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EP-4737452-A1 - NOVEL PYRIMIDINE DERIVATIVES

EP4737452A1EP 4737452 A1EP4737452 A1EP 4737452A1EP-4737452-A1

Abstract

The present invention provides a compound defined by chemical formula 1 or a tautomer thereof, and pharmaceutically acceptable salts thereof. The compound of the present invention can inhibit the activity of ubiquitin-specific protease 1.

Inventors

  • LEE, KWANG-OK
  • LEE, HO-JEONG
  • KIM, SUNKYU
  • KIM, JIHYE
  • PARK, Sejeong
  • LEE, SANGHOON
  • YOO, Kiwoong
  • YOO, Hyerim

Assignees

  • Aigen Sciences Inc.

Dates

Publication Date
20260506
Application Date
20240628

Claims (10)

  1. A compound of Chemical Formula 1 or a tautomer thereof and a pharmaceutically acceptable salt thereof: in Chemical Formula 1, R 1 and R 2 are each independently hydrogen, deuterium, halogen, C 1-4 alkyl, -O-C 1-4 alkyl, -CN or -NHC 1-4 alkyl; are rings each independently selected from the group consisting of substituted or non-substituted C 6-10 aryl, substituted or non-substituted 5- to 6-membered heteroaryl, substituted or non-substituted C 5-10 cycloalkyl and substituted or non-substituted cubanyl; wherein the substituted 5- to 6-membered heteroaryl represents a ring in which at least one of the ring hydrogens is substituted with a functional group each independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl substituted with deuterium, haloC 1-6 alkyl, C 3-8 cycloalkyl, -OC 1-4 alkyl, -OC 1-4 alkyl substituted with deuterium, haloC 1-4 alkyloxy and halogen, wherein the substituted C 6-10 aryl, substituted C 5-10 cycloalkyl, substituted C 5-10 cycloalkyl and substituted cubanyl represent rings in which at least one of the ring hydrogens is substituted with a functional group each independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl substituted with deuterium, haloC 1-6 alkyl, C 3-8 cyclo alkyl, -OC 1-4 alkyl, -OC 1-4 alkyl substituted with deuterium, haloC 1-4 alkyloxy, halogen, 5- to 6-membered heteroaryl and functionality bearing 5- to 6-membered heteroaryl, wherein the functionality bearing 5- to 6-membered heteroaryl represents a heteroaryl ring in which one or more of the ring hydrogens thereof is substituted with C 1-6 alkyl, haloC 1-6 alkyl or C 3-8 cycloalkyl.
  2. The compound according to claim 1, wherein the compound or a tautomer thereof and a pharmaceutically acceptable salt thereof has a structure of Chemical Formula 2: in Chemical Formula 2, R 1 and R 2 are each independently hydrogen, deuterium, halogen, C 1-4 alkyl, -O-C 1-4 alkyl, -CN or -NHC 1-4 alkyl; is selected from the group consisting of substituted or non-substituted C 6-10 aryl, substituted or non-substituted 5- to 6-membered heteroaryl, substituted or non-substituted C 5-10 cycloalkyl and substituted or non-substituted cubanyl; is selected from the group consisting of substituted or non-substituted phenylene, substituted or non-substituted 5- to 6-membered heteroarylene, substituted or non-substituted C 5-10 bicycloalkylene, substituted or non-substituted adamantylene, substituted or non-substituted norbornenyl and substituted or non-substituted cubanylene; is selected from substituted or non-substituted phenyl and substituted or non-substituted 5- to 6-membered heteroarylene; wherein the substituted C 6-10 aryl, substituted phenylene, substituted 5- to 6-membered heteroaryl, substituted 5- to 6-membered heteroarylene, substituted C 5-10 cycloalkyl, substitute C 5-10 bicycloalkyl, substituted C 5-10 bicycloalkylene, substituted adamantylene, substituted norbornenylene, substituted cubanyl, and substituted cubanylene represent that one or more hydrogen is substituted with a functional group each independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl substituted with deuterium, haloC 1-6 alkyl, C 3-8 cycloalkyl, -OC 1-4 alkyl, -OC 1-4 alkyl substituted with deuterium, haloC 1-4 alkyloxy and halogen.
  3. The compound according to claim 2, wherein is substituted pyrimidine, substituted pyrazole, or substituted pyridine.
  4. The compound according to claim 2, wherein the C 5-10 bicycloalkylene is bicyclo[1.1.1]pentanylene, bicyclo[2.2.1]heptanylene, bicyclo[2.1.1]hexanylene or bicyclo[2.2.2]octanylene.
  5. The compound according to claim 2, wherein the compound or a tautomer thereof has a structure of Chemical Formula 3: in Chemical Formula 3, R 1 and R 2 are each independently hydrogen, deuterium, halogen, C 1-4 alkyl, -O-C 1-4 alkyl, -CN or -NHC 1-4 alkyl; is selected from the group consisting of substituted or non-substituted phenylene, substituted or non-substituted 5- to 6-membered heteroarylene, substituted or non-substituted C 5-10 bicycloalkylene, substituted or non-substituted adamantylene, substituted or non-substituted norbornenyl and substituted or non-substituted cubanylene; Q 1 to Q 5 are so selected from the group consisting of C, CH, N and NH as to form any one of the rings represented in Chemical Formula 4, wherein m is an integer of 0 to 3, and R 3 is, in each case, a substituent independently selected for each occurrence leading up to the value of m, from the group consisting of C 1-6 alkyl, C 1-6 alkyl substituted with deuterium, haloC 1-6 alkyl, C 3-8 cycloalkyl, -OC 1-4 alkyl, -OC 1-4 alkyl substituted with deuterium, haloC 1-4 alkyloxy, and halogen, is a ring selected from Chemical Formula 5; wherein n is an integer of 0 to 5, l is an integer of 0 to 4, p is an integer of 0 to 3, R 4 is, in each case, a substituent independently selected, for each occurrence leading up to the respective value of n, l or p , from the group consisting of C 1-6 alkyl, C 1-6 alkyl substituted with deuterium, haloC 1-6 alkyl, C 3-8 cycloalkyl, -OC 1-4 alkyl, -OC 1-4 alkyl substituted with deuterium, haloC 1-4 alkyloxy and halogen, and wherein the substituted phenylene, substituted 5- to 6-membered heteroarylene, substituted C 5-10 bicycloalkylene, substituted adamantylene, substituted norbornenyl and substituted cubanylene represent that one or more hydrogen is substituted with a functional group each independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkyl substituted with deuterium, haloC 1-6 alkyl, C 3-8 cycloalkyl, -OC 1-4 alkyl, -OC 1-4 alkyl substituted with deuterium, haloC 1-4 alkyloxy and halogen.
  6. The compound according to claim 5, wherein is non-substituted phenylene or phenylene substituted with halogen.
  7. The compound according to claim 5, wherein the compound or tautomer thereof has a structure of Chemical Formula 6: in Chemical Formula 6, X 1 and X 2 are each independently CH or N; X 3 and X 4 are each independently C or N; Z 1 , Z 2 , Z 4 and Z 5 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted with deuterium, haloC 1-6 alkyl, C 3-8 cycloalkyl, -OC 1-4 alkyl, -OC 1-4 alkyl substituted with deuterium, haloC 1-4 alkyloxyl and halogen, Z 3 is a substituent each independently selected at each occurrence up to l times from the group consisting of C 1-6 alkyl, C 1-6 alkyl substituted with deuterium, haloC 1-6 alkyl, C 3-8 cycloalkyl, -OC 1-4 alkyl, -OC 1-4 alkyl substituted with deuterium, haloC 1-4 alkyloxy and halogen, and l is an integer of 0 to 4.
  8. The compound according to claim 7, wherein Z 3 is hydrogen or halogen, and Z 4 and Z 5 are each independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl or haloC 1-6 alkyl.
  9. A compound selected from the group consisting of the following compounds, stereoisomer, tautomer, solvate or a pharmaceutically acceptable salt thereof: (2-(2-cyclopropyl-6-methoxyphenyl)-4-((4-(1-methyl-4-(trifluoromethyl)-1 H -imidazol-2-yl)benzyl)amino)pyrimidin-5-yl)dimethylphosphine oxide; (4'-cyclopropyl-6'-methoxy-4-((4-(1-methyl-4-(trifluoromethyl)-1 H- imidazol-2-yl)benzyl)amino)-[2,5'-bipyrimidine]-5-yl)dimethylphosphine oxide; (2-(1-isopropyl-4-methyl-1H-pyrazole-5-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1 H -imidazol-2-yl)benzyl)amino)pyrimidin-5-yl)dimethylphosphine oxide; (2-(2-isopropylpyridine-3-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1 H- imidazol-2-yl)benzyl)amino)pyrimidin-5-yl)dimethylphosphine oxide; (4'-cyclopropyl-6'-(methoxy- d 3 )-4-((4-(1-methyl-4-(trifluoromethyl)-1 H- imidazol-2-yl)benzyl)amino)-[2,5'-bipyrimidine]-5-yl)dimethylphosphine oxide; (2-(2-(difluoromethoxy)pyridine-3-yl)-4-((4-(1-methyl-4-(trifluoromethyl)-1 H -imidazol-2-yl)benzyl)amino)pyrimidin-5-yl)dimethylphosphine oxide; (4'-cyclopropyl-4-((3-fluoro-4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)amino)-6'-methoxy-[2,5'-bipyrimidine]-5-yl)dimethylphosphine oxide; (4'-cyclopropyl-4-((4-(1-cyclopropyl-4-(trifluoromethyl)-1 H -imidazol-2-yl)benzyl)amino)-6'-methoxy-[2,5'-bipyrimidine]-5-yl)dimethylphosphine oxide; (4'-cyclopropyl-6'-methoxy-4-((4-(5-methyl-3-(trifluoromethyl)-1 H- pyrazole-1-yl)benzyl)amino)-[2,5'-bipyrimidine]-5-yl)dimethylphosphine oxide; (4'-cyclopropyl-6'-methoxy-4-(((4-(1-methyl-4-(trifluoromethyl)-1 H- imidazol-2-yl)bicyclo[2.2.2]octan-1-yl)methyl)amino)-[2,5'-bipyrimidine]-5-yl)dimethylphosphine oxide; (4'-cyclopropyl-6'-methoxy-4-((((1 s ,2 R ,3 s ,4 r ,5 S ,6 r ,7 R ,8 S )-4-(1-methyl-4-(trifluoromethyl)-1 H -imidazol-2-yl)cuban-1-yl)methyl)amino)-[2,5'-bipyrimidine]-5-yl)dimethylphosphine oxide; (4'-cyclopropyl-4-((4-(1-isopropyl-4-(trifluoromethyl)-1 H -imidazol-2-yl)benzyl)amino)-6'-methoxy-[2,5'-bipyrimidine]-5-yl)dimethylphosphine oxide; (4'-cyclopropyl-4-((3-fluoro-4-(1-isopropyl-4-(trifluoromethyl)-1 H- imidazol-2-yl)benzyl)amino)-6'-methoxy-[2,5'-bipyrimidine]-5-yl)dimethylphosphine oxide; (4'-cyclopropyl-4-((3-fluoro-4-(5-methyl-3-(trifluoromethyl)-1 H- pyrazole-1-yl)benzyl)amino)-6'-methoxy-[2,5'-bipyrimidine]-5-yl)dimethylphosphine oxide; (4'-cyclopropyl-4-((4-(5-isopropyl-3-(trifluoromethyl)-1 H -pyrazole-1-yl)benzyl)amino)-6'-methoxy-[2,5'-bipyrimidine]-5-yl)dimethylphosphine oxide; (4'-cyclopropyl-4-((3-fluoro-4-(5-isopropyl-3-(trifluoromethyl)-1 H- pyrazole-1-yl)benzyl)amino)-6'-methoxy-[2,5'-bipyrimidine]-5-yl)dimethylphosphine oxide; (4'-cyclopropyl-4-((4-(5-cyclopropyl-3-(trifluoromethyl)-1 H -pyrazole-1-yl)benzyl)amino)-6'-methoxy-[2,5'-bipyrimidine]-5-yl)dimethylphosphine oxide; and (4'-cyclopropyl-4-((4-(5-cyclopropyl-3-(trifluoromethyl)-1 H -pyrazole-1-yl)-3-fluorobenzyl)amino)-6'-methoxy[2,5'-bipyrimidine]-5-yl)dimethylphosphine oxide.
  10. A pharmaceutical composition for treating cancer, comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable excipient.

Description

[TECHNICAL FIELD] The present invention relates to small organic compounds exhibiting an inhibitory activity against biological enzymes. In addition, the present invention relates to a pharmaceutical composition including the small organic compounds. [BACKGROUND ART] Ubiquitin is a small protein composed of 76 amino acids and plays an important role in the regulation of intracellular protein function. Ubiquitination and de-ubiquitination are enzymatically mediated processes in which ubiquitin is covalently attached to and removed from target protein, respectively. Ubiquitination and de-ubiquitination are involved in important functions such as the regulation of the cell cycle, apoptosis, the marking of membrane proteins like receptors for removal, and the regulation of DNA transcription and repair. Proteins in cells become targets for proteasomal degradation when they are tagged with three or more ubiquitin molecules. De-ubiquitination serves to recycle ubiquitin and restores the function of proteins from which ubiquitin has been removed. There are approximately 95 distinct deubiquitinating enzymes present in human cells. Among these, ubiquitin-specific protease 1 (USP1) is known to be involved in the repair of DNA damage caused by agents that induce DNA crosslinks, such as ionizing radiation, ultraviolet light, and cisplatin. USP1 forms a complex with USP1 associated factor 1 (UAF1) and is activated by UAF1 (Cohn et al., 2007, Mol Cell 28:786-797). Ubiquitin-specific protease 1 (USP1) is known to be overexpressed in various cancer cells. Therefore, selective inhibition of USP1 can lead to cancer cell death by suppressing DNA damage repair in these cells. Recently, USP1 has been identified through CRISPR-Cas9 screening as a novel synthetic lethality target in BRCA1-mutant cancers, and USP1 has also been shown to serve as a synthetic lethal target in BRCA2-mutant cancers. Furthermore, USP1 inhibitors have been reported to exhibit potent anticancer activity against BRCA-mutant cancers when used in combination with PARP inhibitors. Additionally, recent studies have shown that USP1 inhibitors demonstrate therapeutic potential for diabetes by suppressing pancreatic beta cell apoptosis. USP1 plays a critical role in adipogenesis by regulating the ubiquitination of the transcription factor C/EBPβ, and selective inhibitor of USP1 shows its potential as a treatment for metabolic disorders including obesity. Therefore, USP1 inhibitors could be developed as therapeutic agents not only for cancer including BRCA-mutant cancers, but also for metabolic diseases such as diabetes and obesity. [DISCLOSURE] [TECHNICAL PROBLEM] The technical object of the present invention is to provide a novel small organic molecule compound capable of inhibiting an activity of USP1 as a deubiquitinating enzyme. [TECHNICAL SOLUTION] In one aspect of the present invention, a compound defined by chemical formula 1 having an inhibitory activity against USP1 or a tautomer thereof, and a pharmaceutically acceptable salt thereof are provided. In Chemical Formula 1, R1 and R2 are each independently hydrogen, deuterium, halogen, C1-4 alkyl, -O-C1-4 alkyl, -CN or -NHC1-4 alkyl; are rings independently selected from the group consisting of substituted or non-substituted C6-10 aryl, substituted or non-substituted 5- to 6-membered heteroaryl, substituted or non-substituted C5-10 cycloalkyl and substituted or non-substituted cubanyl;wherein the substituted 5- to 6-membered heteroaryl represents a ring in which at least one hydrogen of the ring is substituted with a functional group independently selected from the group consisting of C1-6 alkyl, C1-6 alkyl substituted with deuterium, haloC1-6 alkyl, C3-8 cycloalkyl, -OC1-4 alkyl, -OC1-4 alkyl substituted with deuterium, haloC1-4 alkyloxy and halogen, andwherein the substituted C6-10 aryl, substituted C5-10 cycloalkyl, substituted C5-10 cycloalkyl and substituted cubanyl represents a ring in which at least one hydrogen of the ring is substituted with a functional group independently selected from the group consisting of C1-6 alkyl, C1-6 alkyl substituted with deuterium, haloC1-6 alkyl, C3-8 cycloalkyl, -OC1-4 alkyl, -OC1-4 alkyl substituted with deuterium, haloC1-4 alkyloxy, halogen, 5- to 6-membered heteroaryl, and functionality bearing 5- to 6-membered heteroaryl,wherein the functionality bearing 5- to 6-membered heteroaryl represents a heteroaryl ring in which one or more of the ring hydrogens thereof is substituted with C1-6 alkyl, haloC1-6 alkyl or C3-8 cycloalkyl. In one embodiment of the present invention, a compound defined by Chemical Formula 2 or a tautomer thereof and a pharmaceutically acceptable salt thereof are provided. In Chemical Formula 2, R1 and R2 are each independently hydrogen, deuterium, halogen, C1-4 alkyl, -O-C1-4 alkyl, -CN or -NHC1-4 alkyl; is selected from the group consisting of substituted or non-substituted C6-10 aryl, substituted or non-substituted 5- to 6-membered heteroar