independently selected in each case from H or C ₁ -C ₄ alkyl;
R ⁹ and R ¹⁰ are independently selected in each case from H, C ₁ -C ₄ alkyl, or C ₃ -C ₆ cycloalkyl;
R ¹¹ is selected from H, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or C ₃ -C ₆ cycloalkyl;
R ¹² is C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl;
R ¹³ is C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₈ alkoxyalkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₁₂ cycloalkylalkyl, aryl, aryl (C ₁ -C ₄ alkyl)-, heteroaryl, heteroaryl (C ₁ -C ₄ alkyl)-
R ¹⁴ is C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ alkenyl, C ₃ -C ₁₀ alkynyl, C ₃ -C ₈ cycloalkyl, or C ₄ -C ₁₂ cycloalkyl alkyl (each group is Independently, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halo, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) _n R ¹⁵ , COR ¹⁵ , CO ₂ R ¹⁵ , OC (O) R ¹⁵ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ₂ , NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹⁵ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , and C ₁ -C Optionally substituted with 1 to 3 substituents selected from ₆ alkylthio, C ₁ -C ₆ alkylsulfinyl and C ₁ -C ₆ alkylsulfonyl )
R ¹⁵ and R ¹⁶ are independently in each case H, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₁₆ cycloalkylalkyl (in the case of S (O) _n R ¹⁵ , R ¹⁵ is not H)
Aryl is phenyl or naphthyl (each group independently in each case C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halo, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) _n R ¹⁵ , COR ¹⁵ , CO ₂ R ¹⁵ , OC (O) R ¹⁵ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ₂ , NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹⁵ , NR ¹⁶ R ¹⁵ , and optionally substituted with 1 to 5 substituents selected from CONR ¹⁶ R ¹⁵ )
Heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2 , 3-dihydrobenzofuranyl (each group independently in each case C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halo, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH , S (O) _n R ¹⁵ , —COR ¹⁵ , CO ₂ R ¹⁵ , OC (O) R ¹⁵ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ₂ , NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹⁵ , ^NR 16 ^{R 15,} Oyo Optionally is selected from is substituted) with 1 to 5 substituents selected from CONR ¹⁶ R ^15,
Heterocyclic groups are saturated or partially saturated heteroaryl (each group is independently in each case C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halo, C ₁ -C ₄ haloalkyl, _{^{cyano, OR 15, SH, S (}} O) n R 15, COR 15, CO 2 R 15, OC (O) R 15, NR 8 COR 15, n (COR 15) 2, NR 8 CONR 16 R ¹⁵ , optionally substituted with 1 to 5 substituents selected from NR ⁸ CO ₂ R ¹⁵ , NR ¹⁵ R ¹⁶ , and CONR ¹⁶ R ¹⁵ ),
n is independently 0, 1 or 2 in each case;
However,
(1) When A is N, Z is CR ² , R ² is H, R ³ is —OR ⁷ or —OCOR ¹³ , and R ⁷ is H, R ¹ is not H, OH, or SH,
(2) A is N, Z is ^CR 2, ^{R 1} is CH ₃ or _C ² _H 5, ^R 2 is H, and ^{R 3} is _{OH, H, CH 3, C} 2 H 5, C 6 H 5, n _{-C 3 H 7, i-C} 3 H 7, SH, SCH 3, NHC 4 H 9 or _{N (C 2} H _5), when the _2, Ar is not in any of the phenyl and m-CH ₃ phenyl,
(3) When A is N, Z is CR ² , R ² is H, and Ar is pyridyl, pyrimidinyl or pyrazinyl, and R ³ is NR ^6a R ^7a , R ^6a and R ^7a are either H or alkyl Not
(4) When A is N, Z is CR ² , and R ² is SO ₂ NR ⁶ R ⁷ , R ³ is neither OH nor SH,
(5) When A is CR and Z is CR ² , R ² is neither —NR ⁶ SO ₂ R ⁷ nor —SO ₂ NR ⁶ R ⁷ ,
(6) When A is N, Z is CR ² and R ² is —NR ⁶ SO ₂ R ⁷ or —SO ₂ NR ⁶ R ⁷ , R ³ is neither OH nor SH,
(7) A is N, Z is ^CR 2, ^{R 1} is methyl or ethyl, ^{R 2} is H, and ^{R 3} is _{H, OH, CH 3, C} 2 H 5, C 6 H 5, n-C 3 H ₇ , iso-C ₃ H ₇ , SH, SCH ₃ , NH (n-C ₄ H ₉ ), or N (C ₂ H ₅ ) ₂ , Ar is either unsubstituted phenyl or m-methylphenyl Not
(8) When A is CR, Z is CR ² , R ² is H, phenyl or alkyl, R ³ is NR ⁸ COR ⁷ and Ar is phenyl substituted with phenyl or phenylthio, R ⁷ is aryl, aryl ( C ₁ -C ₄ alkyl), heteroaryl, heteroaryl _(C 1 -C ₄ alkyl), without any of the heterocyclic radicals and heterocyclic _(C 1 -C ₄ alkyl),
(9) When A is CR, Z is CR ² , R ² is H or alkyl, Ar is phenyl, and R ³ is SR ¹³ or NR ^6a R ^7a , R ¹³ is neither aryl nor heteroaryl, R ^6a and R ^7a are neither H nor aryl, or
(10) When A is CH, Z is CR ² , R ¹ is OR ¹¹ , R ² is H, R ³ is OR ⁷ and R ⁷ and R ¹¹ are both H, Ar is phenyl, p-Br - phenyl, p-Cl @ - phenyl, p-NHCOCH ₃ - phenyl, p-CH ₃ - phenyl, nor any of pyridyl and naphthyl,
(11) If A is CH, and Z is ^CR 2, ^{R 2} is H, Ar is an unsubstituted phenyl, and ^{R 3} is _{CH 3, C 2 H 5,} CF 3 or _C 6 _{H 4} F, ^{R 1} is Neither CF ₃ nor C ₂ F ₅
(12) When A is CR, R is H, Z is CR ² , R ² is OH, and R ¹ and R ³ are H, Ar is not phenyl,
(13) When A is CR, R is H, Z is CR ² , R ² is OH or NH ₂ , and R ¹ and R ³ are CH ₃ , Ar is 4-phenyl-3-cyano-2-aminopyrido- Not 2-yl.

[5] Preferred compounds of the invention include compounds of formulas (1) and (2) and their isomers, stereoisomers, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or pros (1) A is N, R ¹ is H, C ₁ -C ₄ alkyl, halo, CN, C ₁ -C ₁₂ hydroxyalkyl, C ₁ -C ₄ alkoxyalkyl or SO ₂ (C ₁ -C ₄ alkyl), if ^{R 6a} with ^{R 3} is ^NR 6a ^{R 7a} is _C 1 -C ₄ alkyl ^{unsubstituted, R 7a} is phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl , Benzofuranyl, benzothiazolyl, indolyl and C ₃ -C ₆ cycloalkyl, (2) A is N, R ¹ is H, C ₁ -C ₄ alkyl, halo , CN, C ₁ -C ₁₂ hydroxyalkyl, C ₁ -C ₄ alkoxyalkyl or SO ₂ (C ₁ -C ₄ alkyl), R ³ is NR ^6a R ^7a and R ^7a is unsubstituted C ₁ -C ₄ alkyl In this case, R ^6a has the additional condition that it is neither phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or C ₃ -C ₆ cycloalkyl.

[6] Preferred compounds of the invention are those wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R ⁴ substituents. ) And (2) compounds and isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof.

[7] Preferred compounds of the invention are those wherein A is N, Z is CR ² , Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R ¹ and R ² are CH ₃ , compounds of formula (1) and (2) wherein R ³ is NR ^6a R ^7a and isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts thereof Or a prodrug form is also included.

  [11] More preferred compounds of the invention include compounds wherein A is N and isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof. is there.

  [12] More preferred compounds of the invention include compounds and isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof.

[13] A more preferred compound of the invention is a compound wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each of which is optionally substituted with 1 to 4 R ⁴ substituents, and Also included are isomers, stereoisomers thereof or mixtures of stereoisomers thereof and pharmaceutically acceptable salts or prodrugs thereof.

[14] More preferred compounds of the invention include compounds wherein R ³ is NR ^6a R ^7a or OR ⁷ and isomers, stereoisomers, or mixtures of the stereoisomers, and pharmaceutically acceptable The salt or prodrug form thereof is also included.

[15] In a more preferred compound of the invention, Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R ⁴ substituents, wherein R ³ is Also included are compounds that are NR ^6a R ^7a or OR ⁷ and isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof.

[16] More preferable compounds of the invention include compounds wherein Z is CR ² and isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof Including.

[17] More preferred compounds of the invention are compounds wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each of which is optionally substituted with 1 to 4 R ⁴ substituents, and Also included are isomers, stereoisomers thereof or mixtures of stereoisomers thereof and pharmaceutically acceptable salts or prodrugs thereof.

[18] More preferred compounds of the invention include compounds wherein R ³ is NR ^6a R ^7a or OR ⁷ and isomers, stereoisomers, or mixtures of the stereoisomers, and pharmaceutically acceptable The salt or prodrug form thereof is also included.

[19] Further, the more preferred compound of the invention is
R ^6a is independently
-H,
-C ₁ -C _{10 alkyl,} C 3 _{-C 10 alkenyl,} C 3 _{-C 10} alkynyl, _C 1 _{-C 10} haloalkyl having 1 to 10 halogen _atoms, C 2 -C _{8 alkoxyalkyl,} C 3 -C ₆ cycloalkyl Alkyl, C ₄ -C ₁₂ cycloalkylalkyl, C ₅ -C ₁₀ cycloalkenyl, or C ₆ -C ₁₄ cycloalkenylalkyl (each group is independently C ₁ -C ₆ alkyl, C _{3 in} each case) -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, _{^{cyano, OR 15, SH, S (}} O) n R 13, COR 15, CO 2 R 15, OC (O) R 13, NR 8 COR 15, _{^{N (COR 15) 2, NR}} 8 CONR 16 R 15, NR 8 CO 2 R 13, NR 16 R 15, CONR 16 R 15, Ali Le is optionally substituted with 1-3 substituents selected from heteroaryl and heterocyclic group),
Selected from -aryl, aryl (C ₁ -C ₄ alkyl), heteroaryl, heteroaryl (C ₁ -C ₄ alkyl), heterocyclic group or heterocycle (C ₁ -C ₄ alkyl);
R ^7a is independently in each case
-H,
-C ₅ -C _{10 alkyl,} C 3 _{-C 10 alkenyl,} C 3 _{-C 10} alkynyl, _C 1 _{-C 10} haloalkyl having 1 to 10 halogen _atoms, C 2 -C _{8 alkoxyalkyl,} C 3 -C ₆ cycloalkyl Alkyl, C ₄ -C ₁₂ cycloalkylalkyl, C ₅ -C ₁₀ cycloalkenyl, or C ₆ -C ₁₄ cycloalkenylalkyl (each group is independently C ₁ -C ₆ alkyl, C _{3 in} each case) -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, _{^{cyano, OR 15, SH, S (}} O) n R 13, COR 15, CO 2 R 15, OC (O) R 13, NR 8 COR 15, _{^{N (COR 15) 2, NR}} 8 CONR 16 R 15, NR 8 CO 2 R 13, NR 16 R 15, CONR 16 R 15, Ali Le is optionally substituted with 1-3 substituents selected from heteroaryl and heterocyclic group),
- aryl, aryl _(C 1 -C ₄ alkyl), heteroaryl, heteroaryl _(C 1 -C ₄ alkyl), or is selected from a heterocyclic group or a heterocyclic _(C 1 -C ₄ alkyl),
Alternatively, NR ⁶ R ⁷ and NR ^6a R ^7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine (each group is optionally selected from _{1 to} 3 C ₁ -C ₄ alkyl groups Selected from)
Also included are compounds and isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof.

[20] More preferred compounds of the invention are
R ^6a and R ^7a are the same,
-C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl (each group is independently in each case C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halo, C ₁ -C ₄ haloalkyl, _{^{cyano, OR 15, SH, S (}} O) n R 13, -COR 15, CO 2 R 15, OC (O) R 13, NR 8 COR 15, n (COR 15) 2, NR 8 CONR 16 R ¹⁵ , optionally substituted with 1 to 3 substituents selected from NR ⁸ CO ₂ R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclic groups), and − A compound selected from aryl or heteroaryl and its isomer, its stereoisomer, or a mixture of its stereoisomers, and pharmaceutically acceptable salts thereof. Also includes prodrug forms.

[21] More preferred compounds of the invention are
R ^6a is
-H,
-C ₁ -C _{10 alkyl,} C 3 _{-C 10 alkenyl,} C 3 _{-C 10} alkynyl, _C 1 _{-C 10} haloalkyl having 1 to 10 halogen _atoms, C 2 -C _{8 alkoxyalkyl,} C 3 -C ₆ cycloalkyl Alkyl, C ₄ -C ₁₂ cycloalkylalkyl, C ₅ -C ₁₀ cycloalkenyl, or C ₆ -C ₁₄ cycloalkenylalkyl (each group is independently C ₁ -C ₆ alkyl, C _{3 in} each case) -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, _{^{cyano, OR 15, SH, S (}} O) n R 13, COR 15, CO 2 R 15, OC (O) R 13, NR 8 COR 15, _{^{N (COR 15) 2, NR}} 8 CONR 16 R 15, NR 8 CO 2 R 13, NR 16 R 15, CONR 16 R 15, Ali Le is optionally substituted with 1-3 substituents selected from heteroaryl and heterocyclic group),
Selected from -aryl, aryl (C ₁ -C ₄ alkyl), heteroaryl, heteroaryl (C ₁ -C ₄ alkyl), heterocyclic group or heterocycle (C ₁ -C ₄ alkyl);
R ^7a is
-C ₁ -C ₄ alkyl and each _C 1 -C ₆ alkyl, independently _if, C 3 -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, ^{cyano, OR 15, SH, S (} O) _{^{n R 13, COR 15, CO}} 2 R 15, OC (O) R 13, NR 8 COR 15, n (COR 15) 2, NR 8 CONR 16 R 15, NR 8 CO 2 R 13, NR 16 R 15, CONR ¹⁶ R ¹⁵ , selected from C ₁ -C ₄ alkyl optionally substituted with 1 to 3 substituents selected from aryl, heteroaryl and heterocyclic groups,
Also included are compounds and isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof.

[22] More preferred compounds of the invention are
One of R ^6a and R ^7a is
-C ₃ -C ₆ cycloalkyl (each of _C 3 -C ₆ cycloalkyl, _C 1 -C ₆ alkyl, independently in each _case, C 3 -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl , Cyano, OR ¹⁵ , SH, S (O) _n R ¹³ , COR ¹⁵ , CO ₂ R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ₂ , NR ⁸ CONR ¹⁶ R ¹⁵ , Optionally substituted with 1 to 3 substituents selected from NR ⁸ CO ₂ R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclic groups),
-Aryl,
Selected from -heteroaryl or -heterocyclic group,
The other of R ^6a and R ^7a is unsubstituted C ₁ -C ₄ alkyl and its isomers, its stereoisomers, or mixtures of its stereoisomers, and pharmaceutically acceptable salts thereof Or a prodrug form is also included.

[23] More preferred compounds of the invention include
R ^6a and R ^7a are independently H or C ₁ -C ₁₀ alkyl (each C ₁ -C ₁₀ alkyl is independently in each case C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl) , Halo, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) _n R ¹³ , COR ¹⁵ , CO ₂ R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ₂ , optionally substituted with 1 to 3 substituents selected from NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclic groups And isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof. .

[24] More preferred compounds of the invention wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R ⁴ substituents, wherein R ³ is Also included are compounds that are NR ^6a R ^7a or OR ⁷ and isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof.

[25] More preferred compounds of the invention are
R ^6a is independently
-H,
-C ₁ -C _{10 alkyl,} C 3 _{-C 10 alkenyl,} C 3 _{-C 10} alkynyl, _C 1 _{-C 10} haloalkyl having 1 to 10 halogen _atoms, C 2 -C _{8 alkoxyalkyl,} C 3 -C ₆ cycloalkyl Alkyl, C ₄ -C ₁₂ cycloalkylalkyl, C ₅ -C ₁₀ cycloalkenyl, or C ₆ -C ₁₄ cycloalkenylalkyl (each group is independently C ₁ -C ₆ alkyl, C _{3 in} each case) -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, _{^{cyano, OR 15, SH, S (}} O) n R 13, COR 15, CO 2 R 15, OC (O) R 13, NR 8 COR 15, _{^{N (COR 15) 2, NR}} 8 CONR 16 R 15, NR 8 CO 2 R 13, NR 16 R 15, CONR 16 R 15, Ali Le is optionally substituted with 1-3 substituents selected from heteroaryl and heterocyclic group),
Selected from -aryl, aryl (C ₁ -C ₄ alkyl), heteroaryl, heteroaryl (C ₁ -C ₄ alkyl), heterocyclic group or heterocycle (C ₁ -C ₄ alkyl);
R ^7a is independently in each case
-H,
-C ₅ -C _{10 alkyl,} C 3 _{-C 10 alkenyl,} C 3 _{-C 10} alkynyl, _C 1 _{-C 10} haloalkyl having 1 to 10 halogen _atoms, C 2 -C _{8 alkoxyalkyl,} C 3 -C ₆ cycloalkyl Alkyl, C ₄ -C ₁₂ cycloalkylalkyl, C ₅ -C ₁₀ cycloalkenyl, or C ₆ -C ₁₄ cycloalkenylalkyl (each group is independently C ₁ -C ₆ alkyl, C _{3 in} each case) -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, _{^{cyano, OR 15, SH, S (}} O) n R 13, COR 15, CO 2 R 15, OC (O) R 13, NR 8 COR 15, _{^{N (COR 15) 2, NR}} 8 CONR 16 R 15, NR 8 CO 2 R 13, NR 16 R 15, CONR 16 R 15, Ali Le is optionally substituted with 1-3 substituents selected from heteroaryl and heterocyclic group),
- aryl, aryl _(C 1 -C ₄ alkyl), heteroaryl, heteroaryl _(C 1 -C ₄ alkyl), or is selected from a heterocyclic group or a heterocyclic _(C 1 -C ₄ alkyl),
Alternatively, NR ⁶ R ⁷ and NR ^6a R ^7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine (each group is optionally selected from _{1 to} 3 C ₁ -C ₄ alkyl groups). And isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrug forms thereof.

[26] More preferred compounds of the invention are
R ^6a and R ^7a are the same,
-C ₁ -C ₄ alkyl or _C 3 -C ₆ cycloalkyl (each group, _C 1 -C ₆ alkyl, independently in each _case, C 3 -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, _{^{cyano, OR 15, SH, S (}} O) n R 13, -COR 15, CO 2 R 15, OC (O) R 13, NR 8 COR 15, n (COR 15) 2, NR 8 CONR 16 R ¹⁵ , optionally substituted with 1 to 3 substituents selected from NR ⁸ CO ₂ R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclic groups), and
-Compounds selected from aryl or heteroaryl and isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof.

[27] More preferred compounds of the invention include
R ^6a and R ^7a are the same,
-C ₁ -C ₄ alkyl (each C ₁ -C ₄ alkyl is independently in each case C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halo, C ₁ -C ₄ haloalkyl, cyano , OR ¹⁵ , SH, S (O) _n R ¹³ , —COR ¹⁵ , CO ₂ R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ₂ , NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , optionally substituted with 1 to 3 substituents selected from aryl, heteroaryl and heterocyclic groups) and isomers thereof As well as its stereoisomers, or a mixture of its stereoisomers, and pharmaceutically acceptable salts or prodrugs thereof.

[28] More preferred compounds of the invention are
R ^6a is
-H,
-C ₁ -C _{10 alkyl,} C 3 _{-C 10 alkenyl,} C 3 _{-C 10} alkynyl, _C 1 _{-C 10} haloalkyl having 1 to 10 halogen _atoms, C 2 -C _{8 alkoxyalkyl,} C 3 -C ₆ cycloalkyl Alkyl, C ₄ -C ₁₂ cycloalkylalkyl, C ₅ -C ₁₀ cycloalkenyl, or C ₆ -C ₁₄ cycloalkenylalkyl (each group is independently C ₁ -C ₆ alkyl, C _{3 in} each case) -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, _{^{cyano, OR 15, SH, S (}} O) n R 13, COR 15, CO 2 R 15, OC (O) R 13, NR 8 COR 15, _{^{N (COR 15) 2, NR}} 8 CONR 16 R 15, NR 8 CO 2 R 13, NR 16 R 15, CONR 16 R 15, Ali Le is optionally substituted with 1-3 substituents selected from heteroaryl and heterocyclic group),
Selected from -aryl, aryl (C ₁ -C ₄ alkyl), heteroaryl, heteroaryl (C ₁ -C ₄ alkyl), heterocyclic group or heterocycle (C ₁ -C ₄ alkyl);
R ^7a is
-C ₁ -C ₄ alkyl and each _C 1 -C ₆ alkyl, independently _if, C 3 -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, ^{cyano, OR 15, SH, S (} O) _{^{n R 13, COR 15, CO}} 2 R 15, OC (O) R 13, NR 8 COR 15, n (COR 15) 2, NR 8 CONR 16 R 15, NR 8 CO 2 R 13, NR 16 R 15, CONR ¹⁶ R ¹⁵ , a compound that is C ₁ -C ₄ alkyl optionally substituted with 1 to 3 substituents selected from aryl, heteroaryl and heterocyclic groups, and isomers thereof, stereoisomers thereof, Alternatively, a mixture of stereoisomers thereof and a pharmaceutically acceptable salt or prodrug form thereof are also included.

[29] More preferred compounds of the invention are
One of R ^6a and R ^7a is
-C ₃ -C ₆ cycloalkyl _(C 3 -C ₆ cycloalkyl each, _C 1 -C ₆ alkyl, independently in each _case, C 3 -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, Cyano, OR ¹⁵ , SH, S (O) _n R ¹³ , COR ¹⁵ , CO ₂ R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ₂ , NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , optionally substituted with 1 to 3 substituents selected from aryl, heteroaryl and heterocyclic groups),
-Aryl,
Selected from -heteroaryl or -heterocyclic group,
The other of R ^6a and R ^7a is unsubstituted C ₁ -C ₄ alkyl and its isomers, its stereoisomers, or mixtures of its stereoisomers, and pharmaceutically acceptable salts thereof Or a prodrug form is also included.

[30] In the more preferred compounds of the invention, R ^6a and R ^7a are independently H or C ₁ -C ₁₀ alkyl (wherein each C ₁ -C ₁₀ alkyl is independently C _1- C _{6 alkyl,} C 3 -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, _{^{cyano, OR 15, SH, S (}} O) n R 13, COR 15, CO 2 R 15, OC (O) R 13 , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ₂ , NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclic groups Compounds optionally substituted with 1 to 3 substituents) and isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically Description Possible salt or prodrug forms also include.

[31] More preferred compounds of the invention include
-Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl optionally substituted with 1 to 4 R ⁴ substituents;
-R ³ is ^NR 6a ^{R 7a} or OR ^7,
-R ¹ and R ² are independently a compound selected from H, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₁₀ cycloalkylalkyl and its isomer, its stereoisomer, Or a mixture of stereoisomers thereof and pharmaceutically acceptable salts or prodrugs thereof.

[32] More preferred compounds of the invention are
R ^6a is independently
-H,
-C ₁ -C _{10 alkyl,} C 3 _{-C 10 alkenyl,} C 3 _{-C 10} alkynyl, _C 1 _{-C 10} haloalkyl having 1 to 10 halogen _atoms, C 2 -C _{8 alkoxyalkyl,} C 3 -C ₆ cycloalkyl Alkyl, C ₄ -C ₁₂ cycloalkylalkyl, C ₅ -C ₁₀ cycloalkenyl, or C ₆ -C ₁₄ cycloalkenylalkyl (each group is independently C ₁ -C ₆ alkyl, C _{3 in} each case) -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, _{^{cyano, OR 15, SH, S (}} O) n R 13, COR 15, CO 2 R 15, OC (O) R 13, NR 8 COR 15, _{^{N (COR 15) 2, NR}} 8 CONR 16 R 15, NR 8 CO 2 R 13, NR 16 R 15, CONR 16 R 15, Ali Le is optionally substituted with 1-3 substituents selected from heteroaryl and heterocyclic group),
Selected from -aryl, aryl (C ₁ -C ₄ alkyl), heteroaryl, heteroaryl (C ₁ -C ₄ alkyl), heterocyclic group or heterocycle (C ₁ -C ₄ alkyl);
R ^7a is
-H,
-C ₅ -C _{10 alkyl,} C 3 _{-C 10 alkenyl,} C 3 _{-C 10} alkynyl, _C 1 _{-C 10} haloalkyl having 1 to 10 halogen _atoms, C 2 -C _{8 alkoxyalkyl,} C 3 -C ₆ cycloalkyl Alkyl, C ₄ -C ₁₂ cycloalkylalkyl, C ₅ -C ₁₀ cycloalkenyl, or C ₆ -C ₁₄ cycloalkenylalkyl (each group is independently C ₁ -C ₆ alkyl, C _{3 in} each case) -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, _{^{cyano, OR 15, SH, S (}} O) n R 13, COR 15, CO 2 R 15, OC (O) R 13, NR 8 COR 15, _{^{N (COR 15) 2, NR}} 8 CONR 16 R 15, NR 8 CO 2 R 13, NR 16 R 15, CONR 16 R 15, Ali Le is optionally substituted with 1-3 substituents selected from heteroaryl and heterocyclic group),
- aryl, aryl _(C 1 -C ₄ alkyl), heteroaryl, heteroaryl _(C 1 -C ₄ alkyl), or is selected from a heterocyclic group or a heterocyclic _(C 1 -C ₄ alkyl),
Alternatively, NR ⁶ R ⁷ and NR ^6a R ^7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine (each group is represented by 1 to 3 C ₁ -C ₄ alkyl groups). As well as isomers, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof.

[33] More preferred compounds of the invention include
R ^6a and R ^7a are the same,
-C ₁ -C ₄ alkyl or _C 3 -C ₆ cycloalkyl (each group, _C 1 -C ₆ alkyl, independently in each _case, C 3 -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, _{^{cyano, OR 15, SH, S (}} O) n R 13, -COR 15, CO 2 R 15, OC (O) R 13, NR 8 COR 15, n (COR 15) 2, NR 8 CONR 16 R ¹⁵ , optionally substituted with 1 to 3 substituents selected from NR ⁸ CO ₂ R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclic groups), and
-Also included are compounds selected from aryl or heteroaryl and isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof.

[34] More preferred compounds of the invention are
R ^6a and R ^7a are the same,
-C ₁ -C ₄ alkyl (each C ₁ -C ₄ alkyl is independently in each case C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halo, C ₁ -C ₄ haloalkyl, cyano , OR ¹⁵ , SH, S (O) _n R ¹³ , —COR ¹⁵ , CO ₂ R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ₂ , NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , optionally substituted with 1 to 3 substituents selected from aryl, heteroaryl and heterocyclic groups) and isomers thereof As well as its stereoisomers, or a mixture of its stereoisomers, and pharmaceutically acceptable salts or prodrugs thereof.

[35] More preferred compounds of the invention include
R ^6a is
-H,
-C ₁ -C _{10 alkyl,} C 3 _{-C 10 alkenyl,} C 3 _{-C 10} alkynyl, _C 1 _{-C 10} haloalkyl having 1 to 10 halogen _atoms, C 2 -C _{8 alkoxyalkyl,} C 3 -C ₆ cycloalkyl Alkyl, C ₄ -C ₁₂ cycloalkylalkyl, C ₅ -C ₁₀ cycloalkenyl, or C ₆ -C ₁₄ cycloalkenylalkyl (each group is independently C ₁ -C ₆ alkyl, C _{3 in} each case) -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, _{^{cyano, OR 15, SH, S (}} O) n R 13, COR 15, CO 2 R 15, OC (O) R 13, NR 8 COR 15, _{^{N (COR 15) 2, NR}} 8 CONR 16 R 15, NR 8 CO 2 R 13, NR 16 R 15, CONR 16 R 15, Ali Le is optionally substituted with 1-3 substituents selected from heteroaryl and heterocyclic group),
Selected from -aryl, aryl (C ₁ -C ₄ alkyl), heteroaryl, heteroaryl (C ₁ -C ₄ alkyl), heterocyclic group or heterocycle (C ₁ -C ₄ alkyl);
R ^7a is
-C ₁ -C ₄ alkyl and each _C 1 -C ₆ alkyl, independently _if, C 3 -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, ^{cyano, OR 15, SH, S (} O) _{^{n R 13, COR 15, CO}} 2 R 15, OC (O) R 13, NR 8 COR 15, n (COR 15) 2, NR 8 CONR 16 R 15, NR 8 CO 2 R 13, NR 16 R 15, CONR ¹⁶ R ¹⁵ , compounds that are C ₁ -C ₄ alkyl optionally substituted with 1 to 3 substituents selected from aryl, heteroaryl and heterocyclic groups, and isomers and stereoisomers thereof Or a mixture of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof.

[36] More preferred compounds of the invention are
One of R ^6a and R ^7a is
-C ₃ -C ₆ cycloalkyl (each of _C 3 -C ₆ cycloalkyl, _C 1 -C ₆ alkyl, independently in each _case, C 3 -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl , Cyano, OR ¹⁵ , SH, S (O) _n R ¹³ , COR ¹⁵ , CO ₂ R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ₂ , NR ⁸ CONR ¹⁶ R ¹⁵ , Optionally substituted with 1 to 3 substituents selected from NR ⁸ CO ₂ R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclic groups),
-Aryl,
Selected from -heteroaryl or -heterocyclic group,
The other of R ^6a and R ^7a is unsubstituted C ₁ -C ₄ alkyl and its isomers, its stereoisomers, or mixtures of its stereoisomers, and pharmaceutically acceptable salts thereof Or a prodrug form is also included.

[37] More preferred compounds of the invention include
R ^6a and R ^7a are independently H or C ₁ -C ₁₀ alkyl (each C ₁ -C ₁₀ alkyl is independently in each case C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl) , Halo, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) _n R ¹³ , COR ¹⁵ , CO ₂ R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ₂ , optionally substituted with 1 to 3 substituents selected from NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclic groups And isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof. .

  [38] Specifically preferred compounds of the invention include compounds of formula (50),

And its isomers, its stereoisomers, or a mixture of its stereoisomers, and pharmaceutically acceptable salts or prodrugs thereof,
A compound of formula (50) wherein R ³ is —NHCH (n—Pr) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is -N (Et) (n-Bu), R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (n-Pr) (CH ₂ cPr), R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (Et) (n—Bu), R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (Et) (CH ₂ OMe), R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (CH ₂ OMe) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (Et) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (CH ₂ OEt) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (Et) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (Me) (Ph), R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (n-Pr) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is -NHCH (Et) (n-Pr), R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is Me;
A compound of formula (50) wherein R ³ is —NHCH (CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (Et) (CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (Et) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is -OEt, R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (Et) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (CH ₂ CN) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (Me) (CH ₂ OMe), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —OCH (Et) (CH ₂ OMe), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (n—Pr) (CH ₂ cPr), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
R ³ is —NHCH (Me) (CH ₂ N (Me) ₂ ), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H, and R ^4e is H. Compound,
A compound of formula (50) wherein R ³ is —N (cPr) (CH ₂ CH ₂ CN), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
R ³ is _{-N (n-Pr) (CH} 2 CH 2 CN), R 4a is ^{Me, R 4b} is ^{H, R 4c} is ^{Me, R 4d} is H ^{R 4e} is formula (50) is H Compound,
A compound of formula (50) wherein R ³ is -N (n-Bu) (CH ₂ CN), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (Et) (CH ₂ OMe), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is Me;
A compound of formula (50) wherein R ³ is —NHCH (Et) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is Me;
A compound of formula (50) wherein R ³ is —N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is Me;
A compound of formula (50) wherein R ³ is —NHCH (CH ₂ OMe) ₂ , R ^4a is Br, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (Et) (CH ₂ OMe), R ^4a is Br, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (Et) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is Me;
A compound of formula (50) wherein R ³ is —NHCH (CH ₂ OEt) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is Me;
Formula (50), wherein R ³ is —NHCH (CH ₂ CH ₂ OMe) (CH ₂ OMe), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H, and R ^4e is Me. Compound,
A compound of formula (50) wherein R ³ is morpholino, R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Br, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (Et) ₂ , R ^4a is Br, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (Et) ₂ , R ^4a is Br, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;
R ³ is -NH ^(c-Pr), a compound of formula (50) ^{R 4a} is ^{Me, R 4b} is ^{H, R 4c} is ^Me, is ^{R 4d} is H ^{R 4e} is H,
A compound of formula (50) wherein R ³ is —NHCH (CH ₂ OMe) ₂ , R ^4a is CN, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;
In the formula (50), R ³ is —N (c—Pr) (CH ₂ CH ₂ CN), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H, and R ^4e is Me. Compound,
A compound of formula (50) wherein R ³ is —NHCH (CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Br, R ^4d is H and R ^4e is H;
Formula (50), wherein R ³ is —NHCH (CH ₂ OMe) (CH ₂ CH ₂ OMe), R ^4a is Me, R ^4b is H, R ^4c is Br, R ^4d is H, and R ^4e is H. Compound,
A compound of formula (50) wherein R ³ is —NHCH (CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is Me and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is Me and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (Et) ₂ , R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is Me and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (Et) ₂ , R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is Me and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (CH ₂ OMe) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (Et) (CH ₂ OMe), R ^4a is Cl, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
R ³ is —NHCH (CH ₂ OMe) (CH ₂ CH ₂ OMe), R ^4a is Cl, R ^4b is H, R ^4c is Me, R ^4d is H, and R ^4e is H. Compound,
Formula (50) in which R ³ is —N (c—Pr) (CH ₂ CH ₂ CN), R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is Me and R ^4e is H. Compound,
R ³ is _{-N (c-Pr) (CH} 2 CH 2 CN), R 4a is ^{Cl, R 4b} is ^{H, R 4c} is ^{Cl, R 4d} is H ^{R 4e} is formula (50) is H Compound,
Formula where R ³ is (S) —NHCH (CH ₂ OMe) (CH ₂ CH ₂ OMe), R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H 50) compounds,
R ³ is —NHCH (CH ₂ OMe) (CH ₂ CH ₂ OMe), R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H, and R ^4e is H. Compound,
A compound of formula (50) wherein R ³ is —NHCH (Et) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Br, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Br, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NH (CH ₂ OMe) (CH ₂ —iPr), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H ,
A compound of formula (50) wherein R ³ is —N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is H, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is NMe ₂ , R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (CH ₂ OMe) (n—Pr), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (CH ₂ OEt) (Et), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
Formula (50) wherein R ³ is —NHCH (CH ₂ OMe) (CH ₂ CH ₂ OMe), R ^4a is Me, R ^4b is H, R ^4c is NMe ₂ , R ^4d is H and R ^4e is H A compound of
A compound of formula (50) wherein R ³ is —N (Et) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (Et) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (Et) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Br, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (Et) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (Et) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (Et) ₂ , R ^4a is Me, R ^4b is H, R ^4c is NMe ₂ , R ^4d is H and R ^4e is H;
Formula where R ³ is (S) —NHCH (CH ₂ OMe) (CH ₂ CH ₂ OMe), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H 50) compounds,
Formula (50), wherein R ³ is —NHCH (CH ₂ OMe) (CH ₂ CH ₂ OMe), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H, and R ^4e is H. Compound,
Formula where R ³ is (S) —NHCH (CH ₂ OMe) (CH ₂ CH ₂ OMe), R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H, and R ^4e is H 50) compounds,
R ³ is —NHCH (CH ₂ OMe) (CH ₂ CH ₂ OMe), R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H, and R ^4e is H. Compound,
R ³ is —N (c—Pr) (CH ₂ CH ₂ CN), R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H, and R ^4e is H. Compound,
A compound of formula (50) wherein R ³ is —NH (Et) (CH ₂ CN), R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (Et) ₂ , R ^4a is Me, R ^4b is Me, R ^4c is OMe, R ^4d is H and R ^4e is H;
Formula (50) wherein R ³ is —N (CH ₂ CH ₂ OMe) (CH ₂ CH ₂ OH), R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H ) Compounds,
A compound of formula (50) wherein R ³ is —N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is Me, R ^4c is OMe, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (Et) ₂ , R ^4a is Me, R ^4b is Me, R ^4c is OMe, R ^4d is H and R ^4e is H;
R ³ is _{-N (CH 2 c-Pr)} (n-Pr), R 4a is ^{Me, R 4b} is ^{H, R 4c} is ^{Cl, R 4d} is H ^{R 4e} is formula (50) is H Compound,
Formula (50), wherein R ³ is —N (c—Pr) (CH ₂ CH ₂ CN), R ^4a is Me, R ^4b is Me, R ^4c is OMe, R ^4d is H, and R ^4e is H. Compound,
A compound of formula (50) wherein R ³ is —NHCH (Et) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (Et) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —NHCH (Et) (CH ₂ OMe), R ^4a is Cl, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;
A compound of formula (50) wherein R ³ is —N (Et) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is CN, R ^4d is H and R ^4e is H;
R ³ is —N (c—Pr) (CH ₂ CH ₂ CN), R ^4a is Cl, R ^4b is H, R ^4c is OMe, R ^4d is H, and R ^4e is H. Compound,
A compound of formula (50) wherein R ³ is —NHCH (CH ₂ OH) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
The group consisting of compounds of formula (50), wherein R ³ is N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H. Selected from.

  [39] More specifically preferred is 4- (bis- (2-methoxyethyl) amino) -2,7-dimethyl-8- (2-methyl-4-methoxyphenyl)-[1,5-a ] -Pyrazolo-1,3,5-triazine and its isomer, its stereoisomer, or a mixture of its stereoisomers, and a pharmaceutically acceptable salt or prodrug thereof.

  [40] More specifically preferred is 4- (bis- (2-methoxyethyl) amino) -2,7-dimethyl-8- (2,5-dimethyl-4-methoxyphenyl)-[1,5 -A] -pyrazolo-1,3,5-triazine and its isomer, its stereoisomer, or a mixture of its stereoisomers, and a pharmaceutically acceptable salt or prodrug thereof.

  [41] More preferred compounds of the invention include compounds wherein A is CR and isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof. is there.

  [42] More preferred compounds of the invention also include compounds and isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof.

[43] A more preferred compound of the invention is a compound wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R ⁴ substituents And isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof.

[44] More preferred compounds of the invention include compounds wherein R ³ is NR ^6a R ^7a or OR ⁷ and isomers, stereoisomers, or mixtures of the stereoisomers, and pharmaceutically acceptable The salt or prodrug form is also included.

[45] In a more preferred compound of the invention, Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each Ar is optionally substituted with 1 to 4 R ⁴ substituents, and R ^{Also included} are compounds wherein ³ is NR ^6a R ^7a or OR ⁷ and isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof.

[46] More preferred compounds of the invention include compounds wherein Z is CR ² and isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof Including.

[47] A more preferred compound of the invention is a compound wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R ⁴ substituents And isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof.

[48] More preferred compounds of the invention include compounds wherein R ³ is NR ^6a R ^7a or OR ⁷ and isomers, stereoisomers, or mixtures of the stereoisomers, and pharmaceutically acceptable The salt or prodrug form thereof is also included.

[49] More preferred compounds of the invention wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each Ar is optionally substituted with 1 to 4 R ⁴ substituents, and R ^{Also included} are compounds wherein ³ is NR ^6a R ^7a or OR ⁷ and isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof.

[50] More preferred compounds of the invention wherein R ^6a and R ^7a are independently H or C ₁ -C ₁₀ alkyl, and each C ₁ -C ₁₀ alkyl is independently C in each case ₁ -C _{6 alkyl,} C 3 -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, _{^{cyano, OR 15, SH, S (}} O) n R 13, COR 15, CO 2 R 15, OC (O) Selected from R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ₂ , NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclic groups Compounds optionally substituted with 1 to 3 substituents and isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable Possible salt or prodrug forms also include.

[51] More preferred compounds of the invention include
-Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl optionally substituted with 1 to 4 R ⁴ substituents;
-R ³ is ^NR 6a ^{R 7a} or OR ⁷ and -R ¹ and ^{R 2} are independently selected _H, C 1 -C _{4 alkyl,} C 3 -C _{6 cycloalkyl,} a C 4 _{-C 10} cycloalkylalkyl And isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable salts or prodrugs thereof.

[52] More preferred compounds of the invention wherein R ^6a and R ^7a are independently H or C ₁ -C ₁₀ alkyl, and each C ₁ -C ₁₀ alkyl is independently C in each case ₁ -C _{6 alkyl,} C 3 -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl, _{^{cyano, OR 15, SH, S (}} O) n R 13, COR 15, CO 2 R 15, OC (O) Selected from R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ₂ , NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclic groups Compounds optionally substituted with 1 to 3 substituents as defined above and isomers thereof, stereoisomers thereof, or mixtures of stereoisomers thereof, and pharmaceutically acceptable Possible salt or prodrug forms also include.

  [53] Specifically preferred compounds of the invention include compounds of formula (51),

And its isomers, its stereoisomers, or a mixture of its stereoisomers, and pharmaceutically acceptable salts or prodrugs thereof,
A compound of formula (51) wherein R ³ is -NHCH (n-Pr) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —NHCH (CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
Formula (51) wherein R ³ is —N (c—Pr) (CH ₂ CH ₂ CN), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H. Compound,
A compound of formula (51) wherein R ³ is —N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —NHCH (CH ₂ OMe) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —NHCH (Et) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —N (Et) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
In formula (51), R ³ is —N (n—Pr) (CH ₂ CH ₂ CN), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H, and R ^4e is H. Compound,
In formula (51), R ³ is —N (n—Bu) (CH ₂ CH ₂ CN), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H, and R ^4e is H. Compound,
A compound of formula (51) wherein R ³ is —NHCH (n—Pr) (CH ₂ OMe), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —NHCH (Et) ₂ , R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —NHCH (CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;
Formula (51) wherein R ³ is (S) —NH (CH ₂ CH ₂ OMe) CH ₂ OMe, R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H A compound of
A compound of formula (51) wherein R ³ is —NH (CH ₂ CH ₂ OMe) CH ₂ OMe, R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —NH (Et), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —NHCH (n-Pr) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —NHCH (CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
Formula (51) wherein R ³ is (S) —NH (CH ₂ CH ₂ OMe) CH ₂ OMe, R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H A compound of
A compound of formula (51) wherein R ³ is —NH (CH ₂ CH ₂ OMe) CH ₂ OMe, R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
Formula (51), wherein R ³ is —N (n—Pr) (CH ₂ CH ₂ CN), R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is H, and R ^4e is H. Compound,
A compound of formula (51) wherein R ³ is —N (Et) ₂ , R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;
Formula (51) wherein R ³ is (S) —NH (CH ₂ CH ₂ OMe) CH ₂ OMe, R ^4a is Cl, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H A compound of
A compound of formula (51) wherein R ³ is —NH (CH ₂ CH ₂ OMe) CH ₂ OMe, R ^4a is Cl, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —N (Et) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
In formula (51), R ³ is —N (c—Pr) (CH ₂ CH ₂ CN), R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is H, and R ^4e is H. Compound,
In formula (51), R ³ is —N (c—Pr) (CH ₂ CH ₂ CN), R ^4a is Cl, R ^4b is H, R ^4c is Me, R ^4d is H, and R ^4e is H. Compound,
A compound of formula (51) wherein R ³ is —NHCH (n—Pr) (CH ₂ OMe), R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is -NHCH (n-Pr) (CH ₂ OMe), R ^4a is Cl, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —NHCH (Et) ₂ , R ^4a is Br, R ^4b is H, R ^4c is OMe, R ^4d is OMe and R ^4e is H;
A compound of formula (51) wherein R ³ is —NHCH (Et) ₂ , R ^4a is Br, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Br, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —NHCH (CH ₂ OMe) ₂ , R ^4a is Br, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —N (Et) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —N (Et) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is OMe, R ^4d is OMe and R ^4e is H;
A compound of formula (51) wherein R ³ is —NHCH (Et) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is OMe, R ^4d is OMe and R ^4e is H;
A compound of formula (51) wherein R ³ is —N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —NHCH (CH ₂ OMe) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —N (Pr) (CH ₂ CH ₂ CN), R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —N (Bu) (Et), R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —NHCH (Et) CH ₂ OMe, R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —NHCH (Et) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —NHCH (Et) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —NHCH (Et) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —NHCH (Et) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is -NEt ₂ , R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;
A compound of formula (51) wherein R ³ is —N (Pr) (CH ₂ CH ₂ CN), R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H; Selected from the group consisting of

  [54] More specifically preferred is 7- (3-pentylamino) -2,5-dimethyl-3- (2-methyl-4-methoxyphenyl)-[1,5-a] -pyrazolopyrimidine. And its isomers, its stereoisomers, or a mixture of its stereoisomers, and pharmaceutically acceptable salts or prodrugs thereof.

  [55] More specifically preferred is 7- (diethylamino) -2,5-dimethyl-3- (2-methyl-4-methoxyphenyl- [1,5-a] -pyrazolopyrimidine and its isomers , Its stereoisomers, or mixtures of its stereoisomers, and pharmaceutically acceptable salts or prodrugs thereof.

  [56] More specifically preferred is 7- (N- (3-cyanopropyl) -N-propylamino) -2,5-dimethyl-3- (2,4-dimethylphenyl)-[1,5 -A] -pyrazolopyrimidine and its isomers, its stereoisomers, or mixtures of its stereoisomers, and pharmaceutically acceptable salts or prodrugs thereof.

  The present invention also provides a pharmaceutical composition comprising a compound of formula (1) and (2) and a pharmaceutically acceptable carrier.

  Many compounds of the present invention have one or more asymmetric centers or planes. All chiral forms (enantiomers and diastereomers) and racemates are included in the present invention unless otherwise indicated. Many geometric isomers such as olefins, C═N double bonds, etc. are also present in the compounds of the present invention, and all these stable isomers are contemplated in the present invention. The compounds of the present invention can be isolated in optically active or racemic forms. Methods for producing optically active forms, such as resolution of racemates or synthesis from optically active starting materials, are well known in the art. All chiral isomers (enantiomers and diastereomers) and racemates, and all geometric isomers are contemplated unless a specific stereochemistry or isomer is specifically indicated.

  The term “alkyl” includes both branched and straight chain alkyls having the specified number of carbon atoms. Commonly used abbreviations have the following meanings. Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl. The prefix “n” means straight chain alkyl. The prefix “c” means cycloalkyl. The prefix “(S)” refers to the S enantiomer, and the prefix “(R)” refers to the R enantiomer. “Alkenyl” refers to a hydrocarbon chain of either straight or branched structure, such as ethenyl, propenyl, and the like, and one or more unsaturated carbons that may be in any stable site along the carbon chain -Including carbon bonds. “Alkynyl” is one or more carbon-carbon triplets that may be at any stable site along a carbon chain, either straight or branched, such as ethynyl, propynyl, and the like. Includes bonds. “Haloalkyl” is meant to include both branched and straight chain alkyl substituted with one or more halogen atoms and having the specified number of carbon atoms. “Alkoxy” refers to an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. “Cycloalkyl” is meant to include saturated cyclic groups including monocyclic, bicyclic or polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. “Halo” and “halogen” include fluoro, chloro, bromo, and iodo.

  The term “substituted” as used herein means that one or more hydrogen atoms on a specified atom is selected and replaced from the indicated group, provided that the specified The normal valence of the atoms should not be exceeded and the substitution shall give a stable compound. When the substitution is keto (ie, ═O), two hydrogen atoms on the atom are replaced.

  Combinations of substituents and / or variables are only allowed if the combination provides a stable compound. By “stable compound” or “stable structure” is meant a compound that is isolated from the reaction mixture in useful purity and that is sufficiently robust to withstand formulation into 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 are described by Greene and Wuts, “Protective Groups in Organic Synthesis”, John Wiley & Sons, New York, 1991, and “Peptides: Analysis, Synthesis, Biology”. , Synthesis, Biology), Vol. 3, Academic Press, New York, 1981 (Non-Patent Documents 35, 36), the disclosure of which is incorporated herein by reference. Any amine protecting group known in the art can be used. Examples of amine protecting groups include, but are not limited to, the following examples. 1) acyl forms such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl, 2) benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1- (p-biphenyl) -1-methylethoxycarbonyl, and Aromatic carbamate type such as 9-fluorenylmethyloxycarbonyl (Fmoc) 3) Aliphatic carbamate type such as t-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl 4) Cyclopentyl Cyclic alkyl carbamate types such as oxycarbonyl and adamantyloxycarbonyl, 5) alkyl types such as triphenylmethyl and benzyl, 6) trialkylsilanes such as trimethylsilane, and ) Type containing a thiol such as phenylthiocarbonyl and dithiasuccinoyl.

  The term “pharmaceutically acceptable salts” includes salts of the compounds of formula (1) and (2) with acids or bases. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids. Is not to be done.

  A pharmaceutically acceptable salt of a compound of the invention is a free acid or base form of the compound described above in a stoichiometric amount of the appropriate base or acid and water or an organic solvent, or a mixture of both. It can be prepared by reacting. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in “Remington's Pharmaceutical Sciences”, 17th edition, Mack Publishing Company, Easton, PA, page 1418 (1985), the disclosure of which Incorporated herein by reference.

  A “prodrug” is considered to be a covalently bonded carrier that releases the active original drug of formula (I) and (II) in vivo when the prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula (I) and (II) modify the functional groups present in the compounds of the invention so that the modification is cleaved either in the usual manner or in vivo to the original compound. It is prepared by. Prodrugs include compounds in which a hydroxy, amine, or sulfhydryl group is attached to any group that cleaves to give a free hydroxy, amino, or sulfhydryl group, respectively, when administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in compounds of formulas (I) and (II).

  By “therapeutically effective amount” of a compound of the invention is meant an effective amount for antagonizing abnormal levels of CRF and treating symptoms such as host affective disorder, anxiety or depression.

Synthetic Methods Some compounds of formula (1) can be prepared from intermediate compounds of formula (7) using the methods outlined in Scheme 1.

Halogenating agent with a compound of formula (7) wherein Y is O, with or without an inert solvent and with or without a base at a reaction temperature in the range of −80 ° C. to 250 ° C. Alternatively, treatment with a sulfonylating agent provides a product of formula (8), wherein X is halogen, alkanesulfonyloxy, arylsulfonyloxy, or haloalkane-sulfonyloxy. The halogenating _{agent, SOCl 2, POCl 3, PCl} 3, PCl 5, POBr 3, including but PBr ₃ or PBr _5, but is not limited to them. Examples of sulfonylating agents include alkane sulfonic acid halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic acid anhydride), aryl sulfonic acid halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride). Or haloalkyl sulfonic acid halides or anhydrides (preferably trifluoromethane sulfonic acid anhydride), but is not limited thereto. Bases include alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (C1-6) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metals Dialkylamides (preferably lithium di-isopropylamide), alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-di-isopropyl-N -Ethylamine or triethylamine) or aromatic amines (preferably pyridine) may be included but are not limited thereto. Examples of the inert solvent include lower alkane nitriles (having 1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N -Dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) , Aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes having 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably dichloromethane) may be included, but are not limited thereto. Absent. The preferred reaction temperature is in the range of -20 ° C to 100 ° C.

A compound of formula (8) is reacted with a compound of formula R ³ H (wherein, with or without an inert solvent, with or without a base at reaction temperatures ranging from −80 ° C. to 250 ° C. R ³ is as defined above but is reacted with a compound of SH, COR ⁷ , CO ₂ R ⁷ , which is neither aryl nor heteroaryl) to produce a compound of formula (1) it can. Bases include alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (C1-6) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metals Dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal hydrogencarbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably May include, but is not limited to, N, N-di-isopropyl-N-ethylamine) or aromatic amines (preferably pyridine). Examples of the inert solvent include alkyl alcohols (having 1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (having 1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), Cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N -Methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes having 1 to 10 carbon atoms and 1 to 10 halogen atoms ( Preferably Dichloromethane) may include, but is not limited to them. The preferred reaction temperature is in the range of 0 ° C to 140 ° C.

  Scheme 2 outlines a method for converting an intermediate compound of formula (7) where Y is S to some compounds of formula (1).

A compound of formula (7), wherein Y is S, is represented by formula R ^{13 with} or without an inert solvent and with or without a base at reaction temperatures ranging from −80 ° C. to 250 ° C. It can be treated with an alkylating agent of X (wherein R ¹³ is as defined above but is neither aryl nor heteroaryl). Bases include alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (C1-6) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metals Dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines ( Preferably, N, N-di-isopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine) may be included, but are not limited thereto. Examples of the inert solvent include alkyl alcohols (having 1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (having 1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), Cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N -Methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes having 1 to 10 carbon atoms and 1 to 10 halogen atoms ( Preferably Dichloromethane) may include, but is not limited to them. The preferred reaction temperature is in the range of -80 ° C to 100 ° C.

Used to convert a compound of formula (12) (R ^{3 in} formula (1) is SR ¹³ ) to a compound of formula (8) as outlined in Scheme 1 above to a compound of formula (1). The compound of the formula (1) can be obtained by reacting with the compound of the formula R ³ H using the same conditions and reagents. Alternatively, the compound of formula (12) (R ^{3 in} formula (1) is SR ¹³ ) is treated with an oxidant in the presence of an inert solvent at a temperature in the range of −80 ° C. to 250 ° C. Can be oxidized to a compound of formula (13) (R ^{3 in} formula (1) is S (O) _n R ¹³ and n is 1, 2). Oxidizing agents include, but are not limited to, hydrogen peroxide, alkanes or aryl peracids (preferably peracetic acid or m-chloro-perbenzoic acid), dioxirane, oxone or sodium periodate. Absent. Inert solvents include alkanones (3 to 10 carbon atoms, preferably acetone), water, alkyl alcohols (1 to 6 carbon atoms), aromatic hydrocarbons (preferably benzene or toluene) or carbon atoms. 1-10 and haloalkanes having 1-10 halogen atoms (preferably dichloromethane) or combinations thereof may be included, but are not limited thereto. Selection of oxidants and solvents is known to those skilled in the art (Uemura, S., “Oxidation of Sulfur, Selenium and Tellurium”, Comprehensive Organic Synthesis) , Trost, BM, (Elmsford, NY: Pergamon Press, 1991), Vol. 7, pages 762-769 (see Non-Patent Document 38)). The preferred reaction temperature is in the range of -20 ° C to 100 ° C. The compound of formula (13) (wherein R ^{3 in} formula (1) is S (O) _n R ¹³ and n is 1, 2) is then converted to formula (8) as outlined in Scheme 1 above. The compound of the formula (1) can be obtained by reacting the compound of the formula (1) with the compound of the formula R ³ H using the same conditions and reagents as those used for converting the compound of the formula (1).

Equation (1) (wherein, ^{R 3} is _{^{-NR 8 COR 7, -N (COR}} 7) 2, -NR 8 CONR 6 R 7, -NR 8 CO 2 R 13, -NR 6 R 7, -NR 8 compound of SO ₂ is R ⁷⁾ has the formula (7) (in the formula, Y may be prepared by the method shown in scheme 3 from compounds of a is) NH.

Continuous reaction of a compound of formula (7) (wherein Y is NH) with an alkylating agent, sulfonylating agent or acylating agent, or a combination thereof, in the range of −80 ° C. to 250 ° C. By carrying out the reaction in an inert solvent with or without a base at the reaction temperature, the formula (1) (wherein R ³ is —NR ⁸ COR ⁷ , —N (COR ⁷ ) ₂ , —NR ⁸ CONR _{^{6 R 7, -NR 8 CO 2}} R 13, -NR 6 R 7, to give compounds of a -NR 8 _SO 2 ^{R 7).} Alkylating agents include C ₁ -C ₁₀ alkyl halides, tosylate, mesylate or triflate; C ₁ -C ₁₀ haloalkyl (halogen number 1 to 10) halides, tosylate, mesylate s or triflates; C ₂ -C ₈ alkoxy halides of alkyl, tosylates, mesylates or triflates; C ₃ -C ₆ halides cycloalkyl, tosylates, mesylates or triflates; C ₄ -C ₁₂ cycloalkylalkyl halides, tosylate, mesylate or triflate; aryl (C ₁ -C ₄ alkyl) halide, tosylate, mesylate or triflate; heteroaryl ( C ₁ -C ₄ alkyl) halides of Tosylates, mesylates or triflates; or halides of heterocyclic (C ₁ -C ₄ alkyl), tosylates, may contain mesylates or triflates, but are not limited to, . Acylating agents include C ₁ -C ₁₀ alkanoic acid halides or anhydrides, C ₁ -C ₁₀ haloalkanoic acid halides or anhydrides having _{1 to} 10 halogen atoms, C ₂ -C ₈ alkoxyalkanes. acid halides or anhydrides, C ₃ -C ₆ cycloalkane acid halides or anhydrides, C ₄ -C ₁₂ cycloalkyl alkanoic acid halides or anhydrides, aromatic carboxylic acid halides or Anhydrides, aryl (C ₁ -C ₄ ) alkanoic acid halides or anhydrides, aromatic heterocyclic carboxylic acid halides or anhydrides, heteroaryl (C ₁ -C ₄ ) alkanoic acid halides or anhydrides, halides, or anhydrides heterocyclic carboxylic acids or heterocyclic (C 1 _{-C 4),} alkanoic acid halide Or it may include anhydrides, but is not limited to them. The sulfonylating _agent, C 1 _{-C 10} alkyl sulfonic acid halides or anhydrides, _C 1 _{-C 10} haloalkylsulfonyl acid halides or anhydrides having 1 to 10 halogen _atoms, C 2 -C ₈ alkoxyalkyl acid halides or anhydrides, C ₃ -C ₆ cycloalkyl sulfonic acid halides or anhydrides, C ₄ -C ₁₂ cycloalkylalkyl acid halides or anhydrides, aryl sulfonic acid Halides or anhydrides, aryl (C ₁ -C ₄ alkyl)-, heteroaryl sulfonic acid halides or anhydrides, heteroaryl (C ₁ -C ₄ alkyl) sulfonic acid halides or anhydrides , heterocyclic sulfonic acid halides or anhydrides or heterocyclic, (C ₁ C ₄ alkyl) acid halides or include but are anhydrides, but is not limited to them. Bases include alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (C1-6) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metals Dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably -di-isopropyl Ethylamine) or aromatic amines (preferably pyridine) may be included, but are not limited thereto. Examples of the inert solvent include alkyl alcohols (having 1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (having 1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), Cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N -Methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene) may be included, but are not limited thereto. The preferred reaction temperature is in the range of 0 ° C to 100 ° C.

Scheme 4, equation (7) (in the formula, Y is O, S, Z is CR ² in which) shows a schematic of a method which can be employed in the preparation of intermediate compounds of.

A compound of formula ArCH ₂ CN is represented by formula R ² COR ^b , wherein R ² is as defined above, and R ^b is halogen, cyano, lower alkoxy (1 to 6 carbon atoms) or lower alkanoyloxy (carbon The compound of formula (3) is obtained by reacting the compound of formula 1-6) with a base in an inert solvent at a reaction temperature in the range of −78 ° C. to 200 ° C. Bases include alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (C1-6) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metals Dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines ( Preferably, N, N-di-isopropyl-N-ethylamine) or aromatic amines (preferably pyridine) may be included, but not limited thereto. Examples of the inert solvent include alkyl alcohols (C1-8, preferably methanol or ethanol), lower alkanenitriles (C1-6, preferably acetonitrile), water, dialkyl ethers (preferably diethyl ether). ), Cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably May include, but is not limited to, N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). The preferred reaction temperature is in the range of 0 ° C to 100 ° C.

By reacting a compound of formula (3) with hydrazine hydrate in the presence of an inert solvent at a temperature in the range of 0 ° C. to 200 ° C., preferably at a temperature of 70 ° C. to 150 ° C. A compound is obtained. Inert solvents include water, alkyl alcohols (C1-C8, preferably methanol or ethanol), lower alkanenitriles (C1-C6, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one) , Dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene), but are not limited thereto. A compound of formula (4) can be prepared by formula (5) (wherein R ^c is 1 to 6 carbon atoms) with or without an inert solvent at a temperature ranging from 0 ° C. to 200 ° C. The compound of formula (6) can be produced by reacting with a compound of alkyl). Examples of the acid include alkanoic acids having 2 to 10 carbon atoms (preferably acetic acid), haloalkanoic acids having 2 to 10 carbon atoms such as trifluoroacetic acid having 1 to 10 halogen atoms, and aryl sulfonic acids (preferably p-toluene sulfone). Acid or benzenesulfonic acid), alkanesulfonic acid having 1 to 10 carbon atoms (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid, but is not limited thereto. Stoichiometric or catalytic amounts of acid can be used. Examples of the inert solvent include water, alkanenitriles (having 1 to 6 carbon atoms, preferably acetonitrile), haloalkanes having 1 to 6 carbon atoms and 1 to 6 halogen atoms (preferably dichloromethane or chloroform), 1 carbon atom. To 10 alkyl alcohols (preferably ethanol), dialkyl ethers (4 to 12 carbon atoms, preferably diethyl ether or di-isopropyl ether) or cyclic ethers such as dioxane or tetrahydrofuran, It is not limited. A preferred temperature is in the range of ambient temperature to 100 ° C.

A compound of formula (6) is reacted with a compound of formula Y = C (R ^d ) ₂ in the presence or absence of a base in an inert solvent at reaction temperatures ranging from −50 ° C. to 200 ° C. Or R ^d is treated with a compound of halogen (preferably chlorine), alkoxy (carbon number 1-4) or alkylthio (carbon number 1-4) to form a compound of formula (7). Can be converted. Bases include alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (C1-6) (preferably sodium methoxide or sodium ethoxide), alkali metal carbonates, alkali metal hydroxides. , Trialkylamines (preferably N, N-di-isopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine), but are not limited thereto. Inert solvents include alkyl alcohols (C1-8, preferably methanol or ethanol), lower alkanenitriles (C1-6, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1, 4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl Sulphoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene) may be included, but are not limited thereto. A preferred temperature is 0 ° C to 150 ° C.

  Intermediate compounds of formula (7) (wherein Z is N) can be synthesized according to the method outlined in Scheme 5.

A compound of formula ArCH ₂ CN is substituted with the formula R ^q CH ₂ N ₃ , wherein R ^q is optionally substituted with H, alkyl (C 1-6) or alkoxy (C 1-6). And the compound of formula (9) can be produced by reacting with a compound in the presence of or without a base in an inert solvent at a temperature in the range of 0 ° C to 200 ° C. Bases include alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (C1-6) (preferably sodium methoxide, sodium ethoxide or potassium t-butoxide), alkaline earth metal hydrogen Compounds, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), Trialkylamines (preferably N, N-di-isopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine) may be included, but are not limited thereto. Examples of the inert solvent include alkyl alcohols (having 1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (having 1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), Cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N -Methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene) may be included, but are not limited thereto. Preferred reaction temperatures range from ambient temperature to 100 ° C.

By treating the compound of formula (9) with a reducing agent in an inert solvent at −100 ° C. to 100 ° C., a compound of formula (10) is obtained. The reducing agent includes (a) a combination of a noble metal catalyst such as Pd-carbon, PtO ₂ , Pt-carbon, Rh-alumina or Raney nickel and hydrogen gas, and (b) a combination of liquid ammonia and alkali metals (preferably sodium). Or (c) ceric ammonium nitrate, but is not limited thereto. Examples of the inert solvent include alkyl alcohols (C1-8, preferably methanol or ethanol), lower alkanenitriles (C1-6, preferably acetonitrile), water, dialkyl ethers (preferably diethyl ether). ), Cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably May include, but is not limited to, N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). The preferred reaction temperature is −50 ° C. to 60 ° C. The compound of formula (9) is then subjected to the reagents and reaction conditions outlined in Scheme 4 when converting formula (4) to a compound of formula (7) (wherein Z is CR ² ). And converted to a compound of formula (7) (wherein Z is N) via an intermediate of formula (11).

  A compound of formula (1) can be prepared from a compound of formula (7) where Y is O, S and Z is as defined above, as outlined in Scheme 6.

The compound of formula (7) can be reacted with the compound of formula R ³ H in the presence of a dehydrating agent in an inert solvent at a reaction temperature ranging from 0 ° C. to 250 ° C. Dehydrating agents include, but are not limited to, P ₂ O ₅ , molecular sieves or inorganic or organic acids. Examples of the acid include alkanoic acids having 2 to 10 carbon atoms (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), and alkanesulfonic acids having 1 to 10 carbon atoms (preferably methanesulfonic acid). ), Hydrochloric acid, sulfuric acid or phosphoric acid, but are not limited thereto. Examples of the inert solvent include alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkane nitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably glyme or diglyme). , Cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes having 1 to 10 carbon atoms and 1 to 10 halogen atoms (Preferred Ku may include chloroform) is, but not limited to them. Preferred reaction temperatures range from ambient temperature to 150 ° C.

  Some compounds of formula (1) (wherein A is N) can also be prepared by the method shown in Scheme 7.

Intermediate compounds of formula (14) (wherein Z is as defined above) are converted to formula R with or without acid in an inert solvent at a temperature in the range of 0 ° C to 250 ° C. It can be reacted with a compound of ³ C (OR ^e ) ₃ (wherein R ^e is alkyl (C 1-6)). Examples of the acid include alkanoic acids having 2 to 10 carbon atoms (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), and alkanesulfonic acids having 1 to 10 carbon atoms (preferably methanesulfonic acid). ), Hydrochloric acid, sulfuric acid or phosphoric acid, but are not limited thereto. Stoichiometric or catalytic amounts of these acids can be used. Examples of the inert solvent include lower alkane nitriles (having 1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N -Dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) , Aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes having 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably dichloromethane) may be included, but are not limited thereto. Absent. The preferred reaction temperature is in the range of 50 ° C to 150 ° C.

  The intermediate compound of formula (7) can also be synthesized by the reaction shown in Scheme 8.

Formula (15) wherein Y is OH, SH, NR ⁶ R ⁷ , Z is as defined above, and X is Br, Cl, I, O ₃ SCF ₃ or B (OR ′ ″ ') ₂ and R ″ ″ is H or alkyl (C 1-6) in the presence of a base in an inert solvent at a temperature in the range of −100 ° C. to 200 ° C., or And with or without an organometallic catalyst of formula ArM (wherein M is halogen, alkali metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl ₂ , CeBr ₂ or copper halides) Can be reacted with the compound. As one skilled in the art will appreciate, the reagent ArM can be generated during the reaction. Organometallic catalysts include palladium phosphine complexes (such as Pd (PPh ₃ ) ₄ ), palladium halides or palladium alkanoic acid salts (such as PdCl ₂ (PPh ₃ ) ₂ or Pd (OAc) ₂ ) or nickel complexes ( NiCl ₂ (PPh ₃ ) _{2 and the} like), but is not limited thereto. Bases may include, but are not limited to, alkali metal carbonates or trialkylamines (preferably N, N-di-isopropyl-N-ethylamine or triethylamine). Inert solvents include dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkyl. Acetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or water May be included, but is not limited thereto. The preferred reaction temperature is in the range of -80 ° C to 100 ° C.

The selection of M and X is known to those skilled in the art (Imamoto, T., “Organocerium Reagents”), Comprehensive Organic Synthesis, Trost, BM, (Elmsford, NY: Pergamon Press, 1991), Volume 1, pp. 231-250 (Non-Patent Document 39), Knochel, P., “Organic zinc, organic cadmium, and organic mercury reagents (Organozinc, Organocadmium, and Organomercury Reagents)”, Comprehensive organic synthesis, Trost, BM edition (Elmsford, NY: Pergamon Press, 1991), Volume 1, pages 211 to 230 (Non-Patent Document 40), Knight, DW, “coupling reaction between sp ² carbon centers (See Coupling Reactions between sp ² Carbon Centers), Comprehensive Organic Synthesis, Trost, BM, (Elmsford, NY: Pergamon Press, 1991), Volume 3, pages 481-520 (Non-patent Document 41)).

  Compounds of formula (1) can also be prepared using the method shown in Scheme 9.

Formula (16) wherein A, Z, R ¹ and R ³ are as defined above, X is Br, Cl, I, O ₃ SCF ₃ or B (OR ″ ″) ₂ ; R ″ ″ is H or alkyl having 1 to 6 carbon atoms) in the presence or absence of a base in an inert solvent at a temperature in the range of −100 ° C. to 200 ° C. A compound of formula ArM with or without a catalyst, wherein M is a halogen, an alkali metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl ₂ , CeBr ₂ or copper halides; Can be reacted. As one skilled in the art will appreciate, the reagent ArM can be generated during the reaction. (See the above references in “Comprehensive Organic Synthesis”). Organometallic catalysts include palladium phosphine complexes (such as Pd (PPh ₃ ) ₄ ), palladium halides or palladium alkanoic acid salts (such as PdCl ₂ (PPh ₃ ) ₂ or Pd (OAc) ₂ ) or nickel complexes ( NiCl ₂ (PPh ₃ ) _{2 and the} like), but is not limited thereto. Bases may include, but are not limited to, alkali metal carbonates or trialkylamines (preferably N, N-di-isopropyl-N-ethylamine or triethylamine). Inert solvents include dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkyl. Acetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or water May be included, but is not limited thereto. The preferred reaction temperature is in the range of -80 ° C to 100 ° C.

An intermediate compound of formula (7) (wherein Y is O, S, NH, Z is CR ² and R ¹ , R ² and Ar are as defined above) is illustrated in Scheme 10. Can be manufactured.

A compound of formula (3) is reacted with H ₂ NNH (C═Y) NH ₂ (wherein Y is O, in the presence or absence of a base or acid in an inert solvent at a temperature of 0 ° C. to 250 ° C. The compound of formula (17) can be formed by reaction with a compound of S or NH. Examples of the acid include alkanoic acids having 2 to 10 carbon atoms (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), and alkanesulfonic acids having 1 to 10 carbon atoms (preferably methanesulfonic acid). ), Hydrochloric acid, sulfuric acid or phosphoric acid, but are not limited thereto. Stoichiometric or catalytic amounts of these acids can be used. Bases include alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (C1-6) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metals Dialkylamides (preferably lithium di-isopropylamide), alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-di-isopropyl-N -Ethylamine or triethylamine) or aromatic amines (preferably pyridine) may be included but are not limited thereto. Examples of the inert solvent include alkyl alcohols (having 1 to 6 carbon atoms), lower alkanenitriles (having 1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), and cyclic ethers (preferably tetrahydrofuran). Or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one) ), Dialkyl sulfoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or toluene), or haloalkanes having 1 to 10 carbon atoms and preferably 1 to 10 halogen atoms (preferably dichloromethane). You can, but it The present invention is not limited to.

A preferred reaction temperature is in the range of 0 ° C to 150 ° C. The compound of formula (17) is then reacted with R ³ C (OR ^e ) ₃ in the presence of an acid in an inert solvent at a temperature in the range of 0 ° C. to 250 ° C., where R ^e is It can be made to react with the compound of alkyl (C1-C6). Examples of the acid include alkanoic acids having 2 to 10 carbon atoms (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), and alkanesulfonic acids having 1 to 10 carbon atoms (preferably methanesulfonic acid). ), Hydrochloric acid, sulfuric acid or phosphoric acid, but are not limited thereto. Stoichiometric or catalytic amounts of these acids can be used. Examples of the inert solvent include lower alkane nitriles (having 1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N -Dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) , Aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes having 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably dichloromethane) may be included, but are not limited thereto. Absent. The preferred reaction temperature is in the range of 50 ° C to 150 ° C.

Scheme 11 includes compounds of formula (1) wherein R ³ is COR ⁷ , CO ₂ R ⁷ , NR ⁸ COR ⁷ and CONR ⁶ R ⁷ , at temperatures ranging from −80 ° C. to 250 ° C. Treatment with a reducing agent in an inert solvent in the presence or absence of an acid, wherein R ³ is CH (OH) R ⁷ , CH ₂ OH, NR ⁸ CH ₂ R ⁷ and illustrates a method that can be used to be converted into other compounds of CH ₂ is NR ⁶ R ^7).

  Examples of the reducing agent include alkali metal or alkaline earth metal boron hydrides (preferably lithium borohydride or sodium), borane, dialkylboranes (such as di-isoamyl borane), alkali metal aluminum hydrides (preferably hydrogen). Lithium aluminum hydride), alkali metal (trialkoxy) aluminum hydrides or dialkylaluminum hydrides (such as di-isobutylaluminum hydride), but are not limited thereto. Inert solvents include alkyl alcohols (C1-6), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably Benzene or toluene), but is not limited thereto. The preferred reaction temperature is in the range of -80 ° C to 100 ° C.

The Scheme 12, equation (1) (wherein, ^{R 3} is COR ⁷ or _CO 2 ^{R 7)} a compound of an inert solvent at temperatures ranging from -80 ° C. to 250 DEG ° C., wherein ^R 7 M Figure ₂ shows a method that can be used to convert to another compound of formula (1) wherein R ³ is C (OH) (R ⁷ ) ₂ .

M is halogen, alkali metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl ₂ , CeBr ₂ or copper halides. Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran) or aromatic hydrocarbons (preferably benzene or toluene). It is not a thing. The preferred reaction temperature is in the range of -80 ° C to 100 ° C.

Equation (1) (wherein, ^{R 3} is _{^{-NR 8 COR 7, -N (COR}} 7) 2, -NR 8 CONR 6 R 7, -NR 8 CO 2 R 13, -NR 6 R 7, -NR 8 The compound of SO ₂ R ⁷ can be synthesized as shown in Scheme 13.

The compound of formula (18) (wherein R and R ¹ are as defined above) is allowed to occur in an inert solvent at temperatures ranging from −50 ° C. to 250 ° C. with or without a base. It can be reacted with a compound of formula (4) or (10) to produce a compound of formula (19). Bases include alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (C1-6) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metals Dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably di-isopropylethylamine) ) Or aromatic amines (preferably pyridine), but are not limited thereto. Examples of the inert solvent include alkyl alcohols (having 1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (having 1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), Cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N -Methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene) may be included, but are not limited thereto. The preferred reaction temperature is in the range of 0 ° C to 100 ° C.

The reaction of the compound of formula (19) with the reaction of an alkylating agent, sulfonylating agent or acylating agent, or a combination thereof is then carried out with an inert solvent at a reaction temperature in the range of −80 ° C. to 250 ° C. By carrying out the reaction in the presence or absence of a base in the formula (1) (wherein R ³ is —NR ⁸ COR ⁷ , —N (COR ⁷ ) ₂ , —NR ⁸ CONR ⁶ R ⁷ , —NR ⁸ CO ₂ R ¹³ , —NR ⁶ R ⁷ , —NR ⁸ SO ₂ R ⁷ ). Alkylating agents include C ₁ -C ₁₀ alkyl halides, tosylate, mesylate or triflate; C ₁ -C ₁₀ haloalkyl (halogen number 1 to 10) halides, tosylate, mesylate s or triflates; C ₂ -C ₈ alkoxy halides of alkyl, tosylates, mesylates or triflates; C ₃ -C ₆ halides cycloalkyl, tosylates, mesylates or triflates; C ₄ -C ₁₂ cycloalkylalkyl halides, tosylate, mesylate or triflate; aryl (C ₁ -C ₄ alkyl) halide, tosylate, mesylate or triflate; heteroaryl ( C ₁ -C ₄ alkyl) halides of Tosylates, mesylates or triflates; or halides of heterocyclic (C ₁ -C ₄ alkyl), tosylates, may contain mesylates or triflates, but are not limited to, . Acylating agents include C ₁ -C ₁₀ alkanoic acid halides or anhydrides, C ₁ -C ₁₀ haloalkanoic acid halides or anhydrides having _{1 to} 10 halogen atoms, C ₂ -C ₈ alkoxyalkanes. acid halides or anhydrides, C ₃ -C ₆ cycloalkane acid halides or anhydrides, C ₄ -C ₁₂ cycloalkyl alkanoic acid halides or anhydrides, aromatic carboxylic acid halides or Anhydrides, aryl (C ₁ -C ₄ ) alkanoic acid halides or anhydrides, aromatic heterocyclic carboxylic acid halides or anhydrides, heteroaryl (C ₁ -C ₄ ) alkanoic acid halides or anhydrides, halides, or anhydrides heterocyclic carboxylic acids or heterocyclic (C 1 _{-C 4),} alkanoic acid halide Or it may include anhydrides, but is not limited to them. The sulfonylating _agent, C 1 _{-C 10} alkyl sulfonic acid halides or anhydrides, _C 1 _{-C 10} haloalkylsulfonyl acid halides or anhydrides having 1 to 10 halogen _atoms, C 2 -C ₈ alkoxyalkyl acid halides or anhydrides, C ₃ -C ₆ cycloalkyl sulfonic acid halides or anhydrides, C ₄ -C ₁₂ cycloalkylalkyl acid halides or anhydrides, aromatic sulfonic acid halides or anhydrides, aryl (C ₁ -C ₄ alkyl) -, heteroaryl sulfonic acid halides or anhydrides, heteroaryl (C ₁ -C ₄ alkyl) acid halides or anhydrides s, heterocyclic sulfonic acid halides or anhydrides or heterocyclic (C _1, - ₄ alkyl) include acid halides or anhydrides, but is not limited to them. Bases include alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (C1-6) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metals Dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably di-isopropylethylamine) ) Or aromatic amines (preferably pyridine), but are not limited thereto. Examples of the inert solvent include alkyl alcohols (having 1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (having 1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), Cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N -Methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene) may be included, but are not limited thereto. The preferred reaction temperature is in the range of 0 ° C to 100 ° C.

  Compounds of formula (1) (wherein A is CR and R is as defined above) can be synthesized by the method shown in Scheme 14.

A compound of formula (4) or (10) is reacted with a compound of formula (20) in the presence or absence of a base in an inert solvent at a temperature in the range of 0 ° C. to 250 ° C. (wherein R ¹ and R ³ are By treatment with a compound of the above definition, a compound of formula (1) (wherein A is CR and R is as defined above) can be obtained. Bases include alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (C1-6) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metals Dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably di-isopropylethylamine) ) Or aromatic amines (preferably pyridine), but are not limited thereto. Examples of the inert solvent include alkyl alcohols (having 1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (having 1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), Cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N -Methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene) may be included, but are not limited thereto. The preferred reaction temperature is in the range of 0 ° C to 100 ° C. Alternatively, a compound of formula (1) (wherein A is CR and R is as defined above) is synthesized via an intermediate of formula (22) and (23). Can do.

A compound of formula (4) or (10) is compounded with formula (21) in the presence or absence of a base in an inert solvent at a temperature ranging from 0 ° C. to 250 ° C., wherein R ¹ is as defined above. R ^e is treated with a compound of alkyl (having 1 to 6 carbon atoms) to give a compound of formula (1) (wherein A is CR and R is as defined above). Bases include alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (carbon number 1 to 6) (preferably sodium methoxide or sodium ethoxide), alkaline earth Metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably Thorium bis (trimethylsilyl) amide), trialkylamines (preferably di-isopropylethylamine) or aromatic amines (preferably pyridine), but are not limited to these. Are alkyl alcohols (C1-C8, preferably methanol or ethanol), lower alkanenitriles (C1-C6, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers ( Preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidine- 2 -One), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene), but are not limited to these. In the range of 100 ° C. Halogenating agent with a compound of formula (22) in the presence or absence of an inert solvent, with or without a base at a reaction temperature in the range of −80 ° C. to 250 ° C. Alternatively, a compound of formula (23) (wherein X is halogen, alkanesulfonyloxy, arylsulfonyloxy or haloalkanesulfonyloxy) can be obtained by treatment with a sulfonylating agent. _{SOCl 2, POCl 3, PCl 3} , PCl 5, POBr 3, include PBr ₃ or PBr ₅ But it is not limited to them. Examples of sulfonylating agents include alkane sulfonic acid halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic acid anhydride), aryl sulfonic acid halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride). Or haloalkyl sulfonic acid halides or anhydrides (preferably trifluoromethane sulfonic acid anhydride), but is not limited thereto. Bases include alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (C1-6) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metals Dialkylamides (preferably lithium di-isopropylamide), alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-di-isopropyl-N -Ethylamine or triethylamine) or aromatic amines (preferably pyridine) may be included but are not limited thereto. Examples of the inert solvent include lower alkane nitriles (having 1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N -Dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) , Aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes having 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably dichloromethane) may be included, but are not limited thereto. Absent. The preferred reaction temperature is in the range of -20 ° C to 100 ° C.

The compound of formula (23), in the presence of an inert solvent at reaction temperatures ranging from -80 ° C. to 250 DEG ° C., or without, the formula R ^{3 H} (where without a base in the presence of, or is, R ³ Can be reacted with a compound of formula (1) as defined above, but not SH, COR ⁷ , CO ₂ R ⁷ , any of aryl and heteroaryl. Bases include alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (C1-6) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metals Dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal hydrogencarbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably May include, but is not limited to, N, N-di-isopropyl-N-ethylamine) or aromatic amines (preferably pyridine). Examples of the inert solvent include alkyl alcohols (having 1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (having 1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), Cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N -Methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes having 1 to 10 carbon atoms and 1 to 10 halogen atoms ( Preferably Dichloromethane) may include, but is not limited to them. The preferred reaction temperature is in the range of 0 ° C to 140 ° C.

  Some compounds of formula (1) can also be prepared using the method shown in Scheme 15.

Reaction of a compound of formula (24) (wherein R _c is a lower alkyl group and Ar is as defined above) with hydrazine in the presence or absence of an inert solvent gives formula (25 ) (Wherein Ar is as defined above). The conditions are the same as those used in Scheme 4 to produce the intermediate of formula (4) from the compound of formula (3). A compound of formula (25) (wherein A is N) may be represented by the formula R ¹ C (═NH) OR _e (wherein R ¹ is as defined above) with or without an acid in an inert solvent. And R _e is a lower alkyl group, and then the formula Y═C (R _d ) ₂ in the presence or absence of a base in an inert solvent, where Y is When reacted with a compound of halogen (preferably chlorine), alkoxy (carbon number 1 to 4) or alkylthio (carbon number 1 to 4), R _d is O or S. , A is N and Y is O, S). These conversion conditions are the same as those used in Scheme 4 for converting the compound of formula (4) to the compound of formula (7).

Alternatively, using the same conditions used in Scheme 14 to convert the compound of formula (21) to the compound of formula (22), formula (25) (wherein A is CR) Is reacted with a compound of formula R ¹ (C═O) CHR (C═Y) OR _c , wherein R ¹ and R are as defined above, and R _c is a lower alkyl group. And a compound of formula (27) wherein A is CR. An intermediate of formula (27) (wherein Y is O) is treated with a halogenating or sulfonylating agent in an inert solvent with or without a base, and then in an inert solvent with a base Reaction with R ³ H or R ² H in the presence or absence of can give compounds of formula (1) wherein Z is CR ² .

As one skilled in the art will appreciate, to obtain compounds of formula (1), in Scheme 15, various combinations of halogenating agents, sulfonylating agents, R ³ H or R ² H are used in various sequences of reaction sequences. Can be used. For example, in some cases, a compound is reacted with a stoichiometric amount of a halogenating or sulfonylating agent, reacted with R ² H (or R ³ H), and then reacted with a halogenating or sulfonylating agent. It may be desirable to repeat and further react with R ³ H (or R ² H) to obtain a compound of formula (1). The reaction conditions and reagents used for these conversions are the same as those in the case of converting the compound of formula (22) into the compound of formula (23) and further to the compound of formula (1) in Scheme 14 (when A is CR), or in the scheme The conditions are the same as those used for converting the compound of formula (7) into a compound of formula (8) and further a compound of formula (1) in 1 (wherein A is N).

Alternatively, a compound of formula (27) (wherein Y is S) can be converted to a compound of formula (1) in Scheme 15. Alkylating an intermediate compound of formula (27) with a compound of R ^f X in an inert solvent, wherein R ^f is lower alkyl, X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy (and then Optionally oxidized with an oxidizing agent in an inert solvent) and further reacted with R ³ H in an inert solvent with or without a base to give a compound of formula (1). The reaction conditions and reagents used are the same as those used in Scheme 2 to convert the intermediate compound of formula (7) to the compound of formula (12) (or formula (13)) and further to the compound of formula (1). It is.

The compound of the formula (1) can be produced from the compound of the formula (24) using a separate route shown in Scheme 15. The compound of formula (24) is converted into an acid in an inert solvent using the conditions used for converting the compound of formula (3) to the compound of formula (17) and further to the compound of formula (7) in Scheme 10. Reaction with a compound of formula NH ₂ NH (C═NH) NH ₂ , with or without, followed by formula R ¹ C (OR _c ) ₃ , where R _c is lower alkyl and R ¹ is as defined above Can be converted to the compound of formula (27) via reaction with the compound of

  Some compounds of formula (2) can be prepared by the method illustrated in Scheme 16.

A compound of formula (27b) is reacted with R ¹⁴ X in the presence or absence of a base in an inert solvent, wherein R ¹⁴ is as defined above, where X is a halogen, alkanesulfonyloxy or haloalkane. Treatment with various alkylating agents (which is sulfonyloxy) provides the structure of formula (28). Treating a compound of formula (28) (wherein Y is O) with a halogenating or sulfonylating agent in an inert solvent, with or without a base, followed by a base in an inert solvent Reaction with R ³ H in the presence or absence of provides the compound of formula (2). The reaction conditions for these conversions are as follows when the compound of formula (22) is converted to the compound of formula (23), further to the compound of formula (1) in Scheme 14 (when A is CR), or in scheme 1 (wherein The conditions are the same as those used when the compound of formula (7) is converted to the compound of formula (8) and further to the compound of formula (1).

Alternatively, the compound of formula (28) (wherein Y is S) is R ^f X (wherein R ^f is lower alkyl and X is halogen, alkanesulfonyloxy or Alkylated with a compound of (which is a haloalkanesulfonyloxy) (and optionally oxidized with an oxidant in an inert solvent) and R ³ H with or without a base in the inert solvent. The compound of Formula (1) is obtained by making it react. The reaction conditions and reagents used are the same as those used in Scheme 2 to convert the intermediate compound of formula (7) to the compound of formula (12) (or formula (13)) and further to the compound of formula (1). It is.

Compounds of formula (1) (wherein Z is COH) can be converted to compounds of formula (2) as illustrated in Scheme 16. A variety of compounds of formula R ¹⁴ X in which R ¹⁴ is as defined above and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy, with or without a base in an inert solvent; By treatment with an alkylating agent, the structure of (2) is obtained. As one skilled in the art will appreciate, the method used in Scheme 16 can also be used to prepare compounds of formula (1), where Z is COR ⁷ .

  In the case of Scheme 16, the terms “base” and “inert solvent” can have the following meanings: Bases include alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (C1-6) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metals Dialkylamides (preferably lithium di-isopropylamide), alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-di-isopropyl-N -Ethylamine or triethylamine) or aromatic amines (preferably pyridine) may be included but are not limited thereto. Examples of the inert solvent include lower alkanenitriles (having 1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N -Dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) , Aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes having 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably dichloromethane) may be included, but are not limited thereto. Absent. The preferred reaction temperature is in the range of -20 ° C to 100 ° C.

(Example)
Analytical data was recorded for the compounds described below using the following general method. Proton NMR spectra were recorded with IBM-Bruker FT-NMR (300 MHz). Chemical shifts were recorded in ppm (δ) based on the internal standard tetramethylsilane in deuterated chloroform or deuterated dimethyl sulfoxide as specified below. Mass spectra (MS) or high resolution mass spectra (HRMS) were obtained using a Finnegan MAT 8230 spectrometer (using chemical ionization (CI) or gas chromatography (GC) with ammonia as the carrier gas as specified below). Or recorded on a Hewlett Packard 5988A spectrometer. Melting points were recorded with a Buchi Model 510 melting point analyzer and uncorrected. Boiling point is uncorrected. All pH measurements during the reaction procedure were made with pH test paper.

  Reagents purchased commercially, if necessary D. Perrin and WLF Armarego, Purification of Laboratory Chemicals, 3rd edition (New York: Pergamon Press, 1988) (Non-patent document 42) Purified prior to use according to the general procedure outlined in. Chromatography was performed on silica gel using the solvent system indicated below. In the case of a mixed solvent system, the volume ratio is shown. Otherwise, parts and percentages are based on weight.

  The following examples describe the invention in more detail. These examples are illustrative of the best means presently contemplated for carrying out the invention and are provided for purposes of illustration only and are not intended to limit the invention.

( Reference Example 1)
Preparation of 2,7-dimethyl-8- (2,4-dimethylphenyl) [1,5-a] -pyrazolo- [1,3,5] -triazin-4 (3H) -one (formula 7, Y is O, R ¹ is CH ₃ , Z is C—CH ₃ , and Ar is 2,4-dimethylphenyl)
A. 1-Cyano-1- (2,4-dimethylphenyl) propan-2-one sodium pellet (9.8 g, 0.43 mol) was added to 2,4-dimethylphenylacetonitrile (48 g, 0.33 mol) in ethyl acetate (150 mL). ) Added in portions into the solution at ambient temperature. The reaction mixture was heated to reflux temperature and stirred for 16 hours. The resulting suspension was cooled to room temperature and filtered. The collected precipitate was washed with a large amount of ether and air-dried. The solid was dissolved in water and 1N HCl solution was added to pH = 5-6. The mixture was extracted with ethyl acetate (3 × 200 mL). The organic layers were combined, dried over MgSO ₄ and filtered. The solvent was distilled off under reduced pressure to obtain a white solid (45.7 g, yield 74%).

_{NMR (CDCl 3, 300MHz) :;} CI-MS: 188 (M + H).

B. 5-Amino-4- (2,4-dimethylphenyl) -3-methylpyrazole 1-cyano-1- (2,4-dimethylphenyl) propan-2-one (43.8 g, 0.23 mol), hydrazine- A mixture of hydrate (22 mL, 0.46 mol), glacial acetic acid (45 mL, 0.78 mol) and toluene (500 mL) was stirred at reflux temperature for 18 hours in an apparatus equipped with a Dean-Stark trap. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. A solution obtained by dissolving the residue in 6N HCl was extracted three times with ether. Concentrated aqueous ammonia was added to the aqueous layer to adjust pH = 11. The resulting half solution was extracted three times with ethyl acetate. The organic layers were combined, dried over MgSO ₄ and filtered. The solvent was distilled off under reduced pressure to obtain a pale brown viscous oil (34.6 g, yield 75%).

NMR (CDCl ₃ , 300 MHz): 7.10 (s, 1H), 7.05 (d, 2H, J = 1), 2.37 (s, 3H), 2.10 (s, 3H).

  CI-MS: 202 (M + H).

C. While stirring a mixture of 5-acetamidino-4- (2,4-dimethylphenyl) -3-methylpyrazole, acetate potassium carbonate (69.5 g, 0.50 mol), dichloromethane (120 mL) and water (350 mL) Ethylacetimidate hydrochloride (60 g, 0.48 mol) was quickly added. The two layers were separated and the aqueous layer was extracted with dichloromethane (2 × 120 mL). The organic layers were combined, dried over MgSO ₄ and filtered. The solvent was distilled off by atmospheric distillation, and the residue (35.0 g) in the container, which was a clear pale yellow liquid, was used without further purification.

  While stirring a mixture of 5-amino-4- (2,4-dimethylphenyl) -3-methylpyrazole (34 g, 0.17 mol), ethylacetimidate (22 g, 0.25 mol) and acetonitrile (500 mL), Glacial acetic acid (9.7 mL, 0.17 mol) was added. The resulting reaction mixture was stirred at room temperature for 3 days, and after completion of stirring, the reaction mixture was concentrated under reduced pressure to about one third of the original volume. The resulting suspension was filtered and the collected solid was washed with a large amount of ether. The white solid was dried under reduced pressure (31.4 g, 61% yield).

NMR (DMSO-d ₆ , 300 MHz): 7.00 (s, 1H), 6.90 (dd, 2H, J = 7, 1), 2.28 (s, 3H), 2.08 (s, 3H) ), 2.00 (s, 3H), 1.90 (s, 3H), 1.81 (s, 3H).

  CI-MS: 243 (M + H).

D. 2,7-dimethyl-8- (2,4-dimethylphenyl) [1,5-a] -pyrazolo- [1,3,5] -triazin-4 (3H) -one sodium pellet (23 g, 1 mol) Small portions were added to vigorously stirred ethanol (500 mL). After all the sodium has reacted, add 5-acetamidino-4- (2,4-dimethylphenyl) -3-methylpyrazole, acetate (31.2 g, 0.1 mol) and diethyl carbonate (97 mL, 0.8 mol) It was. The resulting reaction mixture was heated to reflux temperature and stirred for 18 hours. The mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. The residue was dissolved in water and 1N HCl solution was added slowly to pH = 5-6. The aqueous layer was extracted 3 times with ethyl acetate. The organic layers were combined, dried over MgSO ₄ and filtered. The solvent was distilled off under reduced pressure to obtain a light tan solid (26 g, yield 98%).

NMR (CDCl ₃ , 300 MHz): 7.15 (s, 1H), 7.09 (s, 2H), 2.45 (s, 3H), 2.39 (s, 3H), 2.30 (s, 3H).

  CI-MS: 269 (M + H).

( Reference Example 2)
Of 5-methyl-3- (2,4,6-trimethylphenyl) [1,5-a]-[1,2,3] triazolo- [1,3,5] -triazin-7 (6H) -one Production (Formula 7, wherein Y is O, R ¹ is CH ₃ , Z is N, Ar is 2,4,6-trimethylphenyl)
A. 1-phenylmethyl-4- (2,4,6-trimethylphenyl) -5-aminotriazole 2,4,6-trimethylbenzyl cyanide (1.0 g, 6.3 mmol), benzyl azide (0.92 g, 6.9 mmol) and potassium t-butoxide (0.78 g, 6.9 mmol) in tetrahydrofuran (10 mL) was stirred at ambient temperature for 2.5 days. The resulting suspension was diluted with water and extracted three times with ethyl acetate. The organic layers were combined, dried over MgSO ₄ and filtered. The solvent was distilled off under reduced pressure to obtain a brown oily substance. This was triturated with ether and filtered to give a yellow solid (1.12 g, 61% yield).

NMR (CDCl ₃ , 300 MHz): 7.60-7.30 (m, 5H), 7.30-7.20 (m, 2H), 5.50 (s, 2H), 3.18 (broad s, 2H), 2.30 (s, 3H), 2.10 (s, 6H).

  CI-MS: 293 (M + H).

B. 4- (2,4,6-trimethylphenyl) -5-aminotriazole liquid ammonia (30 mL) and 1-phenylmethyl-4- (2,4,6-trimethylphenyl) -5-aminotriazole (1.1 g, 3.8 mmol) sodium (500 mg, 22 mmol) was added with stirring. The reaction mixture was stirred until a dark green color persisted. Ammonium chloride solution (mL) was added and stirred for 16 hours while warming to ambient temperature. The residue was treated with 1M HCl and filtered. The aqueous layer was made basic with concentrated aqueous ammonia (pH = 9) and extracted three times with ethyl acetate. The organic layers were combined, dried over MgSO ₄ and filtered. The solvent was distilled off under reduced pressure to obtain a single yellow solid (520 mg) by thin layer chromatography (ethyl acetate).

_{NMR (CDCl 3, 300MHz):} 6.97 (s, 2H), 3.68~3.50 ( broad s, 2H), 2.32 (s , 3H), 2.10 (s, 6H).

  CI-MS: 203 (M + H).

C. 4- (2,4,6-trimethylphenyl) -5-acetamidinotriazole, acetate 4- (2,4,6-trimethylphenyl) -5-aminotriazole (400 mg, 1.98 mmol), ethylacetimidate A solution of (261 mg, 3 mmol) and glacial acetic acid (0.1 mL, 1.98 mmol) in acetonitrile (6 mL) was stirred at ambient temperature for 4 hours. The resulting suspension was filtered and the collected solid was washed with a large amount of ether. Drying under reduced pressure gave a white solid (490 mg, 82% yield).

_{NMR (DMSO-d 6, 300MHz} ): 7.90~7.70 ( broad s, 0.5H), 7.50~7.20 (broad s, 0.5H), 6.90 (s , 2H) 6.90 (s, 2H), 3.50 to 3.10 (broad s, 3H), 2.30 to 2.20 (broad s, 3H), 2.05 (d, 1H, J = 7) 1.96 (s, 6H), 1.87 (s, 6H). CI-MS: 244 (M + H)
D. 5-Methyl-3- (2,4,6-trimethylphenyl) [1,5-a]-[1,2,3] -triazolo- [1,3,5] -triazin-7 (4H) -one Sodium (368 mg, 16.2 mmol) was added to ethanol (10 mL) at room temperature with stirring. After the sodium had reacted, 4- (2,4,6-trimethylphenyl) -5-acetamidinotriazole, acetate (490 mg, 1.6 mmol) and diethyl carbonate (1.6 mL, 13 mmol) were added. The reaction mixture was stirred at reflux temperature for 5 hours and then cooled to room temperature. The reaction mixture was diluted with water, 1N HCl solution was added to pH = 5-6, and extraction with ethyl acetate was performed three times. The organic layers were combined, dried over MgSO ₄ and filtered. The solvent was distilled off under reduced pressure to obtain a yellow residue. Trituration with ether and filtration gave a yellow solid (300 mg, 69% yield).

_{NMR (CDCl 3, 300MHz):} 6.98 (s, 2H), 2.55 (s, 3H), 2.35 (s, 3H), 2.10 (s, 6H).

  CI-MS: 270 (M + H).

( Reference Example 3)
Preparation of 4- (di (carbomethoxy) methyl) -2,7-dimethyl-8- (2,4-dimethylphenyl) [1,5-a] -pyrazolo- [1,3,5] -triazine (formula 1. In the formula, R ³ is CH (CHCO ₂ CH ₃ ) ₂ , R ¹ is CH ₃ , Z is C—CH ₃ , and Ar is 2,4-dimethylphenyl)
A. 4-chloro-2,7-dimethyl-8- (2,4-dichlorophenyl)
[1,5-a] -pyrazolotriazine 2,7-dimethyl-8- (2,4-dimethylphenyl) [1,5-a] -pyrazolo-1,3,5-triazin-4-one ( reference Example 1, 1.38 g, 4.5 mmol), a mixture of N, N-dimethylaniline (1 mL, 8 mmol) and phosphorus oxychloride (10 mL) was stirred at reflux temperature for 48 hours. Excess phosphorus oxychloride was distilled off under reduced pressure. The residue was poured into ice water, stirred for a short time and extracted quickly three times with ethyl acetate. The organic layers were combined and washed with water, then dried over MgSO ₄ and filtered. The solvent was distilled off under reduced pressure to obtain a brown oily substance. One fraction (Rf = 0.5) was obtained by flash column chromatography (ethyl acetate: hexane :: 1: 4). The solvent was distilled off under reduced pressure to obtain a yellow oil. (1.0 g, yield 68%). NMR (CDCl ₃ , 300 MHz): 7.55 (d, 1H, J = 1), 7.38 (dd, 1H, J = 7, 1), 7.30 (d, 1H, J = 7), 2 .68 (s, 3H), 2.45 (s, 3H); CI-MS: 327 (M + H).

B. 4- (Di (carbomethoxy) methyl) -2,7-dimethyl-8- (2,4-dimethylphenyl) [1,5-a] -pyrazolo-1,3,5-triazine While discarding, sodium hydride (60% in oil, 80 mg, 2 mmol) was washed twice with hexane and added into anhydrous tetrahydrofuran (THF, 1 mL). A solution of diethyl malonate (0.32 g, 2 mmol) in THF (2 mL) was added dropwise over 5 minutes. During that time, intense gas evolution occurred. 4-Chloro-2,7-dimethyl-8- (2,4-dichlorophenyl) [1,5-a] -pyrazolotriazine (0.5 g, 1.75 mmol) in THF (2 mL) was added and the reaction mixture was added. Was stirred for 48 hours under a nitrogen atmosphere. The resulting suspension was poured into water and extracted three times with ethyl acetate. The organic layers were combined, washed once with brine, dried over MgSO ₄ and filtered. The solvent was distilled off under reduced pressure to obtain a brown oily substance. Column chromatography (ethyl acetate: hexane :: 1: 9) was performed, and the solvent was distilled off under reduced pressure to obtain a pale yellow solid (Rf = 0.2, 250 mg, yield 35%).

  Mp 50-52 ° C.

NMR (CDCl ₃ , 300 MHz): 12.35 (broad s, 1H), 7.15-7.00 (m, 3H), 4.40 (q, 2H, J = 7), 4.30 (q, 2H, J = 7), 2.4, 2.35, 2.3, 2.2, 2.1 (5s, 12H), 1.4 (t, 3H, J = 7), 1.35 to 1 .25 (m, 3H);
CI-HRMS: Calculated value: 411.302, Measured value: 411.20203.

( Reference Example 6)
Preparation of 4- (1,3-dimethoxy-2-propylamino) -2,7-dimethyl-8- (2,4-dichlorophenyl) [1,5-a] -pyrazolo-1,3,5-triazine Formula 1, wherein R ³ is NHCH (CH ₂ OCH ₃ ) ₂ , R ¹ is CH ₃ , Z is C—CH ₃ , and Ar is 2,4-dichlorophenyl)
A. 4-chloro-2,7-dimethyl-8- (2,4-dichlorophenyl) [1,5-a] -pyrazolotriazine 2,7-dimethyl-8- (2,4-dimethylphenyl) [1,5 -A] -pyrazolo-1,3,5-triazin-4-one ( Reference Example 1, 1.38 g, 4.5 mmol), N, N-dimethylaniline (1 mL, 8 mmol) and phosphorus oxychloride (10 mL) The mixture was stirred at reflux temperature for 48 hours. Excess phosphorus oxychloride was distilled off under reduced pressure. The residue was poured into ice water, stirred for a short time and extracted quickly three times with ethyl acetate. The organic layers were combined and washed with ice water, then dried over MgSO ₄ and filtered. The solvent was distilled off under reduced pressure to obtain a brown oily substance. One fraction (Rf = 0.5) was obtained by flash column chromatography (ethyl acetate: hexane :: 1: 4). The solvent was distilled off under reduced pressure to obtain a yellow oil. (1.0 g, yield 68%).

NMR (CDCl ₃ , 300 MHz): 7.55 (d, 1H, J = 1), 7.38 (dd, 1H, J = 7, 1), 7.30 (d, 1H, J = 7), 2 .68 (s, 3H), 2.45 (s, 3H); CI-MS: 327 (M + H).

B. 4- (1,3-Dimethoxy-2-propylamino) -2,7-dimethyl-8- (2,4-dichlorophenyl) [1,5-a] -pyrazolo-1,3,5-triazine 4-chloro -2,7-dimethyl-8- (2,4-dichlorophenyl) [1,5-a] -pyrazolo-1,3,5-triazine (part A, 570 mg, 1.74 mmol), 1,3-dimethoxypropyl A mixture of 2-aminopropane (25 mg, 2.08 mmol) and ethanol (10 mL) was stirred at ambient temperature for 18 hours. The reaction mixture was poured into water (25 mL) and extracted three times with ethyl acetate. The organic layers were combined, dried over MgSO ₄ and filtered. The solvent was removed under reduced pressure. One fraction was obtained by column chromatography (CH ₂ Cl ₂ : CH ₃ OH :: 50: 1). The solvent was distilled off under reduced pressure to obtain a solid (250 mg, yield 35%).

  Melting point 118-120 ° C.

NMR (CDCl ₃ , 300 MHz): 7.50 (s, 1H), 7.28 (dd, 2H, J = 8, 1), 6.75 (d, 1H, J = 8), 4.70-4 .58 (m, 1H), 3.70-3.55 (m, 4H), 3.43 (s, 6H), 2.50 (s, 3H), 2.35 (s, 3H).

  CI-HRMS: Calculated value: 409.1072, Measured value: 409.1085.

Elemental analysis:
Calculated _{(C 18 H 21 Cl 2 N} 5 O 2): C, 52.69, H, 5.17, N, 17.07, Cl, 17.28.

  Found: C, 52.82, H, 5.06, N, 16.77, Cl, 17.50.

The compounds of the following reference examples shown in Tables 1 to 4 can be produced using the above-described production methods and modifications known to those skilled in the art and skilled in organic synthesis.

The compounds of the reference examples outlined in Table 1 can be prepared by the methods outlined in Reference Examples 1, 2, 3 or 6. Abbreviations commonly used, Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, and Ex in Table 1 represents a reference example .

NMR (CDCl ₃ , 300 MHz): δ 7.28 (d, J = 10 Hz, 1H), 7.03 (d, J = 8 Hz, 1H), 6.96 (s, 1H), 6.7 (d, J = 9, 1H), 4.63 (m, 1H), 3.79 (s, 3H), 3.6 (m, 4H), 3.42 (s, 6H), 2.47 (s, 3H) 2.32 (s, 3H).

( Reference Example 431)
Preparation of 2,4,7-dimethyl-8- (4-methoxy-2-methylphenyl) [1,5-a] -pyrazolo-1,3,5-triazine (Formula 1, wherein R ³ is CH ₃ and R ¹ are CH ₃ , Z is C—CH ₃ , and Ar is 2,4-dimethylphenyl)
5-acetamidino-4- (4-methoxy-2-methylphenyl) -3-methylpyrazole, acetate (602 mg, 2 mmol) was mixed with saturated NaHCO ₃ solution (10 mL). The aqueous mixture was extracted 3 times with EtOAc. The organic layers were combined, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was added to toluene (10 mL) and trimethyl orthoacetate (0.36 g, 3 mmol) to give a suspension. The reaction mixture was heated to reflux temperature under a nitrogen atmosphere and stirred for 16 hours. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo to give an oily solid. Column chromatography (CHCl ₃ : MeOH :: 9: 1) was performed, and the solvent was distilled off under reduced pressure to obtain a yellow viscous oil (Rf = 0.6, 210 mg, yield 37%).

NMR (CDCl ₃ , 300 MHz): 7.15 (d, 1H, J = 8), 6.9 (d, 1H, J = 1), 6.85 (dd, 1H, J = 8, 1), 3 .85 (s, 3H), 2.95 (s, 3H), 2.65 (s, 3H), 2.4 (s, 3H), 2.15 (s, 3H); CI-HRMS: calculated value : 283.1559, found: 283.1554 (M + H).

( Reference Example 432)
Preparation of 7-hydroxy-5-methyl-3- (2-chloro-4-methylphenyl) pyrazolo [1,5-a] pyrimidine (Formula 1, wherein A is CH, R ¹ is Me, R ³ is OH and Z are C-Me and Ar is 2-chloro-4-methylphenyl)
5-Amino-4- (2-chloro-4-methylphenyl) -3-methylpyrazole (1.86 g, 8.4 mmol) was dissolved in glacial acetic acid (30 mL) with stirring. Then, ethyl acetoacetate (1.18 mL, 9.2 mmol) was added dropwise to the resulting solution. The reaction mixture was heated to reflux temperature, stirred for 16 hours, and then cooled to room temperature. Ether (100 mL) was added and the resulting precipitate was collected by filtration. Drying under reduced pressure gave a white solid (1.0 g, 42%).

NMR (CDCl ₃ , 300 Hz): 8.70 (broad s, 1H), 7.29 (s, 1H), 7.21 to 7.09 (m, 2H), 5.62 (s, 1H), 2 .35 (s, 6H), 2.29 (s, 3H); CI-MS: 288 (M + H).

( Reference Example 433)
Preparation of 7-chloro-5-methyl-3- (2-chloro-4-methylphenyl) pyrazolo [1,5-a] pyrimidine (Formula 1, wherein A is CH, R ¹ is Me, R ³ is Cl and Z are C-Me, and Ar is 2-chloro-4-methylphenyl)
7-hydroxy-5-methyl-3- (2-chloro-4-methylphenyl) pyrazolo [1,5-a] pyrimidine (1.0 g, 3.5 mmol), phosphorus oxychloride (2.7 g, 1.64 mL) , 17.4 mmol), N, N-diethylaniline (0.63 g, 0.7 mL, 4.2 mmol) and toluene (20 mL) were stirred at reflux for 3 hours and then cooled to ambient temperature. Volatile components were removed under reduced pressure. The residue was subjected to flash column chromatography (EtOAc: hexane :: 1: 2) to give 7-chloro-5-methyl-3- (2-chloro-4-methylphenyl) pyrazolo [1,5-a] pyrimidine as a yellow oil (900 mg, 84% yield).

NMR (CDCl ₃ , 300 Hz): 7.35 (s, 1H), 7.28-7.26 (m, 1H), 7.16 (d, 1H, J = 7), 6.80 (s, 1H) ), 2.55 (s, 3H), 2.45 (s, 3H), 2.40 (s, 3H); CI-MS: 306 (M + H).

( Reference Example 434)
Preparation of 7- (pentyl-3-amino) -5-methyl-3- (2-chloro-4-methylphenyl) pyrazolo1,5-a] pyrimidine (Formula 1, wherein A is CH, R ¹ is Me, R ³ is pentyl-3-amino, Z is C-Me, Ar is 2-chloro-4-methylphenyl)
Dimethyl of 3-pentylamine (394 mg, 6.5 mmol) and 7-chloro-5-methyl-3- (2-chloro-4-methylphenyl) pyrazolo [1,5-a] pyrimidine (200 mg, 0.65 mmol) The sulfoxide (DMSO, 10 mL) solution was stirred at 150 ° C. for 2 hours and then cooled to ambient temperature. The reaction mixture was then poured into water (100 mL) and mixed. Extracted 3 times with dichloromethane, and the combined organic layers were washed with brine. After drying over MgSO ₄ and filtration, the solvent was distilled off under reduced pressure to obtain a yellow solid. Flash chromatography (EtOAc: hexane :: 1: 4) gave a white solid (140 mg, 60% yield).

Melting point: 139-141 ° C .; NMR (CDCl ₃ , 300 Hz): 7.32 (s, 1H), 7.27 (d, 1H, J = 8), 7.12 (d, 1H, J = 7), 6 .02 (d, 1H, J = 9), 5.78 (s, 1H), 3.50 to 3.39 (m, 1H), 2.45 (s, 3H), 2.36 (s, 6H) ), 1.82~1.60 (m, 4H) , 1.01 (t, 6H, J = 8); elemental analysis: calculated _{(C 20 H 25 ClN 4)} : C, 67.31, H, 7.06, N, 15.70, Cl, 9.93. Found: C, 67.32, H, 6.95, N, 15.50, Cl, 9.93.

The compounds of the reference examples outlined in Table 2 can be prepared by the methods outlined in Reference Examples 1A, 1B, 432, 433, 434. Abbreviations commonly used, Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex in Table 2 is a reference example , and EtOAc is ethyl acetate.

The compounds of the reference examples detailed in Table 3 can be prepared by the methods outlined in Reference Examples 1, 2, 3 or 6. Commonly used abbreviations are Ph for phenyl, Pr for propyl, Me for methyl, Et for ethyl, Bu for butyl, and Ex in Table 3 for reference .

The compounds of the reference examples detailed in Table 4 can be prepared by the methods outlined in Reference Examples 1A, 1B, 432, 433, 434. Commonly used abbreviations are Ph for phenyl, Pr for propyl, Me for methyl, Et for ethyl, Bu for butyl, Table 4 for Ex as a reference example , EtOAc for Ethyl acetate.

The compounds of the examples in Table 5 or 6 can be prepared by the methods shown in Reference Examples 1A, 1B, 2, 3, 6, 431, 432, 433, 434 or an appropriate combination thereof. Commonly used abbreviations are Ph for phenyl, Pr for propyl, Me for methyl, Et for ethyl, Bu for butyl, and Ex in Tables 5 and 6 are examples.

Utility CRF-R1 Receptor Binding Assay for Physiological Activity Evaluation The following describes the separation of cloned human CRF-R1 receptor-containing cell membranes for use in standard binding assays and also describes the assay itself. Describe.

Messenger RNA was isolated from the human hippocampus. The mRNA was reverse transcribed using oligo (dt) 12-18 and the coding region was amplified by PCR from the start codon to the stop codon. The resulting PCR fragment was cloned into the EcoRV site of pGEMV and the insert was regenerated from it using XhoI + XbaI to contain the vector pm3ar (including the CMV promoter, SV40't 'splice and early poly A signal, Epstein Barr). It was cloned into XhoI + XbaI of the viral origin of replication, as well as the hygromycin selectable marker. The thus obtained expression vector called phchCRFR was transfected into 293EBNA cells, and cells retaining episomes were selected in the presence of 400 μM hygromycin. Cells that survived 4 weeks of selection with hygromycin were pooled and adapted for growth in suspension before being used to generate membranes for binding assays described below. Each aliquot containing about 1 × 10 ⁸ suspended cells was then centrifuged into pellets and frozen.

The frozen pellet containing 293EBNA cells transfected with hCRFR1 receptor was transferred to ice-cold tissue buffer (50 mM HEPES buffer, pH 7.0, 10 mM MgCl ₂ , 2 mM EGTA, 1 μg for binding assay). / L aprotinin, containing 1 μg / l leupeptin and 1 μg / ml pepstatin). The homogenate is centrifuged at 40,000 × g for 12 minutes and the resulting pellet is rehomogenized in 10 ml tissue buffer. After further centrifugation at 40,000 × g for 12 minutes, the pellet is resuspended until the protein concentration is 360 μg / ml and used in the assay.

The binding assay is performed in a 96 well plate with each well having a volume of 300 μl. In each well, 50 μl of diluted test agent (final concentration of drug ranges from 10 ⁻¹⁰ to 10 ⁻⁵ M) and 100 μl of ¹²⁵ I-sheep-CRF ( ¹²⁵ Io-CRF) (final concentration 150 pM) and Add 150 μl of the cell homogenate. The plate is then incubated at room temperature for 2 hours, after which the culture is filtered through a GF / F filter (previously wetted with 0.3% polyethyleneimine) using an appropriate cell harvester. After rinsing the filters twice with ice-cold tissue buffer, each filter is removed and their radioactivity is evaluated with a gamma counter.

The ¹²⁵ Io-CRF binding inhibition curve to the cell membrane was changed with the reciprocal curve fitting program LIGAND [PJ Munson and D. Rodbard, Anal. Biochem. 107: 220 (1980) (non-patented) Reference 43)] Analyze. This program gives Ki values that represent inhibition, and these values are used to assess bioactivity.

  A compound is considered active if the Ki value representing inhibition of CRF is less than about 10,000 nM.

Inhibition of CRF-stimulated adenylate cyclase activity Inhibition of CRF-stimulated adenylate cyclase activity is performed as described by G. Battaglia et al., Synapse 1: 572 (1987). be able to. In brief, 10 minutes at 37 ° C., Tris-HCl (pH 7.4 at 37 ° C.) 100 mM, MgCl ₂ 10 mM, EGTA 0.4 mM, 0.1% BSA, isobutylmethylxanthine (IBMX) 1 mM, Phosphocreatine kinase 250 units / ml, creatine phosphate 5 mM, guanosine 5′-triphosphate 100 mM, oCRF 100 nM, antagonist peptide (concentration range 10 ⁻⁹ to 10 ⁻⁶ m) and 0 at the original wet weight The assay is performed in 200 ml buffer containing 8 mg tissue (about 40-60 mg protein). The reaction is started by adding 1 mM ATP / [ ³² P] ATP (approximately 2-4 mCi / tube) and terminated by adding 100 ml of 50 mM Tris-HCL, 45 mM ATP and 2% sodium dodecyl sulfate. To monitor cAMP recovery, 1 μl of [ ³ H] cAMP (approximately 40,000 dpm) is added to each tube prior to separation. Separation of [ ³² P] cAMP from [ ³² P] ATP is performed by eluting sequentially on Dowex and alumina columns.

In vivo bioassay The in vivo activity of the compounds of the present invention can be assessed using any bioassay that is available and acceptable within the art. Examples of these tests include a sound startle test, a stair climb test, and a chronic dosing test. These and other models useful for testing the compounds of the present invention are outlined in CW Berridge and AJ Dunn, Brain Research Reviews 15:71 (1990) (Non-Patent Document 45). Has been.
The compound may be tested in either rodent or small mammal species.

  The compounds of the present invention are useful in the treatment of imbalances associated with abnormal levels of corticotropin releasing factor in patients suffering from depression, affective disorders and / or anxiety.

  The compounds of the present invention can be administered to treat these abnormalities by contacting the active ingredients with the active ingredient site of action of the mammalian body. These compounds can be administered by any conventional method as long as they are available for use as a formulation with individual therapeutic agents or in combination with therapeutic agents. These compounds can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

  Dosage depends on how it is used and the pharmacodynamic properties of each drug, its mode of administration and route, recipient age, weight and health, nature and extent of symptoms, type of combination therapy, number of treatments, desired effect Depends on known factors such as For the purpose of use in the treatment of the above diseases or conditions, the compound of the present invention can be orally administered at a dose of 0.002 to 200 mg / kg body weight of active ingredient per day. In order to obtain a desired pharmacological effect, 0.01 to 10 mg / kg body weight is usually effective in divided doses of 1 to 4 times a day or in a continuous preparation.

Formulations (composition) suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. Usually, these pharmaceutical compositions contain about 0.5% to 95% active ingredient by weight with respect to the total weight of the composition.

  The active ingredient can be administered orally in solid formulations such as capsules, tablets and powders, or in liquids such as elixirs, syrups and / or suspensions. The compounds of the present invention can also be administered parenterally in sterile solutions.

  Gelatin capsules can also 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 diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained-release pharmaceutical products, allowing the drug to be released continuously over a period of time. Compressed tablets can be sugar coated or film coated to block unpleasant tastes, protect the active ingredient from the air, or selectively disintegrate the tablets in the gastrointestinal tract.

  In order to make it easier for patients to receive, coloring agents and flavoring agents can be included in the liquid for oral administration.

  In general, water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose) solutions and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral administration solutions. A parenteral solution preferably contains a water-soluble salt of the active ingredient, a suitable stabilizer, and optionally a buffer substance. Antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid, either alone or in combination, are suitable stabilizers. Citric acid and its salts, and EDTA are also used. In addition, a solution for parenteral administration may contain preservatives such as benzalkonium chloride, methyl or propylparaben, and chlorobutanol.

  Suitable pharmaceutical carriers are described in Remington Pharmaceutical Sciences, A. Osol (46), a standard reference in the art.

  Pharmaceutical dosage forms useful for administration of the compounds of the invention can be described as follows.

Capsules A number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg powdered active ingredient, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate.

Soft gelatin capsules A mixture of digestible oils such as soybean oil, cottonseed oil or olive oil and the active ingredient was prepared and injected into gelatin with a positive displacement pump to form a soft gelatin capsule containing 100 mg of the active ingredient. The capsule was washed and dried.

Tablets A number of tablets were prepared in a conventional manner and the dosage units were 100 mg active ingredient, 0.2 mg colloidal silicon dioxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 mg lactose. Appropriate coatings can be applied to increase palatability or slow absorption.

  The compounds of the present invention can also be used as reagents or standard drugs in biochemical studies of neurological function, neurological dysfunction and neurological disease.

While the invention has been described and illustrated with reference to certain preferred embodiments, other embodiments will be apparent to those skilled in the art. The present invention is therefore not limited to the specific embodiments described and illustrated, but may be varied or modified without departing from the spirit of the invention, the full scope of which is set forth in the appended claims. It is stated.

Claims (4)

A compound of formula (2),

And its isomers, its stereoisomers, or a mixture of its stereoisomers, and pharmaceutically acceptable salts or acetate, formate, or benzoate of alcohol and amine functional groups in formula (2) Prodrug form which is a derivative .
[In the above formula,
A is CR,
Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4 -Dihydro-1,2-benzopyranyl, tetralinyl (each Ar is unsubstituted or substituted with 1-5 R ⁴ groups, each Ar is bonded to an unsaturated carbon atom) Selected from
R is independently, _H in each _case, C 1 -C _{4 alkyl,} C 2 -C _{4 alkenyl,} C 2 -C _{4 alkynyl,} C 3 -C _{6 cycloalkyl,} C 4 -C ₇ cycloalkylalkyl, halo, _CN, selected from C 1 -C ₄ haloalkyl,
R ¹ is independently in each case H, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, halo, CN, C ₁ -C ₄ haloalkyl, C ₁ -C _{12 hydroxyalkyl,} C 2 _{-C 12 alkoxyalkyl,} C 2 _{-C 10 cyanoalkyl,} C 3 -C _{6 cycloalkyl,} C 4 _{-C 10 ^{cycloalkylalkyl, NR 9 R 10, C 1}} -C 4 alkyl -NR ⁹ Selected from R ¹⁰ , NR ⁹ COR ¹⁰ , OR ¹¹ , SH or S (O) _n R ¹² ;
R ³ is
_{^{-H, OR 7, SH, S}} (O) n R 13, COR 7, CO 2 R 7, OC (O) R 13, NR 8 COR 7, N (COR 7) 2, NR 8 CONR 6 R 7, NR ⁸ CO ₂ R ¹³ , NR ⁶ R ⁷ , NR ^6a R ^7a , N (OR ⁷ ) R ⁶ , CONR ⁶ R ⁷ , aryl, heteroaryl and heterocyclic groups,
Or -C ₁ -C _{10 alkyl,} C 2 _{-C 10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 -C _{8 cycloalkyl,} C 5 -C _{8 cycloalkenyl,} C 4 _{-C 12} cycloalkylalkyl or _{C 6} -C ₁₀ cycloalkenylalkyl (each group is unsubstituted or substituted by, _C 1 -C ₆ alkyl, independently in each _case, C 3 -C ₆ cycloalkyl, _halo, C 1 -C ₄ haloalkyl , Cyano, OR ¹⁵ , SH, S (O) _n R ¹³ , COR ¹⁵ , CO ₂ R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ₂ , NR ⁸ CONR ¹⁶ R ¹⁵ , 1-3 selected from NR ⁸ CO ₂ R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclic groups Substituted with a substituent of
R ⁴ is independently in each case C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₁₂ cycloalkylalkyl, NO _2, halo, _CN, C 1 -C ₄ ^{haloalkyl, NR 6 R 7, NR 8} COR 7, NR 8 CO 2 R 7, COR 7, OR 7, CONR 6 R 7, CO (NOR 9) R 7, CO ₂ R ^7, or _{^{S (O) n R 7 (}} C 1 -C 10 _alkyl, C 2 _{-C 10 alkenyl,} C 2 _{-C 10 alkynyl,} C 3 -C ₆ cycloalkyl and _C 4 _{-C 12} cycloalkylalkyl, each of which is unsubstituted or substituted by, _C 1 -C ₄ alkyl independently in each case, NO _2, ^{halo, CN, NR 6 R 7,} NR 8 COR 7, N In _{^{8 CO 2 R 7, COR 7}} , OR 7, CONR 6 R 7, CO 2 R 7, CO 1~3 substituents selected from ^(NOR 9) ^{R 7} or S _(O) n ^{R 7,} Selected from)
R ⁶ and R ⁷ , R ^6a and R ^7a are independently in each case
-H,
-C ₁ -C _{10 alkyl,} C 3 _{-C 10 alkenyl,} C 3 _{-C 10} alkynyl, halogen atoms 1-10 _C 1 _{-C 10 haloalkyl,} C 2 -C _{8 alkoxyalkyl,} C 3 -C _{6 cycloalkyl,} C 4 _{-C 12 cycloalkylalkyl,} C 5 _{-C 10} cycloalkenyl, or _C 6 _{-C 14} cycloalkenylalkyl (each group is unsubstituted or, independently in each case C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halo, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) _n R ¹³ , COR ¹⁵ , CO ₂ R ¹⁵ , OC (O ^{) R 13, NR 8 COR 15} , N (COR 15) 2, NR 8 CONR 16 R 15, NR 8 CO 2 R 13, NR 16 R 15, ONR ¹⁶ R ^15, aryl, substituted with 1-3 substituents selected from heteroaryl and heterocyclic group),
- aryl, aryl _(C 1 -C ₄ alkyl), heteroaryl, heteroaryl _(C 1 -C ₄ alkyl), or is selected from a heterocyclic group or a heterocyclic _(C 1 -C ₄ alkyl),
Alternatively, NR ⁶ R ⁷ and NR ^6a R ^7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine (each group is unsubstituted or 1 to 3 C an ₁ -C ₄ substituted with alkyl group),
R ⁸ is independently selected in each case from H or C ₁ -C ₄ alkyl;
R ⁹ and R ¹⁰ are independently selected in each case from H, C ₁ -C ₄ alkyl, or C ₃ -C ₆ cycloalkyl;
R ¹¹ is selected from H, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or C ₃ -C ₆ cycloalkyl;
R ¹² is C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl;
R ¹³ is C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₈ alkoxyalkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₁₂ cycloalkylalkyl, aryl, aryl (C ₁ -C ₄ alkyl)-, heteroaryl, heteroaryl (C ₁ -C ₄ alkyl)-
R ¹⁴ is C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ alkenyl, C ₃ -C ₁₀ alkynyl, C ₃ -C ₈ cycloalkyl, or C ₄ -C ₁₂ cycloalkylalkyl (each group is unsubstituted) Or independently in each case C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halo, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) _n R ¹⁵ , COR ¹⁵ , CO ₂ R ¹⁵ , OC (O) R ¹⁵ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ₂ , NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹⁵ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ and 1-3 substitutions selected from C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylsulfinyl and C ₁ -C ₆ alkylsulfonyl Substituted with a group)
R ¹⁵ and R ¹⁶ are independently in each case H, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₁₆ cycloalkylalkyl (in the case of S (O) _n R ¹⁵ , R ¹⁵ is not H)
Aryl is phenyl or naphthyl (each group is unsubstituted or independently in each case C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halo, C ₁ -C ₄ haloalkyl , Cyano, OR ¹⁵ , SH, S (O) _n R ¹⁵ , COR ¹⁵ , CO ₂ R ¹⁵ , OC (O) R ¹⁵ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ₂ , NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹⁵ , NR ¹⁶ R ¹⁵ , and 1 to 5 substituents selected from CONR ¹⁶ R ¹⁵ )
Heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2 , 3-dihydrobenzofuranyl (each group is unsubstituted or independently in each case C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halo, C ₁ -C ₄ haloalkyl, _{^{cyano, OR 15, SH, S (}} O) n R 15, -COR 15, CO 2 R 15, OC (O) R 15, NR 8 COR 15, n (COR 15) 2, NR 8 CONR 16 R ¹⁵ , NR ⁸ CO ₂ R ¹⁵ , NR ¹⁶ R ¹⁵ , and 1 to 5 substituents selected from CONR ¹⁶ R ¹⁵ )
Heterocyclic groups are saturated or partially saturated heteroaryl (each group is unsubstituted or independently in each case C ₁ -C ₆ alkyl, C ₃ -C ₆ cyclo alkyl, _halo, C 1 -C ₄ haloalkyl, _{^{cyano, OR 15, SH, S (}} O) n R 15, COR 15, CO 2 R 15, OC (O) R 15, NR 8 COR 15, n (COR 15 ) ₂ , substituted with 1 to 5 substituents selected from NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹⁵ , NR ¹⁵ R ¹⁶ , and CONR ¹⁶ R ¹⁵ ),
n is independently 0, 1 or 2 in each case. ] Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each Ar is The compound according to claim 1, characterized in that optionally substituted with 1-4 R ⁴ substituents And its isomers, its stereoisomers, or a mixture of its stereoisomers, and pharmaceutically acceptable salts or acetate, formate, or benzoate of alcohol and amine functional groups in formula (2) Prodrug form which is a derivative . The compound according to claim 1 , wherein R ³ is NR ^6a R ^7a or OR ⁷ , and its isomer, its stereoisomer, or a mixture of its stereoisomers, and pharmaceutically acceptable A prodrug form that is an acetate, formate, or benzoate derivative of the salt or alcohol and amine functional groups in formula (2) . Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each of Ar is unsubstituted or substituted with 1 to 4 R ⁴ substituents, and R ³ is NR ^6a The compound of claim 1 and its isomer, its stereoisomer, or a mixture of its stereoisomers, and a pharmaceutically acceptable salt or formula thereof, wherein R ^7a or OR ⁷ Prodrugs that are acetate, formate, or benzoate derivatives of alcohol and amine functional groups in 2) .