Title of Invention	SUBSTITUTED THIAZOLE PYRAZOLOPYRIMIDINE COMPOUNDS AS CRF1 RECEPTOR ANTAGONISTS
Abstract	The present invention relates to compounds of Formula I: pharmaceutical compositions thereof, and use thereof as corticotropin releasing factor 1 (CRF1) receptor antagonists in the treatment of psychiatric and neuroendocrine disorders, neurological diseases, and metabolic syndrome.

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FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION (See section 10, rule 13) THIAZOLE PYRAZOLOPYRIMIDINE COMPOUNDS" VAA LILLY AND COMPANY, a corporation of the State of Indiana, having a principal place of business at Lilly Corporate Center. City of Indianapolis. Slate oi Indiana 46285, United States of America. The following specification particularly describes the invention and the manner in which it is to be performed. WO 2008/036579 PCT/US2007/078605 THIA20LE PYRAZOLOPYRIMIDINES AS CRFl RECEPTOR ANTAGONISTS FIELD OF THE INVENTION This invention relates to novel thiazole pyrazolopyrimidine compounds, 5 pharmaceutical compositions thereof, and use thereof as CRFl receptor antagonists in the treatment of psychiatric and neuroendocrine disorders, neurological diseases, and metabolic syndrome. BACKGROUND OF THE INVENTION 10 Corticotropin releasing factor (CRF) is a 41 amino acid peptide that is the primary physiological regulator of proopiomelanocortin (POMC) derived peptide secretion from the anterior pituitary gland. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypotbalamic distribution in the central nervous system and produces a wide 15 spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in the brain. There is also evidence that CRF plays a significant role in integrating the response in the immune system to physiological, psychological, and immunological stressors. CRF has been implicated in psychiatric disorders and neurological diseases 20 including depression and anxiety, as well as the following: Alzheimer's disease, Huntington's disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, Parkinson's disease, epilepsy, migraine, alcohol and substance abuse and associated withdrawal symptoms, obesity, metabolic syndrome, congenital adrenal hyperplasia. Cushing's disease, hypertension, stroke, irritable bowel syndrome, stress-induced gastric 25 ulceration, premenstrual syndrome, sexual dysfunction, premature labor, inflammatory disorders, allergies, multiple sclerosis, visceral pain, sleep disorders, pituitary tumors or ectopic pituitary-derived tumors, chronic fatigue syndrome and fibromyalgia. CRF receptor subtypes, CRFl and CRF2, have been identified and are distributed heterogeneously within the brain thereby suggesting potential functional diversity. For 30 example, widely distributed brain CRFl receptors are strongly implicated in emotionality accompanying exposure to environmental stressors. Significantly, CRFl, not CRF2, receptors appear to mediate select angiogenic like behaviors. A more discrete WO 2008/036579 PCTAJS2007/078605 septal/hypothalmic distribution and the availability of alternative endogenous Iigands suggest a different functional role for the CRF2 receptor. For example, a novel CRF-family neuropeptide with preferential affinity for CRF2 relative to CRFI receptors is reported to suppress appetite without producing the profile of behavioral activation 5 observed with selective CRF1 agonism. in other cases, CRF2 agonism produces similar effects to those reported for CRF1 antagonists or CRF1 gene deletion. For example, while CRF2 agonists have been proposed as antiobesity agents, CRF1 antagonists may be an important treatment for obesity as well. Certain pyrrolo[2,3-pyrimidines, pyrroio[3,2-tf]pyrimidines, pyrazolo[l,5- 10 a]pyrimidines, ],2,3-triazolo[4,5-blpyridines, and pyrazolori.S-al-l.S.S-triazines, useful as CRF antagonists, are described in WO 94/13676, WO 97/29109, WO 98/08847, and WO 98/03510. The present invention provides novel thiazole pyrazolopyrimidines useful as CRFI receptor antagonists. In view of the above, it is desirable to discover new 15 efficacious and selective antagonists of CRFI as potentially valuable therapeutic agents for the treatment of psychiatric and neuroendocrine disorders, neurological diseases, and metabolic syndrome. Further, since a majority of commercial CNS and cardiovascular drugs exhibit unfavorable bioavailability and pharmacokinetic profiles, it is also desirable to discover new compounds with favorable bioavailability and pharmacokinetic profiles 20 relative to known CRF antagonists such as CP154526 and NBI30775. SUMMARY OF THE INVENTION In one embodiment, the present invention provides a compound of Formula I WO 2008/036579 PCI7US2007/078605 R" is hydrogen, CI, Br, methyl, trifluoromethyl or methoxy; R4 is hydrogen, Br, R3RbN- methoxymcihvl, n-butyl, acetamido, pyridin-4-vl. Ra and R° are independently hydrogen, CrC3alkyi, H2NCH;CH2-, 5 (CH3)3COC(0)NHCH2CH2-, or CH3CH2CH2NHCH2CH2-; or a pharmaceutically acceptable salt thereof. Jn another embodiment, the present invention provides a pharmaceutical composition comprising; a compound of Formula I, or a pharmaceutical acceptable salt 10 thereof, and a pharmaceutically acceptable excipient. In another embodiment, the present invention relates to a method of treating depression, anxiety, alcohol or substance abuse, obesiry, hypertension, metabolic syndrome, irritable bowel syndrome, epilepsy, stroke, sleep disorders, allergy, migraine, premenstrual syndrome, infertility, sexual dysfunction, congenital adrenal hyperplasia, 15 Cushing's disease, premature labor, stress-induced gastric ulceration, inflammatory disorders, pituitary or ectopic pituitary-derived tumors, chronic fatigue syndrome, fibromyalgia, visceral pain or multiple sclerosis in a patient, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. 20 In another embodiment, the present invention relates to use of a compound of Formula I. or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of depression, anxiety, alcohol or substance abuse, obesity, hypertension, metabolic syndrome, irritable bowel syndrome, epilepsy, stroke, sleep disorders, allergy, migraine, premenstrual syndrome, infertility, sexual dysfunction, 25 congenital adrenal hyperplasia, Cushing's disease, premature labor, stress-induced gastric ulceration, inflammatory disorders, pituitary or ectopic pituitary-derived tumors, chronic fatigue syndrome, fibromyalgia, visceral pain or multiple sclerosis. In another embodiment, the present invention relates to a compound of Formula I, OT a pharmaceutically acceptable salt thereof, for use in the treatment of depression. WO 2008/036579 PCT/US2007/078605 anxiety, alcohol or substance abuse, obesity, hypertension, metabolic syndrome, irritable bowel syndrome, epilepsy, stroke, sleep disorders, allergy, migraine, premenstrual syndrome, infertility, sexual dysfunction, congenital adrenal hyperplasia, Cushing's disease, premature labor, stress-induced gastric ulceration, inflammatory disorders, 5 pituitary or ectopic pituitary-derived tumors, chronic fatigue syndrome, fibromyalgia, visceral pain or multiple sclerosis. In another embodiment, the present invention relates TO a compound of Formula 1, or a pharmaceutically acceptable salt thereof, for use in therapy. 10 DETAILED DESCRIPTION OF THE INVENTION As used above, and throughout Ihe description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings: "Alky!" means a saturated aliphatic hydrocarbon group, which may be straight or branched, having 1 to 5 carbon atoms in the chain. 15 "Pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable formulation carrier, solution, or additive to enhance the formulation characteristics. Such excipients must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof and arc well known to the skilled artisan (see e.g. Remingtons Pharmaceutical Sciences, I9'h Edition, Mack Publishing Company, 1995). 20 "Pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic acid addition salts, and base addition salts, of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds. In particular, acid addition salts can be prepared by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and 25 isolating the salt thus formed (see e.g. Remingtons Pharmaceutical Sciences, 19lh Edition, Mack Publishing Company, 1995). "Therapeutically effective amount" or "effective amount" means the amount of the compound of formula I of the present invention or pharmaceutical composition containing a compound of formula I of the present invention that will elicit the biological 30 or medicai response of or desired therapeutic effect on a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. WO 2008/036579 PCT/US2007/078605 The terms "treatment," "treat," "treating," and the like, are meant to include both slowing and reversing the progression of a disorder. These terms also include alleviating, ameliorating, attenuating, eliminating, or reducing one or more symptoms of a disorder or condition, even if the disorder or condition is nol actually eliminated and even if 5 progression of the disorder or condition is not itself slowed or reversed. The term "treatment" and like terms also include preventive (e.g., prophylactic) and palliative treatment. Prevention of the disease is manifested by a prolonging or delaying of the onset of the symptoms of the disease. The symbol " " in a molecular structure indicates the position of attachment 10 for that particular substituent. When any variable occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substitucnts and/or variables are permissible only if such combinations result in stable compounds. 3n choosing compounds of the present 15 invention, one of ordinary skill in the art will recognize that the various substituents, i.e. R1, R2, etc., are lo be chosen in conformity with well-known principles of chemical structure connectivity. Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality 20 toward the point of attachment. For example, an arylcarbonylaminoalkyl substituent is equivalent to aryl-C(0)-NH-alkyl-. The present invention contemplates the following embodiments, which can alternatively be further combined: (a) A compound of Formula I wherein R1 and R2 are ethyl; 25 (b) A compound of Formula I wherein R1 and R3 are n-propyl; (c) A compound of Formula I wherein R3 is CI, Br, methyl or trifluoromcthyl; (d) A compound of Formula I wherein R3 is CI; (e) A compound of Formula I wherein R is Br; (f) A compound of Formula I wherein R4 is RaRTJ-, pyridin-4-yl, morpholin-4-yl, WO 2008/036579 PCTAJS2 007/078605 (g) A compound of Formula I wherein R4 is morpholin-4-yl; (h) A compound of Formula I wherein R4 is (i) A compound of Formula I wherein Ra and Rb are independently C|-CNalkyl; (j) A compound of Formula ] wherein R1 and R2 are ethyl, R3 is CI, and R4 is morpholin-4-yl; " " (k) A compound of Formula I wherein R1 and R2 are n-propyl, R3 is C\t and R4 is morpholin-4-y]; (1) A compound of Formula I wherein R1 and R2 are ethyl, R3 is Br, and R4 is morpholin-4-yl; (m)A compound of Formula I wherein R1 and R2 are w-propyl, R3 is Br, and R4 is morpholin-4-yl; (n) A compound of Formula ] wherein R1 and R2 are ethyl, R"5 is CI, and R4 is (o) A compound of Formula T wherein R1 and R2 are n-propyl, R3 is CI, and R15 is 15 (p) A compound of Formula I wherein R' and R* are eihyl, RJ is Br, and R" is (q) A compound of Formula I wherein R1 and R2 are n-propyl, R3 is Br, and R4 is 20 (r) Use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for treating depression or anxiety; WO 2008/036579 PCTAJS2007/078605 (s) Use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for treating alcohol or substance abuse; (t) Use of a comound of Formula I, or a pharmaceutically acceptable salt thereof, for treating alcohol or substance abuse and associated withdrawal symptoms; 5 (u) A compound of Formula I, or a pharmaceutically acceptable salt thereof, exhibiting a Ki vahie for CRF1 binding of exhibiting a Ki value for CRF1 binding of (w)A compound of Formula I, or a pharmaceutically acceptable salt thereof, 10 exhibiting a Ki value for CRF1 binding of (x) A compound of Formula I, or a pharmaceutically acceptable salt thereof, exhibiting a Ki value for CRF1 binding of £ 500 nM and selectively binding to CRFI (i.e., lower Ki) relative to CRF2; (y) A compound of Formula I, or a pharmaceutically acceptable salt thereof, 15 exhibiting a Ki value for CRFI binding of £ 50 nM and selectively binding to CRFI (i-e.. lower Ki) relative to CRF2; (z) A compound of Formula I, or a pharmaceutical iy acceptable salt thereof, exhibiting a Ki value for CRFI binding of 5 5 nM and selectively binding to CRFI (i.e., lower Ki) relative to CRF2; and/or 20 (aa) Particular exemplified compounds with superior bioavailability and pharmacokinetic profiles relative to some known CRF antagonists (e.g., CP154526 and NBI30775), such as Example 15. The compounds of the present invention are preferably formulated as 25 pharmaceutical compositions administered by a variety of routes. Preferably, such compositions are for oral administration. Such pharmaceutical compositions and processes for preparing same are well known in the art (see, e.g., Remington: The Science and Practice of Pharmacy, A. Gennaro, et al., eds„ 19lh ed.. Mack Publishing Co., 1995). A pharmaceutical composition of the present invention comprising a compound such as herein described, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient showed surprising and enhanced effects. Therefore, the said composition is synergistic in nature. 30 The compounds of Formula 1 are generally effective overawide dosage range. For example, dosages per day normally fall within the range of about 0.0001 to about 30 WO 2008/036579 PCTAJS2007/078605 mg/kg of body weight. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, and therefore the above dosage range is not intended to limit ihe scope of the invenlion in any way. Jt will be understood thai 5 the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms. The compounds of Formula I are CRF-1 antagonists and, as such, are useful for 10 treating a condition which is treatable by reducing CRF1 receptor tone or stimulation. Corticotropin releasing factor (CRF), a 41 amino acid peptide that is the primary physiological regulator of proopiomelanocortin (POMC) derived peptide secretion from the anterior pituitary gland [J. Rivicr ct al., Proc. Natl. Acad. Sci (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)], has been linked to a number of medical 15 conditions. For example, in addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in the brain [W. Vale ei al., Rec. Prog. Horm. 20 Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response in the immune system to physiological, psychological, and immunological stressors [see, e.g., J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)]. 25 CRF is involved in psychiatric disorders and neurological diseases including depression and anxiety [D. M. Nielsen, Life Sci. 78:909-919; H. E. Kunzel et al., J. Psychiatr. Res. 37:525-533; D. R. Gehlert ct al., Eur. J. Pharmacol. 509:145-153]. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral 30 sclerosis, as they relate to the dysfunction of CRF neurons in the central nervous system [for a review, see: E. B. De Souze, Hosp. Practice 23:59 (19&8)]. Chronic administration of CRF has been shown to produce impairment of the dopamine system suggesting a role WO 2008/036579 PCT/US2007/078605 in Parkinson's disease [E. Izzo et al., Pharmacol Biochem. Behav. 81:701-708 (2005)]. Other neurological disorders in which CRF is involved include epilepsy [T. Z. Baram et al., Brain Res. 770:89-95 (1997)] and migraine [T. C. Theoharides et al., Endocrinology 136:5745-5750 (1995)]. CRF has been implicaled in alcohol and substance abuse and 5 associated withdrawal symptoms [D. H. Overstreet et al., Pharmacol Biochem. Behav. 77:405-413; Y. Shaham ct al., Psychopharmacohgy (Berl) 137:184-190]. Moreover, there is evidence that CRF has a role in various endocrine disorders and cardiovascular diseases such as obesity [E. Timofeeva and D. Richard, Neuroendocrinology 66:327-340 (1997)], metabolic syndrome [A. M. Ward et al., Metabolism 53:720-726(2004)], 10 congenital adrenal hyperplasia [D. P. Merke and G. B. Cutler Jr., Endocrinol. Metab. Clin. North Am. 30:121-135 (2001)], Cushing's disease [M. Labeuret al., Curr. Drug Targets Immune Endocr. Metabol. Disord. 4:335-342 (2004)], hypertension [R. J. Briscoe, ct al., Brain Res. 881:204-207 (2000)], and stroke [S. L. Stevens et al., J. Cereb. Blood Flow Metab. 23:1151-1159(2003)]. Gastric disturbances such as irritable bowel 15 syndrome [Y. Tacheet a\.,EurJ. Surg. Suppl: 16-22 (2002)] and stress-induced gastric ulceration [K. E. Gabry et al., Mol Psychiat>y 7:474-483, 433 (2002)] have been shown to be related to CRF. In addition, there is indication that CRF has a role in various areas of human female health, for example, premenstrual syndrome [F. Facchinetti et al., Psychosom. Med. 56:418-422 (1994)], infertility [L. Ghizzoni et al., Endocrinology 20 138:4806-4811 (1997)], sexual dysfunction [ J. E. Jones et al., Am. J. Physiol Regul Jntegr. Comp. Physiol. 283:R591-597 (2002)], and premature labor [P. D. Wadhwa et al., Am. J. Obstet. Gynecol 191:1063-1069 (2004)]. There is also evidence that CRF has a significant role in the immune system indicating therapeutic potential for treating inflammatory disorders [A. Gravanis and A. N. Margioris, Curr. Med. Chem. 12:1503- 25 1512 (2005)], allergies [L. K. Singh et. al., Brain Behav. Immun. 13:225-239 (1999)], multiple sclerosis and other autoimmune disorders [C. Benou et al., J. Immunol. 174:5407-5413 (2005)]. In addition to the preceding, CRF has been implicated in visceral pain [M. Nijsen et al., Neurogastroenterol Motil \l-A11-4yi (2005)], sleep disorders [T. M. Buckley and A. F. Schatzbcrg, J. Clin. Endocrinol. Metab. 90:3106- 30 3114(2005)], pituitary tumors or ectopic pituitary-derived tumors [K. D. Dieterich et al., J. Clin. Endocrinol. Metab. 83:3327-3331 (1998)], chronic fatigue syndrome and WO 2008/036579 PCT/US2 007/078605 fibromyalgia [G. Neeck and L. J. Crofford, Rheum. Dis. Clin. North Am. 26:989-1002 (2000)). CRF receptor subtypes, CRFI and CRF2^ have been identified and are distributed helerogeneously within the brain [D. T. Chalmers et al, TIPS 17:166-72 (1996)] thereby 5 suggesting potential functional diversity [S. C. Heinnchs et ai., Regul. Peptides 71:15 (1997)]. For example, widely distributed brain CRF1 receptors are strongly implicated in emotionality accompanying exposure to environmental stressors [G. Liebsch et al., Regul. Peptides 59: 229-39 (1995); D. W. Schulz, PNAS 93: 10477-82 (1996)]. Significantly, CRF 1, not CRF2, receptors appear to mediate select anxiogenic like behaviors [Heinnchs 10 et al., 1997}- A more discrete septal/hypothalmic distribution [D. T. Chalmers et al., J. Neurosci. 15(10): 6340-50 (1995)] and the availability of alternative endogenous ligands [J. Vaughan et al., Nature 378:287-92 (1995)] suggest a different functional role for the CRF2 receptor [Heinnchs et al., 1997]. For example, a novel CRF-family neuropeptide with preferential affinity for CRF2 relative to CRF1 receptors is reported to suppress 15 appetite without producing the profile of behavioral activation observed with selective CRF1 agoiiism (H. Tezval et al„ PNAS 101(25): 9468-9473 (2004)]. In some cases, CRF2 agonism produces similar effects to those reported for CRF 1 antagonists or CRF1 gene deletion [S. C. Hcinrichs, Trends in Pharmacological Sciences 20{8):3l 1-5 (1999)]. For example, while CRF2 agonists have been proposed as antiobesity agents, CRF 1 20 antagonists may be an important treatment for obesity as well [C. Contoreggi et al., Neuroendocrinohgy 80(2): 111-23 (2004)]- PREPARING COMPOUNDS OF THE INVENTION All of the compounds of the present invention can be chemically prepared, for 25 example, by following the synthetic routes set forth below. However, the following discussion is not intended to be limiting to the scope of the present invention in any way. For example, the specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different schemes, to prepare additional compounds of Formula I. The products of each step can be recovered 30 by conventional methods including extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like. In the Schemes below PCT/US200 7/0 78605 all subsiituenls, unless otherwise indicated, are as previously defined and suitable reagents are well known and appreciated in the art. WO 2008/036579 PCT/US2007/078605 (6a,b), (7), or (8a-c) is one in which R1 and R'are as defined for formula I and R3a = H or CRj, R3b = Br or CH3 and R3c = H, CH3, or Br. In Scheme 1, Step 1, the pyrazolo[l ,5-a]pyrimidine-7-one of formula (1) is convened to 7-chloro-2,5-dimethyl- pyrazolo[I,5-a]pyriiriidme using phosphorous 5 oxychloride and dimethylaniline in an inert solvent, such as toluene, at ihe reflux temperature of the solvent. In Step 2, a Grignard reagent of formula (-3) (X = CI or Br) is reacted with the chloride of formula (2), in an inert solvent such as toluene, at reflux temperature to provide the 7-aIkyl pyrazolopyrimidine of formula (4). 10 Alternatively, a 7-alkyl pyrazolopyrimidine of formula (4) can be obtained as shown in Steps 3,4, and 5. In Step 3 ethyl acetoacetatc is acylated with an acid halide of formula (4a) in ihe presence of magnesium chloride to provide a diketo-ester of formula (4b). The diketo-cstcr of formula (4b) is decarboxylated under Krapcho conditions to provide the diketone of formula (4c). For example, (4b) is heated in dimethyl sulfoxide at 15 a temperature of about 130 to 170 °C to pcrformme decarboxylation. In Step 5, the diketone of formula (4c) is cyclizcd with 3-amino-5-metbylpyrazole to give the 7-alkyl pyrazolopyrimidine of formula (4) in a protic solvent such as methanol, cthanol, or acetic acid. Preferred conditions use acetic acid at a temperature of about 0 to 60 °C. The pyrazolopyrimidine of formula (4) is function a lized to an iodo 20 pyrazolopyrimidine of formula (5) in Step 6 using an excess of N-iodosuccinimide in acetonitrile. In Scheme 1, Step 7 or 8, the iodo pyrazolopyrimidine of formula (5) is reacted wiih a thiazotc zinc halide in al-Jegishi cross-coupling reaction to provide a thiazolvl pyrazolopyrimidine of formula (6a) or (6b) (Jensen, J.; Skjacrbaek, N.; Vcdso, P. 25 Synthesis 2001, 128). The thiazole zinc halide is generated using methods well known to those skilled in the art. For example, in Slep 7, 2-trimelliylsilanyithiazole is treated with n-, sec-, or te/7-butyl lithium, followed by lithium-zinc exchange with ZnClj. The organozinc reagent is coupled with the iodo pyrazolopyrimidine of formula (5) in the presence of a palladium catalyse for example, dichloro[I,r-bis(diphcnyl- 30 phosphino)ferrocene]palladium (IT) dichloromeihane, in an inert solvent, such as THF, at reflux temperature for about 12 to 36 hours, to provide a thiazole pyrazolopyrimidine of formula (6a). WO 2008/036579 PCT/US2007/078605 Altcrnaiivcly, in Slep 8, a thiazole zinc bromide is generated using 5-bromo-4-mcthylthiazole and zinc metal, and used in the Negishi cross-coupling essentially as described for Step 7, to provide a thiazole pyrazolopyrimidine of formula (6b). In Scheme \, Step 9, a thiazole of formula (6a,b) is brominated to give a bromo or 5 dibromo thiazole of formula (7), wherein R3b = Br or CH3. The thiazole is brominated with either 1 or 2 eq of N-bromosuccinimide, depending on whether RSa is CH3 or H, respectively. An alkyl thiazole of formula (8a-c) is obtained from either a thiazole of formula (6a,b) in Step ]l,orfromabromothiazoleofformula(7) in Step 10. In Step 10, halogen- 10 lithium exchange with n-, sec-, or /-butyl lithium provides a thiazole lithium reagent, which is subsequently reacted with electrophiles, such as alkylhalides, like iodomethyi methylether or iodobutane. In Step 11, the thiazole lithium reagent is formed via dcprotonation using n.-, sec-, or ier/-butyl lithium and then subsequently reacted with an electrophile, like iodomethyi methylether or iodobutane. 15 It will be appreciated by one skilled in the art that the thiazole ring system is readily funationalized and that thiazole intermediates such as 2-trimethylsiIanyl-thiazole (Dondoni, A.; et. al. J. Org. Chem. 1988, 53, 1748) can be readily prepared. 5-Bromo-4-mcthylthiazolc is obtained by bromination of 4-mcthyhhiazole with bromine in acetic acid (Collins, I. J., et. al. W02003093252,13 Nov 2003). 2,5-Dimethyl-4//- 20 pyrazolo[l,5-a]pyrirnidine-7-one (1) is readily prepared by condensation of ethyl acetoacetate and 5-meihyl-2H-pyrazol-3-ylamine in refluxing acetic acid. Scheme 2 WO 2008/036579 PCT/US2007/07860S Formation of a compound of formula (9), (10), or (11) can be carried out in accordance with reactions as depicted in Scheme 2. An appropriate compound of formula. (9), (10), or (11) is one in which R1, R2, Ra, and Rh are as defined for formula I and R3b = 5 Br or CH3, and R43 = -NRaRb or -N-morpholinyl and "het" is defined as depicted. In Step 1, a bromothiazole of formula (7) is coupled with a heterocyclic zinc reagent in a Negishi cross-coupling reaction to provide a thiazole heterocycle of formula (9). For example, 1-methyl-1,2,4-triazoIe is treated with n~, sec-, or/er/-butyI lithium, followed by zinc chloride, at about -80 to -65 °C, and reacted in situ with a bromothiazole 10 of formula (7). The reaction is performed preferentially in an inert solvent, such as THF, in the presence of a palladium catalyst, such as dichloro[lJ*-bis(diphenyI-phosphino)fejrocene]palladium (II) dichloromethane or tetrakis(triphenylphosphine)palladium (0). The reaction is warmed to reflux temperature. Alternatively, the heterocyclic zinc reagent is formed from a haloheterocycie, such as 4-15 iodopyridine and zinc metal. In Scheme 2, Step 2, an intermediate 2-formyl thiazole is formed via halogen-lithium exchange usingn-, sec-, or r-butyl lithium followed by reaction with N-formyl morpholine. The formyl thiazole ts subjected to a reductive amination in the presence of an organic amine, such as morpholine, to provide a morpholinyl methyl thiazole of 20 formula (10). Reductive animations are well-known in the an typically using an WO 2008/036579 PCT/US2007/078605 inorganic borohydride reagent such as sodium borohydride or sodium cyanoborohydride. Preferred conditions use sodium macetoxyborohydride in an inert solvent such as dichloromethane orTHF. In Step 3, a bromothiazole of formula (7) undergoes a displacement reaction with an amine of formula-NR"Rb or with morpholine to provide an aminolhiazole of formula (11). The reaction is preformed in an inert solvent, such as THF or dioxane, using an inorganic base, such as cesium carbonate at 70 to 110 °C. 10 Formation of a compound of formula (13), (14), or (15) can be carried out in accordance with reactions as depicted in Scheme 3. An appropriate compound of formula (13), (14), or (15) is one in which R1, R2, and R4 are as defined for formula I. It will be recognized by one skilled in the art that a 4-bromothiazole, such as thai 15 of formula (12) is readily manipulated to other functionality. For example, in Step 1, die bromide can be dehalogenated with cuprous chloride to give a thiazole of formula (13) which is subsequently chlorinated with N-chlorosuccinimide to provide a 4-chloroihiazole of formula (14). In Scheme 3, Step 3, a 4-bromothiazole of formula (12) is displaced with sodium 20 methoxide in the presence of copper (1) iodide in methanol at about 100 to 120 °C in an WO 2008/036579 PCTAJS2007/078605 inert solvent such as dimeihylformamide, to provide a 4-methoxy thiazole of formula (15). 10 (203) CF3—f f Formation of a compound of formula (17), (18), (19), (20), (20a), or (21) can be carried out in accordance with reactions as depicted in Scheme 4. An appropriate compound of formula (17), (18), (19), (20), (20a), or (21) is one in which R1, R2, Ra, and Rb are as defined for formula I and R*8 is -NRDRb or -N-morpholinyl and "het" is defined as depicted. In Scheme 4, Slep 1, an iodopyrazolopyrimidine of formula (5) and a 5-bromothiazoleof formula (16) undergo a Negishi cross-coupling to form a dimethylpyrrolylthiazole of formula (17). For example, the 5-bromothiazole of formula WO 2008/036579 PCT/IIS200 7/078605 (16) is treated with n~, sec-, or ten-buty\ lithium and then with zinc chloride at about -80 to -65 °C. The organozinc reagent is reacted in situ with an iodopyrazolopyrimidine of formula (5). The coupling reaction is performed preferentially in an inert solvent, such as THF, at reflux temperature, in ihc presence of a palladium catalyst, such as bis(tr\-i-5 butylphosphine)palladium (0). In Step 2, a dimethylpyrrolylthiazole of formula (17) is deprotected to provide an aminothiazolc of formula (19). The dimethylpyrrole is treated with hydroxylamine in acetic acid at a temperature of about 60 to 100 °C, for about 4 to 8 h, preferably for about 6 h. In Step 3, to form the thiazole acetamiUe of formula (18), the same conditions are 10 used as in Step 2, with the exception that the reaction is continued for about 72 h. In Scheme 4, Step 4, a 2-aminothiazole of formula (19) is converted to a 2-bromothiazole of formula (20) using a modified Sandmeyer reaction. Preferred conditions use an alkylnitrile, such as r-butylnitritc, and copper (II) bromide, in acetonitrile at a temperature of about 60 to 80 °C. 15 In Step 5, a 2-bromothiazole of formula (20) undergoes a displacement reaction with an amine of formula ~NR°Rb or with morpholine to provide an aminothiazole of formula (21). The reaction is performed in an inert solvent, such as methanol, THF, or dioxane, or is trealed neat, with an excess of the amine at a temperature of about 70 to 110 °C. Alternatively the reaction is performed with the reacting amine and an excess of 20 triethylamine, or an inorganic base, such as cesium carbonate. Also contemplated in the synthesis of aminoihiazoles of formula (21) are various deprotection steps, such as removal of a /^r/-butyl ester carbamic acid (BOC), as may be required or beneficial for carrying out the reactions above wherein -NR3R carries additional amine functionality as defined for formula 1. The selection and use of suitable protecting groups is well known 25 and appreciated in the art (see for example, Proieciing Groups in Organic Synthesis, Theodora Greene (Wiley-Interscience)). In Scheme 4, Step 6, a 2-bromothiazole of formula (20) is coupled with a heterocyclic zinc reagent in a Negishi cross-coupling reaction to provide a thlazole heterocyele of formula (20a) in a manner similar to that as described for Scheme 2, Step 30 1. It will be appreciated by the skilled artisan that a functionalized thiazole of formula (16) can be prepared by means known in the art. For example, cyclization of WO 2008/036579 PCTAJS2007/078605 thiourea with a bromokctone, such as 3-bromo-l,],l-trifiuoropropan-2-one, provides 4-lrifluoromethyi-thiazole-2-ylamine. Subsequent brominaiion and protection of the amine using hexane-2,5-dione provides (16). Formation of a compound of formula (23) can be carried oul in accordance with reactions as depicted in Scheme 5. An appropriate compound of formula (23) is one in which R1 and R are as defined for formula T and R4b is defined as depicted. 10 An iodopyrazolopyrimidinc of formula (5) and a 4-chloro-2-morpholino-thiazole, for example, of formula (22) undergo cross-coupling to form a pyrazolopyrimidine thiazole of formula (23). For example, the reactants are coupled in the presence of copper iodide, palladium acetate, and triphenylphosphine, with a base such as cesium carbonate. The coupling reaction is performed preferentially in an inert solvent, such as DMF, at 15 about 100- 150°Cfor4-24h. It will be appreciated by the skilled artisan that a functionalized thiazole of formula (22) can be prepared by means known in the art. For example, 2,4-dichlorothiazole can be reacted with morpholine to give the 2-morpholino-thiazole of formula (22). 2,4-Dichlorothiazole can also be exhaustively brominated to provide 2,5- 20 dibromo-4-chloTOthiazole. Subsequent bromine-lithium exchange with n-butyl lithium in THF at -90 °C and quench with water provides 2-bromo-4-chlorothiazole [J. Chem. Soc. Perkin Trans 1: Org Bioorg. Chem. (1972-1999), (2):2I5-219 (1992)]. 2-Bromo-4-chlorothiazole can be subjected to aNegishi cross-coupling reaction with a heterocyclic zinc reagent to obtain the thiazol-2-yl triazole or pyridine. 25 Scheme 6 WO 2008/036579 PCT/US2007/O7S6O5 Formation of a compound of formula (27) can be carried out in accordance with reactions as depicted in Scheme 6. An appropriate compound of formula (27) is one in which R1 and R2 arc as defined for formula I and "hct" is defined as depicted for Step 1 or 5 Step 3, respectively. In Scheme 6, Step I, a heterocyclic thiazole, for example, of formula (25) is obtained by reaction of an iodopyrazolopyrimidine of formula (5) with a bromothiazole of formula (24). The reaction is performed in the presence of N-burylammonium bromide and a base, such as potassium acetate with a palladium catalyst such as palladium acetate 10 with tris(2,4-di-rerr-butyi-phenyl)-phosphane, in an inert solvent such as N-methylpyiTolidinone at a temperature of about 100 - 150 °C. Alternatively, in Step 2, a thiazoiyl pyrazolopyrimidine of formula (6a) is iodinated to provide a 2-iodothiazole of formula (26). The thiazole is treated with lithium diisopropylamide at a temperature of-70 to -80 °C for about one hour and then treated 15 with N-iodosuccinimide at about the same temperature in an inert solvent, such as THF. This is followed by Step 3, wherein a triazolyl or 4-pyridyl thiazole of formula (25) is formed using Ncgishi cross-coup ling conditions similar to those described for Scheme 2, Step 1. In Scheme 6, Step 4, a thiazoiyl pyrazolopyrimidine of formula (25) is brominated 20 to give a bromothiazole of formula (27). The bromination is effected using N- WO 2008/036579 PCT/US2007/078605 bromosuccinimide in the presence of a small amount of acetic acid in an inert solvent, such as acetonitrile. A compound of formula (27), wherein hct = 2,5-dimethyl-pyrrol-l-yh can be further elaborated to obtain compounds of the invention as described in Scheme 4, Steps 5 2,3,4, and 5. It will be appreciated by the skilled artisan thai heierocycle thiazolcs of formula (24) can be readily prepared by means known in the art. For example, thiazole-2-. carboxylic acid amide can be cyclized to the triazole with l.l-dimethoxy-N.N-dimethyl-methanamine, followed by N-methyl-hydrazine to obtain the triazolyl thiazole, which can 10 be subsequently brominated wilh N-bromosuccinimide. Literature procedures afford 4-thiazol-2-yl-pyridine which can be brominated to provide 4-(5-bromo-thiazoI-2-yl)-pyridine. 5-Bromo-2-(2,5-dimethyl-pyrrol-l-yl)-thiazole can be readily obtained by reaction of 2-amino-5-brornothiazoJe with hcxane-2,5-dione. As used herein, "TLC" refers to thin layer chromatography; "HPLC" refers to 15 high performance liquid chromatography; "LC/MS" refers to liquid chromatography/mass spectrometry; "GC/MS" refers to gas chromatography/mass spectrometry"; "HR-ToF' refers to high resolution time-of-flight; "APCI" refers to atmospheric pressure chemical ionization; "5" refers to pan per million down-field from tetramethylsilanc; *THF" refers 10 teirahydrofuran; "EtOAc" refers to ethyl acetate; "McOH" refers to methanol; "EtOH" 20 refers to ethanol; "DMF" refers lo dimethylformamide. EXAMPLES Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following 25 preparations and examples are provided to describe the invention in further detail. They arc intended to illustrate and not to limit the invention in any way whatsoever. The reagents and starting materials are readily available to, or may be readily synthesized by, one of ordinary skill in the art. Examples 1- 35 provide representative compounds and illustrate the preparation thereof. Examples A-D illustrates various biological assays that 30 can be used for determining the biological properties of the compounds of the inventions. Those skilled in the art will promptly recognize appropriate variations from the procedures described in the examples. The names of the compounds of the present WO 2008/036579 PCT/US20 07/078605 invention are provided by ChemDraw Ultra® version 7.0.1. Salts are named as the free base plus the conjugate acid- Preparation I 5 2,5-Dimethyl-4H-pyrazolo[l,5-a]pyrimidin-7-one Add ethyl acetoacetate (128 g, 0.98 mo!) dropwise to an acetic acid solution (500 mL) of 5-methyI-2tt-pyrazol-3-y]amine (100 g, 0.95 mol), keeping the temperature at 25-28 °C. Heat the mixture at reflux for 10 h and then cool to room temperature. Add the reaction to tert-buty] methyl ether (5 L) cooled to 5 °C, keeping the temperature below 10 10 °C. Slir for 1 h at 5 °C, and filter. Dry the resulting material in vacuo overnight to provide a while solid (158 g, 96%). Preparation 2 7-ChIoro-2,5-dimethyl-pyrazolo[l,5-a]pyrimidine 15 To a suspension of 2,5-dimethy]-4//-pyrazolo[l,5-a]pyrimidin-7-one (10.0 g, 61.3 mmol) in toluene (150 mL) add /V./V-dimethylaniline (9.7 mL, 76.7 mmol). Add phosphorus oxychloride (11.2 mL, 122.6 mmol) dropwise to this white suspension. Reflux for 3 h under an inert atmosphere, cool to room temperature, and concentrate the reaction to a brown oil using reduced pressure. Dissolve the oil in ethyl acetate (250 mL) 20 and basify with 1.0 N NaOH. Separate the organic phase and extract the basic aqueous phase with ethyl acetate (2 * 100 mL). Combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to yield a brown solid. Purify the material using flash chromatography, eluting with 80% hexane/20% (30% THF/hexane) to 0% hexane/100% (30% THF/hexane) in a step gradient of 20% 25 increments to provide a light green solid (6.65 g, 59%). ES/MS m/z (3SC1) 182.3 (M+l)+. Alternate Procedure: Add2,5-dimethylpyrazolo[l,5-a]pyrimiduv7-one(20 g, 122 mmol) to 1,4-dioxane(60 mL). Stirthe mixture at 22 °C for 10 min and then addN.N-diethylaniline (20.8 mL, 128 mmol). Stir for an additional 5 min and then add phosphorus oxychloride 30 (11.7mL, 126 mmol) over 15 min. Stirthe mixture at 22 °C for 15 min, then heat to 80-85 °C over 35 min and hold the reaction at this temperature for 1.5 h. Add the cooled reaction mixture slowly to a solution of potassium phosphate dibasic (106.7 g, 612.82 WO 2008/036579 PCT/US2007/078605 mmol) in water (325 mL) cooled to 0-5 °C, keeping the temperature below 5 °C during the addition. Stir the mixture at 22 °C and then add methyW-buty 1 ether (150 mL). Separate the organic layer and extract the aqueous layer with methyl-r-butyl ether (2 * 100 mL). Combine the organic portions, dry over sodium sulfate, filter, and evaporate the 5 solvent. Purify by silica gel chromatography, eluiing with hexanes/ethyl acetate (2/1) to provide the title compound as a yellow solid (20.7 g, 88%). ES/MS m/z (35C1) 182 (M+l)+. - - - Preparation 3 10 7-(1-Propyl-bury!-2,5-dimelhyI-pyrazoIo[],5-a]pyrimidme Charge an oven dried flask equipped with a reflux condenser, with anhydrous THF (40 mL), iodine (catalytic amount), magnesium ribbon (1.92 g, 78.9 mmol) and 4-bromoheptane (9.4 mL, 52 mmol). Heat the reaction to reflux in an oil bath. The 15 temperature of the reaction spikes as the Grignard reaction is initiated. Stir the reaction an additional 4 h at 90 °C and cool to room temperature. Allow the magnesium meta] to settle out (can also be centrifuged) and canulate off the Grignard reagent under positive argon pressure into a flask charged with 7-chloro-2,5-dim,ethylpyrdzo]o [l,5-fl]pyrimidine (4.80 g, 26.3 mmol) in anhydrous toluene (20 mL). Reflux the reaction under an inert 20 atmosphere overnight. Cool the reaction to room temperature and quench with water. Dilute with ethyl acetate (150 mL), then add water (100 mL) and saturated ammonium chloride (50 mL). Separate and extract the aqueous phase with dichloromethane (75 mL). Combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue using flash 25 chromatography, eluting with 80% hexane/20% (20% ethyl acetate/hexane) to 0% hexane/100% (20% ethyl acetate/hexane) in a step gradient of 20% increments to give yellow crystals (3.08 g, 48%). ES/MS m/z 246.3 (M+l)*. Alternate Procedure: WO 2008/036579 PCT7US2007/078605 Heat a mixture of magnesium turnings (3.5 g, 144 mmol) and a catalytic amount of iodine (100 mg)in THF(I00 mL) to 65 °C under a nitrogen atmosphere. Add a few-drops of neat 4-bromorieptane and heat the mixture until the reaction starts. Then add a solution of 4-bromoheptane (17.6 mL, 94.9 mmol) inTHF(42 mL) keeping the 5 temperature at 65-70 °C over 2 h. Reflux the mixture for an additional hour and then cool the reaction to 22 °C. Add the prepared Grignard reagent to a solution of 7-chloro-2,5-dimethyl-pyrazolo[l,5-fi]pyrirmdine(l0.2 g; 53.3 mmol)inTHF (60 mL) cooled to 0 °C under a nitrogen atmosphere. Add the magnesium reagent solution via cannula over 45 min while keeping the temperature below 10 °C. Then stir the mixture for an 10 addilional 30 min at 5 °C. Add to Ihis mixture a 10% aqueous ammonium chloride solution (wt/wt)(]25 mL) and stir at 22 °C for 30 min. Separate the organic layer and extract the aqueous layer with ethyl acetate (2 x 25 mL). Combine the organic layers and dry over sodium sulfate. Filter the mixture and evaporate the solvent. Purify the crude material by silica gel flash chromatography using an elucnt of hexanes/ethyl acetate (5/1) 15 to provide the title compound (8 g, 62%). ES/MS m/z 246 (M+l)+. Preparation 3a 7-(l-Propyl-butyI)-2,5-dimethyl-pyrazolo[3,5-rt]pyrimidine Alternate Route Step 1: 3-Acetyl-3-oxo-4-propyl-heptanoic acid ethyl esrer 20 Add magnesium chloride (14.63 g, 153.70 mmol) to dichioromethane (500 mL) followed by addition of ethyl acetoacetate (19-55 mL, 20.00 g, 153.79 mmol) all at once and stir at room temperature for one hour. Cool 1hc mixture in an ice water bath and and add pyridine (24.86 mL, 24.32 g, 307.39 mmol) dropwise. Add di-w-propylacetyl chloride (25.00 g, 153.70 mmoles) dropwise at 0 °C under nitrogen to the white slurry. 25 After the addition is complete remove the cooling bath, warm to ambient temperature, and stir for 16 h. Quench the reaction with 1 N HC1 (400 mL) and separate the bottom layer. Dry the organic portion over magnesium sulfate, filter, and concentrate under vacuum to give a yellow oil (34 g, 86%). Use the material directly in the next step without further purification. 30 Step 2: 5-Propyl-octane-2,4-dione Dissolve 3-acetyl-3-oxo-4-propyl-hcptanoic acid ethyl ester (32.4 g, 126.39 mmoles) in dimethyl sulfoxide (100 mL) and water (5 mL). Heat the solution at 150 °C WO 2008/036579 PCTAJS2007/078605 for 6 to 8 h or follow the reaction by GC/MS. Cool the reaction and extract with heptane (3 * 100 mL). Wash the combined organic portions with water (100 mL) and brine(100 mL). Concentrate under vacuum at 50 °C to remove most of the heptane. Obtain 23.29g of an oil and use directly in the next step. 5 Step3: 7-(l-PropyI-butyI)-2,5-dimethyl-pyrazolo[],5-fl]pyrimidine Mix 5-propyl-octane-2,4-dione (15 g, 81.40 mmoles) in acetic acid (15 mL) and cool in an ice bath. Add 5-amino-3-mcthyIpyrazole (7.91 g, 81.40 mmoJ) ponionwise and stir at ambient temperature. Check for completion of the reaction by GC/MS after 3 h. GC indicates correct region isomer in comparison with an authentic sample. Distill off 10 the excess acetic acid. Add water (50 mL) and extract with heptane (50 mL). Wash the heptane with brine (50 mL). Dry the organic layer over MgSO4, filter, and concentrate under vacuum to give a crude oil (15.8 g, 79%). !H NMR (CDC13): 6.39 (s, 1H); 6.31 (s, 1H); 3.75 (m, 1H); 2.55 (s, 3H); 2.45 (s, 3H); 1.71 (q, 4H); 1.23 (m, 4H); 0.85 (t, 6H). 15 - Prepare the following compound essentially as described in Preparation 3, using either procedure. Use 3-bromopentane to prepare the Grignard reagent. Prep. No. Chemical name Physical data 4 7-(l-Ethyl-propyl)-2;5-dimethyl-pyrazolo[I,5-a]pyrimidine ES/MS m/z 218.1 (M+l)* Preparation 5 7-(l-Propyl-buryl)-3-iodo-2,5-dimethyl-pyrazoIo[l,5-fl]pyrimidine 20 Dissolve 7-(l-propyl-butyI)-2,5-dimethy]-pyrazolo[l,5-a]pyrimidine (3.08 g, 12.5 mmol) in anhydrous acetonitrile (25 mL) and add 6 portions (0.70 g each) of N-iodosuccinimide (4.2 g, 18.7 mmol) at 10 minute intervals. Stir over the weekend at room temperature. Strip off the acetonitrile and dilute the oil with dichloromcthane (100 mL). Wash with saturated ammonium chloride solution (2 * 50 mL). Collect the organic 25 phase, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to yield a dark red oil. Purify (he oil using flash chromatography, eluting with 100% hexane/0% (20% ethyl acetate/hexane) to 0% hexane/100% (20% ethyl acetate/hexane) in a step gradient of 50% increments to give an orange oil (10.97 g, 87%). WO 2008/036579 PCT/US2007/0 78605 'H NMR (400 MHz, CDC13): 6.42 (s, IH), 3.74-3.70 (m, IH), 2.58 (s, 3H), 2.46 (s, 3H), 1.74-1.68 (m, 4H), 1.28-1.14 (m, 4H), 0.84 {\,J= 7.0 Hz, 6H). Prepare the compound below essentially as described in Preparation 5. Prep. No. Chemical name Physical data " 6 7-(l-Ethyl-propyl)-3-iodo-2,5-dimethyI-pyrazolo[l,5-fl] pyrimidine IH NMR (400 MHz, CDCh): 6.44 (s, lH),3.59(m, IH), 2.61 (s,3H), 2.49 (s,3H), 1-86-1.76 (m,4H), 0.85 (W = 7-5 Hz, 6H). Alternate procedure for Preparation 6: Add acetic acid (1 mL) and N-iodosuccinimidc ( 6.7 g, 29.9 mmol) in one portion to a solution of 7-(l-ethyl-propyI)-2,5-dimethyl-pyrazolo[l,5-tf]pyrimidine (6 g, 27.5 mmol) in acetonitrile (60 mL). Stir the mixture at 22 °C for 2 h. Evaporate the solvent 10 and take the residue up in water (50 mL) and methylw-buty 1 ether (100 mL). Separate the organic portions, dry over sodium sulfate, Cher, arid evaporate the solvent to afford the title compound (9.2 g, 96%). ES/MS m/z 344 (M+l)+. Preparation 7 15 2-TrimcthyIsilanyl-thiazole Mix w-buryl lithium (20.4 mL, 51.0 mmol, 2.5 M in hexane) with diethyl ether (50 mL) in a three-necked flask, equipped with a dropping funnel and thermometer. Cool to -78 °C and add dropwise a solution of thiazolc (4.25 g, 50.0 mmol) in diethyl ether (50 mL). After the addition is complete, stir the reaction mixrure at -78 °C for 30 min, 20 followed by addition of chlorotrimethylsilane (5.4 g, 50 .0 mmol). Stir at -78 °C for an hour and then warm to room temperature. Quench the reaction by adding saturated sodium bicarbonate. Extract the aqueous layer with diethyl ether. Wash the combined organic portions with brine and dry over sodium sulfate. Filter and concentrate under reduced pressure to give a residue. Purify by distillation to give 8.33 g (52-56 °C/15 mm 25 Hg) of title compound. 1HNMR(400MHz,CDC]3)8.13 (d, IH, J=2.6 Hz), 7.54 (d, IH, .7=2.6 Hz), 0.43 (s,9H). WO 2008/036579 PCTAJS2007/078605 Preparation 8 5-Bromo-4~meihyIthiazole Add bromine (9.27 mL, 182 mmol)toa solution of 4-methylthiazole (15.0 g, 152 mmol) in acelic acid (30 mL) at 0 °C. Slowly warm the reaction mixture to room 5 temperature and stir overnight. Dilute with dichloromethane and wash with 1 N NaOH and brine. Dry the organic layer over sodium sulfate, filter, and concentrate under vacuum. - Purify the crude product by silica gel column chromatography, elueting with hexanes/ethyl acetate (5/1) to obtain the title compound (9.94 g, 37%). *H NMR (400 MHz, CDCU): 5 8.69 (s, 1H), 2.43 (s, 3H). 10 Preparation 9 ThiazoIe-2-carboxylic acid ethyl ester To a mixture of 2-trimethylsilyhhiazole (135 g, 858-1 mmol) in toluene (1350 mL) add a solution of cthy] chloroformate (98.4 mL, 1.03 mol) in toluene (1350 mL) over 15 min. Stir the reaction at 22 °C for 2 h. Add the solution over aqueous sodium 15 carbonate 25% (wt/wt) (5 L) and stir for 30 min. Separate the organic layer and re-cxtract the aqueous layer with methylene chloride (2 * 1 L). Combine the organic layers and evaporate the solvent to provide the title compound (134 g, 99%). ES/MS m/z 158 (M+l)+. 20 Preparation 10 Thiazole-2-carboxylic acid amide Add thiazole-2-carboxylic acid ethyl ester (150 g, 0.9 mol) to a mixture of methanol (75 mL) and 30% aqueous ammonium hydroxide (750 mL) and heat the mixture at reflux for 1 h. Then cool to 22 °C and evaporate the methanol under vacuum. 25 Stir the mixture for 30 min at room temperature and filter the solid. Dry the isolated solid under vacuum to afford the title compound (98 g, 85%). ES/MS m/z 129 (M+I)+. Preparation II l-Methyl-5-thiazol-2-yHH-[l,2,4]triazo1e 30 Cool 1,1-dimethoxy-N-dimcmyl-mcthanamine (240 mL) to 10 °C and add thiazole-2-carboxylic acid amide (60 g, 421 mmol) in three portions. Stir the mixture at WO 2008/036579 PCTMS2007/078605 10 °C for 30 min. Then heat the mixture gradually to reflux in 45 min. Distill off the methanol formed and then heat the reaction to 100°C for 1.5 h. Cool the mixture to 60 °C and remove the excess l,l-dimethoxy-N,N"dimethyl-methanamine by vacuum distillation. Cool the residue to 22 CC and add hexanes (200 mL). Triturate the mixture 5 for 15 min, filter, and dry the solid to constant weight before using in the next step. Add the solid isolated above (68 g) to aceiic acid (680 mL) and cool the mixture to 10 °C. Add A'-methyl-hydrazine (27 mL, 509 mmol) at such a rate as to keep the temperature below 15 °C. Warm the mixture to 20 °C in 30 min and then heat gradually to 90 °C. Stir at 90 °C for 30 min and then cool to 22 °C. Remove the acetic acid by 10 vacuum disiillalion. Add the residue over waier and adjust to pH = 8 by adding 25% aqueous sodium hydroxide solution. Extract the aqueous layer with mefhyl-r-butyl ether (3 * 600 mL). Combine the organic layers and evaporate the solvent. Purify the resulting residue by silica gel chromatography using an elucnt of hcxanes/isopropanol (9/1) to provide the title compound (49 g, 70%). ES/MS m/z 167 (M+l)4. 15 Preparation 12 5-(5-Bromo-thiazoI-2-yl)-!-meihyl-]H-[l,2,4]triazole To a mixture of mcthyl-thiazol-2-yl-lH-[1,2,3hriazolc (6.55 g; 39.4 mmol) and dimethylformamide(32 mL), addN-bromosuccinimide (14 g, 78.8 mmol) in three 20 portions over 1 h. Stir the mixture at 22 °C for 18 h and then add to water (300 mL) chilled to 0-5 °C. Separate the aqueous layer and extract with methyl-t-butyl ether (2 200 mL). Combine the organic layers and wash with 7% aqueous sodium hydrogen carbonate (100 mL) and then dry over sodium sulfate. Filter and evaporate the solvent to afford the title compound (9.5 g, 93%). ES/MS m/z (79Br/s,Br) 245/247 (M+I)~. 25 Preparation 13 2,5-DimethyI-3-[2-(2-methyl-2H-[],2,4]triazol-3-yl)-thiazol-5-yl]-7-(l-propyl-butyl> pyrazolo[l ,5-a]pyrimidine Combine 55-bromo-thiazol-2-yll-mcthyl-lH-[l,2,4]triazole (6.5 g, 23.8 mmol) 30 and 2,5-dimethyl-7-(l-propyl-butyl)-pyrazolo[l)5-a]pyrimidine (6 g, 24.5 mmol) in N-methylpyrrolidinone (58 mL) and stir to complete solution under nitrogen. Then add tctra-N-butylammonium bromide (5.47 g, 16.7 mmol) and potassium acetate (11.8 g, 1)9 WO 2008/036579 PCT/US2007/078605 mmol) and heat the mixture to 100 °C under a nitrogen atmosphere. Degas the hot mixture by three cycles of vacuum/nitrogen purge. Then add palladium acetate (216 mg, 0.94 mmol) and tris(2,4-dwe/l-butyl-pbenyl)-phosphane (787 mg, 1.2 mmol). Heat the mixture 4 h at 125 °C under nitrogen. Cool the mixture to 22 °C and add to water (750 5 mL). Extract the aqueous layer with methyl-f-butyl ether (3 * 200 mL), combine the organic portions, and evaporate. Purify the residue by filtration through a silica gel pad eluting with hexanes/ethyl acetate (4/1). Combine the product containing fractions and evaporate the solvent to afford the title compound (7 g, 72%). ES/MS m/z 410 (M+I)+. 10 Preparation 14 2,5-Dimethyl-7-(l -propyl-butyl)-3-thiazo]-5-yl-pyrazo]o[] ,5-a] pyrimidine Charge an oven dried flask with 2-trimethylsilanylthiazoIe (1.765 g, 11.24 mmol) dissolved in anhydrous THE (30 mL) and chill under an inert atmosphere to -78 °C. Slowly add n-butyl lithium (2.5 M hexane solution, 4.5 mL, 11.24 mmol) and stir 30 min 15 at -78 °C. Add anhydrous zinc chloride (2.26 g, 16.58 mmol) in one aliquot and stir 30 min at -78 °C. Allow the reaction to rise to room temperature, stir 30 min, and add 7-(l-propyl-butyl)-3-iodo-2,5-dimethyl-pyrazolo[l,5'a] pyrimidine (1.624 g, 5.18 mmol) and dichloro[l,r-bJs(diphenylphosphino) ferrocene] palladium (IT) dichloromethane (0.423 g, 0.518 mmol). Reflux overnight in an oil bath (90 °C) under an inert atmosphere. Cool 20 the reaction to room temperature, quench with saturated sodium bicarbonate, and dilute with ethyl acetate (150 mL). Separate and extract the aqueous with ethyl acetate (75 mL). Combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue using flash chromatography, eluting with 100% hexane/0% (30% THF/hexane) to 0% hexane/100% 25 (30% THF/hexane) in a step gradient of 10% increments to give a white solid (0.720 g, 42%). ES/MS m/z 329.0 (M+l)Prepare the compound below essentially as described in Preparation 14. WO 2008/036579 PCTAJS2007/078605 Alternate procedure for Preparation 15: Add n-butyl lithium (76.5 mL, 191 mmol, 2.5 M in hexanes) to a solution of 2-trirncthylsilylihiazofe (30 g, 191 mmol) in THF (450 mL) at -78 °C under nitrogen, 5 keeping the temperature below -74 °C during the addition. Stir the mixture at -78 °C for 30 min and then add zinc chloride, dry powder, (39.9 g, 286 mmol) in one portion and warm the mixture to 22 °C over one hour. Add 7-(l-ethyI-propyl)-3-iodo-2,5-dimethyl-pyrazolo[l,5-a]pyrimidine, (30 g, 87 mmol) and U'-bis(dipheny]phosphino)ferrocene palladium{H) chloride (6.5 g, 8 mmol) and heat the mixture to reflux under nitrogen for 8 10 h. Cool the mixture to 22 °C and add 10% aqueous ammonium chloride (450 mL). Separate the organic layer and wash the aqueous layer with methyl-J-buryl ether (2 * 100 mL). Combine the organic portions, dry over sodium sulfate, fitter, and evaporate the solvent to afford the title compound (20.4 g, 78%). ES/MS m/z 301 (M+l)~. 15 Preparation 16 7-(l-Ethyl-propy3)-3-(2-iodo-thiazo]-5-yl)-2,5"dimethyl-pyrazolo[l,5-a]pyrimidine Add a freshly prepared solution of lithium di-f-propylamidc (150 ml; 62.4 mmol, 0.6 M in THF) to a mixture of 7-(]-eihyl-propyl)-2,5-dimethyI-3-thiazoI-5-yl-pyrazolo[l,5-a]pyrimidine, (17.8 g, 62.4 mmol) in THF (100 mL) at -78 °C under a 20 nitrogen atmosphere, keeping the temperature below -74 °C during the addition. Stir the mixture at -78 °C for one hour and then add a solution of N-iodosuccinimide (15 g, 63 mmol) in THF (100 mL) keeping temperature below -74 °C. Warm the reaction gradually to 22 °C and then add a ]0% aqueous solution of ammonium chloride (300 mL). Separate the organic layer and wash the aqueous layer with methyf-/-buty] ether (2 25 * 200 mL). Combine the organic layers, dry over sodiurn sulfate, filter, and evaporate the WO 2008/036579 PCT/US2007/078605 solvent. Purify the resulting residue by silica gel chromatography, eluting with hexanes/acetone (5/1) to afford the title compound (15 g, 60%). ES/MS m/z 427 (M+I)Example 1 5 7-( 1 -Ethyl-propy])-2,5-dimethyl-3-(4-meihyl-thiazol-5-y l)-pyrazolo[ 1,5-a]pyrimidine AddRieke®zinc(10gin lOOmLofTHF, 13.2 mL, 18.48 mmol) to 5-bromo-4-meihylthiazole (2.13 g, 18.48 mmol) and heat-at reflux for2h: -Cool the mixture to room temperature and settle the zinc down by centrifuge. Bubble nitrogen gas through 7-(l-ethyl-propyl)'3-iodo-2,5-dimethyl-pyrdzolo[l,5-a]pyrimidine (900 mg, 2.62 mmol) in dry 10 letrahydrofuran (10 mL) and add the organozinc bromide solution followed by addition of [1 fr-bis(diphenylphosphino)ferrocene]-dichIoropalladium(n) (106 mg, 0.13 mmol). Stir the reaction mixture under reflux overnight and cool to room temperature. Add ammonium chloride solution to the reaction mixture and extract with dichloromethane. Dry the organic portion over sodium sulfate, filter, and remove the solvent under vacuum. 15 Purify the crude product by silica gel column chromatography, elueting with hexane/ethyl acetate (3/1) to obtain the title compound (652 mg, 79%). 'H NMR (400 MHz, CDC13): 8 8.80 (s, 1H), 6.48 (s, 1H), 3.63 (m, 1H), 2.57 (s, 3H), 2.43 (s, 3H), 2.40 (s, 3H), 1.85 (m, 4H), 0.90 (t, 6H, J= 7.3Hz). ES/MS m/z 315 (M+J)+. 20 Preparation 17 3-(2,4-dibromo-thiazol-5-yl)-2,5-dimethyI-7-(J-propyl-butyl)-pyrazolo[l,5-a] pyrimidine Dissolve 2,5-dimethyl-7-(l-propyI-bmyl)-3-thiazol-5-yl-pyrazolo[l,5-a] pyrimidine (3.15 g, 9.59 mmol) in acetonitrile (100 mL) and add N-bromosuccinimide (4.27 g, 24.0 mmol) in one aliquot. Stir overnight under an inert atmosphere and confirm 25 the reaction is compleie using TLC. Concentrate under reduced pressure, dilute the oil with dichloromcthanc (150 mL), and wash with water (75 mL). Dry the organic phase over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the resulting oil using flash chromatography, eluting with 100% hexane/0% (30% THF/hexane) to 0% hexane/100% (30% THF/hexane) in a step gradient (0-I0-15-2Q-25- 30 30-35-40-45-50-100% of 30% THF/hexane) to give yellow crystals (3.70 g, 79%). ES/MS m/z (79Br8,Br) 486.7 (M+l)f. WO 2008/036579 PCTAJS2007/078605 Prepare ihe compounds below essentially as described in Preparation 17, with the exception that dichloromethane is used as the solvent. 5 Example 4 3-(4-Bromo-2-morpholin-4-yl-thiazol-5-yl)-2,5-dimethyl-7-(l-propyl-butyl)-pyrazolo[I,5-a] pyrimidine Charge an oven dried flask with 3-(2,4-dibromoihiazol-5-yl)-2,5-dimethyl-7-(l-10 propyl-butyl)-pyrazo]o[I,5-a] pyrimidine (0.973 g, 2.00 mmol), anhydrous dioxane (20 mL), morpholine (0.872 g, 10.0 mmol), and cesium carbonate (1.95 g, 6.00 mmol). Reflux in an oil bath (105 °C) under an inert atmosphere overnight Confirm the reaction is complete using LC/MS. Dilute with ethyl acetate (100 mL), wash with water (50 mL), and back extract the aqueous with ethyl acetate (50 mL). Combine the organic phases, 15 dry over magnesium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue using flash chromatography, eluting with 100% hex.ane/0% (40% dichloromethane/20% ethyl acetate/2% 7 N ammonia in methanol/38% hexane) to 0% hexane/100% (40% dichloromethane/20% ethyl acetate/2% 7 N ammonia in mcthanol/38% hexane) in a step gradient of 10% increments to yield an off-white solid 20 (0.878 g, 89%). ES/MS m/z(79Br)49I.7(M+I)+. WO 2008/036579 PCT/US20O7/0786O5 Prepare the following examples essentially as described in Example 4, using as the amine either 2.0 dimethy[amine/THF or morpholine, and using THF or dioxane as the solvent. Run reactions in a sealed vessel or Schlenk tube. Ex. No. Chemical name Physical data 5* {4-Bromo-5-[2,5-dimethyl-7-(l-propy]-buty1)-pyra2olo[l,5-a]pyrimidin-3-yl]-thiazol-2-yl}-dimethylamine ES/MS (79Br) 449.8 (M+l)6 3-(4-Bromo-2-rnorpholin-4-yl-thiazol-5-yl)-7-(l- cthyl-propyl)-2,5-dimethyl-pyrazolo[I,5- a]pyrimidine MS (APCI) m/z (8,Br) 466.5 7 {4-Bromo-5-[7-(l-ethyl-propyl2,5-dimethyl-pyrazolo[l ,5-a]pyrimidin-3-yl]-thiazol-2-yl} -dimethyl-am ine MS (APCJ) m/z (81Br) 424.4 (M+l)+ 8 {5-[7-Cl'Ethyl-propyl)-2,5-dimethyI-pyrazolo[l,5- fl]pyrimidin-3-yl]-4-methyl-thiazol-2-yl}-dimethyl- amine ES/MS m/z 358 (M+l)+ 9 7-(l-Eihy]-propyl)-2,5-dimcthyl-3-(4-mclhyl-2- morphoIin-4-yl-thiazol-5-yl)-pyrazolo[l,5- a]pyrimidine ES/MS m/z 400 (M+l)+ Use 6 eq of cesium carbonate. Example 10 3-[4-Bromo-2-(2-methyI-2//-[l,2,4]triazoI-3-yl)-thiazol-5-yl]-2,5-dimethyl-7-(l-propyl-butyl)-pyrazolo[l ,5-Q]pymidine 10 WO 2008/036579 PCT/US2007/078605 Charge an oven dried flask with l-methyl-l,2,4-triazole (0.498, 6.00 mmol) and anhydrous THF (20 mL) and chill under an inert atmosphere to -78 °C. Slowly add n-butyl lithium (2.5 M hexane solution, 2.4 mL, 6.0 mmol) a"d stir 30 min. Add anhydrous zinc chloride (1.36 g, 10.0 mmol) in one aliquot and stir 10 min at -78 °C. Allow the 5 reaction lo warm to room temperature, stir 30 min, and add 3-(2,4-dibromothiazol-5-yI)-2,5-dimethyl-7-(]-propyl-bury])-pyrazolo[l,5-] pyrimidine (0.973 g, 2.00 mmol) and dichloro[l,]'-bis(diphenylphosphino) ferrocene] palladium (IT)dichloromethane (0.163 g, 0.200 mmol). Reflux the reaction overnight in an oil batt' (90 °C) under an inert atmosphere. Cool the reaction to room temperature, quetfeh with water, and dilute with 10 ethyl acetate (100 mL). Separate and extract the aqueous portion with dichloromethane (50 mL). Combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue using flash chromatography, eluting with 100% hexane/0% (10% ac^tonitrile/40% THF/50% hexane) to 0% hcxanc/100% (10% acctonitrilc/40% THF/50% hexane) in a step gradient of 10% 15 increments to give a white solid (0.090 g, 9%). ES/MS rp/z (79Br) 487.7 (M+l f. Alternate preparation: To a solution of 2,5-dimethyl-3-[2-(2-methyl-2rL[] ,2,4]iriazo!-3-yI)-thiazol-5-yl]-7-(l-propyl-butyiypyrazolo[l,5-a]pyrimidme (6 g, 14.65 mmol) in acetonimle (60 mL) add N-bromosuccinimide (2.74 g, 15.4 mmol) in one portion and slir at 22 °C for 10 h. 20 Evaporate the solvent and dissolve the residue in a mixture of water (50 mL) and methy]-/-butyl ether (100 mL). Separate the organic layer and extract the aqueous layer with additional rnethyW-butyl ether (2 * 50 mL). Combine the organic portions and evaporate the solvent. Purify the resulting material by filtration through a silica gel pad, eluting with hcxanes/cthyl acetate (3/1). Combine the product containing fractions and 25 evaporate the solvent. Add heptanes (25 mL) and triturate the solid. Filter the solid and dry under vacuum to afford the title compound (5.5 g, 77%)- ES/MS m/z ('W'Br) 488/490 (M+1 )Example 10a 3-[4-Bromo-2-(2-methyl-2-[l,2,4]triazol-3-ylthiazo!-5-yl]-2,5-dimethyl-7-(l-propyl- 30 butyl pyrazolo[1,5-o]pyrimidine, hydrochloride WO 2008/036579 PCT/US2007/078605 Dissolve 3-[4-bromo-2-(2-mcthyl-2H-[]f4]triazol-3-y])-thiazo]-5-yl]-2J5-dimethyl-7-(l-propyl-butyl)- pyrazolo[l,5-a]pyrimidine (750 mg, 1.54 mmol) in acetone (5 mL) and add 1 M HCI in diethyl ether (1.84 mL, 1.84 mmol). Stir the mixture at room 5 temperature for 3 h and concentrate in vacuo. Dissolve the residue in diethyl ether/hexane = 1/1 (5 mL) and crystallize the desired HCI salt (526 mg, 65%). ES/MS m/z (8IBr) 490 (M+l)*; -NMRtCDCh): 8.20 (s, 1H), 6.82 (s, 1H), 4.21 (s, 3H), 3.64 (m, 1H), 2.49 (m, 3H), 2.44 (s, 3H), 1.75 (m, 4H), 1.96(m, 4H), 0.81 ( m, 6H). 10 Prepare the following compound essentially as described in Example 10. Ex. No. Chemical name Physical data • 11 7-(LEthy!-propyl)-2,5-dimethy]-3-[4-methyl-2-(2-methyl-2H-[l,2,4]triazol-3-y])-miazol-5-yV]-pyrazolo[ 1,5-a]pyrimidine ES/MS m/z 396 (M+lf * Use 0.5 M zinc chloride in THF instead of anhydrous zinc chloride. Heat at 80 °C for 3 days. Example 12 15 3-(4-Bromo-2-(2-melhyl-2H-[I,2,4]triazol-3-yl)-thiazoL5-yl)-7-(l-ethyl-propyl)-2,5- dirrtethy!-pyrazolo[l,5-a]pyrimidine WO 2008/036579 PCmJS2WV7/©?8605 Under nitrogen atmosphere, add w-buiyl lithium (2.5 M in hexanc, 0.6 mL, 1.5 mmol) TO a solution of I-methyl-I,2,4-triazole (124.5 mg, 1.5 mmol) in THF (3 mL) at -78 °C and stir for 30 min. Add anhydrous zinc chloride (409 mg, 3.0 mmol), continue stirring for 30 min, warm up to room temperature and stir for 2 h. Add 3-(2,4-dibromo-5 thiazol-S-yOl-cthyl-propylH.S-dimethyl-pyrazolotl.S-flJpyrimidine (229 mg, 0.5 mmol), followed by tetrakis(triphenyIphosine)palladium (58 mg, 0.05 mmol) and reflux —overnight. Gool to room temperature, dilute with ethyl achate, and wash with saturated ammonia chloride. Dry the organic portion over sodium sulfate, filter, and concentrate to a residue. Purify the crude material by flash chromatography, eluting with hexanes:ethyl 10 acetate (10:2.5) to give the title compound as a yellow foam (77 mg). MS (APCI) m/z (79Br) 460.4 (M+l)*. Alternate preparation from Example 21: Add acetic acid (1 mL) and "N-bromosuccinimide (4.1 g, 22 mmol) to a solution of 7-(l-ethyl-propyl)-2J5-dimethyl-3-[2-(2-methy!-2H-[l,2]rriazol-3-yl)-thiazol-5-yl]-15 pyrazolo[ 1,5-a]pyrimidine (8 g, 21 mmol) in aceionitnle (80 mL). Stir the mixture 2 h at 22 °C. Then evaporate the solvent and add water (50 mL) and methyl-/-butyl ether (100 mL) to the resulting residue. Separate the organic portion dry over sodium sulfate, filter, and evaporate the solvent. Rccrystallize the resulting residue from isopropyl alcohol to afford the title compound (8.7 g, 90%). ES/MS (m/z): (Br/Br) 460/462 (M+l)\ 20 Example 12a 3'(4-BromO'2-(2-methyl-2H-[l,2,4]triazo]-3-ylVthiazG,]-5-y!)-7-(l-ethyl-propyl)-2T5-dimethyl-pyrazo!o[l,5-tf]pyrimidine,/Moluene sulfonic acid Dissolve 3-(4-bromo-2-(2-methyl-2H-[l,2,4]triazol-3-yl)-thiazo]-5-yl)-7-(]-ethyl-25 propyI)-2,5-dimethyl-pyrazolo[l,5-a]pyrimidine (50 mg, 0.109 mmol) in acetone (3 mL). Add a 0.25 M aqueous solution of p-toluene sulfonic acid, (434.4 uL, 0.109 mmol) and evaporate the resulting mixture to dryness. Add ethyl actuate (12 mL) to get partial dissolution of the solids. Add methanol (1 mL) to achieve a clear solution. Concentrate the solution by slow evaporation until crystals are observed. Isolate the crystals by 30 filtration and dry under vacuum at 25 °C to obtain about 50 mg of the title compound. Determine the stoichiometry of the salt by ion chromatography using the following HPLC conditions: column: PhenomenexPhenC)sphcre SAX, 4.6 x 150 mm at WO 2008/036579 PCTAJS2007/078605 30 °C; mobile phase: 50% acctoniirile/50% 0.025 M sodium phosphate buffer at pH = 4.5; flow rate = 1.5 mL/min; detection: UV at 205 nm; injection volume = 5 ^L; run time = 3 min. Theoretical amount calc: 27.2% tosylate; found: 28.4% tosylate (average of three HPLC runs). 5 Example 13 {4-Chloro-5-[2,5-dimethyl-7-(l-propyl-butyl)-pyrazolo[l,5-a] pyrimidin-3-yl]-thiazol-2- ylj-dimelhylamine Charge an oven dried flask with {4-bromo-5-[2,5-dimethyl-7-(l-propyl-butyl)- 10 pyrazolo[l,5-a] pyrimidin-3-yl]-thiazol-2-yl-dimethylamine (0.20,0.44 mmol) and anhydrous THF (3.0 mL) and chill under an inert atmosphere to -78°C. Slowly add n-butyl lithium (1.6 M hcxane solution, 0.42 mL, 0.67 mmol) and stir 30 min. Add N-chlorosuccinimide (0.120 g, 0.889 mmol) in one aliquot and stir 30 min at -78 °C. Allow the reaction to warm to room temperature, and stir for 5 h, checking the progress using 15 LC/MS. Dilute with ethyl acetate (100 mL), wash with saturated ammonium chloride (50 mL), and back-extract the aqueous with dichloromethane (50 mL). Combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue using flash chromatography, eluting with 100% hexane/0% (25% THF/hexane) to 0% hexane/100% (25% THF/hexane) in a step gradient 20 of 10% increments to give a white solid (0.087 g, 48%). ES/MS m/z (35CI) 406.0 (M+l)+. Prepare the following examples essentially as described in Example 13 using the appropriate bromothiazole prepaied above. Ex. No. Chemical name Physical data 14 3-(4-Chloro-2-morpholin^-yl-thiazoI-5-yl)-2,5- dimethyI-7-(l-propyl-butyl)-pyrazolo[I,5-a] pyrimidine ES/MS m/z (5SC1) 448.0 (M+l)+ 15 {4-Chloro-5-[7-(I-ethyl-propyi)-2,5-dimethyl-pyrazolofl ,5-2]pyrirmdin-3-yl]-tbiazol-2-y]} -dimethyl-amine MS (APCI) m/z (35C1) 378.0 (M+])+ 25 Preparation 18 WO 2008/036579 PCT/US2007/078605 2,4-dichloroihiazoIe Cool to 5 °C a mixture of thiazolidine-2,4-dione (50 g, 0.43 mol) in phosphorus oxychloride (240 mL) and add pyridine (34 mL, 0.43 mol) over 15 min. Heat ihe mixture to 325 °C for 4 h and then cool to 22 °C. Remove the excess phosphorus oxychloride by 5 vacuum distillation and add the residue to water (1 L) chilled to a temperature of 5 °C. Extract the mixture with methylene chloride (3 x 400 mL). Combine the organic portions and evaporate the solvent to afford the title compound (50 g, 76%). EI/MS m/z : (35CI35C1/3SC137C1/37C137CI) 153/155/157 (M+l)*. 10 Preparation 19 4-chloro-2-morpholino-thiazole To a mixture of 2,4-dichlorothiazole (34 g, 0.22 mol) in acetonitrile (425 mL) add potassium carbonate (60.9 g, 0.44 mo!) and then morpholine (21.2 mL, 0.225 mol) dropwise over 30 min. Reflux the mixture at 40 °C and then cool to 22 °C Filter the 15 mixture and evaporate the filtrate. Triturate the residue with /-propyl alcohol (60 mL) at 22 °C for one hour. Filter the solids and dry under vacuum to a constant weight to afford the title compound (34.5 g, 76%). ES/MS m/z(55Cl) 205 (M+l)4. Example 16 20 3-(4-Chloro-2-morphol"m-4-yl-thiazoU5-yl)-7-(l-ethyl-propyl)-2,5-dimcthyl- pyrazolo[l ,5-a]pyrimidine Under a nitrogen atmosphere dissolve 3-(4-bromo-2-rnorpholin-4-yl-thiazol-5-yl)-7-(]-cthyl-propyl)-2,5-dimethyl-pyrazolo[l,5-ff]pyrimidine (116 mg, 0.25 mmol) in THF 25 (1.5 mL) and chill to -78 °C. Add n-butyllithium(0.1 mL. 2.5 M in hexane, 0.25 mmol) and stir at -78 °C for 30 min. Add N-chlorosuccinimide (33.4 mg, 0.25 mmol) and stir WO 2008/036579 PCT/US2007/078605 for another 30 min, slowly warming to room temperature.. After stirring overnight, quench the reaction by adding a solution of saturated ammonia chloride and extract with ethyl acetate. Wash the organic layer with brine, dry over sodium sulfate, filter, and concentrate to a residue. Purify the crude materia] by flash chromatography, ehiting with 5 hexanes:dichloromethane:ethyl acetate (5:5:2) to provide the title compound (54 mg). MS (APCI) m/z (35C1) 420.6 (M+l)+; 'H NMR (400 MHz, CDC13): 6.44 (s, 1H), 3.79 (t, -4H»4.8 Hz), 3.63-3.56 (m, lH),-3.47 (t, 4H, .7=4.8 Hz), 2.55 (s, 3H), 2.45 (s, 3H), 1.88-1.75 (m, 4H), 0.87 (t, 6H, .7=7.5 Hz). Alternate Preparation from Preparation 6: 10 Combine 7-(l-ethyl-propyl)-3-iodo-2,5-dimethyUpyrazolo[l,5-^]pyrimidine, (9 g, 26.2 mmol) and 4-chloro-2-morpho!ino-thiazole(7.5 g, 36.7 mmol) in dimethylformamide (90 mL) previously degassed with nitrogen. Add cesium carbonate (17.8 g, 55 mmol), copper iodide (250 mg, ] .31 mmol), iriphenylphosphinc (550 mg, 2.09 mmol) and palladium acetate (117 mg, 0.52 mmol). Heaj the mixture to 125 °C for 16 h 15 and then cool to 22 °C. Add water (900 mL) and extract with methyl-i-butyl ether (3 * 200 mL). Combine the organic portions and evaporate the solvent. Purify by silica gel chromatography eluting with hexanes/cthyl acetate (4/1) 10 afford the title compound (6.4 g,62%). ES/MSm/z(35CI)420(M+l)+. 20 Example 16a 3-(4-Chloro-2-morpholin-4-y]-thiazol-5-yl)-7-(I-^thyl-propyl)-2,5-dimethyl-pyrazolo[l ,5-a]pyrimidine, hydrochloride 25 Dissolve 3-(4-chloro-2-morphoIin-4-yl-thiazol-5-.yj)-7_(i-ethy]-propy])-2,5- dimethyl-pyrazolo[lf5-a]pyrimidine (1.40 g, 3.33 mmol) in acetone (10 mL) at 50 °C and cool to room temperature. Add hydrogen chloride (2 M in diethyl ether, 2.0 mL, 4.0 mmol) and stir well in a sonicator. Concentrate the solution a little and add a minimal amount of diethyl ether to crystallize the HC1 salt. Cool the mixture in a refrigerator 30 overnight. Add additional hydrogen chloride (2 M in diethyl ether, 2.0 mL, 4.0 mmol) and cool in a refrigerator. Filter the crystalline material and dry to obtain the title compound (1.15 g, 75%). ES/MS m/z (35C1) 420 (M+l)+; 'a NMR(CDCB): 9.18 (br, WO 2008/036579 PCT/US2007/078605 1H), 6.86 (s, 1H), 3.72 (m, 4H), 3.49(m, 1H), 3.39 (m, 4H), 2.48 (s, 3H), 2.38(s, 3H), 1.79 (m,4H), 0.79 (m,6H). Example 17 5 3-(4-Bromo-2-butyMhiazol-5-yl)-7-(l-ethyl-propyI2>5-dimethyl-pyrazolo[l,5- fljpyrimidine Under a nitrogen atmosphere, add n-butyl lithium (2.5 M in hexane, 0.2 mL, 0.5 mmol) to a solution of 3-(2,4-dibromo-thiazol-5-yl7-(l-ethyl-propyl2,5-dimethyl-pyrazolo[l,5-fl]pyrimidine (230 mg, 0.5 mmol) in THF(3 mL) at-78 °C. After 30 min, 10 add 1-iodobutane (138 mg, 0.75 mmol) and continue stirring for 1 hour. Warm up to room temperature and stir for one hour. Quench the reaction by adding saturated ammonia chloride solution and extract with ethyl acetate. Dry the organic portion over sodium sulfate, filter, and concentrate to a residue. Purify the crude material by flash chromatography, eluting wiih hexanes/ethyl acetate (10/1.5) to give the title compound as 15 orange foam (78 mg). ES/MS m/z (81Br) 437.4 (M+l)+. Prepare the following example essentially as described in Example 17. Ex. No. Chemical name Physical data 18 3-(4-Bromo-2-melhoxymethyl-thiazol-5-yl)-7-(l- cthy]-propyl)-2,5-dimcthyl-pyrazolo[l,5- a]pyrimidine MS (A PCI) m/z(8,Br) 424.6 (M+l)+ Example 19 20 7-(l-Ethyl-propyl)-3-(2-methoxymethyl-thia20]-5-yl)-2,5-dimethyl-pyrazolo[l,5- a]pyrimidine Under a nitrogen atmosphere, add n-butyl lithium (2.5 M in hexane, 0.4 mL, 1.0 mmol) to a solution of 7-(l-ethyl-propyl)-2,5-dimethyl-3-thiazol-5-yl-pyrazolo[l,5-a]pyrimidine(300 mg, 1.0 mmol) in THF (3 mL)at-78°C. Stir 30 min and add 1-25 iodomethyl methyl ether (205 mg, 1.2 mmol). Continue stirring for one hour and Ihen slowly warm up to room temperature and stir overnight. Quench the reaction by adding saturated ammonium chloride solution and extract with ethyl acetate. Wash the organic layer with brine, dry over sodium sulfate, filter, and concentrate under vacuum to a WO 2008/036579 PCT/US2007/078605 residue. Purify the crude material by flash chromatography, eluting with hexanes/ethyl acetate (10/2) to give the title compound as a yellow foam (184 mg), MS (APCI) m/z 345.3 (M+l)5 Example 20 3-(4-Chloro-2-meihoxymethyl-thiazol-5-yl)-7-(l-ethyl-propyl)-2,5-dimethyl- - - - - - pyrazolo[l,5-a]pyrimidine Add fl-buryl lithium (2.5 M in hexanes, 174 mL, 0.43 mmol) to a stirred solution of7-(l-ethyl-propyl)-3-(2-meilioxymethyl-thiazol-5-yl)-2,5-dimethyl-pyrd2oIotl>5-10 a]pyrimidine (150 mg, 0.43 mmol) in THF (3 mL) at -78 °C. Stir for 30 min and add N-chlorosuccinirnide (87 mg, 0.653 mmol). Stir 30 min and then warm the reaction slowly to room temperature allowing the reaction to continue overnight. Quench the reaction by adding saturated ammonium chloride solution, extract with ethyl acetate, dry over sodium sulfate, filter, and concentrate to a residue. Purify by flash chromatography, eluting with 15 hexanes/ethyl acetate (10/2) to give the title compound (7 mg). MS (APCI) m/z (35C1) 379.3 (M+l)Example 21 7-(]-Ethyl-propyl)-2,5-dimethyl-3-[2-(2-methyl-2H-[l,2,4]triazol-3-yl)-thiazol-5-yl> 20 pyrazolo[l ,5-ojpyrimidine Mix3-(4-bromo-2-(2-methyl-2H-[l,2,4]triazol-3-yl)-thiazol-5-yI)-7-(l-ethyI-propyl)-2,5-dimethyl-pyrazoIo[l,5-a]pyrimidine (175 mg, 0.38 mmol) and copper(I) chloride (132 mg, 1.33 mmol) in DMF (5 mL) and heat to 120 DC for 24 h. Cool to room temperature, dilute with ethyl acetate, and wash with brine. Dry the organic layer over 25 sodium sulfate, filter, and concentrate under vacuum to a residue. Purify by flash chromatography, eluting with hexanes and then hexanes/EtOAc (10/1.8) to give a yellow-orange solid (45 mg). ES/MS m/z 382.0 (M+l)\ Alternate Preparation: Add »-butyl lithium (2.5 M in hexanes, 57.6 mL, 144 mmol) to a solution of N-30 methyltriazole (11.95 g, 144 mmol) in THF (600 mL) at -78 °C under a nitrogen atmosphere, keeping the temperature below -74 °C during the addition. Then add zinc chloride, dry powder, (26 g, 192 mmol) in one portion and warm the mixture to 22 °C in WO 2008/036579 PCT/US2007/0 78605 one hour. Add 7"(l-ethyl-propyt)-3-(2-iodo-thiazol-5-yl)-2,5-dimethyl-pyra2;olo[l,5-tf]pyrimidine(I2.5 g, 29 mmol) and tetrakis(triphenyl)phosphine palladium catalyst (1.15 g, 0.01 mol) in one portion and heat the mixture 10 reflux under nitrogen for 8 h. Cool the mixture to 22 °C and add water (300 mL). Separate the organic layer and extract the 5 aqueous layer with methyW-butyl ether (2 x 200 mL). Combine the organic portions, dry over sodium sulfate, filter, and evaporate the solvent. Purify by passing over a silica gel pad eluting with hexanes/ethyl acetate (4/1) to afford the title compound (8 g, 72%). ES/MS m/z 382 (M+l)+. Example 22 10 3-(4-Chloro-2-(2-methy]-2H-[ 1,2,4]triazol-3-ylthiazot-5-yi)-7-0 -ethyl-propyl)-2,5- dimethyl-pyrazolo[l,5-a]pyrimidine Stir a mixture of 7-(l-ethyl-propyl)-2,5-dimethyl-3-[2-(2-methyl-2H-[1,2)4]triazol-3-yl)-thia2ol-5-yl)-pyrazolo[l)5-a]pyrimidine (20 mg, 0.052 mmol) and N-chlorosuccinimide (7.6 mg, 0.0569 mmol) in dichloromefhane (0.5 mL) and acetonitrile !5 (0.5 mL) at room temperature overnight in a vial. Concentrate to a residue. Purify by flash chromatography, eluting with hexanes and then with hexanes/ethyl acetate (10/1.5) to give the title compound (16 mg). ES/MS m/z (35C1) 416.0 (M+l)Example 23 20 7-(l-Ethyl-propyl)-3-(4-methoxy-2-morpholin-4-yl-thiazol-5-yl)- 2,5-dimethyl- pyrazolo[l,5-a]pyrimidine Stir a mixture of 3-(4-bromo-2-morpholin-4-yl-thiazol-5-yl)-7-(l-ethyl-propyl)-2,5-dimethyl-pyrazolo[I,5-a]pyrimidine(162 mg, 0.35 mmol), sodium methoxide (57 mg, 1.05 mmol) and copper(I) iodide (67 mg, 0.35 mmol) in methanol (3 mL) in a sealed 25 4-mL vial for 15 hat 120°C. Cool to room temperature, remove the solid by filtration, and concentrate the filtrate under vacuum. Purify (he residue by flash chromatography, eluting with hexanes/THF (10/2). Recrystallize the material from methanol to give the title compound (20 mg). ES/MS m/z 416.0 (M+1)+. 30 Preparation 20 4-BromO'5-[7-(l-ethyl-propyl)- 2,5-dimethyl-pyrazolo[l,5-a]pyrimidin-3-yl]-thia2ole-2- carbaldehydc WO 2008/036519 PCTA3S2007/078605 Under a nitrogen atmosphere, add w-butyl lithium (1.6 M in hexanes, 0.312 mL, 0.50 mmol) to a THF solution (2.5 mL) of 3-(2,4-dibromo-thiazol-5-yl)-7-( 1 -ethyl-propy])-2,5-dimemyI-pyrazo!o[ 1,5-a]pyrimidine (230 mg, 0.50 mmol) at -78 °C and stir for 30 min. Add a THF (0.5 mL) solution of N-formyl morpholine (58 mg, 0.50 mmol). 5 Stir for one hour, then store the reaction at -20 °C overnight Warm the reaction to room temperature, dilute with ether, and quench by adding 4 N HC1 (4 mL). Separate and extract the organic phase with 4-N HC1 (2 x 4 mL): Combine the aqueous portions, treat with solid sodium bicarbonate to pH = 8 to 9 and then extract with diethyl ether. Combine all the organic layers, wash with brine, dry over sodium sulfate, filter, and 10 concentrate to a residue. Purify the crude material by flash chromatography, eluting with hexanes/dichloromethane/ethyl acetate (5/5/1) to give the title compound (154 mg). MS (APCI) m/z (81Br) 409.0 (M+lf. 15 Example 24 3-(4'Bromo-2-morpholin-4-yl-methyl-thiazol-5-yl)-7-(l-ethyl-propyl)-2,5-dimethyl- pyrazolo[l ,5-fl]pyrimidine Combine 4-bromo-5-[7-(Lethyl-propyl)- 2,5-dimethyl-pyrazolo[l,5-a]pyrimidin-20 3-yl]-thia2ole-2-carbaldehyde (150 mg, 0.368 mmol), morpholine (35 mg, 0.405 mmol) and sodium triacetoxyborohydride (97 mg, 0.46 mmol), in dichloromethane (3 mL) and meihanol (0.5 mL). Stir overnight, add additional morpholine (35 mg, 0.405 mmol), and sodium triacetoxyborohydride (97 mg, 0.46 mmol), and stir 4 h more. Remove the solvent under vacuum, dilute with dichloromethane, and wash with brine. Dry the 25 organic phase over sodium sulfate, filter, and concentrate under vacuum. Purify the resulting material using flash chromatography, eluting with dichloromethane:2 M ammonia in methanol (10:1) to give a mixture. Purify the mixture using a reverse phase column, eluting with water/acetonitrile (80/20) to water/acetonitrile (10/90) to give the title compound (20 mg). ES/MS m/z (8lBr) 480.0 (M+l)+. 30 Example 25 WO 2008/036579 PCTAJS2 007/0 78605 3-(4-Bromo-2-pyridin-4-y]-thia2ol'5-yl)-7-(l-ethyl-propyl)-2,5-dimethyI-pyrazo]o[lI5- a]pyrimidine Under a nitrogen atmosphere, add n-butyl lithium (1.6 M in hexane, 0.312 mL, 0.5 mmol) to a solution of 3-(2,4-dibromo-thiazol-5-yI)-7-(l-ethy]-propyl)-2,5-dimethyl-5 pyrazolo[ 1,5-a]pyrimidine (229 mg, 0.5 mmol) in THF (4 mL) at -78 °C. After stirring for 30 min, add anhydrous zinc chloride (264 mg, 1.5 mmol) and continue stirring for 30 miti. Warm the reaction to room temperature and stir for one hour. Add 4-iodopyridine (103 mg, 0.5 mmol), followed by l.l'-bis (diphenylphosphino)fenrocene palladium (II) chloride (dichloTomethane adduct) (0.40.8 mg, 0.05 mmol). Heat the reaction to reflux 10 overnight. Cool to room temperature, dilule with ethyl acelate, and wash with water and brine. Dry the organic layer over sodium sulfate, filter, and concentrate to a residue. Purify the crude material by flash chromatography, eluting with dichloromethane:2 N ammonia in methanol (10:0.75) to give a mixture. Purify the mixture using a reverse phase column, eluting with water:acetonitrile = 80:20 to water: acetonitrile = 10:90, to 15 give the title compound (19 mg). ES/MS m/z (79Br) 456.0 (M+1)+. Preparation 21 4-Trifluoromcthyl-thiazo]e-2-ylamine Add thiourea (4.0 g, 52.3 mmol) and 3-bromo-l,l,l-trifluoropropan-2-one (5.5 20 mL, 10 g, 52.3 mmol) to ethanol (100 mL) and heat at 50 °C for 2 h. Cool to room temperature and concentrate to dryness. Dissolve the residue in water and adjust the pH to>12 with 2 M NaOH. Extract with diethyl ether (4*). Dry the combined organic extracts with sodium sulfate, filler, and concentrate under vacuum. Purify the resulting material by silica gel chromatography (CHJCIJ) to obtain the title compound (6.9 g, 79%). 25 ES/MS m/z 169 (M+ If. Preparation 22 5-BTomo-4-trifluoromethyl-thia2ol-2-ylamine, hydrobromide Add bromine (2.0 mL, 6.28 g, 39.3 mmol) dropwise to an ice-bath cooled solution 30 of 4-trifluoromethyl-thiazole-2-ylamine (6.0 g, 35.7 mmol) in diethyl ether (60 mL). Stir for one hour after the addition is complete and then warm to room temperature. Collect WO 2008/036579 PCT/US2007/018605 the solids by filtration and wash with diethyl ether to obtain the title compound (10.5 g, 90%). ES/MS m/z (7WBr) 247/249 (M+1)Preparation 23 5 5-Bromo-2-(2,5-dimethyl-pyrrol-I-yl)-4-trifluoromethyl-thiazole Add hexane-2,5-dione (3.5 mL, 3.4 g, 30.2 mmol) to a solution of 5-bromo-4-• trifluoromethyI-thiazol-2-ylamine hydrobromide (9.0 g, 27.4 mmol)-in-methanol (60 mL). Stir at room temperature overnight. Add phosphate buffer (50 mLf pH = 7). Collect the resulting precipitate by filtration, washing with water. Dissolve the filter cake in CH3CI2 10 and dry over sodium sulfate. Filter and concentrate under vacuum to obtain the title compound (8.2 g, 92%). 'H NMR (400 MHz, CDC13) 5 5.91 (s, 2H), 2.27 (s, 6H). Example 26 3"(2-(2J5-Dimethyl-pyrrol-l-yI)-4-trifluoromethyl-thiazol-5-yl]-7-(l-cihyl-propyl>2J5- 15 di methyl-pyrazolo[l ,5-a]pyrimidine Cool a solution of 5-bromo-2-(2,5-dimclhyl-pyrrol-]-yl)-4-trifluoromethyl-thiazo!c(2.2 g, 6.6 mmol) in THF (25 mL) in a dry ice bath. Add/-butyl lithium (1.7 M in pentanc, 8.5 mL, 14.5 mmol) dropwise. Stir for 45 min and then add zinc chloride (0.5 20 M in THF, 14.6 mL, 7.3 mmol) dropwise. Slir 5 min and remove the cooling bath. Stir 30 min and then add 7-(l-ethyl-propyl)-3-iodo-2,5-dimethyl-pyrazolo[l!5-fl]pyrimidine (1.5 g, 4.4 mmol) and bis(tri-/-butylphosphine)palladium (0) (450 mg, 0.9 mmol). Reflux for 24 h. Cool (he reaction, pour the mixture into diethyl ether, and wash with water (2*). Extract the combined water layers with diethyl ether. Dry the combined organic portions 25 over sodium sulfate, filter, and concentrate to dryness under vacuum. Purify the resulting residue by silica gel chromatography (75-100% CH2CI2 in hexanes) to give the title WO 2008/036579 PCT/US2007/078605 compound (].47 g, 72%). HR-ToF-MS m/zcalcd forC23H2&F3N5S+H': 462.1939, found: 462.1915. Example 27 5 5-{7-(l-Ethyl-propyl)-2,5-dimethyl-pyra2olo[l,5-a]pyrjmidin-3-yl]-4-trifluoromethyl- thiazol-2-ylamine Add hydroxylamine (2 mL;- 50% in water) to a solution of 3-[2-(2,5-dimethyI-pyrrol-l-yt)-4-trifluoromethyl-thiazol-5-yl]-7-(l-ethyl-propyl)-2,5-dimethyl-pyra2olo[l,5-a]pyrimidine (1.1 g, 2.3 mmol) in acetic acid (10 mL). Heat the reaction to 10 80 °C for 6 h. Cool to room temperature. Pour into diethyl ether and wash with 2 M NaOH (2*) and then once with water. Dry the organic portion over sodium sulfate, filter, and concentrate to dryness under vacuum. Purify the resulling residue by silica gel chromatography (40% ethyl acetate in hcxancs) to give the title compound (0.76 g, 87%). ES/MSm/z384(M+l)+. 15 Preparation 24 3'(2-Bromo-4-trifluoromcthyl-thiazol-5-yl)-7-(l-cihyl-propyl)'2,5-dimcthy]-pyrazolo[l ,5-«]pyrimidine 20 Heat a mixture of copper(Il) bromide (540 mg, 2,4 mmoi) and f-butylnitrite (0.36 mL, 310 mg, 3.0 mmol) in acetonitrile (20 mL) to 60 °C. Add 5-[7-(l-ethyl-propyl)-2,5-dimclhyl-pyrazoio[l,5-a]pyrimidin-3-yl]-4-trifluorome%l-\hia2ol-2-ylamme(755mg, 2.0 mmol) as a solid. Heat the reaction to 80 °C for 2 h. Cool the reaction, pour into diethyl ether and extract with water (3 *). Dry the organic layer over sodium sulfate, 25 filter, and concentrate to dryness under vacuum. Purify (he resulting residue by silica gel chromatography in CH2Cl2 to give the litle compound (0.77 g, 87%). ES/MS m/z ('WBr) 447, 449 (M-Hf. Example 28 30 {5-[7-(LEthyl-propyl)-2,5-dimethy]-pyrazolo[],5-a]pyrimidin-3-yl]-4-trinuoromethyl- thiazol-2-yl}-dimethyl-arrtine 'O 2008/036579 PCT/US2007/078605 Heat a sealed tube containing 3-(2-bromo-4-triflUoromethyI-thiazol-5-yl)-7-(l-ethyl-propy))-2,5-dimethyl-pyrazo1o[l,5- Prepare the following example essentially as described for Example 28 with the exception that the reaction is refluxed for 8 h. Ex. No. Chemical name Physical data 29 7 (l-Ethyl-propyl)-215-dimethyl-3-(2-mQrpholin-4-y 1-4- trifluoramethy 1-th iazol-5-yl)-pyrazalo[ l,5-a]pymnidme HR-ToF-MS m/z calcd forC2iH26F3N5OS+H+: 454.1873, found: 454.1888 10 Example 30 Af-{5-[7-(I-EthyI-propyl)-2,5-dimethyl-pyrazolo[l,5-a]pyrimidin-3-yl]-4-trifluoromethyl- 15 thiazol-2-y]}-aceiamide Add hydroxylamine (50% in water, 5 mL,) to a solution of 3-[2-(2,5-dimethyl-pyrrol-1 -yl)-4-trifluoromethyl-thiazol-5-yl]-7-(l -ethyl-propyl2,5-dirnethyl-pyrazolo[l,5-rt]pyrimidine (2.4 g, 5.2 mmol) in acetic acid (25 mL). Heat the reaction to 80 °C for 72 h. Cool the reaction to room temperature, pour into diethyl ether and wash 20 with 2 M NaOH (2*) and then once with water. Dry the organic portion over sodium sulfate, filter, and concentrate to dryness. Purify the resulting residue by column chromatography, ehiting with 40% ethyl acetate in hexanes to give the title compound (0.28 g, 13%). HR-ToF-MS m/z calcd for C,9H22F3N5OS+H* 426.1575, found: 426.1565. 25 Example 31 WO 2008/036579 PCTAJS2007/078605 (2-{5-[7-(I-Ethyl-propyl)-2,5-dimethyl-pyra2olo[l,5-a]pyrimidin-3-yl]-4-trifluoromethyl-thiazol-2-ylamtno}-ethyl)-carbamic acid tert-buvy] ester Add (2-aminO'ethyl)-carbamic acid leri-buty 1 ester (0.5 mL, 506 mg, 3,2 mmol) to 5 a solution of 3-(2-bromo-4-trifluoromethyl-thia2ol-5-yl)-7-(I-ethyl-propyl)-2,5-dime1hyl-pyrazolo[l,5-a]pyrimidine (100 mg, 0.22 mmoi) and tricthylamine (0.3 mL, 222 mg, 2.2 mmol) in methanol (1 mL). Evaporate off (he methanol and heat to 80 °C overnight. Cool the reaction to room temperature and concentrate under vacuum. Purify the resulting residue by column chromatography, eluting with 10-50% elhyl acetate in 10 CH2C\2, to give the title compound (0.11 g, 97%). ES/MS m/z 527.2 (M+I)+- Prepare the compounds below as essentially described in Example 31 using the appropriate amine. Prep, or Ex. No. Chemical name Physical data Prep. 25* [2-({5-[7-(l-ethyl-propyl)-2,5-dimethyl-pyrazo]o[l,5-fl]pyrimidin-3-yI]-4-trifluoromethyl-thiazo]-2-yl}-propyl-arnino)-ethyl]-carbamic acid tert-butyl ester ES/MS m/z 569.3 (M+lf Prep. 26** (S)-(l-{5-[7-(I-ethyl-propyl)-2,5-dimethyI-pyrazolo[lJ5-a]pyrimidin-3-yl]-4-irifluoromethyl-thiazol-2-yl}-pyrrolidin-3-ylcarbamic acid tert-butyl ester ES/MS m/z 553.3 (M+l)+ WO 2008;036579 PCTAJS2007/078605 Ex.32'" N-{ 5-[7-( 1 -Ethyl-propyl2)5-dimethyl-pyrazolo[ 1,5-tf ]pyrimidi^-3-yl]-4-t^if1uoromethyl-tr]iazol-2-y]}-/V,A'-d^p^opyI-eIhane-l,2-diamie) hydrochloride ES/MS m/z 511.2(M+iy Heal at reflux in EtOH overnight. Evaporate EiOH and heat at 110 °C for 24 h. " Heat at 80 °C in EtOH overnight. "* Make the HCl salt and recrystaflize from EtOAc/hexanes. 5 Example 33 A',-{5-[7-(l-Ethyl-propyl)-2J5-dimethyl-pyrazolo[lJ5-a]pyrimidin-3-yl]-4- miluoromethyl-ihia2ol-2-yl}-ethane-V,2-diamine, hydrochloride Add (2-{5-[7-(l-ethyl-propyl)-2>5-dimethyl-pyrazolo[l,5-£r]pyrimidin-3-yl]-4-trifluoromethyl-thiazo!-2-ylamino}-ethyl)-carbamic acid /er/-buryl ester (101 mg, 0.192 10 mmol) to 1 M HCl in methanol (I mL). Heat the reaction at 70 °C overnight. Cool the reaction and concentrate under vacuum from meihanol/ethyl acetate. Triturate the resulting residue with ethyl acetate to obtain the title compound (64 mg, 78%). ES/MS m/z 427.0 (M+l)+. 15 Prepare the following examples essentially as described for Example 33. Ex. No. Chemical name Physical data 34 A/l-{5-[7-(l-Ethyl-propyl)-2,5-dimethyl-pyrazolo[l,5-a]pyrimidm-3-yl]-4-triftuoromcthyl-thia£ol-2-yl}- propyl-ethane-l,2-diamine, hydrochloride ES/MS m/z 469.2 (M+l)4 35 (51 - {5-[7-( 1 -Ethy]-propyl)-2,5-dimethyl-pyrazolo[l,5-a]pyrimidin-3-yl]-4-trifluoromemyl-thiazol-2-y!}-pyrrolidin-3-yIamine, hydrochloride ES/MS m/z 453.0 (M-H)+ Example A In Vivo Potency Assessment Using Ex Vivo Binding To assess in vivo polency, a compound of the present invention is evaluated using 20 ex vivo binding. Using the procedures as provided in D. R. Gchlcrt ei ai, EJP 509: 145-153 (2005), a compound is administered to a rat via the oral route. The binding of 1- WO 2008/036579 PCmJS2007/078605 sauvagine to the cerebellum is then assessed ex vivo as described in Gehlert et ah For example, Example 15 provides 65% inhibition at 10 mg/kg. Example B 5 CRF1 Filter Binding Assay The limitations of plasmid-based human CRF1 expression, in terms of generating a recombinant cell line with sufficient receptor density to develop a binding assay, are overcome by using a Phoenix retroviral expression system licensed from Stanford. The stable HEK-hCRFl cell line is used to prepare membranes and binding reactions (200 pL) 10 are set up as follows: 50 pX of'"i-sauvagine (0.2 nM final), 50 uX compound and 100 uX CRFJ membrane (25 pg/reaction). The reactions are incubated at room temperature for 2 h and then terminated by filtration through pre-treated FB Millipore glass fiber filter plates (96 well). The plates arc washed twice with ice-cold assay buffer (50 mM tris, 12.5 mM NaCl, 1 mM EDTA, 10 mM MgCh, 0.05% BSA, pH 7.2), air dried over night 15 and counted with 100 uL Microscint 40 in a MicroBeta counter. Non-specific binding (NSB) is determined in the presence of 0.5 uM non-labeled sauvagine. Triplicate determinations are typically run and the median data points plotted by Graph Pad Prism. Using this assay, the exemplified compounds of the present invention inhibit the binding of ,iSI-Sauvagine (4 nM) in roller/adherent cells with a Ki (inhibition constant) 20 below 1 uM. For example, Example 15 exhibits a Ki of 6.2 nM. Example C CRJ2 Filter Binding Assay The limitations of plasmid-based human CRF2 expression, in terms of generating 25 a recombinant cell line with sufficient receptor density to develop a binding assay, are overcome by using a Phoenix retroviral expression system licensed from Stanford. The stable HEK-hCRF2 cell line is used to prepare membranes and binding reactions (200 uX) are set up as follows: 50 pX of' I-sauvagine (0.2 nM final concentration), 50 uX compound and 100 uL CRF2 membrane (25 ug/reaction). The reactions are incubated at 30 room temperarure for 2 hours and then terminated by filtration through pre-treated FB Millipore glass fiber filter plates (96 well). The plates are washed twice with ice-cold assay buffer (50 mM tris, 12.5 mM NaCl, I mM EDTA, 10 mM MgCI2. 0.05% BSA, pH WO 2008/036579 PCT/US2O07/078605 7.2), air dried over night and counted with 100 jiL Microscint 40 in a MicroBeta counter. Non-specific binding (NSB) is determined in the presence of 0.5 pM non-labeled sauvagine. Alternatively, compounds are evaluated using a Scintillation Proximity assay. This assay is set up as follows: 50 pL of I2SI-Sauvagine (0.2 nM final concentration), 50 5 pL compound or non-labelled sauvagine (NSB) and 100 pL containing 250 pg wheat germ agglutinin (WGA) SPA beads and CRF2 membrane (1.5 pg/reaction). Plates are - -incubated for 4-5 h at roonvtemperature and then centrifuged at 200 X g for 10 min. Bound radioactivity is assessed using a Wallac Trilux scintillation counter. Binding is assessed typically using triplicate determinations and the median data points plotted by 10 Graph Pad Prism. Compounds are initially screened at a fixed concentration and, if sufficient activity is noted, subsequent concentration-response curves are generated. Particular exemplified compounds of the present invention are tested in the CRP2 binding assay and exhibit weak affinity for the CRF2 receptor. For example, Example 15 exhibits 11% inhibition at a concentration of 50 pM. This result suggests that the 15 compounds of the present invention are selective for the CRF1 receptor, (relative to CRF2). Example D Bioavailability and Pharmacokinetic Properties 20 The volume of distribution (Vdist) relates the amount of the drug in the body to the concentration of the drug in the blood or plasma. The volume of distribution refers to the fluid volume that would be required to contain the total amount of the drug in the body a! the same concentration as in the blood or plasma: Vdist - amount of drug in the body/ concentration of drug in blood or plasma (Goodman and Gillman's). For a 10 mg 25 dose and a plasma concentration of 10 mg/L, the volume of distribution would be 1 liter. The volume of distribution reflects the extent to which the drug is present in the extravascular tissue. A large volume of distribution reflects the tendency of a compound to bind to the tissue components compared with plasma protein binding. In a clinical setting, Vdist can be used to determine a loading dose to achieve a steady state 30 concentration. To test for volume of distribution, Male Sprague Dawlcy rats (N=3) arc administered a single 1 mg/kg intravenous dose of compound. Multiple plasma samples WO 2008/036579 PCT/US2007/078605 are collected at time points from 0.08 to 24 hours post-dose. The plasma samples are analyzed by LC/MS/MS to determine the plasma concentrations. Plasma pharmacokinetic calculations are performed to determine the pharmacokinetic parameters including Vdist and plasma clearance (Clp). 5 Compounds of the present invention preferably have favorable bioavailability profiles. For example, a majority of commercial CNS and cardiovascular drugs exhibit a human Vdist of 10 L/Kg, respectively, when analyzed separately. Example 15 of the present invention, when analyzed separately, exhibits a rat Vdist of only 7.2 L/Kg following a single intravenous dose of I mg/kg. Further, the plasma clearance (CLp) is a measure of the rale of removal of the drug from the body. Following an intravenous dose and first-order kinetics, the plasma 15 clearance may be determined using the following equation: CLp = Dose/ AUC, where AUC is the total area under the curve that describes the concentration of the drug in the plasma as a funciion of time from zero to infinity. Reference CRF antagonists CP154526 and NBI37582 exhibit rat clearance (CLp) of 83 and 306 mL/min/kg, respectively, when analyzed separately, following a single intravenous dose, while Example 15 of the present 20 invention, when analyzed separately, exhibits a rat CLp of only 23.6 mL/min/kg. WE CLAIM: I. A compound of Formula I wherein: R and R are independently ethyl or n-propyl; R3 is hydrogen, CI Br. methyl, trifluoromethyl R" is hydrogen, Br, R'RN-. mcthoxymethyl, uty| acetamido, pyridin-4-y R'1 and Rh are independently hydrogen. C)-C3alkv| H]siCM-Cl-h-. (CH3)3COC(0)NHCH2CH2-r or CH3CH2CH2NHCH2CI^_. or a pharmaceutical ly acceptable salt thereof. 2. The compound according to claim 1. or a pr%maceutica!ly acceptable salt thereof, wherein W is CI. Br. methyl or trifluoromethyl. 3. The compound according to claim 1 or 2, or a pharmaceuticals acceptable salt thereof, wherein R is CI or Br. 4. The compound according to any one of clainls | to 3 or a pharmaceutically acceptable salt thereof, wherein R4 is RaRbN-> pyridin-4_y| m0rpholin-4-yl. or 5. The compound according to any one of claims 1 to 4. or a pharmaceutically acceptable salt thereof, wherein R is morphohn-4-yl or 6. The compound according to any one of claims I to 4. or a pharmaceutical)' acceptable salt thereof, wherein R4 is R- and Ra and Rb are independently C(-C3alkyl. 7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is 3-[4-bromo-2-(2-methyl-277-[l,2,4]tria^ol-3-yl)-thiazol-5-yl]-2r5-dimethyl-7-(i7propyl-butyl)- pyrazolo[l,5-a]pyrimidine. 8. The compound according to claim 1. or a pharmaceutical!)' acceptable salt thereof which is 3-(4-bromo-2-(2-methyl-2H-[L2,4]triaZol-3-yl)-thia7.ol-5-yl)-7-(Ncth\T propyl)-2:5-dimethyl-pyrazoIo[l,5-tf]pyrimidine. 9. The compound according to claim 1, or a phamiaccuticaiiy acceptable sail thereof, which is 3-(4-chloro-2-morpholin-4-yl-thiazol-5"yl)-7-(l-cthyl-propyl)-2r5-dimethyl-pyrazolo[l,5-fl]pyrimidine. 10. A pharmaceutical composition comprising: a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and a pharmaceutical!} acceptable excipient. 11. A compound according to any one of Claims I to 9, or a pharmaceutically acceptable salt thereof, for use in therapy. 12. A compound according to any one of claims ' to 9. or a pharmaceutically acceptable salt thereof for use in the treatment of anxieiv or depression. 13. A compound according to any one of claims 1 to 9. or a pharmaceuiically acceptable salt thereof, for use in the treatment of alcohol or substance abuse.

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506-MUMNP-2009-CORRESPONDENCE(20-4-2009).pdf

506-MUMNP-2009-CORRESPONDENCE(7-9-2009).pdf

506-MUMNP-2009-CORRESPONDENCE(IPO)-(15-5-2012).pdf

506-mumnp-2009-correspondence.pdf

506-mumnp-2009-description(complete).doc

506-mumnp-2009-description(complete).pdf

506-MUMNP-2009-DESCRIPTION(GRANTED)-(15-5-2012).pdf

506-MUMNP-2009-EP DOCUMENT(19-1-2012).pdf

506-MUMNP-2009-FORM 1(19-1-2012).pdf

506-mumnp-2009-form 1.pdf

506-mumnp-2009-form 13.pdf

506-mumnp-2009-form 18.pdf

506-MUMNP-2009-FORM 2(GRANTED)-(15-5-2012).pdf

506-MUMNP-2009-FORM 2(TITLE PAGE)-(19-1-2012).pdf

506-MUMNP-2009-FORM 2(TITLE PAGE)-(GRANTED)-(15-5-2012).pdf

506-mumnp-2009-form 2(title page).pdf

506-mumnp-2009-form 2.doc

506-mumnp-2009-form 2.pdf

506-MUMNP-2009-FORM 26(7-9-2009).pdf

506-mumnp-2009-form 3(12-3-2009).pdf

506-MUMNP-2009-FORM 3(19-1-2012).pdf

506-MUMNP-2009-FORM 3(7-9-2009).pdf

506-MUMNP-2009-FORM 3(7-9-2009).tif

506-mumnp-2009-form 3.pdf

506-mumnp-2009-form 5.pdf

506-mumnp-2009-general power of attorney(7-9-2009).pdf

506-mumnp-2009-pct request.pdf

506-mumnp-2009-pct-ib-304.pdf

506-mumnp-2009-pct-ib-311.pdf

506-mumnp-2009-pct-isa-210.pdf

506-mumnp-2009-pct-isa-220.pdf

506-MUMNP-2009-PETITION UNDER RULE 137(19-1-2012).pdf

506-MUMNP-2009-REPLY TO EXAMINATION REPORT(19-1-2012).pdf

506-MUMNP-2009-US DOCUMENT(19-1-2012).pdf

506-mumnp-2009-wo international publication report a1.pdf

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