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WO 2015/150957 Al 8 October 2015 (08.10.2015) 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 2015/150957 Al 8 October 2015 (08.10.2015) P O P C T (51) International Patent Classification: (74) Agent: OLSON, A. Dean; Pfizer Worldwide Research & C07D 471/04 (2006.01) A61P 25/28 (2006.01) Development, Eastern Point Road MS8260-2141, Groton, A61K 31/4985 (2006.01) Connecticut 06340 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/IB20 15/05 1988 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (22) International Filing Date: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 18 March 2015 (18.03.2015) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (26) Publication Language: English MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (30) Priority Data: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 61/973,436 1 April 2014 (01.04.2014) US SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicant: PFIZER INC. [US/US]; 235 East 42nd Street, New York, New York 10017 (US). (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (72) Inventors: AM ENDE, Christopher William; 32 Hunting GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, Ridge Drive, Mystic, Connecticut 06355 (US). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, HUMPHREY, John Michael; 110 Haley Road, Mystic, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, Connecticut 06355 (US). JOHNSON, Douglas Scott; 85 DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Adin Drive, Concord, Massachusetts 01742 (US). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, KAUFFMAN, Gregory Wayne; 30 Boulder Way, East SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Greenwich, Rhode Island 02818 (US). PETTERSSON, GW, KM, ML, MR, NE, SN, TD, TG). Martin Youngjin; 3 Gilson Road, Littleton, Massachusetts 01460 (US). RANKIC, Danica Antonia; 304 Main Street, Declarations under Rule 4.17 : Apt. 1A, Niantic, Connecticut 06357 (US). STEPAN, Ant¬ — as to the identity of the inventor (Rule 4.1 7(Ϊ)) onia Friederike; 1110 Beacon Street, Apt. 2B, Brookline, — as to applicant's entitlement to applyfor and be granted a Massachusetts 02446 (US). VERHOEST, Patrick patent (Rule 4.1 7(H)) Robert; 23 Calvin Road, Newton, Massachusetts 02460 (US). — as to the applicant's entitlement to claim the priority of the earlier application (Rule 4.1 7(in)) [Continued on nextpage] (54) Title: CHROMENE AND 1,1 A,2,7B-TETRAHYDROCYCLOPROPA[C]CHROMENE PYRIDOPYRAZINEDIONES AS GAMMA-SECRETASE MODULATORS , (57) Abstract: Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula (I), wherein X, R 1, R , R , R4 , R , R5 , R5 , R6, R7' y and z are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed. These compounds ¾ are γ -secretase modulators, useful for the treatment of neurodegenerative and/ or neurological disorders such as Alzheimer's disease and Down's syndrome. w o 2015/150957 A llll II II 11III II I I II I II I II I II III II I II Published: CHROMENE AND 1 , 1 A,2,7B-TETRAHYDROCYCLOPROPA[C]CHROMENE PYRIDOPYRAZINEDIONES AS GAMMA-SECRETASE MODULATORS FIELD OF THE INVENTION The present invention relates to novel chromene and cyclopropachromene pyridopyrazinedione compounds of Formula I 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). A D 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 A D 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: Formula I or pharmaceutically acceptable salts thereof, wherein: A is selected from the group consisting of A 1, A2, A3 and A4: A 3 A4 X is a (5- to 14-membered)heteroaryl containing 1-3 heteroatoms; R is selected from the group consisting of hydrogen, halogen, cyano, hydroxy, (Ci-C6)alkyl, (Ci-C 6)alkoxy, (C3-C8)cycloalkyl, and (C2-C6)alkenyl; wherein the ( - Ce)alkyl, (Ci-Ce)alkoxy, (C3-C8 )cycloalkyl, and (C2-Ce)alkenyl are optionally substituted with one to three substituents each independently selected from the group consisting of fluoro, hydroxy and (CrC 6)alkoxy; R2a and R2b, at each occurrence, are independently selected from the group consisting of hydrogen, fluoro, cyano, hydroxy, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, (C-i- C6)alkoxy(Ci-C 6)alkyl, hydroxy(Ci-C 6)alkyl, halo(Ci-C 6)alkyl, (C2-C6)alkenyl, (C2- Ce)alkynyl, (C3-C8 )cycloalkyl, and phenyl; wherein the (C2-Ce)alkenyl, (C2-Ce)alkynyl, (C3-C8)cycloalkyl, and phenyl are optionally substituted with one to three substituents each independently selected from the group consisting of cyano, hydroxy, (CrC 3)alkyl, hydroxy (Ci -C3 )alkyl, and fluoro; or R 2a and R 2b together with the carbon atom(s) to which they are attached form a (C3-C8 )cycloalkyl or a (4- to 10-membered)heterocycloalkyl, wherein the (C 3-C 8)cycloalkyl and the (4- to 10-membered)heterocycloalkyl are optionally substituted with one to three R 8; R 4a and R 4b are each independently selected from the group consisting of hydrogen, hydroxy, (Ci-Ce)alkyl , (Ci-Ce)alkoxy, and (Ci -C6 )alkoxy (Ci -C6 )alkyl, wherein the (Ci-C6)alkyl, (CrC 6)alkoxy, or (Ci -C6 )alkoxy (Ci-C6)alkyl, are optionally substituted with one to three substituents independently selected from the group consisting of cyano, hydroxy, and fluoro; or R 4a and R 4b together with the carbon atom to which they are attached form a (C 3-C 8)cycloalkyl, wherein the (C 3-C 8)cycloalkyl is optionally substituted with one to three substituents each independently selected from the group consisting of cyano, fluoro, hydroxy, (Ci-Ce)alkyl , (Ci-Ce)alkoxy, (Ci -C6 )alkoxy (Ci- C 6)alkyl, hydroxy (Ci-C6)alkyl, and halo(Ci-C6)alkyl; R 5a and R 5b, at each occurrence, are independently selected from the group consisting of hydrogen, hydroxy, (Ci-Ce)alkyl , (Ci-Ce)alkoxy, and (Ci -C6 )alkoxy (Ci- C e)alkyl, wherein the (Ci-Ce)alkyl , (Ci-Ce)alkoxy, or (Ci -C6 )alkoxy (Ci -C6 )alkyl, are optionally substituted with one to three substituents each independently selected from the group consisting of cyano, hydroxy and fluoro; or R 5a and R 5b together with the carbon atom(s) to which they are attached form a (C3-C8)cycloalkyl, wherein said (C3- C 8)cycloalkyl is optionally substituted with one to three substituents each independently selected from the group consisting of cyano, fluoro, hydroxy, (Ci-C6)alkyl, (Ci-C6)alkoxy, (C -C 6)alkoxy (C -C 6)alkyl, hydroxy (C -C 6)alkyl, and halo(C -C 6)alkyl; R 6 and R 7 are each independently selected from the group consisting of (Ci- hydrogen, cyano, halogen, (Ci-C6)alkyl, hydroxy (Ci-C6)alkyl, (CrC 6)alkoxy, 9 6 7 C 6)alkoxy (Ci-C6)alkyl, and halo(Ci-C6)alkyl, and -OR ; provided that R and R cannot both be hydroxy; R 8, at each occurrence, is independently selected from the group consisting of cyano, halogen, hydroxy, (Ci-C6)alkyl, (Ci-C6)alkoxy, (Ci -C6 )alkoxy (Ci-C6)alkyl, hydroxy (Ci -C6 )alkyl and halo(Ci-Ce)alkyl; R 9 is selected from the group consisting of hydrogen and (Ci-Ce)alkyl ; wherein the (CrC 6)alkyl is optionally substituted with one to three substituents each independently selected from the group consisting of cyano, hydroxy and fluoro; z is an integer selected from 1 or 2 ; n integer selected from 1, 2 , 3 or 4 ; is a bond that is connected to any carbon atom of ring B or ring C that is chemically permissible; m is an integer selected from 1, 2 , 3 or 4 ; n is an integer selected from 0 or 1; W is carbon or oxygen; ring B is optionally substituted with up to five R 0, wherein each R 0 is independently selected from the group consisting of halogen, cyano, hydroxy, (C-i - C 6)alkyl, hydroxy(C C 6)alkyl, (C C 6)alkoxy, (C -C 6)alkoxy(C -C 6)alkyl, halo(C C 6)alkyl, halo(Ci -C 6)alkoxy, (Ci -C 6)alkylthio, -S F5 and (C 3-C 6)cycloalkyl, wherein the (C 3- C 6)cycloalkyl is optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxy, (Ci -Ce )alkyl, hydroxy(Ci - C 6)alkyl, (C -C 6)alkoxy, (C -C 6)alkoxy(C -C 6)alkyl, halo(C C 6)alkyl, and halo(d- 0 C 6)alkoxy; or two R substituents taken together with the carbon atom(s) to which they are attached form a geminal (C3-C6 )cycloalkyl that is
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