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WO 2008/117169 Al (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 2 October 2008 (02.10.2008) WO 2008/117169 Al (51) International Patent Classification: (GB). STORER, Robert, Ian [GB/GB]; Pfizer Global C07D 487/04 (2006.01) A61P 15/00 (2006.01) Research and Development, Ramsgate Road, Sandwich, A61K 31/55 (2006.01) A61P 25/00 (2006.01) Kent CT13 9NJ (GB). WHITLOCK, Gavin, Alistair [GB/GB]; Pfizer Global Research and Development, (21) International Application Number: Ramsgate Road, Sandwich, Kent CT13 9NJ (GB). PCT/IB2008/000731 (74) Agent: DROUIN, Stephane; Pfizer Global Research and (22) International Filing Date: 14 March 2008 (14.03.2008) Development, Ramsgate Road, Sandwich, Kent CT13 9NJ (GB). (25) Filing Language: English (81) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of national protection available): AE, AG, AL, AM, AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY,BZ, CA, (30) Priority Data: CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, 60/896,527 23 March 2007 (23.03.2007) US EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, (71) Applicant (for all designated States except US): PFIZER LK, LR, LS, LT, LU, LY,MA, MD, ME, MG, MK, MN, LIMITED [GB/GB]; Ramsgate Road, Sandwich, Kent MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, CT13 9NJ (GB). PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, (72) Inventors; and ZA, ZM, ZW (75) Inventors/Applicants (for US only): ANDREWS, Mark, David [GB/GB]; Pfizer Global Research and Develop (84) Designated States (unless otherwise indicated, for every ment, Ramsgate Road, Sandwich, Kent CT13 9NJ (GB). kind of regional protection available): ARIPO (BW, GH, BLAGG, Julian [GB/GB]; Pfizer Global Research and GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, Development, Ramsgate Road, Sandwich, Kent CT 13 9NJ ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), (GB). BRENNAN, Paul, Edward [US/GB]; Pfizer Global European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, Research and Development, Ramsgate Road, Sandwich, FR, GB, GR, HR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, Kent CT13 9NJ (GB). FISH, Paul, Vincent [GB/GB]; NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, Pfizer Global Research and Development, Ramsgate CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). Road, Sandwich, Kent CT13 9NJ (GB). ROBERTS, Lee, Richard [GB/GB]; Pfizer Global Research and Published: Development, Ramsgate Road, Sandwich, Kent CT 13 9NJ — with international search report (54) Title: PYRIMIDO [4, 5-D] AZEPINE DERIVATIVES AS 5-HT2C AGONISTS 1 2 3a 3b 3c 3 1 (57) Abstract: The present invention relates to compounds of formula (I): wherein R , R , R ,R , R , R and R are as defined in the specification. These compounds act as 5-HT2c agonists. PYRIMIDO [4, 5-D]AZEPINE DERIVATIVES AS 5-HT2C AGONISTS This invention relates to fused azepine derivatives potentially useful in medicine. More particularly, this invention relates to pyrimidine-fused azepine derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. The fused azepine derivatives of the present invention are modulators (preferably agonists) of the 5-HT receptor, preferably the 5-HT2C receptor. 5-HT 2c receptor modulators/agonists are believed to have a number of therapeutic applications, particularly in the treatment of sexual dysfunction, schizophrenia, cognitive deficits including cognitive deficits associated with schizophrenia, anxiety, depression, obsessive-compulsive disorder, epilepsy, obesity, and LUTS, among others. Preferably, the modulators/agonists are selective for the 5-HT 2c receptor over other 5-HT receptors. Bishop, M. J. and Nilsson, B. M., "New 5-HT Receptor Agonists" Expert Opin. Ther. Patents, 2003, 13(1 1): 1691-1705, review patent applications that describe compounds having agonist activity at the 5-HT 2c receptor. The review also addresses indications for which evidence exists to support the use of 5-HT2c agonists in their treatment, such as obesity, schizophrenia, anxiety, depression, obsessive- compulsive disorder, sexual dysfunction, epilepsy, and urinary incontinence, among others. Toxicity and non-selectivity of ligands for the various 5-HT receptors remain a challenge. It is suspected that the non-selectivity of some ligands contributes to various adverse side effects such as hallucinations and cardiovascular complications. Therefore, there remains a need for 5-HT2c selective receptor ligands. It has now been found that compounds of the present invention are modulators, preferably, agonists of the 5-HT2c receptor, preferably selective agonists for this receptor over other 5-HT receptors. The compounds of the present invention are therefore potentially useful in the treatment of a wide range of disorders, particularly in the treatment of 5-HT2c receptor-mediated disorders in animals including humans. The treatment of female sexual dysfunction (FSD) is a preferred use. All forms of female sexual dysfunction (FSD) are potentially treatable with the compounds of the present invention including female sexual arousal disorder (FSAD), female orgasmic disorder (FOD), hypoactive sexual desire disorder (HSDD), or sexual pain disorder. The treatment of male sexual dysfunction, particularly male erectile dysfunction (MED), is another preferred use. Other preferred uses of the present invention include treatment of eating disorders, promotion of weight loss, control of weight, or treatment of obesity. Other conditions that may be treated with the compounds of the present invention include psychoses, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, personality disorder of the paranoid type, or personality disorder of the schizoid type. Compounds of the present invention may also be used for the treatment of dementia, cognitive deficit symptoms of Alzheimer's disease, attention deficit symptoms of Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, AIDS-related dementia, delirium, amnestic disorder, post-traumatic stress disorder, mental retardation, a learning disorder, attention-deficit/hyperactivity disorder, age-related cognitive decline, cognitive deficits associated with psychoses, or cognitive deficits associated with schizophrenia. Conditions that may be treated with the compounds of the present invention also include benign prostactic hyperplasia, overactive bladder or LUTS. The terms "treating", "treat", or "treatment" as used herein are intended to embrace both prevention and control i.e., prophylactic, and palliative treatment of the indicated conditions. Various pyrimidoazepine derivatives useful for the treatment of diseases associated with the 5-HT2c receptor are referred to in WO2006044762. Pyrimidine fused heterocycles useful for the treatment of diseases associated with leucocyte activation are referred to in US2003191 143. N-containing heterocyclic compounds useful for the treatment of diseases such as thrombosis, ischemic heart disease, cerebrovascular disorder, circulatory disorders, migraine, diabetic peripheral nerve disorder and neuralgia afer herpes zoster are disclosed in JP1 1171865. JP2005162673A refers to quaternary ammonium salts of bicyclic pyrimidine derivatives useful for the treatment of inflammation and allergic and autoimmune diseases. International Patent Application publication number WO20070 19083 refers to pyrimidine fused compounds as 5-HT receptor modulators. There is a need to provide new 5-HT2c agonists that are good drug candidates. In particular, preferred compounds should bind potently to the 5-HT2c receptor whilst showing little affinity for other receptors and show functional activity as agonists. They should be well absorbed from the gastrointestinal tract, be metabolically stable and possess favourable pharmacokinetic properties. When targeted against receptors in the central nervous system they should cross the blood brain barrier freely and when targeted selectively against receptors in the peripheral nervous system they should not cross the blood brain barrier. They should be non-toxic and demonstrate few side-effects. Furthermore, the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated. In particular, compounds of the present invention are selective agonists of the 5-HT C receptor. Advantageously, compounds of the invention show little or no affinity for the 5-HT2a and 5-HT2b receptors. In addition, preferred compounds of the invention are metabolically stable. The present invention therefore provides a compound of formula (I): or a pharmaceutically acceptable salt, solvate (including a hydrate), or prodrug thereof, wherein: 1 R is H, (Ci-€4)alkyl, fluoro(Ci-C 4)alkyl, (C3-C6)cycloalkyl, fluoro(C 3-C6)cycloalkyl, 4 5 10 1 fluoro(Ci-C 4)alkoxy, -NR R , -OR , or Het , said alkyl, cycloalkyl and alkoxy being optionally substituted by one or more hydroxyl; Het1 is a 5- or 6-membered heterocyclic ring containing one nitrogen atom at the point of attachment, and comprising up to 2 further heteroatoms selected from oxygen, nitrogen and sulphur, said ring
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