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US 2015/0307518 A1Published application
Spirocyclic dihydro-thiazine and dihydro-oxazine bace inhibitors, and compositions and uses thereof
AssigneeImago Pharmaceuticals, Inc.
InventorsYing-Zi Xu, Dean R. Arlis, Simeon Bowers, Roy K. Hom, Hing L. Sham, Shendong Yuan
Life of this patent
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Abstract
Compounds are provided having a structure according to Formula (I): wherein A1, A2, A3, Y, R1, R2, R3, R4, R5, R6, m, n and p are defined herein. Further provided are pharmaceutical compositions including the compounds provided and methods of making and using the compounds and compositions as provided, e.g., in the treatment and prevention of various disorders, such as Alzheimer's disease.
Claims27
A compound having a structure according to Formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- Y is O or S;
- L is selected from the group consisting of a direct bond, —CR7R8—, —C(O)—, —O—, —S(O)z—, —NR9—, —CR7R8—CR10R11—, —CR7R8—C(O)—, —CR7R8—O—, —CR7R8—S(O)z—, —CR7R8—NR9—, —C(O)—CR10R11—, —C(O)—O—, —C(O)—NR9—, —O—CR10R11—, —O—C(O)—, —S(O)z—CR10R11—, —S(O)2—NR9—, —NR9—CR10R11—, —NR9—C(O)—, and —NR9—S(O)2—;
- A1 is a C3-10 carbocyclic ring or a 3 to 10 membered heterocyclic ring;
- A2 is phenyl, naphthyl or a heteroaryl ring;
- A3 is phenyl, naphthyl or a heteroaryl ring;
- R1 is hydrogen, C1-6 alkyl, or combines with R2 to form a fused monocyclic C3-7 carbocyclic ring or a 3 to 7 membered heterocyclic ring;
- R2 and R3 are independently hydrogen or halogen, or R3 is hydrogen and R2 combines with R1 to form a fused monocyclic C3-7 carbocyclic ring or a 3 to 7 membered heterocyclic ring;
- R4 at each occurrence is independently selected from the group consisting of halogen, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, —OH, ═O, —OR12, —S(O)zR12, —C(O)R12, —NR13R14, and ═NR14, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl are optionally substituted with one or more fluoro, —OH, —NH2, —ORa, —S(O)zRa, —C(O)Ra, —NHRa, —NRaRb, or optionally fluoro substituted C3-6 cycloalkyl;
- R5 and R6 at each occurrence are independently selected from the group consisting of halogen, —CN, —OH, —NH2, —NO2, —C(O)—OH, —C(O)—NH2, —S(O)2—NH2, and L1-R15;
- R7, R8, R9, R10, and R11 are independently selected from the group consisting of hydrogen and C1-6 alkyl;
- L1 at each occurrence is independently selected from the group consisting of a direct bond, —C(O)—, —O—, —S(O)z—, —NR16—, —C(O)—O—, —O—C(O)—, —C(O)—NR16—, —NR16—C(O)—, —S(O)2—NR16—, and —NR16—S(O)2—;
- R12 at each occurrence is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —OH, —NH2, —ORa, —S(O)zRa, —C(O)Ra, —NHRa, —NRaRb, and optionally fluoro substituted C3-6 cycloalkyl;
- R13 and R14 at each occurrence are independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —OH, —NH2, —ORa, —S(O)zRa, —C(O)Ra, —NHRa, —NRaRb, and optionally fluoro substituted C3-6 cycloalkyl, or R13 and R14 combine with the nitrogen to which they are attached to form a 4-7 membered monocyclic heterocyclic ring or a 5 or 7 membered heteroaryl ring, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —CN, ═O, —OH, —NH2, —ORa, —S(O)zRa, —C(O)Ra, —NHRa, —NRaRb, optionally fluoro substituted C1-6 alkyl, optionally fluoro substituted C2-6 alkenyl, optionally fluoro substituted C2-6 alkynyl, and optionally fluoro substituted C3-6 cycloalkyl;
- R15 at each occurrence is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, naphthyl, and heteroaryl, wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of —CN, —OH, —NO2, —C(O)—OH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, —OR17, —S(O)zR17, —NR18R19, —C(O)R17, —C(O)—OR17, —O—C(O)R17, —C(O)—NR18R19, NR16—C(O)R17, —S(O)2—NR18R19, and —NR16—S(O)2R17, and wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, and 3-7 membered heterocycloalkyl, as R15 or as a substituent of phenyl, naphthyl, or heteroaryl, are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —CN, —OH, ═O, ═NH, —NO2, —C(O)—OH, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, —OR17, —S(O)zR17, ═NR17, —NR18R19, —C(O)R17, —C(O)—OR17, —O—C(O)R17, —C(O)—NR18R19, —NR16—C(O)R17, —S(O)2—NR18R19, and —NR16—S(O)2R17;
- R16 at each occurrence is independently selected from the group consisting of hydrogen and C1-6 alkyl;
- R17 at each occurrence is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —OH, —NH2, —ORa, —S(O)zRa, —C(O)Ra, —NHRa, —NRaRb, and optionally fluoro substituted C3-6 cycloalkyl;
- R18 and R19 at each occurrence are independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —OH, —NH2, —ORa, —S(O)zRa, —C(O)Ra, —NHRa, —NRaRb, and optionally fluoro substituted C3-6 cycloalkyl, or R18 and R19 combine with the nitrogen to which they are attached to form a 4-7 membered monocyclic heterocyclic ring or a 5 or 7 membered heteraoryl ring, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —CN, ═O, —OH, —NH2, —ORa, —S(O)zRa, —C(O)Ra, —NHRa, —NRaRb, optionally fluoro substituted C1-6 alkyl, optionally fluoro substituted C2-6 alkenyl, optionally fluoro substituted C2-6 alkynyl, and optionally fluoro substituted C3-6 cycloalkyl;
- Ra and Rb at each occurrence are independently selected from the group consisting of optionally fluoro substituted C1-6 alkyl, optionally fluoro substituted C2-6 alkenyl, optionally fluoro substituted C2-6 alkynyl, and optionally fluoro substituted C3-6 cycloalkyl, or Ra and Rb combine with the nitrogen to which they are attached to form N-linked-heterocycloalkyl;
- m is 0, 1 or 2;
- n is 0, 1, 2 or 3;
- p is 0, 1, 2 or 3;
- and
- z is 0, 1 or 2.
21 more elements
The compound of 5 wherein A1 is a 4 to 6 membered monocyclic heterocyclic ring that contains one oxygen atom or one sulfur atom as the only heteroatom.
A compound having a structure according to Formula II:
- wherein:
- Y is O or S;
- A1 is a C3-10 carbocyclic ring or a 3 to 10 membered heterocyclic ring;
- A2 is phenyl, naphthyl or a heteroaryl ring;
- R1 is hydrogen, C1-6 alkyl, or combines with R2 to form a fused monocyclic C3-7 carbocyclic ring or a 3 to 7 membered heterocyclic ring;
- R2 and R3 are independently hydrogen or halogen, or R3 is hydrogen and R2 combines with R1 to form a fused monocyclic C3-7 carbocyclic ring or a 3 to 7 membered heterocyclic ring;
- R4 at each occurrence is independently selected from the group consisting of halogen, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, —OH, ═O, —OR12, —S(O)zR12, —C(O)R12, —NR13R14, and ═NR14, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl are optionally substituted with one or more fluoro, —OH, —NH2, —ORa, —S(O)zRa, —C(O)Ra, —NHRa, —NRaRb, or optionally fluoro substituted C3-6 cycloalkyl;
- R5 at each occurrence is independently selected from the group consisting of halogen, —CN, —OH, —NH2, —NO2, —C(O)—OH, —C(O)—NH2, —S(O)2—NH2, and L1-R15;
- L1 at each occurrence is independently selected from the group consisting of a direct bond, —C(O)—, —O—, —S(O)z—, —NR16—, —C(O)—O—, —O—C(O)—, —C(O)—NR16—, —NR16—C(O)—, —S(O)2—NR16—, and —NR16—S(O)2—;
- R12 at each occurrence is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —OH, —NH2, —ORa, —S(O)zRa, —C(O)Ra, —NHRa, —NRaRb, and optionally fluoro substituted C3-6 cycloalkyl;
- R13 and R14 at each occurrence are independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —OH, —NH2, —ORa, —S(O)zRa, —C(O)Ra, —NHRa, —NRaRb, and optionally fluoro substituted C3-6 cycloalkyl, or R13 and R14 combine with the nitrogen to which they are attached to form a 4-7 membered monocyclic heterocyclic ring or a 5 or 7 membered heteroaryl ring, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —CN, ═O, —OH, —NH2, —ORa, —S(O)zRa, —C(O)Ra, —NHRa, —NRaRb, optionally fluoro substituted C1-6 alkyl, optionally fluoro substituted C2-6 alkenyl, optionally fluoro substituted C2-6 alkynyl, and optionally fluoro substituted C3-6 cycloalkyl;
- R15 at each occurrence is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, naphthyl, and heteroaryl, wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of —CN, —OH, —NO2, —C(O)—OH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, —OR17, —S(O)zR17, —NR18R19, —C(O)R17, —C(O)—OR17, —O—C(O)R17, —C(O)—NR18R19, —NR16—C(O)R17, —S(O)2—NR18R19, and —NR16—S(O)2R17, and wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, and 3-7 membered heterocycloalkyl, as R15 or as a substituent of phenyl, naphthyl, or heteroaryl, are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —CN, —OH, ═O, ═NH, —NO2, —C(O)—OH, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, —OR17, —S(O)zR17, ═NR17, —NR18R19, —C(O)R17, —C(O)—OR17, —O—C(O)R17, —C(O)—NR18R19, —NR16—C(O)R17, —S(O)2—NR18R19, and —NR16—S(O)2R17;
- R16 at each occurrence is independently selected from the group consisting of hydrogen and C1-6 alkyl;
- R17 at each occurrence is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —OH, —NH2, —ORa, —S(O)zRa, —C(O)Ra, —NHRa, —NRaRb, and optionally fluoro substituted C3-6 cycloalkyl;
- R18 and R19 at each occurrence are independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —OH, —NH2, —ORa, —S(O)zRa, —C(O)Ra, —NHRa, —NRaRb, and optionally fluoro substituted C3-6 cycloalkyl, or R18 and R19 combine with the nitrogen to which they are attached to form a 4-7 membered monocyclic heterocyclic ring or a 5 or 7 membered heteraoryl ring, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —CN, ═O, —OH, —NH2, —ORa, —S(O)zRa, —C(O)Ra, —NHRa, —NRaRb, optionally fluoro substituted C1-6 alkyl, optionally fluoro substituted C2-6 alkenyl, optionally fluoro substituted C2-6 alkynyl, and optionally fluoro substituted C3-6 cycloalkyl;
- Ra and Rb at each occurrence are independently selected from the group consisting of optionally fluoro substituted C1-6 alkyl, optionally fluoro substituted C2-6 alkenyl, optionally fluoro substituted C2-6 alkynyl, and optionally fluoro substituted C3-6 cycloalkyl, or Ra and Rb combine with the nitrogen to which they are attached to form N-linked-heterocycloalkyl;
- R31 is hydrogen or a nitrogen protecting group;
- R32 is halogen or NH2;
- m is 0, 1 or 2;
- n is 0, 1, 2or 3;
- and
- z is 0, 1 or 2.
19 more elements
A compound having a structure selected from the group consisting of:
- wherein:
- A1 is a C3-10 carbocyclic ring or a 3 to 10 membered heterocyclic ring;
- A2 is phenyl, naphthyl or a heteroaryl ring;
- R1 is hydrogen, C1-6 alkyl, or combines with R2 to form a fused monocyclic C3-7 carbocyclic ring or a 3 to 7 membered heterocyclic ring;
- R2 and R3 are independently hydrogen or halogen, or R3 is hydrogen and R2 combines with R1 to form a fused monocyclic C3-7 carbocyclic ring or a 3 to 7 membered heterocyclic ring;
- R4 at each occurrence is independently selected from the group consisting of halogen, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, —OH, ═O, —OR12, —S(O)zR12, —C(O)R12, —NR13R14, and ═NR14, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl are optionally substituted with one or more fluoro, —OH, —NH2, —ORa, —S(O)zRa, —C(O)Ra, —NHRa, —NRaRb, or optionally fluoro substituted C3-6 cycloalkyl;
- R5 at each occurrence is independently selected from the group consisting of halogen, —CN, —OH, —NH2, —NO2, —C(O)—OH, —C(O)—NH2, —S(O)2—NH2, and L1-R15;
- L1 at each occurrence is independently selected from the group consisting of a direct bond, —C(O)—, —O—, —S(O)z—, —NR16—, —C(O)—O—, —O—C(O)—, —C(O)—NR16—, —NR16—C(O)—, —S(O)2—NR16—, and —NR16—S(O)2—;
- R12 at each occurrence is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —OH, —NH2, —ORa, —S(O)zRa, —C(O)Ra, —NHRa, —NRaRb, and optionally fluoro substituted C3-6 cycloalkyl;
- R13 and R14 at each occurrence are independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —OH, —NH2, —ORa, —S(O)zRa, —C(O)Ra, —NHRa, —NRaRb, and optionally fluoro substituted C3-6 cycloalkyl, or R13 and R14 combine with the nitrogen to which they are attached to form a 4-7 membered monocyclic heterocyclic ring or a 5 or 7 membered heteroaryl ring, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —CN, ═O, —OH, —NH2, —ORa, —S(O)zRa, —C(O)Ra, —NHRa, —NRaRb, optionally fluoro substituted C1-6 alkyl, optionally fluoro substituted C2-6 alkenyl, optionally fluoro substituted C2-6 alkynyl, and optionally fluoro substituted C3-6 cycloalkyl;
- R15 at each occurrence is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, naphthyl, and heteroaryl, wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of —CN, —OH, —NO2, —C(O)—OH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, —OR17, —S(O)zR17, —NR18R19, —C(O)R17, —C(O)—OR17, —O—C(O)R17, —C(O)—NR18R19, —NR16—C(O)R17, —S(O)2—NR18R19, and —NR16—S(O)2R17, and wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, and 3-7 membered heterocycloalkyl, as R15 or as a substituent of phenyl, naphthyl, or heteroaryl, are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —CN, —OH, ═O, ═NH, —NO2, —C(O)—OH, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, —OR17, —S(O)zR17, ═NR17, —NR18R19, —C(O)R17, —C(O)—OR17, —O—C(O)R17, —C(O)—NR18R19, —NR16—C(O)R17, —S(O)2—NR18R19, and —NR16—S(O)2R17;
- R16 at each occurrence is independently selected from the group consisting of hydrogen and C1-6 alkyl;
- R17 at each occurrence is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —OH, —NH2, —ORa, —S(O)zRa, —C(O)Ra, —NHRa, —NRaRb, and optionally fluoro substituted C3-6 cycloalkyl;
- R18 and R19 at each occurrence are independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —OH, —NH2, —ORa, —S(O)zRa, —C(O)Ra, —NHRa, —NRaRb, and optionally fluoro substituted C3-6 cycloalkyl, or R18 and R19 combine with the nitrogen to which they are attached to form a 4-7 membered monocyclic heterocyclic ring or a 5 or 7 membered heteraoryl ring, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —CN, ═O, —OH, —NH2, —ORa, —S(O)zRa, —C(O)Ra, —NHRa, —NRaRb, optionally fluoro substituted C1-6 alkyl, optionally fluoro substituted C2-6 alkenyl, optionally fluoro substituted C2-6 alkynyl, and optionally fluoro substituted C3-6 cycloalkyl;
- Ra and Rb at each occurrence are independently selected from the group consisting of optionally fluoro substituted C1-6 alkyl, optionally fluoro substituted C2-6 alkenyl, optionally fluoro substituted C2-6 alkynyl, and optionally fluoro substituted C3-6 cycloalkyl, or Ra and Rb combine with the nitrogen to which they are attached to form N-linked-heterocycloalkyl;
- R35 is halogen;
- R36 is OH, OR39, SH, or Se;
- R37 is OH, SH, or Se;
- R38 is hydrogen or
- wherein
- indicates the attachment point to NH;
- R39 is an oxygen protecting group;
- R40 is a thiol protecting group;
- m is 0, 1 or 2;
- n is 0, 1, 2 or 3;
- and
- z is 0, 1 or 2.
24 more elements
Dependencies are inferred from the claim text.