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EP-4735420-A1 - ARYL INDOL-3-YL KETONE AND ARYL INDAZOL-3-YL KETONE INHIBITORS OF KIF18A

EP4735420A1EP 4735420 A1EP4735420 A1EP 4735420A1EP-4735420-A1

Abstract

The present disclosure relates generally to inhibitors of KIF18A, compositions thereof, and methods of using said compounds and compositions thereof. More specifically, the present disclosure relates to indole and indazole inhibitors of KIF18A and methods of their use for treating disease mediated by KIF18A, such as cancer.

Inventors

  • COGAN, DEREK A.

Assignees

  • Volastra Therapeutics, Inc.

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. 1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein ring A is Ce-14 aryl or 5- to 12-membered heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, Ci-6 alkyl optionally substituted with one or more substituents T 1 , 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents T 2 , -NR al C(O)NR a2 R a3 , -NR a4 C(O)OR a5 , -NR a6 R a7 , -N=S(O)R a8 R a9 , -OR al °, -S(O)R a11 , -S(O)(NR al2 )R a13 , - S(O) 2 NR al4 R a15 , -S(O) 2 R a16 , -(CR al7 R al8 )o-iC(0)NR al9 R a2 °, -SR a21 , and -C(O)R a22 ; each T 1 is independently selected from the group consisting of -OH, cyano, C3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; and each T 2 is independently halo; R al _ Ra22 are each independently hydrogen, C1-6 alkyl, C 2 -6 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocycloalkenyl, Ce-14 aryl, or 5- to 12-membered heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(Ci-6 alkyl), C 2 -6 alkenyl, C3-10 cycloalkyl, -S(Ci-6 alkyl), =CR lal R la2 , and C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, and -O(Ci-6 alkyl), wherein R lal and R la2 are each independently hydrogen or C1-6 alkyl; L is a bond, CR bl R b2 , or O; R bl and R b2 are each independently H or C1-3 alkyl; ring B is C3-8 cycloalkyl, C5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; each R B group is independently halo, C1-6 alkyl optionally substituted with one or more halo, or C2-6 alkenyl; or two vicinal R B groups are taken together with the carbon atoms to which they are attached to form C3-10 cycloalkyl; or two geminal R B groups are taken together with the carbon atom to which they are attached to form C3-10 cycloalkyl; m is 0, 1, 2, 3, or 4; Y 1 is N or CR cl ; Y 2 is N or CR C2 ; Y 3 is N or CR C3 ; Y 4 is N or CH; R C1 , R C2 , and R C3 are each independently hydrogen, halo, cyano, -OH, -OC1-6 alkyl, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH; R c is halo, cyano, -OH, -NO2, -C(O)NR cl R c2 , -NR c3 R c4 , -NR c5 S(O) 2 R c6 , -P(O)R c7 R c8 , -N=S(O)R C9 R C1 °, -S(O)(NR C11 )R C12 , -S(O) 2 R C13 , -NR C14 C(O)OR C15 , or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH; and R cl -R c15 are each independently hydrogen, C3-10 cycloalkyl, or C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo and -OH.
  2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted Ce-14 aryl.
  3. 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted phenyl.
  4. 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted 5- to 10- membered heteroaryl.
  5. 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted pyridyl or optionally substituted furanyl.
  6. 6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein ring A is substituted with one or more substituents selected from the group consisting of -S(O)2NR al4 R a15 , -S(O)2R a16 , Ci-6 alkyl optionally substituted with one or more substituents T 1 , and 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents T 2 ; wherein each T 1 is independently selected from the group consisting of C3-10 cycloalkyl and -OH; and each T 2 is independently halo.
  7. 7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein ring A is substituted with one or more substituents selected from the group consisting of - S(O)2NR al4 R a15 , -S(O)2R a16 , piperidinyl optionally substituted with one or more fluoro, and alkyl optionally substituted with one or more substituents selected from the group consisting of -OH and cyclopentyl.
  8. 8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R al4 is hydrogen; R 15 is tert-butyl; and R 16 is azetidine optionally substituted with one or more halo.
  9. 9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein ring A is substituted with one or more substituents independently selected from the group consisting
  10. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A
  11. 11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein L is a bond.
  12. 12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein L is -CH2-.
  13. 13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein ring B is C3-8 cycloalkyl.
  14. 14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein ring B is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  15. 15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein m is 0.
  16. 16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein m is 2.
  17. 17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein two geminal R B groups are taken together with the carbon atom to which they are attached to form C3-10 cycloalkyl.
  18. 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein two geminal R B groups are taken together with the carbon atom to which they are attached to form cyclopropyl or cyclobutyl.
  19. 19. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein * denotes the point of attachment to the rest of Formula (I).
  20. 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein

Description

ARYL INDOL-3-YL KETONE AND ARYL INDAZOL-3-YL KETONE INHIBITORS OF KIF18A CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority benefit of United States Provisional Patent Application No. 63/524,077, filed June 29, 2023, the disclosure of which is hereby incorporated herein by reference in its entirety. FIELD [0002] The present disclosure relates generally to inhibitors of KIF18A, compositions thereof, and methods of using said compounds and compositions thereof. More specifically, the present disclosure relates to indole and indazole inhibitors of KIF18A and methods of their use for treating disease mediated by KIF18A, such as cancer. BACKGROUND [0003] KIF18A is a kinesin involved in assisting the kinetochore-microtubule (kt- MT) attachment and chromosomal alignment during cell mitosis. Its cargo domain binds directly to protein phosphatase 1 (PPI) and carries it to the plus end of MT where PPI dephosphorylates Heel, a kinetochore complex component, further enhancing kt- MT attachment throughout metaphase and anaphase. Its MT-binding motor domain has ATPase activity that powers the KIF18A translocation along MT lattice, enhanced by its C-terminal MT-binding site, and caps and depolymerizes growing microtubule at the plus end, thus dampening MT dynamics. This modulation of MT dynamics by KIF18A often occurs at the following (or trailing) sister chromatid, thereby providing a counterbalancing tension to the leading sister chromatid movement catalyzed by another kinesin Kif2C/MCAK. Loss of KIF18A function causes defective kt-MT attachments and loss of tension within the spindle in cells of high chromosome instability (CIN), leading to hyper stable, longer and multipolar spindles, mitotic arrest, centrosome fragmentation and spindle assembly checkpoint activation or cell death. KIF18A is identified from DEPMAP RNAi data re-analysis as one of the top candidates essential for CIN-high cells. Reported synthetic lethality screens also singled out KIF18A as a potential anticancer target whose knockdown preferentially renders CIN-high (but not CIN-low), aneuploid and whole-genome doubled cells vulnerable to death. Cellular toxicity assay in isogenic cell lines confirmed the enhanced sensitivity of CIN-high cells to KIF18A inhibitors. Ongoing in vivo mouse models using KIF18A inhibitor or knockdown demonstrated effect of inhibited tumor growth. Thus, there is a need for new compounds for use in treating diseases mediated by KIF18A. BRIEF SUMMARY [0004] The present disclosure provides compounds of Formula (I), compositions thereof, and methods of using said compounds and compositions thereof for the treatment of diseases or conditions associated with KIF18A. In one aspect, provided is a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: ring A is Ce-14 aryl or 5- to 12- membered heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, Ci-6 alkyl optionally substituted with one or more substituents T1, 3- to 10-membered heterocycloalkyl optionally substituted with one or more substituents T2, -NRalC(O)NRa2Ra3, -NRa4C(O)ORa5, -NRa6Ra7, -N=S(O)Ra8Ra9, -ORal°, -S(O)Ra11, -S(O)(NRal2)Ra13, -S(O)2NRal4Ra15, -S(O)2Ra16, - (CRal7Ral8)o-iC(0)NRal9Ra2°, -SRa21, and -C(O)Ra22, each T1 is independently selected from the group consisting of -OH, cyano, C3-10 cycloalkyl, and 3- to 10-membered heterocycloalkyl optionally substituted with one or more halo; each T2 is independently halo; Ral_Ra22 are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, 3- to 10-membered heterocycloalkyl, 3- to 10-membered heterocyclo alkenyl Ce-14 aryl, or 5- to 12-membered heteroaryl, each optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, -OH, -O(Ci-6 alkyl), C2-6 alkenyl, C3-10 cycloalkyl, -S(Ci-6 alkyl), =CRlalRla2, and C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halo, -OH, and -O(Ci-6 alkyl), wherein Rlal and Rla2 are each independently hydrogen or C1-6 alkyl; L is a bond, CRblRb2, or O; Rbl and Rb2 are each independently H or C1-3 alkyl; ring B is C3-8 cycloalkyl, C5-7 cycloalkenyl, or 5- to 7-membered heterocycloalkyl wherein one or two of the ring atoms are each oxygen and the remaining ring atoms are each carbon; each RB group is independently halo, C1-6 alkyl, or C2-6 alkenyl; or two vicinal RB groups are taken together with the carbon atoms to which they are attached to form C3-10 cycloalkyl; or two geminal RB groups are taken together with the carbon atom to which they are attached to form C3-10 cycloalkyl; m is 0, 1, 2, 3, or 4; Y1 is N or CRC1; Y2 is N or CRC2; Y3 is N or CRC3; Y4 is N or CH; RC1, RC2, and RC3 are each independently hydrogen, halo, cyano, -OH, -OC1-6 alkyl, or C1-6 alkyl optionally substituted with one or more