Amino-pyrimidine amides
The invention provides novel compounds having the general formula (I) wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein, compositions including the compounds and methods of using the compounds.
1 . A compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
R 1 , R 2 , and R 3 are independently selected from the group consisting of
i) H,
ii) C 1-6 -alkyl,
iii) C 2-6 -alkynyl,
iv) halogen,
v) halo-C 1-6 -alkyl,
vi) halo-C 1-6 -alkoxy,
vii) cyano, and
viii) cyano-C 1-6 -alkyl,
wherein at least one of R 1 and R 3 is other than H;
R 4 and R 5 are independently selected from the group consisting of
i) H,
ii) C 1-6 -alkyl,
iii) halogen, and
iv) halo-C 1-6 -alkyl,
or R 4 and R 5 together with the carbon atom to which they are attached form a heterocycloalkyl or a substituted C 3-8 -cycloalkyl, wherein the substituted C 3-8 -cycloalkyl is substituted with R 6 and R 7 ; and
R 6 and R 7 are independently selected from the group consisting of halogen, hydroxy, and C 1-6 -alkyl.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R 3 are independently selected from the group consisting of
i) H,
ii) C 1-6 -alkyl,
iii) C 2-6 -alkynyl,
iv) halogen,
v) halo-C 1-6 -alkyl
vi) halo-C 1-6 -alkoxy, and
vii) cyano;
wherein at least one of R 1 and R 3 is other than H.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are independently selected from the group consisting of
i) H and
ii) C 1-6 -alkyl,
or R 4 and R 5 together with the carbon atom to which they are attached form a 4-member heterocycloalkyl with a single oxygen or a substituted C 4 -cycloalkyl, wherein the substituted C 4 -cycloalkyl is substituted with R 6 and R 7 .
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are independently selected from the group consisting of
i) H and
ii) methyl,
or R 4 and R 5 together with the carbon atom to which they are attached form an oxetane ring or a substituted C 4 -cycloalkyl, wherein the substituted C 4 -cycloalkyl is substituted with R 6 and R 7 .
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 6 and R 7 are both halogen; or
R 6 is hydroxy and R 7 is C 1-6 -alkyl.
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 6 and R 7 are both fluorine; or
R 6 is hydroxy and R 7 is methyl.
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 , R 2 , and R 3 are independently selected from the group consisting of
i) H,
ii) C 1-6 -alkyl,
iii) C 2-6 -alkynyl,
iv) halogen,
v) halo-C 1-6 -alkyl,
vi) halo-C 1-6 -alkoxy, and
vii) cyano;
wherein at least one of R 1 and R 3 is other than H;
R 4 and R 5 are independently selected from the group consisting of
i) H and
ii) methyl,
or R 4 and R 5 together with the carbon atom to which they are attached form an oxetane ring or a substituted C 4 -cycloalkyl, wherein the substituted C 4 -cycloalkyl is substituted with R 6 and R 7 ; and
R 6 and R 7 are both fluorine; or
R 6 is hydroxy and R 7 is methyl.
8 . The compound of claim 1 , selected from the group consisting of
(2-((4-chloro-2,3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl) methanone;
(2-((4,6-dichloro-2,3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl) methanone;
(2-((6-chloro-4-methyl-2,3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl) methanone;
(2-((4,5-dichloro-2,3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl) methanone;
2-((5-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl) pyrimidin-2-yl) amino)-6-chloro-2,3-dihydro-1H-indene-4-carbonitrile;
(S)-2-((5-(6-oxa-1-azaspiro[3.3]heptane-1-carbonyl) pyrimidin-2-yl) amino)-6-chloro-2,3-dihydro-1H-indene-4-carbonitrile;
(2-((6-chloro-4-(difluoromethoxy)-2,3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl) methanone;
(2-((5-chloro-4-methyl-2,3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl) methanone;
(2-((6-chloro-4-(prop-1-yn-1-yl)-2,3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl) methanone;
(2-((6-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl) methanone;
(2-((5-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl) methanone;
(S or R)-(2-((6-chloro-4-fluoro-2,3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl) methanone;
(2-((6-chloro-4-(trifluoromethyl)-2,3-dihydro-1H-inden-2-yl) amino) pyrimidin-5-yl)(6-oxa-1-azaspiro[3.3]heptan-1-yl) methanone;
(S)-6-chloro-2-((5-(6,6-difluoro-1-azaspiro[3.3]heptane-1-carbonyl) pyrimidin-2-yl) amino)-2,3-dihydro-1H-indene-4-carbonitrile;
(S)-6-chloro-2-((5-(2,2-dimethylazetidine-1-carbonyl) pyrimidin-2-yl) amino)-2,3-dihydro-1H-indene-4-carbonitrile; and
(cis)-6-chloro-2-(S)-((5-(6-hydroxy-6-methyl-1-azaspiro[3.3]heptane-1-carbonyl) pyrimidin-2-yl) amino)-2,3-dihydro-1H-indene-4-carbonitrile;
or a pharmaceutically acceptable salt thereof.
9 . A process to prepare a compound of claim 1 , or a pharmaceutically acceptable salt thereof, the process comprising the reaction of a compound of formula (II) in the presence of a compound of formula (III) to provide a compound of formula (I), wherein R 1 , R 2 , R 3 , R 4 , and R 5 are as defined in claim 1 :
10 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.
11 . A pharmaceutical composition comprising a compound of claim 8 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.