Tetrahydropyrazolopyrimidine compounds

Patent metadata

Field	Value
Publication number	US-10640500-B2
Application number	US-201715841767-A
Country	US
Kind code	B2
Filing date	Dec 14, 2017
Priority date	May 31, 2012
Publication date	May 5, 2020
Grant date	May 5, 2020

Abstract

Embodiments of the disclosure relate to tetrahydropyrazolopyrimidine compounds that act as antagonists or inhibitors for Toll-like receptors 7 and/or 8, and their use in pharmaceutical compositions effective for treatment of systemic lupus erythematosus (SLE) and lupus nephritis.

First claim

We claim:

1. A method of preparing a compound of formula (I)

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or mixture of stereoisomers thereof, wherein
R 1 is optionally substituted piperidinyl, optionally substituted pyridyl, optionally substituted pyrrolyl, optionally substituted pyrroldinyl, 1,4-dimethylthiazolyl, 2-ethyl-4-methylthiazolyl, 2-isopropylthiazol-5-yl, thiazolyl, 3-ethylthiazol-5-yl, 1-methylsulfonylpiperidin-4-yl, or
R 1 is —C(O)Z, where Z is piperazinyl, (S)-2-(3-ethylpiperazin-1-yl), optionally substituted pyrrolopyrrolyl, piperidin-3-yl amino, or,
R 1 is

 where R 13 is H, methylpyrazolyl, methylimidazolyl, benzyl, 3-hydroxybutyl, 3-(dimethylamino)-2,2-dimethylpropyl, ethylamide, methylpyridyl, methylsulfonyl, (1-methylimidazol-2-yl)methyl, (1,5-dimethylimidazol-4-yl)methyl, (1-methylpyrrol-2-yl)methyl, or where R 13 is C(O)W, where W is —N(CH 3 ) 2 , piperidinyl, piperazinyl, or morpholinyl, or,
R 1 is

 where R 14 is —C(O)CH 3 , H, or (1-methylpyrrol-2-yl)methyl, or,

R 1 is

R 1 is

 where A, B, and D may all be carbon, or where two of A, B, and D are carbon and the other is nitrogen, or where one of A, B, and D is carbon and the remaining two are nitrogen; and when A is nitrogen R 4 is absent, when B is nitrogen R 2 is absent, and when D is nitrogen R 3 is absent; and wherein

R 2 is H, —CH 3 , or F, or, with R 3 and the atoms at positions a and b, forms an optionally substituted pyridine or a pyrazole; and wherein
R 3 is H, F, Cl, —CN, —CH 3 , —OCH 3 , —OH, —NH 2 , methylsulfonyl,

 or, with R 4 and the atoms at b and c, forms an optionally substituted benzene, optionally substituted imidazole, optionally substituted pyrazole, optionally substituted pyrazolidine, optionally substituted imidazolidine, optionally substituted isothiazole,

 or, with R 2 and the atoms at a and b, forms an optionally substituted pyridine or optionally substituted pyrazole; and wherein
R 4 is F, —CN, —OCH 3 , —OEt, H, Cl, Br, —NH—C(O)—CH—(CH 3 ) 2 , —N(CH 3 ) 2 , —CH 3 , —CH 2 OH,

 optionally substituted piperazinyl, 4-hydroxypiperizin-1-yl, optionally substituted piperidinyl not attached to a phenyl group through a nitrogen, or, with R 3 and the atoms at b and c, forms an optionally substituted pyrazole ring or

 or, with R 5 and the atoms at c and d, forms an optionally substituted pyrazole ring or an optionally substituted pyrrole ring, or,
R 4 is -(q)-C(O)X, where q is a bond, is —NH—, or is —CH 2 —, and
where X is —NR 11 R 12 ,
where R 11 and R 12 are both H, both —CH 2 CH 3 , or both —CH 3 , or where one of R 11 and R 12 is H and the other is 1,1-dimethylethyl, cyclobutyl, cyclopropyl, lower alkyl, methyl alcohol, propyl alcohol, cyclobutylmethyl; 2,3-dihydroxypropyl, benzyl, azetidinyl, pyrrolidinyl, piperidinyl, methylazetidinyl, —CH 2 —NH—CH 3 , pyrazolyl, piperazinyl, alcohol, —OCH 3 , or

 or

where X is optionally substituted pyrrolidinyl attached through a nitrogen to the carbonyl group of R 4 , optionally substituted piperidinyl not attached through a nitrogen to the carbonyl group of R 4 , optionally substituted pyrrolidinyl attached through a nitrogen to the carbonyl group of R 4 , optionally substituted piperazinyl attached through a nitrogen to the carbonyl group of R 4 , or optionally substituted morpholinyl attached through a nitrogen to the carbonyl group of R 4 ,

 and wherein

R 5 is H, F, Cl, —CH 3 , —OCH 3 , pyrrolyl, —CH 2 OH, —NH 2 , —OH,

 or, with R 4 and the atoms at c and d, forms an optionally substituted benzene, an optionally substituted pyrazole, or an optionally substituted pyrrole, or, with R 6 and the atoms at d and e, forms an optionally substituted pyridine, or R 5 is C(O)Y, where Y is —NH 2 , —N(CH 3 ) 2 , optionally substituted piperazinyl, optionally substituted piperidinyl,

 and wherein
R 6 is H, F, —CH 3 , —CF 3 , or, with R 5 and the atoms at c and d, forms an optionally substituted benzene or an optionally substituted pyrazole; and wherein
R 7 is —CF 3 or —CHF 2 ; and wherein
R 8 is

 and wherein
R 9 is Br, Cl, F, I, or H;
with the following provisos:
when R 4 is F: R 2 is not —CH 3 or F; R 3 is not —CH 3 , —CN, F, Cl, or —OCH 3 ; R 5 is not —CH 3 , F, Cl, or —OCH 3 ; and R 6 is not —CH 3 or F;
when R 4 is Cl: R 2 is not F; R 3 is not F or —CN; R 5 is not F, —CN, or —C(O)N(CH 3 ) 2 ; R 6 is not —CF 3 or F; D is not nitrogen; and either R 5 is —C(O)NH 2 or one of R 2 , R 3 , R 5 , and R 6 is —CH 3 ;
when R 4 is —CH 3 : R 3 is not F; R 5 is not F; and R 5 and R 6 do not form a pyrimidine together with the atoms at d and e;
when R 4 is —OCH 3 : R 2 is not F; R 3 is not Cl or —OCH 3 , R 5 is not Cl or —OCH 3 ; and R 6 is not F or —CF 3 ;
when R 4 is —CN: R 2 is not F; R 3 is not Cl, F, or —OCH 3 , R 5 is not Cl, F, or —OCH 3 ; and R 6 is not F;
when R 4 is —OCH 2 CH 3 : R 3 is not Cl or F; R 5 is not Cl or F; and R 6 is not —CF 3 ;
when R 4 is

 R 3 is not H or F; and R 5 is not H or F;
when R 4 is

 at least one of R 2 , R 3 , R 5 , and R 6 is not H;
when R 4 is

 R 3 is not F; and R 5 is not F;
when R 2 is F: R 3 is not —OCH 3 or F; R 5 is not —CN; and at least one of R 3 , R 4 , R 5 , and R 6 is not H;
when R 2 is Cl: R 3 is not F;
when R 2 is —CH 3 : R 3 is not Cl; at least one of R 3 , R 4 , R 5 , and R 6 is not —CH 3 ; and R 4 and R 5 do not form a pyrazolyl with the atoms at c and d;

Assignees

• Eisai R&D Man Co Ltd

Inventors

• Boivin Roch
• Carlson Eric
• Endo Atsushi
• Hansen Hans
• Hawkins Lynn D
• Ishizaka Sally
• Mackey Matthew
• Narayan Sridhar
• Satoh Takashi
• Schiller Shawn

Classifications

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P43/00

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