US 11,939,340 B2
CDK inhibitors and their use as pharmaceuticals
Jincong Zhuo, Garnet Valley, PA (US); Xiaowei Wu, Wilmington, DE (US); Katarina Rohlfing, Conshohocken, PA (US); and Andrew Combs, Kennett Square, PA (US)
Assigned to Prelude Therapeutics Incorporated, Wilmington, DE (US)
Filed by Prelude Therapeutics Incorporated, Wilmington, DE (US)
Filed on Jan. 20, 2023, as Appl. No. 18/157,229.
Claims priority of provisional application 63/301,682, filed on Jan. 21, 2022.
Prior Publication US 2023/0234964 A1, Jul. 27, 2023
Int. Cl. C07D 495/14 (2006.01); A61K 45/06 (2006.01); A61P 15/08 (2006.01); A61P 35/00 (2006.01); C07D 498/14 (2006.01)
CPC C07D 495/14 (2013.01) [A61K 45/06 (2013.01); A61P 15/08 (2018.01); A61P 35/00 (2018.01); C07D 498/14 (2013.01); C07B 2200/05 (2013.01)] 24 Claims
 
1. A compound of Formula I:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt or solvate or N-oxide thereof, wherein
ring A is a 4-9-membered cycloalkyl or heterocycloalkyl ring;
ring B is a 5-membered heteroaryl selected from:

OG Complex Work Unit Chemistry
Z is O, S, NRb, NORb or N—CN,
m is 0, 1 or 2;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
s is 0, 1, 2 or 3;
t is 0, 1, 2 or 3;
q is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9;
each R1, when present, is independently H, D, halogen, —OH, —CN, —NO2, oxo, —C1-C6alkyl, C1-6alkoxide, —C2-C6alkenyl, —C2-C6alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, —ORa, —SRa, —NRcRd, —NRaRc, —C(O)Rb, —OC(O)Rb, —C(O)ORb, —C(O)NRcRd, —S(O)Rb, —S(O)2NRcRd, —S(O)(═NR)Rb, —SF5, —P(O)RbRb, —P(O)(ORb)(ORb), —B(ORc)(ORd) or —S(O)2Rb;
or two R1 together with the carbon atom(s) to which they are both attached at same carbon or different carbons, form a carbocyclic or heterocyclic group;
each R2 is independently H, D, halogen, C1-C8 alkoxide, C1-C8 alkyl, haloalkoxide, SF5, or CN, wherein the C1-8alkyl may be optionally substituted with D, halogen, —OH, —CN, or cycloalkyl;
each R4 is independently H, D, halogen, CN, —C2-C6alkenyl, —C2-C6alkynyl, C1-C8 alkoxide, C1-C8 alkyl, haloalkyl, C1-C8 hydroxylalkyl, or C3-C8 cycloalkyl or C3-C8 heteroycloalkyl;
each Ra is independently H, D, —C(O)Rb, —C(O)ORc, —C(O)NRcRd, —C(═NR)NRbRc, —C(═NORb)NRbRc, —C(═NCN)NRbRc, —P(ORc)2, —P(O)ORcRb, —S(O)2Rb, —S(O)2NRcRd, SiR3, —C1-C10alkyl, —C2-C10 alkenyl, —C2-C10 alkynyl, C0-C1alk-aryl, cycloalkyl, cycloalkenyl, C0-C1alk-heteroaryl, heterocycloalkyl, or heterocycloalkenyl;
each Rb, is independently H, D, —C1-C6 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, C0-C1alk-aryl, cycloalkyl, cycloalkenyl, C0-C1alk-heteroaryl, heterocycloalkyl, or heterocycloalkenyl;
each Rc is independently H, D, —C1-C10 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —OC1-C6alkyl, —O-cycloalkyl, aryl, C1alk-aryl, heteroaryl, cycloalkyl, cycloalkenyl, C1alk-heteroaryl, heterocycloalkyl, or heterocycloalkenyl;
each Rd is independently H, D, —C1-C10 alkyl, —C2-C6 alkenyl, —C2-C6 alkynyl, —OC1-C6alkyl, —O-cycloalkyl, aryl, C1alk-aryl, heteroaryl, cycloalkyl, cycloalkenyl, C1alk-heteroaryl, heterocycloalkyl, or heterocycloalkenyl;
or Rc and Rd, together with the atoms to which they are both attached, form a monocyclic or multicyclic heterocycloalkyl, or a monocyclic or multicyclic heterocyclo-alkenyl group;
R5 is H, ORb, C1-4alkyl, wherein the C1-4alkyl may be optionally substituted with at least one of D, halogen, —OH, —CN or an amine, cycloalkyl, heterocycloalkyl; and
each R6, when present, is independently H, D, halogen, —OH, —CN, —NO2, —C1-C6alkyl, —C2-C6alkenyl, —C2-C6alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, —ORa, —SRa, —NRcRd, —NRaRc, —C(O)Rb, —OC(O)Rb, —C(O)OR, —C(O)NRcRd, —S(O)Rb, —S(O)2NRcRd, —S(O)(═NR)Rb, —SF5, —P(O)RaRb, —P(O)(ORb)(ORb), —B(ORc)(ORd) or —S(O)2Rb; wherein said that —C1-C6alkyl, —C2-C6alkenyl, —C2-C6alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is optionally substituted by 1-6 R groups selected from H, D, halogen, —OH, —CN, —ORa, —SRa, —NRcRd, —NRaRc, —C(O)Rb, —OC(O)Rb, —C(O)OR, —C(O)NRcRd, —S(O)Rb, —S(O)2NRcRd, —S(O)(═NR)Rb, —SF5, —P(O)RbRb, —P(O)(ORb)(ORb), —B(ORc)(ORd) or —S(O)2Rb;
or two R6 groups together with the atom(s) to which they attached (same atom or different atoms) can form a spirocyclic group, multicyclic heterocycloalkyl, or a multicyclic cycloalkyl group;
X is O or NR5; and
R10 is H, D, —NRcRd, —NRaRc, C1-6alkyl, C3-7cycloalkyl, C4-7heterocycloalkyl, C3-7cycloalkylalkyl, C4-7heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, or haloalkyl; wherein said that C1-6alkyl, C3-7cycloalkyl, C4-7heterocycloalkyl, C3-7cycloalkylalkyl, C4-7heterocycloalkylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl is optionally substituted by 1-6 R selected from H, D, halogen, —OH, —CN, —ORa, —SRa, —NRcRd, —NRaRc, —C(O)Rb, —OC(O)Rb, —C(O)ORb, —C(O)NRcRd, —S(O)Rb, —S(O)2NRcRd, —S(O)(═NRb)Rb, —SF5, —P(O)RbRb, —P(O)(ORb)(ORb), —B(ORc)(ORd) or —S(O)2Rb.