US 9,850,242 B2Granted

Tetrahydropyrazolopyrimidine compounds

AssigneeEisai R&D Management Co., Ltd.

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

Life of this patent

Estimating the term…

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.

Claims12

Dependent claims

A method for antagonizing TLR7, comprising administering a pharmaceutically effective amount of a compound of formula (I)

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or mixture of stereoisomers thereof, wherein
R1 is optionally substituted piperidinyl, optionally substituted pyridyl, optionally substituted pyrrolyl, optionally substituted pyrrodinyl, 1,4-dimethylthiazolyl, 2-ethyl-4-methylthiazolyl, 2-isopropylthiazol-5-yl, thiazolyl, 3-ethylthiazol-5-yl, 1-methylsulfonylpiperidin-4-yl, or
R1 is —C(O)Z, where Z is piperazinyl, (S)-2-(3-ethylpiperazin-1-yl), optionally substituted pyrrolopyrrolyl, piperidin-3-ylamino, or,
R1 is
where R13 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 R13 is C(O)W, where W is N(CH3)2, piperidinyl, piperazinyl, or morpholinyl, or,
R1 is
where R14 is C(O)CH3, H, or (1-methylpyrrol-2-yl)methyl, or,
R1 is
or
R1 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 R4 is absent, when B is nitrogen R2 is absent, and when D is nitrogen R3 is absent;
and wherein
R2 is H, —CH3, or F, or, with R3 and the atoms at positions a and b, forms an optionally substituted pyridine or a pyrazole;
and wherein
R3 is H, F, Cl, —CN, —CH3, —OCH3, —OH, —NH2, methylsulfonyl,
or, with R4 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 R2 and the atoms at a and b, forms an optionally substituted pyridine or optionally substituted pyrazole;
and wherein
R4 is F, —CN, —OCH3, —OEt, H, Cl, Br, —NH—C(O)—CH—(CH3)2, —N(CH3)2, —CH3, —CH2OH,
optionally substituted piperazinyl, 4-hydroxypiperizin-1-yl, optionally substituted piperidinyl not attached to a phenyl group through a nitrogen, or, with R3 and the atoms at b and c, forms an optionally substituted pyrazole ring or
or, with R5 and the atoms at c and d, forms an optionally substituted pyrazole ring or an optionally substituted pyrrole ring, or,
R4 is -(q)-C(O)X, where q is a bond, is —NH—, or is —CH2—, and
where X is —NR11R12,
where R11 and R12 are both H, both —CH2CH3, or both —CH3, or where one of R11 and R12 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, —CH2—NH—CH3, pyrazolyl, piperazinyl, alcohol, —OCH3, or
or
where X is optionally substituted pyrrolidinyl attached through a nitrogen to the carbonyl group of R4, optionally substituted piperidinyl not attached through a nitrogen to the carbonyl group of R4, optionally substituted pyrrolidinyl attached through a nitrogen to the carbonyl group of R4, optionally substituted piperazinyl attached through a nitrogen to the carbonyl group of R4, or optionally substituted morpholinyl attached through a nitrogen to the carbonyl group of R4,
and wherein
R5 is H, F, Cl, —CH3, —OCH3, pyrrolyl, —CH2OH, —NH2, —OH,
or, with R4 and the atoms at c and d, forms an optionally substituted benzene, an optionally substituted pyrazole, or an optionally substituted pyrrole, or, with R6 and the atoms at d and e, forms an optionally substituted pyridine, or R5 is C(O)Y, where Y is —NH2, —N(CH3)2, optionally substituted piperazinyl, optionally substituted piperidinyl,
and wherein
R6 is H, F, —CH3, —CF3, or, with R5 and the atoms at c and d, forms an optionally substituted benzene or an optionally substituted pyrazole;
and wherein
R7 is —CF3 or —CHF2;
and wherein
R8 is
and wherein
R9 is Br, Cl, F, I, or H;
with the following provisos:
when R4 is F:
R2 is not —CH3 or F;
R3 is not —CH3, —CN, F, Cl, or —OCH3;
R5 is not —CH3, F, Cl, or —OCH3;
and R6 is not —CH3 or F;
when R4 is Cl:
R2 is not F;
R3 is not F or —CN;
R5 is not F, —CN, or —C(O)N(CH3)2;
R6 is not —CF3 or F;
D is not nitrogen;
and either R5 is —C(O)NH2 or one of R2, R3, R5, and R6 is —CH3;
when R4 is —CH3:
R3 is not F;
R5 is not F;
and R5 and R6 do not form a pyrimidine together with the atoms at d and e;
when R4 is —OCH3:
R2 is not F;
R3 is not Cl or —OCH3, R5 is not Cl or —OCH3;
and R6 is not F or —CF3;
when R4 is —CN:
R2 is not F;
R3 is not Cl, F, or —OCH3, R5 is not Cl, F, or —OCH3;
and R6 is not F;
when R4 is —OCH2CH3:
R3 is not Cl or F;
R5 is not Cl or F;
and R6 is not —CF3;
when R4 is
R3 is not H or F;
and R5 is not H or F;
when R4 is
at least one of R2, R3, R5, and R6 is not H;
when R4 is
R3 is not F;
and R5 is not F;
when R2 is F:
R3 is not —OCH3 or F;
R5 is not —CN;
and at least one of R3, R4, R5, and R6 is not H;
when R2 is Cl:
R3 is not F;
when R2 is —CH3:
R3 is not Cl;
at least one of R3, R4, R5, and R6 is not —CH3;
and R4 and R5 do not form a pyrazolyl with the atoms at c and d;
when R3 is —OCH3:
R2 is not F;
and R6 is not F;
when R3 is F:
R2 is not —OCH3;
and X is not
when R3 is Cl:
R5 is not Cl;
R11 is not benzyl;
and R12 is not benzyl;
when R5 is Cl, R6 is not —CH3;
R11 is not benzyl;
and R12 is not benzyl;
when R5 is F or —OCH3:
R6 is not F;
when R6 is F:
at least one of R2, R3, R4, and R5 is not H;
when R3 and R5 are H:
R11 is not cyclopropyl;
and R12 is not cyclopropyl;
when R9 is Cl, R1 is not an amide group;
when B is nitrogen and A and D are carbon:
R4 may not be —CN or
when R7 is —CHF2 and R4 is
then R4 does not have the absolute stereochemistry
and
wherein, when R8 is
then the following provisos are in effect:
when R4 is F:
at least one of R2, R3, R5, and R6 is not H;
R3 is not C(O)N(CH3)2;
and R5 is not C(O)N(CH3)2;
when R4 is Cl:
at least one of R2, R3, R5, and R6 is not H;
when R3 is F:
R4 is not C(O)NHCH2CH2CH2CH3, C(O)N(CH3)2, C(O)NHCH2CH2CH3, or C(O)NHC(CH3)3;
R4 is not C(O)NHCH2CH2CH2OH, C(O)NHCH(CH3)2, —CN, or
R1 is not
R5 is not
R3 is not
when R2 is F:
R5 is not —C(O)NH2;
when R2 is —CH3, R4 and R5 do not form a pyrazole with atoms at c and d;
and
when B is nitrogen, R3 and R4 do not form an optionally substituted imidazole with the atoms at b and c;
and
wherein, when R8 is
then the following provisos are in effect:
R4 is not —CH3, —C(O)NHCH2CH2OH, —NHC(O)CH(CH3)2, or
when R4 is C(O)NHCH3, at least one of R2, R3, R5, and R6 is not H;
when R4 is —OCH3:
R3 is not F or —CH3;
and R5 is not F or —CH3;
when R4 is
R3 is not Cl;
and R5 is not Cl;
when R4 is —C(O)NHCH(CH3)2 or —C(O)N(CH2CH3)2:
at least one of R3 and R5 is not H;
R5 is not —C(O)NH2;
and
R6 is not —CF3.

144 more elements

A method for antagonizing TLR7, comprising administering a pharmaceutically effective amount of a compound of formula (IV)

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or mixture of stereoisomers thereof, wherein:
R7a is H or F;
and wherein
Ring A is:
wherein Y1 and Y2 are independently selected from the group consisting of —CH2— and —CH2CH2—, and wherein each of Y1 and Y2 is optionally substituted by C1-3 alkyl;
wherein X1, X2, and X3 are independently selected from the group consisting of —CH— and N;
wherein X1, X2, and X3 are independently selected from the group consisting of —CH— and N;
wherein X is N or —CH— optionally substituted by —CH3, F, or Cl, and
wherein R9 is —C(O)Z, wherein Z is 2, 3-dihydroxypropylamine;
a five to seven member cyclic diamine that is optionally bridged or optionally substituted at a carbon atom with a lower alkyl;
a seven to ten member bicyclodiamine;
a seven to eleven member spirodiamine;
—NH substituted with a four to seven member cyclic amine optionally substituted with —NH2;
—OH;
—CH2NHR, wherein R is H or lower alkyl;
—NH substituted with a seven to eleven member spiroalkane optionally substituted with —NH2;
or
R9 is CH3NHC(O)—, and a carbon atom on the aryl ring to which R9 is attached is substituted with one of —CH3, F, or Cl;
R9 is (CH3)2CHNHC(O)—, and a carbon atom on the aryl ring to which R9 is attached is substituted with one of —CH3, F, or Cl;
or R9 is (CH3)3CNHC(O)— and a carbon atom on the aryl ring to which R9 is attached is substituted with one of —CH3, F, or Cl;
or
R9 is
wherein the piperazine is optionally bridged or substituted with lower alkyl and R10 is H or —CH3;
or
R9 is
wherein n is 1-3 and the cyclic diamine is optionally bridged or substituted with lower alkyl;
or
R9 is
wherein n is 1-4;
or
R9 is —NHC(O)NH2, —CH2C(O)NH— wherein the nitrogen is substituted with a four to seven member cyclic amine;
—CH2—C(O)— wherein the carbonyl is substituted with a seven to ten member bicyclodiamine;
and a four to seven member cyclic amine substituted with —CH2C(O)NH2;
or
wherein X is N or —CH— wherein the C is optionally substituted by —CH3, F, or Cl, and wherein
R10 is —C(O)NH— wherein the nitrogen is substituted by a four to seven member cyclic amine;
—C(O)— substituted by a seven to ten member bicyclodiamine;
—C(O)— substituted by a seven to eleven member spirodiamine;
pyrazole;
[1,2,4]oxadiazole optionally substituted by —CH3 on a carbon atom of the oxadiazole;
—NHC(O)CH3;
—CH2— substituted by a piperazine;
—CH2— substituted by a piperazine including a methyl substituent;
—C(O)— substituted by a five to seven member cyclic diamine;
—C(O)NHCH2— wherein the —CH2— is substituted by azetidine;
or —C(O)— substituted with a five to seven member cyclic amine wherein the amine includes an —NH2 substituent;
or
cyanophenyl;
isoquinoline;
cyclohexene substituted with —NH2 at the 4′ position;
1,4-dimethylindazole-5-yl;
1,6-dimethylindazole-5-yl;
cyclohexene substituted with spiropiperidine at the 4′ position;
1-piperidinopyrazole;
or o-methoxypyridine.

52 more elements

A method for antagonizing TLR8, comprising administering a pharmaceutically effective amount of a compound of formula (I)

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or mixture of stereoisomers thereof, wherein
R1 is optionally substituted piperidinyl, optionally substituted pyridyl, optionally substituted pyrrolyl, optionally substituted pyrrodinyl, 1,4-dimethylthiazolyl, 2-ethyl-4-methylthiazolyl, 2-isopropylthiazol-5-yl, thiazolyl, 3-ethylthiazol-5-yl, 1-methylsulfonylpiperidin-4-yl, or
R1 is —C(O)Z, where Z is piperazinyl, (S)-2-(3-ethylpiperazin-1-yl), optionally substituted pyrrolopyrrolyl, piperidin-3-ylamino, or,
R1 is
where R13 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 R13 is C(O)W, where W is —N(CH3)2, piperidinyl, piperazinyl, or morpholinyl, or,
R1 is
where R14 is —C(O)CH3, H, or (1-methylpyrrol-2-yl)methyl, or,
R1 is
or
R1 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 R4 is absent, when B is nitrogen R2 is absent, and when D is nitrogen R3 is absent;
and wherein
R2 is H, —CH3, or F, or, with R3 and the atoms at positions a and b, forms an optionally substituted pyridine or a pyrazole;
and wherein
R3 is H, F, Cl, —CN, —CH3, —OCH3, —OH, —NH2, methylsulfonyl,
or, with R4 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 R2 and the atoms at a and b, forms an optionally substituted pyridine or optionally substituted pyrazole;
and wherein
R4 is F, —CN, —OCH3, —OEt, H, Cl, Br, —NH—C(O)—CH—(CH3)2, —N(CH3)2, —CH3, —CH2OH,
optionally substituted piperazinyl, 4-hydroxypiperizin-1-yl, optionally substituted piperidinyl not attached to a phenyl group through a nitrogen, or, with R3 and the atoms at b and c, forms an optionally substituted pyrazole ring or
or, with R5 and the atoms at c and d, forms an optionally substituted pyrazole ring or an optionally substituted pyrrole ring, or,
R4 is -(q)-C(O)X, where q is a bond, is —NH—, or is —CH2—, and
where X is —NR11R12,
where R11 and R12 are both H, both —CH2CH3, or both —CH3, or where one of R11 and R12 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, —CH2—NH—CH3, pyrazolyl, piperazinyl, alcohol, —OCH3, or
or
where X is optionally substituted pyrrolidinyl attached through a nitrogen to the carbonyl group of R4, optionally substituted piperidinyl not attached through a nitrogen to the carbonyl group of R4, optionally substituted pyrrolidinyl attached through a nitrogen to the carbonyl group of R4, optionally substituted piperazinyl attached through a nitrogen to the carbonyl group of R4, or optionally substituted morpholinyl attached through a nitrogen to the carbonyl group of R4,
and wherein
R5 is H, F, Cl, —CH3, —OCH3, pyrrolyl, —CH2OH, —NH2, —OH,
or, with R4 and the atoms at c and d, forms an optionally substituted benzene, an optionally substituted pyrazole, or an optionally substituted pyrrole, or, with R6 and the atoms at d and e, forms an optionally substituted pyridine, or R5 is C(O)Y, where Y is —NH2, —N(CH3)2, optionally substituted piperazinyl, optionally substituted piperidinyl,
and wherein
R6 is H, F, —CH3, —CF3, or, with R5 and the atoms at c and d, forms an optionally substituted benzene or an optionally substituted pyrazole;
and wherein
R7 is —CF3 or —CHF2;
and wherein
R8 is
and wherein
R9 is Br, Cl, F, I, or H;
with the following provisos:
when R4 is F:
R2 is not —CH3 or F;
R3 is not —CH3, —CN, F, Cl, or —OCH3;
R5 is not —CH3, F, Cl, or —OCH3;
and R6 is not —CH3 or F;
when R4 is Cl:
R2 is not F;
R3 is not F or —CN;
R5 is not F, —CN, or —C(O)N(CH3)2;
R6 is not —CF3 or F;
D is not nitrogen;
and either R5 is —C(O)NH2 or one of R2, R3, R5, and R6 is —CH3;
when R4 is —CH3:
R3 is not F;
R5 is not F;
and R5 and R6 do not form a pyrimidine together with the atoms at d and e;
when R4 is —OCH3:
R2 is not F;
R3 is not Cl or —OCH3, R5 is not Cl or —OCH3;
and R6 is not F or —CF3;
when R4 is —CN:
R2 is not F;
R3 is not Cl, F, or —OCH3, R5 is not Cl, F, or —OCH3;
and R6 is not F;
when R4 is —OCH2CH3:
R3 is not Cl or F;
R5 is not Cl or F;
and R6 is not —CF3;
when R4 is
R3 is not H or F;
and R5 is not H or F;
when R4 is
at least one of R2, R3, R5, and R6 is not H;
when R4 is
R3 is not F;
and R5 is not F;
when R2 is F:
R3 is not —OCH3 or F;
R5 is not —CN;
and at least one of R3, R4, R5, and R6 is not H;
when R2 is Cl:
R3 is not F;
when R2 is —CH3:
R3 is not Cl;
at least one of R3, R4, R5, and R6 is not —CH3;
and R4 and R5 do not form a pyrazolyl with the atoms at c and d;
when R3 is —OCH3:
R2 is not F;
and R6 is not F;
when R3 is F:
R2 is not —OCH3;
and X is not
when R3 is Cl:
R5 is not Cl;
R11 is not benzyl;
and R12 is not benzyl;
when R5 is Cl, R6 is not —CH3;
R11 is not benzyl;
and R12 is not benzyl;
when R5 is F or —OCH3:
R6 is not F;
when R6 is F:
at least one of R2, R3, R4, and R5 is not H;
when R3 and R5 are H:
R11 is not cyclopropyl;
and R12 is not cyclopropyl;
when R9 is Cl, R1 is not an amide group;
when B is nitrogen and A and D are carbon:
R4 may not be —CN or
when R7 is —CHF2 and R4 is
then R4 does not have the absolute stereochemistry
and
wherein, when R8 is
then the following provisos are in effect:
when R4 is F:
at least one of R2, R3, R5, and R6 is not H;
R3 is not C(O)N(CH3)2;
and R5 is not C(O)N(CH3)2;
when R4 is Cl:
at least one of R2, R3, R5, and R6 is not H;
when R3 is F:
R4 is not C(O)NHCH2CH2CH2CH3, C(O)N(CH3)2, C(O)NHCH2CH2CH3, or C(O)NHC(CH3)3;
R4 is not C(O)NHCH2CH2CH2OH, C(O)NHCH(CH3)2, —CN, or
R1 is not
R5 is not
R3 is not
when R2 is F:
R5 is not —C(O)NH2;
when R2 is —CH3, R4 and R5 do not form a pyrazole with atoms at c and d;
and
when B is nitrogen, R3 and R4 do not form an optionally substituted imidazole with the atoms at b and c;
and
wherein, when R8 is
then the following provisos are in effect:
R4 is not —CH3, —C(O)NHCH2CH2OH, —NHC(O)CH(CH3)2, or
when R4 is C(O)NHCH3, at least one of R2, R3, R5, and R6 is not H;
when R4 is —OCH3:
R3 is not F or —CH3;
and R5 is not F or —CH3;
when R4 is
R3 is not Cl;
and R5 is not Cl;
when R4 is —C(O)NHCH(CH3)2 or —C(O)N(CH2CH3)2:
at least one of R3 and R5 is not H;
R5 is not —C(O)NH2;
and
R6 is not —CF3.

144 more elements

A method for antagonizing TLR8, comprising administering a pharmaceutically effective amount of a compound of formula (IV)

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or mixture of stereoisomers thereof, wherein:
R7a is H or F;
and wherein
Ring A is:
wherein Y1 and Y2 are independently selected from the group consisting of —CH2— and —CH2CH2—, and wherein each of Y1 and Y2 is optionally substituted by C1-3 alkyl;
wherein X1, X2, and X3 are independently selected from the group consisting of —CH— and N;
wherein X1, X2, and X3 are independently selected from the group consisting of —CH— and N;
wherein X is N or —CH— optionally substituted by —CH3, F, or Cl, and
wherein R9 is —C(O)Z, wherein Z is 2, 3-dihydroxypropylamine;
a five to seven member cyclic diamine that is optionally bridged or optionally substituted at a carbon atom with a lower alkyl;
a seven to ten member bicyclodiamine;
a seven to eleven member spirodiamine;
—NH substituted with a four to seven member cyclic amine optionally substituted with —NH2;
—OH;
—CH2NHR, wherein R is H or lower alkyl;
—NH substituted with a seven to eleven member spiroalkane optionally substituted with —NH2;
or
R9 is CH3NHC(O)—, and a carbon atom on the aryl ring to which R9 is attached is substituted with one of —CH3, F, or Cl;
R9 is (CH3)2CHNHC(O)—, and a carbon atom on the aryl ring to which R9 is attached is substituted with one of —CH3, F, or Cl;
or R9 is (CH3)3CNHC(O)— and a carbon atom on the aryl ring to which R9 is attached is substituted with one of —CH3, F, or Cl;
or
R9 is
wherein the piperazine is optionally bridged or substituted with lower alkyl and R10 is H or —CH3;
or
R9 is
wherein n is 1-3 and the cyclic diamine is optionally bridged or substituted with lower alkyl;
or
R9 is
wherein n is 1-4;
or
R9 is —NHC(O)NH2, —CH2C(O)NH— wherein the nitrogen is substituted with a four to seven member cyclic amine;
—CH2—C(O)— wherein the carbonyl is substituted with a seven to ten member bicyclodiamine;
and a four to seven member cyclic amine substituted with —CH2C(O)NH2;
or
wherein X is N or —CH— wherein the C is optionally substituted by —CH3, F, or Cl, and wherein
R10 is —C(O)NH— wherein the nitrogen is substituted by a four to seven member cyclic amine;
—C(O)— substituted by a seven to ten member bicyclodiamine;
—C(O)— substituted by a seven to eleven member spirodiamine;
pyrazole;
[1,2,4]oxadiazole optionally substituted by —CH3 on a carbon atom of the oxadiazole;
—NHC(O)CH3;
—CH2— substituted by a piperazine;
—CH2— substituted by a piperazine including a methyl substituent;
—C(O)— substituted by a five to seven member cyclic diamine;
—C(O)NHCH2— wherein the —CH2— is substituted by azetidine;
or —C(O)— substituted with a five to seven member cyclic amine wherein the amine includes an —NH2 substituent;
or
cyanophenyl;
isoquinoline;
cyclohexene substituted with —NH2 at the 4′ position;
1,4-dimethylindazole-5-yl;
1,6-dimethylindazole-5-yl;
cyclohexene substituted with spiropiperidine at the 4′ position;
1-piperidinopyrazole;
or o-methoxypyridine.

52 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/233,520Filed 10 Aug 2016 · division
Priority: 31 May 2012
Published: US 2016/0030430 A124 Nov 2016
Granted: 26 Dec 2017
Term ends: Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 31/519
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with heterocyclic rings
A61K 31/55
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having seven-membered rings, e.g. azelastine, pentylenetetrazole
A61P 19/04
Drugs for skeletal disorders: for non-specific disorders of the connective tissue

Family

Application61/654,023Us provisional application · filed 31 May 2012
Application13/907,202Parent of this division · filed 31 May 2013
Application14/806,174Parent of this division · filed 22 Jul 2015
US 9,126,999 B2Parent of this division · filed 8 Sep 2015
US 2016/0339032 A1Pre-grant publication · published 24 Nov 2016
US 9,446,046 B2Parent of this division
US 2013/0324547 A1Published application
US 2016/0030430 A1Published application
US 9,850,242 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A method for antagonizing TLR7, comprising administering a pharmaceutically effective amount of a compound of formula (I)

or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or mixture of stereoisomers thereof, wherein
R1 is optionally substituted piperidinyl, optionally substituted pyridyl, optionally substituted pyrrolyl, optionally substituted pyrrodinyl, 1,4-dimethylthiazolyl, 2-ethyl-4-methylthiazolyl, 2-isopropylthiazol-5-yl, thiazolyl, 3-ethylthiazol-5-yl, 1-methylsulfonylpiperidin-4-yl, or
R1 is —C(O)Z, where Z is piperazinyl, (S)-2-(3-ethylpiperazin-1-yl), optionally substituted pyrrolopyrrolyl, piperidin-3-ylamino, or,
R1 is
where R13 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 R13 is C(O)W, where W is N(CH3)2, piperidinyl, piperazinyl, or morpholinyl, or,
R1 is
where R14 is C(O)CH3, H, or (1-methylpyrrol-2-yl)methyl, or,
R1 is
or
R1 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 R4 is absent, when B is nitrogen R2 is absent, and when D is nitrogen R3 is absent;
and wherein
R2 is H, —CH3, or F, or, with R3 and the atoms at positions a and b, forms an optionally substituted pyridine or a pyrazole;
and wherein
R3 is H, F, Cl, —CN, —CH3, —OCH3, —OH, —NH2, methylsulfonyl,
or, with R4 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 R2 and the atoms at a and b, forms an optionally substituted pyridine or optionally substituted pyrazole;
and wherein
R4 is F, —CN, —OCH3, —OEt, H, Cl, Br, —NH—C(O)—CH—(CH3)2, —N(CH3)2, —CH3, —CH2OH,
optionally substituted piperazinyl, 4-hydroxypiperizin-1-yl, optionally substituted piperidinyl not attached to a phenyl group through a nitrogen, or, with R3 and the atoms at b and c, forms an optionally substituted pyrazole ring or
or, with R5 and the atoms at c and d, forms an optionally substituted pyrazole ring or an optionally substituted pyrrole ring, or,
R4 is -(q)-C(O)X, where q is a bond, is —NH—, or is —CH2—, and
where X is —NR11R12,
where R11 and R12 are both H, both —CH2CH3, or both —CH3, or where one of R11 and R12 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, —CH2—NH—CH3, pyrazolyl, piperazinyl, alcohol, —OCH3, or
or
where X is optionally substituted pyrrolidinyl attached through a nitrogen to the carbonyl group of R4, optionally substituted piperidinyl not attached through a nitrogen to the carbonyl group of R4, optionally substituted pyrrolidinyl attached through a nitrogen to the carbonyl group of R4, optionally substituted piperazinyl attached through a nitrogen to the carbonyl group of R4, or optionally substituted morpholinyl attached through a nitrogen to the carbonyl group of R4,
and wherein
R5 is H, F, Cl, —CH3, —OCH3, pyrrolyl, —CH2OH, —NH2, —OH,
or, with R4 and the atoms at c and d, forms an optionally substituted benzene, an optionally substituted pyrazole, or an optionally substituted pyrrole, or, with R6 and the atoms at d and e, forms an optionally substituted pyridine, or R5 is C(O)Y, where Y is —NH2, —N(CH3)2, optionally substituted piperazinyl, optionally substituted piperidinyl,
and wherein
R6 is H, F, —CH3, —CF3, or, with R5 and the atoms at c and d, forms an optionally substituted benzene or an optionally substituted pyrazole;
and wherein
R7 is —CF3 or —CHF2;
and wherein
R8 is
and wherein
R9 is Br, Cl, F, I, or H;
with the following provisos:
when R4 is F:
R2 is not —CH3 or F;
R3 is not —CH3, —CN, F, Cl, or —OCH3;
R5 is not —CH3, F, Cl, or —OCH3;
and R6 is not —CH3 or F;
when R4 is Cl:
R2 is not F;
R3 is not F or —CN;
R5 is not F, —CN, or —C(O)N(CH3)2;
R6 is not —CF3 or F;
D is not nitrogen;
and either R5 is —C(O)NH2 or one of R2, R3, R5, and R6 is —CH3;
when R4 is —CH3:
R3 is not F;
R5 is not F;
and R5 and R6 do not form a pyrimidine together with the atoms at d and e;
when R4 is —OCH3:
R2 is not F;
R3 is not Cl or —OCH3, R5 is not Cl or —OCH3;
and R6 is not F or —CF3;
when R4 is —CN:
R2 is not F;
R3 is not Cl, F, or —OCH3, R5 is not Cl, F, or —OCH3;
and R6 is not F;
when R4 is —OCH2CH3:
R3 is not Cl or F;
R5 is not Cl or F;
and R6 is not —CF3;
when R4 is
R3 is not H or F;
and R5 is not H or F;
when R4 is
at least one of R2, R3, R5, and R6 is not H;
when R4 is
R3 is not F;
and R5 is not F;
when R2 is F:
R3 is not —OCH3 or F;
R5 is not —CN;
and at least one of R3, R4, R5, and R6 is not H;
when R2 is Cl:
R3 is not F;
when R2 is —CH3:
R3 is not Cl;
at least one of R3, R4, R5, and R6 is not —CH3;
and R4 and R5 do not form a pyrazolyl with the atoms at c and d;
when R3 is —OCH3:
R2 is not F;
and R6 is not F;
when R3 is F:
R2 is not —OCH3;
and X is not
when R3 is Cl:
R5 is not Cl;
R11 is not benzyl;
and R12 is not benzyl;
when R5 is Cl, R6 is not —CH3;
R11 is not benzyl;
and R12 is not benzyl;
when R5 is F or —OCH3:
R6 is not F;
when R6 is F:
at least one of R2, R3, R4, and R5 is not H;
when R3 and R5 are H:
R11 is not cyclopropyl;
and R12 is not cyclopropyl;
when R9 is Cl, R1 is not an amide group;
when B is nitrogen and A and D are carbon:
R4 may not be —CN or
when R7 is —CHF2 and R4 is
then R4 does not have the absolute stereochemistry
and
wherein, when R8 is
then the following provisos are in effect:
when R4 is F:
at least one of R2, R3, R5, and R6 is not H;
R3 is not C(O)N(CH3)2;
and R5 is not C(O)N(CH3)2;
when R4 is Cl:
at least one of R2, R3, R5, and R6 is not H;
when R3 is F:
R4 is not C(O)NHCH2CH2CH2CH3, C(O)N(CH3)2, C(O)NHCH2CH2CH3, or C(O)NHC(CH3)3;
R4 is not C(O)NHCH2CH2CH2OH, C(O)NHCH(CH3)2, —CN, or
R1 is not
R5 is not
R3 is not
when R2 is F:
R5 is not —C(O)NH2;
when R2 is —CH3, R4 and R5 do not form a pyrazole with atoms at c and d;
and
when B is nitrogen, R3 and R4 do not form an optionally substituted imidazole with the atoms at b and c;
and
wherein, when R8 is
then the following provisos are in effect:
R4 is not —CH3, —C(O)NHCH2CH2OH, —NHC(O)CH(CH3)2, or
when R4 is C(O)NHCH3, at least one of R2, R3, R5, and R6 is not H;
when R4 is —OCH3:
R3 is not F or —CH3;
and R5 is not F or —CH3;
when R4 is
R3 is not Cl;
and R5 is not Cl;
when R4 is —C(O)NHCH(CH3)2 or —C(O)N(CH2CH3)2:
at least one of R3 and R5 is not H;
R5 is not —C(O)NH2;
and
R6 is not —CF3.

144 more elements

Facts

Application

15/233,520Filed 10 Aug 2016 · division

Priority

31 May 2012

Published

US 2016/0030430 A124 Nov 2016

Granted

26 Dec 2017

Term ends

Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 31/519
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with heterocyclic rings
A61K 31/55
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having seven-membered rings, e.g. azelastine, pentylenetetrazole
A61P 19/04
Drugs for skeletal disorders: for non-specific disorders of the connective tissue

Family

Application61/654,023Us provisional application · filed 31 May 2012

Application13/907,202Parent of this division · filed 31 May 2013

Application14/806,174Parent of this division · filed 22 Jul 2015

US 9,126,999 B2Parent of this division · filed 8 Sep 2015

US 2016/0339032 A1Pre-grant publication · published 24 Nov 2016

US 9,446,046 B2Parent of this division

US 2013/0324547 A1Published application

US 2016/0030430 A1Published application

US 9,850,242 B2This patent

From the US filing history. Foreign family members aren’t listed.