US 12,012,410 B2
Substituted pyrazolo[1,5-a]pyrazines for spinal muscular atrophy
Koji Fuji, Kanagawa (JP); Takeshi Yamasaki, Kanagawa (JP); Shunya Suzuki, Kanagawa (JP); Koji Ono, Kanagawa (JP); and Hiroki Takahagi, Kanagawa (JP)
Assigned to REBORNA BIOSCIENCES, INC., Kanagawa (JP)
Appl. No. 17/255,843
Filed by REBORNA BIOSCIENCES, INC., Kanagawa (JP)
PCT Filed Jun. 27, 2019, PCT No. PCT/JP2019/025732
§ 371(c)(1), (2) Date Dec. 23, 2020,
PCT Pub. No. WO2020/004594, PCT Pub. Date Jan. 2, 2020.
Claims priority of application No. 2018-122551 (JP), filed on Jun. 27, 2018.
Prior Publication US 2022/0287748 A1, Sep. 15, 2022
Int. Cl. A61K 31/4985 (2006.01); A61P 21/00 (2006.01); C07D 487/04 (2006.01); G01N 33/50 (2006.01); A61C 8/00 (2006.01)
CPC C07D 487/04 (2013.01) [A61P 21/00 (2018.01); G01N 33/5023 (2013.01); A61C 8/0096 (2013.01)] 19 Claims
 
1. A compound represented by formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R1 is H;
Q1 is CRa or N;
Ra is H, halogen, CN, C1-8 alkyl, or OC1-8 alkyl;
Q2 is CRa or N;
Rb is H, halogen, CN, C1-8 alkyl, or OC1-8 alkyl;
W1 is CR3;
R3 is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, 1,4-diazepanyl, 1,4-oxazepanyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl, octahydro-1H-pyrrolo[3,2-b]pyridinyl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-1H-pyrrolo[2,3-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, octahydro-1H-cyclopentapyrazinyl, octahydro-1H-pyrrolo[1,2-a]pyrazinyl, decahydro-1,6-naphthyridinyl, decahydro-1,7-naphthyridinyl, decahydro-2,6-naphthyridinyl, decahydro-2,7-naphthyridinyl, decahydroquinoxalinyl, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexanyl, 1-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 1-azabicyclo[2.2.2]octanyl, 2-azabicyclo[2.2.2]octanyl, 1-azabicyclo[3.2.1]octanyl, 2-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 6-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 1-azabicyclo[3.2.2]nonanyl, 2-azabicyclo[3.2.2]nonanyl, 3-azabicyclo[3.2.2]nonanyl, 6-azabicyclo[3.2.2]nonanyl, 1-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[3.3.1]nonanyl, 3-azabicyclo[3.3.1]nonanyl, 9-azabicyclo[3.3.1]nonanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 1,4-diazabicyclo[2.2.2]octanyl, 2,5-diazabicyclo[2.2.2]octanyl, 1,4-diazabicyclo[3.2.1]octanyl, 2,6-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 1,4-diazabicyclo[3.2.2]nonanyl, 1,5-diazabicyclo[3.2.2]nonanyl, 2,6-diazabicyclo[3.2.2]nonanyl, 3,6-diazabicyclo[3.2.2]nonanyl, 6,8-diazabicyclo[3.2.2]nonanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 1-azaspiro[3.4]octanyl, 2-azaspiro[3.4]octanyl, 5-azaspiro[3.4]octanyl, 6-azaspiro[3.4]octanyl, 1-azaspiro[4.4]nonanyl, 2-azaspiro[4.4]nonanyl, 1-azaspiro[4.5]decanyl, 2-azaspiro[4.5]decanyl, 6-azaspiro[4.5]decanyl, 7-azaspiro[4.5]decanyl, 8-azaspiro[4.5]decanyl, 1,6-diazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,7-diazaspiro[4.4]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 1,6-diazaspiro[3.5]nonanyl, 1,7-diazaspiro[3.5]nonanyl, 2,5-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 5,8-diazaspiro[3.5]nonanyl, 1,7-diazaspiro[4.5]decanyl, 1,8-diazaspiro[4.5]decanyl, 2,6-diazaspiro[4.5]decanyl, 2,7-diazaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl, or 6,9-diazaspiro[4.5]decanyl;
wherein each optionally contains one, two, or three double bonds;
wherein each is optionally substituted with one, two, or three ═O substituents; and
wherein each is optionally substituted with one, two, or three independently selected R5 substituents;
each R5 is independently halogen, CN, NO2, C1-6 alkyl, NH2, NHC1-6 alkyl, NHC3-10 cycloalkyl, OH, OC1-6 alkyl, OC3-10 cycloalkyl, or C3-10 cycloalkyl, wherein each C1-6 alkyl, NHC1-6 alkyl, NHC3-10 cycloalkyl, OC1-6 alkyl, OC3-10 cycloalkyl, and C3-10 cycloalkyl is optionally and independently substituted with one, two, three, four, or five substituents independently selected from the group consisting of halogen, CN, NO2, NHC1-6 alkyl, N(C1-6 alkyl)2, and OC1-6 alkyl;
W2 is CRC or N;
W is H, halogen, CN, C1-8 alkyl, or OC1-8 alkyl;
W3 is CR2;
R2 is pyrazolo[1,5-α]pyrazinyl, wherein the pyrazolo[1,5-c]pyrazinyl is optionally substituted with one, two, or three independently selected R4 substituents; and
each R4 is independently halogen, CN, NO2, C1-6 alkyl, NH2, NHC1-6 alkyl, NHC3-10 cycloalkyl, OH, OC1-6 alkyl, OC3-10 cycloalkyl, or C3-10 cycloalkyl, wherein each C1-6 alkyl, NHC1-6 alkyl, NHC3-10 cycloalkyl, OC1-6 alkyl, OC3-10 cycloalkyl, and C3-10 cycloalkyl is optionally and independently substituted with one, two, three, four, or five substituents independently selected from the group consisting of halogen, CN, NO2, NHC1-6 alkyl, N(C1-6 alkyl)2, and OC1-6 alkyl.
 
11. A medicament comprising one or more pharmaceutically acceptable vehicles and the compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.