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WO 2015/049616 Al 9 April 2015 (09.04.2015) P O P C T

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WO 2015/049616 Al 9 April 2015 (09.04.2015) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/049616 Al 9 April 2015 (09.04.2015) P O P C T (51) International Patent Classification: (74) Agent: OLSON, A. Dean; Pfizer Inc., c/o Eastern Point C07D 471/04 (2006.01) A61K 31/498 (2006.01) Road, Groton, Connecticut 06340 (US). C07D 498/04 (2006.01) A61P 25/00 (2006.01) (81) Designated States (unless otherwise indicated, for every (21) International Application Number: kind of national protection available): AE, AG, AL, AM, PCT/IB2014/064738 AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (22) Date: International Filing DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 22 September 2014 (22.09.2014) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (25) Filing Language: English KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (26) Publication Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (30) Priority Data: SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 61/886,705 4 October 201 3 (04. 10.2013) US TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant: PFIZER INC. [US/US]; 235 East 42nd Street, (84) Designated States (unless otherwise indicated, for every New York, New York 10017 (US). kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (72) Inventors: PETTERSSON, Martin Youngjin; 3 Gilson TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, Road, Littleton, Massachusetts 01460 (US). JOHNSON, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Douglas Scott; 85 Adin Drive, Concord, Massachusetts DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, 01742 (US). SUBRAMANYAM, Chakrapani; 314 Great LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Pond Road, South Glastonbury, Connecticut 06733 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, O'DONNELL, Christopher John; 7 1 Oxford Court, Mys GW, KM, ML, MR, NE, SN, TD, TG). tic, Connecticut 06355 (US). AM ENDE, Christopher Declarations under Rule 4.17 : William; 32 Hunting Ridge Drive, Mystic, Connecticut 06355 (US). GREEN, Michael Eric; 22 Ward Street Apt. — as to the identity of the inventor (Rule 4.1 7(Ϊ)) #2, Boston, Massachusetts 02127 (US). PATEL, Nandini — as to applicant's entitlement to apply for and be granted a Chaturbhai; 70 Hope Avenue, Apt. 205, Waltham, Mas patent (Rule 4.1 7(H)) sachusetts 02453 (US). STIFF, Cory Michael; 883 Mon- tauk Avenue, Apt. 4, New London, Connecticut 06320 — as to the applicant's entitlement to claim the priority of the (US). TRAN, Tuan Phong; 106 Church Hill Road, Ledy- earlier application (Rule 4.1 7(in)) ard, Connecticut 06339 (US). KAUFFMAN, Gregory Published: Wayne; 30 Boulder Way, East Greenwich, Rhode Island 0281 8 (US). STEPAN, Antonia Friederike; 50 Park Row — with international search report (Art. 21(3)) West, Apt. 420, Providence, Rhode Island 02903 (US). VERHOEST, Patrick Robert; 23 Calvin Road, Newton, Massachusetts 02460 (US). (54) Title: NOVEL BICYCLIC PYRIDINONES AS GAMMA-SECRETASE MODULATORS © I (57) Abstract: Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the o structure of Formula 1 1 as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed. NOVEL BICYCLIC PYRIDINONES AS GAMMA-SECRETASE MODULATORS FIELD OF THE INVENTION The present invention relates to novel bicyclic pyridinone compounds useful for the treatment of neurodegenerative and/or neurological disorders, such as Alzheimer's disease and Down's syndrome. BACKGROUND OF THE INVENTION Dementia results from a wide variety of distinctive pathological processes. The most common pathological processes causing dementia are Alzheimer's disease (AD), cerebral amyloid angiopathy (CM) and prion-mediated diseases (see, e.g., Haan et al., Clin. Neurol. Neurosurg. 1990, 92(4):305-31 0; Glenner et al., J. Neurol. Sci. 1989, 94:1 - 28). AD affects nearly half of all people past the age of 85, the most rapidly growing portion of the United States population. As such, the number of AD patients in the United States is expected to increase from about 4 million to about 14 million by 2050. The present invention relates to a group of γ -secretase modulators, useful for the treatment of neurodegenerative and/or neurological disorders such as Alzheimer's disease and Down's syndrome (see Ann. Rep. Med. Chem. 2007, Olsen et al., 42: 27- 47). SUMMARY OF THE INVENTION The present invention is directed to γ -secretase modulators of Formula I or pharmaceutically acceptable salts thereof as represented below: wherein: X is a (5- to 14-membered)heteroaryl containing 1-3 heteroatoms; R is selected from the group consisting of hydrogen, halogen, cyano, (C Ce)alkyl, (Ci-C6)alkoxy, (C3-C8)cycloalkyl, and (C2-C6)alkenyl; wherein the (CrC6)alkyl, (Ci-C6)alkoxy, (C3-C8)cycloalkyl, and (C2-C6)alkenyl are optionally substituted with one to three substituents each independently selected from the group consisting of fluoro, hydroxyl and (Ci-C6)alkoxy; R2a and R2b, at each occurrence, are independently selected from the group consisting of hydrogen, fluoro, cyano, (CrC 6)alkyl, halo(CrC 6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, and phenyl; wherein the (C2-C6)alkenyl, (C2-C6 )alkynyl, (C3-C8)cycloalkyl, and phenyl are optionally substituted with one to three substituents each independently selected from the group consisting of cyano, 2a 2b (CrC 3)alkyl and fluoro; or R and R together with the carbon to which they are attached form a (C3-C8)cycloalkyl or a (4- to 10-membered)heterocycloalkyl, wherein the (C3-C8)cycloalkyl and the (4- to 10-membered)heterocycloalkyl are optionally substituted with one to three R8; A is a (C6-Ci 0)aryl or a (5- to 14-membered)heteroaryl; wherein the (C6-Ci 0)aryl and (5- to 14-membered)heteroaryl are optionally substituted with one to five R 3 ; L, when present, is selected from the group consisting of oxygen, NR 0 , sulfur, and (C3-C8)cycloalkyl, wherein the (C3-C8)cycloalkyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen and (CrC 3)alkyl; 3 2 R is selected from the group consisting of hydrogen, -(C(R ) )t-(C 3- 2 2 C8)cycloalkyl, -(C(R ) ) -(4- to 10-membered)heterocycloalkyl, -(C(R ) ) -(C 6-Ci 0)aryl, 2 and -(C(R )2) -(5- to 14-membered)heteroaryl; wherein the (C3-C8)cycloalkyl, (4- to 10- membered)heterocycloalkyl, (C6-Ci 0)aryl, and (5- to 14-membered)heteroaryl moieties are optionally substituted with one to five R ; R4a and R4b are each independently selected from the group consisting of hydrogen and (CrC 6)alkyl, wherein the (CrC 6)alkyl is optionally substituted with one to three substituents independently selected from the group consisting of cyano and fluoro; 4a 4b or R and R together with the carbon to which they are attached form a (C3- C8)cycloalkyl, wherein the (C3-C8)cycloalkyl is optionally substituted with one to three substituents each independently selected from the group consisting of cyano, fluoro, trifluoromethyl and (CrC 6)alkyl; R5a and R5b, at each occurrence, are independently selected from the group consisting of hydrogen and (CrC6)alkyl, wherein the (CrC6)alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of cyano and fluoro; or R5a and R5b together with the carbon to which they are attached form a (C3-C8)cycloalkyl, wherein said (C3-C8)cycloalkyl is optionally substituted with one to three substituents each independently selected from the group consisting of cyano, fluoro, trifluoromethyl and (CrC 6)alkyl; R6 and R7 are each independently selected from the group consisting of 9 6 hydrogen, cyano, halogen, trifluoromethyl, (CrC6)alkyl, and -OR ; provided that R and R7 cannot both be hydroxyl; R8, at each occurrence, is independently selected from the group consisting of cyano, halogen, trifluoromethyl, hydroxyl and (CrC 6)alkyl; 9 R is selected from the group consisting of hydrogen and (CrC6)alkyl; wherein the (CrC6)alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of cyano and fluoro; R 0 is independently selected from the group consisting of hydrogen and ( - C6)alkyl; wherein the (CrC6)alkyl is optionally substituted with one to three halogen; R , at each occurrence, is independently selected from the group consisting of halogen, cyano, (CrC6)alkyl, halo(CrC6)alkyl, (CrC6)alkoxy, (Ci -C6 )alkoxy (Ci -C6)alkyl, halo(CrC6)alkoxy, (C3-C8 )cycloalkyl, (5- to 10-membered)heterocycloalkyl, -N(CH3)2, oxo, and SF5; wherein the (C3-C8 )cycloalkyl and (5- to 10-membered)heterocycloalkyl are optionally substituted with one to three halogen; R 2 , at each occurrence, is independently selected from the group consisting of hydrogen, halogen, cyano, (CrC 6)alkyl, and -SF5; wherein the (CrC 6)alkyl is optionally substituted with one to three fluoro; R 3 , at each occurrence, is independently selected from the group consisting of halogen, cyano, (CrC6)alkyl, (CrC6)alkoxy, halo(CrC6)alkyl, halo(CrC6)alkoxy, (C C 6)alkylthio, (C3-C8 )cycloalkyl, -SF5, -Si(CH3)3, and propynyloxybenzoylbenzyl; m is an integer selected from 0 or 1; t is an integer selected from 0, 1, 2, 3 or 4; z is an integer selected from 1 or 2; and y is an integer selected from 1, 2, 3 or 4 .
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