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WO2022199652A1 - Composés hétéroaryle-pyrimidine à cinq chaînons utilisés en tant qu'inhibiteurs d'usp1 et leur utilisation - Google Patents

Composés hétéroaryle-pyrimidine à cinq chaînons utilisés en tant qu'inhibiteurs d'usp1 et leur utilisation Download PDF

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Publication number
WO2022199652A1
WO2022199652A1 PCT/CN2022/082686 CN2022082686W WO2022199652A1 WO 2022199652 A1 WO2022199652 A1 WO 2022199652A1 CN 2022082686 W CN2022082686 W CN 2022082686W WO 2022199652 A1 WO2022199652 A1 WO 2022199652A1
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Prior art keywords
methyl
optionally substituted
pyrimidine
benzyl
imidazol
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Sui Xiong Cai
Ye Edward Tian
Xiaozhu WANG
Letian ZHANG
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Impact Therapeutics Shanghai Inc
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Impact Therapeutics Shanghai Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • This disclosure is in the field of medicinal chemistry.
  • the disclosure relates to five-membered heteroaryl pyrimidine compounds, and the use of these compounds as therapeutically effective USP1 inhibitors and anticancer drugs.
  • Ubiquitin is a 76 amino acid long peptide, which is covalently attached to proteins to modulate their stability, localization, or function.
  • the degradation of a target protein by ubiquitination is a multistep process.
  • the ubiquitination is acted through the sequential action involved in enzyme such as a ubiquitin activating enzyme (E1) , a ubiquitin-conjugating enzyme (E2) , and a ubiquitin protein-ligase (E3) .
  • E1 ubiquitin activating enzyme
  • E2 a ubiquitin-conjugating enzyme
  • E3 a ubiquitin protein-ligase
  • the balance of ubiquitination and deubiquitination is responsible for degree of intracellular protein ubiquitination.
  • Deubiquitinating enzymes greatly contribute to deubiquitination, and DUBs act on ubiquitinated substrates to catalyze the removal of ubiquitin moieties.
  • the ubiquitination status is a dynamic regulatory mechanism.
  • Ubiquitination also plays a regulatory role in gene expression, cell cycle progression, apoptosis, DNA repair and cell motility, among others (Garc ⁇ a-Sanstisteban (2013) Mol Cancer 12: 91-103) .
  • USP1 ubiquitin-specific protease 1
  • FA Fanconi Anemia
  • TLS Translesion Synthesis
  • USP1 inhibitors can be used in cancer therapy alone or in combination with other DNA damaging agents.
  • the inhibitions of USP1 can impair DNA damage repair pathways.
  • One of the hallmarks of tumor cells is genetic instability, which cause tumor cells more sensitive to the DNA damage repairing.
  • USP1 inhibitor not only can be used as anticancer drugs but also can increase sensitivity to radiotherapy. Further support for advancing USP1 inhibitors show that USP1 inhibitor also can be used to treat cancer by synthetic lethal mechanism in combination with targeted drugs, like PARP inhibitors.
  • the disclosure provides substituted five-membered heteroaryl pyrimidine compounds and analogues as represented in Formulae I and II, which can be used as USP1 inhibitors.
  • compositions comprising an effective amount of the compound of Formulae I and II for the treatment of cancer.
  • the pharmaceutical composition may also contain one or more pharmaceutically acceptable carriers or diluents, for the treatment of cancer.
  • the pharmaceutical composition may also contain at least one known anticancer drug or pharmaceutically acceptable salts thereof, for the treatment of cancer.
  • the disclosure is also directed to methods for the preparation of novel compounds of Formulae I and II.
  • a 1 and A 2 are each independently N or CR 1 ;
  • R 1 is hydrogen, halogen, cyano, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted cycloalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, or an optionally substituted amino;
  • Q is selected from a group consisting of NR 2 , O and S;
  • each R 2 is independently selected from a group consisting of hydrogen, an optionally substituted alkyl, an optionally substituted C 3-8 cycloalkyl, an optionally substituted alkenyl and an optionally substituted alkynyl;
  • R 3 and R 4 are each independently selected from a group consisting of hydrogen, halogen, cyano, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted cycloalkyl, an optionally substituted alkenyl and an optionally substituted alkynyl; or R 3 and R 4 form a ring together with the attached C;
  • D 1 , D 2 , D 3 and D 4 are each independently N or CR 5 ;
  • R 5 is hydrogen, halogen, cyano, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted cycloalkyl, an optionally substituted alkenyl or an optionally substituted alkynyl;
  • Cy 1 is an optionally substituted aryl or an optionally substituted heteroaryl
  • Cy 2 is an optionally substituted acyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted carbocyclic group, or an optionally substituted heterocyclic group.
  • an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted alkenyl and an optionally substituted alkynyl each are optionally substituted by 1-5 substituents selected from a group consisting of halogen, hydroxyl, NR a R b , C 1-4 alkoxy, halogenated C 1-4 alkoxy, carboxyl and cyano, wherein the said R a and R b are independently H or C 1-4 alkyl.
  • the said groups can be optionally substituted by 1-5 substituents selected from a group consisting of halogen, hydroxyl and NR a R b , wherein the said R a and R b are independently H or C 1-4 alkyl.
  • an optionally substituted carbocyclic group, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclic group each are optionally substituted by 1-5 substituents selected from the group of halogen, hydroxyl, NR a R b , C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkyl substituted by hydroxyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, carboxyl, C 3-8 cycloalkyl, an optionally substituted heteroaryl, an optionally substituted heterocylic groupand cyano, wherein the said R a and R b are independently H or C 1-4 alkyl.
  • the heteroaryl and the heterocylic group as a substituent of the optionally substituted carbocyclic group, aryl, heteroaryl and heterocyclic group can be optionally substituted by 1-3 substituents selected from a group consisting of halogen, hydroxyl, C 1-4 alkyl and halogenated C 1-4 alkyl.
  • the said optionally substituted carbocyclic group, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic group can be optionally substituted by 1-5 substituents selected from a group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, C 3-6 cycloalkyl, a heteroaryl optionally substituted by C 1-4 alkyl, a heterocylic group optionally substituted by C 1-4 alkyl, cyano, hydroxyl and NR a R b , wherein the said R a and R b are independently H or C 1-4 alkyl.
  • the optionally substituted amino may be optionally substituted with 1 or 2 substituents selected from C 1-4 alkyl.
  • the optionally substituted acyl group described in Formula I is an optionally substituted C 1-6 acyl group.
  • the said optionally substituted acyl group may be optionally substituted by 1-3 substituents selected from a group consisting of halogen, optionally substituted amino, hydroxy, C 1-4 alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic group and optionally substituted cycloalkyl.
  • the said optionally substituted acyl group is NR a R b , wherein, the said R a and R b are independently H or C 1-4 alkyl.
  • the said aryl, heteroaryl, heterocyclyl or cycloalkyl as a substituent may be optionally substituted by 1-3 substituents selected from a group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, hydroxyl and NR a R b , wherein the said R a and R b are independently H or C 1-4 alkyl.
  • the carbocyclic group described in Formula I is a cycloalkyl group, preferably C 3-8 cycloalkyl, more preferably C 3-6 cycloalkyl.
  • the aryl group is phenyl or naphthyl.
  • the heteroaryl group is a 5-10 membered nitrogen-containing heteroaryl group, which contains nitrogen and optional oxygen.
  • the heteroaryl group is selected from a group consisting of pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oxadiazolyl and oxazolyl, etc.
  • the heterocyclic group is a 4-10 membered nitrogen-containing heterocyclic group; preferably, the heterocyclic group is seleted from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, etc.
  • a 1 and A 2 are independently N and CR 1 , wherein R 1 is preferably H, C 1-3 alkyl and amino substituted with C 1- 3 alkyl.
  • R 1 is preferably H, C 1-3 alkyl and amino substituted with C 1- 3 alkyl.
  • a 1 is CH
  • a 2 is N or CH.
  • both of A 1 and A 2 are CH.
  • the R 2 in Q is selected from a group consisting of H, C 1-6 alkyl and C 3-8 cycloalkyl, preferably, the R 2 in Q is H or C 1-3 alkyl.
  • Q is NH, N-C 1-3 alkyl, O or S.
  • Q is NH or N-C 1-3 alkyl.
  • the fused bicyclic ring containing A 1 , A 2 and Q is selected from the following groups:
  • R 2 is H or C 1-3 alkyl.
  • the R 2 in B is selected from a group consisting of H, C 1-6 alkyl and C 3-8 cycloalkyl, preferably, the R 2 in B is H or C 1-3 alkyl.
  • R 3 and R 4 are each independently selected from a group consisting of H and C 1-4 alkyl. In some embodiments, R 3 is H and R 4 is H or C 1-4 alkyl.
  • B is CH 2 , C (CH 3 ) H, NH, N-C 1-3 alkyl or O.
  • D 1 , D 2 , D 3 and D 4 are CR 5 .
  • R 5 is hydrogen, halogen, an optionally substituted alkyl, or an optionally substituted alkoxy; preferably, the said optionally substituted alkyl or the optionally substituted alkoxy is an optionally substituted C 1-4 alkyl or an optionally substituted C 1-4 alkoxy; preferably, the said alkyl or alkoxy is substituted by 1-5 substituents selected from a group consisting of halogen, hydroxyl and NR a R b , wherein the said R a and R b are independently H or C 1-4 alkyl.
  • each R 5 is independently H, halogen, C 1-4 alkyl or C 1-4 alkoxy.
  • all of D 1 , D 2 , D 3 and D 4 are CH. In some embodiments, D 1 , D 2 , D 3 and D 4 are independently N or CH. In some preferred embodiments, only 2 of D 1 , D 2 , D 3 and D 4 are N.
  • the aryl or heteroaryl containing D 1 , D 2 , D 3 and D 4 is an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted pyrimidinyl or an optionally substituted pyrazinyl; when the aryl or heteroaryl is substituted, the substituents are selected from the groups described in R 5 , including but not limited to halogen, C 1-4 alkyl or C 1-4 alkoxy optionally substituted with 1-5 substituents selected from a group consisting of halogen, hydroxyl and NR a R b , wherein the said R a and R b are independently H or C 1-4 alkyl.
  • Cy 1 is an optionally substituted 6-14 membered aryl group or an optionally substituted 5-10 membered heteroaryl group.
  • the said 5-10 membered heteroaryl group is a nitrogen-containing monocyclic heteroaryl group.
  • Cy 1 is an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted pyridazinyl, an optionally substituted pyrazolyl or an optionally substituted imidazolyl.
  • Cy 1 when Cy 1 is substituted, its substituent (s) are selected from a group consisting of halogen, an optionally substituted C 1-3 alkyl, an optionally substituted C 1-3 alkoxy, an optionally substituted C 3-6 cycloalkyl, an optionally substituted amino, and cyano; preferably, each of the said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl are optionally substituted by 1-5 substituents selected from a group consisting of halogen, hydroxyl and C 1-4 alkyl substituted with NR a R b , wherein the said R a and R b are independently H or C 1-4 alkyl; the said amino is optionally substituted with 1 or 2 C 1-4 alkyl.
  • substituent (s) are selected from a group consisting of halogen, an optionally substituted C 1-3 alkyl, an optionally substituted C 1-3 alkoxy, an optionally substituted C 3-6 cycloalkyl,
  • Cy 1 when Cy 1 is substituted, the number of substituents is 1-3, preferably 1-2. More preferably, Cy 1 is a 6-membered ring with at least one substituent located ortho to the ring atom to which Cy 1 is attached to the rest of the compound. In one embodiment, Cy 1 is substituted with two substituents and both are located at the said ortho position.
  • Cy 2 is an optionally substituted heteroaryl group, preferably an optionally substituted 5-10 membered nitrogen-containing heteroaryl group, more preferably a 5-membered nitrogen-containing heteroaryl group.
  • the heteroaryl group contains 1-3 nitgrogen atom and optional one oxygen atom.
  • Cy 2 is an optionally substituted imidazolyl, an optionally substituted pyrazolyl, an optionally substituted oxadiazolyl, an optionally substituted oxazolyl or an optionally substituted triazolyl.
  • Cy 2 When Cy 2 is substituted, its substituent (s) are selected from a group consisting of halogen, cyano, optionally substituted C 1-3 alkyl, optionally substituted C 1-3 alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-3 acyl or optionally substituted heterocyclic group.
  • Cy 2 is imidazolyl, pyrazolyl, triazolyl or oxadiazolyl may be optionally substituted by 1-3 substituents selected from a group consisting of cyano, optionally substituted C 1-3 alkyl, optionally substituted C 3-6 cycloalkyl and optionally substituted heterocyclic group.
  • the said C 1-3 alkyl, C 1-3 alkoxy, C 1-3 acyl and C 3-6 cycloalkyl are independently optionally substituted by 1-5 substituents selected from a group consisting of halogen, hydroxyl and C 1-4 alkyl substituted with NR a R b , wherein the said R a and R b are independently H or C 1-4 alkyl.
  • the said heterocyclic group is optionally substituted by 1-5 substituents selected from a group consisting of halogen, hydroxyl and C 1-4 alkyl.
  • the heterocyclic group is a 4-6 membered nitrogen-containing heterocyclic group, such as azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl, optionally substituted by 1-3 C 1-3 alkyl.
  • Cy 2 is an optionally substituted C 1-6 acyl group, which is optionally substituted by 1-3 substituents selected from a group consisting of halogen, optionally substituted amino, hydroxyl, C 1-4 alkoxy, optionally substituted 6-14 membered aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclic group and optionally substituted C 3-8 cycloalkyl.
  • the said aryl is phenyl;
  • the said 5-10 membered heteroaryl group is a nitrogen-containing heteroaryl group, such as pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, etc;
  • the said 4-10 membered heterocyclic group is a nitrogen-containing heterocyclic group, such as pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, etc;
  • the said substituted amino group is NR a R b , wherein, R a and R b are independently H or C 1-4 alkyl.
  • the said optionally substituted C 1-6 acyl group is NR c R d -C (O) -, wherein, R c and R d are independently H or C 1-4 alkyl, or R c and R d together with the N to which they are attached form an optionally substituted 4-6 membered heterocyclic group, such as optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted azetidinyl, etc.
  • the said aryl, heteroaryl, heterocyclyl or cycloalkyl groups may be optionally substituted by 1-3 substituents selected from a group consisting of halogen, hydroxyl, C 1-4 alkyl, halogenated C 1-4 alkyl and NR a R b , wherein, R a and R b are independently H or C 1-4 alkyl; more preferred substituent is C 1-4 alkyl.
  • Q is NH, N-C 1-3 alkyl, O or S.
  • a 2 is CH or N.
  • the fused bicyclic ring containing A 2 and Q is selected from the following groups:
  • R 2 is H or C 1-3 alkyl.
  • D 1 , D 2 , D 3 and D 4 are CR 5 .
  • R 5 is hydrogen, halogen, an optionally substituted alkyl, or an optionally substituted alkoxy; preferably, the said optionally substituted alkyl is an optionally substituted C 1-4 alkyl, and the optionally substituted alkoxy is an optionally substituted C 1-4 alkoxy; preferably, the said alkyl or alkoxy is substituted by 1-5 substituents selected from a group consisting of halogen, hydroxyl and NR a R b , wherein, the said R a and R b are independently H or C 1-4 alkyl.
  • R 5 is halogen or C 1-4 alkoxy.
  • all of D 1 , D 2 , D 3 and D 4 are CH.
  • D 1 , D 2 , D 3 and D 4 are independently N or CH.
  • only 2 of D 1 , D 2 , D 3 and D 4 are N.
  • the aryl or heteroaryl containing D 1 , D 2 , D 3 and D 4 is optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidinyl or optionally substituted pyrazinyl; when substituted, the substituents may be selected from the groups described in R 5 , including but not limited to halogen and C 1-4 alkyl optionally substituted with 1-5 substituents selected from a group consisting of halogen, hydroxyl and NR a R b , wherein the said R a and R b are independently H or C 1-4 alkyl.
  • Cy 1 is an optionally substituted 6-14 membered aryl group or an optionally substituted 5-10 membered heteroaryl group.
  • the said 5-10 membered heteroaryl group is a nitrogen-containing monocyclic heteroaryl group.
  • Cy 1 is an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted pyridazinyl, an optionally substituted pyrazolyl or an optionally substituted imidazolyl.
  • Cy 1 when Cy 1 is substituted, its substituent (s) are selected from a group consisting of halogen, an optionally substituted C 1-3 alkyl, an optionally substituted C 1-3 alkoxy, an optionally substituted C 3-6 cycloalkyl, an optionally substituted amino, and cyano; preferably, the said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl are each optionally substituted by 1-5 substituents selected from a group consisting of halogen, hydroxyl and C 1-4 alkyl substituted with NR a R b , wherein the said R a and R b are independently H or C 1-4 alkyl; the said amino is optionally substituted with 1 or 2 C 1-4 alkyl.
  • substituent (s) are selected from a group consisting of halogen, an optionally substituted C 1-3 alkyl, an optionally substituted C 1-3 alkoxy, an optionally substituted C 3-6 cycloalkyl, an
  • Cy 1 when Cy 1 is substituted, the number of substituents is 1-3, preferably 1-2. More preferably, Cy 1 is a 6-membered ring with at least one substituent located ortho to the ring atom to which Cy 1 is attached to the rest of the compound. In one embodiment, Cy 1 is substituted with two substituents and both are located at the said ortho position.
  • Cy 2 is an optionally substituted heteroaryl group, preferably an optionally substituted 5-10 membered nitrogen-containing heteroaryl group, more preferably a 5-membered nitrogen-containing heteroaryl group.
  • the heteroaryl group contains 1-3 nitgrogen atom and optional one oxygen atom.
  • Cy 2 is an optionally substituted imidazolyl, an optionally substituted pyrazolyl, an optionally substituted oxadiazolyl, an optionally substituted oxazolyl or an optionally substituted triazolyl.
  • Cy 2 When Cy 2 is substituted, its substituent (s) are selected from a group consisting of halogen, cyano, optionally substituted C 1-3 alkyl, optionally substituted C 1-3 alkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 1-3 acyl and optionally substituted heterocyclic group.
  • Cy 2 is imidazolyl, pyrazolyl, triazolyl or oxadiazolyl optionally substituted by 1-3 substituents selected from a group consisting of cyano, optionally substituted C 1-3 alkyl, optionally substituted C 3-6 cycloalkyl and optionally substituted heterocyclic group.
  • the said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl are optionally substituted by 1-5 substituents selected from a group consisting of halogen, hydroxyl and C 1-4 alkyl substituted with NR a R b , wherein the said R a and R b are independently H or C 1-4 alkyl.
  • the said heterocyclic group is optionally substituted by 1-5 substituents selected from a group consisting of halogen, hydroxyl and C 1-4 alkyl.
  • the heterocyclic group is a 4-6 membered nitrogen-containing heterocyclic group, such as azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl, optionally substituted by 1-3 C 1-3 alkyl.
  • Cy 2 is an optionally substituted C 1-6 acyl group, which is optionally substituted by 1-3 substituents selected from a group consisting of halogen, optionally substituted amino, hydroxyl, C 1-4 alkoxy, optionally substituted 6-14 membered aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclic group and optionally substituted C 3-8 cycloalkyl.
  • the said aryl is phenyl;
  • the said 5-10 membered heteroaryl group is a nitrogen- containing heteroaryl group, such as pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, etc;
  • the said 4-10 membered heterocyclic group is a nitrogen-containing heterocyclic group, such as pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, etc;
  • the said substituted amino group is NR a R b , wherein, R a and R b are independently H or C 1-4 alkyl.
  • the said optionally substituted C 1-6 acyl group is NR c R d -C (O) -, wherein R c and R d are independently H or C 1-4 alkyl, or R c and R d together with the N to which they are attached form an optionally substituted 4-6 membered heterocyclic group, such as optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted azetidinyl, etc.
  • the said aryl, heteroaryl, heterocyclyl or cycloalkyl groups may be optionally substituted by 1-3 substituents selected from a group consisting of halogen, hydroxyl, C 1-4 alkyl, halogenated C 1-4 alkyl and NR a R b , wherein R a and R b are independently H or C 1-4 alkyl; more preferred substituent is C 1-4 alkyl.
  • a 2 is N or CH; Q is NH, N-C 1-3 alkyl, or S; D 1 is H or C 1-4 alkoxy; D 2 is H or halogen; D 3 is H or C 1-4 alkoxy; D 4 is H; Cy 1 is a phenyl optionally substituted by 1-3 substituents selected from a group consisting of C 1-4 alkyl, C 1-4 alkoxy, and NR a R b , or a 5-6 membered nitrogen-containing heteroaryl optionally substituted by 1-3 substituents selected from a group consisting of halogen, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, cyano and NR a R b , wherein R a and R b are each independently H or C 1-4 alkyl; Cy 2 is a 5-6 membered nitrogen-containing heteroaryl optionally substituted by 1-3 substituents selected from a group consisting of C 1-4 alkyl
  • the 5-6 membered nitrogen-containing heteroaryl is selected from a group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl and imidazolyl.
  • Cy 1 is the phenyl or the 5-6 membered nitrogen-containing heteroaryl with at least one substituent (s) located at the ortho-position of the ring atom to which Cy 1 is attached to the rest of the compound.
  • Cy 2 is the 5-6 membered nitrogen-containing heteroaryl with at least one ring nitrogen substituted by the substituent as described.
  • Cy 1 is substituted with at least one substituent (s) located at ortho-position to the ring atom to which Cy 1 is attached to the rest of the compound; and/or Cy 2 is a heteroaryl with at least one ring nitrogen being substituted by any of the substituents as described.
  • preferred compounds of Formula I include, without limitation:
  • hydrogen (H) as empolyed herein includes its isotopes D and T.
  • alkyl refers to alkyl itself or a straight or branched chain radical of up to ten carbons.
  • Useful alkyl groups include straight-chain or branched C 1-10 alkyl groups, preferably C 1-6 alkyl groups.
  • alkyl is C 1-4 alkyl.
  • alkyl is C 1-3 alkyl.
  • Typical C 1-10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, 3-pentyl, hexyl and octyl groups, which may be optionally substituted.
  • alkenyl refers to a straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, wherein there is at least one double bond between two of the carbon atoms in the chain; preferably, C 2-6 alkenyl.
  • Typical alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl and 2-butenyl.
  • alkynyl refers to a straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain; preferably, C 2-6 alkynyl.
  • Typical alkynyl groups include ethynyl, 1-propynyl, 1-methyl-2-propynyl, 2-propynyl, 1-butynyl and 2-butynyl.
  • Useful alkoxy groups include oxygen substituted by the above mentioned C 1-10 alkyl groups, preferred C 1-6 alkyl groups or C 1-4 alkyl groups, e.g., methoxy, ethoxy, etc.
  • the alkyl in the alkoxy groups may be optionally substituted.
  • Substituents of alkoxy groups include, without limitation, halogen, morpholino, amino (including alkylamino and dialkylamino) , and carboxy (including esters thereof) .
  • Useful amino and optionally substituted amino groups include -NH 2 , -NHR' and -NR'R”, wherein -NHR' and -NR'R” each are independently hydrogen, an optionally substituted C 1-10 alkyl (preparably C 1-4 alkyl) , an optionally substituted cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl.
  • -NHR' and -NR'R” together with the N to which they are attached form an optionally substituted 4-7 membered cyclic amino group, which optionally comprises one or more (such as 2, 3) additional heteroatoms selected from O, N and S.
  • aryl as used herein by itself or as part of another group refers to monocyclic, bicyclic or tricyclic aromatic groups containing 6 to 14 carbon atoms. Aryl may be substituted by one or more substituents as described herein.
  • Useful aryl groups include C 6-14 aryl groups, preferably C 6-10 aryl groups.
  • Typical C 6-14 aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulyl, biphenyl, biphenylene and fluorenyl.
  • Carbocyclic group as used herein include cycloalkyl and partially saturated carbocyclic groups. Useful cycloalkyl groups are C 3-8 cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Carbocyclic group may be substituted by one or more substituents as described herein.
  • Useful partially saturated carbocyclic groups include cycloalkenyl groups, such as C 3-8 cycloalkenyl groups, e.g., cyclopentenyl, cycloheptenyl and cyclooctenyl.
  • Useful halo or halogen groups include fluoro, chloro, bromo and iodo.
  • heterocyclic group refers to a saturated or partially saturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring system, which consists of carbon atoms and one to four heteroatoms independently selected from O, N, and S, wherein the nitrogen and/or sulfur heteroatoms can be optionally oxidized and the nitrogen can be optionally quaternized, and the term also includes any bicyclic ring system in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocycle can be substituted on carbon atom or nitrogen atom if the resulting compound is stable.
  • Heterocyclic group may be substituted by one or more substituents as described herein.
  • heterocyclyl groups mentioned above also include 5-8 membered heterocycloalkyl groups, ie, heterocyclyl groups in which one or more ring C atoms in the cycloalkyl group are replaced by heteroatoms selected from N, O and S.
  • Useful saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, tetrahydropyranyl, pyranyl, piperidinyl, piperazinyl, oxetanyl, azetidinyl, 1, 4-diazepanyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indoline, isoindolyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidine, pyrazolinyl, Tetrahydroisoquinolyl, tetronoyl, oxadiazolyl, oxazolyl and tetramoyl, which may be optionally substituted by one or more substituents as described herein.
  • heteroaryl refers to a group having 5 to 14 ring atoms, preferably 5 to 10 ring atoms, with 6, 10 or 14 ⁇ electrons shared in a cyclic array. Ring atoms are carbon atoms and 1-3 heteroatoms selected from oxygen, nitrogen and sulfur. Heteroaryl may be optionally substituted by one or more substituents as described herein.
  • Useful heteroaryl groups include thienyl (thiophenyl) , benzo [d] isothiazol-3-yl, benzo [b] thienyl, naphtho [2, 3-b] thienyl, thianthrenyl, furyl (furanyl) , pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl, including without limitation 2-pyridyl, 3-pyridyl, and 4-pyridyl) , pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl
  • heteroaryl group contains a nitrogen atom in a ring
  • nitrogen atom may be in the form of an N-oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.
  • the alkyl, cycloalkyl, alkoxy, alkenyl, alkynyl, amino, heterocyclic, aryl or heteroaryl as described in any embodiment herein may be substituted by one or more (such as 1, 2, 3, or 4) substituents selected from a group consisting of halogen, amino, cyano, C 1-6 alkoxy, C 1-6 alkyl, C 6-10 aryl, C 3-8 cycloalkyl, C 2-6 chain alkenyl, C 2-6 alkynyl, heterocyclic group, heteroaryl, etc.
  • the substituent itself may also be optionally substituted.
  • Preferred substituents include without limitation cyano, halogenated C 1-6 alkyl, halo, amino, halogenated C 1-6 alkoxy, C 1-6 alkyl and C 3-8 cycloalkyl.
  • stereoisomers including optical isomers.
  • the disclosure includes all stereoisomers and the racemic mixtures of such stereoisomers as well as the individual enantiomers that may be separated according to methods that are well known to those of ordinary skill in the art.
  • Examples of pharmaceutically acceptable salts include inorganic and organic acid salts, such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate; and inorganic and organic base salts formed with bases, such as sodium hydroxy, tris (hydroxymethyl) aminomethane (TRIS, tromethamine) and N-methyl-glucamine.
  • inorganic and organic acid salts such as hydrochloride, hydrobromide, phosphate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate and oxalate
  • inorganic and organic base salts formed with bases such as sodium hydroxy, tris (hydroxymethyl) aminomethane (TRIS, tromethamine) and N-methyl-glucamine.
  • prodrugs of the compounds of the disclosure include the simple esters of carboxylic acid-containing compounds (e.g., those obtained by condensation with a C 1-4 alcohol according to methods known in the art) ; esters of hydroxy containing compounds (e.g., those obtained by condensation with a C 1-4 carboxylic acid, C 3-6 diacid or anhydride thereof, such as succinic anhydride and fumaric anhydride according to methods known in the art) ; imines of amino containing compounds (e.g., those obtained by condensation with a C 1-4 aldehyde or ketone according to methods known in the art) ; carbamate of amino containing compounds, such as those described by Leu, et al., (J. Med. Chem.
  • the compounds of this disclosure may be prepared using methods known to those skilled in the art, or the novel methods of this disclosure. Specifically, the compounds of this disclosure with Formula I (including Formula II) can be prepared as illustrated by the exemplary reaction in Scheme 1. Iodination reaction of 2-chloro-5H-pyrrolo [3, 2-d] pyrimidine and N-iodosuccinimide in DMF produced 2-chloro-7-iodo-5H-pyrrolo [3, 2-d] pyrimidine. Methylation reaction of 2-chloro-7-iodo-5H-pyrrolo [3, 2-d] pyrimidine and iodomethane produced 2-chloro-7-iodo-5-methyl-5H-pyrrolo [3, 2-d] pyrimidine.
  • the compounds of this disclosure can be prepared as illustrated by the exemplary reaction in Scheme 2. Iodination reaction of 2-chlorothieno [3, 2-d] pyrimidine and N-iodosuccinimide in AcOH produced 2-chloro-7-iodothieno [3, 2-d] pyrimidine.
  • the compounds of this disclosure can be prepared as illustrated by the exemplary reaction in Scheme 3. Bromination reaction of 5-chloro-1, 3-dimethyl-1H-pyrazolo [4, 3-d] pyrimidine and NBS under the catalysis of AIBN produced 3- (bromomethyl) -5-chloro-1-methyl-1H-pyrazolo [4, 3-d] pyrimidine.
  • the compounds of Formula I are USP1 inhibitors. Therefore, the compounds of Formula I (including the compounds of Formula II as described herein) can be used to treat or prevent diseases associated with USP1 regulation, such as cancer; or be used to prepare medicaments for the treatment or prevention of diseases associated with USP1 regulation, such as cancer.
  • the present disclosure also includes methods for the treatment or prevention of diseases associated with USP1 regulation, especially, methods of for the treatment or prevention of diseases associated with USP1 regulation and methods of treatment or prevention of diseases caused by defects in DDR function, comprising administering to an object (especially mammal, more specifically human) in need an effective amount of the compound of Formula I (including the compound of Formula II as described herein) or stereoisomers, tautomers, N-oxides, hydrates, isotope-substituted derivatives, solvates or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof, or a pharmaceutical composition comprising an effective amount of the compound of Formula I (including the compound of Formulae II as described herein) or stereoisomers, tautomers, N-oxides, hydrates, isotope-substituted derivatives, solvates or pharmaceutically acceptable salts thereof, or mixtures thereof, or prodrugs thereof.
  • the diseases associated with USP1 regulation include cancers.
  • the cancers associated with USP1 regulation exsit defects in DDR function.
  • the diseases associated with USP1 regulation that can be treated or prevented by the methods or pharmaceutical compositions of the disclosure include without limitation liver cancer, melanoma, Hodgkin’s disease, non-Hodgkin’s lymphoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, Wilms tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, malignant melanoma, non-samll lung cancer, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid cancer, choriocarcinoma, mycosis fungoides, head and neck cancer, osteogenic sarcoma,
  • the present disclosure also includes the method for the treatment or prevention of other diseases caused by excessive or abnormal cell proliferation, including proliferative or hyperproliferative diseases, such as myeloproliferative diseases, especially proliferative or hyperproliferative diseases caused by excessive or abnormal cell proliferation related with USP1 regulation. Therefore, the disclosure also includes the compound of Formula I (including the compound of Formula II as described herein) for the treatment or prevention of other diseases caused by excessive or abnormal cell proliferation, especially proliferative or hyperproliferative diseases caused by excessive or abnormal cell proliferation related with USP1 regulation.
  • proliferative or hyperproliferative diseases such as myeloproliferative diseases, especially proliferative or hyperproliferative diseases caused by excessive or abnormal cell proliferation related with USP1 regulation.
  • effective amounts of pharmaceutical preparations are administered to an individual exhibiting the symptoms of one or more of these disorders.
  • the pharmaceutic preparations comprise therapeutically effective concentrations of the compounds of Formula I or II, formulated for oral, intravenous, local or topical application, for the treatment of cancer and other diseases.
  • the amounts are effective to ameliorate or eliminate one or more symptoms of the disorders.
  • An effective amount of a compound for treating a particular disease is an amount that is sufficient to ameliorate or in some manner reduce the symptoms associated with the disease. Such amount may be administered as a single dosage or may be administered according to an effective regimen.
  • the amount may cure the disease but, typically, is administered in order to ameliorate the symptoms of the disease. Typically, repeated administration is required to achieve the desired amelioration of symptom.
  • a pharmaceutical composition comprising a compound of Formula I or II as an USP1 inhibitor, or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.
  • Another embodiment of the present disclosure is directed to a pharmaceutical composition effective to treat cancer comprising a compound of Formula I or II as an USP1 inhibitor, or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof or prodrugs thereof, in combination with at least one known anticancer agent or a pharmaceutically acceptable salt thereof.
  • the compound herein can be combined with other anticancer drugs related to the mechanism of DNA damage and repair, including PARP inhibitors, such as olaparib, niraprib, rucaparib, talazoparib, pamiparib, fluzoparib and senaparib; HDAC inhibitors such as Volinota, Romididesin, Papiseta and Bailesta; and so on.
  • the compound herein can be combined with other anticancer drugs related to cell division detection sites, including Chk1/2 inhibitors, CDK4/6 inhibitors such as Paposinib, ATM inhibitors, Wee1 inhibitors, ATR inhibitors, Myt1 inhibitors, DNA-PK inhibitors, and so on.
  • anticancer agents which may be used for anticancer combination therapy include, but are not limited to alkylating agents, such as busulfan, melphalan, chlorambucil, cyclophosphamide, ifosfamide, temozolomide, bendamustine, cis-platin, mitomycin C, bleomycin and carboplatin; topoisomerase I inhibitors, such as camptothecin, irinotecan and topotecan; topoisomerase II inhibitors, such as doxorubicin, epirubicin, aclacinomycin, mitoxantrone, elliptinium and etoposide; RNA/DNA antimetabolites, such as 5-azacytidine, gemcitabine, 5-fluorouracil, capecitabine and methotrexate; DNA antimetabolites, such as 5-fluorouracil, capecitabine and methotrexate; DNA antimetabolites, such as 5-fluorouracil, capecitabine and
  • anticancer agents which may be used for anticancer combination therapy include tamoxifen, letrozole, fulvestrant, mitoguazone, octreotide, retinoic acid, arsenic, zoledronic acid, bortezomib, carfilzomib, Ixazomib, vismodegib, sonidegib, denosumab, thalidomide, lenalidomide, Venetoclax, Aldesleukin (recombinant human interleukin-2) and Sipueucel-T (prostate cancer treatment vaccine) .
  • the compound of the disclosure may be administered together with at least one known anticancer agent in a unitary pharmaceutical composition.
  • the compound of the disclosure may be administered separately from at least one known anticancer agent.
  • the compound of the disclosure and at least one known anticancer agent are administered substantially simultaneously, i.e. all agents are administered at the same time or one after another, provided that compounds reach therapeutic levels in the blood at the same time.
  • the compound of the disclosure and at least one known anticancer agent are administered according to individual dose schedule, provided that the compounds reach therapeutic levels in the blood.
  • Another embodiment of the present disclosure is directed to a bioconjugate, which functions as a USP1 inhibitor, that comprises a compound described herein and is effective to inhibit tumor.
  • the bioconjugate that inhibits tumor is consisted of the compound described herein and at least one known therapeutically useful antibody, such as trastuzumab or rituximab, or growth factor, such as EGF or FGF, or cytokine, such as IL-2 or IL-4, or any molecule that can bind to cell surface.
  • the antibodies and other molecules could deliver the compound described herein to its targets, making it an effective anticancer agent.
  • the bioconjugates could also enhance the anticancer effect of the therapeutically useful antibodies, such as trastuzumab or rituximab.
  • Another embodiment of the present disclosure is directed to a pharmaceutical composition effective to inhibit tumor comprising the USP1 inhibitor of Formula I (including Formula II) , or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof or prodrugs thereof, in combination with radiation therapy.
  • the compound of the disclosure may be administered at the same time as the radiation therapy or at a different time.
  • Yet another embodiment of the present disclosure is directed to a pharmaceutical composition effective for post-surgical treatment of cancer, comprising the USP1 inhibitor of Formula I or II, or stereoisomers, tautomers, N-oxides, hydrates, solvates, isotope-substituted derivatives, or pharmaceutically acceptable salts thereof or prodrugs thereof.
  • the disclosure also relates to a method of treating cancer by surgically removing tumor and then treating the mammal with the pharmaceutical composition described herein.
  • compositions of this disclosure include all pharmaceutical preperations which contain the compounds of the present disclosure in an amount that is effective to achieve its intended purpose. While individual needs vary, determination of optimal amounts of each component in the pharmaceutical preperations is within the skill of the art.
  • the compounds or the pharmaceutically acceptable salt thereof may be administered to mammals, orally at a dose of about 0.0025 to 50 mg per kg body weight per day. Preferably, from approximately 0.01 mg/kg to approximately 10 mg/kg body weight is orally administered. If a known anticancer agent is also administered, it is administered in an amount that is effective to achieve its intended purpose. The optimal amounts of such known anticancer agents are well known to those skilled in the art.
  • the unit oral dose may comprise from approximately 0.01 to approximately 50 mg, preferably approximately 0.1 to approximately 10 mg of the compound of the disclosure.
  • the unit dose may be administered one or more times, with one or more tablets daily, each containing from approximately 0.1 to approximately 50 mg, conveniently approximately 0.25 to 10 mg of the compound of the disclosure or its solvates.
  • the compound of the disclosure may be present at a concentration of approximately 0.01 to 100 mg per gram of carrier.
  • the compound of the disclosure may be adiministered as a raw chemical.
  • the compounds of the disclosure may also be administered as part of a suitable pharmaceutical preparation containing pharmaceutically acceptable carriers (comprising excipients and auxiliaries) , which facilitate the processing of the compounds into pharmaceutically acceptable preparations.
  • pharmaceutically acceptable carriers comprising excipients and auxiliaries
  • the pharmaceutical preparations particularly oral preparations and those used for the preferred administration, such as tablets, dragees, and capsules, as well as solutions suitable for injection or oral administration, contain from approximately 0.01%to 99%, preferably from approximately 0.25%to 75%of active compound (s) , together with excipient (s) .
  • non-toxic pharmaceutically acceptable salts of the compounds of the present disclosure are also included within the scope of the present disclosure.
  • Acid addition salts are formed by mixing a solution of the compounds of the present disclosure with a solution of a pharmaceutically acceptable non-toxic acid, such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, and the like.
  • Base addition salts are formed by mixing a solution of the compounds of the present disclosure with a solution of a pharmaceutically acceptable non-toxic base, such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, tris (hydroxymethyl) aminomethane, N-methyl-glucamine and the like.
  • a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, tris (hydroxymethyl) aminomethane, N-methyl-glucamine and the like.
  • the pharmaceutical preperations of the disclosure may be administered to any mammal, so long as they may experience the therapeutic effects of the compounds of the disclosure. Foremost among such mammals are humans and veterinary animals, although the disclosure is not intended to be so limited.
  • the pharmaceutical preperations of the present disclosure may be administered by any means that achieve their intended purpose.
  • administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes.
  • administration may be by oral route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, type of concurrent treatment, frequency of treatment, and the nature of the effect desired.
  • the pharmaceutical preparations of the present disclosure are manufactured in a known manner, e.g., by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
  • Pharmaceutical preparations for oral use may be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture, processing the mixture of granules after adding suitable auxiliaries if desired or necessary, thereby obtaining tablets or dragee cores.
  • Suitable excipients are, in particular, fillers, such as saccharides, e.g. lactose or sucrose, mannitol or sorbitol; cellulose preparations and/or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate; as well as binders, such as starch paste, including, e.g., maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
  • fillers such as saccharides, e.g. lactose or sucrose, mannitol or sorbitol
  • cellulose preparations and/or calcium phosphates e.g. tricalcium phosphate or calcium hydrogen phosphate
  • binders such as starch paste, including, e.g., maize starch, wheat starch, rice starch, potato star
  • disintegrating agents may be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries are, in particular, flow-regulating agents and lubricants, e.g., silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices.
  • concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, are used.
  • Dyes or pigments may be added to the tablets or dragee coatings, e.g., for identification or in order to characterize combinations of active compound doses.
  • Other pharmaceutical preparations which may be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules may contain the active compounds in the form of granules, which may be mixed with fillers, such as lactose; binders, such as starches; and/or lubricants, such as talc or magnesium stearate and stabilizers.
  • the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
  • stabilizers may be added.
  • Suitable formulations for parenteral administration include aqueous solutions of the active compounds, e.g., aqueous solutions and alkaline solutions of water-soluble salts.
  • suspensions of the active compounds as appropriate oily injection suspensions may be administered.
  • Suitable lipophilic solvents or vehicles include fatty oils, e.g., sesame oil, or synthetic fatty acid esters, e.g., ethyl oleate or triglycerides or polyethylene glycol-400, or cremophor, or cyclodextrins.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, e.g., sodium carboxymethyl cellulose, sorbitol, and/or dextran.
  • suspension stabilizers may also be contained.
  • compounds of the disclosure are employed in topical and parenteral formulations and are used for the treatment of skin cancer.
  • the topical formulations of this disclosure are formulated preferably as oils, creams, lotions, ointments and the like by choice of appropriate carriers.
  • Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin) , branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C 12 ) .
  • the preferred carriers are those in which the active ingredient is soluble.
  • Emulsifiers, stabilizers, humectants and antioxidants may also be included, as well as agents imparting color or fragrance, if desired.
  • transdermal penetration enhancers may be employed in these topical formulations. Examples of such enhancers are found in U.S. Patent Nos. 3,989,816 and 4,444,762.
  • Creams are preferably formulated from a mixture of mineral oil, self-emulsifying beeswax and water in which the active ingredient, dissolved in a small amount of an oil, such as almond oil, is admixed.
  • an oil such as almond oil
  • a typical example of such a cream is one which includes approximately 40 parts water, approximately 20 parts beeswax, approximately 40 parts mineral oil and approximately 1 part almond oil.
  • Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil, such as almond oil, with warm soft paraffin and allowing the mixture to cool.
  • a vegetable oil such as almond oil
  • a typical example of such an ointment is one which includes approximately 30%almond oil and approximately 70%white soft paraffin by weight.
  • the present disclosure also involves use of the compounds of the disclosure for the preperation of a medicament for the treatment or prevention of clinical symptoms in response to the effect of inhibiting the activity of USP1.
  • the medicament may include the above-mentioned pharmaceutical compositions.
  • Example 5-11 The following compounds of Examples 5-11 were prepared using a synthesis method similar to that described in Example 1 or Example 4.
  • USP1/UAF1 activity was determined by using ubiquitin-rhodamine110-glycine (Ub-Rho; Boston Biochem) assay. Enzymatic reactions were conducted in an assay buffer (50 mM HEPES, pH 7.8, 0.5 mM EDTA, 100 mM NaCl, 1 mM TCEP, 0.1 mg/ml BSA, and 0.01%Tween-20) that contained 1 nM USP1/UAF1. Each individual compound was tested at ten concentrations in the range of 0.0005 to 10 ⁇ M. The plates were incubated for 30 min to attain equilibrium, and then the enzymatic reaction was initiated by dispensing 1 ⁇ L of Ub-Rho solution (150 nM final concentration) . The rhodamine fluorescence was acquired using a 480 nm excitation/540 nm emission filter set by using Envision instrument. The inhibition rate of the compound to USP1/UAF1 enzyme activity was calculated according to the following formula.
  • IC 50 value is obtained by fitting the s-shaped dose response curve equation by using XL Fit software.
  • Table 1 summarizes the inhibitory effects of compounds on USP1/UAF1 activity (IC 50 ) , wherein, +++ indicates1 nM ⁇ IC 50 ⁇ 10 nM; ++ indicates 10 nM ⁇ IC 50 ⁇ 100 nM; + indicates 100 nM ⁇ IC 50 ⁇ 1 ⁇ M.
  • Example 1 2 3 4 5 13 IC 50 (nM) ++ + + + ++ ++ Example 14 15 16 25 26 27 IC 50 (nM) ++ ++ ++ + ++ Example 28 30 38 47 48 49 IC 50 (nM) ++ ++ + ++ ++ ++ Example 50 51 53 54 56 57 IC 50 (nM) ++ ++ +++ ++ ++ ++ Example 63 67 68 72 IC 50 (nM) ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ ++
  • the compounds herein have a good inhibitory effect on USP1/UAF1 enzyme activity.
  • CCK8 cell viability assay was used to determine the inhibition of the invented compound in the patent on human breast cancer MDA-MB-436 cell line
  • the cells were cultured in complete medium (DMEM medium +10%FBS+ Insulin +glutathione) . When the confluence reached about 80%, cells were digested and gently dispensed from the bottom of the dish with a 1mL pipette. Cell suspension was collected and centrifuged at 500rpm for 3min. The supernatant was discarded, and the cell pellet were re-suspended in complete medium. The cells were seeded into a culture dish at an appropriate proportion, and then cultured in a 5%CO 2 incubator at 37°C. The assay was carried out when the cells were in optimum condition and the confluence was reached 80%.
  • complete medium DMEM medium +10%FBS+ Insulin +glutathione
  • cells were harvested in the logarithmic growth phase by using 1 ml liquid receiver gently and then centrifugated at 500rpm for 3min. The cells were resuspended by using refresh medium after removing the supernatant and then the cells were counted. The cells were seeded at 3000/well in a 96 well plate andincubated at 37°C, 5%CO 2 incubator overnight. In the second day, cells were treated with compound at 8 serially diluted dose with 1,000X final concentration in 100%DMSO. The compound was prepared as below: dilution of 1,000X test compound solution to 40X test compound solution by adding 5 ⁇ L 1000X compound solution to 120 ⁇ L Medium (25-fold dilution) . The solution was mixed by oscillation. DMSO was used as the control.
  • Table 2 summarizes the inhibitory effect data (IC 50 ) of the compounds on the proliferation of human breast cancer cells MDA-MB-436, wherein, ++++ indicates IC 50 ⁇ 10 nM; +++indicates 10 nM ⁇ IC 50 ⁇ 100 nM; ++ indicates 100 nM ⁇ IC 50 ⁇ 1 ⁇ M; + indicates IC 50 > 1 ⁇ M.
  • Example 1 2 3 4 5 6 IC 50 (nM) +++ +++ +++ +++ ++ Example 7 8 10 11 13 14 IC 50 (nM) ++ ++ ++ +++ +++ Example 15 16 17 21 23 24 IC 50 (nM) +++ +++ ++ + + ++ Example 25 26 27 28 29 30 IC 50 (nM) +++ +++ +++ +++ Example 31 32 33 34 35 36 IC 50 (nM) ++ + ++ + + + + + + + + + + + + + + + + + + + + + + + + + + + +
  • Example 37 38 39 40 41 42 IC 50 (nM) + + + + + + + + + Example 43 44 45 46 47 48 IC 50 (nM) + ++ + ++ +++ +++ Example 49 50 51 52 53 54 IC 50 (nM) +++ +++ +++ ++ +++ Example 55 56 57 59 60 61 IC 50 (nM) +++ +++ +++ + ++ ++ Example 63 66 67 68 71 72 IC 50 (nM) +++ + +++ +++ ++++ +++ Example 74 75 78 IC 50 (nM) +++ ++ ++ ++ ++ ++
  • the compounds herein have a good inhibitory effect on the proliferation of human breast cancer cells MDA-MB-436.

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Abstract

L'invention concerne des composés hétéroaryle-pyrimidine à cinq chaînons substitués représentés par la formule I et leur utilisation : A1, A2, Q, B, D1, D2, D3, D4, Cy1 et Cy2 étant définis dans la description. Les composés de formule I sont des inhibiteurs d'USP1. Par conséquent, les composés selon l'invention peuvent être utilisés pour traiter des maladies, troubles et affections associés à la régulation d'USP1, tels que le cancer.
PCT/CN2022/082686 2021-03-24 2022-03-24 Composés hétéroaryle-pyrimidine à cinq chaînons utilisés en tant qu'inhibiteurs d'usp1 et leur utilisation Ceased WO2022199652A1 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023083285A1 (fr) * 2021-11-12 2023-05-19 Insilico Medicine Ip Limited Inhibiteurs à petites molécules de la protéase 1 spécifique de l'ubiquitine (usp1) et leurs utilisations
US11739077B2 (en) 2021-11-12 2023-08-29 Insilico Medicine Ip Limited Small molecule inhibitors of ubiquitin specific protease 1 (USP1) and uses thereof
WO2024022266A1 (fr) * 2022-07-25 2024-02-01 Guangdong Newopp Biopharmaceuticals Co., Ltd. Composés hétéroaryle utilisés comme inhibiteurs de usp1
WO2024078436A1 (fr) * 2022-10-09 2024-04-18 海南先声再明医药股份有限公司 Composé pyrimidine hétérocyclique, composition pharmaceutique et application associées
WO2024233665A1 (fr) 2023-05-08 2024-11-14 Tango Therapeutics, Inc. Composés et leur utilisation contre le cancer
WO2024233605A1 (fr) 2023-05-08 2024-11-14 Tango Therapeutics, Inc. Composés et leur utilisation contre le cancer
WO2025010245A1 (fr) 2023-07-06 2025-01-09 Exelixis, Inc. Dérivés de pyrazole fusionnés en tant qu'inhibiteurs d'usp1
WO2025096505A1 (fr) * 2023-10-31 2025-05-08 Bristol-Myers Squibb Company Composés de type protéase 1 spécifique de l'ubiquitine (usp1)
WO2025096487A1 (fr) * 2023-10-31 2025-05-08 Bristol-Myers Squibb Company Composés de type protéase 1 spécifique de l'ubiquitine (usp1)
WO2025096488A1 (fr) * 2023-10-31 2025-05-08 Bristol-Myers Squibb Company Composés relatifs à la protéase 1 spécifique de l'ubiquitine (usp1)
WO2025096539A1 (fr) * 2023-10-31 2025-05-08 Bristol-Myers Squibb Company Composés de protéase 1 de traitement spécifique de l'ubiquitine (usp1)
WO2025102016A1 (fr) 2023-11-10 2025-05-15 Vrise Therapeutics, Inc. Nouvelles molécules utilisées en tant qu'inhibiteurs de la voie de réparation des dommages à l'adn
WO2025151705A1 (fr) 2024-01-10 2025-07-17 Vrise Therapeutics, Inc. Nouveaux inhibiteurs de la voie de réparation des dommages à l'adn
WO2025157241A1 (fr) * 2024-01-26 2025-07-31 成都微芯药业有限公司 Inhibiteur de usp1, son procédé de préparation et son utilisation

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014105952A2 (fr) * 2012-12-28 2014-07-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibiteurs du complexe usp1/uaf1 désubiquitinase et leurs utilisations
WO2018049152A1 (fr) * 2016-09-09 2018-03-15 Incyte Corporation Dérivés de pyrazolopyrimidine en tant que modulateurs de hpk1 et leurs utilisations pour le traitement du cancer
WO2020068729A1 (fr) * 2018-09-25 2020-04-02 Incyte Corporation Composés pyrazolo[4,3-d]pyrimidine en tant que modulateurs des alk2 et/ou fgfr
WO2020227325A1 (fr) * 2019-05-06 2020-11-12 Icahn School Of Medicine At Mount Sinai Composés hétérobifonctionnels en tant qu'agents de dégradation de hpk1
WO2021175270A1 (fr) * 2020-03-03 2021-09-10 轶诺(浙江)药业有限公司 Nouvel inhibiteur de hpk1, son procédé de préparation et son application

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014105952A2 (fr) * 2012-12-28 2014-07-03 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibiteurs du complexe usp1/uaf1 désubiquitinase et leurs utilisations
WO2018049152A1 (fr) * 2016-09-09 2018-03-15 Incyte Corporation Dérivés de pyrazolopyrimidine en tant que modulateurs de hpk1 et leurs utilisations pour le traitement du cancer
WO2020068729A1 (fr) * 2018-09-25 2020-04-02 Incyte Corporation Composés pyrazolo[4,3-d]pyrimidine en tant que modulateurs des alk2 et/ou fgfr
WO2020227325A1 (fr) * 2019-05-06 2020-11-12 Icahn School Of Medicine At Mount Sinai Composés hétérobifonctionnels en tant qu'agents de dégradation de hpk1
WO2021175270A1 (fr) * 2020-03-03 2021-09-10 轶诺(浙江)药业有限公司 Nouvel inhibiteur de hpk1, son procédé de préparation et son application

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023083285A1 (fr) * 2021-11-12 2023-05-19 Insilico Medicine Ip Limited Inhibiteurs à petites molécules de la protéase 1 spécifique de l'ubiquitine (usp1) et leurs utilisations
US11739077B2 (en) 2021-11-12 2023-08-29 Insilico Medicine Ip Limited Small molecule inhibitors of ubiquitin specific protease 1 (USP1) and uses thereof
WO2024022266A1 (fr) * 2022-07-25 2024-02-01 Guangdong Newopp Biopharmaceuticals Co., Ltd. Composés hétéroaryle utilisés comme inhibiteurs de usp1
WO2024078436A1 (fr) * 2022-10-09 2024-04-18 海南先声再明医药股份有限公司 Composé pyrimidine hétérocyclique, composition pharmaceutique et application associées
WO2024233665A1 (fr) 2023-05-08 2024-11-14 Tango Therapeutics, Inc. Composés et leur utilisation contre le cancer
WO2024233605A1 (fr) 2023-05-08 2024-11-14 Tango Therapeutics, Inc. Composés et leur utilisation contre le cancer
WO2025010245A1 (fr) 2023-07-06 2025-01-09 Exelixis, Inc. Dérivés de pyrazole fusionnés en tant qu'inhibiteurs d'usp1
WO2025096505A1 (fr) * 2023-10-31 2025-05-08 Bristol-Myers Squibb Company Composés de type protéase 1 spécifique de l'ubiquitine (usp1)
WO2025096487A1 (fr) * 2023-10-31 2025-05-08 Bristol-Myers Squibb Company Composés de type protéase 1 spécifique de l'ubiquitine (usp1)
WO2025096488A1 (fr) * 2023-10-31 2025-05-08 Bristol-Myers Squibb Company Composés relatifs à la protéase 1 spécifique de l'ubiquitine (usp1)
WO2025096539A1 (fr) * 2023-10-31 2025-05-08 Bristol-Myers Squibb Company Composés de protéase 1 de traitement spécifique de l'ubiquitine (usp1)
WO2025102016A1 (fr) 2023-11-10 2025-05-15 Vrise Therapeutics, Inc. Nouvelles molécules utilisées en tant qu'inhibiteurs de la voie de réparation des dommages à l'adn
WO2025151705A1 (fr) 2024-01-10 2025-07-17 Vrise Therapeutics, Inc. Nouveaux inhibiteurs de la voie de réparation des dommages à l'adn
WO2025157241A1 (fr) * 2024-01-26 2025-07-31 成都微芯药业有限公司 Inhibiteur de usp1, son procédé de préparation et son utilisation

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