Search

EP-4739681-A1 - SUBSTITUTED THIAZOLE COMPOUNDS AS CDK2/4/6 INHIBITORS AND METHODS OF USE THEREOF

EP4739681A1EP 4739681 A1EP4739681 A1EP 4739681A1EP-4739681-A1

Abstract

The disclosure provides for small molecules inhibitory compounds of CDK2/4/6 and compositions comprising the same. The disclosure further provides methods for targeting CDK2/4/6 and methods of treating diseases or disorders related to CDK2/4/6, such as cancer.

Inventors

  • DING, Xiao
  • LIU, Jinxin
  • MENG, Fanye
  • REN, FENG
  • WANG, Yazhou

Assignees

  • Insilico Medicine IP Limited

Dates

Publication Date
20260513
Application Date
20240702

Claims (20)

  1. A compound having the structure of Formula (I) , or a pharmaceutically acceptable salt thereof, wherein, is R 1 is hydrogen, halogen, -NR c R d , C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl, wherein each of the alkyl or heteroalkyl is optionally substituted with one or more R; Y is a bond, -S-, -O-, -NR YN -, or -C (R Y ) 2 -; R YN is hydrogen, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; each R Y is independently hydrogen, halogen, -CN, -OH, -SF 5 , -SH, -NR c R d , -NO 2 , -OR a , -SR a , C 1-6 alkyl, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl; or two R Y are taken together to form an oxo; is a single bond or a double bond; X 1 is N or C; X 2 is N or CR 2 ; X 3 is N or CR 3 ; X 4 is N or CR 4 ; X 5 is N or C; X 6 is N or C; X 7 is O, S, N, NR 7N , CR 7 , or CR 7’ R 7 ; X 8 is NR 8N , CR 8 , or CR 8’ R 8 ; X 9 is O, S, N, NR 9N , CR 9 , or CR 9’ R 9 ; each of R 2 , R 3 , and R 4 is independently hydrogen, halogen, -CN, -OH, -SF 5 , -SH, -NR c R d , -NO 2 , -OR a , -SR a , C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; each of R 7N and R 9N is independently hydrogen, -CN, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; each of R 7 and R 7’ is independently hydrogen, halogen, -CN, OH, -SF 5 , -SH, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; or R 7 and R 7’ are taken together to form an oxo; or R 7 and R 7’ are taken together with the atom to which they are attached to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; each of R 9 and R 9’ is independently hydrogen, halogen, -CN, -OH, -SF 5 , -SH, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R; or R 9 and R 9’ are taken together to form an oxo; or R 9 and R 9’ are taken together with the atom to which they are attached to form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; R 8 is selected from halogen, -CN, -NO 2 , -OH, -OR a , -OC (=O) R a , -OC (=O) OR b , -OC (=O) NR c R d , -SF 5 , -SH, -SR a , -S (=O) R a , -S (=O) 2 R a , -S (=O) 2 NR c R d , -S (=O) (=NR b ) R b , -NR c R d , -NR b C (=O) NR c R d , -NR b C (=O) R a , -NR b C (=O) OR b , -NR b S (=O) 2 R a , -N=S (=O) (R b ) 2 , -C (=O) R a , -C (=O) OR b , -C (=O) NR c R d , -P (=O) R c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1- 6 alkylene-cycloalkyl, -C 1-6 alkylene-heterocycloalkyl, -C 1-6 heteroalkylene-cycloalkyl, -C 1- 6 heteroalkylene-heterocycloalkyl, -C 1-6 alkylene-aryl, -C 1-6 alkylene-heteroaryl, -C 1-6 heteroalkylene-aryl, and -C 1-6 heteroalkylene-heteroaryl, wherein each of the alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 8a ; R 8N is selected from -CN, -NO 2 , -OC (=O) R a , -S (=O) R a , -S (=O) 2 R a , -S (=O) 2 NR c R d , -NR b S (=O) 2 R a , -C (=O) R a , -C (=O) OR b , -C (=O) NR c R d , -P (=O) R c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -C 1-6 alkylene-cycloalkyl, -C 1-6 alkylene-heterocycloalkyl, -C 1-6 heteroalkylene-cycloalkyl, -C 1-6 heteroalkylene-heterocycloalkyl, -C 1-6 alkylene-aryl, -C 1-6 alkylene-heteroaryl, -C 1- 6 heteroalkylene-aryl, and -C 1-6 heteroalkylene-heteroaryl, wherein each of the alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 8a ; R 8’ is independently hydrogen, halogen, -CN, OH, -SF 5 , -SH, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein each of the alkyl, heteroalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R 8a ; each R 8a is independently selected from halogen, -CN, -NO 2 , -OH, oxo, -OR a , -OC (=O) R a , -OC (=O) OR b , -OC (=O) NR c R d , -SF 5 , -SH, -SR a , -S (=O) R a , -S (=O) 2 R a , -S (=O) 2 NR c R d , -S (=O) (=NR b ) R b , -NR c R d , -NR b C (=O) NR c R d , -NR b C (=O) R a , -NR b C (=O) OR b , -NR b S (=O) 2 R a , -N=S (=O) (R b ) 2 , -C (=O) R a , -C (=O) OR b , -C (=O) NR c R d , -P (=O) R c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of R 10 is independently selected from halogen, -CN, -NO 2 , -OH, -OR a , -OC (=O) R a , -OC (=O) OR b , -OC (=O) NR c R d , -P (=O) R c R d , -SF 5 , -SH, -SR a , -S (=O) R a , -S (=O) 2 R a , -S (=O) 2 NR c R d , -S (=O) (=NR b ) R b , -NR c R d , -NR b C (=O) NR c R d , -NR b C (=O) R a , -NR b C (=O) OR b , -NR b S (=O) 2 R a , -N=S (=O) (R b ) 2 , -C (=O) R a , -C (=O) OR b , -C (=O) NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R 10a ; or two R 10 are taken together to form an oxo; each R 10a is independently selected from halogen, -CN, -NO 2 , -OH, oxo, -OR a , -OC (=O) R a , -OC (=O) OR b , -OC (=O) NR c R d , -SF 5 , -SH, -SR a , -S (=O) R a , -S (=O) 2 R a , -S (=O) 2 NR c R d , -S (=O) (=NR b ) R b , -NR c R d , -NR b C (=O) NR c R d , -NR b C (=O) R a , -NR b C (=O) OR b , -NR b S (=O) 2 R a , -N=S (=O) (R b ) 2 , -C (=O) R a , -C (=O) OR b , -C (=O) NR c R d , -P (=O) R c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; n is 0, 1, 2, 3, 4, 5 or 6; each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 - C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene (cycloalkyl) , C 1 -C 6 alkylene (heterocycloalkyl) , C 1 -C 6 alkylene (aryl) , or C 1 -C 6 alkylene (heteroaryl) , wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R; and each R is independently halogen, -CN, -OH, -SF 5 , -SH, -S (=O) C 1 -C 3 alkyl, -S (=O) 2 C 1 -C 3 alkyl, -S (=O) 2 NH 2 , -S (=O) 2 NHC 1 -C 3 alkyl, -S (=O) 2 N (C 1 -C 3 alkyl) 2 , -S (=O) (=NC 1 -C 3 alkyl) (C 1 -C 3 alkyl) , -NH 2 , -NHC 1 -C 3 alkyl, -N (C 1 -C 3 alkyl) 2 , -N=S (=O) (C 1 -C 3 alkyl) 2 , -C (=O) C 1 -C 3 alkyl, -C (=O) OH, -C (=O) OC 1 -C 3 alkyl, -C (=O) NH 2 , -C (=O) NHC 1 -C 3 alkyl, -C (=O) N (C 1 -C 3 alkyl) 2 , -P (=O) (C 1 -C 3 alkyl) 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy, C 1 -C 3 hydroxyalkyl, C 1 -C 3 aminoalkyl, C 1 -C 3 heteroalkyl, or C 3 -C 6 cycloalkyl; or two R on the same atom form an oxo.
  2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula (II) ,
  3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula (III) , wherein ring A is heterocycloalkyl, aryl, heteroaryl, or C 4-12 cycloalkyl; Y is a bond, -S-, -O-, -NR YN -, or -C (R Y ) 2 -; R YN is hydrogen, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, or heterocycloalkyl; each R Y is independently hydrogen, halogen, -CN, -OH, -SF 5 , -SH, -NR c R d , -NO 2 , -OR a , -SR a , C 1-6 alkyl, C 1-6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, or heterocycloalkyl.
  4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula (IIa) ,
  5. The compound of claim 1 or 3, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of Formula (IIIa) ,
  6. The compound of any one of claims 1, 2, or 4, or a pharmaceutically acceptable salt thereof, wherein is
  7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein is
  8. The compound of any one of claims 1, 3, or 5, or a pharmaceutically acceptable salt thereof, wherein is
  9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein is
  10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R 2 is H, F, -CN, Cl, -CH 3 , -CHF 2 , or -C≡CH.
  11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.
  12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R 3 is H, F, -CN, Cl, -CH 3 , -CHF 2 , or -C≡CH.
  13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
  14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R 4 is H, F, -CN, Cl, -CH 3 , -CHF 2 , or -C≡CH.
  15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.
  16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R 7 is H, F, -CH 3 , or
  17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen.
  18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R 7’ is H, F, CH 3 , or
  19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R 7’ is hydrogen.
  20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R 7 and R 7’ are taken together to form an oxo, or R 7 and R 7’ are taken together with the atom to which they are attached to form a cycloalkyl optionally substituted with one or more R.

Description

SUBSTITUTED THIAZOLE COMPOUNDS AS CDK2/4/6 INHIBITORS AND METHODS OF USE THEREOF CROSS-REFERENCE This patent application claims the benefit of International Application No. PCT/CN2023/105592, filed July 03, 2023; which is incorporated herein by reference in its entirety. BACKGROUND Cyclin-dependent kinases (CDKs) are vital enzymes affecting the essential functions in eukaryotic cell division regulation and eukaryotic cell proliferation. Regulatory subunits (cyclins) active the catalytic units of CDK and are also important regulators of cell cycle progression. Furthermore, functions of cyclin/CDK heterodynes also include regulation of transcription, DNA repair, differentiation and apoptosis. Overexpression of CDK2 is associated with abnormal regulation of cell-cycle. Cyclin E, a regulatory cyclin for CDK2, is frequently overexpressed in cancer, and the amplification/overexpression of cyclin E has been associated with breast cancer. SUMMARY The present disclosure addresses the above need and provides additional advantages as well. In one aspect, described herein is a compound having the structure of Formula (I) , or a salt thereof, In some embodiments, the compound has a structure of Formula (II) , or a pharmaceutically acceptable salt thereof, In some embodiments, the compound has a structure of Formula (III) , or a pharmaceutically acceptable salt thereof, In one aspect, described herein is a compound having the structure of Formula (IIa) , or a pharmaceutically acceptable salt thereof, In one aspect, described herein is a compound having the structure of Formula (IIIa) , or a pharmaceutically acceptable salt thereof, In one aspect, described herein is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In one aspect, described herein is a method of treating a cancer in a subject, the method comprising administering to a subject a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein In one aspect, described herein is a method of modulating activity of a cyclin-dependent kinase (CDK) in a subject, the method comprising administering to a subject a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein. In one aspect, described herein is a method of inhibiting activity of a cyclin-dependent kinase (CDK) in a subject, the method comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein. In one aspect, described herein is a method of treating a disease or disorder associated with cyclin-dependent kinase (CDK) in a subject, the method comprising administering to the subject a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound described herein. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is a carcinoma of the bladder, breast, colon, kidney, epidermis, liver, lung, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, nose, head and neck, prostate, or skin; a hematopoietic tumor of lymphoid lineage; a hematopoietic tumor of myeloid lineage; thyroid follicular cancer; a tumor of mesenchymal origin; a tumor of the central or peripheral nervous system; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoacanthoma; thyroid follicular cancer; or Kaposi's sarcoma. In some embodiments, the cancer is pRb+ breast cancer, or hormone receptor (HR) -positive (e.g., estrogen receptor positive (ER+) , progesterone receptor positive (PR+) , or ER+PR+) , HER2/neu-negative cancer. In some embodiments, the cancer is advanced or metastatic or recurrent breast cancer. INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such contradictory material. DETAILED DESCRIPTION While various embodiments of the disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions can occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein can be employed. A. Definitions Unless