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EP-4741386-A1 - PYRIMIDINE COMPOUND, PREPARATION METHOD THEREFOR AND MEDICAL USE THEREOF

EP4741386A1EP 4741386 A1EP4741386 A1EP 4741386A1EP-4741386-A1

Abstract

Disclosed are a pyrimidine compound, a preparation method therefor and a medical use thereof. Specifically, disclosed are a compound represented by the general formula (SI), a preparation method therefor, a pharmaceutical composition containing said compound, and a use thereof as a ubiquitin-specific protease 1 (USP1) inhibitor, particularly a use thereof for treating or preventing cancer. The definitions of the groups in the general formula (SI) are the same as those in the description.

Inventors

  • WU, Maojiang
  • MENG, Zhi
  • Wang, Tielin

Assignees

  • Jiangsu Yahong Meditech Co., Ltd.
  • Asieris Pharmaceuticals (Shanghai) Co., Ltd.

Dates

Publication Date
20260513
Application Date
20240625

Claims (14)

  1. A compound of formula (SI), or a pharmaceutically acceptable salt, hydrate, solvate, isotope substitute or stereoisomer thereof, wherein, ring A and ring B are each independently selected from the group consisting of C 6-10 aryl, 5 to 10 membered heteroaryl, C 3-8 cycloalkyl and 3 to 8 membered heterocyclyl, and ring A and ring B are each independently and optionally substituted by one or more R 1 ; ring E is selected from the group consisting of C 6-10 aryl, 5 to 6 membered heteroaryl, C 6-10 aryl fused with 5 to 6 membered heterocyclyl, and C 6-10 aryl fused with 5 to 6 membered heteroaryl, and ring E is optionally substituted by one or more R 1 ; L is selected from the group consisting of a chemical bond, -O-, -S-, -C 1-6 alkylene-, -O-C 1-6 alkylene-, -C 1-6 alkylene-O-, -S-C 1-6 alkylene- and -C 1-6 alkylene-S-; R a and R b are each independently selected from the group consisting of H atom, - CN, C 1-6 alkyl, -OH, halogen, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy; or R a and R b together form an oxo, C 3-8 cycloalkyl or 3 to 8 membered heterocyclyl; wherein the C 1-6 alkyl is optionally substituted by one or more R 1 ; R 2 is selected from the group consisting of H atom, -OH, -CN, C 1-6 alkyl, -C 1-6 alkylene-C 6-10 aryl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl, C 3-8 cycloalkyl and 3 to 8 membered heterocyclyl, wherein the C 1-6 alkyl or -C 1-6 alkylene-C 6-10 aryl is optionally substituted by one or more R 1 ; R 3 is selected from the group consisting of H atom, -OH, -COOH, -NH 2 , -CN, halogen, C 1-6 alkyl, -S-C 1-6 alkyl, -S(O)-C 1-6 alkyl, -S(O) 2 -C 1-6 alkyl, phosphoryl, phosphonyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-O-, 3 to 8 membered heterocyclyl and -C 1-6 alkylene-C(O)-O-C 1-6 alkyl, wherein the - NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl, C 3-8 cycloalkyl and 3 to 8 membered heterocyclyl are each independently and optionally substituted by one or more R 1 ; R 4 is selected from the group consisting of H atom, -OH, -COOH, -NH 2 , -CN, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl, C 3-8 cycloalkyl and 3 to 8 membered heterocyclyl; R 1 at each occurrence is independently selected from the group consisting of D atom, -OH, -COOH, -NH 2 , -CN, oxo, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-O-, 3 to 8 membered heterocyclyl, -O-C 1-6 alkylene-O-C 1-6 alkyl, wherein the C 6-10 aryl, 5 to 10 membered heteroaryl, C 3-8 cycloalkyl and 3 to 8 membered heterocyclyl are each independently and optionally substituted by one or more substituents selected from the group consisting of D atom, - OH, -COOH, -NH 2 , -CN, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; and n is an integer from 0 to 8.
  2. The compound according to claim 1, wherein, ring B is C 6-10 aryl or 5 to 6 membered heteroaryl, and ring B is optionally substituted by one or more R 1 , R 1 is as defined in claim 1; specifically, ring B is selected from the group consisting of phenyl, naphthyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, thienyl, piperazinyl, naphthyl, pyrrolyl, pyridazinyl, triazolyl, tetrazolyl, and furanyl, and ring B is optionally substituted by one or more R 1 , R 1 is as defined in claim 1; more specifically, ring B is imidazolyl, and ring B is optionally substituted by one or more R 1 , R 1 is as defined in claim 1.
  3. The compound according to claim 1 or 2, being a compound of formula (SII), wherein, R 1a at each occurrence is independently selected from the group consisting of D atom, -OH, -COOH, -NH 2 , -CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, 5 to 6 membered heteroaryl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkyl-O- and 5 to 7 membered heterocyclyl; R 1b at each occurrence is independently selected from the group consisting of D atom, -OH, -COOH, -NH 2 , -CN, oxo, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, 5 to 6 membered heteroaryl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkyl-O- and 5 to 7 membered heterocyclyl; R 1c is selected from the group consisting of H atom, D atom, -OH, -COOH, -NH 2 , - CN, oxo, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, 5 to 6 membered heteroaryl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkyl-O- and 5 to 7 membered heterocyclyl; R 1d is selected from the group consisting of H atom, D atom, -OH, -COOH, -NH 2 , - CN, oxo, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 6-10 aryl, 5 to 6 membered heteroaryl, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, C 3-6 cycloalkyl-O- and 5 to 7 membered heterocyclyl; m is 0, 1 or 2; p is 0, 1 or 2; ring A, ring E, R a , R b , R 2 to R 4 and n are as defined in claim 1.
  4. The compound according to any one of claims 1 to 3, wherein, ring A is selected from the group consisting of C 6-10 aryl, C 3-8 cycloalkyl and 3 to 8 membered heterocyclyl, and ring A is optionally substituted by one or more R 1 , R 1 is as defined in claim 1; specifically, ring A is selected from the group consisting of phenyl, naphthyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, bicyclo[2.2.2]octanyl, 2-oxabicyclo[2.2.2]octanyl, cubanyl, piperidyl, pyranyl, pyrrolidinyl, piperazinyl and morpholinyl, and ring A is optionally substituted by one or more R 1b , R 1b is as defined in claim 3; more specifically, ring A is selected from the group consisting of phenyl, cyclohexyl, bicyclo[2.2.2]octanyl, 2-oxabicyclo[2.2.2]octanyl and cubanyl, and ring A is optionally substituted by one or more R 1b , R 1b is as defined in claim 3.
  5. The compound according to any one of claims 1 to 4, wherein, is selected from the group consisting of
  6. The compound according to any one of claims 1 to 5, wherein, ring E is C 6-10 aryl or 5 to 6 membered heteroaryl, and ring E is optionally substituted by one or more R 1 , R 1 is as defined in claim 1; specifically, ring E is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl and isoxazolyl, and ring E is optionally substituted by one R 1c and one R 1d , R 1c and R 1d is as defined in claim 3; more specifically, ring E is selected from the group consisting of pyridinyl, pyrimidinyl and imidazolyl, ring E is optionally substituted by one R 1c and one R 1d , R 1c and R 1d are as defined in claim 3; even more specifically, is selected from the group consisting of
  7. The compound according to any one of claims 1 to 6, wherein, n is 0 or 1; and/or R a and R b are each independently selected from the group consisting of H atom, - CN, C 1-6 alkyl, -OH and halogen; preferably, R a and R b are each independently H atom or C 1-6 alkyl; more preferably, both of R a and R b are H atom, or R a is H atom and R b is methyl.
  8. The compound according to any one of claims 1 to 7, wherein, R 2 is selected from the group consisting of H atom, -OH, -CN, C 1-6 alkyl, C 1-6 deuterated alkyl, C 2-6 alkynyl, -C 1-6 alkylene-C 6-10 aryl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl and 5 to 7 membered heterocyclyl, preferably, R 2 is selected from the group consisting of H atom, -CN, methyl and trideuteriomethyl; and/or R 3 is selected from the group consisting of H atom, -OH, -COOH, -NH 2 , -CN, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl-O-, 5 to 7 membered heterocyclyl and -C 1-6 alkylene-C(O)-O-C 1-6 alkyl; preferably, R 3 is methoxy or cyclopropyl-O-; and/or R 4 is selected from the group consisting of H atom, -OH, -COOH, -NH 2 , -CN, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; preferably, R 4 is H atom.
  9. The compound according to any one of claims 1 to 8, being selected from the group consisting of
  10. A method for preparing the compound according to claim 1, comprising: reacting a compound of formula (SIA) with a compound of formula (SIB) to obtain the compound of formula (SI); X is a leaving group selected from the group consisting of halogen, sulfonate, boronic acid and borate; and ring A, ring B, ring E, L, R a , R b , R 2 to R 4 and n are as defined in claim 1; or reacting a compound of formula (SIA) with a compound of formula (SIC) to obtain the compound of formula (SI); X is a leaving group selected from the group consisting of halogen, sulfonate, boronic acid and borate; and ring A, ring B, ring E, L, R a , R b , R 2 to R 4 and n are as defined in claim 1.
  11. The method according to claim 10, wherein the compound of formula (SI) is a compound of formula (SII), and the method comprises: reacting a compound of formula (SIIA) with a compound of formula (SIIB) to obtain the compound of formula (SII); X is a leaving group selected from the group consisting of halogen, sulfonate, boronic acid and borate; and ring A, ring B, ring E, R a , R b , R 2 to R 4 , R 1a , R 1b , R 1c , R 1d , m, n and p are as defined in claim 3; reacting a compound of formula (SIIA) with a compound of formula (SIIC) to obtain the compound of formula (SII); X is a leaving group selected from the group consisting of halogen, sulfonate, boronic acid and borate; and ring A, ring B, ring E, R a , R b , R 2 to R 4 , R 1a , R 1b , R 1c , R 1d , m, n and p are as defined in claim 3.
  12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 9, and one or more pharmaceutically acceptable excipients.
  13. A use of the compound according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 12 in the preparation of a medicament for treating or preventing diseases or conditions associated with inhibition of ubiquitin-specific protease 1 (USP1).
  14. A use of the compound according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 12 in the preparation of a medicament for treating or preventing a cancer, specifically, the cancer being selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), colon cancer, bladder cancer, osteosarcoma, ovarian cancer, skin cancer, and breast cancer.

Description

FIELD OF THE INVENTION The present invention relates to a class of compounds with an inhibitory effect on USP1 and compositions comprising the same, and uses thereof in the preparation of a medicament for treating USP1 enzyme-related diseases. Specifically, the present invention relates to a compound of formula (SI) or a pharmaceutically acceptable salt, hydrate, solvate, isotope substitute or stereoisomer thereof. BACKGROUND OF THE INVENTION Ubiquitination, as a dynamic and reversible process, involves a family of deubiquitinases (DUBs). There are approximately 100 DUBs in a human, which can be divided into a cysteine protease family and a metalloproteinase family. Among them, the cysteine protease family mainly includes ubiquitin-specific proteases (USPs), ubiquitin carboxy-terminal hydrolases (UCHs), Machado-Josephin domain proteases (MJDs), MINDY proteases (MINDYs), and ovarian tumor domain proteases (OTUs). The USPs family is the one representing the greatest quantity among known deubiquitinases, with over 50 types encoded by human genes. It plays a role in various physiological functions such as cell cycle, signal transduction, DNA damage repair, chromosome translocation, and gene transcription, by regulating protease substrates. USP1 belongs to the USP subfamily of DUBs and does not exhibit significant activity on its own. However, it obtains complete enzymatic activity by binding to UAF1 to form a heterodimer complex (USP1/UAF1), and may regulate cellular targets in multiple pathways associated with cancer. For example, the USP1/UAF1 complex enables to deubiquitinate proliferating cell nuclear antigen (PCNA) mono-ubiquitinated by a key protein during translesion synthesis (TLS), to prevent excessive repair thereof, and enables to deubiquitinate fanconi anemia complementation group D2 (FANCD2) mono-ubiquitinated by a key protein in the fanconi anemia (FA) pathway, to prevent improper TLS repair in cells, thereby ensuring genomic stability, etc. These two DNA damage response (DDR) pathways are critical pathways for repairing DNA damage induced by a DNA crosslinker such as cisplatin, mitomycin, and ultraviolet radiation. USP1 can also interact with ID proteins and so on, so as to stabilize their expression in cells through deubiquitination. For example, in osteosarcoma cells, USP1 can deubiquitinate ID1, ID2, and ID3 to promote cell proliferation, and inhibition of USP1 can increase the sensitivity of osteosarcoma cells to chemotherapy. In addition, there are studies to demonstrate that USP1 is closely related to development of resistance to various drugs for tumor treatment. For example, in non-small cell lung cancer (NSCLC) cells with the resistance to cisplatin, USP1 has a high level of expression, and knock down of USP1 can significantly enhance cell sensitivity to cisplatin. In breast cancer cells, USP1 is highly expressed, promotes the proliferation of breast cancer cells and is closely related to the poor prognosis of breast cancer. As reported in the literature (J. Med. Chem. 2014, 57, 8099-8110, Synthesis and Structure-Activity Relationship Studies of N-Benzyl-2-phenylpyrimidin-4-amine Derivatives as Potent USP1/UAF1 Deubiquitinase Inhibitors with Anticancer Activity against Nonsmall Cell Lung Cancer), the compounds such as USP1 inhibitor ML323 can be used for non-small cell lung cancer. As reported in the literature (Cui S-Z, Lei Z-Y, Guan T-P, et al. Targeting USP1-dependent KDM4A protein stability as a potential prostate cancer therapy. Cancer Sci. 2020;00:1-15), USP1 inhibitors are used as potential therapeutic drugs for prostate cancer. In summary, USP1 is expected to become a hot target for treating various cancers and other diseases. SUMMARY OF THE INVENTION The present invention provides a compound of formula (I'), or a pharmaceutically acceptable salt, hydrate, solvate, isotope substitute or stereoisomer thereof, wherein, R is selected from the group consisting of C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 hydroxyalkyl, C6-10 aryl, C6-10 aryl fused with 5 to 10 membered heteroaryl, and the above groups are each independently and optionally substituted by one or more R1;ring A and ring B are each independently selected from the group consisting of C6-10 aryl, 5 to 10 membered heteroaryl, C3-8 cycloalkyl and 3 to 8 membered heterocyclyl, and ring A and ring B are each independently and optionally substituted by one or more R1;L is selected from the group consisting of a chemical bond, -O-, -S-, -C1-6 alkylene-, -O-C1-6 alkylene-, -C1-6 alkylene-O-, -S-C1-6 alkylene- and -C1-6 alkylene-S-;Ra and Rb are each independently selected from the group consisting of H atom, - CN, C1-6 alkyl, -OH, halogen, C2-6 alkenyl, C2-6 alkynyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy; or Ra and Rb together form an oxo, C3-8 cycloalkyl or 3 to 8 membered heterocyclyl; wherein the C1-6 alkyl is optionally substituted by one or more R1;R2 is selecte