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CN-122003414-A - Substituted tricyclic compounds as KRAS degradation agents

CN122003414ACN 122003414 ACN122003414 ACN 122003414ACN-122003414-A

Abstract

The present invention provides substituted tricyclic compounds of formula (I) which are useful therapeutically as KRAS degrading agents. These compounds are useful for the treatment and/or prevention of KRAS-dependent diseases or disorders. The invention also provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. (I)。

Inventors

  • CHIKKANNA DINESH
  • E. GREEN
  • J. MURRAY
  • N. Mishra
  • CHEN JUN
  • S. Rikal
  • B. Scheller
  • H. Nguye
  • FERREIRA ANDRE
  • J .mang
  • D. Cole
  • M. Ailuri
  • D. Hrakovsky
  • M. Buyi
  • S. Mulkergi
  • S. Tatiya Sahbugor
  • C o Binet
  • R. Machico Pavitarao
  • D. Bashak
  • S, Mayidaer
  • S. Simonovic

Assignees

  • 奥瑞基尼肿瘤有限公司

Dates

Publication Date
20260508
Application Date
20241010
Priority Date
20231010

Claims (20)

  1. 1. A compound of formula (I) Or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof; Wherein, the R 1 is independently at each occurrence hydrogen, (C 1 -C 6 ) alkyl, hydroxy, halogen, amino, halo (C 1 -C 6 ) alkyl, and/or two R 1 groups adjacent to each other together with the C atom to which they are attached form phenyl or a 5 to 6 membered heterocyclyl, wherein the phenyl and heterocyclyl are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of (C 1 -C 6 ) alkyl, (C 2 -C 4 ) alkynyl, halogen, hydroxy, halo (C 1 -C 6 ) alkyl, amino and cyano; p is 1, 2, 3 or 4; X and X' are independently C or N; r 2 is hydrogen, cyclopropyl, or absent; R 3 is hydrogen or oxo; R 4a and R 4b are independently hydrogen, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, 5-to 10-membered heteroaryl (C 1 -C 6 ) alkyl or 4-to 7-membered heterocycloalkyl, wherein said cycloalkyl and heteroarylalkyl are unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of halogen, (C 1 -C 6 ) alkyl and amino, and/or R 4a and R 4b together with the nitrogen to which they are attached form a 4 to 14 membered heterocyclyl optionally containing one or two additional heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein the heterocyclyl is unsubstituted or substituted with 1,2 or 3 groups each independently selected from the group consisting of (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, hydroxy, cyano and-C (O) -R 4c , wherein the alkyl is unsubstituted or independently substituted with one or more of halogen, hydroxy, amino, cyano or (C 3 -C 6 ) cycloalkyl, and/or R 4c is hydrogen, amino, (C 1 -C 6 ) alkylamino, 4 to 7 membered heterocycloalkyl, (C 3 -C 6 ) cycloalkyl, (C 1 -C 6 ) alkyl or (C 1 -C 6 ) alkylamino (C 1 -C 6 ) alkyl, wherein said heterocycloalkyl and cycloalkyl are unsubstituted or substituted with 1,2 or 3 groups each independently selected from the group consisting of halogen, hydroxy and (C 1 -C 6 ) alkyl; l is-O- (CH 2 ) m ) 、-C(O)- Or-C (O) -NH- Wherein the asterisk indicates the point of attachment to R 5 ; R 5 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, - (CH 2 ) m -NR c R d , 5 to 14 membered heterocycloalkyl, or (C 3 -C 6 ) cycloalkyl, wherein said heterocycloalkyl and cycloalkyl are unsubstituted or substituted with 1, 2, or 3 substituents each independently selected from the group consisting of (C 1 -C 6 ) alkyl, halogen, amino, and- (CH 2 ) m NR y R z ); m is 0, 1, 2 or 3; R c and R d are independently hydrogen or (C 1 -C 6 ) alkyl, or R c and R d together with the N atom to which they are attached form a 4 to 7 membered heterocycloalkyl; R y and R z are independently hydrogen or (C 1 -C 6 ) alkyl, or R y and R z together with the N atom to which they are attached form a4 to 7 membered heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of (C 1 -C 6 ) alkyl, halogen and (C 2 -C 4 ) acyl; R 6 is independently at each occurrence hydrogen, amino, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy or hydroxy, or two R 6 groups on the same carbon represent an oxo group; q is 1, 2 or 3; Y 1 、Y 2 and Y 3 are independently a bond, C, N or O, wherein at most one of Y 1 、Y 2 or Y 3 is a bond; Z 1 、Z 2 、Z 3 and Z 4 are independently C, CR 7' 、NR 7 or N, wherein at least two of Z 1 、Z 2 、Z 3 and Z 4 are N; R 7 and R 7' are independently hydrogen, halogen, (C 1 -C 6 ) alkyl, halo (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy or halo (C 1 -C 6 ) alkoxy; M is M1, M2, M3, M4, M5, M6 、 M7, M8 or M9; ; ; ; ; ; ; Or (b) ; Wherein, the R 8 is (C 1 -C 6 ) alkyl, hydroxy, halogen or amino; Z is hydrogen, (C 1 -C 6 ) alkyl, halogen or-CH 2 OH; R a' and R b' are independently hydrogen, halogen or (C 1 -C 6 ) alkyl, or R a' and R b' together with the C atom to which they are attached form a 5-to 6-membered heterocyclyl ring optionally containing one or two heteroatoms selected independently from the group consisting of O, S and N; R 9 is independently at each occurrence hydrogen, 4-to 8-membered heterocycloalkyl, -O- (C 1 -C 6 ) alkyl; Wherein heterocycloalkyl is unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of halogen or (C 1 -C 6 ) alkyl; Wherein the alkyl in the-O- (C 1 -C 6 ) alkyl is unsubstituted or substituted with 1, 2, or 3 substituents each independently selected from the group consisting of (C 1 -C 6 ) alkylamino or 5-to 8-membered heterocycloalkyl, wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen or (C 1 -C 6 ) alkyl; P 1 、P 2 、P 3 and P 4 are independently C, N or S, wherein at least one of P 1 、P 2 、P 3 and P 4 is N; R 10 is hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 4 ) alkynyl, hydroxy, 3 to 7 membered heterocycloalkyl or (C 3 -C 6 ) cycloalkyl; Wherein the alkyl and alkynyl groups are unsubstituted or substituted with halogen, cycloalkyl, -NH- (CO) -NH 2 、-NR m R n , or 4-to 6-membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1,2, or 3 substituents each independently selected from the group consisting of (C 1 -C 6 ) alkyl, hydroxy, halogen, or amino; Wherein the 3-to 7-membered heterocycloalkyl is unsubstituted or substituted with 1,2 or 3 substituents each independently selected from the group consisting of halogen, hydroxy or (C 1 -C 6 ) alkyl; R m and R n are independently hydrogen or (C 1 -C 6 ) alkyl; R 11 is independently at each occurrence hydrogen, hydroxy or (C 1 -C 6 ) alkyl, wherein the alkyl is unsubstituted or substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen or hydroxy; R 12 is independently at each occurrence hydrogen or amino; X 1 is C or N; r 13 is hydrogen or (C 1 -C 6 ) alkyl; Each of X 2 、X 3 、X 4 and X 5 is independently C, CH or N, wherein each of X 3 or X 4 is N and the other is C; R 14 is independently at each occurrence hydrogen, halogen, hydroxy, (C 1 -C 6 ) alkyl, halo (C 1 -C 6 ) alkyl or (C 2 -C 6 ) alkynyl; cy is (C 3 -C 10 ) cycloalkyl or 3-to 10-membered heterocycloalkyl; the dotted line [ - - - - - - - - - ] indicates a chemical bond or absence, and N is 1, 2 or 3.
  2. 2. The compound of claim 1, wherein R 1 at each occurrence is (C 1 -C 6 ) alkyl, amino, hydroxy, or halo.
  3. 3. The compound of claim 1, wherein two R 1 's adjacent to each other, together with the C atom to which they are attached, form a phenyl group or a 5-to 6-membered heterocyclic group, wherein the phenyl and heterocyclic groups are unsubstituted or substituted with 1, 2, or 3 substituents each independently selected from (C 1 -C 6 ) alkyl, (C 2 -C 4 ) alkynyl, halogen, and amino.
  4. 4. A compound according to claims 1 and 3 wherein two R 1 adjacent to each other together with the C atom to which they are attached form 、 、 、 、 Or (b) 。
  5. 5. The compound of claim 1, wherein R 2 is cyclopropyl or absent.
  6. 6. The compound of claim 1, wherein R 4a and R 4b are independently (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, 5-to 10-membered heteroaryl (C 1 -C 6 ) alkyl, or 4-to 7-membered heterocycloalkyl.
  7. 7. The compound of claims 1 and 6, wherein R 4a and R 4b are independently methyl, ethyl, cyclopropyl, 、 、 、 Or (b) 。
  8. 8. The compound of claim 1, wherein R 4a and R 4b , together with the nitrogen to which they are attached, form an unsubstituted or substituted heterocyclyl selected from 、 、 、 、 、 Or (b) 。
  9. 9. The compound of claim 8, wherein the heterocyclyl is substituted with 1, 2, or 3 groups each independently selected from (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, hydroxy, and-C (O) -R 4c , wherein the alkyl is independently substituted with one or more of halo, hydroxy, or (C 3 -C 6 ) cycloalkyl.
  10. 10. The compound of claim 9, wherein R 4c is amino, (C 1 -C 6 ) alkylamino, (C 1 -C 6 ) alkyl, or 4-to 7-membered heterocycloalkyl that is unsubstituted or substituted, wherein said heterocycloalkyl is substituted with (C 1 -C 6 ) alkyl.
  11. 11. The compound according to claim 1, wherein L is-O-, -O- (CH 2 ) m ] 、-C(O)- Or-C (O) -NH- Wherein the asterisk marks indicate the point of attachment to R 5 .
  12. 12. The compound of claims 1 and 11 wherein L is-O- (CH 2 ) m - Wherein the asterisk marks indicate the point of attachment to R 5 .
  13. 13. The compound of claim 1, wherein R 5 is (C 1 -C 6 ) alkoxy, - (CH 2 ) m -NR c R d ) or 5-to 14-membered heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1,2 or 3 substituents each independently selected from (C 1 -C 6 ) alkyl, halogen and- (CH 2 ) m -NR y R z ).
  14. 14. The compound of claim 13, wherein R c and R d are (C 1 -C 6 ) alkyl, or R c and R d together with the N atom to which they are attached form a4 to 7 membered heterocycloalkyl.
  15. 15. The compound of claim 13, wherein R y and R z are (C 1 -C 6 ) alkyl, or R y and R z together with the N atom to which they are attached form a 4-to 7-membered heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1,2 or 3 substituents each independently selected from (C 1 -C 6 ) alkyl and (C 2 -C 4 ) acyl.
  16. 16. The compound of claims 1 and 13, wherein R 5 is 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) 。
  17. 17. The compound of claim 1, wherein R 6 is hydrogen, amino, (C 1 -C 6 ) alkoxy or hydroxy, or two R 6 groups on the same carbon represent an oxo group.
  18. 18. The compound of claim 1, wherein R 7 and R 7' are independently halo, (C 1 -C 6 ) alkyl, halo (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, or halo (C 1 -C 6 ) alkoxy.
  19. 19. The compound of claim 1, wherein M1 is 、 、 Or (b) 。
  20. 20. The compound of claims 1 and 19, wherein M1 is 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) 。

Description

Substituted tricyclic compounds as KRAS degradation agents The present application claims the benefit of indian provisional application number 202341067839 filed 10/2023 and indian provisional application number 202441054021 filed 7/15/2024, the entire contents of which are incorporated herein by reference. Technical Field The present invention relates to substituted tricyclic compounds or pharmaceutically acceptable salts, stereoisomers or tautomers thereof useful as KRAS degradants and for treating KRAS-dependent diseases, conditions or disorders. The invention also relates to a preparation method of the substituted tricyclic compound and a pharmaceutical composition comprising the compound. Background Cancer is one of the leading causes of mortality worldwide. Cancer therapy is gradually moving from organ-centric to pathway-centric approaches. Cancer cells are generally dependent on signals generated by oncogenes. Thus, targeted cancer drugs that selectively inhibit activated oncogene products can have a significant impact on cancer cell viability. RAS is a family of related proteins that are ubiquitously expressed in all cell lineages and organs. All RAS protein family members (of which the key human members are KRAS, NRAS and HRAS) belong to a class of proteins known as small gtpases and are involved in cell signaling. RAS represents a closely related group of monomeric globular proteins comprising 189 amino acids (21 kDa molecular weight) which associate with the cytoplasmic membrane and bind GDP or GTP. The RAS functions as a molecular switch. When the RAS comprises bound GDP, it is in a resting or off state and is "inactive". In response to exposure of the cells to a specific growth promoting stimulus, the RAS is induced to replace its bound GDP with GTP. When GTP is bound, the RAS is "turned on" and is able to interact with and activate other proteins (its "downstream targets"). The inherent ability of RAS proteins themselves to hydrolyze GTP back to GDP and thereby turn to an "off" state is extremely low. Turning off the RAS requires a foreign protein called Gtpase Activating Protein (GAP), which interacts with the RAS and accelerates the conversion of GTP to GDP. Thus, in the RAS, affecting its ability to interact with GAP or convert GTP back to GDP will result in long-term activation of the protein, which in turn allows the cell to receive growth signals for long periods. Since these signals can lead to cell growth and cell division, overactive RAS signaling may ultimately lead to cancer. Activating mutations of RAS oncogenes (KRAS, NRAS or HRAS) are found in about 30% of human tumors. Although mutations in any of the three RAS subtypes (KRAS, NRAS or HRAS) have been shown to result in oncogenic transformation, KRAS mutations are by far the most common in human cancers. Oncogenic KRAS mutations occur in （Bos J L., Bos JL. RAS oncogenes in human cancer: a review. Cancer Res. 1989 Sep 1;49(17):4682-9. Erratum in: Cancer Res 1990 Feb 15;50(4):1352 and in 90% of pancreatic epithelial-derived cancers (carpinoma), 45% of colorectal epithelial-derived cancers and 35% of lung epithelial-derived cancers Downward J., Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003 Jan;3(1):11-22）. The well-known role of KRAS in malignancy and the discovery of these frequent mutations in KRAS of various tumor types make KRAS an extremely attractive target for the pharmaceutical industry in the field of cancer treatment. Despite the last three decades, extensive discovery efforts have been made in developing KRAS inhibitors for the treatment of cancer. Compounds that inhibit KRAS activity remain highly desirable and under investigation, including those that interfere with effectors such as guanine nucleotide exchange factors （Sun Q, Burke JP, Phan J, Burns MC, Olejniczak ET, Waterson AG, Lee T, Rossanese OW, Fesik SW. Discovery of small molecules that bind to KRAS and inhibit Sos-mediated activation. Angew Chem Int Ed Engl. 2012 Jun 18;51(25):6140-3）, and advances made in covalently targeting the KRAS G12C allosteric pocket (Ostrem JM, peters U, sos ML, wells JA, shokat KM). KRAS (G12C) inhibitors allosteric controls GTP affinity and effector interactions (Nature 2013 Nov 28; 503 (7477): 548-51). Clearly, there is a continuing interest in developing KRAS inhibitors, particularly inhibitors directed to activating KRAS mutants (particularly KRAS G12D). In recent years, the use of ubiquitin-proteasome pathways to specifically degrade protein substrates with the help of proteolytically targeted chimeras (PROTAC) has become more influential than inhibition. PROTAC is a compound having two heterofunctional ligands linked by a linker, one of which targets a target protein of interest (POI) and the other of which specifically recruits E3 ligase. When PROTAC binds to the E3 ligase and the protein of interest to form a ternary complex, PROTAC provides a favorable spatial location for the POI by h