Pyrazolo[1,5-a]pyridine derivatives and their use as neurotransmitter modulators Number:7,151,109 from the United States Patent and Trademark Office (PTO) owispatent The present invention relates to novel pyrazolo[1,5-a]pyridine derivatives of general formula I: ##STR00001## that bind with high affifnity to CRF.sub.1 receptors, including human CRF.sub.1 receptors. This invention also relates to methods of using the compounds of the invention to treat a disorder or condition, the treatment of which can be effected or facilitated by antagonizing a CRF receptor, such as CNS disorders or diseases, particularly anxiety disorders, and depression and stress related disorders.<H neurotransmitter, derivatives, Pyrazolo, 1, 5, a, , 7151109.html, Patent, pto, 7151109

Title: Pyrazolo[1,5-a]pyridine derivatives and their use as neurotransmitter modulators

Abstract: The present invention relates to novel pyrazolo[1,5-a]pyridine derivatives of general formula I: ##STR00001## that bind with high affifnity to CRF.sub.1 receptors, including human CRF.sub.1 receptors. This invention also relates to methods of using the compounds of the invention to treat a disorder or condition, the treatment of which can be effected or facilitated by antagonizing a CRF receptor, such as CNS disorders or diseases, particularly anxiety disorders, and depression and stress related disorders.

Patent Number: 7,151,109 Issued on 12/19/2006 to Fu

Inventors: Fu; Jian-Min (Kalamazoo, MI)
Assignee: Pharmacia & Upjohn Company LLC (Kalamazoo, MI)

Appl. No.: 10/387,159

Filed: March 12, 2003

Current U.S. Class: 514/300 ; 546/121

Current International Class: A61K 31/44 (20060101)

Field of Search: 546/121 514/300

References Cited [Referenced By]

U.S. Patent Documents


5525480	June 1996	Zimmermann et al.
6043260	March 2000	Chen et al.
6589947	July 2003	Hamanaka et al.

Foreign Patent Documents


0433855	Dec., 1990	EP
433855	Jun., 1991	EP
2822689	Mar., 2001	FR
2822690	Mar., 2001	FR
2822691	Mar., 2001	FR
2822692	Mar., 2001	FR
61097285	May., 1986	JP
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WO 99/01454	Jan., 1999	WO
WO 00/39127	Jul., 2000	WO
WO 00/59907	Oct., 2000	WO
WO 00/59908	Oct., 2000	WO
WO 01/35917	May., 2001	WO
WO 01/35917	May., 2001	WO
WO 01/87889	Nov., 2001	WO
WO 02/088121	Jan., 2002	WO
WO 02/076416	Oct., 2002	WO

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Primary Examiner: Owens; Amelia A.
Attorney, Agent or Firm: Zhang; Austin Young; Robert Ashbrook; Charles W.

Parent Case Text

CROSS-REFERENCE TO OTHER APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser. No. 60/363,766 filed on Mar. 13, 2002, U.S. Provisional Application Ser. No. 60/380,576 filed on May 14, 2002, and U.S. Provisional Application Ser. No. 60/403,547 filed on Aug. 14, 2002.

Claims

What is claimed is:

1. A compound of formula I: ##STR00102## a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein: R.sup.1 is selected fron --H, --NR.sup.7R.sup.8, --OR.sup.7, --S(O).sub.mR.sup.7, --C(O)R.sup.7, --C(S)R.sup.7, --C(O)OR.sup.7, --C(S)OR.sup.7, --C(O)NR.sup.7R.sup.8, --C(S)NR.sup.7R.sup.8, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heteracycloalkyl; R.sup.2 is selected from --NR.sup.7R.sup.8; R.sup.3, R.sup.4 and R.sup.5 can be the same or different and are independently selected from --H, alkyl, substituted alkyl, R.sup.6 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl, and --NR.sup.11R.sup.12; R.sup.7 and R.sup.8 (1) can be the same or different and are independently selected from --H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, hereroaryl, and substituted heteroaryl, provided that R.sup.7 and R.sup.8 are not both H; or (2) when both R.sup.7 and R.sup.8 are alkyls and attached to a nitrogen, may form, along with the nitrogen, a 3 8 membered mono heterocyclic ring, which may be optionally substituted with 1 to 3 substituents selected from halogen, --R.sup.9, --OR.sup.9, --S(O).sub.mR.sup.9, --NR.sup.9R.sup.10, --C(O)R.sup.9, --C(S)R.sup.9, --CN, --C(O)NR.sup.9R.sup.10, --C(S)NR.sup.9R.sup.10, --NR.sup.9C(O)R.sup.10, --NR.sup.9C(S)R.sup.10, --S(O).sub.nNR.sup.9R.sup.10, --NR.sup.9S(O).sub.nR.sup.10, --NO.sup.2, --C(O)OR.sup.9 and --C(S)R.sup.9, or (3) when R.sup.7 and R.sup.8 are attached to a nitrogen and R.sup.7 is alkyl and R.sup.8 is either cycloalkyl or aryl, substituted aryl, heteroaryl, and substituted heteroaryl, form a 7 12 meinbered bicyclic heterocyclic ring, which may be optionally substituted with 1 to 3 substituents selected from halogen, --R.sup.9, --OR.sup.9, --S(O).sub.mR.sup.9, --NR.sup.9R.sup.10, --C(O)R.sup.9, --C(S)R.sup.9, --CN, --C(O)NR.sup.9R.sup.10, --C(S)NR.sup.9R.sup.10, --NR.sup.9C(O)R.sup.10, --NR.sup.9C(S)R.sup.10, --S(O).sub.nNR.sup.9R.sup.10, --NR.sup.9S(O).sub.nR.sup.10, --NO.sub.2, --C(O)OR.sup.9 and --C(S)OR.sup.9; R.sup.9 and R.sup.10 can be the same or different and are independently selected from --H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R.sup.11 and R.sup.12 (1) can be the same or different and are independently selected from H, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or (2) can form a 5- or 6-membered monocylic or a 8 10-membered bicyclic heteroaryl ring system, which may optionally contain, in addition to the nitrogen, an additional heteroatom selected from N, S, and O, and which may optionally have an oxo substituent on the ring and also may be optionally substituted with 1 to 3 substituents selected from halogen, --R.sup.9, --OR.sup.9, --S(O).sub.mR.sup.9, --NR.sup.9R.sup.10, --C(O)R.sup.9, --C(S)R.sup.9, --CN, --C(O)NR.sup.9R.sup.10, --C(S)NR.sup.9R.sup.10, --NR.sup.9C(O)R.sup.10, --NR.sup.9C(S)R.sup.10, --S(O).sub.nNR.sup.9R.sup.10, --NR.sup.9S(O).sub.nR.sup.10, --NO.sub.2, --C(O)OR.sup.9 and --C(S)OR.sup.9; m is 0, 1 or 2; and n is 1 or 2.

2. A compound according to claim 1, wherein in formula I, R.sup.1 is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, --NR.sup.7R.sup.8, --OR.sup.7, and --S(O).sub.mR.sup.7; R.sup.2 is selected from heterocycloalkyl, substituted heterocycloalkyl, R.sup.3, R.sup.4, and R.sup.5 can be the same or different and are independently selected from --H, alkyl, substituted alkyl; and R.sup.6 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl, and --NR.sup.11R.sup.12.

3. A compound according to claim 2, wherein in formula I, R.sup.1 is selected from alkyl, substituted alkyl, --NR.sup.7R.sup.8, --OR.sup.7, and --S(O).sub.mR.sup.7; R.sup.2 is selected from heterocycloalkyl, substituted heterocycloalkyl; R.sup.3, R.sup.4, and R.sup.5 can be the same or different and are independently selected from H, alkyl, substituted alkyl; and R.sup.6 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl and --NR.sup.11R.sup.12.

4. A compound according to claim 3, wherein in formula I, R.sup.1 is selected from alkyl and substituted alkyl; R.sup.3, R.sup.4, and R.sup.5 each is selected from --H, alkyl, and substituted alkyl.

5. A compound according to claim 4, wherein in formula I, R.sup.3, R.sup.4, and R.sup.5 each is selected from --H.

6. A compound selected from the group consisting of: 7-(2,4-Dichlorophenyl)-N,N-diethylpyrazolo[1,5-a]pyridin-3-amine; 7-(2,4-Dichlorophenyl)-N,N-dipropylpyrazolo[1,5-a]pyridin-3-amine; N-(Cyclopropylmethyl)-N-ethyl-7-(2,4-dichlorophenyl)pyrazolo[1,5-a]pyridi- n-3-amine; 7-(2,4-Dichlorophenyl)-N,N-diethyl-2-methylpyrazolo[1,5-a]pyrid- in-3-amine; 7-(2,4-Dichlorophenyl)-2-methyl-N,N-dipropylpyrazolo[1,5-a]pyridin-3-amin- e; 7-(2,4-Dichlorophenyl)-N,N,2-triethylpyrazolo[1,5-a]pyridin-3-amine; 7-(2-Methyl-4-chlorophenyl)-N,N,2-triethylpyrazolo[1,5-a]pyridin-3-amine; 7-(2-Chloro-4-trifluoromethylphenyl)-N,N,2-triethylpyrazolo[1,5-a]pyridin- -3-amine; 7-(2,4,6-Trimethylphenyl)-N,N,2-triethylpyrazolo[1,5-a]pyridin-3- -amine; 7-(2,4-Dichlorophenyl)-2-ethyl-N,N-dipropylpyrazolo[1,5-a]pyridin-- 3-amine; 2-Ethyl-7-(4-methoxy-2-methylphenyl)-N,N-dipropylpyrazolo[1,5-a]p- yridin-3-amine; 7-(2-Chloro-4-methoxyphenyl)-2-ethyl-N,N-dipropylpyrazolo[1,5-a]pyridin-3- -amine; 7-[4-(Dimethylamino)-2-(trifluoromethyl)phenyl]-2-ethyl-N,N-diprop- ylpyrazolo[1,5-a]pyridin-3-amine; 2-Ethyl-7-(2-methoxy-4,6-dimethylphenyl)-N,N-dipropylpyrazolo[1,5-a]pyrid- in-3-amine; 7-[2-Chloro-4-(dimethylamino)phenyl]-2-ethyl-N,N-dipropylpyrazolo[1,5-a]p- yridin-3-amine; 7-(2,4-Dimethoxyphenyl)-2-ethyl-N,N-dipropylpyrazolo[1,5-a]pyridin-3-amin- e; 7-[6-(Dimethylamino)-4-methylpyridin-3-yl]-2-ethyl-N,N-dipropylpyrazolo- [1,5-a]pyridin-3-amine; 7-(2-Chloro-4-methoxyphenyl)-2-ethyl-N-(3-fluoropropyl)-N-(2-methoxyethyl- )pyrazolo[1,5-a]pyridin-3-amine; 7-(2,4-Dimethoxyphenyl)-2-ethyl-N-(3-fluoropropyl)-N-(2-methoxyethyl)pyra- zolo[1,5-a]pyridin-3-amine; 7-(2-Chloro-4-methoxyphenyl)-N,2-diethyl-N-(3-fluoropropyl)pyrazolo[1,5-a- ]pyridin-3-amine; 7-(2,4-Dimethoxyphenyl)-N,2-diethyl-N-(3-fluoropropyl)pyrazolo[1,5-a]pyri- din-3-amine; 7-(2-Chloro-4-methoxyphenyl)-2-ethyl-N-(3-fluoropropyl)-N-methylpyrazolo[- 1,5-a]pyridin-3-amine; 7-(2,4-Dimethoxyphenyl)-N,2-diethyl-N-(2-fluoroethyl)pyrazolo[1,5-a]pyrid- in-3-amine; 7-(2-Chloro-4-methoxyphenyl)-2-ethyl-N-(2-fluoroethyl)-N-(2-methoxyethyl)- pyrazolo[1,5-a]pyridin-3-amine; 7-(2,4-Dimethoxyphenyl)-2-ethyl-N-(2-fluoroethyl)-N-(2-methoxyethyl)pyraz- olo[1,5-a]pyridin-3-amine; N-(Cyclopropylmethyl)-7-(2,4-dichlorophenyl)-N,2-diethylpyrazolo[1,5-a]py- ridin-3-amine; 7-(2-Chloro-4-methoxyphenyl)-N-(cyclopropylmethyl)-N,2-diethylpyrazolo[1,- 5-a]pyridin-3-amine; N-(Cyclopropylmethyl)-7-(2,4-dichlorophenyl)-2-ethyl-N-propylpyrazolo[1,5- -a]pyridin-3-amine; 7-(2-Chloro-4-methoxyphenyl)-N-(cyclopropylmethyl)-2-ethyl-N-propylpyrazo- lo[1,5-a]pyridin-3-amine; 7-(2,4-Dichlorophenyl)-N-(1-ethylpropyl)-2-methylpyrazolo[1,5-a]pyridin-3- -amine; 7-(2,4-Dichlorophenyl)-N-[2-methoxy-1-(methoxymethyl)ethyl]-2-meth- ylpyrazolo[1,5-a]pyridin-3-amine; 7-(2,4-Dichlorophenyl)-2-ethyl-N-(1-ethylpropyl)pyrazolo[1,5-a]pyridin-3-- amine; 7-(2,4-Dichlorophenyl)-2-ethyl-N-[2-methoxy-1-(methoxymethyl)ethyl]- pyrazolo[1,5-a]pyridin-3-amine; N-(sec-Butyl)-7-(2-chloro-4-methoxyphenyl)-2,6-dimethylpyrazolo[1,5-a]pyr- idin-3-amine; 7-(2,4-Dichlorophenyl)-N-(1-ethylpropyl)-2,6-dimethylpyrazolo[1,5-a]pyrid- in-3-amine; 7-{[4-(Benzyloxy)pyridin-2-yl]oxy}-N,N-diethylpyrazolo[1,5-a]pyridin-3-am- ine; N,N-Diethyl-2-methyl-7-[(4-methylpyridin-2-yl)oxy]pyrazolo[1,5-a]pyri- din-3-amine; 3-sec-Butyl-7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridine; 7-(2-Chloro-4-methoxyphenyl)-3-isopropyl-2-methylpyrazolo[1,5-a]pyridine; 1-[7-(2,4-Dichlorophenyl)-2-methylpyrazolo[1,5-a]pyridin-3-yl]-1,2,3,6-te- trahydropyridine-4-carboxamide; 1-[7-(2-Chloro-4-methoxyphenyl)-2-methylpyrazolo[1,5-a]pyridin-3-yl]-1,2,- 3,6-tetrahydropyridine-4-carboxamide; 1-[7-(6-Methoxy-2-methylpyridin-3-yl)-2-methylpyrazolo[1,5-a]pyridin-3-yl- ]-1,2,3,6-tetrabydropyridine-4-carboxamide; 1-[7-(2,4-Dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-1,2,3,6-tet- rahydropyridine-4-carboxamide; 1-[7-(2-Chloro-4-methoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-1,2,3- ,6-tetrahydropyridine-4-carboxamide; 1-[7-(6-Methoxy-2-methylpyridin-3-yl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]- -1,2,3,6-tetrahydropyridine-4-carboxamide; and a pharmaceutically acceptable salt of any of said compounds.

7. A compound according to claims 6, which is selected from the group consisting of 3-sec-Butyl-7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridine; 7-(2-Chloro-4-methoxyphenyl)-3-isopropyl-2-methylpyrazolo[1,5-a]pyridine; 1-[7-(2,4-Dichlorophenyl)-2-methylpyrazolo[1,5-a]pyridin-3-yl]-1,2,3,6-te- trahydropyridine-4-carboxamide; 1-[7-(2-Chloro-4-methoxyphenyl)-2-methylpyrazolo[1,5-a]pyridin-3-yl]-1,2,- 3,6-tetrahydropyridine-4-carboxamide; 1-[7-(6-Methoxy-2-methylpyridin-3-yl)-2-methylpyrazolo[1,5-a]pyridin-3-yl- ]-1,2,3,6-tetrahydropyridine-4-carboxamide; 1-[7-(2,4-Dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-1,2,3,6-tet- rahydropyridine-4-carboxamide; 1-[7-(2-Chloro-4-methoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-1,2,3- ,6-tetrahydropyridine-4-carboxamide; 1-[7-(6-Methoxy-2-methylpyridin-3-yl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]- -1,2,3,6-tetrahydropyridine-4-carboxamide; and a pharmaceutically acceptable salt of any of said compounds.

8. A pharmaceutical composition comprising a compound of claim 1 and optionally a pharmaceutically acceptable carrier.

9. An article of manufacture comprising: a) a packaging material; b) a pharmaceutical agent comprising a compound of claim 1, which pharmaceutical agent is contained within the packaging material, and c) a label or package insert contained within said packaging material indicating that said pharmaceutical agent is for treating, anxiety, or depression.

10. A method of treating a disorder in a human, comprising administering to the human in need thereof an effective amount of a compound of claim 1, wherein the disorder is selected from anxiety; and depression.

Description

FIELD OF THE INVENTION

The present invention relates generally to compounds that bind to CRF receptors and particularly to pyrazolo[1,5-a]pyridine derivatives useful as CRF.sub.1 receptor antagonists, and to the use thereof as a treatment for disorders that are associated with CRF or CRF.sub.1 receptors.

BACKGROUND OF THE INVENTION

Corticotropin releasing factor (CRF) is a 41 amino acid peptide that is the primary physiological regulator of proopiomelanocortin (POMC) derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Natl. Acad. Sci (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in the brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response in the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].

There is evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis, as they relate to the dysfunction of CRF neurons in the central nervous system [for a review, see: E. B. De Souze, Hosp. Practice 23:59 (1988)].

Anxiety disorders are a group of diseases, recognized in the art, that includes phobic disorders, anxiety states, post-traumatic stress disorder and a typical anxiety disorders [The Merck Manual of Diagnosis and Therapy, 16.sup.th edition (1992)]. Emotional stress is often a precipitating factor in anxiety disorders, and such disorders generally respond to medications that lower response to stress.

In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol. Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Memeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [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 Engl. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is also preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of receptors in the brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].

CRF has also been implicated in the etiology of anxiety-related disorders, and is known to produce anxiogenic effects in animals. Interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn, Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist .alpha.-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrates that the antagonist produces "anxiolytic-like" effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn, Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)].

Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics, providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the "anxiogenic" effects of CRF both in the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist Ro 15-1788, which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist FG 7142 enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:396 (1988)]. The mechanisms and sites of action through which conventional anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. Preliminary studies, examining the effects of a CRF.sub.1 receptor antagonist peptide (.alpha.-helical CRF.sub.9-41) in a variety of behavioral paradigms, have demonstrated that the CRF.sub.1 antagonist produces "anxiolytic-like" effects qualitatively similar to the benzodiazepines [for a review, see: G. F. Koob and K. T. Britton, In: Corticotrbpin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p. 221 (1990)].

The use of CRF, antagonists for the treatment of Syndrome X has also been described in U.S. patent application Ser. No. 09/696,822, filed Oct. 26, 2000, and European Patent Application No. 003094414, filed Oct. 26, 2000, which are also incorporated in their entireties herein by reference. Methods for using CRF.sub.1 antagonists to treat congestive heart failure are described in U.S. Ser. No. 09/248,073, filed Feb. 10, 1999, now U.S. Pat. No. 6,043,260 (Mar. 28, 2000) which is also incorporated herein in its entirety by reference.

CRF is known to have a broad extrahypothalmic distribution in the CNS, contributing therein to a wide spectrum of autonomic behavioral and physiological effects [see, e.g., Vale et al., 1983; Koob, 1985; and E. B. De Souze et al., 1985]. For example, CRF concentrations are significantly increased in the cerebral spinal fluid of patients afflicted with affective disorder or major depression [see, e.g., Nemeroff et al., 1984; Banki et al., 1987; France et al., 1988; Arato et al., 1989]. Moreover, excessive levels of CRF are known to produce anxiogenic effects in animal models [see, e.g., Britton et al., 1982; Berridge and Dunn, 1986 and 1987], and CRF.sub.1 antagonists are known to produce anxiolytic effects; accordingly, therapeutically effective amounts of compounds provided herein are, for example, determined by assessing the anxiolytic effects of varying amounts of the compounds in such animal models.

WO 99/01454, WO 00/39127, WO 00/59907, WO 00/59908 and WO 02/088121 disclose various compounds that can bind with high affinity and high selectivity to CRF.sub.1 receptors. The compounds are useful for treating CNS-related disorders particularly affective disorders and diseases, and acute and chronic neurological disorders and diseases.

It is an object of the invention to provide novel pyrazolo[1,5-a]pyridine derivatives, which are CRF.sub.1 receptor antagonists.

It is another object of the invention to provide novel compounds as treatment of disorders or conditions that are associated with CRF or CRF.sub.1 receptors, such as anxiety disorders, depression, and stress related disorders.

It is another object of the invention to provide a method of treating disorders or conditions that are associated with CRF or CRF.sub.1 receptors, such as anxiety disorders, depression, and stress related disorders.

It is yet another object of the invention to provide a pharmaceutical composition useful for treating disorders or conditions that are associated with CRF or CRF.sub.1 receptors, such as anxiety disorders, depression, and stress related disorders.

There are other objects of the invention which will be evident or apparent from the description of the invention in the specification of the application.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound of general formula I:

##STR00002##

Formula I

a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a derivative thereof, or a prodrug thereof, wherein:

R.sup.1 is selected from --H, --NR.sup.7R.sup.8, --OR.sup.7, --S(O).sub.mR.sup.7, --C(O)R.sup.7, --C(S)R.sup.7, --C(O)OR.sup.7, --C(S)OR.sup.7, --C(O)NR.sup.7R.sup.8, --C(S)NR.sup.7R.sup.8, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl;

R.sup.2 is selected from --NR.sup.7R.sup.8, --OR.sup.7, --S(O).sub.mR.sup.7, --C(O)R.sup.7, --C(S)R.sup.7, --C(O)OR.sup.7, --C(S)OR.sup.7, C(O)NR.sup.7R.sup.8, --C(S)NR.sup.7R.sup.8, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, Ar, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, substituted heteroaryl heterocycloalkyl, --NHC(O)alkyl, --NHC(S)alkyl, --NHC(O)aryl, --NHC(S)aryl, --NHC(O)OR.sup.7, --NHC(O)SR.sup.7, --NHC(S)OR.sup.7, --NHC(O)NR.sup.7R.sup.8, --NHC(S)NR.sup.7R.sup.8, --NHS(O).sub.nalkyl, --NHS(O).sub.naryl, --NHS(O).sub.n NR.sup.7R.sup.8,

##STR00003##

R.sup.3, R.sup.4 and R.sup.5 can be the same or different and are independently selected from --H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, Ar, halogen, --NR.sup.9R.sup.10, --OR.sup.9, --S(O).sub.mR.sup.9, --C(O)R.sup.9, --C(S)R.sup.9, --C(O)OR.sup.9, --C(S)OR.sup.9, --C(O)NR.sup.9R.sup.10, and --C(S)NR.sup.9R.sup.10;

R.sup.6 is selected from Ar, --OAr, --S(O).sub.mAr, --N(H)Ar, and --NR.sup.11R.sup.12;

R.sup.7 and R.sup.8 (1) can be the same or different and are independently selected from --H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, Ar, or (2) when both R.sup.7 and R.sup.8 are alkyls and attached to a nitrogen, may form, along with the nitrogen, a 3 8 membered mono heterocyclic ring, which may be optionally substituted with 1 to 3 substituents selected from halogen, --R.sup.9, --OR.sup.9, --S(O).sub.mR.sup.9, --NR.sup.9R.sup.10, --C(O)R.sup.9, --C(S)R.sup.9, --CN, --C(O)NR.sup.9R.sup.10, --C(S)NR.sup.9R.sup.10, --NR.sup.9C(O)R.sup.10, --NR.sup.9C(S)R.sup.10, --S(O).sub.nNR.sup.9R.sup.10, --NR.sup.9S(O).sub.nR.sup.10, --NO.sub.2, --C(O)OR.sup.9 and --C(S)OR.sup.9, or (3) when R.sup.7 and R.sup.8 are attached to a nitrogen and R.sup.7 is alkyl and R.sup.8 is either cycloalkyl or Ar, form a 7 12 membered bicyclic heterocyclic ring, which may be optionally substituted with 1 to 3 substituents selected from halogen, --R.sup.9, --OR.sup.9, --S(O).sub.mR.sup.9, --NR.sup.9R.sup.10, --C(O)R.sup.9, --C(S)R.sup.9, --CN, --C(O)NR.sup.9R.sup.10, --C(S)NR.sup.9R.sup.10, --NR.sup.9C(O)R.sup.10, --NR.sup.9C(S)R.sup.10, --S(O)--NR.sup.9R.sup.10, --NR.sup.9S(O).sub.nR.sup.10, --NO.sub.2, --C(O)OR.sup.9 and --C(S)OR.sup.9;

R.sup.9 and R.sup.10 can be the same or different and are independently selected from--H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and Ar;

R.sup.11 and R.sup.12 (1) can be the same or different and are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, Ar, or (2) can form a 5- or 6-membered monocylic or a 8 10-membered bicyclic heteroaryl ring system, which may optionally contain, in addition to the nitrogen, an additional heteroatom selected from N, S, and O, and which may optionally have an oxo substituent on the ring and also may be optionally substituted with 1 to 3 substituents selected from halogen, --R.sup.9, --OR.sup.9, --S(O).sub.mR.sup.9, --NR.sup.9R.sup.10, --C(O)R.sup.9, --C(S)R.sup.9, --CN, --C(O)NR.sup.9R.sup.10, --C(S)NR.sup.9R.sup.10, --NR.sup.9C(O)R.sup.10, --NR.sup.9C(S)R.sup.10, --S(O).sub.nNR.sup.9R.sup.10, --NR.sup.9S(O).sub.nR.sup.10, --NO.sub.2, --C(O)OR.sup.9 and --C(S)OR.sup.9;

m is 0, 1 or 2; and

n is 1 or 2.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a pharmaceutically acceptable salt of the prodrug thereof. The compositions can be prepared in any suitable forms such as tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, and ointments.

The compounds of the inventions are CRF.sub.1 receptor antagonists and are useful for treating disorders or conditions associated with CRF or CRF.sub.1 receptors, including human CRF1 receptors.

Thus, in another aspect, the present invention provides a method of antagonizing CRF.sub.1 receptors in a warm-blooded animal, comprising administering to the animal a compound of the invention at amount effective to antagonize CRF.sub.1 receptors.

In still another aspect, the present invention provides a method for screening for ligands for CRF.sub.1 receptors, which method comprises: a) carrying out a competitive binding assay with CRF.sub.1 receptors, a compound of formula I which is labelled with a detectable label, and a candidate ligand; and b) determining the ability of said candidate ligand to displace said labelled compound.

In still another aspect, the present invention provides a method for detecting CRF receptors in a tissue comprising: a) contacting a compound of formula I, which is labelled with a detectable label, with a tissue, under conditions that permit binding of the compound to the tissue; and b) detecting the labelled compound bound to the tissue.

In yet another aspect, the present invention provides a method of inhibiting the binding of CRF to CRF.sub.1 receptors, comprising contacting a compound of the invention with a solution comprising cells expressing the CRF.sub.1 receptor, wherein the compound is present in the solution at a concentration sufficient to inhibit the binding of CRF to the CRF.sub.1 receptor.

In yet a further aspect the present invention provides a method of treating a disorder, in warm-blooded animal, the treatment of which disorder can be effected or faciliated by antagonizing CRF.sub.1 receptors, which method comprises administration to a patient in need thereof an effective amount of a compound of formula (I). In a particular embodiment the invention provides a method for the treatment of disorders that manifests hypersecretion of CRF. Examples of disorders that can be treated with the compounds of the invention include generalized anxiety disorder; social anxiety disorder; anxiety; obsessive-compulsive disorder; anxiety with co-morbid depressive illness; panic disorder; and mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression. It is preferred that the warm-blooded animal is a mammal, and more preferred that the animal is a human.

In addition, a method of inhibiting the binding of CRF to the CRF.sub.1 receptor, which method comprises contacting, in the presence of CRF, a solution comprising a compound of formula I with cells expressing the CRF.sub.1 receptor, wherein the compound is present in the solution at a concentration sufficient to reduce levels of CRF binding to IMR.sup.32 cells in vitro is provided.

DETAILED DESCRIPTION OF THE INVENTION

In the first aspect, the present invention provides a compound of general formula I:

##STR00004## a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a derivative thereof, or a prodrug thereof, wherein:

R.sup.1 is selected from --H, --NR.sup.7R.sup.8, --OR.sup.7, --S(O).sub.mR.sup.7, --C(O)R.sup.7, --C(S)R.sup.7, --C(O)OR.sup.7, --C(S)OR.sup.7, --C(O)NR.sup.7R.sup.8, --C(S)NR.sup.7R.sup.8, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl;

R.sup.2 is selected from --NR.sup.7R.sup.8, --OR.sup.7, --S(O),R.sup.7, --C(O)R.sup.7, --C(S)R.sup.7, --C(O)OR.sup.7, --C(S)OR.sup.7, --C(O)NR.sup.7R.sup.8--C(S)C(S)NR.sup.7R.sup.8, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, Ar, aryl cycloalkyl, substituted aryl cycloalkyl, heteroaryl cycloalkyl, substituted heteroaryl cycloalkyl, aryl heterocycloalkyl, substituted aryl heterocycloalkyl, heteroaryl heterocycloalkyl, substituted heteroaryl heterocycloalkyl, --NHC(O)alkyl, --NHC(S)alkyl, --NHC(O)aryl, --NHC(S)aryl, --NHC(O)OR.sup.7, --NHC(O)SR.sup.7, --NHC(S)OR.sup.7, --NHC(O)NR.sup.7R.sup.8, --NHC(S)NR.sup.7R.sup.8, --NHS(O).sub.nalkyl, --NHS(O).sub.naryl, --NHS(O).sub.n NR.sup.7R.sup.8,

##STR00005##

R.sup.3, R.sup.4 and R.sup.5 can be the same or different and are independently selected from --H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, Ar, halogen, --NR.sup.9R.sup.10, --OR.sup.9, --S(O).sub.mR.sup.9, --C(O)R.sup.9, --C(S)R.sup.9, --C(O)OR.sup.9, --C(S)OR.sup.9, --C(O)NR.sup.9R.sup.10, and --C(S)NR.sup.9R.sup.10;

R.sup.6 is selected from Ar, --OAr, --S(O).sub.mAr, --N(H)Ar, and --NR.sup.11R.sup.12;

R.sup.7 and R.sup.8 (1) can be the same or different and are independently selected from --H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, Ar, or (2) when both R.sup.7 and R.sup.8 are alkyls and attached to a nitrogen, may form, along with the nitrogen, a 3 8 membered mono heterocyclic ring, which may be optionally substituted with 1 to 3 substituents selected from halogen, --R.sup.9, --OR.sup.9, --S(O).sub.mR.sup.9, --NR.sup.9R.sup.10, --C(O)R.sup.9, --C(S)R.sup.9, --CN, --C(O)NR.sup.9R.sup.10, --C(S)NR.sup.9R.sup.10, --NR.sup.9C(O)R.sup.10, --NR.sup.9C(S)R.sup.10, --S(O).sub.nNR.sup.9R.sup.10, --NR.sup.9S(O).sub.nR.sup.10, --NO.sub.2, C(O)OR.sup.9 and --C(S)OR.sup.9, or (3) when R.sup.7 and R.sup.8 are attached to a nitrogen and R.sup.7 is alkyl and R.sup.8 is either cycloalkyl or Ar, form a 7 12 membered bicyclic heterocyclic ring, which may be optionally substituted with 1 to 3 substituents selected from halogen, --R.sup.9, OR.sup.9, --SR.sup.9, --NR.sup.9R.sup.10, --C(O)R.sup.9, --C(S)R.sup.9, --CN, --C(O)NR.sup.9R.sup.10, --C(S)NR.sup.9R.sup.10, --NR.sup.9C(O)R.sup.10, --NR.sup.9C(S)R.sup.10, --S(O).sub.nNR.sup.9R.sup.10, --NR.sup.9S(O).sub.nR.sup.10, --NO.sub.2, --C(O)OR.sup.9 and --C(S)OR.sup.9;

R.sup.9 and R.sup.10 can be the same or different and are independently selected from --H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, and Ar;

R.sup.11 and R.sup.12 (1) can be the same or different and are independently selected from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, Ar, or (2) can form a 5- or 6-membered monocylic or a 8 10-membered bicyclic heteroaryl ring system, which may optionally contain, in addition to the nitrogen, an additional heteroatom selected from N, S, and O, and which may optionally have an oxo substituent on the ring and also may be optionally substituted with 1 to 3 substituents selected from halogen, --R.sup.9, --OR.sup.9, --S(O).sub.mR.sup.9, --NR.sup.9R.sup.10, --C(O)R.sup.9, --C(S)R.sup.9, --CN, --C(O)NR.sup.9R.sup.10, --C(S)NR.sup.9R.sup.10, --NR.sup.9C(O)R.sup.10, --NR.sup.9C(S)R.sup.10, --S(O).sub.nNR.sup.9R.sup.10, --NR.sup.9S(O).sub.nR.sup.10, --NO.sub.2, --C(O)OR.sup.9 and --C(S)OR.sup.9; illustrative examples of the heteroaromatic ring systems that can be formed from R.sup.11 and R.sup.12 together with the nitrogen to which they are attached being:

##STR00006## where one of P, Q, R, S is N and the others represent C.

m is 0, 1 or 2; and

n is 1 or 2.

Preferably, the present invention provide a compound of formula I above, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a derivative thereof, or a prodrug thereof, wherein in formula I:

R.sup.1 is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, --NR.sup.7R.sup.8, --OR.sup.7, and --S(O).sub.mR.sup.7;

R.sup.2 is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, Ar, --NHC(O)alkyl, --NHC(S)alkyl, --NHC(O)aryl, --NHC(S)aryl, --NHC(O)OR.sup.7, --NHC(O)SR.sup.7, --NHC(S)OR.sup.7, --NHC(O)NR.sup.7R.sup.8, --NHC(S)NR.sup.7R.sup.8, --NHS(O).sub.nalkyl, --NHS(O).sub.naryl, --NHS(O).sub.n NR.sup.7R.sup.8,

##STR00007##

R.sup.3, R.sup.4, and R.sup.5 can be the same or different and are independently selected from --H, alkyl, substituted alkyl, halogen, and Ar; and

R.sup.6 is selected from Ar, --OAr, and --NR.sup.11R.sup.12.

More preferably, the present invention provide a compound of formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a derivative thereof, or a prodrug thereof, wherein in formula I,

R.sup.1 is selected from alkyl, substituted alkyl, --NR.sup.7R.sup.8, --OR.sup.7, and --S(O).sub.mR.sup.7;

R.sup.2 is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, and Ar;

R.sup.3, R.sup.4, and R.sup.5 can be the same or different and are independently selected from --H, alkyl, substituted alkyl, and halogen; and

R.sup.6 is selected from Ar and --NR.sup.11R.sup.12.

Further preferably, the present invention provide a compound of formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a derivative thereof, or a prodrug thereof, wherein in formula I,

R.sup.1 is selected from alkyl and substituted alkyl;

R.sup.2 is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, and Ar;

R.sup.3, R.sup.4, and R.sup.5 each is selected from --H, alkyl, and substituted alkyl; and

R.sup.6 is selected from Ar and --NR.sup.11R.sup.12.

Following are examples of particular compounds of the invention, with each compound being identified both by a chemical name and a structural formula immediately below the chemical name: 7-(2,4-Dichlorophenyl)-N,N-diethylpyrazolo[1,5-a]pyridin-3-amine

##STR00008## 7-(2,4-Dichlorophenyl)-N,N-dipropylpyrazolo[1,5-a]pyridin-3-amine

##STR00009## N-(Cyclopropylmethyl)-N-ethyl-7-(2,4-dichlorophenyl)pyrazolo[1,5-a]pyridi- n-3-amine

##STR00010## 7-(2,4-Dichlorophenyl)-N,N-diethyl-2-methylpyrazolo[1,5-a]pyridin-3-amine

##STR00011## 7-(2,4-Dichlorophenyl)-2-methyl-N,N-dipropylpyrazolo[1,5-a]pyridin-3-amin- e

##STR00012## 7-(2,4-Dichlorophenyl)-N,N,2-triethylpyrazolo[1,5-a]pyridin-3-amine

##STR00013## 7-(2-Methyl-4-chlorophenyl)-N,N,2-triethylpyrazolo[1,5-a]pyridin-3-amine

##STR00014## 7-(2-Chloro-4-trifluoromethylphenyl)-N,N,2-triethylpyrazolo[1,5-a]pyridin- -3-amine

##STR00015## 7-(2,4,6-Trimethylphenyl)-N,N,2-triethylpyrazolo[1,5-a]pyridin-3-amine

##STR00016## 7-(2,4-Dichlorophenyl)-2-ethyl-N,N-dipropylpyrazolo[1,5-a]pyridin-3-amine

##STR00017## 7-(2,4-Dichlorophenyl)-2-ethyl-N,N-dipropylpyrazolo[1,5-a]pyridin-3-amine maleic acid salt

##STR00018## 2-Ethyl-7-(4-methoxy-2-methylphenyl)-N,N-dipropylpyrazolo[1,5-a]pyridin-3- -amine

##STR00019## 7-(2-Chloro-4-methoxyphenyl)-2-ethyl-N,N-dipropylpyrazolo[1,5-a]pyridin-3- -amine

##STR00020## 7-[4-(Dimethylamino)-2-(trifluoromethyl)phenyl]-2-ethyl-N,N-dipropylpyraz- olo[1,5-a]pyridin-3-amine

##STR00021## 2-Ethyl-7-(2-methoxy-4,6-dimethylphenyl)-N,N-dipropylpyrazolo[1,5-a]pyrid- in-3-amine

##STR00022## 7-[2-Chloro-4-(dimethylamino)phenyl]-2-ethyl-N,N-dipropylpyrazolo[1,5-a]p- yridin-3-amine

##STR00023## 7-(2,4-Dimethoxyphenyl)-2-ethyl-N,N-dipropylpyrazolo[1,5-a]pyridin-3-amin- e

##STR00024## 7-[6-(Dimethylamino)-4-methylpyridin-3-yl]-2-ethyl-N,N-dipropylpyrazolo[1- ,5-a]pyridin-3-amine

##STR00025## 7-(2-Chloro-4-methoxyphenyl)-2-ethyl-N-(3-fluoropropyl)-N-(2-methoxyethyl- )pyrazolo[1,5-a]pyridin-3-amine

##STR00026## 7-(2,4-Dimethoxyphenyl)-2-ethyl-N-(3-fluoropropyl)-N-(2-methoxyethyl)pyra- zolo[1,5-a]pyridin-3-amine

##STR00027## 7-(2-Chloro-4-methoxyphenyl)-N,2-diethyl-N-(3-fluoropropyl)pyrazolo[1,5-a- ]pyridin-3-amine

##STR00028## 7-(2,4-Dimethoxyphenyl)-N,2-diethyl-N-(3-fluoropropyl)pyrazolo[1,5-a]pyri- din-3-amine

##STR00029## 7-(2-Chloro-4-methoxyphenyl)-2-ethyl-N-(3-fluoropropyl)-N-methylpyrazolo[- 1,5-a]pyridin-3-amine

##STR00030## 7-(2,4-Dimethoxyphenyl)-N,2-diethyl-N-(2-fluoroethyl)pyrazolo[1,5-a]pyrid- in-3-amine

##STR00031## 7-(2-Chloro-4-methoxyphenyl)-2-ethyl-N-(2-fluoroethyl)-N-(2-methoxyethyl)- pyrazolo[1,5-a]pyridin-3-amine

##STR00032## 7-(2,4-Dimethoxyphenyl)-2-ethyl-N-(2-fluoroethyl)-N-(2-methoxyethyl)pyraz- olo[1,5-a]pyridin-3-amine

##STR00033## N-(Cyclopropylmethyl)-7-(2,4-dichlorophenyl)-N,2-diethylpyrazolo[1,5-a]py- ridin-3-amine

##STR00034## 7-(2-Chloro-4-methoxyphenyl)-N-(cyclopropylmethyl)-N,2-diethylpyrazolo[1,- 5-a]pyridin-3-amine

##STR00035## N-(Cyclopropylmethyl)-7-(2,4-dichlorophenyl)-2-ethyl-N-propopylpyrazolo[1- ,5-a]pyridin-3-amine

##STR00036## 7-(2-Chloro-4-methoxyphenyl)-N-(cyclopropylmethyl)-2-ethyl-N-propylpyrazo- lo[1,5-a]pyridin-3-amine

##STR00037## 7-(2,4-Dichlorophenyl)-N-(1-ethylpropyl)-2-methylpyrazolo[1,5-a]pyridin-3- -amine

##STR00038## 7-(2,4-Dichlorophenyl)-N-[2-methoxy-1-(methoxymethyl)ethyl]-2-methylpyraz- olo[1,5-a]pyridin-3-amine

##STR00039## 7-(2,4-Dichlorophenyl)-2-ethyl-N-(1-ethylpropyl)pyrazolo[1,5-a]pyridin-3-- amine

##STR00040## 7-(2,4-Dichlorophenyl)-2-ethyl-N-[2-methoxy-1-(methoxymethyl)ethyl]pyrazo- lo[1,5-a]pyridin-3-amine

##STR00041## N-(sec-Butyl)-7-(2-chloro-4-methoxyphenyl)-2,6-dimethylpyrazolo[1,5-a]pyr- idin-3-amine

##STR00042## 7-(2,4-Dichlorophenyl)-N-(-ethylpropyl)-2,6-dimethylpyrazolo[1,5-a]pyridi- n-3-amine

##STR00043## 7-{[4-(Benzyloxy)pyridin-2-yl]oxyl}-N,N-diethylpyrazolo[1,5-a]pyridin-3-a- mine

##STR00044## N,N-Diethyl-2-methyl-7-[(4-methylpyridin-2-yl)oxy]pyrazolo[1,5-a]pyridin-- 3-amine

##STR00045## 3-sec-Butyl-7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridine

##STR00046## 7-(2-Chloro-4-methoxyphenyl)-3-isopropyl-2-methylpyrazolo[1,5-a]pyridine

##STR00047## 1-[7-(2,4-Dichlorophenyl)-2-methylpyrazolo[1,5-a]pyridin-3-yl]-1,2,3,6-te- trahydropyridine-4-carboxamide

##STR00048## 1-[7-(2-Chloro-4-methoxyphenyl)-2-methylpyrazolo[1,5-a]pyridin-3-yl]-1,2,- 3,6-tetrahydropyridine-4-carboxamide

##STR00049## 1-[7-(6-Methoxy-2-methylpyridin-3-yl)-2-methylpyrazolo[1,5-a]pyridin-3-yl- ]-1,2,3,6-tetrahydropyridine-4-carboxamide

##STR00050## 1-[7-(2,4-Dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-1,2,3,6-tet- rahydropyridine-4-carboxamide

##STR00051## 1-[7-(2-Chloro-4-methoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-1,2,3- ,6-tetrahydropyridine-4-carboxamide

##STR00052## 1-[7-(6-Methoxy-2-methylpyridin-3-yl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]- -1,2,3,6-tetrahydropyridine-4-carboxamide

##STR00053##

It should be understood that compounds provided herein can have one or more asymmetric centers or planes, and all chiral (enantiomeric and diastereomeric) and racemic forms of the compound are included in the present invention. Many geometric isomers of olefins, C.dbd.N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention.

Compounds of the invention are isolated in either the racemic form, or in the optically pure form, for example, by resolution of the racemic form by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral HPLC column, or synthesized by an asymmetric synthesis route enabling the preparation of enantiomerically enriched material. The present invention encompasses all possible tautomers of the compounds of formula (I).

Compounds of the invention can generally be prepared using the synthetic routes illustrated in the Charts A H indicated below. Starting materials can be prepared by procedures described in these charts or by procedures that would be well known to one of ordinary skill in organic chemistry. The variables used in the charts are as defined below or as in the claims.

Preparation of compound of formula I, where R.sup.2.dbd.NR.sup.7R.sup.8, is depicted in Chart A. The starting material A-1 is either available from a commercial source or can be prepared by adopting the known method described in the literature (see Tamura, Y. et al., Synthesis 1977, 1). The 1-aminopyridium salts A-1 can react with the alkyne esters A-2 in the presence of base such as potassium carbonate in an open reaction vessel to form the bicyclic pyrazolo[1,5-a]pyridine compounds A-3. The 3-position carboxylate group can be removed by treatment in a strong acidic media, for example, in refluxing 50% sulfuric acid (Lober, S. et al J. Med. Chem. 2001, 44, 2691). Nitration of A-4 gave the 3-nitro compounds A-5. The nitro group is reduced to the amino by a reduction method such as zinc/calcium chloride/aqEtOH to form A-6. Reductive amination with aldehydes thus provides the dialkylated amino products (A-7, R.sup.7.dbd.R.sup.8=alkyl) or with ketone leads to the formation of the secondary amines (A-7, one of R.sup.7 and R.sup.8 is H). The reductive amination is carried out in the presence of a reducing agent such as sodium cyanoborohydride (see for example Lane, C. F., "Sodium Cyanoborohydride--A Highly Selective Reducing Agent for Organic Functional Groups", Synthesis, 1975, 135). The 3-amino compound A-7 can be treated with a strong base such as n-BuLi in THF at -78.degree. C. to form an anion, which can be quenched with an electrophile such as 1,2-diiodoethane to form the 7-iodo products A-8 (see Aboul-Fadl, T. et. al. Synthesis 2000, 1727). The iodo compounds can undergo a cross-coupling reaction with a metalloaryl reagents, for example, aryl boronic acids (see for example Miyaura, N.; et al Chem. Rev. 1995, 95, 2457), aryl stannanes (see for example Mitchell, T. N. Synthesis 1992, 803), or aryl Grignards (see for example Miller, J. A. Tetrahedron Lett. 1998, 39, 7275), to provide the final products A-9.

##STR00054##

Alternatively, see Chart B, the bicyclic compounds A-4 can be lithiated with, for example, butyllithium, to generate an anion, which can be quenched with an electrophile such as 1,2-diiodoethane to form the products B-1. The iodo compounds can undergo a cross-coupling reaction with a metalloaryl reagents, for example, aryl boronic acids to provide the 7-aryl pyrazolo[1,5-a]pyridine compounds B-2. General nitration reaction provides the 3-nitro compounds B-3. The nitro group can be reduced to the amino by the method of zinc/calcium chloride/aqEtOH. The amino compounds B-4 can react with aldehyde in the presence of a reducing agent such as sodium cyanoborohydride to form the tertiary amines, or with ketones to form the secondary amines of A-9.

##STR00055##

Alternatively, see Chart C, the 3-amino pyrazolo[1,5-a]pyridine compounds A-6 can be converted with acyl chloride reagents in the presence of a base such as triethylamine to amides C-1. Treatment of C-1 with a strong base such as sodium hydride followed by reaction with an electrophile such as alkyl halides provides the tertiary amides C-2, which can be reduced to the tertiary amines A-7 (R.sup.8.dbd.CH.sub.2W) by reducing agent such as lithium aluminum hydride, or borane-dimethyl sulfide complex. In certain cases, lithium aluminum hydride reaction leads to deacetylation, whereas the tertiary amine products A-7 can be still obtained by treating the deacetylated products with a base such as potassium carbonate and alkyl halides. Formation of the final products A-9 can be accomplished from A-7 as similarly as shown in Chart A.

##STR00056##

Chart D outlines the synthesis of compounds of formula I, where R.sup.2 is alkyl. The bicyclic pyrazolo[1,5-a]pyridine intermediates D-2 can be synthesized from the reaction of A-1 and an alkyne ketone D-1 in the presences of a base such as potassium carbonate. Reaction of D-2 with a Grignard reagent can form an olefin intermediate, which can be reduced to the saturated compound D-3 with, for example, cyclohexene in the presence of palladium on carbon and aluminum chloride, or triethylsilane in the presence of trifluoroacetic acid. Similarly as shown in Chart A, intermediates D-3 can be converted to the halogen compounds D-4 and subsequently transformed to the targets D-5.

##STR00057##

Alternatively, see Chart E, for the compounds of formula I having substitutents on the pyridine ring, where at least one of R.sup.3, R.sup.4 and R.sup.5 is not H, the aromatic ring can be introduced onto the pyridine template E-1 by carrying out a cross coupling reaction of 2-halopyridines E-1 with a metalloaryl reagent such as aryl boronic acid to form the 2-aryl pyridines E-2. The pyridium salts E-3 can be prepared from E-2 by reacting with an aminating reagent such as O-mesitylenesulfonylhydroxylamine which is generated in situ from ethyl O-mesitylsulfonylacetohydroxamate. Cycloaddition of E-3 with the alkyne reagent A-2 leads to the formation of pyrazolo[1,5-a]pyridine compounds E-4. After hydrolysis, the carboxylic acid intermediates E-5 can undergo Curtius-Schmidt rearrangement by reaction with an azide reagent such as diphenylphosphoryl azide to form the 3-amino pyrazolo[1,5-a]pyridine compounds B-4.

##STR00058##

Chart F illustrates the synthesis of compounds of formula T. The products F-2 can be prepared from the halogenated intermediates F-1 by reaction with an aryl hydroxy compound in the presence of a metal promoting agent such as palladium or copper reagents and base such as potassium carbonate (see Sugahara, M. et al Chem. Pharm. Bull. 1997, 45, 719 and Marcoux, J.-F. et al J. Am. Chem. Soc. 1997, 119, 10539 and Aranyos, A. et al J. Am. Chem. Soc. 1999, 121, 4369).

##STR00059##

Chart G illustrates the synthesis of compounds of formula I where R.sup.6 is pyridone and linked at the nitrogen. Intermediates A-7 (U.dbd.H) can be treated with a strong base such as butyllithium and the generated anion can react with tosyl azide (see Reed, J. N. et al Tetrahedron Lett. 1983, 24, 3795) to provide the 7-amino pyrazolo[1,5-a]pyridine compounds G-1. Alternatively, intermediates A-8 (U=halogen) can react with benzophenone imine under the catalysis of palladium to form the 7-amino pyrazolo[1,5-a]pyridine compounds G-1 (see Wolfe, J. P. et al Tetrahedron Lett. 1997, 38, 6367). The amino compounds G-I can react with a 2-pyrone to produce the pyridone compound G-2 (see Wiley, R. H. et al J. Am. Chem. Soc. 1956, 78, 2393).

##STR00060##

Compounds of formula I where R.sup.2 is a cyclic amine and linked at nitrogen can be synthesized as illustrated in Chart H (see Nakazato, A. et al WO 0202549). The 3-amino pyrazolo[1,5-a]pyridine compounds B-4 can react with 1,5-dichloro-3-pentanone to form the piperidone products H-1. Reaction of H-1 with potassium cyanide provides the cyano compounds H-2, which can undergo acidic hydrolysis to produce the amides H-3. Introduction of R.sup.9 and R.sup.10 can be accomplished by treatment of H-3 with a strong base such as sodium hydride and an electrophile such as alkyl halides or palladium catalysis with aryl halides (see Kang, S.-K. et al Synlett 2002, 427).

##STR00061##

The present invention also encompasses pharmaceutically acceptable salts of compounds of formula I. Examples of pharmaceutically acceptable salts are salts prepared from inorganic acids or organic acids, such as inorganic and organic acids of basic residues such as amines, for example, acetic, benzenesulfonic, benzoic, amphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, barbaric acid, p-toluenesulfonic and the like; and alkali or organic salts of acidic residues such as carboxylic acids, for example, alkali and alkaline earth metal salts derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, trimethylammonia, triethylammonia, ethylenediamine, lysine, arginine, omithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, n-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.

Pharmaceutically acceptable salts of the compounds of the invention can be prepared by conventional chemical methods. Generally, such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17.sup.th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

In another aspect, the present invention provide a prodrug of a compound of formula I. The prodrug is prepared with the objective(s) of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity). See e.g. T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems", Vol. 14 of the A.C.S. Symposium Series; Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, (1987). Prodrugs include, but are not limited to, compounds derived from compounds of formula I wherein hydroxy, amine or sulfhydryl groups, if present, are bonded to any group that, when administered to the subject, cleaves to form the free hydroxyl, amino or sullhydryl group, respectively. Selected examples include, but are not limited to, biohydrolyzable amides and biohydrolyzable esters and biohydrolyzable carbamates, carbonates, acetate, formate and benzoate derivatives of alcohol and amine functional groups.

The prodrug can be readily prepared from the compounds of formula I using methods known in the art. See, e.g. See Notari, R. E., "Theory and Practice of Prodrug Kinetics," Methods in Enzymology, 112:309 323 (1985); Bodor, N., "Novel Approaches in Prodrug Design," Drugs of the Future, 6(3):165 182 (1981); and Bundgaard, H., "Design of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities," in Design of Prodrugs (H. Bundgaard, ed.), Elsevier, N.Y. (1985); Burger's Medicinal Chemistry and Drug Chemistry, Fifth Ed., Vol. 1, pp. 172 178, 949 982 (1995). For example, the compounds of formula I can be transformed into prodrugs by converting one or more of the hydroxy or carboxy groups into esters. For example, prodrugs of the compounds of formula I can be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.

The invention also includes isotopically-labeled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as .sup.3H, .sup.11C, .sup.14C, .sup.18F, .sup.123I, and .sup.125I. Compounds of formula I that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the invention. Isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as .sup.3H and .sup.14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., .sup.3H, and carbon-14, i.e., .sup.14C, isotopes are particularly useful in PET (positron emission tomography), and .sup.125I isotopes are particularly useful in SPECT (single photon emission computed tomography); all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., .sup.2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, maybe preferred in some circumstances. Isotopically labeled compounds of formula I of this invention can generally be prepared by carrying out the synthetic procedures by substituting a isotopically labeled reagent for a non-isotopically labeled reagent.

Preferably compounds of the invention exhibit an IC.sub.50 value for CRF binding of 1 micromolar or less, more preferably of 100 nanomolar or less and even more preferably of 10 nanomolar or less.

The compounds of formula I are antagonists at the CRF receptor and are useful in the treatment of anxiety disorders, depression and stress related disorders. The compounds are also useful in smoking cessation programs. The method of treatment involves administration to a mammal (e.g. a human) an effective amount of a compound of the invention. In particular, therapeutically effective amounts of the compounds of this invention are amounts effective to antagonize, or lower, levels of corticotropin releasing factor (CRF) in mammals, thereby alleviating in t