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CN-122003428-A - Irreversible 17 beta-HSD 1 inhibitors

CN122003428ACN 122003428 ACN122003428 ACN 122003428ACN-122003428-A

Abstract

Disclosed are compounds of formula (I), pharmaceutical compositions or kits thereof. Wherein A 1 is C (O) or CHR z1 ,R z1 is OH, amino, imino, halogen, (C 1 -C 5 ) alkoxy, OC (O) (C 1 -C 5 ) alkyl and OSO 2 -amino, A 2 is CH 2 or O, R 1 is hydrogen, (C 1 -C 5 ) alkyl optionally substituted with one or more Z substituents, (C 1 -C 5 ) alkoxy optionally substituted with one or more Z substituents, (C 2 -C 5 ) alkenyl optionally substituted with one or more Z substituents, (C 2 -C 5 ) alkynyl optionally substituted with one or more Z substituents, (C 3 -C 8 ) cycloalkyl, Aryl or heteroaryl, Z is halogen, OH, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) haloalkyl, (C 1 -C 5 ) alkoxy, (C 1 -C 5 ) haloalkoxy or amino, R 2 is a compound having 5, 6 or 7 members and having at least one N, S and/or O, R 3 is (C 1 -C 5 ) alkyl substituted with one or more Br, br 76 ;I、I 123 、I 124 or I 131 , m is an integer selected from 0 to 2, n is an integer selected from 0 to 2, and p is an integer selected from 0 to 5. the compounds of formula I are inhibitors of 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD 1) for the treatment or prophylaxis of steroid hormone dependent diseases such as breast cancer, lung cancer, prostate cancer, ovarian cancer, uterine cancer, endometrial cancer and endometrial hyperplasia. (I)。

Inventors

  • Ren e Maltes
  • Donald Polil

Assignees

  • 拉瓦尔大学

Dates

Publication Date
20260508
Application Date
20240814
Priority Date
20230815

Claims (20)

  1. 1. A compound of formula (I) or a stereoisomer or salt thereof: (I) Wherein: A 1 is selected from C (O) and CHR z1 ; A 2 is selected from CH 2 and O; R 1 is selected from the group consisting of hydrogen, (C 1 -C 5 ) alkyl optionally substituted with one or more Z substituents, (C 1 -C 5 ) alkoxy optionally substituted with one or more Z substituents, (C 2 -C 5 ) alkenyl optionally substituted with one or more Z substituents, (C 2 -C 5 ) alkynyl optionally substituted with one or more Z substituents, (C 3 -C 8 ) cycloalkyl, aryl and heteroaryl; R 2 is a heterocyclic aromatic ring having 5, 6, or 7 members selected from CR z2 , N, S, and O, provided that at least one member is N, S or O; R 3 is (C 1 -C 5 ) alkyl substituted with one or more Br, br 76 ;I、I 123 、I 124 or I 131 ; R z1 is selected from OH, NR x1 R x2 、=N-OR x3 , halogen, (C 1 -C 5 ) alkoxy, OC (O) (C 1 -C 5 ) alkyl and OSO 2 NR x4 NR x5 ; R z2 is selected from hydrogen, OH, optionally substituted (C 1 -C 10 ) alkyl with one or more Z substituents, and optionally substituted (C 1 -C 10 ) alkoxy with one or more Z substituents; Z is selected from halogen, OH, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) haloalkyl, (C 1 -C 5 ) alkoxy, (C 1 -C 5 ) haloalkoxy and NR x1 R x2 ; R x1 、R x2 、R x4 and R x5 are the same or different and are selected from the group consisting of hydrogen, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) haloalkyl, (C 1 -C 5 ) alkoxy, and (C 1 -C 5 ) haloalkoxy; r x3 is selected from H and (C 1 -C 5 ) alkyl; m represents an integer value selected from 0 to 2; n represents an integer value selected from 0 to 2; p represents an integer value selected from 0 to 5; Wherein: Aryl is an aromatic ring system comprising 5 or 6 CR c members, wherein R c is selected from H, halogen, cyano, nitro, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) haloalkyl, -O- (C 1 -C 5 ) alkyl, and-O- (C 1 -C 5 ) haloalkyl, and Heteroaryl is an aromatic ring system comprising 5 or 6 members selected from the group consisting of CR d , O, N, NH, and S, wherein R d is selected from the group consisting of H, halogen, cyano, nitro, (C 1 -C 5 ) alkyl, (C 1 -C 5 ) haloalkyl, -O- (C 1 -C 5 ) alkyl, and-O- (C 1 -C 5 ) haloalkyl.
  2. 2. The compound of claim 1, which is one of formula (Ia) or (Ib): (Ia) (Ib) Wherein R 1 to R 3 、A 1 、A 2 , m, n and p are as defined in claim 1.
  3. 3. The compound of claim 1 or 2, which is one of formula (Ic) or (Id): (Ic) (Id) Wherein R 1 to R 3 、A 1 、A 2 , m, n and p are as defined in claim 1.
  4. 4. A compound according to any one of claims 1 to 3, wherein a 1 represents C (O) or CHOH.
  5. 5. The compound of any one of claims 1 to 4, wherein m is not 0 and a 2 =CH 2 .
  6. 6. The compound of claim 5, wherein m is 1, a 2 =CH 2 and n is 0.
  7. 7. The compound according to any one of claims 1 to 4, wherein m = 0 and a 2 = -O-.
  8. 8. The compound of claim 7, wherein m = 0, a 2 = -O-and n is not 0.
  9. 9. The compound of claim 8, wherein n = 1.
  10. 10. The compound according to any one of claims 1 to 9, wherein R 1 is hydrogen.
  11. 11. A compound according to any one of claims 1 to 10, wherein R 3 is bromoethyl.
  12. 12. A compound according to any one of claims 1 to 11, wherein R 3 is 2-bromoethyl.
  13. 13. The compound of any one of claims 1 to 12, wherein R 2 is a heterocyclic aromatic ring having 5 or 6 members.
  14. 14. The compound of any one of claims 1 to 13, wherein R 2 is a heterocyclic aromatic ring having one or two heteroatoms.
  15. 15. The compound of claim 14, wherein the one or two heteroatoms are N or S.
  16. 16. A compound according to any one of claims 1 to 15, wherein when R 2 represents a 5 membered heterocyclic aromatic ring, p is 0.
  17. 17. A compound according to any one of claims 1 to 15, wherein when R 2 represents a 6 membered heterocyclic aromatic ring, p is 1.
  18. 18. A compound according to any one of claims 1 to 17, wherein R 2 is a thiazolyl ring, wherein Rz 2 is as defined in claim 1.
  19. 19. The compound of claim 18, wherein Rz 2 is selected from H and (C 1 -C 5 ) alkyl.
  20. 20. A compound according to any one of claims 1 to 15 and 17, wherein R 2 represents a pyridinyl ring, wherein Rz 2 is as defined in claim 1.

Description

Irreversible 17 beta-HSD 1 inhibitors Cross Reference to Related Applications This patent application claims the benefit of priority from U.S. provisional patent application No. 63/519,779, entitled "irreversible 17 beta-HSD 1 inhibitor," filed by the U.S. patent and trademark office on day 8 and 15 of 2023, the contents of which are incorporated herein by reference. Technical Field The present invention relates to the inhibition of 17β -HSD 1. In particular, the present invention provides compounds of formula (I) and compositions comprising the same, which provide potent, non-estrogenic and irreversible inhibitory effects on 17β -HSD 1. The invention further provides therapeutic methods and uses based on the novel compounds and compositions. Background Estradiol (E2) is produced in the ovaries mainly in pre-menopausal women. E2 reaches the target tissue via the endocrine pathway where it exerts its effect by interacting with the Estrogen Receptor (ER) α. After menopause, plasma E2 levels decreased to 1/10 of the E2 levels in pre-menopausal women. Then E2 is produced mainly in peripheral tissues (e.g. breast tissue, endometrium, adipose tissue, skin) from inactive precursors etc. These reactions occur in the peripheral tissues where active estrogens exert their effects in the presence of various steroid-producing enzymes (hydroxysteroid dehydrogenases, aromatases). Due to this endocrinological mechanism of E2 formation, E2 is present in higher concentrations in peripheral tissues, especially in estrogen dependent diseases, than in healthy tissues. In particular, the growth of many cancer cell lines is stimulated by locally increased E2 concentrations. Furthermore, the occurrence and progression of diseases such as endometriosis, leiomyomas, adenomyosis, menorrhagia, uterine bleeding and dysmenorrhea depend on significantly elevated E2 levels in the corresponding diseased tissue. Endometriosis is an estrogen dependent disease affecting about 5-10% of women of childbearing age, 35-50% of women suffering from abdominal pain and/or infertility have signs of endometriosis. The disease is defined as histologically confirmed ectopic endometrial glands and interstitial tissue. Such chronic diseases, which are prone to relapse, lead to pain of different intensity and different nature and, if present in the corresponding form, may also lead to infertility. Three macroscopic states are distinguished, endometriosis peritoneum, deep invasive endometriosis after peritoneum (including adenomyosis) and endometriosis ovarian cyst. 17 Beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD 1) converts estrone (E1) to E2, E2 being the most potent natural ligand for ERalpha. The enzyme also catalyzes the reduction of Dehydroepiandrosterone (DHEA) to 5-androsten-3 beta, 17 beta-diol (A5-diol), a weaker estrogen, but is particularly important after menopause. Thus, 17β -HSD1 inhibitors are attractive therapeutic agents for controlling estrogen dependent diseases such as breast cancer and endometriosis. Over the last three decades, tremendous efforts have been directed to designing effective inhibitors of this key steroid-producing enzyme, but lead candidates with very good inhibitory activity have not been recently reported. The presence of residual estrogenic activity associated with steroid inhibitors (typically built around the estra backbone) represents a major obstacle to their development. 16 Beta- (m-carbamoylbenzyl) estradiol (CC-156) has been reported to be a potent 17 beta-HSD 1 inhibitor. Despite its good inhibitory potency, it was found to stimulate MCF-7 and T-47D estrogen sensitive breast cancer cell lines in vitro, thereby greatly reducing their therapeutic potential. Many efforts have been made to overcome the undesirable residual estrogenic activity without negatively affecting the inhibitory effect. Among the new series of compounds developed in this field, the E2 derivative 3- { [ (16β,17β) -3- (2-bromoethyl) -17-hydroxyestra-1, 3,5 (10) -trien-16-yl ] methyl } benzamide (hereinafter also referred to as "PBRM") has been reported as the first non-estrogenic irreversible steroid 17β -HSD1 inhibitor (Trottier A. et al., "Insight into the mode of action and selectivity of PBRM, a covalent steroidal inhibitor of 17β-hydroxysteroid dehydrogenase type 1", Biochemical Pharmacology, 2017, 144, 149–161)： By identifying the covalent binding of PBRM to 17β -HSD1, it was demonstrated that the irreversible nature of the interaction (Maltais R. et al., "Discovery of a non-estrogenic irreversible inhibitor of 17β-hydroxysteroid dehydrogenase type 1 from 3-substitted-16β-(m-carbamoylbenzyl)-estradiol derivatives", 2014, J. Med. Chem., 55(7), 204-222;Li T. et al., "Combined biophysical chemistry reveals a new covalent inhibitor with low-reactivity alkyl halide", 2018, J. Phys. Chem. Lett. 9, 5275-5280). is particularly advantageous from a therapeutic point of view to increase the effectiveness and prolongation by this mechanism.