Substituted-aryl 7-aza[2.2.1]bicycloheptanes for the treatment of disease

A compound of formula I:

• 21
• wherein the stereochemistry of the of the 7-azabicyclo[2.2.1]heptane ring is 1S, 4R and the nitrogen substituent at the C-2 carbon has the exo orientation and is R;
• X is O or S;
• W is -Q, —C═C-Q, or —C≡C-Q;
• Q is aryl wherein the aryl can have a bond to the core molecule at any position where valency allows provided that there is only one said bond to the core molecule, or a group of formula II
• 22
• wherein the phenyl ring of formula II is optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, R3, or a bond to the core molecule at any position where valency allows, provided that there is only one said bond to the core molecule;
• Z is —C(RZ)2—C(RZ)2—C(RZ)2—, —C(RZ)═C(RZ)—C(RZ)2—, —C(RZ)2—C(RZ)2—C(RZ)2—C(RZ)2—, —C(RZ)═C(RZ)—C(RZ)2—C(RZ)2—, or —C(RZ)2—C(RZ)═C(RZ)—C(RZ)2—;
• RZ is H, R3, or a bond to the core molecule at any position where valency allows, provided that there is only one said bond to the core molecule;
• R1 is H, alkyl, cycloalkyl, halogenated alkyl, or aryl;
• R2 is H, alkyl, halogenated alky, substituted alkyl, cycloalkyl, or aryl;
• Each R3 is independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alky, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted heterocycloalkyl, lactam heterocycloalkyl, R7, R9, —OR8, —SR8, —S(O)2R8, —S(O)R8, —OS(O)2R8, F, Cl, Br, I, —N(R8)2, —C(O)R8, —C(S)R8, —C(O)OR8, —CN, —C(O)N(R8)2, —NR8C(O)R8, —S(O)2N(R8)2, —NR8S(O)2R8, —NO2, —N(R8)C(O)N(R8)2, phenyl optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, R13, and R15, or naphthyl optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, R13, and R15, or optionally two R3 groups bound to the same carbon atom together form ═O or ═S;
• Each R4 is independently H, alkyl, or substituted alkyl;
• R6 is H, alkyl, an amino protecting group, or an alkyl group having 1-3 substituents selected from F, Cl, Br, I, —OH, —CN, —NH2, —NH(alkyl), or —N(alkyl)2;
• R7 is 5-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms independently selected from the group consisting of ═N—, —N(R20)—, —O—, and —S—, and having 0-1 substituent selected from R17 and further having 0-3 substituents independently selected from F, Cl, Br, or I, or R7 is 9-membered fused-ring moieties having a 6-membered ring fused to a 5-membered ring including the formula
• 23
• wherein G1 is O, S or NR20,
• 24
• wherein G is C(R14) or N, and each G2 and G3 are independently selected from C(R14)2, C(R14), O, S, N, and N(R20), provided that both G2 and G3 are not simultaneously O or S, or
• 25
• wherein G is C(R14) or N, and each G2 and G3 are independently selected from C(R14)2, C(R14), O, S, N, and N(R20), each 9-membered bicyclic ring having 0-1 substituent selected from R17 and 0-3 substituents independently selected from F, Cl, Br, or I, wherein the R7 moiety attaches to other substituents as defined in formula I at any position on either ring as valency allows;
• Each R8 is independently H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, substituted heterocycloalkyl, R7, R9, phenyl optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, R13, and R15, or naphthyl optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, R13, and R15;
• R9 is 6-membered heteroaromatic mono-cyclic moieties containing within the ring 1-3 heteroatoms selected from ═N— and having 0-1 substituent selected from R17 and 0-3 substituent(s) independently selected from F, Cl, Br, or I, or R9 is 10-membered heteroaromatic bi-cyclic moieties containing within one or both rings 1-3 heteroatoms selected from ═N—, including, but not limited to, quinolinyl or isoquinolinyl, each 10-membered fused-ring moiety having 0-1 substituent selected from R17 and 0-3 substituent(s) independently selected from F, Cl, Br, or I, wherein the R9 moiety attaches to other substituents as defined in formula I at any position on either ring as valency allows;
• Each R10 is independently H, alkyl, cycloalkyl, heterocycloalkyl, R7, R9, alkyl substituted with 1 substituent selected from R13, cycloalkyl substituted with 1 substituent selected from R13, heterocycloalkyl substituted with 1 substituent selected from R13, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, or phenyl optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, R13, and R15;
• Each R11 is independently H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, or halogenated heterocycloalkyl;
• R12 is alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl, —OR11, —SR11, —S(O)R11, —S(O)2R11, —OS(O)2R11, —NR11R11, —C(O)R11, —C(S)R11, —C(O)OR11, —NO2, —CN, —C(O)N(R11)2, —NR11C(O)R11, —NR11C(O)N(R11)2, —S(O)2N(R11)2, or —NR11S(O)2R11;
• R13 is —OR11, —SR11, —SOR11, —SO2R11, —OSO2R11, —N(R11)2, —C(O)R11, —C(O)OR11, —C(S)R11, —C(O)N(R11)2, —NO2—CN, —CF3, —NR11C(O)R11, —NR11C(O)N(R11)2, —S(O)2N(R11)2, or —NR11S(O)2R11;
• R14 is H or R19;
• R15 is lactam heterocycloalkyl, R7, R9, or R19;
• Each R16 is independently H, alkyl, cycloalkyl, halogenated alkyl, or halogenated cycloalkyl;
• R17 is alkyl, cycloalkyl, or heterocycloalkyl, each optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, —OR16, —SR16, —S(O)2R16, —S(O)R16, —OS(O)2R16, —N(R16)2, —C(O)R16, —C(S)R16, —C(O)OR16, —NO2, —C(O)N(R16)2, —CN, —NR16C(O)R16, —NR16C(O)N(R16)2, —S(O)2N(R16)2, and —NR16S(O)2R16, and the cycloalkyl and heterocycloalkyl also being further optionally substituted with ═O or ═S;
• R19 is alkyl, cycloalkyl, heterocycloalkyl, phenyl, or naphthyl, each optionally substituted with 1-4 substituents independently selected from F, Cl, Br, I, —OR16, —SR16, —S(O)2R16, —S(O)R16, —OS(O)2R16, —N(R16)2, —C(O)R16, —C(S)R16, —C(O)OR16, —NO2, —C(O)N(R16)2, —CN, —NR16C(O)R16, —NR16C(O)N(R16)2, —S(O)2N(R16)2, or —NR16S(O)2R16, and the cycloalkyl and heterocycloalkyl also being further optionally substituted with ═O or ═S;
• R20 is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl, phenyl, —SO2R8, or phenyl having 1 substituent selected from R12 and further having 0-3 substituents independently selected from F, Cl, Br, or I;
• or pharmaceutically acceptable salt thereof.