Triazolo[4,5-D]pyrimidines

Patent metadata

Field	Value
Publication number	US-10183946-B2
Application number	US-201715478435-A
Country	US
Kind code	B2
Filing date	Apr 4, 2017
Priority date	Nov 7, 2014
Publication date	Jan 22, 2019
Grant date	Jan 22, 2019

Abstract

The invention relates to a compound of formula (I)

wherein R 1 to R 4 and n are defined as in the description and in the claims. The compound of formula (I) can be for treating.

First claim

We claim:

1. A compound of formula (I)

wherein
n is 0, 1 or 2;
R 1 is phenyl, halophenyl, alkyl sulfonylphenyl, alkyltetrazolyl, alkyloxadiazolyl, halohydroxyalkyl, oxolanyl, oxetanyl, haloalkyl, halopyridinyl or alkyloxetanyl;
R 2 is hydrogen, hydroxyl, halogen or haloalkyl; and
R 3 and R 4 are independently selected from alkyl; or
R 3 and R 4 , together with the carbon atom to which they are attached, form cycloalkyl, thiethanyl, haloalkylcycloalkyl or oxothietanyl;
or
R 2 is absent; and
R 3 and R 4 , together with the carbon atom to which they are attached, form alkylphenyl, halophenyl, alkoxyphenyl, halopyridinyl, alkylpyridinyl, alkylpyrazolyl, phenyl, alkyloxazolyl, pyrazolyl, imidazolyl, benzyltriazolyl or cycloalkenyl;
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, halophenyl, alkyltetrazolyl or alkyloxadiazolyl.

3. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, chlorophenyl, methyltetrazolyl or methyloxadiazolyl.

4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is absent and R 3 and R 4 , together with the carbon atom to which they are attached, form halopyridinyl, alkylpyrazolyl or alkyloxazolyl.

5. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is absent and R 3 and R 4 , together with the carbon atom to which they are attached, form fluoropyridinyl, methylpyrazolyl or methyloxazolyl.

6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1.

7. The compound according to claim 1 , wherein the compound is selected from the group consisting of:
5-tert-butyl-3-[(2-chlorophenyl)methyl]-7-(4-methylphenyl)triazolo[4,5-d]pyrimidine;
5-tert-butyl-3-[(2-chlorophenyl)methyl]-7-(4-fluorophenyl)triazolo[4,5-d]pyrimidine;
5-tert-butyl-3-[(2-chlorophenyl)methyl]-7-(4-methoxyphenyl)triazolo[4,5-d]pyrimidine;
5-tert-butyl-3-[(2-chlorophenyl)methyl]-7-(2-fluorophenyl)triazolo[4,5-d]pyrimidine;
5-tert-butyl-7-(4-chloro-2-fluorophenyl)-3-[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidine;
5-tert-butyl-3-[(2-chlorophenyl)methyl]-7-(6-fluoropyridin-3-yl)triazolo[4,5-d]pyrimidine;
5-tert-butyl-3-[(2-chlorophenyl)methyl]-7-(5-methylpyridin-2-yl)triazolo[4,5-d]pyrimidine;
5-tert-butyl-3-[(2-chlorophenyl)methyl]-7-(1-methylpyrazol-4-yl)triazolo[4,5-d]pyrimidine;
5-tert-butyl-3-[(2-chlorophenyl)methyl]-7-(2-methylpyrazol-3-yl)triazolo[4,5-d]pyrimidine;
5-tert-butyl-3-[(2-chlorophenyl)methyl]-7-phenyltriazolo[4,5-d]pyrimidine;
4-[5-tert-butyl-3-[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidin-7-yl]-5-methyl-1,2-oxazole;
5-tert-butyl-7-(2-methylpyrazol-3-yl)-3-[(2-methylsulfonylphenyl)methyl]triazolo[4,5-d]pyrimidine;
5-tert-butyl-7-(2-methylpyrazol-3-yl)-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidine;
3-[[5-tert-butyl-7-(2-methylpyrazol-3-yl)triazolo[4,5-d]pyrimidin-3-yl]methyl]-4-methyl-1,2,5-oxadiazole;
2-[[5-tert-butyl-7-(2-methylpyrazol-3-yl)triazolo[4,5-d]pyrimidin-3-yl]methyl]-5-methyl-1,3,4-oxadiazole;
1-[5-tert-butyl-7-(2-methylpyrazol-3-yl)triazolo[4,5-d]pyrimidin-3-yl]-4,4,4-trifluorobutan-2-ol;
(2S)-3-[5-tert-butyl-7-(2-methylpyrazol3-yl)triazolo[4,5-d]pyrimidin-3-yl]-1,1,1-trifluoropropan-2-ol;
5-tert-butyl-7-(2-methylpyrazol3-yl)-3-(oxolan-3-yl)triazolo[4,5-d]pyrimidine;
5-tert-butyl-7-(2-methylpyrazol3-yl)-3-(oxetan-3-yl)triazolo[4,5-d]pyrimidine;
5-tert-butyl-7-(2-methylpyrazol3-yl)-3-(3,3,3-trifluoropropyl)triazolo[4,5-d]pyrimidine;
5-tert-butyl-3-[(3-chloropyridin-2-yl)methyl]-7-(2-methylpyrazol-3-yl)triazolo[4,5-d]pyrimidine;
1-[5-tert-butyl-7-(2-methylpyrazol-3-yl)triazolo[4,5-d]pyrimidin-3-yl]-2-methylpropan-2-ol;
5-tert-butyl-3-[(3-methyloxetan-3-yl)methyl]-7-(2-methylpyrazol-3-yl)triazolo[4,5-d]pyrimidine;
5-tert-butyl-7-(1-methylpyrazol-4-yl)-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidine;
5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]-7-(1H-pyrazol-4-yl)triazolo[4,5-d]pyrimidine;
5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]-7-(1H-pyrazol-3-yl)triazolo[4,5-d]pyrimidine;
4-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]-5-methyl-1,2-oxazole;
5-tert-butyl-7-(1H-imidazol-2-yl)-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidine;
7-(3-benzyltriazol-4-yl)-5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidine;
3-[[5-tert-butyl-7-(6-fluoropyridin-3-yl)triazolo[4,5-d]pyrimidin-3-yl]methyl]-4-methyl-1,2,5-oxadiazole;
1-(3-benzyl-5-tert-butyltriazolo[4,5-d]pyrimidin-7-yl)cyclobutan-1-ol;
3-benzyl-5-tert-butyl-7-(1-fluorocyclobutyl)triazolo[4,5-d]pyrimidine;
1-[5-tert-butyl-3-[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidin-7-yl]cyclobutan-1-ol;
1-[5-tert-butyl-3-[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidin-7-yl]cyclopentan-1-ol;
1-[5-tert-butyl-3-[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidin-7-yl]cyclohexan-1-ol;
1-[5-tert-butyl-3-[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidin-7-yl]cycloheptan-1-ol;
1-[5-tert-butyl-3-[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidin-7-yl]cyclooctan-1-ol;
3-[5-tert-butyl-3-[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pentan-3-ol;
3-[5-tert-butyl-3-[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidin-7-yl]thietan-3-ol;
1-[5-tert-butyl-3-[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidin-7-yl]-3-(difluoromethyl)cyclobutan-1-ol;
1-[5-tert-butyl-3-[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidin-7-yl]-3-(difluoromethyl)cyclobutan-1-ol;
3-[5-tert-butyl-3-[(2-chlorophenyl)methyl]triazolo[4,5-d]pyrimidin-7-yl]-1-oxothietan-3-ol;
5-tert-butyl-3-[(2-chlorophenyl)methyl]-7-[1-(fluoromethyl)cyclopropyl]triazolo[4,5-d]pyrimidine;
5-tert-butyl-3-[(2-chlorophenyl)methyl]-7-(cyclopenten-1-yl)triazolo[4,5-d]pyrimidine;
5-tert-butyl-3-[(2-chlorophenyl)methyl]-7-cyclopentyl-triazolo[4,5-d]pyrimidine; and
3-benzyl-5-tert-butyl-7-cyclopentyl-triazolo[4,5-d]pyrimidine;
or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 , wherein the compound is:
5-tert-butyl-3-[(2-chlorophenyl)methyl]-7-(6-fluoropyridin-3-yl)triazolo[4,5-d]pyrimidine;
or a pharmaceutically acceptable salt thereof.

9. A process for the preparation of a compound according to claim 1 , comprising reacting a compound of formula (II):

wherein Y is chloride or bromide;
with a compound of the formula B(OH) 2 CR 2 R 3 R 4 or a compound of the formula B(OR) 2 CR 2 R 3 R 4 where B(OR) 2 is 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl; in the presence of a base and a palladium catalyst.

10. A pharmaceutical composition comprising a compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier selected from the group consisting of Microcrystalline cellulose, Lactose hydrous, Povidone K30, Sodium starch glycolate, and Magnesium stearate.

11. The compound according to claim 1 , wherein the compound is:
3-[[5-tert-butyl-7-(2-methylpyrazol-3-yl)triazolo[4,5-d]pyrimidin-3-yl]methyl]-4-methyl-1,2,5-oxadiazole;
or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 , wherein the compound is:
4-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]-5-methyl-1,2-oxazole;
or a pharmaceutically acceptable salt thereof.

13. The compo

Assignees

• Hoffmann—La Roche Inc
• Hoffmann La Roche

Inventors

• Grether Uwe
• Nettekoven Matthias
• Rogers-Evans Mark
• Schmitt Sebastien
• Stenton Benjamin James

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title