التفاصيل البيبلوغرافية
| العنوان: |
SPIRO-TETRACYCLIC RING COMPOUNDS AS BETA-SECRETASE MODULATORS AND METHODS OF USE |
| Document Number: |
20110251190 |
| تاريخ النشر: |
October 13, 2011 |
| Appl. No: |
13/047734 |
| Application Filed: |
March 14, 2011 |
| مستخلص: |
The present invention comprises a new class of compounds useful for the modulation of Beta-secretase enzyme activity and for the treatment of Beta-secretase mediated diseases, including Alzheimer's disease (AD) and other related conditions. In one embodiment, the compounds have a general Formula I [chemical expression included] wherein A1, A2, A3, A4, A5, A6, R2, R7, X and Y of Formula I are defined herein. The invention also includes use of these compounds in pharmaceutical compositions for treatment, prophylactic or therapeutic, of disorders and conditions related to the activity of beta-secretase protein. Such disorders include, for example, Alzheimer's Disease, cognitive deficits, cognitive impairment, schizophrenia and other central nervous system conditions related to and/or caused by the formation and/or deposition of plaque on the brain. The invention also comprises further embodiments of Formula I, intermediates and processes useful for the preparation of compounds of Formula I. |
| Inventors: |
CHENG, Yuan (Newbury Park, CA, US); White, Ryan (Somerville, MA, US); Amegadzie, Albert (Moorpark, CA, US); Brown, James (Moorpark, CA, US); Cheng, Alan C. (San Francisco, CA, US); Dimauro, Erin F. (Cambridge, MA, US); Dineen, Thomas (Somerville, MA, US); Epstein, Oleg (Belmont, MA, US); Gore, Vijay Keshav (Thousand Oaks, CA, US); Human, Jason Brooks (Boston, MA, US); Judd, Ted (Simi Valley, CA, US); Kreiman, Charles (Watertown, MA, US); Liu, Qingyian (Camarillo, CA, US); Lopez, Patricia (West Hills, CA, US); Ma, Vu Van (Simi Valley, CA, US); Marx, Isaac (Somerville, MA, US); Minatti, Ana (Woodland Hills, CA, US); Nguyen, Hanh Nho (Arlington, MA, US); Paras, Nick A. (Glendale, CA, US); Patel, Vinod F. (Acton, MA, US); Qian, Wenyuan (Camarillo, CA, US); Weiss, Matthew (Boston, MA, US); Xue, Qiufen (Newbury Park, CA, US); Zheng, Xiao Mei (Natick, MA, US); Zhong, Wenge (Thousand Oaks, CA, US) |
| Assignees: |
Amgen Inc. (Thousand Oaks, CA, US) |
| Claim: |
1. A compound of Formula I: [chemical expression included] or a stereoisomer, tautomer, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein A1 is CH, CF or N; A2 is CH, CF or N; A3 is CH, CF, OH, OCH3, OCF3 or N; A4 is CH, CF, OH, OCH3, OCF3 or N; A5 is CH, CR1 or N; A6 is CH, CF or N, provided that no more than one of A1, A2, A3, A4, A5 and A6 is N; R1 is F, Br or [chemical expression included] R2 is Cl, Br, CN, C1-6-alkyl, C2-6alkenyl, C2-6alkynyl, CN, —OC1-6alkyl, —SC1-6alkyl, —NHC1-6alkyl, —N(C1-6alkyl)2, —NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, thienyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl, cyclohexyl or —Si(CH3)3, wherein the C1-6-alkyl, C2-6alkenyl, C2-6alkynyl, —OC1-6alkyl, —SC1-6alkyl, —NHC1-6alkyl, —N(C1-6alkyl)2, —NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl and cyclohexyl are optionally substituted, independently, with 1-5 substituents of R8; R7 is C1-6-alkyl, C2-4alkenyl, C2-4alkynyl, CN, —OC1-6alkyl, —SC1-6alkyl, —NHC1-6alkyl, —N(C1-3alkyl)2, —NH-phenyl, —NH-benzyl, —O-phenyl or ring selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl and cyclohexyl, wherein the C1-6-alkyl, C2-4alkenyl, C2-4alkynyl, —OC1-6alkyl, —SC1-6alkyl, —NHC1-6alkyl, —N(C1-3alkyl)2, —NH-phenyl, —NH-benzyl, —O-phenyl and ring are optionally substituted, independently, with 1-5 substituents of R8; each R8, independently, is halo, haloalkyl, CN, OH, NO2, NH2, acetyl, —C(O)NHCH3, oxo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkylamino-, C1-6dialkylamino-, C1-6alkoxyl, C1-6thioalkoxyl, or a ring selected from the group consisting of pyridyl, pyrimidyl, phenyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, piperazinyl, oxetanyl and dioxolyl, wherein each of the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkylamino-, C1-6dialkylamino-, C1-6alkoxyl, C1-6thioalkoxyl and ring is optionally substituted independently with 1-5 substituents of F, Cl, Br, CN, CF3, OCF3, NO2, NH2, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, C1-3alkylamino-, C1-3dialkylamino-, C1-3thioalkoxyl or oxetanyl; alternatively, two adjacent R8 substituents together with the same atom to which they are attached form a 3-6 membered spirocyclic ring including 0-3 heteroatoms selected from N, O and S, the spirocyclic ring optionally substituted with 1-3 substituents of 1-5 substituents of F, Cl, CN, CF3, OCF3, NO2, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, C1-3alkylamino-, C1-3dialkylamino-, C1-3thioalkoxyl or oxetanyl; X is O, S or CF2; and Y is CR9R9 wherein each R9, independently, is H, F, C1-4alkyl or —CH2OCH3. |
| Claim: |
2. The compound of claim 1, or a stereoisomer, tautomer, hydrate, solvate or pharmaceutically acceptable salt thereof, having a general formula II [chemical expression included] wherein A1 is CH or CF; A3 is CH, CF or N; A3 is CH, CF or N, provided no more than one of A3 and A4 is N; R2 is Cl, Br, CN, C1-6-alkyl, C2-6alkenyl, C2-6alkynyl, CN, —OC1-6alkyl, —SC1-6alkyl, —NHC1-6alkyl, —N(C1-6alkyl)2, —NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, diazolyl, thiadiazolyl, thienyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl, cyclohexyl or —Si(CH3)3, wherein the C1-6-alkyl, C2-6alkenyl, C2-6alkynyl, —OC1-6alkyl, —SC1-6alkyl, —NHC1-6alkyl, —N(C1-6alkyl)2, —NH-phenyl, —NH-benzyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl and cyclohexyl are optionally substituted, independently, with 1-5 substituents of R8; R7 is C1-6-alkyl, C2-4alkenyl, C2-4alkynyl, CN, —OC1-6alkyl, —SC1-6alkyl, —NHC1-6alkyl, —N(C1-3alkyl)2, —NH-phenyl, —NH-benzyl, —O-phenyl or ring selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl and cyclohexyl, wherein the C1-6-alkyl, C2-4alkenyl, C2-4alkynyl, —OC1-6alkyl, —SC1-6alkyl, —NHC1-6alkyl, —N(C1-3alkyl)2, —NH-phenyl, —NH-benzyl, —O-phenyl and ring are optionally substituted, independently, with 1-5 substituents of R8; each R8, independently, is halo, haloalkyl, CN, OH, NO2, NH2, acetyl, —C(O)NHCH3, oxo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkylamino-, C1-6dialkylamino-, C1-6alkoxyl, C1-6thioalkoxyl, or a ring selected from the group consisting of pyridyl, pyrimidyl, phenyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, piperazinyl, oxetanyl and dioxolyl, wherein each of the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkylamino-, C1-6dialkylamino-, C1-6alkoxyl, C1-6thioalkoxyl and ring is optionally substituted independently with 1-5 substituents of F, Cl, Br, CN, CF3, OCF3, NO2, NH2, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, C1-3alkylamino-, C1-3dialkylamino-, C1-3thioalkoxyl or oxetanyl; alternatively, two adjacent R8 substituents together with the same atom to which they are attached form a 3-6 membered spirocyclic ring including 0-3 heteroatoms selected from N, O and S, the spirocyclic ring optionally substituted with 1-3 substituents of 1-5 substituents of F, Cl, CN, CF3, OCF3, NO2, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, C1-3alkylamino-, C1-3dialkylamino-, C1-3thioalkoxyl or oxetanyl; and X is O, S or CF2. |
| Claim: |
3. The compound of claim 2, or a stereoisomer or pharmaceutically acceptable salt thereof, having a general formula V [chemical expression included] wherein A3 is CH, CF or N; A4 is CH, CF or N, provided no more than one of A3 and A4 is N; R2 is Cl, Br, C1-6-alkyl, C2-6alkenyl, C2-6alkynyl, CN, —OC1-6alkyl, tert-butoxymethyl, —SC1-6alkyl, —NR8C1-6alkyl, —NR8C1-6alkyl, —N(C1-63alkyl)2, —NH-phenyl, —NH-benzyl, 2-fluoro-3-pyridyl, 3-methyl-3-oxetanyl-ethynyl, 3-methyl-3-oxetanyl-methoxyl, 3-pyridinylethynyl, 4-pyridyl, 2-methyl-4-pyridyl, 2-methyl-3-pyridyl, 5,6-dihydro-2H-pyran-3-yl, 5,6-dihydro-2H-pyran-2-yl, 3,6-dihydro-2H-pyran-4-yl, 3,4-dihydro-2H-pyran-6-yl, 3-pyridyl, 2-fluoro-4-pyridyl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, tetrahydrofuran-3-yl, 2-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 2-pyrrolidinyl, 4-morpholinyl, 2(5H)-furanyl, phenyl, cyclopropyl, isoxazol-5-yl, 1-methyl-1H-pyrazol-4-yl, 3-methyl-1H-pyrazol-1-yl, -oxo-5-azabicyclo[2.2.1]hept-5-yl, 3-methyl-3,3-dimethanol-1-propynyl, propyn-1-yl, 3-aza-bicyclo[3.1.0]hex-3-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, azetidinyl or —Si(CH3)3, wherein the C1-6-alkyl, C2-6alkenyl, C2-6alkynyl, —OC1-6alkyl, —SC1-6alkyl, —NR8C1-6alkyl, —N(C1-6alkyl)2, —NH-phenyl, —NH-benzyl, 2-fluoro-3-pyridyl, 3-methyl-3-oxetanyl-ethynyl, 3-methyl-3-oxetanyl-methoxyl, 3-pyridinylethynyl, 4-pyridyl, 2-methyl-4-pyridyl, 2-methyl-3-pyridyl, 5,6-dihydro-2H-pyran-3-yl, 5,6-dihydro-2H-pyran-2-yl, 3,6-dihydro-2H-pyran-4-yl, 3,4-dihydro-2H-pyran-6-yl, 3-pyridyl, 2-fluoro-4-pyridyl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, tetrahydrofuran-3-yl, 2-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyridazinyl, 2-pyrrolidinyl, 4-morpholinyl, 2(5H)-furanyl, phenyl, cyclopropyl, isoxazol-5-yl, 1-methyl-1H-pyrazol-4-yl, 3-methyl-1H-pyrazol-1-yl, -oxo-5-azabicyclo[2.2.1]hept-5-yl, 3-methyl-3,3-dimethanol-1-propynyl, propyn-1-yl, 3-aza-bicyclo[3.1.0]hex-3-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, azetidinyl or —Si(CH3)3 are optionally substituted, independently, with 1-3 substituents of R8; R7 is C1-6-alkyl, C2-4alkenyl, C2-4alkynyl, CN, —OC1-6alkyl, —SC1-6alkyl, —NHC1-6alkyl, —N(C1-3alkyl)2, —NH-phenyl, —NH-benzyl, 3-methyl-3-oxetanylmethoxyl, 3,3-dimethyl-3-cyanoethoxyl, 2,2-dimethylpropoxyl, cyclopropylethynyl, 3-methyl-3-oxetanylethynyl, 3,3-dimethylbutyn-1-yl, phenyl, 3-chlorophenyl, 3-cyanophenyl, 5-methyl-3-pyridyl, 5-methoxy-3-pyridyl, 2,4-difluoropyridyl, 2-fluoro-3-pyridyl, 5-fluoro-3-pyridyl, 6-fluoro-3-pyridyl, 5-chloro-2-fluoro-3-pyridyl, 5-(1-propynyl)-3-pyridyl, 2-fluoro-5-(1-propynyl)-3-pyridyl, 5-(3-methyl-3-oxetanylethynyl)-3-pyridyl, 5-(cyclopropylethynyl)-3-pyridyl, 5-pyrimidyl, pyrazin-2-yl, pyridazinyl or pyrazolyl, wherein the C1-6-alkyl, C2-4alkenyl, C2-4alkynyl, CN, —OC1-6alkyl, —SC1-6alkyl, —NHC1-6alkyl, —N(C1-3alkyl)2, —NH-phenyl, —NH-benzyl, 3-methyl-3-oxetanylmethoxyl, 3,3-dimethyl-3-cyanoethoxyl, 2,2-dimethylpropoxyl, cyclopropylethynyl, 3-methyl-3-oxetanylethynyl, 3,3-dimethylbutyn-1-yl, phenyl, 3-chlorophenyl, 3-cyanophenyl, 5-methyl-3-pyridyl, 5-methoxy-3-pyridyl, 2,4-difluoropyridyl, 2-fluoro-3-pyridyl, 5-fluoro-3-pyridyl, 6-fluoro-3-pyridyl, 5-chloro-2-fluoro-3-pyridyl, 5-(1-propynyl)-3-pyridyl, 2-fluoro-5-(1-propynyl)-3-pyridyl, 5-(3-methyl-3-oxetanylethynyl)-3-pyridyl, 5-(cyclopropylethynyl)-3-pyridyl, 5-pyrimidyl, pyrazin-2-yl, pyridazinyl and pyrazolyl are optionally substituted, independently, with 1-3 substituents of R8; each R8, independently, is halo, haloalkyl, CN, OH, NO2, NH2, acetyl, —C(O)NHCH3, oxo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkylamino-, C1-6dialkylamino-, C1-6alkoxyl, C1-6thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, piperazinyl, oxetanyl or dioxolyl, wherein each of the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C1-6alkylamino-, C1-6dialkylamino-, C1-6alkoxyl, C1-6thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetanyl or dioxolyl, is optionally substituted independently with 1-5 substituents of F, Cl, CN, NO2, NH2, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl, C1-3alkylamino-, C1-3dialkylamino, C1-3thioalkoxyl, or oxetanyl; and X is O or S. |
| Claim: |
4. The compound of claim 2, or a stereoisomer or pharmaceutically acceptable salt thereof, selected from 4-((5S)-2′-amino-7-(5-methyl-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-3-yl)-2-pyridinecarbonitrile; (5S)-3,7-diphenylspiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; 3-((5S)-2′-amino-3-(3,6-dihydro-2H-pyran-4-yl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-7-yl)benzonitrile; (5S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(5-methoxy-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(3-(trifluoromethyl)phenyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(2,4-difluoro-3-pyridinyl)-3-(3,6-dihydro-2H-pyran-4-yl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-2-fluoro-7-(2-fluoro-3-pyridinyl)-3-(trimethylsilyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; 2-fluoro-3,7-bis(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; 3-(3,3-dimethyl-1-butyn-1-yl)-2-fluoro-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; 2-fluoro-7-(2-fluoro-3-pyridinyl)-3-((3-methyl-3-oxetanyl)ethynyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; 3-(3,6-dihydro-2H-pyran-4-yl)-2-fluoro-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; 2-fluoro-7-(2-fluoro-3-pyridinyl)-3-(2-fluoro-4-pyridinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-1-fluoro-7-(2-fluoro-3-pyridinyl)-3-(2-fluoro-4-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(5-fluoro-3-pyridinyl)-3-((3-methyl-3-oxetanyl)ethynyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-((3-methyl-3-oxetanyl)ethynyl)-7-(3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-((3-methyl-3-oxetanyl)ethynyl)-7-phenylspiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(6-fluoro-3-pyridinyl)-3-((3-methyl-3-oxetanyl)ethynyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(3-chlorophenyl)-3-((3-methyl-3-oxetanyl)ethynyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(5-chloro-2-fluoro-3-pyridinyl)-3-((3-methyl-3-oxetanyl)ethynyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(cyclopropylethynyl)-3-(3,6-dihydro-2H-pyran-4-yl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-((3-methyl-3-oxetanyl)ethynyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(3,3-dimethyl-1-butyn-1-yl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(3,3-dimethyl-1-butyn-1-yl)-3-(2-fluoro-4-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(3,3-difluoro-1-pyrrolidinyl)-7-((3-methyl-3-oxetanyl)ethynyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; 3-((5S)-2′-amino-3-((3-methyl-3-oxetanyl)ethynyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-7-yl)benzonitrile; (5S)-7-(2,4-difluoro-3-pyridinyl)-3-(3,3-dimethyl-1-butyn-1-yl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(3-chlorophenyl)-3-(2-pyrazinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(6-fluoro-3-pyridinyl)-3-((3-methyl-3-oxetanyl)ethynyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-((3-methyl-3-oxetanyl)ethynyl)-7-(2-pyrazinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; 3-((5S)-2′-amino-3-(3,6-dihydro-2H-pyran-4-yl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-7-yl)benzonitrile; 3-((5S)-2′-amino-3-((3-methyl-3-oxetanyl)ethynyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-7-yl)benzonitrile; (5S)-7-(3-chloro-2-fluorophenyl)-3-(3,6-dihydro-2H-pyran-4-yl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(5,6-dihydro-2H-pyran-3-yl)-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(5-chloro-2-fluorophenyl)-3-(5,6-dihydro-2H-pyran-3-yl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(3-chlorophenyl)-3-(5,6-dihydro-2H-pyran-3-yl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(2-fluoro-3-pyridinyl)-3-((3S)-tetrahydro-2H-pyran-3-yl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(2-fluoro-3-pyridinyl)-3-((E)-2-(3-methyl-3-oxetanyl)ethenyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(6-fluoro-3-pyridinyl)-3-((E)-2-(3-methyl-3-oxetanyl)ethenyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(5-chloro-2-fluorophenyl)-3-((E)-2-(3-methyl-3-oxetanyl)ethenyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(cyclopropylethynyl)-3-(3,3-difluoro-1-pyrolidinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(cyclopropylethynyl)-3-(2,2-dimethyl-4-morpholinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(3,3-dimethyl-1-butyn-1-yl)-3-(1-methyl-1H-pyrazol-3-yl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(cyclopropylethynyl)-3-(4,4-difluoro-1-piperidinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(cyclopropylethynyl)-3-(3,3-dimethyl-1-pyrrolidinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(cyclopropylethynyl)-3-(1-methyl-1H-pyrazol-3-yl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-((2-methylpropyl)sulfanyl)-7-(3-pyridinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(5-chloro-3-pyridinyl)-3-((3-methyl-3-oxetanyl)ethynyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-((3-methyl-3-oxetanyl)ethynyl)-7-(5-(trifluoromethyl)-3-pyridinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-((2-methylbutyl)sulfanyl)-7-(3-pyridinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(3,4-difluorophenyl)-3-((3-methyl-3-oxetanyl)ethynyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (4S)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-2′-(2-oxa-7-azaspiro[3.5]non-7-yl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (4R)-2′-(3,6-dihydro-2H-pyran-4-yl)-7′-(2-fluoro-3-pyridinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; 5-((4R)-2-amino-7′-(3,6-dihydro-2H-pyran-4-yl)spiro[1,3-oxazole-4,9′-xanthen]-2′-yl)-3-pyridinecarbonitrile; (4R)-2′-(3,6-dihydro-2H-pyran-4-yl)-7′-(2-fluoro-5-methyl-3-pyridinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (4R)-2′-(3,6-dihydro-2H-pyran-4-yl)-7′-(2-pyrazinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (4R)-2′-(3,6-dihydro-2H-pyran-4-yl)-7′-(5-fluoro-3-pyridinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (4R)-2′-(3,6-dihydro-2H-pyran-4-yl)-7′-(5-methoxy-3-pyridinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; 3-((4R)-2-amino-7′-(3,6-dihydro-2H-pyran-4-yl)spiro[1,3-oxazole-4,9′-xanthen]-2′-yl)benzonitrile; (4S)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-2′-(2-pyridinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (4S)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-2′-(2-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (4S)-7′-(3,6-dihydro-2H-pyran-4-yl)-5′-fluoro-N˜2˜′-(3-methoxyphenyl)spiro[1,3-oxazole-4,9′-xanthene]-2,2′-diamine; (4S)-5′-fluoro-N˜2˜′-(3-methoxyphenyl)-7′-(4-morpholinyl)spiro[1,3-oxazole-4,9′-xanthene]-2,2′-diamine; 4-((4S)-2-amino-4′-fluoro-7′-(2-fluoro-3-pyridinyl)spiro[1,3-oxazole-4,9′-xanthen]-2′-yl)-2-methyl-3-butyn-2-ol; 4-((4S)-2-amino-4′-fluoro-7′-(2-fluoro-3-pyridinyl)spiro[1,3-oxazole-4,9′-xanthen]-2′-yl)-2-methyl-2-butanol; and 4-((4S)-2-amino-4′-fluoro-7′-(2-fluoro-3-pyridinyl)spiro[1,3-oxazole-4,9′-xanthen]-2′-yl)-6-methyl-2H-pyran-2-one. |
| Claim: |
5. The compound of claim 2, or a stereoisomer or pharmaceutically acceptable salt thereof, selected from (5S)-7-(2,4-difluoro-3-pyridinyl)-3-(3,6-dihydro-2H-pyran-4-yl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]thiazol]-2′-amine; 3-((5S)-2′-amino-3-((3-methyl-3-oxetanyl)ethynyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-7-yl)benzonitrile; (4S)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-2′-(2-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (4S)-2′-(5,6-dihydro-2H-pyran-3-yl)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (5S)-3-(3,6-dihydro-2H-pyran-4-yl)-1-fluoro-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-1-fluoro-7-(2-fluoro-3-pyridinyl)-3-(tetrahydro-2H-pyran-4-yl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (4S)-4′-fluoro-7′-(2-fluoro-5-methyl-3-pyridinyl)-2′-(4-morpholinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (5S)-7-(2-fluoro-3-pyridinyl)-3-((3S)-3-fluoro-1-pyrrolidinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; 3-((5S)-2′-amino-3-(3,3-difluoro-1-pyrrolidinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-7-yl)benzonitrile; (5S)-3-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-7-(5-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (4R)-2′-(3,6-dihydro-2H-pyran-4-yl)-7′-(2-fluoro-3-pyridinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (5S)-3-(4,4-difluoro-1-piperidinyl)-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(3,3-difluoro-1-pyrrolidinyl)-7-(3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (4S)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-2′-(4-morpholinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (5S)-3-(3,3-difluoro-1-pyrrolidinyl)-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (4S)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-2′-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (4S)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-2′-(2-methyl-5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (5S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoro-4-methyl-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (4S)-4′-fluoro-7′-(6-fluoro-3-pyridinyl)-2′-(1-methyl-1H-pyrazol-4-yl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (4S)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-2′-((3S)-3-fluoro-1-pyrrolidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (5R)-3-(3,3-dimethyl-1-butyn-1-yl)-8-fluoro-7-(5-pyrimidinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-7-(6-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; and (5S)-3-(5,6-dihydro-2H-pyran-3-yl)-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine. |
| Claim: |
6. The compound of claim 2, or a stereoisomer or pharmaceutically acceptable salt thereof, selected from (5S)-3-(4,4-difluoro-1-piperidinyl)-7-(3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(4,4-difluoro-1-piperidinyl)-7-(5-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; 3-(((4S)-2-amino-5′-fluoro-7′-(6-methyl-3-pyridinyl)spiro[1,3-oxazole-4,9′-xanthen]-2′-yl)oxy)-2,2-dimethylpropanenitrile; (4S)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-7′-(2-pyrazinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (5S)-7-(3-chloro-2-fluorophenyl)-3-((3-methyl-3-oxetanyl)ethynyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-1-fluoro-7-(2-fluoro-3-pyridinyl)-3-(3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (4R)-7′-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-3′-fluoro-2′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (4S)-3′,5′-difluoro-7′-(2-fluoro-2-methylpropoxy)-2′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (5S)-3-(5,6-dihydro-2H-pyran-3-yl)-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]thiazol]-2′-amine; (5S)-1-fluoro-7-(2-fluoro-3-pyridinyl)-3-((3R)-3-fluoro-1-pyrrolidinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(2,4-difluoro-3-pyridinyl)-3-(5,6-dihydro-2H-pyran-3-yl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-7-(3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-1-fluoro-7-(2-fluoro-3-pyridinyl)-3-(6-methyl-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-1-fluoro-7-(5-(1-propyn-1-yl)-3-pyridinyl)-3-(3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (4S)-2′-(5,6-dihydro-2H-pyran-3-yl)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)spiro[1,3-thiazole-4,9′-xanthen]-2-amine; (5S)-3-(2-fluoro-4-pyridinyl)-1-methoxy-7-(3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; 3-(((4S)-2-amino-4′,6′-difluoro-7′-(3-pyridinyl)spiro[1,3-oxazole-4,9′-xanthen]-2′-yl)oxy)-2,2-dimethylpropanenitrile; (4S)-7′-(3,6-dihydro-2H-pyran-4-yl)-3′,5′-difluoro-2′-(2-fluoro-3-pyridinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (4S)-3′,5′-difluoro-2′-(2-fluoro-3-pyridinyl)-7′-(4-morpholinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (5S)-1-fluoro-7-(2-fluoro-3-pyridinyl)-3-(4-morpholinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-1-fluoro-7-(5-fluoro-3-pyridinyl)-3-(4-morpholinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; 3-((5S)-2′-amino-1-fluoro-3-(4-morpholinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-7-yl)benzonitrile; and (5S)-2-fluoro-7-(2-fluoro-3-pyridinyl)-3-((3-methyl-3-oxetanyl)ethynyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine. |
| Claim: |
7. The compound of claim 2, or a stereoisomer or pharmaceutically acceptable salt thereof, selected from (5S)-3-(3,3-difluoro-1-pyrrolidinyl)-1-fluoro-7-(3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(3,3-difluoro-1-pyrrolidinyl)-1-fluoro-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(3,3-difluoro-1-pyrrolidinyl)-1-fluoro-7-(5-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(4,4-difluoro-1-piperidinyl)-1-fluoro-7-(5-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(5,6-dihydro-2H-pyran-3-yl)-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]thiazol]-2′-amine; (5S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(5-(1-propyn-1-yl)-3-pyridinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (4S)-4′-fluoro-2′-(1-methyl-1H-pyrazol-4-yl)-7′-(5-(1-propyn-1-yl)-3-pyridinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; 4-((4S)-2-amino-4′-fluoro-7′-(5-(1-propyn-1-yl)-3-pyridinyl)spiro[1,3-oxazole-4,9′-xanthen]-2′-yl)-2-methyl-3-butyn-2-ol; (5S)-1-fluoro-7-(2-fluoro-3-pyridinyl)-3-(2-fluoro-4-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]thiazol]-2′-amine; (5S)-7-(2-fluoro-3-pyridinyl)-3-(4-morpholinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]thiazol]-2′-amine; (5S)-7-(2-fluoro-3-pyridinyl)-3-(2-fluoro-4-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]thiazol]-2′-amine; (5S)-3-(3,6-dihydro-2H-pyran-4-yl)-1-fluoro-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]thiazol]-2′-amine; (5S)-1-fluoro-7-(2-fluoro-3-pyridinyl)-3-(tetrahydro-2H-pyran-4-yl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]thiazol]-2′-amine; (5S)-3-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-1-fluoro-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]thiazol]-2′-amine; (5S)-1-fluoro-7-(2-fluoro-3-pyridinyl)-3-(2-methyl-4-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]thiazol]-2′-amine; (4S)-4′-fluoro-2′-(2-fluoro-2-methylpropoxy)-7′-(2-fluoro-3-pyridinyl)spiro[1,3-thiazole-4,9′-xanthen]-2-amine; (4S)-2′-(4,4-difluoro-1-piperidinyl)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)spiro[1,3-thiazole-4,9′-xanthen]-2-amine; (4S)-2′-(3,3-difluoro-1-pyrrolidinyl)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)spiro[1,3-thiazole-4,9′-xanthen]-2-amine; (4S)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-2′-(2-pyrimidinyl)spiro[1,3-thiazole-4,9′-xanthen]-2-amine; (4S)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-2′-(3-pyridinyl)spiro[1,3-thiazole-4,9′-xanthen]-2-amine; and (4S)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-2′-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)spiro[1,3-thiazole-4,9′-xanthen]-2-amine. |
| Claim: |
8. The compound of claim 2, or a stereoisomer or pharmaceutically acceptable salt thereof, selected from (5S)-7-(2,4-difluoro-3-pyridinyl)-3-(3,6-dihydro-2H-pyran-4-yl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-7-(3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (4S)-2′-(5,6-dihydro-2H-pyran-3-yl)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)spiro[1,3-thiazole-4,9′-xanthen]-2-amine; (5S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoro-4-methyl-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (4S)-7′-(3,6-dihydro-2H-pyran-4-yl)-3′,5′-difluoro-2′-(2-fluoro-3-pyridinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (4S)-2′-(5,6-dihydro-2H-pyran-3-yl)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (5S)-3-(5,6-dihydro-2H-pyran-3-yl)-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-7-(5-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (4S)-2′-(3,6-dihydro-2H-pyran-4-yl)-4′-fluoro-7′-(2-pyrazinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (5S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(5-(1-propyn-1-yl)-3-pyridinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]thiazol]-2′-amine; (5S)-3-(3,6-dihydro-2H-pyran-4-yl)-1-fluoro-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]thiazol]-2′-amine; (5S)-3-(3,6-dihydro-2H-pyran-4-yl)-1-fluoro-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; and (5S)-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]thiazol]-2′-amine. |
| Claim: |
9. The compound of claim 2, or a stereoisomer or pharmaceutically acceptable salt thereof, selected from (4S)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-2′-(4-morpholinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (5S)-1-fluoro-7-(2-fluoro-3-pyridinyl)-3-(4-morpholinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-1-fluoro-7-(5-fluoro-3-pyridinyl)-3-(4-morpholinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; 3-((5S)-2′-amino-1-fluoro-3-(4-morpholinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-7-yl)benzonitrile; and (4S)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-2′-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)spiro[1,3-thiazole-4,9′-xanthen]-2-amine. |
| Claim: |
10. The compound of claim 2, or a stereoisomer or pharmaceutically acceptable salt thereof, selected from (5S)-3-(3,3-difluoro-1-pyrrolidinyl)-1-fluoro-7-(3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(4,4-difluoro-1-piperidinyl)-1-fluoro-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(3,3-difluoro-1-pyrrolidinyl)-1-fluoro-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(3,3-difluoro-1-pyrrolidinyl)-1-fluoro-7-(5-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(4,4-difluoro-1-piperidinyl)-1-fluoro-7-(5-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(3,3-difluoro-1-pyrrolidinyl)-7-(3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(3,3-difluoro-1-pyrrolidinyl)-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-3-(4,4-difluoro-1-piperidinyl)-7-(2-fluoro-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-7-(2-fluoro-3-pyridinyl)-3-((3S)-3-fluoro-1-pyrrolidinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; 3-((5S)-2′-amino-3-(3,3-difluoro-1-pyrrolidinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-7-yl)benzonitrile; (5S)-1-fluoro-7-(2-fluoro-3-pyridinyl)-3-(tetrahydro-2H-pyran-4-yl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; and (4S)-2′-(3,3-difluoro-1-pyrrolidinyl)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)spiro[1,3-thiazole-4,9′-xanthen]-2-amine. |
| Claim: |
11. The compound of claim 2, or a stereoisomer or pharmaceutically acceptable salt thereof, selected from (4S)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-2′-(2-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (5S)-1-fluoro-7-(2-fluoro-3-pyridinyl)-3-(6-methyl-3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (5S)-1-fluoro-7-(5-(1-propyn-1-yl)-3-pyridinyl)-3-(3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (4S)-4′-fluoro-2′-(1-methyl-1H-pyrazol-4-yl)-7′-(5-(1-propyn-1-yl)-3-pyridinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine; (5S)-1-fluoro-7-(2-fluoro-3-pyridinyl)-3-(2-fluoro-4-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]thiazol]-2′-amine; (5S)-7-(2-fluoro-3-pyridinyl)-3-(2-fluoro-4-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]thiazol]-2′-amine; (5S)-1-fluoro-7-(2-fluoro-3-pyridinyl)-3-(3-pyridinyl)spiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazol]-2′-amine; (4S)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-2′-(2-pyrimidinyl)spiro[1,3-thiazole-4,9′-xanthen]-2-amine; and (4S)-4′-fluoro-7′-(2-fluoro-3-pyridinyl)-2′-(3-pyridinyl)spiro[1,3-thiazole-4,9′-xanthen]-2-amine. |
| Claim: |
12. A pharmaceutical composition comprising a compound according to any of claim 3 and a pharmaceutically acceptable excipient. |
| Claim: |
13. A pharmaceutical composition comprising a compound according to any of claim 4 and a pharmaceutically acceptable excipient. |
| Claim: |
14. A pharmaceutical composition comprising a compound according to any of claim 5 and a pharmaceutically acceptable excipient. |
| Claim: |
15. A pharmaceutical composition comprising a compound according to any of claim 6 and a pharmaceutically acceptable excipient. |
| Claim: |
16. A pharmaceutical composition comprising a compound according to any of claim 7 and a pharmaceutically acceptable excipient. |
| Claim: |
17. A pharmaceutical composition comprising a compound according to any of claim 8 and a pharmaceutically acceptable excipient. |
| Claim: |
18. A pharmaceutical composition comprising a compound according to any of claim 9 and a pharmaceutically acceptable excipient. |
| Claim: |
19. A pharmaceutical composition comprising a compound according to any of claim 10 and a pharmaceutically acceptable excipient. |
| Claim: |
20. A pharmaceutical composition comprising a compound according to any of claim 11 and a pharmaceutically acceptable excipient. |
| Claim: |
21. A method of reducing the levels of beta amyloid peptide in the cerebral spinal fluid of a subject, the method comprising administering to the subject an effective dosage amount of a compound according to claim 5. |
| Claim: |
22. A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject an effective dosage amount of a compound according to claim 5. |
| Claim: |
23. A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject an effective dosage amount of a compound according to claim 6. |
| Claim: |
24. A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject an effective dosage amount of a compound according to claim 7. |
| Claim: |
25. A method of treating Alzheimer's disease, cognitive impairment or a combination thereof in a subject, the method comprising administering to the subject an effective dosage amount of a pharmaceutical composition of claim 14. |
| Claim: |
26. A method of treating a neurological disorder selected from the group consisting of mild cognitive impairment, Down's syndrome, Hereditary cerebral hemorrhage with dutch-type amyloidosis, cerebral amyloid angiopathy, degenerative dementia, dementia associated with Parkinson's disease, dementia associated with supranuclear palsy, dementia associated with cortical basal degeneration, diffuse lewy body type of Alzheimer's disease or a combination thereof, in a subject, the method comprising administering to the subject an effective dosage amount of a compound of claim 1. |
| Claim: |
27. A method of treating a neurological disorder selected from the group consisting of mild cognitive impairment, Down's syndrome, Hereditary cerebral hemorrhage with dutch-type amyloidosis, cerebral amyloid angiopathy, degenerative dementia, dementia associated with Parkinson's disease, dementia associated with supranuclear palsy, dementia associated with cortical basal degeneration, diffuse lewy body type of Alzheimer's disease or a combination thereof, in a subject, the method comprising administering to the subject an effective dosage amount of a compound of claim 5. |
| Claim: |
28. A method of treating a neurological disorder selected from the group consisting of mild cognitive impairment, Down's syndrome, Hereditary cerebral hemorrhage with dutch-type amyloidosis, cerebral amyloid angiopathy, degenerative dementia, dementia associated with Parkinson's disease, dementia associated with supranuclear palsy, dementia associated with cortical basal degeneration, diffuse lewy body type of Alzheimer's disease or a combination thereof, in a subject, the method comprising administering to the subject an effective dosage amount of a pharmaceutical composition according to claim 14. |
| Claim: |
29. A process for preparing a compound of claim 1, the process comprising the step of reacting a compound 20 [chemical expression included] wherein A1, A2, A3, A4, A5, A6, R2, X and Y of Formula I are as defined in claim 1, with a compound having the structure [chemical expression included] or R7—B(OH)2, wherein R7 is as defined in claim 1, to prepare a compound of Formula I. |
| Current U.S. Class: |
5142/305 |
| Current International Class: |
61; 61; 07; 07; 61; 61; 07; 61; 07; 61; 61; 61; 07; 61 |
| رقم الانضمام: |
edspap.20110251190 |
| قاعدة البيانات: |
USPTO Patent Applications |