N-[2-(2-amino-6,6-disubstituted-4,4a,5,6-tetrahydropyrano[3,4-d][1,3]thiazin-8a(8H)-YL)-1,3-thiazol-4-YL] amides

Patent metadata

Field	Value
Publication number	US-10112958-B2
Application number	US-201715646572-A
Country	US
Kind code	B2
Filing date	Jul 11, 2017
Priority date	Sep 24, 2015
Publication date	Oct 30, 2018
Grant date	Oct 30, 2018

Abstract

The present invention is directed to compounds, tautomers and pharmaceutically acceptable salts of the compounds which are disclosed, wherein the compounds have the structure of Formula I,

and the variables R 1 , R 2 and R 3 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 selected from the group consisting of:
C 1-6 alkyl optionally substituted with one to three fluoro or C 1-3 alkoxy;
C 5-9 bicycloalkyl optionally substituted with one to three R 4 ; and
a 5- to 6-membered heteroaryl, having one to four heteroatoms independently selected from N, O or S, wherein at least one of the heteroatoms is N and wherein said N is optionally substituted with R 5 ; and wherein said 5- to 6-membered heteroaryl is optionally substituted on carbon with one to three R 4 ;
R 2 and R 3 are each independently selected from C 1-6 alkyl or C 3-7 cycloalkyl; wherein the C 1-6 alkyl is optionally substituted with one to three fluoro or C 1-3 alkoxy; or R 2 and R 3 taken together with the carbon to which they are attached form a C 3-6 cycloalkyl ring or a 4- to 6-membered heterocycloalkyl ring, each of which is optionally and independently substituted with one to three fluoro, C 1-3 alkyl or C 1-3 alkoxy;
R 4 at each occurrence is independently selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 alkenyl, C 3-6 alkenyloxy, C 3-6 alkynyl, C 3-6 alkynyloxy, C 1-6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3-6 cycloalkyl-C 1-6 alkoxy, 4- to 6-membered heterocycloalkyl and 4- to 6-membered heterocycloalkyl-C 1-6 alkyl; wherein said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 alkenyl, C 3-6 alkenyloxy, C 3-6 alkynyl, C 3-6 alkynyloxy, C 1-6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 3-6 cycloalkyl-C 1-6 alkoxy, 4- to 6-membered heterocycloalkyl and 4- to 6-membered heterocycloalkyl-C 1-6 alkyl are each optionally substituted with one to three substituents independently selected from fluoro, chloro, hydroxy, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy and trifluoromethoxy; and
R 5 is hydrogen, C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, 4- to 6-membered heterocycloalkyl and 4- to 6 membered heterocycloalkyl-C 1-6 alkyl; wherein said C 1-6 alkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, 4- to 6-membered heterocycloalkyl and 4-to 6-membered heterocycloalkyl-C 1-6 alkyl are each optionally substituted with one to three substituents independently selected from fluoro, chloro, hydroxy, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy and trifluoromethoxy; or R 4 and R 5 taken together can be a C 3-5 alkylene;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

2. The compound of claim 1 of Formula 1a

or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

3. The compound of claim 1 of Formula 1b

or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

4. The compound of claim 1 wherein R 1 is a 5-membered heteroaryl selected from the group consisting of pyrazolyl and oxazolyl; each optionally substituted on carbon with one to two R 4 ; and wherein said pyrazolyl is substituted on N with R 5 ;
R 4 at each occurrence is independently selected from the group consisting of halogen, C 1-3 alkyl, C 3-6 cycloalkyl, and C 1-3 alkoxy-C 1-3 alkyl; wherein said C 1-3 alkyl is optionally substituted with one to three fluoro; and
R 5 is C 1-3 alkyl or C 3-6 cycloalkyl, wherein said C 1-3 alkyl is optionally substituted with one to three fluoro;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

5. The compound of claim 4 wherein R 1 is selected from the group consisting of

R 4 at each occurrence is independently selected from the group consisting of chloro, methyl, ethyl, isopropyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl and methoxymethyl; and
R 5 is methyl, ethyl, isopropyl, difluoromethyl, cyclopropyl or cyclobutyl;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

6. The compound according to claim 5 wherein R 1 is selected from the group consisting of

R 2 and R 3 are each methyl;
R 4 is fluoromethyl; and
R 5 is difluoromethyl;

or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

7. The compound according to claim 1 wherein R 1 is a 6-membered heteroaryl selected from the group consisting of pyridinyl and pyrazinyl; each optionally substituted on carbon with one to two R 4 ; and
R 4 at each occurrence is independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 alkoxy and C 3-6 alkynyloxy; wherein said C 1-6 alkyl and C 1-6 alkoxy are optionally substituted with one to three fluoro;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

8. The compound according to claim 7 wherein
R 1 is selected from the group consisting of

 and
R 4 at each occurrence is independently selected from the group consisting of fluoro, chloro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, fluoromethoxy, difluoromethoxy, 1,1-difluoroethoxy, trifluoromethoxy, difluoropropoxy and butynyloxy;
or a tautomer thereof or pharmaceutically acceptable salt of said compound or tautomer.

9. The compound according to claim 8 wherein
R 1 is

 and
R 4 at each occurrence is independently selected from the group consisting of chloro, fluoro, methyl, but-2-ynyloxy, difluoromethoxy and 1,1-difluoroethoxy;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

10. The compound according to claim 9 wherein R 2 and R 3 are each independently selected from the group consisting of methyl, fluoromethyl, methoxymethyl, ethyl and cyclopropyl;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

11. The compound according to claim 9 wherein
R 2 and R 3 taken together with the carbon to which they are attached form a cyclopropyl, cyclobutyl or oxetanyl ring;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

12. The compound according to claim 8 wherein
R 1 is

 and
R 4 is selected from the group consisting of difluoromethoxy, 2,2-difluoropropoxy and but-2-ynyloxy;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or tautomer.

13. The compound according to claim 12 wherein
R 2 and R 3 are each methyl;
or a tautomer thereof or a pharmaceutically acceptable salt of said compound or

Assignees

• Pfizer

Inventors

• Brodney Michael Aaron
• Butler Christopher Ryan
• Zhang Lei
• O'Neill Brian Thomas
• Verhoest Patrick Robert
• Mikochik Peter Justin
• Murray John Charles
• Hou Xinjun

Classifications

• C07D513/04 Primary

  Ortho-condensed systems · CPC title

• C07D513/20

  Spiro-condensed systems · CPC title

• C07D513/10

  Spiro-condensed systems · 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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title