Benzylamine derivatives and their utility as cholesterol ester-transfer protein inhibitors

Patent metadata

Field	Value
Publication number	US-9765030-B2
Application number	US-201314052954-A
Country	US
Kind code	B2
Filing date	Oct 14, 2013
Priority date	Dec 31, 2004
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

The present invention provides, among other things, new benzylamine compounds, compositions comprising benzylamine compounds, methods of making benzylamine compounds, and methods of using benzylamine compounds for treating or preventing a variety of conditions or diseases associated with lipoprotein metabolism.

First claim

We claim:

1. A compound having the formula:

or a salt, diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, of any combination thereof, wherein:
R 1 and R 2 are selected independently from: 1) alkyl, having up to 12 carbon atoms; 2) COR 8 ; or 3)(CH 2 ) n R 5 wherein n, in each occurrence, is 1 or 2;
R a is 1) hydrogen, or 2) an alkyl having up to 12 carbon atoms;
R a2 is hydrogen or an alkyl having up to 12 carbon atoms;
R 3 is a substituted or an unsubstituted group selected from tetrazolyl, 1,3,4-oxadiazolyl, oxazolyl, pyrimidinyl, 4,5-dihydro-oxazolyl, pyridyl, thiazolyl, or isooxazolyl; wherein any optional substituent on R 3 is selected independently from: 1) a halogen; or 2) an alkyl, a haloalkyl, a cycloalkyl, and a heterocyclyl comprising at least one heteroatom or heterogroup selected independently from O and N any of which having up to 12 carbon atoms
R 4 , in each occurrence, is selected independently from: 1) halogen and 2) an alkyl or a haloalkyl, either of which having up to 12 carbon atoms;
m is an integer from 0 to 3, inclusive;
R 5 , in each occurrence, is selected independently from: cycloalkyl, and heterocyclyl, any of which having up to 12 carbon atoms, wherein any heterocyclyl comprises at least one heteroatom selected independently from O and N; and
R 8 , in each occurrence, is selected independently from an alkyl, or a cycloalkyl, any of which having up to 12 carbon atoms.

2. The compound according to claim 1 , having the formula:

or a salt, a diastereomeric mixture, are enantiomer, a tautomer, or a racemic mixture thereof, or any combination thereof, wherein:
R 11 is selected independently from: 1) hydrogen; and 2) an alkyl having up to 12 carbon atoms.

3. The compound according to claim 2 , wherein,
R 1 and R 2 are (cycloalkyl)alkyl-having up to 10 carbon atoms; wherein the alkyl is methyl or ethyl;
R a is selected independently from: 1) a hydrogen; and 2) an alkyl having up to 10 carbon atoms; and
R a2 is hydrogen or an alkyl having up to 10 carbon atoms.

4. The compound according to, claim 1 , having the formula:

or a salt, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, or any combination thereof, wherein:
R 11 is selected from; 1) a hydrogen or a halogen; 2) an alkyl or a heterocyclyl comprising at least one heteroatom or heterogroup selected independently from O, and any of which having up to 12 carbon atoms;
Y 1 , and Y 2 , are selected independently from CH or N; and Y 3 is CH, with the proviso that at least one of the Y 1 , or Y 2 is N; and R 11 is substituent present on the C atom;
R 1 and R 2 are a (cycloalkyl)alkyl-having up to 10 carbon atoms, wherein the alkyl is methyl or ethyl;
R a is selected independently from: 1) a hydrogen; and 2) an alkyl having up to 10 carbon atoms: and
R a2 is selected from hydrogen or an alkyl having up to 10 carbon atoms.

5. The compound according to claim 4 , having the formula:

or a salt, a diastereomeric mixture, an enantiomer, a tautomer, or a racemic mixture thereof, or any combination thereof, wherein:
R 11 is selected independently from: 1) a hydrogen or a halogen; 2) an alkyl or a heterocyclyl comprising at least one heteroatom or heterogroup selected independently from O-any of which having up to 12 carbon atoms.

6. The compound according to claim 4 , wherein:
R 1 and R 2 are a (cycloalkyl)alkyl having up to 10 carbon, atoms, wherein the alkyl is methyl or ethyl;
R a , in each occurrence, is selected independently from: 1) hydrogen; and 2) an alkyl-having up to 10 carbon atoms; and
R a2 is selected from hydrogen or an alkyl having up to 10 carbon atoms.

7. The compound according to claim 1 selected from:
(5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazole-5-yl)-amino]methyl}-1,3-dimethyl-1H-pyrazolo[3,4-b]-pyridin-6-yl)-cyclobutylmethyl-ethyl-amine;
(5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazole-5-yl)-amino]methyl}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-bis-cyclopropylmethylethyl-amine;
(5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazole-5-yl)-amino]methyl}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-cyclopropylmethyl-ethyl-amine;
(5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazole-5-yl)-amino]methyl}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-cyclobutylmethyl-methyl-amine;
(5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazole-5-yl)-amino]methyl}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-cyclobutylmethyl-cyclopropylmethyl-amine;
(5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazole-5-yl)-amino]methyl}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-(2,2-dimethyl-propyl)-ethyl-amine;
(5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazole-5-yl)-amino]methyl}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-ethyl-isopropyl-amine;
(5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazole-5-yl)-amino]methyl}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-cyclopentyl-ethyl-amine;
(5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazole-5-yl)-amino]methyl}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-cyclopentyl-cyclopropylmethyl-amine;
(5-{[(3,5-bis-trifluoromethyl-benzyl)-(5-methyl-isoxazol-3-yl)-amino]-methyl}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-cyclobutylmethyl-ethyl-amine;
(5-{[(3,5-bis-trifluoromethyl-benzyl)-(5-methyl-isoxazol-3-yl)-amino]-methyl}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-bis-cyclopropylmethyl-amine;
(5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazole-5-yl)-amino]methyl}-1-meltyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-cyclobutylmethyl-ethyl-amine;
(5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazole-5-yl)-amino]methyl}-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-bis-cyclopropylmethyl-amine;
(5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazole-5-yl)-amino]methyl}-1-ethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-bis-cyclopropylmethyl-amine;
(5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazole-5-yl)-amino]methyl}-1-ethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-cyclobutylmethyl-ethyl-amine;
Cyclopentylmethyl-ethyl-(5-{[(3,5-difluoro-benzyl)-(2-methy-2H-tetrazole-5-yl)-amino]-methyl}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-amine;
Cyclopentylmethyl-(1,3-dimethyl-5-{[(2-methyl-2H-tetrazole-5-yl)-(3,5-dichlorobenzyl)-amino]-methyl}-1H-pyrazolo[3,4-b]pyridin-6-yl)-ethyl-amine;
Cyclopentylmethyl-ethyl-(5-{[(3-fluoro-5-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazole-5-yl)-amino]-methyl}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-ethyl-amine;
Bis-cyclopropylmethyl-(5-{[(3,5-dichlorobenzyl)-(2-methyl-2H-tetrazole-5-yl)-amino]-methyl}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin6-yl)-amine;
(5-{[(3,5-bis-trifluoromethyl-benzyl)-(4-trifluoromethyl-oxazol-2-yl)-amino]-methyl}-1,3-dimethyl-1H-pyrazolo[3,4-b]-pyridin-6-yl)-cyclopentylmethyl-ethyl-amine;
(5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazole-5-yl)-amino]-methyl}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-cyclopentylmethyl-ethyl-amine;
(5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazole-5-yl)-amino]-methyl}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-diisobutyl-amine;
(5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazole-

Assignees

• Dr Reddys Laboratories Ltd

Inventors

• Baruah Anima
• De Dibyendu
• Khanna Ish Kumar
• Pillarisetti Sivaram
• Maitra Santanu
• Alexander Christopher W
• Sreenu Jennepalli
• Dager Indu
• Alikunju Shanavas

Classifications

• C07D215/14 Primary

  Radicals substituted by oxygen atoms · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D213/73

  Unsubstituted amino or imino radicals · CPC title

• C07D213/74

  Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals · CPC title

• C07D241/20

  Nitrogen atoms (nitro radicals C07D241/16) · CPC title