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CN-121986099-A - Semi-saturated bicyclic derivatives and related uses

CN121986099ACN 121986099 ACN121986099 ACN 121986099ACN-121986099-A

Abstract

The present disclosure relates to compounds of formula (I): And prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods of making the same. The compounds disclosed herein are useful for modulating DNA polymerase Θ activity, and for treating disorders involving DNA polymerase Θ activity, such as cancer.

Inventors

  • BAI YONGHONG
  • H.WANG
  • T.J. Goods
  • L. B. Shenkel
  • M. H. Reuters Mountain
  • M. A. mcgorn
  • J.R. BUTLER
  • C.Gao

Assignees

  • 摩玛治疗公司

Dates

Publication Date
20260505
Application Date
20240405
Priority Date
20230405

Claims (20)

  1. 1. A compound of formula (I): or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X 1 is CH, S or N; X 2 is N, S or O; R 1 and R 2 together with the atoms to which they are attached form a C 5 -C 10 cycloalkyl or 5 to 10 membered heterocycloalkyl, wherein said C 5 -C 10 cycloalkyl or 5 to 10 membered heterocycloalkyl is optionally substituted with one or more R a ; Each R a is independently oxo, halo, cyano 、-OR a1 、-N(R a1 ) 2 、-C(O)R a1 、-C(O)N(R a1 ) 2 、-C(O)OR a1 、-S(O) 2 N(R a1 ) 2 、-S(O) 2 (R a1 )、C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, or 3 to 10 membered heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, or 3 to 10 membered heterocycloalkyl is optionally substituted with one or more R a1 ; Each R a1 is independently H, oxo, halo, cyano, -OH, -NH 2 、-C(O)(C 1 -C 6 alkyl), -C (O) (C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, 3 to 10 membered heterocycloalkyl, C 6 -C 10 aryl or 5 to 10 membered heteroaryl, wherein said-C (O) (C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, 3-to 10-membered heterocycloalkyl, and, C 6 -C 10 aryl or 5 to 10 membered heteroaryl optionally substituted with one or more R a2 ; Each R a2 is independently oxo, halo, cyano, -OH, -NH 2 、-NH(C 1 -C 6 alkyl), -N (C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl optionally substituted with C 1 -C 6 alkoxy or-OH, C 3 -C 10 cycloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, 3 to 10 membered heterocycloalkyl optionally substituted with oxo, or 5 to 10 membered heteroaryl; R 3 is C 6 -C 10 aryl or 5 to 10 membered heteroaryl, wherein the C 6 -C 10 aryl or 5 to 10 membered heteroaryl is substituted with one or more R 3a ; Each R 3a is independently halo, cyano, -OH, -NH 2 、C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, 3 to 10 membered heterocycloalkyl, C 6 -C 10 aryl, or 5 to 10 membered heteroaryl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, 3 to 10 membered heterocycloalkyl, C 6 -C 10 aryl, or 5 to 10 membered heteroaryl are optionally substituted with one or more R 3a1 , and Each R 3a1 is independently oxo, halo, cyano, -OH, -C (O) (C 1 -C 6 alkyl), -C (O) (O- (C 1 -C 6 alkyl)), C 1 -C 6 alkyl optionally substituted with C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkoxy, -O (C 1 -C 6 haloalkyl), C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, or a 5 to 10 membered heteroaryl.
  2. 2. A compound of formula (I): or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X 1 is CH, S or N; X 2 is N, S or O; R 1 and R 2 together with the atoms to which they are attached form a C 5 -C 10 cycloalkyl or 5 to 10 membered heterocycloalkyl, wherein said C 5 -C 10 cycloalkyl or 5 to 10 membered heterocycloalkyl is optionally substituted with one or more R a ; Each R a is independently oxo, halo, cyano 、-OR a1 、-N(R a1 ) 2 、-C(O)R a1 、-C(O)N(R a1 ) 2 、-C(O)OR a1 、-S(O) 2 N(R a1 ) 2 、-S(O) 2 (R a1 )、C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, or 3 to 10 membered heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, or 3 to 10 membered heterocycloalkyl is optionally substituted with one or more R a1 ; Each R a1 is independently H, oxo, halo, cyano, -OH, -NH 2 、-C(O)(C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, 3 to 10 membered heterocycloalkyl, C 6 -C 10 aryl, or 5 to 10 membered heteroaryl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, 3 to 10 membered heterocycloalkyl, C 6 -C 10 aryl, or 5 to 10 membered heteroaryl are optionally substituted with one or more R a2 ; Each R a2 is independently oxo, halo, cyano, -OH, -NH 2 , C 1 -C 6 alkyl optionally substituted with C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, 3 to 10 membered heterocycloalkyl optionally substituted with oxo, or 5 to 10 membered heteroaryl; R 3 is C 6 -C 10 aryl or 5 to 10 membered heteroaryl, wherein the C 6 -C 10 aryl or 5 to 10 membered heteroaryl is substituted with one or more R 3a ; Each R 3a is independently halo, cyano, -OH, -NH 2 、C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, 3 to 10 membered heterocycloalkyl, C 6 -C 10 aryl, or 5 to 10 membered heteroaryl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, 3 to 10 membered heterocycloalkyl, C 6 -C 10 aryl, or 5 to 10 membered heteroaryl are optionally substituted with one or more R 3a1 , and Each R 3a1 is independently oxo, halo, cyano, -OH, -C (O) (C 1 -C 6 alkyl), -C (O) (O- (C 1 -C 6 alkyl)), C 1 -C 6 alkyl optionally substituted with C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkoxy, -O (C 1 -C 6 haloalkyl), C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, or a 5 to 10 membered heteroaryl.
  3. 3. The compound of claim 1 or claim 2, wherein: x 1 is S or N; X 2 is N or S; R 1 and R 2 together with the atoms to which they are attached form a C 5 -C 6 cycloalkyl or 5 to 6 membered heterocycloalkyl, wherein said C 5 -C 6 cycloalkyl or 5 to 6 membered heterocycloalkyl is optionally substituted with one or more R a ; Each R a is independently oxo 、-OR a1 、-N(R a1 ) 2 、-C(O)R a1 、-C(O)N(R a1 ) 2 、-C(O)OR a1 、-S(O) 2 N(R a1 ) 2 、-S(O) 2 (R a1 )、C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, or 3 to 10 membered heterocycloalkyl, wherein said C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, or 3 to 10 membered heterocycloalkyl is optionally substituted with one or more R a1 ; Each R a1 is independently H, halo, cyano, -C (O) (C 1 -C 6 alkyl), -C (O) (C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, 3 to 10 membered heterocycloalkyl, C 6 -C 10 aryl, or 5 to 10 membered heteroaryl, wherein the-C (O) (C 3 -C 10 cycloalkyl), C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, 3 to 10 membered heterocycloalkyl, C 6 -C 10 aryl, or 5 to 10 membered heteroaryl is optionally substituted with one or more R a2 ; Each R a2 is independently oxo, cyano, -OH, -N (C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl optionally substituted with C 1 -C 6 alkoxy or-OH, C 3 -C 10 cycloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, 3 to 10 membered heterocycloalkyl optionally substituted with oxo, or5 to 10 membered heteroaryl; R 3 is a5 to 10 membered heteroaryl substituted with one R 3a ; R 3a is C 6 -C 10 aryl optionally substituted with one or more R 3a1 , and Each R 3a1 is independently cyano or C 1 -C 6 alkoxy.
  4. 4. The compound of claim 1 or claim 2, wherein R 1 and R 2 together with the atoms to which they are attached form a 5-membered heterocycloalkyl or C 6 cycloalkyl.
  5. 5. The compound of any one of the preceding claims, wherein each R a is independently:
  6. 6. The compound of any one of the preceding claims, wherein each R a1 is independently:
  7. 7. The compound of any one of the preceding claims, wherein each R a2 is independently oxo 、-CH 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 、-Cl、-F、-CN、-CHF 2 、-OCH 3 、-CF 3 、-OCHF 2 、-OH、-CH 2 CHF 2 、-CH 2 CF 3 、-CH 2 OH、-CH 2 OCH 3 、-OCF 3 、-N(CH 3 ) 2 、-OCH(CH 3 ) 2 、
  8. 8. The compound of any one of the preceding claims, wherein R 3 is:
  9. 9. The compound of any one of the preceding claims, wherein R 3a is-CH 3 , cyclopropyl,
  10. 10. The compound of any one of the preceding claims, wherein each R 3a1 is independently oxo, methyl, -CF 2 H, cyano, -F, -Cl, -OH, -OCF 2 H, or-OCH 3 .
  11. 11. The compound of any one of claims 1-4, wherein the compound has formula (I-a): Or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.
  12. 12. The compound of any one of claims 1-4, wherein the compound is of formula (I-B), (I-C), (I-D), or (I-E): Or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein m is from 0 to 6;n is from 0 to 8, and p is from 0 to 6.
  13. 13. The compound of any one of claims 1-4, wherein the compound has formula (I-F) or (I-Fa): Or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein p is 0 to 4.
  14. 14. The compound of any one of claims 1-4, wherein the compound has the formula (I-Fb), (I-Fb '), (I-Fc '), (I-Fd), or (I-Fd '): Or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein p is 0to 4 and q is 0to 4.
  15. 15. The compound of any one of claims 1-4, wherein the compound has formula (I-G), (I-Ga), or (I-Ga'): Or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein q is 1 to 4.
  16. 16. The compound of any one of the preceding claims, wherein the compound is selected from compound numbers 7,9,10,15,18,379,387,389,400,404,415,425,450,508,548,584,585,586,592,594,2,5,14,49,146,652,653,655,691,793,820,828,908,922,951,952,964,980,987,990,996,1003,1005,1010,1013,1014,1016,1019,1023,1029,1032,1039,1041, and 1046, or a pharmaceutically acceptable salt thereof.
  17. 17. The compound of any one of the preceding claims, wherein the compound is selected from the compounds described in table 1, table 2 or table 3, or a pharmaceutically acceptable salt thereof.
  18. 18. A compound obtainable by or obtained by a process as described herein; Optionally, the method comprises one or more of the steps described in schemes 1-7.
  19. 19. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  20. 20. The pharmaceutical composition of claim 18, wherein the compound is selected from the group consisting of the compounds described in table 1, table 2, or table 3.

Description

Semi-saturated bicyclic derivatives and related uses RELATED APPLICATIONS The present application claims priority and benefit from U.S. provisional application Ser. No. 63/457,353, filed on 5 at 4 at 2023, and U.S. provisional application Ser. No. 63/542,486, filed on 4 at 10 at 2023, the disclosures of which are incorporated herein by reference in their entireties. Background The present disclosure relates to small molecule antagonists of DNA polymerase Θ designed for the treatment of cancer. Correct repair of DNA Double Strand Breaks (DSBs) is critical to maintaining genome integrity. Erroneous repair of DSBs may result in mutations in critical coding or regulatory regions, whereas accumulation of unrepaired DNA lesions may trigger mitotic stress, which may lead to genomic changes or cell death. In normal cells, DSBs are repaired primarily by two key mechanisms. DNA damage that occurs during the DNA replication phase (S phase) is typically repaired by Homologous Recombination (HR), a mechanism that uses the replicated "sister chromatids" as templates to achieve error-free repair. In contrast, non-homologous end joining (NHEJ) is the primary repair method for DSBs when no DNA template is available for template dependent repair. The third DSB repair pathway is called alternative end ligation (Alt-EJ), micro-homology mediated end ligation (MMEJ) or θ mediated end ligation (TMEJ), performed by polymerase θ (POL Θ). In contrast to NHEJ and HR, TMEJ is believed to play a limited role in healthy cells under normal conditions. Some tumors contain inactivating mutations in homologous repair genes, most commonly, the loss of function of BRCA1 or BRCA 2. Thus, these tumors have an intrinsic sensitivity to DNA damaging agents and inhibitors of specific DNA repair proteins. Accordingly, DNA cross-linking agents (such as platinum-based chemotherapeutics) have better efficacy against BRCA mutant tumors than tumors with intact BRCA function. Similarly, small molecule inhibitors of PARP1/2 have therapeutic effects on BRCA1/2 deficient tumors that rely on PARP enzymes to repair single stranded DNA breaks and prevent their conversion to toxic DSB that overwhelm the repair capacity of HR deficient cells. An alternative approach to therapeutic targeting of HR deficient tumors is by inhibiting alternative repair pathways (such as POL Θ -mediated TMEJ). Consistent with the role of POLΘ as a backup DNA repair enzyme, ablation of this locus was well tolerated in the mouse model, leading to only a slight phenotype, characterized by micronuclei in reticulocytes, and increased sensitivity of the cells (but not the individual) to DNA cross-linking agents. In contrast, when NHEJ or HR is inactivated, POL Θ DNA repair activity has been demonstrated to be essential for cell survival, suggesting that POL Θ is a potential target for cancer treatment in the context of specific mutations. POLΘ is unique in the human genome, containing both an N-terminal SF2 DNA helicase domain and a C-terminal DNA polymerase domain. In the context of chromosomal DSBs, these domains work cooperatively to repair DSBs containing long 3' -single stranded DNA overhangs. Specifically, the helicase domain is thought to strip the RPA protein complex from the overhanging end and promote annealing to the opposite DNA end via a region of DNA microhomology. The annealed DNA is then used as a primer for the POL Θ polymerase domain, which extends the annealed DNA to fill the single-stranded DNA gap. Given the role of POLΘ catalytic activity in the key DNA repair process of HR deficient tumors, POLΘ represents an attractive target for the development of chemical inhibitors to exploit newly discovered functional dependencies. The present disclosure stems from the need to provide compounds for modulating DNA polymerase Θ activity with improved therapeutic potential. In particular compounds having improved physicochemical, pharmacological and/or pharmaceutical properties. Disclosure of Invention In some aspects, the present disclosure provides compounds of formula (I): or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X 1 is CH, S or N; X 2 is N, S or O; R 1 and R 2 together with the atoms to which they are attached form a C 5-C10 cycloalkyl or 5 to 10 membered heterocycloalkyl, wherein C 5-C10 cycloalkyl or 5 to 10 membered heterocycloalkyl is optionally substituted with one or more R a; Each R a is independently oxo, halo, cyano 、-ORa1、-N(Ra1)2、-C(O)Ra1、-C(O)N(Ra1)2、-C(O)ORa1、-S(O)2N(Ra1)2、-S(O)2(Ra1)、C1-C6 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 haloalkyl, C 3-C10 cycloalkyl, C 6-C10 aryl, 5 to 10 membered heteroaryl, or 3 to 10 membered heterocycloalkyl, wherein C 1-C6 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 haloalkyl, C 3-C10 cycloalkyl, C 6-C10 aryl, 5 to 10 membered heteroaryl, or 3 to 10 membered heterocycloalkyl is optionally substituted with one or more R a1; Each R a1 is independently H, oxo