Tri-substituted 2-benzhydryl-5-benzylamino-tetrahydro-pyran-4-ol and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-ol analogues, and novel 3,6-disubstituted pyran derivatives

1. A substituted pyran compound having the structural formula I:

or a pharmaceutically acceptable salt, ester, carbamate, imide, or amide thereof, wherein

A and A′ are individually selected from the group consisting of optionally substituted C 4 -C 14 aryl and heteroaryl wherein heteroatoms of heteroaryl A and/or A′ are selected from the group consisting of O, N, and S;

Z is a chemical bond or —Y—(CH 2 ) o —;

Y is NH or O;

o is 0, 1, 2, 3, or 4;

R is H, C 1-8 alkyl, C 2-8 alkenyl, or C 2-8 alkynyl;

W is —OH or —NHR;

B is optionally substituted C 4 -C 14 aryl or optionally substituted C 4 -C 14 heteroaryl; and

n and m are each independently 0, 1, 2, 3, or 4.

2. The compound of claim 1 wherein:

any carbon of —(CH 2 ) n may be substituted by —OR 4 or —COOR 5 ;

R 4 is H, C 1-18 alkyl, C 5-10 cycloalkyl, or C 2-18 alkylene; and

R 5 is C 1-18 alkyl or C 2-18 alkylene.

3. The compound of claim 2 , wherein A and A′ are both unsubstituted phenyl.

4. The compound of claim 2 , having formula IIa:

or a pharmaceutically acceptable salt, ester, carbamate, imide, or amide thereof.

5. The compound of claim 1 , having a formula selected from the group consisting of:

or a pharmaceutically acceptable salt, ester, carbamate, imide, or amide thereof, wherein:

R 1 , R 6 , and R 7 are each independently C 1-4 alkyl, C 2-6 alkenyl, C 2-6 optionally halogenated alkynyl, C 2-6 hydroxyalkynyl, halo, —CN, —COOR 4 , —OH, —NO 2 , —NH 2 , —NHR 4 , —SO 2 NH 2 , —NHSO 2 R 8 , —OCF 3 , or —OR 8 ;

R 4 is H, C 1-18 alkyl, C 5-10 cycloalkyl, or C 2-18 alkylene; and

R 8 is C 1-8 alkyl, C 5-6 cycloalkyl, C 2-8 alkenyl, or a 5 or 6-member aromatic ring including heterocyclic rings.

6. The compound of claim 1 , having a formula selected from the group consisting of:

or a pharmaceutically acceptable salt, ester, carbamate, imide, or amide thereof, wherein:

m is 0-4;

B is selected from the group consisting of:

p is 0-6;

R 1 is C 1-4 alkyl, C 2-6 alkenyl, C 2-6 optionally halogenated alkynyl, C 2-6 hydroxyalkynyl, halo, —CN, —COOR 4 , —OH, —NO 2 , —NH 2 , —NHR 4 , —SO 2 NH 2 , —NHSO 2 R 8 , —OCF 3 , or —OR 8 ;

R 2 has the meaning of R 1 and also a 5 or 6 membered heterocycle containing 1 or more heteroatoms selected from the group consisting of N, O, and S;

X 2 is N, O, or S;

R 4 is H, C 1-18 alkyl, C 5-10 cycloalkyl, or C 2-18 alkylene; and

R 8 is C 1-8 alkyl, C 5-6 cycloalkyl, C 2-8 alkenyl, or a 5 or 6-member aromatic ring including heterocyclic rings.

7. A compound having a formula selected from the group consisting of:

or a pharmaceutically acceptable salt, ester, carbamate, imide, or amide thereof, wherein:

m and n are 0-4;

X is H, OH, NH 2 , or NHR;

Z 1 and Y 1 are C- or N-atom;

Z is selected from the group consisting of a chemical bond and —Y—(CH 2 ) o —;

Y is NH or O;

o is 0, 1, 2, 3, or 4;

A and A′ are individually selected from the group consisting of optionally substituted C 4 -C 14 aryl and heteroaryl wherein heteroatoms of heteroaryl A and/or A′ are selected from the group consisting of O, N, and S, wherein at least one of A and A′ are selected from the group consisting of:

p is 0-6;

R 1 is C 1-4 alkyl, C 2-6 alkenyl, C 2-6 optionally halogenated alkynyl, C 2-6 hydroxyalkynyl, halo, —CN, —COOR 4 , —OH, —NO 2 , —NH 2 , —NHR 4 , —SO 2 NH 2 , —NHSO 2 R 8 , —OCF 3 , or —OR 8 ;

R 2 has the meaning of R 1 and also a 5 or 6 membered heterocycle containing 1 or more heteroatoms selected from the group consisting of N, O, and S;

X 2 is N, O, or S;

R 4 is H, C 1-18 alkyl, C 5-10 cycloalkyl, or C 2-18 alkylene; and

R 8 is C 1-8 alkyl, C 5-6 cycloalkyl, C 2-8 alkenyl, or a 5 or 6-member aromatic ring including heterocyclic rings.

8. A compound having formula VII:

or a pharmaceutically acceptable salt, ester, carbamate, imide, or amide thereof, wherein:

m is 0-4;

X is —H, —OH, —NH 2 , or —NHR;

A is selected from the group consisting of:

p is 0-6;

R 1 is C 1-4 alkyl, C 2-6 alkenyl, C 2-6 optionally halogenated alkynyl, C 2-6 hydroxyalkynyl, halo, —CN, —COOR 4 , —OH, —NO 2 , —NH 2 , —NHR 4 , —SO 2 NH 2 , —NHSO 2 R 8 , —OCF 3 , or —OR 8 ;

R 2 has the meaning of R 1 and also a 5 or 6 membered heterocycle containing 1 or more heteroatoms selected from the group consisting of N, O, and S;

X 2 is N, O, or S;

R 4 is H, C 1-18 alkyl, C 5-10 cycloalkyl, or C 2-18 alkylene; and

R 8 is C 1-8 alkyl, C 5-6 cycloalkyl, C 2-8 alkenyl, or a 5 or 6-member aromatic ring including heterocyclic rings; and

B is selected from the group consisting of

9. The compound of claim 1 , having a formula selected from the group consisting of:

or a pharmaceutically acceptable salt, ester, carbamate, imide, or amide thereof, wherein:

m is 0-4;

X is H, OH, NH 2 , or NHR;

at least one of A and A′ are selected from the group consisting of:

p is 0-6;

R 1 is C 1-4 alkyl, C 2-6 alkenyl, C 2-6 optionally halogenated alkynyl, C 2-6 hydroxyalkynyl, halo, —CN, —COOR 4 , —OH, —NO 2 , —NH 2 , —NHR 4 , —SO 2 NH 2 , —NHSO 2 R 8 , —OCF 3 , or —OR 8 ;

R 2 has the meaning of R 1 and also a 5 or 6 membered heterocycle containing 1 or more heteroatoms selected from the group consisting of N, O, and S;

X 2 is N, O, or S;

R 4 is H, C 1-18 alkyl, C 5-10 cycloalkyl, or C 2-18 alkylene; and

R 8 is C 1-8 alkyl, C 5-6 cycloalkyl, C 2-8 alkenyl, or a 5 or 6-member aromatic ring including heterocyclic rings;

B is selected from the group consisting of:

10. The compound of claim 1 , having a formula selected from the group consisting of:

or a pharmaceutically acceptable salt, ester, carbamate, imide, or amide thereof, wherein:

m is 0-4,

X is H, OH, NH 2 , or NHR;

Z is a chemical bond or —Y—(CH 2 ) o —;

Y is NH or O;

o is 0, 1, 2, 3, or 4;

at least one of A and A′ are selected from the group consisting of:

p is 0-6;

R 1 is C 1-4 alkyl, C 2-6 alkenyl, C 2-6 optionally halogenated alkynyl, C 2-6 hydroxyalkynyl, halo, —CN, —COOR 4 , —OH, —NO 2 , —NH 2 , —NHR 4 , —SO 2 NH 2 , —NHSO 2 R 8 , —OCF 3 , or —OR 8 ;

R 2 has the meaning of R 1 and also a 5 or 6 membered heterocycle containing 1 or more heteroatoms selected from the group consisting of N, O, and S;

X 2 is N, O, or S;

R 8 is C 1-8 alkyl, C 5-6 cycloalkyl, C 2-8 alkenyl, or a 5 or 6-member aromatic ring including heterocyclic rings; and

B is selected from the group consisting of:

11. The compound of claim 1 wherein at least one of A and A′ are selected from the group consisting of:

p is 0-6;

R 1 is C 1-4 alkyl, C 2-6 alkenyl, C 2-6 optionally halogenated alkynyl, C 2-6 hydroxyalkynyl, halo, —CN, —COOR 4 , —OH, —NO 2 , —NH 2 , —NHR 4 , —SO 2 NH 2 , —NHSO 2 R 8 , —OCF 3 , or —OR 8 ;

R 2 has the meaning of R 1 and also a 5 or 6 membered heterocycle containing 1 or more heteroatoms selected from the group consisting of N, O, and S;

X 2 is N, O, or S;

R 4 is H, C 1-18 alkyl, C 5-10 cycloalkyl, or C 2-18 alkylene; and

R 8 is C 1-8 alkyl, C 5-6 cycloalkyl, C 2-8 alkenyl, or a 5 or 6-member aromatic ring including heterocyclic rings.

12. The compound of claim 11 wherein B is selected from the group consisting of:

13. A compound selected from the group consisting of:

Cis-(6-benzhydryl-tetrahydropyran-3-yl)-(4-hydroxy-benzyl)-amine;

Cis-(6-benzhydryl-tetrahydropyran-3-yl)-(1H-iodo-5-ylmethyl)-amine;

Cis-(6-benzhydryl-tetrahydropyran-3-yl)-(4-amino-benzyl)-amine;

Cis-(6-benzhydryl-tetrahydropyran-3-yl)-(3,4-dichloro-benzyl)-amine;

(2S,4R,5R)-2-benzhydryl-5-(4-methoxy-benzylamino)-tetrahydropyran-4-ol-);

(2S,4R,5R)-2-benzhydryl-5-benzylamino-tetrahydro-pyran-4-ol (−);

(2S,4R,5R)-2-benzhydryl-5-(2,4-dimethoxy-benzylamino)-tetrahydropyran-4-ol (−);

(2S,4R,5R)-2-benzhydryl-5-(3,5-dimethoxy-benzylamino)-tetrahydropyran-4-ol (−);

(2S,4R,5R)-2-benzhydryl-5-(4-hydroxy-benzylamino)-tetrahydropyran-4-ol (−);

(2S,4R,5R)-2-benzhydryl-5-[(1H-indol-5-ylmethyl)-amino]-tetrahydropyran-4-ol (−);

(2R,4S, 5S)-2-benzhydryl-5-(4-hydroxy-benzylamino)-tetrahydro-pyran-4-ol (+);

(2R,4S, 5S)-2-benzhydryl-5-[(1H-indol-5-ylmethyl)-amino]-tetrahydropyran-4-ol (+);

cis-(3S,6S)-(6-benzhydryl-tetrahydropyran-3-yl)-(4-hydroxy-benzyl)-amine (−); and

cis-(3R,6R)-(6-benzhydryl-tetrahydropyran-3-yl)-(4-hydroxy-benzyl)-amine (+).

14. A compound selected from the group consisting of:

(2S,4R,5R)-2-benzhydryl-5-(4-methoxy-benzylamino)-tetrahydropyran-4-ol(−);

(2S,4R,5R)-2-benzhydryl-5-(4-fluoro-benzylamino)-tetrahydro-pyran-4-ol (−);

(2S,4R,5R)-2-benzhydryl-5-benzylamino-tetrahydro-pyran-4-ol (−);

(2S,4R,5R)-2-benzhydryl-5-(2,4-dimethoxy-benzylamino)-tetrahydropyran-4-ol (−);

(2S,4R,5R)-2-benzhydryl-5-(3,5-dimethoxy-benzylamino)-tetrahydropyran-4-ol (−);

(2S,4R,5R)-2-benzhydryl-5-(4-hydroxy-benzylamino)-tetrahydropyran-4-ol (−);

(2S,4R,5R)-2-benzhydryl-5-[(1H-indol-5-ylmethyl)-amino]-tetrahydropyran-4-ol (−);

(2R,4S, 5S)-2-benzhydryl-5-(4-hydroxy-benzylamino)-tetrahydro-pyran-4-ol (+);

(2R,4S, 5 S)-2-benzhydryl-5-[(1H-indol-5-ylmethyl)-amino]-tetrahydropyran-4-ol (+);

cis-(3S,6S)-(6-benzhydryl-tetrahydropyran-3-yl)-(4-hydroxy-benzyl)-amine (−); and

cis-(3R,6R)-(6-benzhydryl-tetrahydropyran-3-yl)-(4-hydroxy-benzyl)-amine (+).

15. A compound having a formula selected from the group consisting of:

or a pharmaceutically acceptable salt, ester, carbamate, imide, or amide thereof, wherein:

A is selected from the group consisting of optionally substituted C 4 -C 14 aryl and heteroaryl wherein heteroatoms of heteroaryl A and/or A′ are selected from the group consisting of O, N, and S,

n and m are each independently 0, 1, 2, 3, or 4;

B is optionally substituted C 4 -C 14 aryl or optionally substituted C 4 -C 14 heteroaryl;

R 1 is C 1-4 alkyl, C 2-6 alkenyl, C 2-6 optionally halogenated alkynyl, C 2-6 hydroxyalkynyl, halo, —CN, —COOR 4 , —OH, —NO 2 , —NH 2 , —NHR 4 , —SO 2 NH 2 , —NHSO 2 R 8 , —OCF 3 , or —OR 8 ;

R 4 is H, C 1-18 alkyl, C 5-10 cycloalkyl, or C 2-18 alkylene; and

R 8 is C 1-8 alkyl, C 5-6 cycloalkyl, C 2-8 alkenyl, or a 5 or 6-member aromatic ring including heterocyclic rings.

16. The compound of claim 1 wherein A and A′ are an optionally substituted phenyl, napthyl, anthryl, furanyl, thienyl, or pridinyl group.

17. The compound of claim 16 wherein B is an optionally substituted phenyl, napthyl, anthryl, furanyl, thienyl, or pridinyl group.

18. The compound of claim 1 wherein B is an optionally substituted phenyl, napthyl, anthryl, furanyl, thienyl, or pridinyl group.