Hexahydropyrano[3,4-d][1,3]thiazin-2-amine compounds

Patent metadata

Field	Value
Publication number	US-9045498-B2
Application number	US-201414325409-A
Country	US
Kind code	B2
Filing date	Jul 8, 2014
Priority date	Dec 11, 2012
Publication date	Jun 2, 2015
Grant date	Jun 2, 2015

Abstract

The present invention provides compounds of Formula I, and the tautomers thereof, and the pharmaceutically acceptable salts of the compounds and tautomers, wherein the compounds have the structure

wherein the variables R 1 , R 2 , R 3 , R 4 and x are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

First claim

We claim:

1. A compound of Formula I,

wherein
R 1 is hydrogen or methyl, wherein said methyl is optionally substituted with one to three substituents independently selected from halogen or methoxy;
R 2 is C 1-6 alkyl, —(C(R 5 ) 2 ) m —(C 3-6 cycloalkyl), —C(R 5 ) 2 ) m —(C 6-10 aryl), —(C(R 5 ) 2 ) m — (5- to 10-membered heteroaryl) or —(C(R 5 ) 2 ) t —OR 6 ; wherein said alkyl, cycloalkyl, aryl or heteroaryl moieties are optionally substituted with one to three substituents independently selected from halogen, C 1-6 alkyl, —CH 2 F, —CHF 2 , —CF 3 , —CN or —OR 7 ;
R 3 is —C(R 5 ) 2 ) m —(CN);
R 4 is independently selected from halogen, C 1-6 alkyl or C 1-6 alkoxy; wherein said alkyl or alkoxy is optionally substituted with one to three fluoro;
R 5 at each occurrence is independently selected from hydrogen or C 1-3 alkyl, wherein said alkyl is optionally substituted with one to three halogen;
R 6 is hydrogen, C 1-6 alkyl or —C(R 5 ) 2 ) n —(C 6-10 aryl), wherein said alkyl and aryl are optionally substituted with one to three substituents independently selected from halogen, C 1-3 alkyl, —CH 2 F, —CHF 2 , —CF 3 , —CN or —OH;
R 7 for each occurrence is hydrogen or C 1-6 alkyl, wherein said alkyl is optionally substituted with one to three substituents independently selected from halogen or C 1-6 alkoxy;
m at each occurrence is independently 0, 1 or 2;
n at each occurrence is independently is 1 or 2;
t is 1 or 2; and
x is 0, 1, 2 or 3;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

2. The compound of claim 1 wherein m is 0 or 1; and R 5 at each occurrence is hydrogen; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

3. The compound of claim 1 wherein m is 0; R 2 is C 1-6 alkyl optionally substituted with one to three fluoro, or —(C(R 5 ) 2 ) t —OR 6 ; wherein t is 1; R 5 at each occurrence is hydrogen, and R 6 is C 1-3 alkyl optionally substituted with one to three fluoro, or —(C(R 5 ) 2 ) n —(C 6-10 aryl), wherein said aryl is optionally substituted with one to three substituents selected from halogen, C 1-6 alkyl, —CH 2 F, —CHF 2 , —CF 3 , —CN or —OH; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

4. The compound of claim 3 wherein R 6 is —(C(R 5 ) 2 ) n —(C 6-10 aryl), said aryl is phenyl optionally substituted with one to three substituents independently selected from halogen, C 1-6 alkyl, —CH 2 F, —CHF 2 , —CF 3 , —CN or —OH; n is 1; and R 5 at each occurrence is hydrogen; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

5. The compound of claim 1 wherein R 2 is —(C(R 5 ) 2 ) m —(C 3-6 cycloalkyl) or —(C(R 5 ) 2 ) m -(5- to 10-membered heteroaryl), wherein said cycloalkyl or heteroaryl is optionally substituted with one to three substituents independently selected from halogen, C 1-6 alkyl, —CH 2 F, —CHF 2 , and —CF 3 m is 0; and R 5 at each occurrence is hydrogen; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

6. The compound of claim 1 wherein R 4 is independently selected from fluoro, chloro, methyl, ethyl, propyl, methoxy or ethoxy; wherein said methyl, ethyl and propyl groups are optionally substituted with one to three fluoro; and x is 0, 1 or 2; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

7. A compound of claim 1 of Formula Ia,

wherein
R 1 is hydrogen or methyl, wherein said methyl is optionally substituted with one to three halogen;
R 2 is C 1-6 alkyl, —(C(R 5 ) 2 ) m —(C 3-6 cycloalkyl), —(C(R 5 ) 2 ) m -(5- to 10-membered heteroaryl) or —(C(R 5 ) 2 ) t —OR 6 ; wherein said alkyl, cycloalkyl or heteroaryl moieties are optionally substituted with one to three substituents independently selected from halogen, C 1-6 alkyl, —CH 2 F, —CHF 2 , —CF 3 , —CN or —OH;
R 4 is independently halogen, C 1-6 alkyl or C 1-6 alkoxy; wherein said alkyl or alkoxy moieties are optionally substituted with one to three fluoro;
R 5 at each occurrence is hydrogen or C 1-3 alkyl, wherein said alkyl is optionally substituted with one to three halogen;
R 6 is hydrogen, C 1-6 alkyl or —(C(R 5 ) 2 ) n —(C 6-10 aryl), wherein said alkyl and aryl are optionally substituted with one to three substituents selected from halogen, C 1-3 alkyl, —CH 2 F, —CHF 2 , —CF 3 , —CN or —OH;
m is 0, 1 or 2;
n is 1 or 2;
t is 1 or 2; and
x is 0, 1 or 2 or 3;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

8. The compound of claim 7 wherein R 4 is independently selected from fluoro, chloro, methyl, ethyl, propyl, methoxy and ethoxy, wherein said methyl, ethyl and propyl groups are optionally substituted with one to three fluoro; and x is 0, 1 or 2; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

9. The compound of claim 8 wherein R 2 is methyl, optionally substituted with one to three fluoro; R 4 is independently selected from methoxy, chloro or fluoro; and x is 0, 1 or 2; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

10. The compound of claim 8 wherein R 2 is —(C(R 5 ) 2 ) m -(5-membered heteroaryl); R 4 is independently methoxy, chloro or fluoro; m is 0; and x is 0, 1 or 2; or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

11. The compound of claim 8 wherein R 2 is —(C(R 5 ) 2 ) t —OR 6 ;
R 6 is hydrogen, methyl or —(C(R 5 ) 2 ) n —(C 6-10 aryl), wherein the aryl of R 6 is phenyl optionally substituted with one to three substituents selected from halogen, C 1-3 alkyl, —CH 2 F, —CHF 2 , —CF 3 , —CN or —OH;
R 4 is independently methoxy, chloro or fluoro;
x is 0, 1 or 2;
n is 1; and
t is 1;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

12. The compound of claim 8 wherein R 2 is —(C(R 5 ) 2 ) m —(C 3-6 cycloalkyl), wherein said cycloalkyl is optionally substituted with one to three substituents selected from halogen or C 1-6 alkyl, optionally substituted with one to three fluoro;
R 4 is independently methoxy, chloro or fluoro;
m is 0 or 1; and x is 0, 1 or 2;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

13. The compound according to claim 1 , or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer;
wherein
R 1 is hydrogen or methyl;
R 2 is methyl, fluoromethyl, hydroxymethyl, methoxymethyl, benzyloxymethyl, cyclopropyl, 3-methyl-1,2-oxazol-5-yl, 4-methyl-1,3-oxazol-2-yl or 1-methyl-1H-pyrazol-4-yl;
R 3 is —CN;
R 4 is independently fluoro, chloro or methoxy; and
x is 0, 1 or 2.

14. The compound according to claim 13 selected from the group consisting of
5-[(4aR,6R,8aS)-2-Amino-6-[(benzyloxy)methyl]-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-4-fluoro-2-methoxybenzonitrile;
5-[(4aR,6R,8aS)-2-Amino-6-[(benzyloxy)methyl]-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzonitrile;
5-[(4aR,6R,8aS)-2-Amino-6-(hydroxymethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzonitrile;
5-[(4aR,6R,8aS)-2-Amino-6-(fluoromethyl)-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-yl]-2,4-difluorobenzonitrile;
5-[(4aR,6R,8aS)-2-Amino-6-(methox

Assignees

• Pfizer

Inventors

• Brodney Michael Aaron
• Beck Elizabeth Mary
• Butler Christopher Ryan
• Davoren Jennifer Elizabeth
• O'Neill Brian Thomas

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title