MXPA06007283A - Crf receptor antagonists and methods relating thereto - Google Patents

Abstract

CRF receptor antagonists are disclosed which have utility in the treatment of a variety of disorders, including the treatment of disorders manifesting hypersecretion of CRF in a warm-blooded animals, such as stroke. The CRF receptor antagonists of this invention have the following structure (I), including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, Y, Ar, and Het are as defined herein. Compositions containing a CRF receptor antagonist in combination with a pharmaceutically acceptable carrier are also disclosed, as well as methods for use of the same.

Description

ANTAGONISTS OF THE RECEIVER OF THE CORTICOTROPIN LIBERATOR FACTOR AND METHODS RELATED TO THEM REFERRAL TO RELATED REQUEST This application claims priority to the serial number of provisional US application. 60 / 532,031, filed on December 22, 2003, the full description of which is incorporated for reference herein.

FIELD OF THE INVENTION This invention relates generally to CRF receptor antagonists and to methods of treating disorders by administering such antagonists to a mammal in need thereof.

BACKGROUND OF THE INVENTION The first corticotropin-releasing factor (CRF) was isolated from the ovine hypothalamus and was identified as a 41 amino acid peptide (Vale et al., Science 213? 394-1397, 1981). Subsequently, human and rat CRF sequences were isolated and determined to be identical but different from sheep CRF in 7 of the 41 amino acid residues (Rivier et al., Proc.

Nati Acad. Sci. USA 80: 4851, 1983; Shibahara et al., EMBO J. 2: 775, 1983). It has been found that CRF produces profound alterations in the function of the endocrine, nervous and immune system. CRF is thought to be the main physiological regulator of the basal and stress release of adrenocorticotropic hormone ("ACTH"), β-endorphin, and other peptides derived from pro-opiomelanocortin ("POMC") from the anterior lobe of the hypophysis (Vale et al., Science 273: 1394-1397, 1981). Briefly, it is believed that CRF initiates its physiological effects by binding to a plasma membrane receptor that has been found to be distributed throughout the brain (DeSouza et al., Science 224: 1449-1451, 1984), the pituitary gland (DeSouza et al. others, Methods Enzymol, 124: 560, 1986, Wynn et al., Biochem Biophys, Res.Comm. 110: 602-608, 1983), the adrenal glands (Udelsman et al., Nature 379: 147-150, 1986) and the spleen (Webster, EL, and EB DeSouza, Endocrinology 722: 609-617, 1988). The CRF receptor is coupled to a GTP-binding protein (Perrin et al., Endocrinology 778: 1171-1179, 1986) which mediates the increase stimulated by CRF in the intracellular production of cAMP (Bilezi jian, LM, and WW Vale , Endocrinology 773: 657-662, 1983). The receptor for CRF has now been cloned from rat brain (Perrin et al., Endo 733 (6): 3058-3061, 1993), and human brain (Chen et al., PNAS 90 (19): 8967- 8971, 1993; Vita et al., FEBS 335 (1): 1-5, 1993). This receptor is a 415 amino acid protein comprising seven transmembrane domains. An identity comparison between the rat and human sequences shows a high degree of homology (97%) at the amino acid level. In addition to its role in stimulating the production of ACTH and POMC, CRF is also thought to coordinate many of the endocrine, autonomic, and behavioral responses to stress, and may be involved in the pathophysiology of affective disorders. In addition, CRF is believed to be a key intermediary in the communication between the immune, central nervous, endocrine and cardiovascular systems (Crofford et al., J. Clin Invest 90, 2555-2564, 1992, Sapolsky et al., Science 238 : 522-524, 1987; Tilders et al., Regul. Peptides 5: 77-84, 1982). In general terms, CRF appears to be one of the central neurotransmitters of the central nervous system and plays a crucial role in integrating the body's total response to stress. The administration of CRF directly to the brain obtains behavioral, physiological, and endocrine responses identical to those observed for an animal exposed to a stressful environment. For example, intracerebroventricular injection of CRF results in psychomotor activation (Sutton et al., Nature 297: 331, 1982), persistent activation of the electroencephalogram (Ehlers et al., Brain Res. 278: 332, 1983), stimulation of the sympathetic-medullary pathway. (Brown et al., Endocrinology 710: 928, 1982), an increase in heart rate and blood pressure (Fisher et al., Endocrinology 110: 2222, 1982), an increase in oxygen consumption (Brown et al., Life Sciences 30: 207, 1982), alteration of gastrointestinal activity (Williams et al., Am. J. Physiol. 253: G582, 1987), suppression of food consumption (Levine et al., Neuropharmacology 22: 337, 1983), modification of sexual behavior (Sirinathsinghji et al., Nature 305: 232, 1983), and compromise of immune function (Irwin et al., Am. J. Physiol. 255: R744, 1988). In addition, clinical data suggest that CRF can be hypersecreted in the brain in depression, anxiety-related disorders, and anorexia nervosa. (DeSouza, Ann, Reports in Med. Chem. 25: 215-223, 1990). Accordingly, clinical data suggest that CRF receptor antagonists may represent novel antidepressant and / or anxiolytic drugs that may be useful in the treatment of neuropsychiatric disorders that manifest hypersecretion of CRF. The first CRF receptor antagonists were peptides (see, for example, Rivier et al., US Patent No. 4,605,642; Rivier et al., Science 224: 889, 1984). Although these peptides established that CRF receptor antagonists can attenuate pharmacological responses to CRF, peptide antagonists of the CRF receptor suffer from the usual drawbacks of peptide therapeutic substances, including lack of stability and limited oral activity. . Some published patents include US6313124, WO 01/23388, and WO 97/29109, all of which describe pyrazolopyrimidine compounds as CRF antagonists. The published application WO 98/54093 discloses certain pyrazolopyrimidine compounds as tyrosine kinase inhibitors.

Due to the physiological importance of CRF, the development of biologically active small molecules that have significant CRF receptor binding activity and that are capable of antagonizing the CRF receptor remains a desirable goal. Such CRF receptor antagonists would be useful in the treatment of endocrine, psychiatric and neurological diseases or conditions, including disorders related to stress in general. Although significant progress has been made towards achieving CRF regulation through the administration of CRF receptor antagonists, there remains a need in the art for effective small molecule antagonists of the CRF receptor. There is also a need for pharmaceutical compositions containing such CRF receptor antagonists, as well as methods that relate to their use to treat, for example, stress-related disorders. The present invention satisfies these needs, and provides other related advantages.

BRIEF DESCRIPTION OF THE INVENTION In summary, this invention is generally directed to CRF receptor antagonists, and more specifically to CRF receptor antagonists having the following general structure (I): (1) and its pharmaceutically acceptable salts, esters, solvates, stereoisomers and prodrugs, wherein R-i, R2 > R3, Y, Ar, and Het are as defined below. The CRF receptor antagonists of this invention may have utility over a wide range of therapeutic applications, and may be used to treat various disorders or diseases, including stress-related disorders. Such methods include administering a pharmaceutically effective amount of a CRF receptor antagonist of this invention, preferably in the form of a pharmaceutical composition, to an animal in need thereof. Accordingly, in another embodiment, pharmaceutical compositions are described that contain one or more CRF receptor antagonists of this invention and a pharmaceutically acceptable carrier and / or diluent. These and other aspects of the invention will become apparent upon reference to the following detailed description. To this end, various references are presented herein that describe in more detail certain procedures, compounds and / or compositions, and are incorporated by reference herein in their entirety.

DETAILED DESCRIPTION OF THE INVENTION The present invention is generally directed to corticotropin releasing factor (CRF) receptor antagonists. In a first embodiment, the CRF receptor antagonists of this invention have the following structure (I): or a pharmaceutically acceptable salt, ester, solvate, stereoisomer or prodrug thereof, wherein: "-" represents the second bond of an optional double bond; RT is hydrogen, alkyl, substituted alkyl, heteroaryl, substituted heteroaryl, -NH2, or halogen; R 2 is alkyl, substituted alkyl, -C (O) NR 7 R 8, aryl, substituted aryl, aryloxyalkyl, substituted aryloxyalkyl, heteroarylalkoxyalkyl, substituted heteroarylalkoxyalkyl, heterocycloalkyl, substituted heterocycloalkyl, arylalkyl, substituted arylalkyl, heteroaryl, or substituted heteroaryl, wherein said heteroaryl or substituted heteroaryl is attached to the pyrimidine ring via a carbon-carbon bond; R3 is zero, hydrogen, or alkyl; Y is = (CR4) - or - (C = O) -; R 4 is hydrogen, alkyl, substituted alkyl, thioalkyl, alkylsulfinyl, or alkylsulfonyl; Ar is phenyl, phenyl substituted with 1 or 2 R5, pyridyl or pyridyl substituted with 1 or 2 R5; R5 in each occurrence is hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cyano, halogen, alkylsulfonyl, or alkylsulfinyl; Het is heteroaryl optionally substituted with 1 or 2 R6; R6 in each occurrence is hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cyano, or halogen; and R7 and R8 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, arylalkyl, substituted arylalkyl, heterocyclealkyl, or substituted heterocyclealkyl; or R7 and R8 taken together with the nitrogen to which they are attached form a heterocyclic ring or a substituted heterocyclic ring. As used herein, the above-mentioned terms have the following meaning: "Alkyl" means a straight or branched, acyclic or cyclic, unsaturated or saturated hydrocarbon containing from 1 to 10 carbon atoms, while the terminology "lower alkyl" has the same meaning as alkyl but contains from 1 to 6 carbon atoms. Saturated linear straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, and the like; while branched saturated alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl-CH2-cyclobutyl, -CH-cyclopentyl, -CH2-cyclohexyl, and the like; while unsaturated cyclic alkyls include cyclopentenyl and cyclohexenyl, and the like. Cyclic alkyls, also referred to as "homocyclic rings", include di- and poly-homocyclic rings such as decalin and adamantyl. The unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as an "alkenyl" or "alkynyl", respectively). Representative branched and straight chain alkenyls include ethylene, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3 -dimethyl-2-butenyl, and the like; while branched and straight chain alkynyl alkyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, and the like. "Alkylidene" represents a divalent alkyl from which two hydrogen atoms have been taken from the same carbon atom, such as = CH2, = CHCH3, = CHCH2CH3, = C (CH3) CH2CH3l and the like. "Aryl" means an aromatic carbocyclic moiety such as phenyl or naphthyl. "Arylalkyl" means an alkyl having at least one hydrogen atom of the alkyl substituted with an aryl, such as benzyl (ie, -CH2-phenyl), -CH2- (1- or 2-naphthyl), - (CH2 ) 2-phenyl, - (CH 2) 3-phenyl, -CH 2 - (phenyl) 2, and the like. "Aryloxyalkyl" means an aryl bonded through an oxygen bridge to an alkyl (i.e., aryl-O-alkyl-) such as -methyl-O-phenyl, and the like. "Heteroaryl" means a 5- to 10-membered aromatic heterocyclic ring and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including mono- and bicyclic ring systems . Representative heteroaryls include (but are not limited to) furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl. , pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinolinyl, phthalazinyl, and quinazolinyl. "Heteroarylalkyl" means an alkyl having at least one hydrogen atom of the alkyl substituted with a heteroaryl, such as -CH 2 -pyridinyl, -CH 2 -pyrimidinyl, and the like. "Heterocycle" (also referred to herein as a "heterocyclic ring") means a heterocyclic ring, 5- to 7-membered monocycle, or 7- to 14-membered polycycle, which is saturated, unsaturated or aromatic, and containing from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, including bicyclic rings in which any of the The aforementioned heterocycles are fused with a benzene ring in addition to tricyclic (and higher) heterocyclic rings. The heterocycle can be attached via any heteroatom or carbon atom. Heterocycles include heteroaryls are defined above. A) Yes, in addition to the aromatic heteroaryls listed above, the heterocycles also include (but are not limited to) morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperizinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl , tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. "Heterocycloalkyl" means an alkyl having at least one hydrogen atom of the alkyl substituted with a heterocycle, such as -CH 2 -morpholinyl, and the like. The term "substituted" as used herein refers to any group (e.g., alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclealkyl) wherein at least one hydrogen atom is replaced with a substituent . In the case of a keto substituent ("-C (= O) -"), two hydrogen atoms are replaced. "Substituents" within the context of this nvención ncludes halogen, hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, alkyl, alkoxy, thioalkyl, haloalkyl, hydroxyalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl , heteroarylalkyl, substituted heteroarylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl, substituted heterocyclealkyl, -NRaRb, -NRaC (= O) Rb, -NRaC (= 0) NRaRb, - NRaC (= O) ORb, -NRaS02Rb, -ORa, - C (= O) Ra, -C (= O) ORa, -C (= O) NRaRb, - OC (= 0) NRaRb, -SH, -SRa, -SORa, -S (= O) 2Ra, -OS (= 0) 2Ra, -S (= O) 2OR <a>, where Ra and Rb are equal or different and independently hydrogen, alkyl, haloalkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl , heteroarylalkyl, substituted heteroarylalkyl, heterocycle, substituted heterocycle, heterocyclealkyl or substituted heterocyclealkyl. "Halogen" means fluorine, chlorine, bromine or iodine. "Haloalkyl" means an alkyl having at least one hydrogen atom replaced with halogen, such as trifluoromethyl and the like. The haloalkyl is a specific embodiment of the substituted alkyl, wherein the alkyl is substituted with one or more halogen atoms. "Alkoxy" means an alkyl bonded through an oxygen bridge (i.e., -O-alkyl) such as -O-methyl, -O-ethyl, and the like. "Thioalkyl" means an alkyl attached through a sulfur bridge (ie, -S-alkyl) such as -S-methyl, -S-ethyl, and the like. "Alkylamino" and "dialkylamino" mean one or two alkyl moieties linked through a nitrogen bridge (i.e., -NHalkyl or -N (alkyl) (alkyl)) such as methylamino, ethylamino, dimethylamino, diethylamino, and the like. ? Idroxialquilo "means an alkyl substituted with at least one hydroxy group." Mono- or di (cycloalkyl) methyl "represents a methyl group substituted with one or two cycloalkyl groups, such as cyclopropylmethyl, dicyclopropylmethyl, and the like." Alkylcarbonylalkyl "represents an alkyl substituted with a group -C (= 0) alkyl "Alkylcarbonyloxyalkyl" represents an alkyl substituted with a group -C (= 0) Oalkyl or a group -OC (= O) alkyl. "Alkoxyalkyl" represents an alkyl substituted with an -O-alkyl group "Alkylthioalkyl" represents an alkyl substituted with an -S-alkyl group "Mono- or di (alkylamino) amino" represents an amino substituted with an alkyl or with two alkyls, respectively. or di (alkyl) aminoalkyl "represents an alkyl substituted with a mono- or di (alkyl) amino." Alkylsufonyl or alkylsulfinyl "represent an alkyl substituted with a functionality (-S (= O) 2-) or (-S (= 0) -), respectively The embodiments of this invention presented in FIG. The present report is given by way of example and is not intended to limit it. In a first embodiment of the invention, R3 is zero and Y is = (CR4) - in structure (II) below, and in an additional embodiment Y is - (C = 0) - in structure (III) below.

(II) OH) Additional modalities of this invention have the structure (IV) when R2 is phenyl, R is an optional substituent of said phenyl, and Y is = (CR4) -.

In further embodiments of this invention wherein Y is = (CR 4) -, Ar is phenyl substituted with 2 R 5 in structure (V) and Het is pyridyl substituted with 1 R 6 in structure (VI).

(V) (VI) The compounds of the present invention can generally be used as the free base. Alternatively, the compounds of this invention can be used in the form of acid addition salts. The acid addition salts of the free amino base compounds of the present invention can be prepared by methods well known in the art, and can be formed from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids. Thus, the terminology "pharmaceutically acceptable salt" of structure (I) is intended to encompass any and all pharmaceutically acceptable salt forms. In general, the compounds of structure (I) can be made in accordance with the techniques of organic synthesis known to those skilled in the art, in addition to the representative methods set forth in the Examples. Examples of synthetic procedures that can be used to prepare the compounds according to the invention are illustrated in Reaction Schemes 1-3.

Reaction Scheme 1 The amino functionality of the 4-aminobenzoate a can be condensed with a malonaldehyde, optionally substituted to give the corresponding 4-pyrazol-1-yl benzoate b. After the reaction with LAH, SOCI2l and NaCN to give the conversion to the pyrazolophenylacetonitrile compound c, the reaction with Na / ethyl ester of the carboxylic acid and hydrazine produces the bis-pyrazole d. Reaction with the appropriate substituted β-keto ester gives the pyrazolopyrimidine e which reacts with POCI 3 to give the chloride f. The reaction of chloride f with an appropriate organometallic reagent R2M in the presence of a suitable catalyst or promoter gives compound g. Examples of suitable organometallic reagents and suitable catalysts / promoters include: 1. alkyl (substituted) grignard reagents R2MgX (Fe (acac) 3 promoter); 2. aryl, heteroaryl, or alkenyl boronic acids or esters (Pd (PhP) 4 catalyst); and 3. aryl or heteroaryl zinc reagents (Pd catalyst (PhP)). The R2 group thus additionally installed can be manipulated or reacted, using standard methods known to those skilled in the art (eg oxidation / reduction, hydrolysis, and the like), to provide additional examples of the invention.

Reaction Scheme 2 Bi Multiple synthetic routes are available to the pyrazolopyrimidine core of the invention. In Reaction Scheme 2, the optionally substituted halobenzaldehyde h reacts with tosylmethyl isocyanide (TosMIC) to form phenylacetonitrile i. Reaction of i with NaH and EtOAc gives 3-hydroxybut-2-enenitrile j which undergoes ring closure in the reaction with hydrazine HBr to give 3-amino 2-phenyl pyrazole k. The addition of the β-keto ester gives the pyrazolo [1,5-a] pyrimidine-7ol I. The substitution of oxygen as in Reaction Scheme 1 and the substitution of distal bromine with Het gives the compounds in accordance with the invention.

Reaction Scheme 3 The reaction of the substituted acetonitrile m with the ketone n, wherein R 'is a good leaving group such as alkoxy, cyano, or halo and wherein R "is a group such as hydroxy or alkoxy, gives the cyanoketone or reacts with hydrazine to give the substituted pyrazole p The reaction of p with the β-keto ester gives the pyrazole pyrimidine R. The reaction with POCI 3 gives the chloride, and the substitution of the chloride for R2 gives the compound t. The effectiveness of a compound as an antagonist of the CRF receptor can be determined by various test methods. Suitable CRF antagonists of this invention may be capable of inhibiting the specific binding of CRF to its receptor and of antagonizing the activities associated with CRF. A compound of structure (I) can be assessed for activity as a CRF antagonist by one or more generally accepted assays for this purpose, including (but not limited to) the analyzes described by DeSouza et al. (J. Neuroscience 7: 88, 1987) and Battaglia et al.

(Synapse 1: 572, 1987). In accordance with mentioned above, suitable CRF antagonists include compounds that demonstrate affinity for the CRF receptor. The affinity for the CRF receptor can be determined by binding studies that measure the ability of a compound to inhibit the binding of a radiolabelled CRF (eg, [125l] tyrosine-CRF) to its receptor (e.g. from rat cerebral cortex membranes). The radioligand binding analysis described by DeSouza et al. (Supra, 1987) provides an analysis to determine the affinity of a compound for the CRF receptor. Such activity is typically calculated from the IC 50 as the concentration of a compound necessary to displace 50% of the radiolabelled ligand of the receptor, and is expressed as a "K" value calculated by the following equation: wherein L = radioligand and KD = affinity of the radioligand for the receptor (Cheng and Prusoff, Biochem Pharmacol 22: 3099, 1973). In addition to inhibiting binding to the CRF receptor, the CRF receptor antagonist activity of a compound can be established by the ability of the compound to antagonize an activity associated with CRF. For example, it is known that CRF stimulates various biochemical processes, including adenylate cyclase activity. Therefore, the compounds can be evaluated as CRF antagonists for their ability to antagonize the CRF-stimulated activity of adenylate cyclase, for example, by measuring cAMP levels. The analysis of the CRF stimulated activity of adenylate cyclase described by Battaglia et al. (Supra, 1987) provides an analysis to determine the ability of a compound to antagonize CRF activity. Accordingly, the CRF receptor antagonist activity can be determined by assay techniques that generally include an initial binding assay (such as that described by DeSouza (supra, 1967)) followed by a cAMP systematic screening protocol (such as the one described by Battaglia and others (supra, 1987)). With reference to the binding affinities to the CRF receptor, the CRF receptor antagonists of this invention have a Ki of less than 10 μM, more preferably less than 0.25 μM (ie, 250 nM). In accordance with more detailed below, the values of K, can be assessed by the methods set forth in Example 27. The CRF receptor antagonists of the present invention can demonstrate activity at the CRF receptor site, and they can be used as therapeutic agents for the treatment of a wide range of disorders or diseases including endocrine, psychiatric, and neurological disorders or diseases. More specifically, the CRF receptor antagonists of the present invention may be useful in treating diseases or physiological disorders that arise from hypersecretion of CRF. Because CRF is believed to be a fundamental neurotransmitter that activates and coordinates the endocrine, behavioral and automatic responses to stress, the CRF receptor antagonists of the present invention can be used to treat neuropsychiatric disorders. Neuropsychiatric disorders that may be treatable by the CRF receptor antagonists of this invention include affective disorders such as depression; anxiety-related disorders such as generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, abnormal aggression, cardiovascular abnormalities such as unstable angina and reactive hypertension; and eating disorders such as anorexia nervosa, bulimia, and irritable bowel syndrome. CRF antagonists may also be useful in the treatment of immune suppression induced by stress associated with various disease states, in addition to stroke. Other uses of the CRF antagonists of this invention include the treatment of inflammatory conditions (such as rheumatoid arthritis)., uveitis, asthma, inflammatory bowel disease and motility G.I.), pain, Cushing's disease, infantile spasms, epilepsy and other crises in young children and adults, and abuse and detoxification of various substances (including alcoholism). In another embodiment of the invention, pharmaceutical compositions containing one or more CRF receptor antagonists are described. For the purposes of administration, the compounds of the present invention can be formulated as pharmaceutical compositions. The pharmaceutical compositions of the present invention comprise a CRF receptor antagonist of the present invention (ie, a compound of structure (I)) and a pharmaceutically acceptable carrier and / or diluent. The CRF receptor antagonist is present in the composition in an amount that is effective to treat a particular disorder ie, in an amount sufficient to achieve the activity of CRF receptor antagonist, and preferably with acceptable toxicity to the patient. Preferably, the pharmaceutical compositions of the present invention can include a CRF receptor antagonist in an amount of 0.1 mg to 250 mg per dosage depending on the route of administration, and more preferably 1 mg to 60 mg. One skilled in the art can easily determine the appropriate concentrations and dosages. Those skilled in the art are familiar with pharmaceutically acceptable carriers and / or diluents. For compositions formulated as liquid solutions, acceptable carriers and / or diluents include saline and sterile water, and optionally may include antioxidants, pH regulators, bacteriostats and other common additives. The compositions can also be formulated as pills, capsules, granules, or pellets containing, in addition to a CRF receptor antagonist, diluents, dispersants and surfactants, binders, and lubricants. One skilled in the art can further formulate the CRF receptor antagonist in an appropriate manner, and in accordance with accepted practices, such as those described in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, PA 1990 .

In addition, prodrugs are also included within the context of this invention. Prodrugs are any covalently linked vehicle that releases a compound of living structure (I) when such a prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in such a way that the modification is broken, or by routine manipulation or in vivo, yielding the precursor. With respect to the stereoisomers, the compounds of structure (I) can have chiral centers and can occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including their mixtures. In addition, some of the crystalline forms of the compounds of structure (I) may exist in crystalline, amorphous or polymorphic forms, alternatively as polymorphs, all of which are included in the present invention. In addition, some of the compounds of structure (I) can also form solvates with water or other organic solvents. Such solvates are also included within the scope of this invention. In another embodiment, the present invention provides a method for treating a variety of disorders or diseases, including endocrine, psychiatric and neurological disorders and diseases. Such methods include administering a compound of the present invention to a warm-blooded animal in an amount sufficient to treat the disorder or disease. Such methods include the systemic administration of a CRF receptor antagonist of this invention, preferably in the form of a pharmaceutical composition. In accordance with the present invention, systemic administration includes oral and parenteral methods of administration. For oral administration, suitable pharmaceutical compositions of CRF receptor antagonists include powders, granules, pills, pills, and capsules in addition to liquids, syrups, suspensions, and emulsions. These compositions may also include flavorants, preservatives, suspending agents, thickening and emulsifying agents, and other pharmaceutically acceptable additives. For parenteral administration, the compounds of the present invention can be prepared in aqueous solutions for injection which may contain, in addition to the CRF receptor antagonist, pH regulators, antioxidants, bacteriostats, and other additives commonly employed in such solutions. In another embodiment, the present invention allows the diagnostic visualization of specific sites within the body through the use of radioactive or non-radioactive pharmaceutical agents. The use of a compound of the present invention can provide a physiological, functional, or biological evaluation of a patient or provide an evaluation and detection of disease or pathology. The radioactive pharmaceutical substances are used in scintigraphy, positron emission tomography (PET), computerized tomography (CT), and single-photon emission computed tomography (SPECT). For such applications, radioisotopes of elements such as iodine (I) including 1231 (PET), 125l (SPECT), and 131l, technetium (Te) including "Te (PET), phosphorus (P) including 31P and 32P, chrome are incorporated. (Cr) including 51Cr, carbon (C) including 11C, fluorine (F) including 18F, thallium (TI) including 201TI, and similar emitters of positrons and ionizing radiation.The non-radioactive pharmaceutical substances are used in magnetic resonance imaging (MRI), fluoroscopy, and ultrasound For such applications, isotopes of elements such as gadolinium (Gd) including 153Gd, iron (Fe), barium (Ba), manganese (Mn), and thallium (TI) are incorporated. they are also useful for identifying the presence of particular target sites in a mixture and for labeling molecules in a mixture, as mentioned above., administration of a compound of the present invention can be used to treat a wide variety of disorders or diseases. In particular, the compounds of the present invention can be administered to a warm-blooded animal for the treatment of depression, anxiety disorder, panic disorder, obsessive-compulsive disorder, abnormal aggression, unstable angina, reactive hypertension, anorexia nervosa, bulimia, irritable bowel syndrome, immune suppression induced by stress, stroke, inflammation, pain, Cushing's disease, infantile spasms, epilepsy, and substance abuse or detoxification. The following examples are provided for purposes of illustration, not limitation.I hated EXAMPLES The CRF receptor antagonists of this invention can be prepared by the methods described in Examples 1 to 26. Example 27 presents a method for determining binding affinity to the receptor, and Example 28 describes an assay for the systematic screening of the compounds of the invention for the activity of adenylate cyclase stimulated with CRF.

Analytical Method HPLC-MS 1 Platform: Agilent 1100 series: equipped with an automatic sampler, a UV detector (220 nm and 254 nm), an MS detector (APCI); HPLC Column: YMC ODS AQ, S-5, 5μ, 2.0x50 mm cartridge; HPLC gradient: 1.0 ml / minute, 10% acetonitrile in 90% acetonitrile water in water in 2.5 minutes, maintain 90% for 1 minute. Both acetonitrile and water have 0.025% TFA.

Analytical Method HPLC-MS 2 Platform: Agilent 1100 series: equipped with an automatic sampler, a UV detector (220 nm and 254 nm), an MS detector (APCI); HPLC Column: Phenomenex Synergi-Max RP, 2.0x50 mm column; HPLC gradient: 1.0 ml / minute, 5% acetonitrile in 95% acetonitrile water in water in 13.5 minutes, maintain 95% for 2 minutes. Both acetonitrile and water have 0.025% TFA.

Analytical Method HPLC-MS 3 Platform: Agilent 1100 series: equipped with an automatic sampler, a UV detector (220 nm and 254 nm), an MS detector (electrospray); HPLC Column: XTerra MS, C15, 5μ, 3.0 x 250 mm column; HPLC gradient: 1.0 ml / minute, 10% acetonitrile in 90% acetonitrile water in 46 minutes, jump to 99% acetonitrile and maintain 99% acetonitrile for 8.04 minutes. Both acetonitrile and water have 0.025% TFA.

HPLC-MS Analytical Method 4 Platform: Agilent 1100 series: equipped with an automatic sampler, a UV detector (220 nm and 254 nm), an MS detector (APCI) and CO2 pump module Berger FCM 1200; HPLC Column: Berger Pyridine, PYR 60A, 6μ, column of 4. 6x150 mm; HPLC gradient: 4.0 ml / minute, 120 bar; from 10% methanol in supercritical CO2 to 60% methanol in supercritical CO2 in 1.67 minutes, maintain 60% for 1 minute. Methanol has 1.5% water. Back pressure regulated at 140 bar.

HPLC-MS Preparative Platform: Shimadzu HPLC equipped with Gilson 215 automatic sampler / fraction collector, UV detector and a Sciez API150EX PE mass detector; HPLC Column: BHK ODS-O / B, 5 μ, 30x75 mm HPLC gradient: 35 ml / minute, 10% acetonitrile in 100% acetonitrile water in 7 minutes, maintain 100% acetonitrile for 3 minutes, with 0.025% of TFA.

Abbreviations: AA: Acetyl acetate LAH: Lithium aluminum hydride DCM: Dichloromethane DMSO: Dimethyl sulfoxide EAA: Acetoacetate ethyl LC-MS: liquid chromatography - mass spectroscopy NaBH (OAc) 3: Sm triacetoxyborohydride Pd-C: Palladium (10%) on Carbon TFA: Tosmic trifluoroacetic acid: Tosylmethyl acacia: acetylacetonate EDCI: N-ethyl-N'- (dimethylaminopropyl) carbmide hydrochloride) THF: Tetrahydrofuran TEA: Triethylamine tR: Retention time EXAMPLE 1 7- (2-methoxy-phenyl) -3- (2-methoxy-4-pyrazol-1-yl-phenyl) -2,5-dimethyl-pyrazolop, 5- a] pyrimidine Step 1A: To a cooled suspension of methyl 4-amino-2-methoxybenzoate (6.82 g, 37.7 mmol) in 6N HCl (aqueous) was added a solution of sm nitrite (2.60 g, 37.7 mmol) dropwise. After stirring at 0 ° C for 20 min., Stannous dihydrochloride (24.7 g, 109.3 mmol) was added little by little. The resulting suspension was stirred at 0 ° C for 1.5 hours before filtration. The collected solid was suspended in EtOH to which the bis (dimethyl acetal) of malonaldehyde (7.5 ml, 45.7 mmol) was added, and this reaction mixture was refluxed overnight. After evaporation of the EtOH, the residue was extracted between EtOAc and water, and the organic phase was dried and evaporated to dryness. The residue was passed through a small pad of silica gel (25% EtOAc / hexane) to give Compound 1b (7.43 g) as a mixture of methyl and ethyl benzoate.

Step 1 B: To a solution of 1b (10.6 g) in dry diethyl ether (200 ml) was slowly added LAH powder (1.74 g) at 0 ° C. After stirring for 45 min. at 0 ° C the reaction mixture was decanted in ice-water, and the aqueous phase was acidified to pH 4.0. After isolation, the alcohol (8.8 g) was heated to reflux with thionyl chloride (10 ml) in DCM for 2.5 hours, decanted in ice-water, and extracted with DCM. The benzyl chloride (8.26 g) was heated with NaCN (3.65 g, 74.4 mmol) in DMSO (100 ml) at 80 ° C for 45 min. After removal of DMSO, Compound 1c (5.98 g) was obtained after column chromatography with 30% EtOAc / hexane.

Step 1C: To a solution of 1c (5.98 g, 28.1 mmol) in EtOAc (150 mL) was added little by little metallic sodium (1.0 g, 43.5 mmol), and the mixture was heated to reflux overnight. The resulting suspension was decanted over ice-water and acidified to pH 4.0. The organic phase was dried and evaporated to dryness. The resulting compound (9.5 g) was mixed with hydrazine monohydrobromide (15.3 g, 135.4 mmol), and heated to reflux in EtOH / H2O (6: 1) for 5 hours. After evaporation of EtOH and extraction with EtOAc, the organic phase was dried and evaporated to dryness to yield Compound 1d (7.5 g).

Step 1 D: A mixture of 1d (7.5g, 27.9 mmol) was heated to reflux with ethyl acetoacetate (5.0 mL) in AcOH (100 mL) for 3 hours. After evaporation of AcOH and precipitation in diethyl ether, Compound 1e (10.4 g) was obtained after filtration.

Step 1: To a suspension of 1e (2.1 g, 6.3 mmol) in acetonitrile was added POCI3 (2.2 mL, 24.1 mmol), and this mixture was refluxed for 5 hours, decanted in ice-water, and extracted with EtOAc to give Compound 1f (1.88 g) after chromatographic purification.

Step 1 F: A mixture of Compound 1f (1.0 mmole), 2-methoxyphenylboronic acid (1.2 mmole), K2CO3 (2.0 mmole) and Pd (PPh3) 4 (0.05 mmole) was heated in 1,4-dioxane / H2O (2 : 1) at 110 ° C throughout the night. After evaporation of the solvent, the mixture was extracted between CHCl3 / H20, and the organic phase was dried and evaporated to dryness. Compound 1-1 (402 mg) was obtained after column chromatography. Depending on the aryl functionality in the arylboronic acid reagent, the compounds listed in the following table were synthesized and purified by preparative LC-MS: EXAMPLE 1A Alternative Intermediate Synthesis 1 F Step 1A-A: To a 3-neck flask equipped with a mechanical stirrer were charged 250 g (1.12 mol) of 2-methoxy-4-acetylaminobenzoic acid methyl ester followed by 1 l of methanol. Agitation was started and 94 ml (3.36 mmol, 3 eq.) Of concentrated sulfuric acid was slowly added creating a slight reflux. The mixture was stirred for 24 hours. The mixture was concentrated in vacuo to provide a slurry. The suspension was filtered using a Buchner funnel and washed with 300 ml of cold methanol. The filter cake was collected and dried under vacuum at 45 ° C for 24 hours providing 302 g of 1a as a hemi-sulfate salt in 96% yield.

Step 1A-B: 200 g (716 mmol) of methyl 4-amino-2-methoxybenzoate 1a was charged into a three-neck 2 liter Morton flask equipped with a mechanical stirrer and thermocouple. The solid was suspended with 700 ml of 6N hydrochloric acid and cooled in an ice bath. To the mixture, 54.3 g (788 mmol, 1.1 eq.) Of sodium nitrite in 100 ml of water were charged dropwise maintaining a temperature of < 15 ° C during the addition. The mixture was stirred an additional 1.5 hours giving a homogeneous clear yellow solution. To the mixture, 272 g (1432 mmol, 2 eq.) Of anhydrous stannous chloride were carefully added. The temperature during the addition was maintained < 10 ° C. The mixture was stirred at 0 ° C for 1 hour, and then stored at 5 ° C for 16 hours. The precipitate was collected by filtration through a Buchner funnel and the filter cake was air dried for 2 hours. The filter cake was transferred to a round bottom 2 liter flask equipped with a magnetic stir bar and diluted with 600 ml of ethanol. To the suspension, 142 ml (859 mmoles) were charged, 1.2 eq.) Of bis (dimethyl acetal) of the malonaldehyde and the mixture was heated to reflux for 6 hours. After evaporation of the ethanol, the residue was diluted with ethyl acetate and neutralized with sodium hydroxide. The organic phase was separated, dried and concentrated in vacuo. The crude product was passed through a small pad of silica gel eluting with 25% ethyl acetate in hexane to provide 96 g of Compound 1b in 58% yield as a mixture of the methyl and ethyl esters.

Step 1A-C: To a 1 l round-bottom flask containing 500 ml of dry THF was added LAH (14.5 g, 380 mmol, 0.95 eq), and the mixture was cooled to 0 ° C. To this mixture was added dropwise a solution of 1b (96 g, 400 mmol, 1.0 eq) in 300 ml of THF. The temperature was kept below 15 ° C during the addition. After the addition was complete, the mixture was stirred for 1 hour, then the reaction mixture was carefully quenched with water (14.5 ml), 10% aqueous sodium hydroxide (14.5 ml), and water (43.5 ml). The resulting mixture was filtered through a small pad of Celite® and concentrated to give 1b.1 as a slightly yellow oil (63.9 g, 75.7%), which was used without further purification.

Step 1A-D: Thionyl chloride (95 ml, 1.30 mol, 3.1 eq) was added dropwise over 1 hour to a solution of 1b.1 (85.0 g, 0.42 mol) in 400 ml of DCM, maintaining the speed of addition such that a gentle reflux was maintained. A precipitate formed, which was redissolved upon completion of the addition. The resulting dark solution was heated to reflux for 4 hours. The cooled reaction mixture was poured onto 500 g of ice, and the resulting mixture was extracted with 2 x 700 ml of DCM. The combined organic layers were washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated to provide 1b.2 (76.5 g) as a brown solid, which was used without further purification.

Step 1A-E: A solution of 1b.2 (76 g, 340 mmol, 1.0 eq.) In DMF (100 mL) was added dropwise over 20 min. to a mixture of sodium cyanide (24.5 g, 500 mmol, 1.5 eq) and DMF (300 ml) heated to 100 ° C. The mixture was heated at 100 ° C for 4 hours, then the cooled mixture was filtered through Celite®. The filtrate was concentrated, then the residue was taken up in 300 ml of DCM and washed with saturated aqueous sodium bicarbonate solution (200 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated to provide a dark brown solid residue. This residue was suspended in ethanol (100 ml), then the solid was collected by filtration and washed with cold ethanol and ether, yielding 1c (48.0 g) as an off-white solid. The mother liquor was concentrated and purified by chromatography on silica gel, eluting with hexane / ethyl acetate 1: 1, to give an additional 15.4 g of 1c as a white solid. Combined yield 63.4 g.

Step 1A-F: To a solution of 1c (63.4 g, 0.30 mol, 1 eq) in ethyl acetate (800 ml) was added little by little metallic sodium (10.3 g, 0.45 mol, 1.5 eq), and the mixture was heated refluxed for 16 hours. The cooled suspension was poured onto 500 g of ice, acidified to pH 5, then extracted with 2 x 300 ml of ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and concentrated to a crude yellow oil (86.5 g). The crude yellow oil (86.5 g) was dissolved in ethanol (480 ml) and water (80 ml) then was added monohydrobromide hydrazine (100 g, 0.88 mol, 3 eq) and the mixture was heated at 85 ° C for 16 hours. The solvents were evaporated, brine (200 ml) was added, and the mixture was extracted with 2 x 300 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to provide 1d (68 g) as a brown crude foam, which was used without further purification.

Step 1A-G: A mixture of 1d (68 g, 250 mmol, 1.0 eq), ethyl acetoacetate (100 ml), acetic acid (150 ml), and ethanol (150 ml) was refluxed for 24 hours. The cooled mixture was concentrated to provide a solid residue, which was then deposited on a porous glass filter and washed with ether, yielding 1e (52.0 g, 51.2%) as an off-white solid. The mother liquor was concentrated, then chromatographed on silica gel using 10% methanol in DCM as eluent. The solid product thus obtained was washed with ether to provide an additional 17.0 g of 1e as an off-white solid (69.0 g of combined yield).

Step 1A-H: To a suspension of 1e (41.2 g, 123 mmole) in acetonitrile (200 ml) was added POCI3 (45.0 ml, 493 mmol), and this mixture was heated to reflux for 16 hours. The cooled reaction mixture was poured onto ice-water, and the resulting mixture was extracted with chloroform. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel, eluting with hexanes / ethyl acetate 3: 1, to yield 1f (29.0 g) as a tan solid.

EXAMPLE 2 7-isopropyl-3- (2-methoxy-4-pyrazyl-l-1-IL-phenyl) -2,5-dimethyl-pyrazolop, 5-alpyrimidine Step 2A: To a solution of Compound 1f (1.41 g, 4.0 mmol) and Fe (acac) 3 (424 mg, 1.2 mmol) in THF / NMP (v / v = 8: 1) was added slowly at room temperature PrMgCI (2.0 M in THF, 4.0 ml). The reaction mixture was stirred for 1.5 hours before being quenched with 1N HCl (aqueous). After extraction with EtOAc, the crude product was purified by column chromatography (25% EtOAc / Hexane) to yield Compound 2 1 (628 mg). Depending on the alkyl functionality in the alkyl magnesium halide, the compounds listed in the following table were synthesized: EXAMPLE 3 Ethyl 3- (2-methoxy-4-pyrazol-1-yl-phenyl) -2,5-dimethyl-pyrazolofl.5-alpyrimidine-7-carboxylic acid ethyl ester Step 3A: To 20 ml of EtOH was added Compound 1d (1.0 g, Example 1, Step 1 C) and ethyl 2,4-dioxovalerate (0.82 g) followed by 0.5 ml of acetic acid. The reaction mixture was heated at 80 ° C for 12 hours. Concentration and purification by silica gel column chromatography yielded Compound 3-1 (0.66 g, 46.1% yield) and Compound 3-2 (0.47 g, 32.2% yield) of reverse addition.

Step 3B: To Compound 3-1 (30 mg) dissolved in THF (1.5 ml) was added DIBAL (150 μL of DIBAL 2M in hexane). The reaction mixture was stirred at room temperature for 2 hours and was quenched with water (0.4 ml). After purification via LC-MS, Compound 3-3 (3.3 mg) was obtained. Following the same procedure, reduction of Compound 3-2 yielded Compound 3-4 (2.6 mg) after purification.

Step 3C: Compound 3-1 (30 mg) was added to 1.5 ml of THF followed by CH3MgBr (150 μL of 2M CH3MgBr in THF). The reaction mixture was stirred at room temperature for 2 hours and was quenched with water. The resulting product was purified by LC-MS to yield Compound 3-5 (3.8 mg). Following this procedure with Compound 3-1 and CH3CH2MgBr Compound 3-6 (4.1 mg) was produced after purification. Following the same reaction procedure using Compound 3-2 as starting reagent and CH3MgBr as nucleophile, Compound 3-7 (4.0 mg) was provided after purification.

Step 3D: Acetamidoxime (20 mg) and NaH (10 mg) were added to THF (1.5 ml) with stirring at room temperature for 30 min. Added the Compound 3-2 (40 mg), and the mixture was heated at 90 ° C for 2 hours in a closed tube. After purification via LC-MS, Compound 3-8 (5.5 mg) was obtained.

Step 3E: To Compound 3-1 (200 mg) in dioxane: water (9: 1) LiOH (30 mg) was added. The reaction proceeded with stirring for 6 hours at room temperature followed by stopping at pH 4 (HCl, 4N) and extraction between H2O (20 ml) and EtOAc (20 ml). The organic phase was dried over Na2SO4 and concentrated. The resulting concentrate was purified by silica gel column chromatography (50:50 EtOAc / hexane) to give Compound 3-9 (180 mg). The compounds presented in Example 3 are tabulated in the following table: EXAMPLE 4 - (2-methoxy-4-pyrazol-1-yl-phenyl) -2,5-dimethyl-7-trifluoromethyl-pyrazolofl,5-a] pyrimidine Step 4A: A mixture of Compound 1d (40 mg, Example 1, Step 1 C) and 1,1,1-trifluoropentane-2,4-dione (excess) was heated in AcOH at 150 ° C for 15 min. with microwave to provide after purification via LCMS Compound 4-1 (29 mg). Depending on the trifluorodione, the compounds of the following table were synthesized: All HPLC determinations employed Analytical Method 2.

EXAMPLE 5 3- (2-Methoxy-4-pyrazol-1-yl-phenyl) -2,5-dimethyl-pyrazolofl.5-a1-pyrimidine-7-carboxylic acid dimethylamide Step 5A: To a solution of Compound 3-9 (50 mg, 0.14 mmol, 1 eq) in DCM (1 mL) was added HOBT (57 mg, 0.42 mmol, 3 eq), TEA (0.12 mL, 0.84 mmol, 6 mL). eq), dimethylamine hydrochloride (34 mg, 0.42 mmol, 3 eq) and EDCI (79 mg, 0.42 mmol, 3 eq). The mixture was stirred at room temperature for 16 hours, then the solvent was evaporated, and the crude reaction mixture was purified by preparative HPLC / MS to provide Compound 5-1 (10 mg) as a TFA salt. Depending on the amine used in the amidation stage above, the compounds in the following table were synthesized: All HPLC determinations employed Analytical Method 2.

EXAMPLE 6 cyclopentyl. { 2-f3- (2-methoxy-4-pyrazol-1-yl-phenyl) -2,5-dimethyl-pyrazolop, 5- a1-pyrimidin-7-n-benzyl} -amine Step 6A: To a solution of 1f (500 mg, 1.4 mmol, 1 eq) in dioxane / water 1: 1 (6 ml) was added 2-formylphenylboronic acid (255 mg, 1.7 mmol, 1.2 eq), followed by potassium carbonate. (390 mg, 2.8 mmol, 2.0 eq) and tetrakis (trphenophosphine) palladium (0) (82 mg, 0.07 mmol, 0.05 eq). The mixture was heated in a closed tube at 100 ° C for 3 hours, then the solvent was removed in vacuo. The residue was taken up in ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography using hexanes / ethyl acetate 1: 1 as eluent, to give 6a (500 mg, 85%) as a yellow solid. .

Step 6B: Sodium triacetoxyborohydride (80 mg, 0.38 mmol, 2 eq) was added at room temperature to a solution of 6a (80 mg, 0.19 mmoles, 1 eq) and acetic acid (0.011 ml, 0.19 mmoles, 1 eq) in dichloromethane (1 ml). The mixture was stirred at room temperature for 16 hours, then the mixture was concentrated, taken up in methanol, and purified directly by preparative HPLC / MS, yielding 6-1 (36 mg, 38% yield) as a TFA Depending on the amine used in the reductive amination stage above, the compounds in the following table were synthesized: EXAMPLE 7 - (2-Methoxy-4-pyrazol-1-1-phenyl) -2,5-dimethyl-7-f2- (2-morpholin-4-yl-ethyl) -phen- PirazoloM, 5-alpyrimidine Step 7A: Sodium borohydride (62 mg, 1.6 mmol, 2 eq) was carefully added to a suspension of 6a (345 mg, 0.82 mmol) in THF / methanol 1: 1 (4 mL) at room temperature. The mixture was stirred for 30 min., Then water was added and the mixture was extracted with DCM. The combined organic layers were washed with water and brine, then dried over sodium sulfate, filtered, and concentrated to provide 7-1 (450 mg, 90%) as a solid, which was used without further purification.

Step 7B: To a solution of 7-1 (450 mg, 1.05 mmol, 1 eq) in DCM (5 ml) at room temperature was added thionyl chloride (0.17 ml, 2.3 mmol, 2.2 eq). The mixture was stirred at room temperature for 30 minutes, then water was added and the mixture was extracted with DCM. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to provide 7-2 (420 mg, 90%) as a yellow solid.

Step 7C: To a solution of 2-methylimidazole (17 mg, 0.21 mmol, 3 eq) in 2 ml of DMF at room temperature was added sodium hydride (11 mg of 60% dispersion in mineral oil, 0.28 mmol, 4 eq) . The mixture was stirred for 10 min., Then a solution of 7-2 (30 mg, 0.07 mmol, 1 eq) in 0.2 ml of DMF was added and the mixture was stirred at room temperature for 17 h. The mixture was diluted with methanol, then purified directly by preparative HPLC / MS to provide 7-X (6 mg) as a TFA salt.

Step 7D: To a solution of 7-2 (10 mg, 0.023 mmol, 1 eq) in DMSO (3 ml) at room temperature was added sodium cyanide (3.3 mg, 0.067 mmol, 3 eq). The mixture was stirred at room temperature for 2 hours, then water was added and the mixture was extracted with DCM. The combined organic layers were washed with water and brine, then dried over sodium sulfate, filtered, and concentrated to give crude 7-3 (8 mg, 80% yield) as a solid.

Step 7E: To a solution of 7-3 (50 mg, 0.11 mmol) in DCM (1 mL) at -78 ° C was added DIBA-H (0.23 mL of a 1.5 M solution in toluene, 0.35 mmol, 3 eq) . The mixture was stirred at -78 ° C for 20 min., Then allowed to warm to room temperature. Water was added and the mixture was stirred for 10 min., Then the aqueous layer was extracted with two additional portions of DCM. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered through Celite®, and concentrated. The residue was purified by preparative HPLC / MS to provide 7a (15 mg) as a TFA salt.

Step 7F: To a solution at room temperature of 7a (15 mg, 0.034 mmol, 1 eq) and acetic acid (0.002 ml, 0.034 mmol, 1 eq) in DCM (1 ml) was added sodium triacetoxyborohydride (15 mg, 0.069 mmol) , 2 eq). The mixture was stirred at room temperature for 16 hours, then the mixture was concentrated, taken up in methanol, and purified directly by preparative HPLC / MS, yielding 7-4 (11 mg, 50% yield) as a sodium salt. TFA The following table summarizes the compounds of Example 7. By varying the amine used in the reductive amination stage above, Compounds 7-5 and 7-6, included in the table, were synthesized by the methods of Step 7E: EXAMPLE 8 3- (2-Methoxy-4-pyrazol-1-yl-phenyl) -2,5-dimethyl-7- (3-methyl-pyridin-2-yl) -pyrazolof 1,5-alpyrimidine Step 8A: To a solution of 2-bromo-3-methylpyridine (4.85 g, 28.2 mmol) in dry THF (8 mL) cooled to -70 ° C was added dropwise n-BuLi (solution 1. 6 M in hexane, 17.6 ml, 28.2 mmoles). The reaction mixture was stirred at -70 ° C for 30 min., Then added for 5 min. ZnCl 2 (0.5 M solution in THF, 66.0 ml, 34 mmol). The mixture was allowed to warm to 0 ° C for 1 hour, then Compound 1f (1.66 g, 4.70 mmole) and tetrakis (triphenylphosphine) palladium (0) (326 mg, 0.28 mmole) were added. The mixture was then heated to reflux for 4 hours. The cooled reaction mixture was quenched with water, the THF was evaporated and the resulting aqueous mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, concentrated, and the residue was chromatographed on silica gel using hexanes / ethyl acetate 1: 3 to give the free base 8-1 (1.6 g, 83%) as a yellow solid. To a solution of 8-1 (1.6 g, 3.9 mmol) in ethyl acetate / chloroform 7: 1 (100 mL) was added hydrogen chloride (4.0 mL of a 2.0 M solution in ether, 8.0 mmol) at 0 ° C. . The suspension was diluted with ether, then the solid was collected on a porous glass filter and washed with ether to obtain the HCl salt of 8-1 (1.7 g, 98%) after drying under high vacuum. Depending on the halide employed in Step 8A above, the compounds in the following table were synthesized: or so the eterminacones and empeto e to o naí co.

EXAMPLE 9 Synthesis of the 2-methyl-4- (pyrazole-1-D-phenylboronic acid) pinacolic ester reagent Step 9A: 4-Bromo-3-methylaniline (10.2 g) was suspended in 6N HCl (85 ml) and cooled to 0 ° C. A solution of sodium nitrite (4 g in 40 ml of H 2 O) was added over a period of 10 min. The reaction was stirred for 15 min. at 0 ° C followed by the addition of stannous chloride dihydrate (36 g in 25 ml of 12 N HCl). The reaction was stirred for 2 hours at 0 ° C. The reaction was filtered and the filter cake was washed with cold H2O to provide the 4-bromo-3-methylphenylhydrazine Hydrochloride (Compound 9a, 20 g) as a tan solid.

Step 9B: The compound resulting from Step 9A (20 g) was suspended in 50 ml of ethanol. Bis-dimethylacetal of malondialdehyde (11.0 ml, 67 mmol) was added and the reaction was heated at 85 ° C for 2 hours. The reaction mixture was neutralized with sodium bicarbonate and extracted by washing with DCM. The combined organic layers were dried over magnesium sulfate and concentrated. The residue was taken up in ethyl acetate and the mixture was filtered through a small bed of Celite®. The filtrate was evaporated, and the oily residue was purified by column chromatography (ethyl acetate / hexanes 1: 1) to give 1- (4-bromo-3-methylphenyl) pyrazole (Compound 9b, 9.6 g, 73%) like an amber oil.Step 9C: To a solution of Compound 9b (2.0 g in 15 ml of dioxane) was added bis (pinacolato) diboro (2.4 g), potassium acetate (2.4 g) and 1,1'-bis (diphenylphosphino) ferrocene dichloropalladium (II ) (500 mg). The reaction was heated at 85 ° C for 12 hours. The reaction mixture was filtered through a small pad of Celite® and the filter cake was washed with ethyl acetate. The filtrate was concentrated to a brown liquid which was purified by column chromatography (20% ethyl acetate / hexanes) to give the pinacolic ester of 2-methyl-4- (pyrazol-1-yl) phenylboronic acid (Compound 9c, 1.8 g, 75%) as a yellow oil; [M + H] = 285.0. Also prepared by the above methods were the pinacolic ester of 2-chloro-4- (pyrazol-1-yl) phenylboronic acid (9d) and 2-methyl-3- (pyrazol-1-yl) phenylboronic acid pinacolic ester (9e). ).

EXAMPLE 10 7- (2-Fluoro-3-methoxy-phenyl) -2,5-dimethyl-3- (4-methyl-6-pyrazol-1-yl-pyridin-3-yl) -pyrazolofl, 5-alpyrimidine Step 10A: A solution of 3-amino-5-methylpyrazole (20.0 g, 206 mmol), ethyl acetoacetate (32. Og, 247 mmol), acetic acid (6 ml), and dioxane (16 ml) was heated at reflux for 16 hours. 150 ml). A white solid precipitated, which was collected by filtration. The filter cake was washed with ether to provide 10a (29.0 g, 86%) as a white solid.

Step 10B: To a suspension of compound 10a (5.0 g, 31 mmol) in 1,4-dioxane (30 ml) was added triethylamine (8.5 ml, 62 mmol) and phosphorus oxychloride (7.4 ml, 77 mmol). The reaction was heated under nitrogen at 100 ° C for 2 hours. The reaction mixture was cooled in an ice bath, then treated successively with water and aqueous sodium bicarbonate solution (final pH 8). Dichloromethane was added and the mixture was washed 3x with water. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to a dark brown oil. The crude product was purified by chromatography on silica gel using 30% ethyl acetate in hexanes as eluent, yielding 10b (3.8 g, 70%) as a white solid.

Step 10C: To a mixture of 80 ml of dioxane and 8 ml of water was added Compound 10b (3.3 g, 18 mmol, 1 eq), 2-fluoro-3-methoxyphenylboronic acid (4.3 g, 26 mmol, 1.4 eq), potassium carbonate (5.0 g, 36 mmol, 2 eq), and tetrakis (triphenylphosphine) palladium (0) (1.5 g, 1.3 mmol, 0.07 eq). The mixture was stirred and heated at 100 ° C for 16 hours, then allowed to cool and water (75 ml) was added. The mixture was extracted with ethyl acetate, then the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel eluting with hexane / ethyl acetate 4: 1 to provide Compound 10c (3.78 g, 76%) as a white solid.

Step 10D: To a solution of 10c (3.0 g, 11 mmol) in methanol (30 ml) at -10 ° C was added bromine (1.77 g, 11 mmol). After 10 min., The mixture was filtered to collect the precipitate it had formed. The filter cake was washed with cold methanol, and then dried under vacuum to yield 10d (3.15 g, 83%) as a yellow solid.

Step 10E: The Suzuki reaction of Compound 10d (460 mg, 1.3 mmol) in accordance with the procedure of the above Step 10C, using Compound 12-1 in place of 2-fluoro-3-methoxyphenylboronic acid, yielded Compound 10 -1 (15 mg, solid) after purification by preparative HPLC / MS and chromatography on silica gel (eluent hexane / ethyl acetate 4: 1). Depending on the boronate ester or acid used in the final Suzuki reaction, the compounds listed in the following table were synthesized and purified by preparative LC-MS: All HPLC determinations employed Analytical Method 2.

EXAMPLE 11 - (2-Fluoro-3-methoxy-phenyl) -2,5-dimethyl-3- (3-methyl-5-pyrazol-1-yl-pyridin-2-yl) -pyrazolof 1, 5 alpirimidine Step 11 A: To a solution of sodium salt of cyanoacetone (2.5 g, 23 mmol, 1.2 eq) in DMF (40 ml) at room temperature was added sodium hydride (1.54 g of 60% dispersion in oil, 38.5 mmol, 2 eq). The mixture was stirred for 15 min, then a solution of 2-fluoro-3-methyl-5-nitropyridine (3.0 g, 19.2 mmol, 1.0 eq) in 10 mL of DMF was added dropwise. The reaction mixture was stirred at room temperature for 6 hours. The reaction was stopped with 5 g of ice, followed by 150 ml of water and 10 ml of acetic acid. The mixture was extracted with ethyl acetate, then the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel using 30% ethyl acetate in hexane as eluent, yielding 11a (1.85 g, 44% yield) as an orange oil.

Step 11 B: A mixture of 11a (1.8 g, 8.2 mmol, 1.0 eq), ethanol (30 ml) and water (3 ml) was heated at reflux for 17 hours. The solvent was evaporated, and the residue was purified directly by chromatography on silica gel using hexanes / ethyl acetate 1: 1 as eluent, yielding 11b (1.8 g, 94% yield) as a yellow foam.

Step 11 C: A mixture of 11b (1.8 g, 7.7 mmol, 1 eq), ethanol (15 ml), acetic acid (15 ml), and ethyl acetoacetate (1.6 g, 12.4 mmol, 1.6 eq) was heated in a tube closed at 105 ° C for 19 hours. The solvent was evaporated, and the residue was placed on a porous glass filter, washing with ether, to provide 11c (1.0 g, 43% yield) as a yellow solid.

Step 11 D: A mixture of 11c (800 mg, 2.7 mmol, 1.0 eq), phosphorus oxychloride (900 mg, 5.9 mmol, 2.2 eq), and acetonitrile (15 ml) was heated at reflux for 3 hours. The reaction was poured onto ice, then the mixture was extracted with ethyl acetate. The combined ethyl acetate extracts were washed with aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated to provide 11d (640 mg, 76%) as a yellow solid.

Step 11 E: A suspension of 11d (64 mg, 2.0 mmol, 1 eq), 2-fluoro-3-methoxyphenylboronic acid (480 mg, 3.8 mmol, 1.4 eq), potassium carbonate (555 mg, 4.0 mmol, 2 eq) , tetrakis (triphenylphosphine) palladium (0) (230 mg, 0.2 mmol, 0.1 eq) in 20 ml of dioxane and 2 ml of water was stirred and heated at 100 ° C for 16 hours. Water (50 ml) was added and the mixture was extracted with ethyl acetate (50 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was triturated with methanol to obtain 11e (300 mg, 37%) as a yellow solid.

Step 11F: To a solution bubbling with nitrogen of 11e (300 mg, 0.74 mmol, 1.0 eq) in 20 ml of ethanol and 10 ml of THF was added 10% Pd / C (100 mg). The mixture was stirred on a Parr shaker under 40 psi of hydrogen gas at room temperature for 6 hours. The mixture was purged with nitrogen and filtered. The filtrate was concentrated to provide 11f (260 mg, 94% yield) as a yellow oil.

Step 11 G: A solution of sodium nitrite (60 mg, 0.87 mmol, 1.3 eq) in water (10 ml) was added dropwise to an ice-cooled solution of 11f (260 mg, 0.69 mmol, 1.0 eq) in acid 4N hydrochloric acid (5 ml). The mixture was stirred at 0 ° C for 1 hour, followed by the addition of 10 ml of semi-saturated aqueous potassium iodide. The mixture was stirred at room temperature for 6 hours, then 50 ml of saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with 2 x 50 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, concentrated and the residue was purified by chromatography on silica gel using hexanes / ethyl acetate 4: 1 as eluent, yielding 11 g (170 mg, 51% yield) as a yellow solid.

Step 11 H: To a solution of 11 g (170 mg, 0.35 mmol, 1.0 eq) in dioxane (6 ml) were added potassium carbonate (200 mg, 1.45 mmol, 4.1 eq), pyrazole (60 mg, 0.89 mmol, 2.5 eq). ), copper iodide (I) (60 mg, 0.32 mmol, 0.9 eq), trans-1,2-diaminocyclohexane (36 mg, 0.32 mmol, 0.9 eq), and N, N'-dimethylethylenediamine (28 mg, 0.32 mmol) , 0.9 eq). The mixture was stirred and heated in a closed tube at 100 ° C for 19 hours. The reaction mixture was filtered through a small pad of Celite®, concentrated, and purified by preparative HPLC / MS to obtain Compound 11-1 (70 mg, 37% yield) as a TFA salt; PM: 428.47; LC / MS: 429 [MHf; tR: 5.390, Analytical Method 2.

EXAMPLE 12 4-Methyl-2-pyrazol-1-yl-5-pyridylboronic acid Step 12A: 2-Chloro-4-methyl-5-nitropyridine (5.0 g, 29 mmol, 1.0 eq) was dissolved in 50 ml of hydrazine solution (1 M solution in THF) and the mixture was stirred and heated in a tube closed at 80 ° C for 22 hours. The cooled reaction mixture was filtered, and the solid obtained was washed with ether to give 5.7 g of a greenish-brown solid. A mixture of this solid (5.7 g, 24 mmol, 1.0 eq), bis (dimethylacetal) of malonaldehyde (5.9 g, 31 mmol, 1.3 eq), acetic acid (50 ml) was stirred and heated in a closed tube at 80 ° C for 5 hours. The solvent was evaporated, then aqueous sodium bicarbonate solution (200 ml) was added and the mixture was extracted with 2 x 200 ml of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was recrystallized from ethanol to obtain 12a (2.6 g, 53% yield) as a yellow solid.

Step 12B: A mixture of 12a (2.6 g, 13 mmol) and 10% Pd / C (200 mg) in 30 ml of THF / methanol 1: 1 was stirred in a Parr apparatus under 40 psi of hydrogen at room temperature during 2 hours. The reaction mixture was filtered through a small pad of Celite® and the filtrate was concentrated to a light green oil. The oil was resuspended in 10 ml of 3N hydrobromic acid, cooled to 0 ° C, then treated dropwise with a solution of sodium nitrite (835 mg, 12 mmol, 1.1 eq) in 2 ml of water. The mixture was stirred at 0 ° C for 1 hour, then 2 ml of half-saturated potassium iodide was added and the mixture was stirred at room temperature for 22 hours. Saturated aqueous sodium bicarbonate solution was added, then the mixture was extracted with 2 x 100 ml of ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel using hexanes / ethyl acetate 4: 1 as eluent, to give 12b (1.23 g, 33%) as a yellow solid.

Step 12C: To a solution of Compound 12b (600 mg, 2.1 mmol) and triisopropyl borate (900 mg, 4.8 mmol) in 5 mL of THF at -78 ° C was added dropwise n-butyllithium (1.8 mL of a 2.0 M solution in pentane, 3.6 mmol). The mixture was allowed to warm to room temperature over a period of 1 hour, then the mixture was cooled to -78 ° C and treated with additional triisopropyl borate (400 mg, 2.1 mmol), followed by n-butyllithium (0.5 ml. a 2.0 M solution in pentane, 1.0 mmole) additional. The mixture was again allowed to warm to room temperature over a period of 1 hour, then 0.8 ml of 1N hydrochloric acid was added and the mixture was stirred for 1 hour. The mixture was filtered, the solid was rinsed with methanol and ethyl acetate, then the filtrate was concentrated. The residue was chromatographed on silica gel, eluting with 1: 1 hexanes / ethyl acetate to provide Compound 12-1 (220 mg, 52% yield) as a red solid. EXAMPLE 13 7- (4-Chloro-phenoxymethyl) -3- (2-methoxy-4-pyrazol-1-phenyl) -2,5-dimethyl-pyrazoloM, 5-alpyrimidine Step 13A: To a solution of Compound 3-3 (25 mg, 0.072 mmol, 1 eq) in THF (1.5 ml) were added di-tert-butyl azodicarboxylate (30 mg, 0.11 mmol, 1.5 eq), triphenylphosphine (30 mg, 0.11 mmol, 1.5 eq) and 4-chlorophenol (30 mg, 0.023 mmol, 3.3 eq). The mixture was stirred at room temperature for 17 hours, then the solvent was evaporated and the residue was purified by chromatography on silica gel, eluting with hexanes / ethyl acetate to provide Compound 13-1 (8 mg) as a solid. . Depending on the phenol used, the compounds listed in the following table were synthesized and purified or preparative LC-MS: EXAMPLE 14 6- (3-r3- (2-METOXY-4-PIRAZOL-1-IL-PHENYL) -2,5-DIMETHYL-PIRAZOL? P, 5- A1PIRIMIDIN-7-IL1-PROPOXI.}. -NICOTINONITRILO Step 14A: To a solution of compound 1f (1.06 g, 3.0 mmol) and iron acetylacetonate (III) (353 mg, 1.0 mmol) in 10 mL of anhydrous THF / NMP (7: 1) was slowly added 3-chloro. Butenilmagnesium (9.0 ml of a 0.5 M solution in THF, 4.5 mmol). The reaction mixture was stirred at room temperature for 1 hour, then more iron acetylacetonate (III) (1.0 g, 2.8 mmol) and Grignard reagent (6.0 mL, 3.0 mmol) were added. The reaction mixture was stirred for 2 hours, then water was added. The mixture was extracted with ethyl acetate, then the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel using hexanes / ethyl acetate as eluent to provide 14a (638 mg, 48% yield).

Step 14B: To a solution of 14a (380 mg, 1.02 mmol) in 10 ml of THF / water (4: 1) was added osmium tetroxide (26 mg, 0.10 mmol) followed by sodium periodate (642 mg, 3.0 mmol) at room temperature. The mixture was stirred at room temperature for 1 hour, then ethyl acetate and water were added. The organic layer was dried over sodium sulfate, filtered, and evaporated to give the crude aldehyde, which was dissolved in methanol (20 ml). Sodium borohydride (152 mg, 4.0 mmol) was added little by little. After stirring at room temperature for 20 min., The reaction mixture was concentrated. The residue was purified by chromatography on silica gel, eluting with hexanes / ethyl acetate to provide Compound 14-1 (230 mg, 60% yield).

Step 14C: A mixture of 14-1 (30 mg, 0.08 mmol, 1 eq), copper iodide (1) (15 mg, 0.08 mmol, 1 eq), cesium carbonate (52 mg, 0.16 mmol 2 eq), and 1, 10-phenanthroline (14 mg, 0.08 mmol, 1 eq) was heated in 1 ml of toluene in a closed vial at 110 ° C for 17 hours. The cooled mixture was filtered through Celite®, then concentrated. The residue was purified by chromatography on silica gel using hexanes / ethyl acetate as eluent to provide 14-2 (5 mg) as a solid. Depending on the aryl halide used in the method of Step 14C, the compounds listed in the following table in addition to Compound 14-1 were synthesized and purified by preparative LC-MS: All HPLC determinations employed Analytical Method 2.

EXAMPLE 15 7-lmidazo-1-ylmethyl-3- (2-methoxy-4-pyrazol-1-yl-phenyl) -2,5-dimethyl-pyrazolori, 5-alpyrimidine Step 15 A: A solution of methanesulfonyl chloride (100 mg, 0.86 mmol, 1.5 eq) in DCM (0.5 ml) was added dropwise to a solution at 0 ° C of Compound 3-3 (200 mg, 0.57 mmol, 1 eq) in 5 ml of DCM. The mixture was allowed to warm to room temperature over a period of 1 hour, then a saturated aqueous solution of sodium bicarbonate was added and the mixture was extracted with 2 x 20 ml of DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain 15a (180 mg, 49% yield) as a yellow foam.

Step 15B: To a solution of 15a (23 mg, 0.054 mmol, 1 eq) in DMF (1 ml) were added potassium carbonate (20 mg, 0.14 mmol, 2.6 eq) and imidazole (20 mg, 0.30 mmol, 5.5 eq) . The reaction mixture was stirred at room temperature for 16 hours, then methanol (1 ml) was added and the reaction mixture was purified directly by preparative HPLC / MS to give 15-1 (10 mg) as a TFA salt. Depending on the nucleophilic heterocycle or amine used, the compounds listed in the following table were synthesized and purified by preparative LC-MS: EXAMPLE 16 4-Methyl-2-pyrrol-1-yl-5-pyridylboronic acid Step 16A: A solution of 2-amino-5-bromo-4-methylpyridine (1 g, 5.4 mmol) and 2,5-dihydroxytetrahydrofuran (2.8 g, 27 mmol) in acetic acid (10 ml) was heated at 90 ° C in a closed tube for 2 hours. The reaction mixture was concentrated and the residue was purified by gel chromatography. of silica using hexanes / ethyl acetate 4: 1, giving 16a (900 mg, 71% yield) as a light yellow oil.

Step 16B: To a solution of Compound 16a (860 mg, 3.6 mmol) and triisopropyl borate (1.4 g, 7.3 mmol) in 6 mL of THF at -78 ° C was added n-butyllithium (3.6 mL of a 2.0 M solution). in pentane, 7.2 mmol). The mixture was allowed to warm to room temperature over a period of 1 hour, then 0.5 ml of 4N hydrochloric acid was added and the mixture was stirred for 10 min. The mixture was extracted with 2 x 25 ml of DCM, then the organic layer was dried over sodium sulfate, filtered, and concentrated to provide 16-1 (250 mg) as a yellow oil. The aqueous layer was concentrated, then the solid residue was washed with ethanol. The combined ethanolic filtrates were concentrated to provide additional 16-1 (500 mg) as a yellow oil.

EXAMPLE 17 7-Ethyl-2,5-d-methyl-3-f2-r2- (1-methyl-pyrrolidin-2-yn-ethoxy-4-pyrazol-1-yl-phenyl > -pyrazolo [1, 5-alpyrimidine Step 17A: To a solution of Compound 2-6 (350 mg) in chloroform (5 ml) was added BBr3 (1.0 M in DCM, 5 ml). The mixture was stirred overnight at room temperature and was quenched with water. The mixture was extracted with chloroform (2 x 10 ml), then the combined organic extracts were dried over sodium sulfate, filtered, and concentrated to provide Compound 17-1 (280 mg) as an oil. An aliquot (10 mg) was purified by preparative HPLC / MS to provide purified Compound 17-1 (2.9 mg).

Step 17B: A mixture of Compound 17-1 (45 mg, 0.14 mmole, 1 eq), potassium carbonate (56 mg, 0.41 mmol, 3 eq), sodium iodide (20 mg, 0.13 mmol, 1 eq), 2- (2-chloroethyl) -1-methylpyrrolidine hydrochloride (39 mg , 0.21 mmole, 1.5 eq), acetone (1 ml) and water (1 ml) was heated in a closed tube in a microwave reactor at 150 ° C for 25 min. The acetone was evaporated, then the residue was diluted with methanol, filtered, and subjected directly to purification by preparative HPLC / MS, yielding Compound 17-2 (14 mg, 20%) as a TFA salt.; PM: 444.58; LC / MS: 444 [MHf; tR: 6.010, Analytical Method 2.

EXAMPLE 18 7- (3-Methoxy-propyl) -3- (2-methoxy-4-pyrazol-1-yl-phenyl) -2,5-dimethyl-pyrazolo [1,5-alpyrimidine] Step 18A: To a solution of 14-1 (30 mg) in dry DMF was added NaH (10 mg, 60% dispersion). After stirring at room temperature for 10 min., Methyl iodide (0.015 ml) was added. The mixture was stirred for 1 hour, then methanol (1 ml) was added and the mixture was subjected directly to purification by preparative HPLC / MS to provide Compound 18-1 (12 mg) as a TFA salt; PM: 391.47; LC / MS: 391 [MH] +; tR: 7.050, Analytical Method 2.

EXAMPLE 19 2-f7- (2-Methoxymethyl-phenyl) -2,5-dimethyl-pyrazolofl.5-a1-pyrimidin-3-ill-5-pyrazole- Step 19A: The procedure of Example 18 was followed using Compound 7-1 as starting material. Depending on the alkyl halide employed, the compounds listed in the following table were synthesized and purified by preparative LC-MS.

All HPLC determinations employed Analytical Method 2.

EXAMPLE 20 Step 20A: A mixture of Compound 1f (710 mg, 2.0 mmol), (2-ethoxycarbonyl) phenylboronic acid (470 mg, 2.4 mmol), tetrakis (triphenylphosphine) palladium (0) (116 mg, 0.1 mmol), and potassium carbonate (550 mg, 4.0 mmol) was heated in dioxane / water 9: 1 (10 ml) at 100 ° C for 2.5 hours. A solution of sodium hydroxide (3N, 10 ml) was added, and the mixture was stirred at 100 ° C for an additional 30 minutes. The cooled mixture was concentrated, then water was added and the pH adjusted to 2 with hydrochloric acid. The mixture was extracted with chloroform, then the combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated to give a crude solid, which was recrystallized from chloroform to provide Compound 20a (420 mg, 48% yield) as a yellow solid.

Step 20B: Compound 20a (420 mg, 0.96 mmol) was heated in 10 ml of chloroform with thionyl chloride (1.0 ml, 14 mmol) at 70 ° C for 2 hours. The volatiles were evaporated to provide Compound 20b (450 mg) as a dark solid.

Step 20C: A solution of 20b (32 mg, 0.07 mmol) in chloroform (1 ml) was treated with morpholine (0.1 ml, 1 mmol) at room temperature. The mixture was allowed to stand at room temperature for 30 min., Then the solvent was evaporated. The residue was taken up in methanol, filtered and purified directly by preparative HPLC / MS to give 20-1 (13 mg, 30%) as a TFA salt. Depending on the amine used, the compounds listed in the following table were synthesized and purified by preparative HPLC-MS: All determinations of LC used the Analytical Method 2.

EXAMPLE 21 7- (1-Ethyl-1h-pyrrol-2-yn-3- (2-methoxy-4-pyrazol-1-yl-phenyl) -2,5-dimethyl-pyrazolof 1,5-alpyrimidine Step 21 A: A mixture of Compound 1f (210 mg, 0.6 mmol), N-Boc-pyrrole-2-boronic acid (158 mg, 0.75 mmol), tetrakis (triphenylphosphine) palladium (0) (40 mg, 0.035 mmol) , and potassium carbonate (166 mg, 1.2 mmol) was heated in dioxane / water 9: 1 (5 ml) at 110 ° C for 3 hours in a closed tube. The cooled mixture was concentrated, then water was added and the mixture was extracted with chloroform. The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated to give a crude solid, which was stirred in TFA / DCM 1: 1 (3 mL) for 16 hours. The mixture was diluted with ethyl acetate, then treated with aqueous ammonia. The organic layer was dried over sodium sulfate, filtered, and concentrated, then the residue was chromatographed on silica gel using hexanes / ethyl acetate as eluent to provide 21a (110 mg, 48% yield) as a yellow solid. .

Step 21 B: To a solution of 21a (110 mg, 0.28 mmol) in dry DMF (2 ml) was added sodium hydride (20 mg of a 60% dispersion in mineral oil, 0.5 mmol) at room temperature. The mixture was stirred for 5 min., then ethyl iodide (0.050 ml, 0.060 mmol) was added and the mixture was stirred at room temperature for 2 hours. Water and ethyl acetate were added, then the ethyl acetate layer was washed with water and brine, then dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel using hexanes / ethyl acetate as eluent to provide Compound 21-1 (84 mg, 73% yield) as a yellow solid.; PM: 412.50; LC / MS: 412 [MHf; RT: 7.630, Analytical Method 2.

EXAMPLE 22 7- (3-Ethyl-3h-imidazol-4-yl) -3- (2-methoxy-4-pyrazol-1-yl-phenyl) -2,5-dimethyl-pyrazolofl, 5- alpirimidine Step 22A: A mixture of Compound 1f (1.50 g, 4.25 mmol), 2-phenylethenylboronic acid (692 mg, 4.68 mmol), potassium carbonate (1.17 g, 8.50 mmol), and tetrakis (triphenylphosphine) palladium (O) (250 mg , 0.225 mmol) in dioxane (9 ml) and water (1 ml) was heated at 105 ° C for 16 hours. The mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated, and the residue was chromatographed on silica gel using hexanes / ethyl acetate as eluent to provide 22a (1.60 g, 89% yield) as a yellow solid.

Step 22B: A mixture of ozone / oxygen was bubbled through a solution of 22a (1.60 g, 3.8 mmol) in DCM / dry 2: 1 methanol (20 ml) at -70 ° C for 8 minutes. Dimethyl sulfide (1.5 ml) was added and the mixture was stirred and allowed to warm to room temperature over a period of 16 hours. The solvent was evaporated and the residue was chromatographed on silica gel using hexanes / ethyl acetate as eluent to provide Compound 22b (1.0 g, 76% yield) as a yellow solid.

Step 22C: A mixture of 22b (35 mg, 0.10 mmol), ethylamine (1.0 ml of a 2.0 M solution in THF, 2.0 mmol), and magnesium sulfate in 1,2-dichloroethane was stirred at room temperature for 15 hours. The mixture was filtered, then the filtrate was evaporated to dryness. The residue was taken up in Ethanol / DME 1: 1 (2 ml), then TOSMIC (38 mg, 0.19 mmol) and potassium carbonate (55 mg, 0.4 mmol) were added and the mixture was heated to reflux for 17 hours. Water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel using hexanes / ethyl acetate as eluent, providing Compound 22-1 (5 mg) as an oil; PM: 413.48; LC / MS: 413 [MHf; RT: 5,000, Analytical Method 2.

EXAMPLE 23 3- (2-Methoxy-4-pyrazol-1-yl-phenyl) -2,5-dimethyl-7- (4-methyl-oxazol-5-y0-pyrazolofl, 5-alpyrimidine A mixture of 22b (208 mg, 0.60 mmol), alpha-methyl-TOSMIC (251 mg, 1.2 mmol) and potassium carbonate (248 mg, 1.8 mmol) was heated in 5 ml of DME / ethanol 1: 1 at 80 ° C. for 14 hours. Water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel using hexanes / ethyl acetate as eluent, providing 23-1 (60 mg, 23%) as an oil; MW: 400.44; LC / MS: 400 [MHf; tR: 5.250, Analytical Method 2.

EXAMPLE 24 7- (4-Fluoro-benzyl) -2,5-dimethyl-3- (4-methyl-6-pyrrol-1-yl-pyridin-3-yl) -pyrazolofl, 5-a] pyrimidine Step 24A: To a solution of 4-fluorophenyl-zinc chloride (20 ml of a 0.5 M solution in THF, 10 mmol) was added Compound 10b (1.0 g, 5.5 mmol) and tetrakis (triphenylphosphine) palladium (0) ( 300 mg, 0.26 mmol). The reaction mixture was heated at 90 ° C in a closed tube for 3 hours. The cooled reaction mixture was treated with 4N hydrochloric acid (4 ml), then water was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel, eluting with 30% ethyl acetate in hexanes to obtain 24a (1.0 g, 71% yield) as an off-white solid.

Step 24B: Compound 24a (1.0 g, 3.9 mmol) was dissolved in 15 ml of methanol. Bromine (0.62 g, 3.9 mmol) was added dropwise to the solution, resulting in the formation of a white precipitate. The solid was collected on a porous glass filter and rinsed with methanol. The compound was further purified by silica gel column chromatography, eluting with hexanes / ethyl acetate 4: 1 to first provide a dibromination product (110 mg, 7% yield), followed by 24b (1.0 g, 77%) as a white solid.

Step 24C: A mixture of compound 24b (800 mg, 2.4 mmol), Compound 16-1 (500 mg, 2.5 mmol), tetrakis (triphenylphosphine) palladium (0) (280 mg, 0.24 mmol), and potassium carbonate (600 mg, 4.3 mmol) was heated in dioxane / water 9: 1 (3.5 ml ) at 95 ° C for 3 hours in a closed tube. Aqueous sodium bicarbonate solution (5 ml) was added to the cooled mixture, which was then extracted twice with DCM. The combined DCM extracts were dried over sodium sulfate, filtered, and concentrated to give a crude oil, which was partially purified by preparative HPLC / MS. The partially purified product was then chromatographed on silica gel using hexanes / ethyl acetate 4: 1 as eluent, affording Compound 24-1 (3 mg) as a yellow solid; PM: 411.48; LC / MS: 412 [MHf; tR: 9.160, Analytical Method 2.

EXAMPLE 25 3- (2-Methoxy-4-pyrazole-1H-phenyl) -2,5-dimethyl-7- (1-methyl-1 h-imidazol-2-yl) -pyrazoloH, 5-alpyrimidine Step 25A: To a solution of 1-methylimidazole (246 mg, 3.0 mmol) in dry THF (3 mL) cooled to -70 ° C was added dropwise n-BuLi (2.5 M solution in hexane, 1.7 mL, 4.2 mmol ). The reaction mixture was stirred at -70 ° C for min., Then ZnCl 2 (0.5 M solution in THF, 20 ml, 10 mmol) was added over a period of 5 min. The mixture was stirred at -70 ° C for 1 hour, then heated to 0 ° C. Compound 1f (106 mg, 0.30 mmol) and tetrakis (triphenylphosphine) palladium (0) (70 mg, 0.06 mmol) were added. The mixture was then heated to reflux for 3 hours. The cooled reaction mixture was quenched with water, the THF was evaporated and the resulting aqueous mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, concentrated, and the residue chromatographed on silica gel using ethyl acetate as eluent for da 25-1 (15 mg) as a yellow solid; HPLC retention time 4.13 min. (method 2); PM 399.5; observed MS 399.

EXAMPLE 26 3- (2-Methoxy-4-pyrrazol-1- (1-phenyl) -2,5-dimethyl-7- (2-methyl-2h-imidazol-3-yl) -pyrazolofl, 5-alpyrimidine w / Step 26A: To a solution of 1-methylpyrazole (820 mg, 10 mmol) in dry THF (20 ml) cooled to -70 ° C was added dropwise n-BuLi (1.6 M solution in hexane, 6.3 ml, 10 mmol). The reaction mixture was stirred at -70 ° C for 5 min., Then triisopropyl borate (2.5 ml, 11 mmol) was added over a period of 5 min. The mixture was allowed to warm to room temperature over a period of 1 hour, then 6N hydrochloric acid (5 ml) was added. The mixture was stirred for 30 min., Then evaporated to dryness to give crude 26a as a solid, which was used without further purification.

Step 26B: Compound 1f (530 mg, 1.5 mmol) and crude 26a (the entire amount, approximately 10 mmol) were subjected to the Suzuki reaction in accordance with the procedure of Example 1. The reaction mixture was concentrated, then water was added and the mixture was extracted with chloroform. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated, then the residue was purified by chromatography on silica gel using hexanes / ethyl acetate as eluent. The product was further purified by crystallization from acetonitrile to provide Compound 26-1 (280 mg) as a yellow solid; HPLC retention time 6.42 min. (method 2); PM 399.5; observed MS 399.

EXAMPLE 27 CRF receptor binding activity The compounds of this invention can be evaluated for CRF receptor binding activity by a standard radioligand binding assay in accordance with generally described by Grigoriadis et al. (Mol.Pharmacol vol50, pp679-686, 1996) and Hoare et al. others (Mol.Phamacol vol63 pp751-765, 2003). Using radiolabeled CRF ligands, the assay can be used to evaluate the binding activity of the compounds of the present invention with any subtype of CRF receptor. In summary, the binding assay involves the displacement of a radiolabelled CRF ligand from the CRF receptor. More specifically, the binding assay is performed in 96-well assay plates using 1-10 μg of cell membranes from cells stably transfected with human CRF receptors. Each well receives approximately 0.05 ml of assay buffer (e.g., Dulbecco's phosphate buffer saline, 10 mM magnesium chloride, 2 mM EGTA) containing the compound of interest or a reference ligand (e.g., sauvagine, urocortin I or CRF), 0.05 ml of [125l] tyrosine-sauvagine (final concentration -150 pM or approximately the KD according to is determined by the Scatchard analysis) and 0.1 ml of a cell membrane suspension containing the CRF receptor . The mixture is incubated for 2 hours at 22 ° C followed by separation of the bound and free radioligand by rapid filtration on glass fiber filters. After three washes, the filters are dried and the radioactivity is counted (Auger electrons of 125l) using a scintillation counter. All radioligand binding data can be analyzed using the non-linear least squares curve fitting software Prism (GraphPad Software Inc.) or XL / Y (IC Business Solutions Ltd.).

EXAMPLE 28 Activity of adenylate cyclase stimulated with CRF The compounds of the present invention can also be evaluated by various functional tests. For example, the compounds of the present invention can be systematically screened for CRF-stimulated adenylate cyclase activity. An assay for the determination of CRF-stimulated adenylate cyclase activity can be performed in accordance with is generally described by Battaglia et al. (Synapse 1: 572, 1987) with modifications to adapt the assay to whole cell preparations. More specifically, the standard assay mixture may contain the following in a final volume of 0.1 ml: 2mM L-glutamine, 20mM HEPES, and 1mM IMBX in DMEM buffer. In stimulation studies, whole cells with transfected CRF receptors are deposited in 96-well plates and incubated for 30 min. at 37 ° C with various concentrations of related and non-CRF related peptides to establish ordered profile by pharmacological category of the particular receptor subtype. After incubation, cAMP is measured in the samples using commercially available standard kits, such as cAMP-Screen ™ from Applied Biosystems. For functional evaluation of the compounds, cells are incubated and a single concentration of CRF or related peptides causing 50% stimulation of cAMP production together with various concentrations of competing compounds for 30 min. at 37 ° C, and the cAMP is determined as described above. It will be appreciated that, although the specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited except by the appended claims

Claims (30)

NOVELTY OF THE INVENTION CLAIMS

1. A compound that has the following structure: or a pharmaceutically acceptable salt, ester, solvate, stereoisomer or prodrug thereof, wherein: "-" represents the second bond of an optional double bond; R-i is hydrogen, alkyl, substituted alkyl, heteroaryl, substituted heteroaryl, -NH2, or halogen; R 2 is alkyl, substituted alkyl, -C (0) NR 7 R 8, aryl, substituted aryl, aryloxyalkyl, substituted aryloxyalkyl, heteroarylalkoxyalkyl, substituted heteroarylalkoxyalkyl, heterocycloalkyl, substituted heterocycloalkyl, arylalkyl, substituted arylalkyl, heteroaryl, or substituted heteroaryl, wherein said heteroaryl or substituted heteroaryl is attached to the pyrimidine ring via a carbon-carbon bond; R3 is zero, hydrogen, or alkyl; Y is = (CR) - or - (C = O) -; R 4 is hydrogen, alkyl, substituted alkyl, thioalkyl, alkylsulfinyl, or alkylsulfonyl; Ar is phenyl, phenyl substituted with 1 or 2 R5, pyridyl or pyridyl substituted with 1 or 2 R5; R5 in each occurrence is hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cyano, halogen, alkylsulfonyl, or alkylsulfinyl; Het is heteroaryl optionally substituted with 1 or 2 R6; Re each occurrence is hydroxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cyano, or halogen; and R7 and R8 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, arylalkyl, substituted arylalkyl, heterocyclealkyl, or substituted heterocyclealkyl; or R7 and R3 taken together with the nitrogen to which they are attached form a heterocyclic ring or a substituted heterocyclic ring.

2. The compound according to claim 1, further characterized in that R-i is hydrogen, alkyl, substituted alkyl, -NH2, or halogen.

3. The compound according to claim 1, further characterized in that R2 is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, wherein said substituted heteroaryl or heteroaryl is attached to the pyrimidine ring via a carbon bond -carbon.

4. The compound according to claim 1, further characterized in that R3 is zero.

5. The compound according to claim 4, further characterized in that Y is = (CR) -.

6. The compound according to claim 5, further characterized in that R4 is hydrogen, alkyl, substituted alkyl.

7. The compound according to claim 1, further characterized in that R3 is hydrogen or alkyl.

8. The compound according to claim 7, further characterized in that Y is - (C = O) -.

9. The compound according to claim 1, further characterized in that Ar is phenyl substituted with 1 R5.

10. The compound according to claim 9, further characterized in that R5 is alkyl, substituted alkyl, alkoxy, substituted alkoxy, cyano, halogen, alkylsulfonyl, or alkylsulfinyl.

11. The compound according to claim 1, further characterized in that Het is substituted with 1 R6.

The compound according to claim 11, further characterized in that Rβ is alkyl, substituted alkyl, alkoxy, substituted alkoxy, cyano, or halogen.

The compound according to claim 1, further characterized in that: R-i is hydrogen, alkyl or substituted alkyl; R3 is null; And it is = (CR4) -; R is hydrogen, alkyl or substituted alkyl; Ar is phenyl substituted with an R5; R5 is alkyl, substituted alkyl, alkoxy or substituted alkoxy; and Het is heteroaryl.

The compound according to claim 13, further characterized in that: Ri is lower alkyl; R is lower alkyl; R5 is alkoxy; and Het is pyrazolyl.

15. The compound according to claim 14, further characterized in that: R-i is methyl; R is methyl; and R5 is methoxy.

16. The compound according to claim 15, further characterized in that: R 2 is alkyl, substituted arylalkyl, substituted aryl, heteroaryl, substituted heteroaryl, substituted heteroaryloxyalkyl, heteroarylalkyl or substituted heteroarylalkyl.

17. The compound according to claim 16, further characterized in that: R2 is substituted arylalkyl, substituted aryl, heteroaryl or substituted heteroaryl.

18. The compound according to claim 17, further characterized in that: R2 is substituted benzyl, substituted phenyl, substituted pyrazolyl, pyridinyl or substituted pyridinyl.

19. The compound according to claim 18, further characterized in that: R2 is substituted pyrazolyl, pyridinyl or substituted pyridinyl.

20. The compound according to claim 19, further characterized in that: R2 is substituted pyridinyl.

21. The compound according to claim 20, further characterized in that: R2 is pyridinyl substituted with methyl or pyridinyl substituted with methoxy.

22. The compound according to claim 21, further characterized in that said compound is represented by the formula:

23. A pharmaceutical composition comprising a compound as defined in claim 1 in combination with a pharmaceutically acceptable carrier or diluent.

24. The use of a pharmaceutical composition as claimed in claim 23, for preparing a medicament for treating a disorder that manifests hypersecretion of CRF in a mammal.

25. The use claimed in claim 24, wherein the disorder is apoplexy.

26. The use claimed in claim 24, wherein the disorder is depression.

27. The use claimed in claim 24, wherein the disorder is an anxiety-related disorder.

28. The use claimed in claim 24, wherein the disorder is obsessive-compulsive disorder.

29. The use claimed in claim 24, wherein the disorder is irritable bowel syndrome.

30. The use claimed in claim 24, wherein the disorder is anorexia nervosa.