US 11,858,937 B2
Substituted pyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-a][1,3,5]triazines as CDK inhibitors
Kiyean Nam, Gyeonggi-do (KR); Jaeseung Kim, Seoul (KR); Yeejin Jeon, Gyeonggi-do (KR); Donghoon Yu, Gyeonggi-do (KR); Mooyoung Seo, Gyeonggi-do (KR); Dongsik Park, Gyeonggi-do (KR); Jan Eickhoff, Herdecke (DE); Gunther Zischinsky, Dortmund (DE); and Uwe Koch, Dortmund (DE)
Assigned to QURIENT CO., LTD., Gyeonggi-Do (KR); and LEAD DISCOVERY CENTER GMBH, Dortmund (DE)
Appl. No. 17/045,009
Filed by QURIENT CO., LTD., Gyeonggi-do (KR); and LEAD DISCOVERY CENTER GMBH, Dortmund (DE)
PCT Filed Apr. 11, 2019, PCT No. PCT/EP2019/059289
§ 371(c)(1), (2) Date Oct. 2, 2020,
PCT Pub. No. WO2019/197546, PCT Pub. Date Oct. 17, 2019.
Claims priority of provisional application 62/656,041, filed on Apr. 11, 2018.
Prior Publication US 2021/0139483 A1, May 13, 2021
Int. Cl. A61K 31/519 (2006.01); A61K 31/53 (2006.01); C07D 487/04 (2006.01)
CPC C07D 487/04 (2013.01) 47 Claims
 
1. A compound having Formula I:

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or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
X is CH or N;
R1 is H;
R2 is C1-C6 alkyl, C1-C3 haloalkyl, or C(O)CH3;
Q is —C(O)—, —C(O)CH2—, —C(O)NH—, —NH—, —NHCH2—, —NHCH2CH2—, —NHC(O)—, —NHS(O)2—, —O—, or —OCH2—;
Y is C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
wherein the C1-C6 alkyl is substituted with one or two substituents independently selected from the group consisting of NR5R5, OR5, heterocyclyl, aryl, and heteroaryl;
wherein the C3-C8 cycloalkyl or heterocyclyl is optionally substituted with one or two substituents independently selected from the group consisting of R3, R4, and C(O)R5; and
wherein the aryl or heteroaryl is optionally substituted with one or two substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C(O)R5, NR5R5, OR5, heterocyclyl, heteroaryl, and R3;
each R3 is independently H, halogen, C1-C6 alkyl, C(O)NH2, NR5R5, NHC(O)R5, OR5, heterocyclyl, aryl, or heteroaryl, wherein each C1-C6 alkyl is optionally and independently substituted with one substituent selected from the group consisting of NH2 and OH;
each R4 is independently H, halogen, C1-C6 alkyl, NR5R5, OR5, ═O, heterocyclyl, aryl, or heteroaryl, wherein each C1-C6 alkyl is optionally and independently substituted with one substituent selected from the group consisting of NH2 and OH;
each R5 is independently H, C1-C6 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl, heterocyclyl, or heteroaryl;
wherein each heterocyclyl and heteroaryl is optionally and independently substituted with one or two substituents independently selected from the group consisting of halogen, C1-C6 alkyl, NR11R11, and OR11; and
wherein each C1-C6 alkyl substituent of each heterocyclyl and heteroaryl is optionally and independently substituted with one substituent selected from the group consisting of NH2 and OH;
each R11 is independently H, C1-C6 alkyl, C3-C10 cycloalkyl, or W;
Z is:

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(i) R6 is a ring selected from the following Group B:

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R12 is H;
R16 is W;
R17 is H, C1-C6 alkyl, or C1-C3 haloalkyl;
R18 is H, halogen, CN, C1-C6 alkyl, C1-C3 haloalkyl, NH2, or Ole; and
is 1, 2, or 3; or
(ii) R6 is a ring selected from the following Group B:

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R12 is W;
R16 is H, halogen, CN, C1-C6 alkyl, C1-C3 haloalkyl, NH2, or OW;
R17 is H, C1-C6 alkyl, or C1-C3 haloalkyl;
R18 is H, halogen, CN, C1-C6 alkyl, C1-C3 haloalkyl, NH2, or OW; and
is 1, 2, or 3; or
(iii) R6 is a ring selected from the following Group B:

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and
R15 is W; or
(iv) R6 is a ring selected from the following Group B:

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and
R15 is H; and
R19 is W; or
(v) R6 is a ring selected from the following Group B:

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R7 is H;
R8 is H, halogen, CN, C1-C6 alkyl, C1-C3 haloalkyl, or OR5, wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of NHR5 and OR5;
R9 is H, halogen, CN, C1-C6 alkyl, C1-C3 haloalkyl, or OR5, wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of NHR5 and OR5;
R10 is H, halogen, CN, C1-C6 alkyl, C1-C3 haloalkyl, or OR5, wherein the C1-C6 alkyl is optionally substituted with one substituent selected from the group consisting of NHR5 and OR5;
W is a structure selected from the following Group C:

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each L is independently absent, —NH—, or —O—;
each R20 is independently H, halogen, CN, C1-C6 alkyl, C1-C3 haloalkyl, OR5, or heterocyclyl;
each R21 is independently H, halogen, CN, C1-C6 alkyl, C1-C3 haloalkyl, OR5, or heterocyclyl;
each R22 is independently H, halogen, CN, C1-C6 alkyl, NR5R5, NR19R20, NR19CH2C(O)NH2, OR5, C3-C10 cycloalkyl, or heterocyclyl, wherein each R19 is independently H, C1-C6 alkyl, C3-C10 cycloalkyl, or W; and
each n is independently 1, 2, or 3.
 
11. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, excipient, and/or diluent together with a compound according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, as an active ingredient.