Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
The present invention provides a new class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula I: wherein variables A 4 , A 5 , A 6 , A 8 , R 1 , R 2 , R 3 , R 7 and n of Formula I, independently, are defined herein. The invention also provides pharmaceutical compositions comprising the compounds, and corresponding uses of the compounds and compositions for treatment of disorders and/or conditions related to A-beta plaque formation and deposition, resulting from the biological activity of BACE. Such BACE mediated disorders include, for example, Alzheimer's Disease, cognitive deficits, cognitive impairments, schizophrenia and other central nervous system conditions. The invention further provides compounds of Formula II and sub-formula embodiments thereof, intermediates and processes and methods useful for the preparation of compounds of Formulas I-II.
1. A compound of Formula II-B
or a stereoisomer, tautomer, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein
A 4 is CR 4 or N;
A 5 is CR 5 or N;
A 6 is CR 6 or N;
A 8 is CR 8 or N, provided that no more than one of A 4 , A 5 , A 6 and A 8 is N;
each of R 1 and R 2 , independently, is H, F, Cl, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, CN, —CH 2 OC 1-3 -alkyl, —OC 1-3 -alkyl, wherein each of the C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl and C 1-3 -alkyl portion of —CH 2 OC 1-3 -alkyl and —OC 1-3 -alkyl are optionally substituted with 1-4 substituents of F;
alternatively, each R 1 taken together with the carbon atom to which they are attached form a C 3-6 spirocarbocyclic ring optionally including one heteroatom selected from O and N and optionally substituted with 1-4 F atoms on the carbon atoms and a substituent of C 1-3 -alkyl, CH 2 OC 1-2 -alkyl or C 1-3 -haloalkyl on the nitrogen atom;
alternatively, each R 2 taken together with the carbon atom to which they are attached form a C 3-6 spirocarbocyclic ring optionally including one heteroatom selected from O and N and optionally substituted with 1-4 F atoms on the carbon atoms and a substituent of C 1-3 -alkyl, CH 2 OC 1-2 -alkyl or C 1-3 -haloalkyl on the nitrogen atom;
R 3 is C 1-4 -alkyl, CH 2 OC 1-4 -alkyl, CH 2 OH, C 1-4 -haloalkyl or cyclopropyl, wherein each of the C 1-4 -alkyl, CH 2 OC 1-4 -alkyl, C 1-4 -haloalkyl and cyclopropyl is optionally substituted with 1-4 F atoms;
alternatively, one R 2 and R 3 taken together with the carbon atoms to which they are attached form a C 3-6 carbocyclic ring optionally including 1-2 heteroatoms selected from O and N and optionally substituted with 1-4 F atoms on the carbon atoms and a substituent of C 1-3 -alkyl, CH 2 OC 1-2 -alkyl or C 1-3 -haloalkyl on the nitrogen atom;
each of R 4 , R 5 , R 6 and R 8 , independently, is H or F;
each R 10 , independently, is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , SF 5 , acetyl, —C(O)NHCH 3 , oxo, cycloproylmethoxy, 2-butynyloxy, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkylamino-, C 1-6 -dialkylamino-, C 1-6 -alkoxyl, C 1-6 -thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein each of the C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkylamino-, C 1-6 -dialkylamino-, C 1-6 -alkoxyl, C 1-6 -thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl, is optionally substituted independently with 1-5 substituents of F, Cl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl, tert-butyl, C 1-3 -alkylamino-, C 1-3 -dialkylamino, C 1-3 -thioalkoxyl or oxetan-3-yl; and
each W, independently, is CH, CF, CCl or N.
2. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein
A 4 is CR 4 ;
A 5 is CR 5 ;
A 6 is CR 6 ;
A 8 is CR 8 ; wherein each of R 4 , R 5 , R 6 and R 8 , independently, is H or F;
each of R 1 and R 2 , independently, is H, F, CH 3 , C 2 H 5 , CF 2 H, CH 2 F, CH 2 OCH 2 F, CH 2 OCF 2 H or CH 2 OCF 3 ;
alternatively, each R 1 taken together with the carbon atom to which they are attached form a C 3-6 spirocarbocyclic ring optionally including one heteroatom selected from O and N and optionally substituted with 1-3 F atoms;
alternatively, each R 2 taken together with the carbon atom to which they are attached form a C 3-6 spirocarbocyclic ring optionally including one heteroatom selected from O and N and optionally substituted with 1-3 F atoms; and
R 3 is CH 3 , C 2 H 5 , CF 2 H or CH 2 F.
3. The compound according to claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein
A 4 is CR 4 or N;
A 5 is CR 5 or N;
A 6 is CR 6 or N;
A 8 is CR 8 or N, wherein each of R 4 , R 5 , R 6 and R 8 , independently, is H or F and provided no more than one of A 4 , A 5 , A 6 and A 8 is N;
each of R 1 and R 2 , independently, is H, F, Cl, CF 3 , CH 3 , CF 2 H or CH 2 F; and
R 3 is CF 3 , CH 3 , CF 2 H or CH 2 F.
4. A compound of Formula III-B-1
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein
A 4 is CR 4 or N;
A 5 is CR 5 or N;
A 6 is CR 6 or N;
A 8 is CR 8 or N, provided that no more than one of A 4 , A 5 , A 6 and A 8 is N;
each of R 1 and R 2 , independently, is H, F, Cl, C 2-4 -alkenyl, C 2-4 -alkynyl, CN, —CH 2 OC 1-6 -alkyl, —S(O)C 1-6 -alkyl, —NHC 1-6 -alkyl or —C(O)C 1-6 -alkyl, wherein each of the C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, and C 1-6 -alkyl portion of —CH 2 OC 1-6 -alkyl, —S(O)C 1-6 -alkyl, —NHC 1-6 -alkyl and —C(O)C 1-6 -alkyl are optionally substituted with 1-4 substituents of F, oxo or OH;
alternatively, each R 1 taken together with the carbon atom to which they are attached form a C 3-6 spirocarbocyclic ring optionally including one heteroatom selected from O and N and optionally substituted with 1-4 F atoms on the carbon atoms and a substituent of C 1-3 -alkyl, CH 2 OC 1-2 -alkyl or C 1-3 -haloalkyl on the nitrogen atom;
alternatively, each R 2 taken together with the carbon atom to which they are attached form a C 3-6 spirocarbocyclic ring optionally including one heteroatom selected from O and N and optionally substituted with 1-4 F atoms on the carbon atoms and a substituent of C 1-3 -alkyl, CH 2 OC 1-2 -alkyl or C 1-3 -haloalkyl on the nitrogen atom;
R 3 is C 1-4 -alkyl, CH 2 OH, CH 2 OC 1-4 -alkyl, C 1-4 -haloalkyl or cyclopropyl, wherein each of the C 1-4 -alkyl, CH 2 OC 1-4 -alkyl, C 1-4 -haloalkyl and cyclopropyl is optionally substituted with 1-4 F atoms;
alternatively, one R 2 and R 3 taken together with the carbon atoms to which they are attached form a C 3-6 -carbocyclic ring optionally including 1-2 heteroatoms selected from O and N and optionally substituted with 1-4 F atoms on the carbon atoms and a substituent of C 1-3 -alkyl, CH 2 OC 1-2 -alkyl or C 1-3 -haloalkyl on the nitrogen atom;
each of R 4 , R 5 , R 6 and R 8 , independently, is H, halo, haloalkyl, haloalkoxyl, C 1-4 -alkyl, CN, OH, OC 1-4 -alkyl, S(O)C 1-4 -alkyl, NHC 1-4 -alkyl or C(O)C 1-4 -alkyl;
each R 10 , independently, is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , SF 5 , acetyl, —C(O)NHCH 3 , oxo, cyclopropylmethoxy, 2-butynyloxy, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkylamino-, C 1-6 -dialkylamino-, C 1-6 -alkoxyl, C 1-6 -thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein each of the C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkylamino-, C 1-6 -alkoxyl, C 1-6 -thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl, is optionally substituted independently with 1-5 substituents of F, Cl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl, tert-butyl, C 1-3 -alkylamino-, C 1-3 -dialkylamino, C 1-3 -thioalkoxyl or oxetan-3-yl; and
each W, independently, is CH, CF, CCl or N.
5. A compound of Formula III-E
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein
A 4 is CR 4 or N;
A 5 is CR 5 or N;
A 6 is CR 6 or N;
A 8 is CR 8 or N, provided that no more than two of A 4 , A 5 , A 6 and A 8 is N;
R is a C 3-6 -spirocarbocyclic ring optionally including one heteroatom selected from O and N and optionally substituted with 1-4 F atoms on the carbon atoms and/or a substituent of C 1-3 -alkyl, CH 2 OC 1-2 -alkyl or C 1-3 -haloalkyl on the nitrogen atom;
each of R 1 , independently, is H, F, Cl, C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, CN, —CH 2 OC 1-6 -alkyl, —OC 1-6 -alkyl, —S(O)C 1-6 -alkyl, —NHC 1-6 -alkyl or —C(O)C 1-6 -alkyl, wherein each of the C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, and C 1-6 -alkyl portion of —CH 2 OC 1-6 -alkyl, —OC 1-6 -alkyl, —S(O)C 1-6 -alkyl, —NHC 1-6 -alkyl and —C(O)C 1-6 -alkyl are optionally substituted with 1-4 substituents of F, oxo or OH;
alternatively, each R 1 taken together with the carbon atom to which they are attached form a C 3-6 spirocarbocyclic ring optionally including one heteroatom selected from O and N and optionally substituted with 1-4 F atoms on the carbon atoms and a substituent of C 1-3 -alkyl, CH 2 OC 1-2 -alkyl or C 1-3 -haloalkyl on the nitrogen atom;
R 3 is C 1-4 -alkyl, CH 2 OH, CH 2 OC 1-4 -alkyl, C 1-4 -haloalkyl or cyclopropyl, wherein each of the C 1-4 -alkyl, CH 2 OC 1-4 -alkyl, C 1-4 -haloalkyl and cyclopropyl is optionally substituted with 1-4 F atoms;
each of R 4 , R 5 , R 6 and R 8 , independently, is H, halo, haloalkyl, haloalkoxyl,
C 1-4 -alkyl, CN, OH, OC 1-4 -alkyl, S(O)C 1-4 -alkyl, NHC 1-4 -alkyl or C(O)C 1-4 -alkyl;
R 7 is —NH—R 9 , —NH—C(═O)—R 9 , —C(═O)NH—R 9 , —O—R 9 , —S—R 9 ;
or R 7 is
wherein V is NR 10 , O or S; and
each W, independently, is CH, CF, CCl or N;
R 9 is acetyl, C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl or a ring selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl, furanyl, dihydrofuranyl, thienyl, and pyrrolyl, wherein the C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl and ring are optionally substituted, independently, with 1-5 substituents of R 10 ; and
each R 10 , independently, is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , SF 5 , acetyl, —C(O)NHCH 3 , oxo, cyclopropylmethoxy, 2-butynyloxy, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkylamino-, C 1-6 -dialkylamino-, C 1-6 -alkoxyl, C 1-6 -thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein each of the C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkylamino-, C 1-6 -dialkylamino-, C 1-6 -alkoxyl, C 1-6 -thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl, is optionally substituted independently with 1-5 substituents of F, Cl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl, tert-butyl, C 1-3 -alkylamino-, C 1-3 -dialkylamino-, C 1-3 -thioalkoxyl or oxetan-3-yl.
6. The compound of claim 5 , or a stereoisomer or pharmaceutically acceptable salt thereof, as defined by Formula III-E-1
wherein
A 4 is CR 4 or N;
A 5 is CR 5 or N;
A 6 is CR 6 or N;
A 8 is CR 8 or N, provided that no more than one of A 4 , A 5 , A 6 and A 8 is N;
each R a , independently, is H or F;
each of R 1 , independently, is H, F, Cl, CF 3 , OCF 3 , methyl, ethyl, CN, OCH 3 , NHCH 3 , C(O)CH 3 or CH 2 OCHF 2 ;
alternatively, each R 1 taken together with the carbon atom to which they are attached form a C 3-6 spirocarbocyclic ring optionally including one heteroatom selected from O and N and optionally substituted with 1-4 F atoms on the carbon atoms and a substituent of C 1-3 -alkyl, CH 2 OC 1-2 -alkyl or C 1-3 -haloalkyl on the nitrogen atom;
R 3 is C 1-4 -alkyl, C 1-4 -haloalkyl, CH 2 OH, CH 2 OCHF 2 or cyclopropyl;
each of R 4 , R 5 , R 6 and R 8 , independently, is H, F, Cl, CF 3 , OCF 3 , methyl, ethyl, CN, OH, OCH 3 , NHCH 3 or C(O)CH 3 ;
R 7 is —NH—R 9 , —NH—C(═O)—R 9 , —C(═O)NH—R 9 , —O—R 9 , —S—R 9 ;
or R 7 is
wherein V is NR 10 , O or S; and
each W, independently, is CH, CF, CCl or N;
R 9 is acetyl, C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl or a ring selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl, furanyl, dihydrofuranyl, thienyl, and pyrrolyl, wherein the C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl and ring are optionally substituted, independently, with 1-5 substituents of R 10 ; and
each R 10 , independently, is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , SF 5 , acetyl, —C(O)NHCH 3 , oxo, cyclopropylmethoxy, 2-butynyloxy, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkylamino-, C 1-6 -dialkylamino-, C 1-6 -alkoxyl, C 1-6 -thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein each of the C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkylamino-, C 1-6 -dialkylamino-, C 1-6 -alkoxyl, C 1-6 -thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl, is optionally substituted independently with 1-5 substituents of F, Cl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl, tert-butyl, C 1-3 -alkylamino-, C 1-3 -dialkylamino-, C 1-3 -thioalkoxyl or oxetan-3-yl.
7. A compound of Formula III-F
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein
A 4 is CR 4 or N;
A 5 is CR 5 or N;
A 6 is CR 6 or N;
A 8 is CR 8 or N, provided that no more than two of A 4 , A 5 , A 6 and A 8 is N;
M is a C 3-6 -carbocyclic ring optionally including one or two heteroatoms selected from O and N and optionally substituted with 1-4 F atoms on the carbon atoms and/or a substituent of C 1-3 =alkyl, CH 2 OC 1-2 -alkyl or C 1-3 -haloalkyl on a nitrogen atom;
each of R 1 , independently, is H, F, C 2-4 -alkenyl, C 2-4 -alkynyl, CN, —CH 2 OC 1-6 -alkyl, —OC 1-6 -alkyl, —S(O)C 1-6 -alkyl, —NHC 1-6 -alkyl or —C(O)C 1-6 -alkyl, wherein each of the C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, and C 1-6 -alkyl portion of —CH 2 OC 1-6 -alkyl, —S(O)C 1-6 -alkyl, —NHC 1-6 -alkyl and —C(O)C 1-6 -alkyl are optionally substituted with 1-4 substituents of F, oxo or OH;
alternatively, each R 1 taken together with the carbon atom to which they are attached form a C 3-6 spirocarbocyclic ring optionally including one heteroatom selected from O and N and optionally substituted with 1-4 F atoms on the carbon atoms and a substituent of C 1-3 -alkyl, CH 2 OC 1-2 -alkyl or C 1-3 -haloalkyl on the nitrogen atom;
R 2 is H, F, C 2-4 -alkenyl, C 2-4 -alkynyl, CN, —CH 2 OC 1-6 -alkyl, —S(O)C 1-6 -alkyl, —NHC 1-6 -alkyl or —C(O)C 1-6 -alkyl, wherein each of the C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, and C 1-6 -alkyl portion of —CH 2 OC 1-6 -alkyl, —S(O)C 1-6 -alkyl, —NHC 1-6 -alkyl and —C(O)C 1-6 -alkyl are optionally substituted with 1-4 substituents of F, oxo or OH;
each of R 4 , R 5 , R 6 and R 8 , independently, is H, halo, haloalkyl, haloalkoxyl, CN, OH, OC 1-4 -alkyl, S(O)C 1-4 -alkyl, NHC 1-4 -alkyl or C(O)C 1-4 -alkyl;
R 7 is —NH—R 9 , —NH—C(═O)—R 9 , —C(═O)NH—R 9 , —O—R 9 , —S—R 9 ;
or R 7 is
wherein V is NR 10 , O or S; and
each W, independently, is CH, CF, CCl or N;
R 9 is acetyl, C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl or a ring selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl, furanyl, dihydrofuranyl, thienyl, and pyrrolyl, wherein the C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl and ring are optionally substituted, independently, with 1-5 substituents of R 10 ; and
each R 10 , independently, is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , SF 5 , acetyl, —C(O)NHCH 3 , oxo, cyclopropylmethoxy, 2-butynyloxy, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkylamino-, C 1-6 -dialkylamino-, C 1-6 -alkoxyl, C 1-6 -thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein each of the C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkylamino-, C 1-6 -dialkylamino-, C 1-6 -alkoxyl, C 1-6 -thioalkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl, is optionally substituted independently with 1-5 substituents of F, Cl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl, tert-butyl, C 1-3 -alkylamino-, C 1-3 -dialkylamino-, C 1-3 -thioalkoxyl or oxetan-3-yl.
8. The compound of claim 7 , or a stereoisomer or pharmaceutically acceptable salt thereof, as defined by Formula III-F-1
wherein
A 4 is CR 4 or N;
A 5 is CR 5 or N;
A 6 is CR 6 or N;
A 8 is CR 8 or N, provided that no more than two of A 4 , A 5 , A 6 and A 8 is N;
each R a , independently, is H or F;
each R 1 , independently, is H, F, C 2-4 -alkenyl, C 2-4 -alkynyl, CN, —CH 2 OC 1-6 -alkyl, —S(O)C 1-6 -alkyl, —NHC 1-6 -alkyl or —C(O)C 1-6 -alkyl, wherein each of the C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, and C 1-6 -alkyl portion of —CH 2 OC 1-6 -alkyl, —S(O)C 1-6 -alkyl, —NHC 1-6 -alkyl and —C(O)C 1-6 -alkyl are optionally substituted with 1-4 substituents of F, oxo or OH;
alternatively, each R 1 taken together with the carbon atom to which they are attached form a C 3-6 spirocarbocyclic ring optionally including one heteroatom selected from O and N and optionally substituted with 1-4 F atoms on the carbon atoms and a substituent of C 1-3 -alkyl, CH 2 OC 1-2 -alkyl or C 1-3 -haloalkyl on the nitrogen atom;
R 2 is H, F, C 2-4 -alkenyl, C 2-4 -alkynyl, CN, —CH 2 OC 1-6 -alkyl, —S(O)C 1-6 -alkyl, —NHC 1-6 -alkyl or —C(O)C 1-6 -alkyl, wherein each of the C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, and C 1-6 -alkyl portion of —CH 2 OC 1-6 -alkyl, —S(O)C 1-6 -alkyl, —NHC 1-6 -alkyl and —C(O)C 1-6 -alkyl are optionally substituted with 1-4 substituents of F, oxo or OH;
each of R 4 , R 5 , R 6 and R 8 , independently, is H, halo, haloalkyl, haloalkoxyl, CN, OH, OC 1-4 -alkyl, S(O)C 1-4 -alkyl, NHC 1-4 -alkyl or C(O)C 1-4 -alkyl;
R 7 is —NH—R 9 , —NH—C(═O)—R 9 , —C(═O)NH—R 9 , —O—R 9 , —S—R 9 ;
or R 7 is
wherein V is NR 10 , O or S; and
each W, independently, is CH, CF, CCl or N;
R 9 is acetyl, C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl or a ring selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl, furanyl, dihydrofuranyl, thienyl, and pyrrolyl, wherein the C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl and ring are optionally substituted, independently, with 1-5 substituents of R 10 ;
each R 10 , independently, is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , SF 5 , acetyl, —C(O)NHCH 3 , oxo, cyclopropylmethoxy, 2-butynyloxy, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein each of the C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkylamino-, C 1-6 -dialkylamino-, C 1-6 -alkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl, is optionally substituted independently with 1-5 substituents of F, Cl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl, tert-butyl, C 1-3 -alkylamino-, C 1-3 -dialkylamino-, C 1-3 -thioalkoxyl or oxetan-3-yl; and
p is 0, 1, 2 or 3.
9. The compound of claim 7 , or a stereoisomer or pharmaceutically acceptable salt thereof, as defined by Formula III-F-2
wherein
A 4 is CR 4 or N;
A 5 is CR 5 or N;
A 6 is CR 6 or N;
A 8 is CR 8 or N, provided that no more than two of A 4 , A 5 , A 6 and A 8 is N;
each R a , independently, is H or F;
each R 1 , independently, is H, F, Cl, C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, CN, —CH 2 OC 1-6 -alkyl, —OC 1-6 -alkyl, —S(O)C 1-6 -alkyl, —NHC 1-6 -alkyl or —C(O)C 1-6 -alkyl, wherein each of the C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, and C 1-6 -alkyl portion of —CH 2 OC 1-6 -alkyl, —OC 1-6 -alkyl, —S(O)C 1-6 -alkyl, —NHC 1-6 -alkyl and —C(O)C 1-6 -alkyl are optionally substituted with 1-4 substituents of F, oxo or OH;
alternatively, each R 1 taken together with the carbon atom to which they are attached form a C 3-6 spirocarbocyclic ring optionally including one heteroatom selected from O and N and optionally substituted with 1-4 F atoms on the carbon atoms and a substituent of C 1-3 -alkyl, CH 2 OC 1-2 -alkyl or C 1-3 -haloalkyl on the nitrogen atom;
R 2 is H, F, Cl, C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, CN, —CH 2 OC 1-6 -alkyl, —OC 1-6 -alkyl, —S(O)C 1-6 -alkyl, —NHC 1-6 -alkyl or —C(O)C 1-6 -alkyl, wherein each of the C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, and C 1-6 -alkyl portion of —CH 2 OC 1-6 -alkyl, —OC 1-6 -alkyl, —S(O)C 1-6 -alkyl, —NHC 1-6 -alkyl and —C(O)C 1-6 -alkyl are optionally substituted with 1-4 substituents of F, oxo or OH;
each of R 4 , R 5 , R 6 and R 8 , independently, is H, halo, haloalkyl, haloalkoxyl, C 1-4 -alkyl, CN, OH, OC 1-4 -alkyl, S(O)C 1-4 -alkyl, NHC 1-4 -alkyl or C(O)C 1-4 -alkyl;
R 7 is —NH—R 9 , —NH—C(═O)—R 9 , —C(═O)NH—R 9 , —O—R 9 , —S—R 9 ;
or R 7 is
wherein V is NR 10 , O or S; and
each W, independently, is CH, CF, CCl or N;
R 9 is acetyl, C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl or a ring selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl, furanyl, dihydrofuranyl, thienyl, and pyrrolyl, wherein the C 1-6 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl and ring are optionally substituted, independently, with 1-5 substituents of R 10 ; and
each R 10 , independently, is H, halo, haloalkyl, CN, OH, NO 2 , NH 2 , SF 5 , acetyl, —C(O)NHCH 3 , oxo, cyclopropylmethoxy, 2-butynyloxy, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkylamino-, C 1-6 -dialkylamino-, C 1-6 -alkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein each of the C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, C 1-6 -alkylamino-, C 1-6 -dialkylamino-, C 1-6 -alkoxyl, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl, is optionally substituted independently with 1-5 substituents of F, Cl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl, tert-butyl, C 1-3 -alkylamino-, C 1-3 -dialkylamino-, C 1-3 -thioalkoxyl or oxetan-3-yl.
10. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, selected from
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
8-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonitrile;
N-(3-((3R)-5-amino-6,6-dimethyl-1,1-dioxido-3-(trifluoromethyl)-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
Racemic mixture of N-(3-((3R)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine and N-(3-((3S)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
N-(3-((8R)-10-amino-8-methyl-6,6-dioxido-6-thia-9-azaspiro[4.5]dec-9-en-8-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
N-(3-((6R)-8-amino-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-7-en-6-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-chloro-5-fluoro-1,7-naphthyridin-8-amine;
Racemic mixture of N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4,5-difluorophenyl)-3-chloro-1,7-naphthyridin-8-amine and N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4,5-difluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
N-(3-((3S)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
8-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)amino)-5-fluoro-1,7-naphthyridine-3-carbonitrile;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
8-((3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonitrile;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-fluoro-3-methoxy-1,7-naphthyridin-8-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-7-methoxypyrido[3,2-d]pyrimidin-4-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-7-chloropyrido[3,2-d]pyrimidin-4-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-fluoro-7-methoxy-4-quinazolinamine;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-6-fluoro-3-pyridinyl)-3-methoxy-1,7-naphthyridin-8-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-2-methoxy-5-quinoxalinamine;
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
Racemic mixture of N-(3-((3R)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine and N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4,5-difluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4,5-difluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-2-(trifluoromethyl)pyrido[3,4-b]pyrazin-5-amine;
5-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4,5-difluorophenyl)amino)pyrido[3,4-b]pyrazin-2(1H)-one; or
5-((3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4,5-difluorophenyl)amino)pyrido[3,4-b]pyrazin-2(1H)-one.
11. The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, selected from
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-6-fluoro-3-pyridinyl)-5-fluoro-3-methoxy-1,7-naphthyridin-8-amine;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-6-fluoro-3-pyridinyl)-3-chloro-5-fluoro-1,7-naphthyridin-8-amine;
8-((5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-6-fluoro-3-pyridinyl)amino)-5-fluoro-1,7-naphthyridine-3-carbonitrile;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-6-fluoro-3-pyridinyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-6-fluoro-3-pyridinyl)-3-chloro-1,7-naphthyridin-8-amine;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-6-fluoro-3-pyridinyl)-2-(trifluoromethyl)pyrido[3,4-b]pyrazin-5-amine;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-(2-butyn-1-yloxy)-1,7-naphthyridin-8-amine;
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-7-chloropyrido[3,2-d]pyrimidin-4-amine;
4-((3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)amino)pyrido[3,2-d]pyrimidine-7-carbonitrile;
N-(5-((7R)-9-amino-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7-yl)-6-fluoro-3-pyridinyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
N-(3-((7R)-9-amino-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
N-(3-((7R)-9-amino-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-chloro-5-fluoro-1,7-naphthyridin-8-amine;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-7-chloropyrido[3,2-d]pyrimidin-4-amine;
4-((3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)amino)pyrido[3,2-d]pyrimidine-7-carbonitrile;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-2-ethoxypyrido[3,4-b]pyrazin-5-amine;
N-(3-((7 S)-9-amino-7-(fluoromethyl)-5, 5-dioxido-5-thia-8-azaspiro[3 5]non-8-en-7-yl)-4-fluorophenyl)-2-ethoxypyrido[3,4-b]pyrazin-5-amine;
N-(3-((7 S)-9-amino-7-(fluoromethyl)-5, 5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin-8-amine;
N-(3-((7 S)-9-amino-7-(fluoromethyl)-5, 5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7-yl)-4-fluorophenyl)-7-chloropyrido[3,2-d]pyrimidin-4-amine;
8-((3-((7 S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7-yl)-4-fluorophenyl)amino)-5-fluoro-1,7-naphthyridine-3-carbonitrile;
N-(3-((7 S)-9-amino-7-(fluoromethyl)-5, 5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7-yl)-4-fluorophenyl)-7-methoxypyrido[3,2-d]pyrimidin-4-amine;
Mixture of N-(3-((7R)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine and N-(3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3 5]non-8-en-7-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
N-(3-((7 S)-9-amino-7-(fluoromethyl)-5, 5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine;
N-(3-((7 S)-9-amino-7-(fluoromethyl)-5, 5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
8-((3-((7R)-9-amino-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonitrile;
8-((3-((7R)-9-amino-6-fluoro-7-methyl-5, 5-dioxido-5-thia-8-azaspiro [3.5]non-8-en-7-yl)-4-fluorophenyl)amino)-1, 7-naphthyridine-3-carbonitrile;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-(2-butyn-1-yloxy)-1, 7-naphthyridin-8-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-(cyclopropylmethoxy)-1,7-naphthyridin-8-amine;
8-((3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonitrile;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-7-methoxypyrido[3,2-d]pyrimidin-4-amine;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-fluoro-3-methoxy-1,7-naphthyridin-8-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-2-(2-fluoroethoxy)pyrido[3,4-b]pyrazin-5-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-2-(2,2,2-trifluoroethoxy)pyrido[3,4-b]pyrazin-5-amine;
((5-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)amino)pyrido[3,4-b]pyrazin-2-yl)oxy)acetonitrile;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-2-(2,2-difluoroethoxy)pyrido[3,4-b]pyrazin-5-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-2-(2-butyn-1-yloxy)pyrido[3,4-b]pyrazin-5-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-7-(cyclopropylmethoxy)pyrido[3,2-d]pyrimidin-4-amine;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-bromopyrido[2,3-d]pyridazin-8-amine;
N-(3-((5R,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-7-en-6-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
N-(3-((4aR,7aR)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
N-(3-((4aS,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
5-((3-((4aS,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)amino)pyrido[3,4-b]pyrazin-2(1H)-one;
N-(3-((8R)-6-amino-5,5,8-trimethyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-6-en-8-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
Mixture of N-(3-((4aR,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine and N-(3-((4aS,7aR)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine; or
N-(3-((1R,6R)-4-amino-3,3-dimethyl-2,2-dioxido-2-thia-5-azabicyclo[4.1.0]hept-4-en-6-yl)-4-fluorophenyl)-3-chloro-1,7-naphthyridin-8-amine.
12. The compound of claim 5 , or a stereoisomer or pharmaceutically acceptable salt thereof, selected from
N-(3-((8R)-6-amino-5,5,8-trimethyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-6-en-8-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
N-(3-((8R)-6-amino-5,5,8-trimethyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-6-en-8-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxamide;
N-(3-((1R,6R)-4-amino-3,3-dimethyl-2,2-dioxido-2-thia-5-azabicyclo[4.1.0]hept-4-en-6-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
Mixture of N-(3-((4aR,7aR)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxamide and N-(3-((4aS,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxamide;
Mixture of N-(3-((4aR,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide and N-(3-((4aS,7aR)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide;
Mixture of N-(3-((4aR,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide and N-(3-((4aS,7aR)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
Mixture of N-(3-((4aR,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-methoxy-3-methyl-2-pyridinecarboxamide and N-(3-((4aS,7aR)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-methoxy-3-methyl-2-pyridinecarboxamide;
N-(3-((4aS,7aS)-3-amino-2,2-dimethyl-1,1-dioxido-7,7a-dihydro-2H-furo[3,4-b][1,4]thiazin-4a(5H)-yl)-4-fluorophenyl)-5-methoxy-3-methyl-2-pyridinecarboxamide;
N-(5-47R)-9-amino-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7-yl)-6-fluoro-3-pyridinyl)-3-methyl-5-(2,2,2-trifluoroethoxy)-2-pyridinecarboxamide;
N-(5-((7R)-9-amino-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7-yl)-6-fluoro-3-pyridinyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
N-(3-((7R)-9-amino-2,2-difluoro-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide;
Mixture of N-(3-((7R)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxamide and N-(3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxamide;
N-(3-((7S)-9-amino-7-(fluoromethyl)-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxamide;
N-(3-((6S,7R)-9-amino-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide;
N-(3-((7R)-9-amino-6-fluoro-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-7-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxamide;
N-(5-((6R)-8-amino-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-7-en-6-yl)-6-fluoro-3-pyridinyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxamide;
N-(3-((5 S,6R)-8-amino-5-fluoro-6-methyl-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-7-en-6-yl)-4-fluorophenyl)-5-(difluoromethyl)-3-methyl-2-pyridinecarboxamide; or
N-(3-((6S)-8-amino-6-(fluoromethyl)-4,4-dioxido-4-thia-7-azaspiro[2.5]oct-7-en-6-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide.
13. A compound, or a stereoisomer or pharmaceutically acceptable salt thereof, selected from
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(2,2-difluoroethoxy)-2-pyrazinecarboxamide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(2-butyn-1-yloxy)-2-pyrazinecarboxamide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyridinecarboxamide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(difluoromethyl)-2-pyridinecarboxamide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-fluoro-2-pyridinecarboxamide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxamide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-cyano-3-methyl-2-pyridinecarboxamide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyrazinecarboxamide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-chloro-5-(difluoromethyl)-2-pyridinecarboxamide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-chloro-5-cyano-2-pyridinecarboxamide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-(methoxymethyl)-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-fluoro-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(2-butyn-1-yloxy)-2-pyrazinecarboxamide;
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyrazinecarboxamide;
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(difluoromethyl)-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-(methoxymethyl)-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-chloro-5-methoxy-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-2-fluoro-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-3-methyl-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-(1-methylethenyl)-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-ethenyl-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-ethyl-2-pyridinecarboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-ethyl-2-pyridinecarboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3yl)-4-fluorophenyl)-5-chloro-3-(1-methylethyl)-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(difluoromethoxy)-2-pyrazinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyrazinecarboxamide;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-6-fluoro-3-pyridinyl)-3-chloro-5-(difluoromethyl)-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-3-bromo-5-chloro-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-cyano-3-methyl-2-pyridinecarboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-3-methyl-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxamide;
N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-((4-fluoro-2-butyn-1-yl)oxy)-2-pyridinecarboxamide;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-6-fluoro-3-pyridinyl)-5-chloro-2-pyridinecarboxamide;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-6-fluoro-3-pyridinyl)-5-fluoro-2-pyridinecarboxamide;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-6-fluoro-3-pyridinyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxamide;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-6-fluoro-3-pyridinyl)-5-methoxy-2-pyridinecarboxamide;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-6-fluoro-3-pyridinyl)-5-(2,2,2-trifluoroethoxy)-2-pyrazinecarboxamide;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-6-fluoro-3-pyridinyl)-5-cyano-2-pyridinecarboxamide;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-6-fluoro-3-pyridinyl)-5-(difluoromethyl)-2-pyridinecarboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyrazinecarboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-cyano-2-pyridinecarboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-(1-methylethenyl)-2-pyridinecarboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-fluoro-2-pyridinecarboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-6-chloro-3-methylimidazo[1,2-a]pyridine-2-carboxamide;
N-(5-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinyl)-5-(difluoromethoxy)-3-methyl-2-pyridinecarboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyridinecarboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-(methoxymethyl)-2-pyridinecarboxamide;
N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
N-(3-((3R)-5-amino-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-3-methyl-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
Racemic mixture of N-(3-((3R,6R)-5-amino-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide and N-(3-((3R,6S)-5-amino-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
N-(3-((3R)-5-amino-6,6-dimethyl-1,1-dioxido-3-(trifluoromethyl)-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
Racemic mixture of N-(3-((3R)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide and N-(3-((3S)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
N-(3-((3S)-5-amino-3-(difluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
Racemic mixture of N-(3-((3R,6R)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide and N-(3-((3R,6S)-5-amino-6-fluoro-3,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(difluoromethyl)-2-pyridinecarboxamide;
Racemic mixture of N-(3-((3R)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide and N-(3-((3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-5-(2-butyn-1-yloxy)-2-pyrazinecarboxamide;
N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-2-methyl-1,3-thiazole-4-carboxamide;
Racemic mixture of N-(4-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-5-fluoro-2-pyridinyl)-5-methoxy-2-pyrazinecarboxamide and N-(4-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-5-fluoro-2-pyridinyl)-5-methoxy-2-pyrazinecarboxamide;
N-(6-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-5-fluoro-2-pyridinyl)-5-methoxy-2-pyrazinecarboxamide;
(5R)-5-(2-fluoro-5-(1-naphthalenylsulfanyl)phenyl)-2,2,5-trimethyl-5,6-dihydro-2H-1,4-thiazin-3-amine 1,1-dioxide;
Racemic mixture of N-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-6-chloroisoxazolo[4,5-b]pyridin-3-amine and N-(3-((3S)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-6-chloroisoxazolo[4,5-b]pyridin-3-amine;
3-((3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)amino)thieno[3,2-b]pyridine-6-carbonitrile;
(5R)-5-(2-fluoro-5-(3-fluoro-2-pyridinyl)oxy)phenyl)-2,2,5-trimethyl-5,6-dihydro-2H-1,4-thiazin-3-amine 1,1-dioxide;
2-(3-((3R)-5-amino-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenoxy)-4-pyridinecarbonitrile; or
(5R)-5-(5-(4-bromo-2-pyridinyl)oxy)-2-fluorophenyl)-2,2,5-trimethyl-5,6-dihydro-2H-1,4-thiazin-3-amine 1,1-dioxide.
14. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
15. A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 1 .
16. 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 the compound of claim 1 .
17. 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 the compound of claim 1 .
18. A method of reducing the formation of plaque on the brain of a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 1 .
19. A pharmaceutical composition comprising the compound of claim 4 and a pharmaceutically acceptable excipient.
20. A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 4 .
21. 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 the compound of claim 4 .
22. 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 the compound of claim 4 .
23. A method of reducing the formation of plaque on the brain of a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 4 .
24. A pharmaceutical composition comprising the compound of claim 5 and a pharmaceutically acceptable excipient.
25. A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 5 .
26. 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 the compound of claim 5 .
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 the compound of claim 5 .
28. A method of reducing the formation of plaque on the brain of a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 5 .
29. A pharmaceutical composition comprising the compound of claim 7 and a pharmaceutically acceptable excipient.
30. A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 7 .
31. 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 the compound of claim 7 .
32. 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 the compound of claim 7 .
33. A method of reducing the formation of plaque on the brain of a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 7 .
34. A pharmaceutical composition comprising the compound of claim 13 and a pharmaceutically acceptable excipient.
35. A method of reducing beta amyloid peptide levels in the cerebral spinal fluid of a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 13 .
36. 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 the compound of claim 13 .
37. 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 the compound of claim 13 .
38. A method of reducing the formation of plaque on the brain of a subject, the method comprising administering to the subject an effective dosage amount of the compound of claim 13 .