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WO 2007/105050 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 20 September 2007 (20.09.2007) WO 2007/105050 Al (51) International Patent Classification: 06340 (US). ZENG, Dongxiang [CN/US]; Pfizer Global C07D 257/06 (2006.01) A61K 31/165 (2006.01) Research & Development, Eastern Point Road, Groton, CT C07C 233/18 (2006.01) A61P 3/06 (2006.01) 06340 (US). C07C 271/16 (2006.01) A61P 9/10 (2006.01) C07C 275/24 (2006.01) A61K 31/27 (2006.01) (74) Agents: FULLER, Grover, E , Jr. et al; c/o A61K 31/41 (2006.01) LAWRENCE, Jackie, Pfizer Inc. Ms8260-1615, Eastern Point Road, Groton, CT 06340 (US). (21) International Application Number: PCT/IB2007/000527 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, 26 February 2007 (26.02.2007) CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, (25) Filing Language: English JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LV,LY, MA, MD, MG, MK, MN, MW, MX, MY, (26) Publication Language: English MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, (30) Priority Data: RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, 60/780,993 10 March 2006 (10.03.2006) US TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW 11/619,277 3 January 2007 (03.0 1.2007) US (84) Designated States (unless otherwise indicated, for every (71) Applicant (for all designated States except US): PFIZER kind of regional protection available): ARIPO (BW, GH, PRODUCTS INC. [US/US]; Eastern Point Road, Groton, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, CT 06340 (US). ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (72) Inventors; and FR, GB, GR, HU, IE, IS, IT, LT, LU, LV,MC, NL, PL, PT, (75) Inventors/Applicants (for US only): CHANG, George RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, [US/US]; Pfizer Global Research & Development, East GN, GQ, GW, ML, MR, NE, SN, TD, TG). ern Point Road, Groton, CT 06340 (US). GARIGIPATI, Ravi Shanker [US/US]; Pfizer Global Research & D e Published: velopment, Eastern Point Road, Groton, CT 06340 (US). — with international search report LEFKER, Bruce Allen [US/US]; Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340 For two-letter codes and other abbreviations, refer to the "G uid (US). PERRY, David Austen [GB/US]; Pfizer Global R e ance Notes on Codes and Abbreviations" appearing at the beg in search & Development, Eastern Point Road, Groton, CT ning of each regular issue of the PCT Gazette. (54) Title: DIBENZYL AMINE COMPOUNDS AND DERIVATIVES (57) Abstract: Dibenzyl amine compounds and derivatives, pharmaceutical compositions containing such compounds and the use of such compounds to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in some mammals, including humans. DIBENZYL AMINE COMPOUNDS AND DERIVATIVES BACKGROUND OF INVENTION This invention relates to dibenzyl amine compounds and derivatives, pharmaceutical compositions containing such compounds and their use to elevate certain plasma lipid levels, including high density lipoprotein (HDL)-cholesterol and to lower certain other plasma lipid levels, such as low density lipoprotein (LDL)-cholesterol and triglycerides and accordingly to treat diseases which are affected by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in certain mammals (i.e., those which have CETP in their plasma), including humans. Atherosclerosis and its associated coronary artery disease (CAD) is the leading cause of mortality in the industrialized world. Despite attempts to modify secondary risk factors (smoking, obesity, lack of exercise) and treatment of dyslipidemia with dietary modification and drug therapy, coronary heart disease (CHD) remains the most common cause of death in the U.S., where cardiovascular disease accounts for 44% of all deaths, with 53% of these associated with atherosclerotic coronary heart disease. Risk for development of this condition has been shown to be strongly correlated with certain plasma lipid levels. While elevated LDL-C may be the most recognized form of dyslipidemia, it is by no means the only significant lipid associated contributor to CHD. Low HDL-C is also a known risk factor for CHD (Gordon, DJ., et al.,: "High-density Lipoprotein Cholesterol and Cardiovascular Disease", Circulation, (1989), 79: 8-15). High LDL-cholesterol and triglyceride levels are positively correlated, while high levels of HDL- cholesterol are negatively correlated with the risk for developing cardiovascular diseases. Thus, dyslipidemia is not a unitary risk profile for CHD but may be comprised of one or more lipid aberrations. Among the many factors controlling plasma levels of these disease dependent principles, cholesteryl ester transfer protein (CETP) activity affects all three. The role of this 70,000 dalton plasma glycoprotein found in a number of animal species, including humans, is to transfer cholesteryl ester and triglyceride between lipoprotein particles, including high density lipoproteins (HDL), low density lipoproteins (LDL), very low density lipoproteins (VLDL), and chylomicrons. The net result of CETP activity is a lowering of HDL cholesterol and an increase in LDL cholesterol. This effect on lipoprotein profile is believed to be pro- atherogenic, especially in subjects whose lipid profile constitutes an increased risk for CHD. No wholly satisfactory HDL-elevating therapies are on the market today. Niacin can significantly increase HDL, but has serious toleration issues which reduce compliance. Fibrates and the HMG CoA reductase inhibitors raise HDL-C, but in some patients, the result is an increase of modest porportions (-10- 12%). As a result, there is an unmet medical need for an approved therapeutic agent that elevates plasma HDL levels, thereby reversing or slowing the progression of atherosclerosis. Thus, although there are a variety of anti-atherosclerosis therapies, there is a continuing need and a continuing search in this field of art for alternative therapies. SUMMARY OF THE INVENTION This invention is directed to compounds according to Formula I Formula I or a pharmaceutically acceptable salt of said compound; wherein A is -COO(C r C4)alkyl, cyano, -CHO, -CONH 2, -CO(C 1-C4)alkyl or Q wherein Q is a five or six membered fully saturated, partially unsaturated or fully unsaturated ring wherein each ring atom, except for the atom connected to N of Formula I, may be replaced by a nitrogen, oxygen or sulfur atom, and wherein each ring atom may optionally be mono- or di-substituted by oxo, cyano, a fully saturated, partially unsaturated or fully unsaturated straight or branched chain having 1 to 6 carbon atoms, or a fully saturated, partially unsaturated or fully unsaturated ring having 3 to 8 carbon atoms, wherein each carbon atom of said chain or ring is optionally replaced by a heteroatom selected from nitrogen, oxygen or sulfur, and said carbon atom of said chain or ring is optionally mono-, di- or tri-substituted with amino, halo, cyano, hydroxy, oxo, carboxyl, (CrC^alkoxycarbonyl, ((Cr C6)alkyl optionally substituted with one to nine halo or one or two hydroxyl), ((C1-C6JaIkOXy optionally substituted with one to nine halo or one or two hydroxyl), or ((C1- C6)alkylthio optionally substituted with one to nine halo or one or two hydroxyl), and said nitrogen atom of ι said chain or ring is optionally mono- or disubstituted with cyano, oxo, (CrC^alkoxycarbonyl or ((C- -C6)alkyl optionally substituted with one to nine halo or one or two hydroxyl), said sulfur atom of said chain or ring is substituted with one or two oxo, one to five fluorines or amino, and said chain or ring is optionally mono-, di- or trisubstituted with a group V wherein V is a three to six membered fully saturated, partially saturated or fully unsaturated ring containing zero to four heteroatoms selected from nitrogen, oxygen or sulfur and optionally substituted by one to five groups selected from hydrogen, halo, cyano, hydroxy, oxo, carboxyl, (Cr C6)alkoxycarbonyl, ((Cr C6)alkyl optionally substituted with one to nine halo or one or two hydroxyl), ((Cr C6)alkoxy optionally substituted with one to nine halo or one or two hydroxyl), or ((CrCeJalkylthio optionally substituted with one to nine halo or one or two hydroxyl); 17 18 B iS-OR Or-S(O) nR X is C or N, wherein if X is N, R4 is absent; Y is -CR 11R12; 1 2 3 4 5 6 7 R , R , R , R , R , R , and R are each independently hydrogen, halo, cyano, hydroxy, nitro, ((C 1- ι C6)alkyl optionally substituted with one to nine halo, one or two hydroxyl, one or two (C- -C6)alkoxy, one or two amino, cyano, oxo, or carboxy), ((Cr C6)alkoxy optionally substituted with one to nine halo, one or two hydroxyl, or cyano), or ((C r C6)alkylthio optionally substituted with one to nine halo, one or two hydroxyl, or cyano), or R1 and R2 or R2 and R3 are taken together
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