Tetrahydropyrazolopyrimidine compounds

1. A method for treatment of a systematic lupus erythematosus or lupus, 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

R 1 is optionally substituted piperidinyl, optionally substituted pyridyl, optionally substituted pyrrolyl, optionally substituted pyrroldinyl, 1,4-dimmethylthiazolyl, 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-ylamino, 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

 or

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,

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 3 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 3 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;

when R 3 is —OCH 3 : R 2 is not F; and R 6 is not F;

when R 3 is F: R 2 is not —OCH 3 ; and X is not

when R 3 is Cl: R 5 is not Cl; R 11 is not benzyl; and R 12 is not benzyl;

when R 5 is Cl, R 6 is not —CH 3 ; R 11 is not benzyl; and R 12 is not benzyl;

when R 5 is F or —OCH 3 : R 6 is not F;

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

when R 3 and R 5 are H: R 11 is not cyclopropyl; and R 12 is not cyclopropyl;

when R 9 is Cl, R 1 is not an amide group;

when B is nitrogen and A and D are carbon: R 4 may not be —CN or

when R 7 is —CHF 2 and R 4 is

 then R 4 does not have the absolute stereochemistry

 and

wherein, when R 8 is

 then the following provisos are in effect;

when R 4 is F: at least one of R 2 , R 3 , R 5 , and R 6 is not H; R 3 is not C(O)N(CH 3 ) 2 ; and R 5 is not C(O)N(CH 3 ) 2 ;

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

when R 3 is F: R 4 is not C(O)NHCH 2 CH 2 CH 2 CH 3 , C(O)N(CH 3 ) 2 , C(O)NHCH 2 CH 2 CH 3 , or C(O)NHC(CH 3 ) 3 ;

R 4 is not C(O)NHCH 2 CH 2 CH 2 OH, C(O)NHCH(CH 3 ) 2 , —CN, or

R 1 is not

R 5 is not

R 3 is not

when R 2 is F: R 5 is not —C(O)NH 2 ;

when R 2 is —CH 3 , R 4 and R 5 do not form a pyrazole with atoms at c and d; and

when B is nitrogen, R 3 and R 4 do not form an optionally substituted imidazole with the atoms at b and c; and

wherein, when R 8 is

 then the following provisos are in effect;

R 4 is not —CH 3 , —C(O)NHCH 2 CH 2 OH, —NHC(O)CH(CH 3 ) 2 , or

when R 4 is C(O)NHCH 3 , at least one of R 2 , R 3 , R 5 , and R 6 is not H;

when R 4 is —OCH 3 : R 3 is not F or —CH 3 ; and R 5 is not F or —CH 3 ;

when R 4 is

 R 3 is not Cl; and R 5 is not Cl;

when R 4 is —C(O)NHCH(CH 3 ) 2 or —C(O)N(CH 2 CH 3 ) 2 ; at least one of R 3 and R 5 is not H;

R 5 is not —C(O)NH 2 ; and

R 6 is not —CF 3 .

2. The method of claim 1 , wherein said compound is administered as a pharmaceutically acceptable salt.

3. A method for treatment of a systematic lupus erythematosus or lupus, comprising administering a pharmaceutically effective amount of 4-((5S,7R)-5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)phenyl)(piperazin-1-yl)methanone or a pharmaceutically acceptable salt thereof.

4. The method of claim 3 , wherein said compound is administered as a pharmaceutically acceptable salt.

5. A method for treatment of a systematic lupus erythematosus or lupus, 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: R 7a is H or F; and wherein

Ring A is:

wherein Y 1 and Y 2 are independently selected from the group consisting of —CH 2 — and —CH 2 CH 2 —, and wherein each of Y 1 and Y 2 is optionally substituted by C 1-3 alkyl;

wherein X 1 , X 2 , and X 3 are independently selected from the group consisting of —CH— and N;

wherein X 1 , X 2 , and X 3 are independently selected from the group consisting of —CH— and N;

wherein X is N or —CH— optionally substituted by —CH 3 , F, or Cl, and

wherein R 9 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 —NH 2 ; —OH; —CH 2 NHR, wherein R is H or lower alkyl; —NH substituted with a seven to eleven member spiroalkane optionally substituted with —NH 2 ; or

R 9 is CH 3 NHC(O)—, and a carbon atom on the aryl ring to which R 9 is attached is substituted with one of —CH 3 , F, or Cl; R 9 is (CH 3 ) 2 CHNHC(O)—, and a carbon atom on the aryl ring to which R 9 is attached is substituted with one of —CH 3 , F, or Cl; or R 9 is (CH 3 ) 3 CNHC(O)— and a carbon atom on the aryl ring to which R 9 is attached is substituted with one of —CH 3 , F, or Cl; or

R 9 is

 wherein the piperazine is optionally bridged or substituted with lower alkyl and R 10 is H or —CH 3 ; or

R 9 is

 wherein n is 1-3 and the cyclic diamine is optionally bridged or substituted with lower alkyl; or

R 9 is

 wherein n is 1-4; or

R 9 is —NHC(O)NH 2 , —CH 2 C(O)NH— wherein the nitrogen is substituted with a four to seven member cyclic amine; —CH 2 —C(O)— wherein the carbonyl is substituted with a seven to ten member bicyclodiamine; and a four to seven member cyclic amine substituted with —CH 2 C(O)NH 2 ; or

wherein X is N or —CH— wherein the C is optionally substituted by —CH 3 , F, or Cl, and wherein

R 10 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 —CH 3 on a carbon atom of the oxadiazole; —NHC(O)CH 3 ; —CH 2 — substituted by a piperazine; —CH 2 — substituted by a piperazine including a methyl substituent; —C(O)— substituted by a five to seven member cyclic diamine; —C(O)NHCH 2 — wherein the —CH 2 — is substituted by azetidine; or —C(O)— substituted with a five to seven member cyclic amine wherein the amine includes an —NH 2 substituent; or

cyanophenyl; isoquinoline; cyclohexene substituted with —NH 2 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.

6. The method of claim 5 , wherein said compound is administered as a pharmaceutically acceptable salt.