WO2023125841A1 - 作为Polθ抑制剂的杂环化合物及其制备方法和用途 - Google Patents

作为Polθ抑制剂的杂环化合物及其制备方法和用途 Download PDF

Info

Publication number
WO2023125841A1
WO2023125841A1 PCT/CN2022/143548 CN2022143548W WO2023125841A1 WO 2023125841 A1 WO2023125841 A1 WO 2023125841A1 CN 2022143548 W CN2022143548 W CN 2022143548W WO 2023125841 A1 WO2023125841 A1 WO 2023125841A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
group
ring
independently
pharmaceutically acceptable
Prior art date
Application number
PCT/CN2022/143548
Other languages
English (en)
French (fr)
Inventor
张学军
李金平
陈浩民
陈登辉
宋小波
刘礼飞
赵心
张辛
程智逵
杨俊�
李莉娥
Original Assignee
武汉人福创新药物研发中心有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 武汉人福创新药物研发中心有限公司 filed Critical 武汉人福创新药物研发中心有限公司
Publication of WO2023125841A1 publication Critical patent/WO2023125841A1/zh

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicine, in particular, the invention relates to a heterocyclic compound as a Pol ⁇ inhibitor and its preparation method and application.
  • Synthetic lethality is an emerging research direction in the field of anti-tumor at present, and the treatment targeting the DNA repair pathway is the focus of this patent. Due to gene mutation, some tumor cells will cause the loss of a certain DNA repair pathway, which makes them overly dependent on the remaining DNA repair pathway. At this time, targeted inhibition of this remaining DNA repair pathway can specifically Kill this type of tumor cells, but has no killing effect on normal somatic cells.
  • the method of treating breast and ovarian cancer susceptibility gene (breast and ovarian cancer susceptibility gene, BRCA) mutated tumors by poly(ADP-ribose) polymerase [poly(ADP-ribose) polymerase, PARP] inhibitors is the use of Synthetic lethal mechanism of action targeting DNA repair defects.
  • DNA double strand breaks are one of the most serious DNA damage.
  • DNA double strand break repair (DNA double strand breaks repair, DSBR) in cells can be roughly divided into three ways to complete, one is non-homologous end-joining (NHEJ), and the other is homologous recombination (homologous recombination, HR), the last pathway is end joining (alt-EJ) mediated by DNA polymerase ⁇ (Polymerase ⁇ , Pol ⁇ , POLQ) when NHEJ or HR is damaged, also known as micro-homology mediated Guided end junction (MMEJ). Pol ⁇ plays a central role in microhomology-mediated end joining.
  • Pol ⁇ has an N-terminal helicase domain and a C-terminal DNA polymerase domain (S. Black et al. 2016. Genes.). Studies have shown that the helicase domain of Pol ⁇ can promote the annealing of microhomology, after annealing, all overhanging bases are removed by nucleases, and the gaps are filled by Pol ⁇ . Therefore, Pol ⁇ has received more and more attention as an important target of DNA repair defects. Pol ⁇ is barely expressed in normal tissues, but is overexpressed in multiple tumor types such as breast cancer, ovarian cancer, HNSCC and lung cancer and is associated with poor prognostic outcome.
  • the object of the present invention is to provide a heterocyclic compound as a Pol ⁇ inhibitor and its preparation method and use, the heterocyclic compound has a structure as shown in the first aspect of the present invention, and the heterocyclic compound can be used to inhibit Pol ⁇ polymerase activity to prevent or treat diseases or conditions mediated by Pol ⁇ .
  • the first aspect of the present invention provides a heterocyclic compound represented by formula I, its tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug:
  • the group Q is
  • Ring A is a 5- or 6-membered heteroaryl group
  • ring B is a 5-8-membered heterocycloalkyl group or a 5- or 6-membered heteroaryl group
  • R 8 , R 9 , R 10 and R 11 are each independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl or -NH-C 1 -C 6 alkyl;
  • said R 8 , R 9 , R 10 and R 11 are each independently substituted by 1, 2, 3 or 4 substituents selected from the group consisting of deuterium, halogen, hydroxyl, amino, cyano and C 1 -C 6 alkyl; when there are multiple substituents, the substituents are the same or different;
  • n, f and g are each independently 0, 1, 2 or 3; when there are multiple substituents R 8 , R 9 , R 10 and R 11 , the substituents R 8 , R 9 , R 10 same or different from R11 ;
  • R 1 , R 2 and R 3 are each independently hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 3-6 membered cycloalkyl or 4-8 membered heterocycloalkyl ;
  • R 4 , R 5 and R 6 are each independently hydrogen, deuterium, halogen, hydroxyl, amino, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 deuterated alkyl or C 1 -C 6 haloalkyl.
  • the present invention provides a heterocyclic compound as shown in formula I, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:
  • the group Q is
  • Ring A is a 5- or 6-membered heteroaryl group
  • ring B is a 5-8-membered heterocycloalkyl group or a 5- or 6-membered heteroaryl group
  • R 8 , R 9 , R 10 and R 11 are each independently hydrogen, halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl or -NH-C 1 -C 6 alkyl;
  • said R 8 , R 9 , R 10 and R 11 are each independently substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxyl, amino, cyano and C 1 -C 6 alkyl groups; when there are multiple substituents, the substituents are the same or different;
  • n, f and g are each independently 0, 1, 2 or 3; when there are multiple substituents R 8 , R 9 , R 10 and R 11 , the substituents R 8 , R 9 , R 10 same or different from R11 ;
  • R 1 , R 2 and R 3 are each independently hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;
  • R 4 , R 5 and R 6 are each independently hydrogen, halogen, hydroxyl, amino, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl;
  • R 7 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
  • the solvate may be a hydrate.
  • heterocyclic compound shown in formula I its tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug:
  • the group Q is
  • Ring A is a 5- or 6-membered heteroaryl group
  • ring B is a 5-8-membered heterocycloalkyl group or a 5- or 6-membered heteroaryl group
  • R 8 , R 9 , R 10 and R 11 are each independently hydrogen or halogen
  • n, f and g are each independently 0, 1 or 2; when there are multiple substituents R 8 , R 9 , R 10 and R 11 , the substituents R 8 , R 9 , R 10 and R 11 same or different;
  • R 1 , R 2 and R 3 are each independently hydrogen or C 1 -C 6 alkyl, C 1 -C 6 haloalkyl;
  • R 4 , R 5 and R 6 are each independently hydroxyl or
  • R 7 is C 1 -C 6 alkyl or C 1 -C 6 deuterated alkyl.
  • the halogen is independently fluorine , chlorine, bromine or iodine, such as fluorine or chlorine.
  • the C 1 -C 6 Alkyl is independently C 1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and is also, for example, methyl.
  • the halogen in the C 1 -C 6 haloalkyl is independently fluorine, chlorine, bromine or iodine, such as fluorine.
  • the C 1 -C 6 alkane in the -OC 1 -C 6 alkyl or -NH-C 1 -C 6 alkyl is independently C 1-4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • the C 1 -C 6 haloalkyl is independently a C 1 -C 4 haloalkyl , such as C 1 -C 4 alkyl substituted by 1, 2 or 3 F, also such as monofluoromethyl, difluoromethyl or trifluoromethyl.
  • the 3-6 membered cycloalkyl is independently propyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the number of heteroatoms in the 4-8 membered heterocycloalkyl group is 1, and the heteroatom is N, O or S (such as N) .
  • the C 1 -C 6 deuterated alkyl is a C 1 -C 4 deuterated alkyl, such as C 1 substituted by 1, 2 or 3 deuteriums -C 4 alkyl, also for example
  • the number of heteroatoms in the 5- or 6-membered heteroaryl is 1, and the heteroatoms can be N, O or S (such as N).
  • the number of heteroatoms in the 5-8 membered heterocycloalkyl group is 1, and the heteroatoms can be N, O or S (such as N).
  • the number of heteroatoms in the 5- or 6-membered heteroaryl is 1, and the heteroatoms can be N, O or S (such as N).
  • R 8 , R 9 , R 10 and R 11 are each independently hydrogen, deuterium, halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, -OC 1 -C 6 alkyl or -NH-C 1 -C 6 alkyl.
  • m, n, f and g are each independently 0, 1 or 2; when there are multiple substituents R 8 , R 9 , R 10 and R 11 , the substituent R 8 , R 9 , R 10 and R 11 are the same or different.
  • R 1 , R 2 , and R 3 are each independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
  • R 4 , R 5 and R 6 are each independently hydroxyl or
  • R 7 is C 1 -C 6 alkyl or C 1 -C 6 deuterated alkyl.
  • R 1 is methyl or trifluoromethyl.
  • R2 is hydrogen
  • R3 is trifluoromethyl
  • R 4 is
  • R 5 is hydroxyl
  • R6 is hydroxyl
  • R 7 is methyl or deuterated methyl (-CD 3 ).
  • R 8 is hydrogen or halogen; further, R 8 is hydrogen, fluorine or chlorine.
  • R9 is hydrogen
  • R10 is hydrogen
  • R 11 is hydrogen, fluorine or chlorine.
  • the R 2 is hydrogen; R 1 and R 3 are each independently fluorine, chlorine, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl or C 1 -C 3 Chloroalkyl.
  • R 1 is methyl or trifluoromethyl
  • R 2 is hydrogen
  • R 3 is trifluoromethyl
  • R 1 is methyl
  • R 2 is hydrogen
  • R 3 is trifluoro methyl
  • R 4 is R 5 and R 6 are hydroxyl groups.
  • R 7 is methyl, ethyl, propyl or C 1 -C 3 fluoroalkyl; preferably, R 7 is methyl.
  • R 7 is C 1 -C 3 deuterated alkyl; preferably, R 7 is deuterated methyl (-CD 3 ).
  • R 1 is methyl
  • R 2 is hydrogen
  • R 3 is 3-6 membered cycloalkyl; preferably, R 3 is cyclopropyl.
  • the heterocyclic compound shown in formula I has the structure Ia , Ib, Ic or Id;
  • the heterocyclic compound shown in formula I has the structure Ie, If or Ig;
  • ring A and ring B jointly contain 1, 2 or 3 N heteroatoms; optionally also contain 1 O or S heteroatom.
  • ring A is a 5- or 6-membered heteroaryl group
  • ring B is a 5- or 6-membered heteroaryl group
  • ring A and ring B together contain 1, 2 or 3 N heteroatoms.
  • ring A is a 5- or 6-membered heteroaryl group
  • ring B is a 5-8-membered heterocycloalkyl group; wherein, ring A and ring B together contain 1 or 2 N heteroatoms; optionally , Ring B also contains 1 O or S heteroatom.
  • ring A is a 5- or 6-membered heteroaryl group
  • ring B is a 5- or 6-membered heterocycloalkyl group.
  • Ring A is a 5- or 6-membered N-containing heteroaryl.
  • R 8 , R 9 , R 10 , and R 11 are each independently hydrogen, fluorine, chlorine, hydroxyl, amino, cyano, C 1 -C 6 alkyl, -OC 1 -C 6 alkane Group or -NH-C 1 -C 6 alkyl;
  • said R 8 , R 9 , R 10 , R 11 are each independently substituted by 1, 2, 3 or 4 substituents selected from the group consisting of fluorine, chlorine, C 1 -C 6 alkyl; when When there are plural substituents, the substituents are the same or different.
  • R 8 , R 9 , R 10 , and R 11 are each independently hydrogen, fluorine, chlorine, C 1 -C 3 alkyl, C 1 -C 3 fluoroalkyl or C 1 -C 3 Chloroalkyl; preferably, R 8 , R 9 , R 10 , R 11 are each independently hydrogen, fluorine or chlorine.
  • heterocyclic compound shown in formula I its tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs include:
  • heterocyclic compound shown in formula I its tautomers, stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs include:
  • a pharmaceutical composition comprising the heterocyclic compound, its tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug as described in the first aspect medicine.
  • a pharmaceutical composition comprising the heterocyclic compound as described in the first aspect, its tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug and
  • the heterocyclic compound represented by formula I its tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug as described in the first aspect, Or the use of the pharmaceutical composition as described in the second aspect, including:
  • the heterocyclic compound shown in formula I as described in the first aspect is used to prevent or to treat cancer.
  • the Pol ⁇ -mediated disease is cancer.
  • the present invention also provides the heterocyclic compound shown in formula I as described in the first aspect, its tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, or the heterocyclic compound shown in the first aspect Use of the pharmaceutical composition described in the second aspect in the preparation of medicines for treating cancer.
  • the present invention also provides the heterocyclic compound represented by formula I as described in the first aspect, its tautomer, stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, or the second
  • the pharmaceutical composition according to one aspect in the preparation of a drug for preventing and/or treating a disease is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.
  • the present invention also provides a method for treating diseases, comprising administering to a patient a therapeutically effective amount of a heterocyclic compound represented by formula I, its tautomers, stereoisomers, solvates, pharmaceutically acceptable salts, At least one of the prodrug or the pharmaceutical composition as described in the second aspect.
  • the disease is a disease mediated by Pol ⁇ .
  • the disease is a cell proliferative disorder; preferably, the cell proliferative disorder is cancer.
  • the patient is a mammal, preferably a human.
  • examples of cancers (and their benign counterparts) that can be treated (or inhibited) by the heterocyclic compound represented by formula I include but are not limited to: tumors of epithelial origin (adenoma and various types cancers, including adenocarcinoma, squamous carcinoma, transitional cell carcinoma, and others) such as bladder and urinary tract, breast, gastrointestinal (including esophageal, gastric (stomach), small intestine, colon, rectum cancer and anal cancer), liver cancer (hepatocellular carcinoma), gallbladder and biliary system cancer, exocrine pancreatic cancer, kidney, lung (such as adenocarcinoma, small cell lung cancer, non-small cell lung cancer, bronchioloalveolar carcinoma and mesothelioma), Cancers of the head and neck (eg, tongue, oral cavity, larynx, pharynx, nasopharynx, tonsils, salivary glands, nasal cavity and sinuse
  • reactions and purifications can be carried out using the manufacturer's instructions for the kit, or by methods known in the art or as described herein.
  • the techniques and methods described above can generally be performed according to conventional methods well known in the art as described in various general and more specific documents that are cited and discussed in this specification.
  • groups and substituents thereof can be selected by those skilled in the art to provide stable moieties and compounds.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left.
  • CH2O is equivalent to OCH2 .
  • halogen means fluorine, chlorine, bromine, iodine alone or as part of another substituent.
  • alkyl alone or as part of another substituent, means consisting solely of carbon and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms, and is bonded to the molecule by a single bond. The rest are connected straight or branched hydrocarbon chain groups.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl.
  • An alkyl group can be unsubstituted or substituted with one or more suitable substituents.
  • the alkyl groups may also be isotopomers of naturally abundant alkyl groups that are rich in carbon and/or hydrogen isotopes (ie, deuterium or tritium).
  • C 1 -C 6 alkyl alone or as part of another substituent is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl group is for example methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3
  • cycloalkyl or “carbocyclyl” by themselves or as part of another substituent refer to a cyclic alkyl group.
  • mn-membered cycloalkyl or " Cm - Cncycloalkyl” is understood to mean a saturated, unsaturated or partially saturated carbocycle having m to n atoms.
  • 3-15 membered cycloalkyl or “C 3 -C 15 cycloalkyl” refers to a cyclic alkyl group containing 3 to 15, 3 to 9, 3 to 6 or 3 to 5 carbon atoms, which May contain 1 to 4 rings.
  • "5-8 membered cycloalkyl” then contains 5-8 carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or bicyclic hydrocarbon groups such as decahydronaphthalene rings.
  • Cycloalkyl groups may be substituted with one or more substituents.
  • a cycloalkyl group can be a cycloalkyl group fused to an aryl or heteroaryl group.
  • C 3 -C 6 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. For example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
  • heterocyclyl or “5-8 membered heterocycloalkyl” is understood to mean a monocyclic, bicyclic or tricyclic ring having 5 to 8 atoms, wherein the heteroatoms are preferably selected from N, O and S, it is understood that when the total number of S atoms and O atoms in the heterocyclyl exceeds 1, these heteroatoms are not adjacent to each other.
  • heterocycloalkyl include, but are not limited to: tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl.
  • 5- or 6-membered heteroaryl is understood to mean an aromatic ring group having 5 or 6 ring atoms - and containing 1-5 heteroatoms independently selected from N, O and S, preferably 1-3 - an aromatic ring group independently selected from N, O and S heteroatoms.
  • heteroaryl groups include, but are not limited to: thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl , Thiadiazolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.
  • salt or “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects.
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects.
  • other salts are contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be useful in the identification, characterization or purification of compounds of the invention.
  • amine salt refers to the product obtained by neutralizing an alkyl primary, secondary or tertiary amine with an acid.
  • the acid includes an inorganic acid or an organic acid as described in this application.
  • stereoisomer refers to isomers resulting from differences in the arrangement of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereoisomers and conformers.
  • the compounds according to the invention may exist as one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as mixtures of isomers, for example as racemic and non- A mixture of enantiomers, depending on the number of asymmetric carbon atoms.
  • the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule.
  • the prefixes D and L or (+) and (-) are symbols used to designate the rotation of plane polarized light by a compound, where (-) or L indicates that the compound is levorotatory.
  • Compounds prefixed with (+) or D are dextrorotatory.
  • tautomer refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist in two or more interconvertible species.
  • Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms.
  • Tautomers generally exist in equilibrium and attempts to isolate a single tautomer usually result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the keto form predominates
  • the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • a "pharmaceutical composition” refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal (eg, a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredient and thus exert its biological activity.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory agency as acceptable for human or livestock use , diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent.
  • solvate means that the compound of the present invention or its salt includes a stoichiometric or non-stoichiometric solvent bonded by intermolecular non-covalent forces, and when the solvent is water, it is a hydrate.
  • prodrug refers to a compound of the invention that can be converted to biological activity under physiological conditions or by solvolysis.
  • the prodrugs of the present invention are prepared by modifying functional groups in the compounds which can be removed routinely or in vivo to yield the parent compound.
  • Prodrugs include compounds formed by linking a hydroxyl or amino group in the compound of the present invention to any group. When the prodrug of the compound of the present invention is administered to a mammalian individual, the prodrug is split to form free hydroxyl, free of amino.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds can be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • examples of categories of the term “excipient” include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flow and/or cohesiveness.
  • treatment and other similar synonyms include the following meanings:
  • the reaction temperature can be appropriately selected according to the solvent, starting material, reagent, etc.
  • the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting material, reagent, etc.
  • the target compound can be separated and purified from the reaction system according to common methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography and other methods. Without affecting the next step reaction, the target compound can also directly enter the next step reaction without separation and purification.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention is that the inventors have unexpectedly developed a heterocyclic compound as a Pol ⁇ inhibitor after extensive and in-depth research, and the heterocyclic compound has the structure shown in formula I in the present invention.
  • the heterocyclic compound of the present invention has a good inhibitory effect on Pol ⁇ protein polymerase, can prevent or treat diseases or diseases mediated by Pol ⁇ , exhibits excellent pharmacokinetic properties, and has high safety and pharmaceutical properties .
  • Embodiment 1 the preparation of compound I-1A and I-1B
  • the synthetic route is as follows:
  • the first step Synthesis of tert-butyl bicyclo[4.2.0]oct-1,3,5-trien-3-ylcarbamate
  • tert-Butyl bicyclo[4.2.0]oct-1,3,5-trien-3-yl(methyl)carbamate (0.4 g, 1.71 mmol) was added to ethyl acetate (5 mL) at 0 Slowly add dioxane/hydrogen chloride (2 mL) dropwise at °C. The reaction solution was reacted at room temperature for 12 hours, and the reaction solution was spin-dried to obtain a crude product.
  • reaction solution was reacted at room temperature for 0.5 hours, then N-methylbicyclo[4.2.0]oct-1,3,5-triene-3-amine (0.16g, 1.19mmol) was added, and the reaction solution was reacted at room temperature After 15 hours, the reaction of raw materials was complete. Water (50 mL) and ethyl acetate (100 mL) were added to the reaction solution, and the reaction solution was extracted with ethyl acetate (100 mL ⁇ 3).
  • the sixth step (2S,3R,4R)-N-(bicyclo[4.2.0]oct-1,3,5-trien-3-yl)-3,4-dihydroxy-N-methyl- 1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-carbonylpyrrolidine-2-carboxamide (I-1A) and (2S,3S,4S)-N-( Bicyclo[4.2.0]oct-1,3,5-trien-3-yl)-3,4-dihydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl ) pyridin-2-yl)-5-carbonylpyrrolidine-2-carboxamide (I-1B) synthesis
  • the synthetic route is as follows:
  • Ethylpyrrolo[1,2-b]pyridazine-2-carboxylate (700mg, 3.68mmol) was dissolved in absolute ethanol (3.50mL), tetrahydrofuran (7.00mL) and water (3.50mL), then After adding lithium hydroxide monohydrate (1.54 g, 36.80 mmol), the reaction solution was stirred at 25° C. for 12 hours.
  • Step 6 (3aS,4S,6aS)-2,2-Dimethyl-5-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-6-oxoylidene-N -(pyrrolo[1,2-b]pyridazin-2-yl)tetrahydro-4H-[1,3]dioxolano[4,5-c]pyrrole-4-carboxamide
  • reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, water (5 mL) was added to dilute, and then extracted with ethyl acetate (5.0 mL*3), the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product.
  • the separation method was: Waters Xbridge 150*25mm*5 ⁇ m; mobile phase: [water(NH 4 HCO 3 )-ACN]; B%:28%-58%, 8min , after purification afforded (2S,3S,4S)-3,4-dihydroxy-N-methyl-1-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-oxo Subunit-N-(pyrrolo[1,2-b]pyridazin-2-yl)pyrrolidine-2-carboxamide (3.00 mg, 10.7% yield).
  • the preparation method of the reference compound I refers to the patent WO2021/028643A1, and the structure is as follows,
  • Test example 1 compound is to Pol ⁇ polymerase active inhibition test
  • the recombinant Pol ⁇ protein polymerase domain (aa 1819-2590) used in this test was expressed and purified through the Bac-to-Bac baculovirus expression system of Invitrogen (Seki, M. et al. 2003 Nucleic Acids Res. ).
  • the assay used to measure Pol ⁇ polymerase activity is the PicoGreen dsDNA quantitative assay.
  • the reaction system consists of compounds dissolved in DMSO, purified recombinant Pol ⁇ (aa 1819-2590) protein, annealing mixture and dNTPs. All the compounds were prepared as 10mM stock solutions in DMSO first, and the experimental buffer (25mM Tris HCl pH 7.5, 12.5mM NaCl, 0.5mM MgCl 2 , 5% glycerol, 0.01% Triton X-100, 0.01% BGG and 1mM DTT) for gradient dilution; the recombinant protein solution is obtained by dissolving the recombinant Pol ⁇ (aa 1819-2590) protein with a final concentration of 30nM in the experimental buffer; the annealing mixture is the primer (5'-GCG GCT GTC ATA AG-3 with a final concentration of 150nM ') and template (5'-GCT ACA TTG ACA ATG GCA TCA AAT CTC AGA TTG CGT CTT ATG ACA GCC
  • test compound IC 50 (nM) Comparative compound I 30 I-1A 31 I-1B 6 I-2 48

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种作为Polθ抑制剂的式（I）化合物及其制备方法和用途。

Description

作为Polθ抑制剂的杂环化合物及其制备方法和用途
本申请要求申请日为2021年12月29日的中国专利申请2021116397603的优先权和2022年8月16日的中国专利申请2022109836085的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于医药领域，具体地，本发明涉及到一种作为Polθ抑制剂的杂环化合物及及其制备方法和用途。
背景技术
合成致死是目前抗肿瘤领域中一个新兴的研究方向，其中针对DNA修复途径的治疗是本专利的重点。部分肿瘤细胞由于基因突变，会造成某一DNA修复途径缺失，从而使得它们对于尚存的DNA修复途径过度依赖，此时针对这一尚存的DNA修复途径进行针对性抑制，就可特异性地杀死该类肿瘤细胞，而对正常的体细胞不具有杀伤作用。近年来，通过聚腺苷二磷酸核糖聚合酶[poly(ADP-ribose)polymerase，PARP]抑制剂治疗乳腺卵巢癌易感基因(breast and ovarian cancer susceptibility gene，BRCA)突变肿瘤的方法正是利用了靶向DNA修复缺陷的合成致死作用机制。
DNA双链断裂(DNA double strand breaks，DSBs)是最严重的DNA损伤之一。细胞中DNA双链断裂修复(DNA double strand breaks repair，DSBR)可大致分为三种途径完成，一种是非同源末端连接(non-homologous end-joining，NHEJ)，一种途径是同源重组(homologous recombination，HR),最后一种途径则是当NHEJ或HR受到损害时由DNA聚合酶θ(Polymeraseθ，Polθ，POLQ)介导的末端连接(alt-EJ)，也称为微同源介导的末端连接(MMEJ)。Polθ在微同源介导的末端连接过程中发挥核心作用。Polθ具有N端解旋酶结构域和C端DNA聚合酶结构域(S.Black et al.2016.Genes.)。研究显示Polθ的解旋酶域可促进微同源性的退火，退火后，通过核酸酶去除所有突出的碱基，并通过Polθ填补缺口。因此Polθ作为DNA修复缺陷的重要靶点受到了越来越多的关注。Polθ在正常组织中的几乎不表达，但在多种肿瘤类型(如乳腺癌、卵巢癌、HNSCC和肺癌)中过度表达而且与不良预后结果相关。研究显示当同源重组介导的修复受到损害时(HRD)，如BRCA1或BRCA2突变，Polθ高度表达并引导DSB修复朝向微同源介导的末端连接(MMEJ)发展，开启MMEJ的DNA修复过程。
由于Polθ在同源重组修复缺陷(HRD)肿瘤中至关重要,因此抑制Polθ是一种有前途的新型的合成致死治疗策略。
发明内容
本发明的目的是提供一种作为Polθ抑制剂的杂环化合物及其制备方法和用途，所述杂环化合物具有如本发明第一方面所示结构，所述杂环化合物可用于抑制Polθ聚合酶的活性，预防或治疗由Polθ 介导的疾病或病症。
本发明的第一方面提供了一种如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药：
Figure PCTCN2022143548-appb-000001
其中，基团Q为
Figure PCTCN2022143548-appb-000002
环A为5或6元杂芳基，环B为5-8元杂环烷基或5或6元杂芳基；
Y表示C；
R 8、R 9、R 10和R 11各自独立地为氢、氘、卤素、羟基、氨基、氰基、C 1-C 6烷基、-O-C 1-C 6烷基或-NH-C 1-C 6烷基；
任选地，所述R 8、R 9、R 10和R 11各自独立地被1、2、3或4个选自下列的取代基取代：氘、卤素、羟基、氨基、氰基和C 1-C 6烷基；当取代基为多个时，所述取代基相同或不同；
m、n、f和g各自独立地为0、1、2或3；当取代基R 8、R 9、R 10和R 11为多个时，所述取代基R 8、R 9、R 10和R 11相同或不同；
R 1、R 2和R 3各自独立地为氢、氘、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、3-6元环烷基或4-8元杂环烷基；
R 4、R 5和R 6各自独立地为氢、氘、卤素、羟基、氨基、
Figure PCTCN2022143548-appb-000003
C 1-C 6烷基或C 1-C 6卤代烷基；
R 7为C 1-C 6烷基、C 1-C 6氘代烷基或C 1-C 6卤代烷基。
本发明提供了一种如式I所示杂环化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：
Figure PCTCN2022143548-appb-000004
Figure PCTCN2022143548-appb-000005
其中，基团Q为
Figure PCTCN2022143548-appb-000006
环A为5或6元杂芳基，环B为5-8元杂环烷基或5或6元杂芳基；
Y表示C；
R 8、R 9、R 10和R 11各自独立地为氢、卤素、羟基、氨基、氰基、C 1-C 6烷基、-O-C 1-C 6烷基或-NH-C 1-C 6烷基；
任选地，所述R 8、R 9、R 10和R 11各自独立地被1、2、3或4个选自下列的取代基取代：卤素、羟基、氨基、氰基和C 1-C 6烷基；当取代基为多个时，所述取代基相同或不同；
m、n、f和g各自独立地为0、1、2或3；当取代基R 8、R 9、R 10和R 11为多个时，所述取代基R 8、R 9、R 10和R 11相同或不同；
R 1、R 2和R 3各自独立地为氢、卤素、C 1-C 6烷基或C 1-C 6卤代烷基；
R 4、R 5和R 6各自独立地为氢、卤素、羟基、氨基、
Figure PCTCN2022143548-appb-000007
C 1-C 6烷基或C 1-C 6卤代烷基；
R 7为C 1-C 6烷基或C 1-C 6卤代烷基。
在本发明中，所述的如式I所示的杂环化合物中某些取代基的定义可如任一方案所述。
在本发明一优选实施方案中，所述溶剂化物可为水合物。
本发明一优选实施方案中，如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药：
Figure PCTCN2022143548-appb-000008
其中，基团Q为
Figure PCTCN2022143548-appb-000009
环A为5或6元杂芳基，环B为5-8元杂环烷基或5或6元杂芳基；
Y表示C；
R 8、R 9、R 10和R 11各自独立地为氢或卤素；
m、n、f和g各自独立地为0、1或2；当取代基R 8、R 9、R 10和R 11为多个时，所述取代基R 8、 R 9、R 10和R 11相同或不同；
R 1、R 2和R 3各自独立地为氢或C 1-C 6烷基、C 1-C 6卤代烷基；
R 4、R 5和R 6各自独立地为羟基或
Figure PCTCN2022143548-appb-000010
R 7为C 1-C 6烷基或C 1-C 6氘代烷基。
在本发明一优选实施方案中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10和R 11中，所述卤素独立地为氟、氯、溴或碘，例如氟或氯。
在本发明一优选实施方案中，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10和R 11中，所述C 1-C 6烷基独立地为C 1-4烷基，例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，还例如为甲基。
在本发明一优选实施方案中，R 1、R 2、R 3、R 4、R 5、R 6和R 7中，所述C 1-C 6卤代烷基中卤素独立地为氟、氯、溴或碘，例如氟。
在本发明一优选实施方案中，R 8、R 9、R 10和R 11中，所述-O-C 1-C 6烷基或-NH-C 1-C 6烷基中C 1-C 6烷基独立地为C 1-4烷基，例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。
在本发明一优选实施方案中，R 1、R 2、R 3、R 4、R 5、R 6和R 7中，所述C 1-C 6卤代烷基独立地为C 1-C 4卤代烷基，例如被1个、2个或3个F取代的C 1-C 4烷基，还例如，一氟甲基、二氟甲基或三氟甲基。
在本发明一优选实施方案中，R 1、R 2和R 3中，所述3-6元环烷基独立地为丙基、环丁基、环戊基或环己基。
在本发明一优选实施方案中，R 1、R 2和R 3中，所述4-8元杂环烷基中的杂原子数为1个，杂原子为N、O或S(例如N)。
在本发明一优选实施方案中，R 7中，所述C 1-C 6氘代烷基为C 1-C 4氘代烷基，例如被1个、2个或3个氘取代的C 1-C 4烷基，还例如
Figure PCTCN2022143548-appb-000011
在本发明一优选实施方案中，环A中，所述5或6元杂芳基中的杂原子数为1个，杂原子可为N、O或S(例如N)。
在本发明一优选实施方案中，环B中，所述5-8元杂环烷基中的杂原子数为1个，杂原子可为N、O或S(例如N)。
在本发明一优选实施方案中，环B中，所述5或6元杂芳基中的杂原子数为1个，杂原子可为N、O或S(例如N)。
在本发明一优选实施方案中，R 8、R 9、R 10和R 11各自独立地为氢、氘、卤素、羟基、氨基、氰基、C 1-C 6烷基、-O-C 1-C 6烷基或-NH-C 1-C 6烷基。
在本发明一优选实施方案中，m、n、f和g各自独立地为0、1或2；当取代基R 8、R 9、R 10和R 11为多个时，所述取代基R 8、R 9、R 10和R 11相同或不同。
在本发明一优选实施方案中，R 1、R 2、R 3各自独立地为氢、C 1-C 6烷基或C 1-C 6卤代烷基。
在本发明一优选实施方案中，R 4、R 5和R 6各自独立地为羟基或
Figure PCTCN2022143548-appb-000012
在本发明一优选实施方案中，R 7为C 1-C 6烷基或C 1-C 6氘代烷基。
在本发明一优选实施方案中，R 1为甲基或三氟甲基。
在本发明一优选实施方案中，R 2为氢。
在本发明一优选实施方案中，R 3为三氟甲基。
在本发明一优选实施方案中，R 4为
Figure PCTCN2022143548-appb-000013
在本发明一优选实施方案中，R 5为羟基。
在本发明一优选实施方案中，R 6为羟基。
在本发明一优选实施方案中，R 7为甲基或氘代甲基(-CD 3)。
在本发明一优选实施方案中，R 8为氢或卤素；进一步地，R 8为氢、氟或氯。
在本发明一优选实施方案中，R 9为氢。
在本发明一优选实施方案中，R 10为氢。
在本发明一优选实施方案中，R 11为氢、氟或氯。
在一优选实施方式中，所述R 2为氢；R 1、R 3各自独立地为氟、氯、C 1-C 3烷基、C 1-C 3氟代烷基或C 1-C 3氯代烷基。
在一优选实施方式中，R 1为甲基或三氟甲基，R 2为氢，R 3为三氟甲基；进一步地，R 1为甲基，R 2为氢，R 3为三氟甲基。
在一优选实施方式中，R 4为
Figure PCTCN2022143548-appb-000014
R 5、R 6为羟基。
在一优选实施方式中，R 7为甲基、乙基、丙基或C 1-C 3氟代烷基；较佳地，R 7为甲基。
在一优选实施方式中，R 7为C 1-C 3氘代烷基；较佳地，R 7为氘代甲基(-CD 3)。
在一优选实施方式中，R 1为甲基，R 2为氢，R 3为3-6元环烷基；较佳地，R 3为环丙基。
在一优选实施方式中，所述的如式I所示杂环化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，具有结构Ia、Ib、Ic或Id；
Figure PCTCN2022143548-appb-000015
Figure PCTCN2022143548-appb-000016
其中，Q的定义如本发明第一方面中所述。
在一优选实施方式中，所述如式I所示杂环化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，具有结构Ie、If或Ig；
Figure PCTCN2022143548-appb-000017
Figure PCTCN2022143548-appb-000018
其中，Q的定义如本发明第一方面中所述。
在一优选实施方式中，环A、环B共同含有1、2或3个N杂原子；任选地还含有1个O或S杂原子。
在一优选实施方式中，环A为5或6元杂芳基，环B为5或6元杂芳基，且环A和环B共同含有1、2或3个N杂原子。
在一优选实施方式中，环A为5或6元杂芳基，环B为5-8元杂环烷基；其中，环A、环B共同含有1或2个N杂原子；任选地，环B还含有1个O或S杂原子。
在一优选实施方式中，环A为5或6元杂芳基，环B为5或6元杂环烷基。
在一优选实施方式中，环A为5或6元含N杂芳基。
在一优选实施方式中，在基团
Figure PCTCN2022143548-appb-000019
中，基团
Figure PCTCN2022143548-appb-000020
选自：
Figure PCTCN2022143548-appb-000021
Figure PCTCN2022143548-appb-000022
较佳地，基团
Figure PCTCN2022143548-appb-000023
选自：
Figure PCTCN2022143548-appb-000024
较佳地，基团
Figure PCTCN2022143548-appb-000025
选自：
Figure PCTCN2022143548-appb-000026
较佳地，基团
Figure PCTCN2022143548-appb-000027
选自：
Figure PCTCN2022143548-appb-000028
较佳地，基团
Figure PCTCN2022143548-appb-000029
选自：
Figure PCTCN2022143548-appb-000030
较佳地，基团
Figure PCTCN2022143548-appb-000031
选自：
Figure PCTCN2022143548-appb-000032
在一优选实施方式中，基团
Figure PCTCN2022143548-appb-000033
选自：
Figure PCTCN2022143548-appb-000034
Figure PCTCN2022143548-appb-000035
在一优选实施方式中，基团
Figure PCTCN2022143548-appb-000036
选自：
Figure PCTCN2022143548-appb-000037
Figure PCTCN2022143548-appb-000038
在一优选实施方式中，R 8、R 9、R 10、R 11各自独立地为氢、氟、氯、羟基、氨基、氰基、C 1-C 6烷基、-O-C 1-C 6烷基或-NH-C 1-C 6烷基；
任选地，所述R 8、R 9、R 10、R 11各自独立地被1、2、3或4个选自下列的取代基取代：氟、氯、C 1-C 6烷基；当取代基为多个时，所述取代基相同或不同。
在一优选实施方式中，R 8、R 9、R 10、R 11各自独立地为氢、氟、氯、C 1-C 3烷基、C 1-C 3氟代烷基或C 1-C 3氯代烷基；较佳地，R 8、R 9、R 10、R 11各自独立地为氢、氟或氯。
在一优选实施方式中，所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，包括：
Figure PCTCN2022143548-appb-000039
Figure PCTCN2022143548-appb-000040
Figure PCTCN2022143548-appb-000041
在一优选实施方式中，所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，包括：
Figure PCTCN2022143548-appb-000042
Figure PCTCN2022143548-appb-000043
Figure PCTCN2022143548-appb-000044
在本发明第二方面，提供了一种药物组合物，包括如第一方面所述的杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药。
提供了一种药物组合物，包括如第一方面所述的杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药和
i)一种或多种活性药物；和/或
ii)药学上可接受的载体。
在本发明第三方面，提供了如第一方面所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，或如第二方面所述的药物组合物的用途，包括：
抑制Polθ活性；
和/或，预防和/或治疗Polθ介导的疾病；
和/或，制备用于抑制Polθ，和/或预防和/或治疗Polθ介导的疾病的药物、药物组合物或制剂。
在一优选实施方式中，如第一方面所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药用于预防或治疗癌症。
在一优选实施方式中，所述Polθ介导的疾病为癌症。
在本发明还提供了如第一方面所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，或如第二方面所述的药物组合物在制备药物中的用途，所述药物用于治疗癌症。
本发明还提供了如第一方面所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，或如第二方面所述的药物组合物在制备预防和/或治疗疾病的药物中的应用，所述疾病为细胞增殖性病症；较佳地，所述细胞增殖性病症为癌症。
本发明还提供一种治疗疾病的方法，包括给与患者治疗有效量的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐、前药或如第二方面所述药物组合物中的至少一 种。
在本发明一优选实施方式中，所述疾病为与Polθ介导的疾病。
在本发明一优选实施方式中，所述疾病为细胞增殖性病症；较佳地，所述细胞增殖性病症为癌症。
在一些实施方案中，所述患者哺乳动物，优选是人。
在一优选实施方式中，所述如式I所示杂环化合物可以治疗(或抑制)的癌症(及其良性对应物)的实例包括但不限于：上皮来源的肿瘤(腺瘤和各种类型的癌，包括腺癌、鳞状癌、移行细胞癌和其他癌)如膀胱癌和泌尿道癌、乳腺癌、胃肠道癌(包括食道癌、胃癌(胃)、小肠癌、结肠癌、直肠癌和肛门癌)、肝癌(肝细胞癌)、胆囊和胆道系统癌、外分泌胰腺癌、肾、肺(例如腺癌、小细胞肺癌、非小细胞肺癌、细支气管肺泡癌和间皮瘤)、头颈癌(例如舌癌、口腔癌、喉癌、咽癌、鼻咽癌、扁桃体癌、唾液腺癌、鼻腔和鼻窦)、生殖系统(如卵巢、输卵管、腹膜、阴道、外阴、阴茎、子宫颈、子宫肌层、子宫内膜)癌、甲状腺癌(例如甲状腺滤泡癌)、肾上腺癌、前列腺癌、皮肤癌(例如黑色素瘤、基底细胞癌、鳞状细胞癌、角化棘皮瘤、发育不良痣)；血液系统恶性肿瘤(即白血病、淋巴瘤)和癌前血液系统疾病和交界性恶性肿瘤疾病，包括血液系统恶性肿瘤和相关淋巴系疾病(例如急性淋巴细胞白血病、慢性淋巴细胞白血病、B细胞淋巴瘤，例如弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、伯基特淋巴瘤、套细胞淋巴瘤、MALT淋巴瘤、T细胞淋巴瘤和白血病、自然杀伤细胞淋巴瘤、霍奇金淋巴瘤、毛细胞白血病、意义不明的单克隆丙种球蛋白病、浆细胞瘤、多发性骨髓瘤、和移植后淋巴组织增生性疾病)，以及血液系统恶性肿瘤和骨髓系相关疾病(例如急性髓性白血病、慢性髓性白血病、慢性粒单核细胞白血病、嗜酸性粒细胞增多症、骨髓增生性疾病，如真性红细胞增多症)、原发性血小板增多症和原发性骨髓纤维化、骨髓增生综合征、骨髓增生异常综合征和早幼粒细胞白血病)；间充质来源的肿瘤，例如软组织、骨或软骨的肉瘤，例如骨肉瘤、纤维肉瘤、软骨肉瘤、横纹肌肉瘤、平滑肌肉瘤、脂肪肉瘤、血管肉瘤、卡波西肉瘤、尤文氏肉瘤、胃肠道上皮肉瘤、上皮肉瘤、恶性上皮肉瘤组织细胞瘤和皮肤纤维肉瘤突起；中枢或外周神经系统肿瘤(例如星形细胞瘤、神经胶质瘤和胶质母细胞瘤、脑膜瘤、室管膜瘤、松果体瘤和神经鞘瘤)；内分泌肿瘤(例如垂体肿瘤、肾上腺肿瘤、胰岛细胞肿瘤、甲状旁腺肿瘤、类癌瘤和甲状腺髓样癌)；眼部和附件肿瘤(例如视网膜母细胞瘤)；生殖细胞和滋养细胞肿瘤(例如畸胎瘤、精原细胞瘤、无性细胞瘤、葡萄胎和绒毛膜癌)；以及儿科和胚胎肿瘤(例如髓母细胞瘤、神经母细胞瘤、Wilms肿瘤和原始神经外胚层肿瘤)；或先天性或使患者易患恶性肿瘤的其他方面的综合征(例如色素性干皮病)。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
术语和定义
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的 涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义，以本章的定义为准。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4THED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，CH 2O等同于OCH 2。如本文所用，
Figure PCTCN2022143548-appb-000045
表示基团的连接位点。
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。
本申请说明书和权利要求书记载的数值范围，当该数值范围被理解为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“1～6的整数”应当理解为记载了0、1、2、3、4、5和6的每一个整数。
在本申请中，在单独或作为其他取代基一部分时，术语“卤素”是指氟、氯、溴、碘。
如本文所用，在单独或作为其他取代基一部分时，术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至6个碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基，叔丁基，戊基，异戊基，新戊基和己基。烷基可以是未取代的或被一个或多个合适的取代基取代。烷基也可以是富含碳和/或氢的同位素(即氘或氚)的天然丰度烷基的同位素异构体。
在单独或作为其他取代基一部分时，术语“C 1-C 6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地，所述基团具有1、2或3个碳原子(“C 1-C 3烷基”)，例如甲基、乙基、正丙基或异丙基。
在单独或作为其他取代基一部分时，术语“环烷基”或“碳环基”是指一种环状烷基。术语“m-n元环烷基”或者“C m-C n环烷基”应理解为表示具有m至n个原子的饱和、不饱和或部分饱和的碳环。例如，“3-15元环烷基”或者“C 3-C 15环烷基”是指含有3至15，3至9，3至6或3至5个碳原子的环状烷基，它可能包含1至4个环。“5-8元环烷基”则含有5-8个碳原子。包括单环、二环、三环、螺环或桥环。未取代的环烷基的实例包括但不限于环丙基，环丁基，环戊基，环己基和金刚烷基，或者是双环烃基如十氢化萘环。环烷基可以被一个或多个取代基取代。在一些实施方案中，环烷基可以是与芳基或杂芳基稠合的环烷基。术语“C 3-C 6环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～6个碳原子，包括稠合或桥接的多环系统。例如环丙基、环丁基、环戊基、环己基。
在单独或作为其他取代基一部分时，“卤代烷基”指包括具有特定数目的碳原子、被一或多个卤素取代的支链和直链的饱和脂族烃基(如-CvFw，其中v＝1至3，w＝1至(2v+1))。卤代烷基的实例包括，但不限于三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。
术语“5-8元杂环基”或“5-8元杂环烷基”应理解为表示具有5至8个原子的单环、二环或三环，其中杂原子优选自N、O和S，应该理解的是，当杂环基中S原子和O原子的总数超过1时，这些杂原子不彼此相邻。杂环烷基的实例包括但不限于：四氢异喹啉基、四氢喹啉基、四氢吡喃基、四氢呋喃基、四氢噻喃基。
术语“5或6元杂芳基”应理解为具有5或6个环原子——且包含1-5个独立选自N、O和S的杂原子的芳族环基团，优选1-3个——独立选自N、O和S的杂原子的芳族环基团。杂芳基的实例包括但不限于：噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等。
在本申请中，“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。
在本申请中，术语“盐”或“药学上可接受的盐”，包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有 机酸所形成的盐。“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。除了药学可接受的盐外，本发明还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。
术语“胺盐”是指用酸中和烷基伯胺、仲胺或叔胺得到的产物。所述酸包括本申请中所述的无机酸或有机酸。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。
依据原料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物的形式存在，例如作为纯旋光异构体，或作为异构体混合物，如作为外消旋和非对映异构体混合物，这取决于不对称碳原子的数量。当描述具有光学活性的化合物时，使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号，其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。
当将本发明式中与手性碳的键描写直成线时，应当理解为，手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。用楔形键和虚线键表示一个立体中心的绝对构型。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
在本申请中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
术语“溶剂化物”指本发明化合物或其盐包括以分子间非共价力结合的化学计量或非化学计量的溶剂，当溶剂为水时，则为水合物。
术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本发明化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如， 可用放射性同位素标记化合物，比如氘( 2H)，氚( 3H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。
本文所用的术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
各步骤的反应，反应温度可因溶剂、起始原料、试剂等适宜选择，反应时间也可因反应温度、溶剂、起始原料、试剂等适宜选择。各步骤反应结束后，目标化合物可按常用方法自反应体系中进行分离、提纯等步骤，如过滤、萃取、重结晶、洗涤、硅胶柱层析等方法。在不影响下一步反应的情况下，目标化合物也可不经过分离、纯化直接进入下一步反应。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明人经过广泛而深入地研究，意外地开发了一种作为Polθ抑制剂的杂环化合物，所述杂环化合物具有本发明中式I所示结构。本发明所述杂环化合物对Polθ蛋白聚合酶有良好的抑制作用，可以预防或治疗由Polθ介导的疾病或病症，表现出优良的药代动力学性质，具备较高的安全性和成药性质。
具体实施方式
以下结合具体实施例，进一步说明本发明。需理解，以下的描述仅为本发明的最优选实施方式，而不应当被认为是对于本发明保护范围的限制。在充分理解本发明的基础上，下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件，本领域技术人员可以对本发明的技术方案作出非本质的改动，这样的改动应当被视为包括于本发明的保护范围之中的。
实施例1：化合物I-1A和I-1B的制备
合成路线如下所示：
Figure PCTCN2022143548-appb-000046
第一步：二环[4.2.0]辛-1,3,5-三烯-3-基氨基甲酸叔丁酯的合成
Figure PCTCN2022143548-appb-000047
将4-氨基苯并环丁烯(0.5g，4.2mmol)和碳酸氢钠(1.41g，16.78mmol)加入到二氧六环(5mL)和水(2mL)中,在室温下加入(Boc) 2O(1.83g,8.39mmol)，反应液在25℃下反应12h，薄层色谱(石油醚:乙酸乙酯(V/V)＝5:1)监测原料反应完全。反应液中加水(50mL)和乙酸乙酯(100mL)，反应液用乙酸乙酯(100mL×3)萃取。合并萃取液用饱和食盐水(50mL)洗涤，硫酸钠干燥，过滤，旋干得粗品，粗品用(石油醚:乙酸乙酯(V/V)＝100:1-1:1)过柱子纯化得到化合物二环[4.2.0]辛-1,3,5-三烯-3-基氨基甲酸叔丁酯(0.8g，产率87％)。
第二步：二环[4.2.0]辛-1,3,5-三烯-3-基(甲基)氨基甲酸叔丁酯的合成
Figure PCTCN2022143548-appb-000048
将二环[4.2.0]辛-1,3,5-三烯-3-基氨基甲酸叔丁酯(0.6g，2.74mmol)加入到四氢呋喃(10mL)中,在0℃下缓慢滴加NaH(0.164g，4.1mmol,60％),反应液在0℃下反应0.5h，再加入碘甲烷(0.47g，3.28mmol)，反应液在室温下反应4h。薄层色谱(石油醚:乙酸乙酯(V/V)＝3:1)监测原料反应完全。反应液中加水(50mL)和乙酸乙酯(100mL)，反应液用乙酸乙酯(100mL×3)萃取。合并萃取液用饱和食盐水(50mL)洗涤，硫酸钠干燥，过滤，旋干得粗品，粗品用(石油醚:乙酸乙酯(V/V)＝100:1-1:1)过柱子纯化得到化合物二环[4.2.0]辛-1,3,5-三烯-3-基(甲基)氨基甲酸叔丁酯(0.4g，产率62.7％)。
第三步：N-甲基二环[4.2.0]辛-1,3,5-三烯-3-胺的合成
Figure PCTCN2022143548-appb-000049
将二环[4.2.0]辛-1,3,5-三烯-3-基(甲基)氨基甲酸叔丁酯(0.4g，1.71mmol)加入到乙酸乙酯(5mL)中，在0℃下缓慢滴加二氧六环/氯化氢中(2mL)。反应液在室温下反应12小时，反应液旋干得到粗品。粗品用(石油醚:乙酸乙酯(V/V)＝5:1,10mL)打浆得到化合物N-甲基二环[4.2.0]辛-1,3,5-三烯-3-胺(0.2g，产率88.0％)。
第四步：(4S)-N-(二环[4.2.0]辛-1,3,5-三烯-3-基)-N,2,2-三甲基-6-羰基四氢-4H-[1,3]二噁唑并[4,5-c]吡咯-4-甲酰胺的合成
Figure PCTCN2022143548-appb-000050
将(4S)-2,2-二甲基-6-羰基四氢-4H-[1,3]二噁唑并[4,5-c]吡咯-4-甲酸(0.2g，0.994mmol)和吡啶(0.2mL)加入到N,N-二甲基甲酰胺(5mL)中，在室温下加入丙基磷酸酐(1.13g，1.49mmol，50％N,N-二甲基甲酰胺溶液)中。反应液在室温下反应0.5小时，再加入N-甲基二环[4.2.0]辛-1,3,5-三烯-3-胺(0.16g，1.19mmol)，反应液在室温下反应15h，原料反应完全。反应液中加水(50mL)和乙酸乙酯(100mL)，反应液用乙酸乙酯(100mL×3)萃取。合并萃取液用饱和食盐水(50mL)洗涤，硫酸钠干燥，过滤，旋干得粗品，粗品用(石油醚:乙酸乙酯(V/V)＝100:1-1:100)过柱子纯化得到化合物(4S)-N-(二环[4.2.0]辛-1,3,5-三烯-3-基)-N,2,2-三甲基-6-羰基四氢-4H-[1,3]二噁唑并[4,5-c]吡咯-4-甲酰胺(0.1g，产率31.8％)。
第五步：(4S)-N-(二环[4.2.0]辛-1,3,5-三烯-3-基)-N,2,2-三甲基-6-羰基四氢-4H-[1,3]二噁唑并[4,5-c]吡咯-4-甲酰胺的合成
Figure PCTCN2022143548-appb-000051
将(4S)-N-(二环[4.2.0]辛-1,3,5-三烯-3-基)-N,2,2-三甲基-6-羰基四氢-4H-[1,3]二噁唑并[4,5-c]吡咯-4-甲酰胺(0.1g，0.32mmol)，Cs 2CO 3(0.154g，0.474mmol)，2-氯-6-甲基-4-(三氟甲基)吡啶(0.074g，0.38mmol)，4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(0.018g，0.032mmol)和Pd 2(dba) 3加入到二氧六环(10mL)中，反应液升温至110℃反应15小时。薄层色谱(石油醚:乙酸乙酯(V/V)＝1:1)监测原料 反应完全。将反应混合物用水(50mL)稀释，然后用乙酸乙酯(100mL×2)萃取，合并有机层，用饱和食盐水(50mL)洗涤有机相，硫酸钠干燥，浓缩得到粗品。粗品用(石油醚:乙酸乙酯(V/V)＝100:1-1:100)过柱子纯化得到化合物(4S)-N-(二环[4.2.0]辛-1,3,5-三烯-3-基)-N,2,2-三甲基-6-羰基四氢-4H-[1,3]二噁唑并[4,5-c]吡咯-4-甲酰胺(0.1g，产率66.5％)。
第六步：(2S,3R,4R)-N-(二环[4.2.0]辛-1,3,5-三烯-3-基)-3,4-二羟基-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-羰基吡咯烷-2-甲酰胺(I-1A)和(2S,3S,4S)-N-(二环[4.2.0]辛-1,3,5-三烯-3-基)-3,4-二羟基-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-羰基吡咯烷-2-甲酰胺(I-1B)合成
Figure PCTCN2022143548-appb-000052
将4S)-N-(二环[4.2.0]辛-1,3,5-三烯-3-基)-N,2,2-三甲基-6-羰基四氢-4H-[1,3]二噁唑并[4,5-c]吡咯-4-甲酰胺(0.1g，0.21mmol)加入到无水二氯甲烷(5mL)中，在-20℃下加入三氯化硼(0.63mL，1.0mmol/L)中。反应液在-20℃下反应2小时，原料反应完全。反应液中加水(50mL)和二氯甲烷(100mL)，反应液用二氯甲烷(100mL×3)萃取。合并萃取液用饱和食盐水(50mL)洗涤，硫酸钠干燥，过滤，旋干得粗品，粗品经反相制备(column:Phenomenex Synergi C18 150*25mm*10μm；流动相:[水(0.225％甲酸)-乙腈]；B％:18％-52％,12min)分离得到(2S,3R,4R)-N-(二环[4.2.0]辛-1,3,5-三烯-3-基)-3,4-二羟基-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-羰基吡咯烷-2-甲酰胺(I-1A)(10mg，产率11％)和(2S,3S,4S)-N-(二环[4.2.0]辛-1,3,5-三烯-3-基)-3,4-二羟基-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-羰基吡咯烷-2-甲酰胺(I-1B)(4mg，产率6.5％)。
化合物I-1A：
1H NMR(400MHz,DMSO)δ8.43(s,1H),7.39(s,2H),7.32(s,1H),7.23(d,J＝7.8Hz,1H),5.85(d,J＝7.4Hz,1H),5.32(d,J＝4.4Hz,1H),4.76(s,1H),4.37–4.31(m,2H),3.17(s,4H),3.15(s,3H),2.57(s,3H)。
LC-MS,M/Z(ESI):436.5[M+H] +。
化合物I-1B：
1H NMR(400MHz,DMSO)δ8.22(s,1H),7.37(s,1H),7.34(d,J＝8.0Hz,1H),7.24(d,J＝6.2Hz,2H),5.49(d,J＝8.6Hz,1H),5.32(d,J＝5.0Hz,1H),4.88(d,J＝5.6Hz,1H),4.23–4.15(m,1H),3.98(dd,J＝10.6,5.4Hz,1H),3.17(s,4H),3.10(s,3H),2.55(s,3H)。
LC-MS,M/Z(ESI):436.5[M+H] +。
实施例2
合成路线如下所示：
Figure PCTCN2022143548-appb-000053
第一步：(E)-4-(二甲氨基)-2-氧亚基丁-3-烯酸乙酯
Figure PCTCN2022143548-appb-000054
将N,N-二甲基甲酰胺二甲基缩醛(10.0g,83.9mmol)和丙酮酸乙酯(9.94g,85.6mmol)混合，反应液在25℃条件下搅拌12小时。反应完成后，直接减压浓缩得到褐色液体粗品(E)-4-(二甲氨基)-2-氧亚基丁-3-烯酸乙酯(16.0g，粗品)。
第二步：吡咯并[1,2-b]哒嗪-2-甲酸乙酯
Figure PCTCN2022143548-appb-000055
将1-氨基吡咯(2.50g,250mmol)和(E)-4-(二甲氨基)-2-氧亚基丁-3-烯酸乙酯(15.6g,91.3mmol)溶于乙醇(25.0mL)中，然后在0℃下缓慢加入浓盐酸(23.50g,23.04mL,37.8％纯度)，反应液在0℃条件下搅拌30分钟。反应完成后，在0℃下慢慢加入饱和碳酸氢钠溶液300mL进行淬灭，直至气泡不再产生，然后用乙酸乙酯(100mL*3)萃取，有机相用饱和氯化钠溶液(200mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到棕色液体的粗品，粗品经反相高效液相色谱法进行分离纯化得到乙基吡咯并[1,2-b]哒嗪-2-甲酸基酯(1.50g,产率：29.5％)。 1H NMR(400MHz,DMSO-d 6)δ＝8.08-8.14(m,1H)8.07(dd,J＝2.38,1.26Hz,1H)7.16(d,J＝9.38Hz,1H)7.08(dd,J＝4.26,2.76Hz,1H)6.69(dd,J＝4.32,1.44Hz,1H)4.37(q,J＝7.10Hz,2H)1.34(t,J＝7.14Hz,3H).
第三步：吡咯并[1,2-b]哒嗪-2-甲酸
Figure PCTCN2022143548-appb-000056
将乙基吡咯并[1,2-b]哒嗪-2-甲酸基酯(700mg,3.68mmol)溶于无水乙醇(3.50mL)、四氢呋喃(7.00mL)和水(3.50mL)中，然后加入氢氧化锂的一水合物(1.54g,36.80mmol)后，反应液在25℃条件下搅拌12小时。反应完成后，用盐酸(1M)调节反应液pH至3～4左右，然后用乙酸乙酯(20mL*3)萃取，有机相用饱和氯化钠溶液(20mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到粗品：吡咯并[1,2-b]哒嗪-2-甲酸(700mg，粗品)。
第四步：吡咯并[1,2-b]哒嗪-2-胺
Figure PCTCN2022143548-appb-000057
将吡咯并[1,2-b]哒嗪-2-甲酸(1.50g,18.5mmol)溶于甲苯(30.0mL)中，然后分别加入三乙胺(3.75g,37.1mmol)、叠氮磷酸二苯酯(10.2g,37.1mmol)和水(1.65g,92.5mmol)，反应液在90℃条件下搅拌2小时。反应完成后，直接浓缩得到粗品，粗品经柱层析(流动相为石油醚：乙酸乙酯＝10:1-3:1)得到：吡咯并[1,2-b]哒嗪-2-胺(750mg，产率：24.3％)。 1H NMR(400MHz,DMSO-d 6)δ＝7.57(d,J＝9.38Hz,1H),7.31(s,1H),6.40-6.52(m,1H),6.23(d,J＝3.26Hz,1H),6.15(d,J＝9.38Hz,1H),5.79-5.96(m,2H).
第五步：(3aS,4S,6aS)-2,2-二甲基-6-氧亚基-N-(吡咯并[1,2-b]哒嗪-2-基)四氢-4H-[1,3]二噁戊环并[4,5-c]吡咯-4-甲酰胺
Figure PCTCN2022143548-appb-000058
将(3aS,6S,6aS)-2,2-二甲基-4-氧亚基-3a,5,6,6a-四氢-[1,3]二噁戊环并[4,5-c]吡咯-6-甲酸(151mg,751μmol)溶解在二氯甲烷(3.00mL)中，然后在0℃条件加入1-氯-N,N,2-三甲基-丙-1-烯-1-胺(301mg,2.25mmol)，反应液在0℃下搅拌30分钟。然后在0℃条件下加入吡啶(237mg,3.00mmol)和N-甲基吡唑并[1,5-a]吡啶-6-胺(100mg,751.03μmol)。最后，反应液在25℃下搅拌2小时。反应完成后，直接浓缩得到黄色油状物(3aS,4S,6aS)-2,2-二甲基-6-氧亚基-N-(吡咯并[1,2-b]哒嗪-2-基)四氢-4H-[1,3]二噁戊环并[4,5-c]吡咯-4-甲酰胺(160mg，粗品)。LCMS,M/Z(ESI):317.2[M+H] +。
第六步：(3aS,4S,6aS)-2,2-二甲基-5-(6-甲基-4-(三氟甲基)吡啶-2-基)-6-氧亚基-N-(吡咯并[1,2-b]哒嗪-2-基)四氢-4H-[1,3]二噁戊环并[4,5-c]吡咯-4-甲酰胺
Figure PCTCN2022143548-appb-000059
将(S)-N-(5-氯-2,4-二氟苯基)-N,4,4-三甲基-5-氧亚基吡咯烷-2-甲酰胺(160mg,505μmol)和2-氯-6-甲基-4-(三氟甲基)吡啶(148mg,758μmol)溶解在1,4-二氧六环(4.00mL)中，然后在室温和氮气保护下分别加入碳酸钾(209mg,1.52mmol)、三(二亚苄基丙酮)二钯(69.5mg,75.8μmol,)和4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(87.8mg,151μmol)，氮气置换三次后，反应液在95℃搅拌12小时。反应完成后，直接过滤浓缩得到棕色的油状物，粗品经Prep-TLC(流动相为石油醚：乙酸乙酯＝2:1)分离纯化得到黄色液体：(3aS,4S,6aS)-2,2-二甲基-5-(6-甲基-4-(三氟甲基)吡啶-2-基)-6-氧亚基-N-(吡咯并[1,2-b]哒嗪-2-基)四氢-3aH-[1,3]二噁戊环并[4,5-c]吡咯-4-甲酰胺(150mg，粗品)。LCMS,M/Z(ESI):476.2[M+H] +。
第七步：(3aS,4S,6aS)-N,2,2-三甲基-5-(6-甲基-4-(三氟甲基)吡啶-2-基)-6-氧亚基-N-(吡咯并[1,2-b]哒嗪-2-基)四氢-3aH-[1,3]二噁戊环并[4,5-c]吡咯-4-甲酰胺
Figure PCTCN2022143548-appb-000060
将(3aS,4S,6aS)-2,2-二甲基-5-(6-甲基-4-(三氟甲基)吡啶-2-基)-6-氧亚基-N-(吡咯并[1,2-b]哒嗪-2-基)四氢-3aH-[1,3]二噁戊环并[4,5-c]吡咯-4-甲酰胺溶解在N,N-二甲基甲酰胺(2.00mL)中，然后加入碳酸铯(68.53mg,210.34μmol)，反应液在25℃下搅拌30分钟，最后缓慢滴加碘甲烷(44.7mg,315μmol)。反应液在25℃下搅拌2小时。反应完成后，加入水(5mL)稀释，然后用乙酸乙酯(5.0mL*3)萃取，有机相用饱和氯化钠溶液(10mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到粗品。粗品：(3aS,4S,6aS)-N,2,2-三甲基-5-(6-甲基-4-(三氟甲基)吡啶-2-基)-6-氧亚基-N-(吡咯并[1,2-b]哒嗪-2-基)四氢-3aH-[1,3]二噁戊环并[4,5-c]吡咯-4-甲酰胺(20.0mg，粗品)。LCMS,M/Z(ESI):490.1[M+H] +。
第八步：(2S,3S,4S)-3,4-二羟基-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-氧亚基-N-(吡咯并[1,2-b]哒嗪-2-基)吡咯烷-2-甲酰胺(I-2)
Figure PCTCN2022143548-appb-000061
将(3aS,4S,6aS)-N,2,2-三甲基-5-(6-甲基-4-(三氟甲基)吡啶-2-基)-6-氧亚基-N-(吡咯并[1,2-b]哒嗪-2- 基)四氢-3aH-[1,3]二噁戊环并[4,5-c]吡咯-4-甲酰胺(10.0mg,20.4μmol)溶解在二氯甲烷(1.00mL)中，然后在-20℃下缓慢滴加三氯化硼的二氯甲烷溶液(1M,61.3μL)，最后，反应液在25℃搅拌12小时。反应完成后，用饱和碳酸氢钠溶液调pH为9，然后用二氯甲烷(10.0mL*3)萃取，有机相用饱和氯化钠溶液(20.0mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到粗品。粗品经反相高效液相色谱法进行分离纯化，分离方法为：Waters Xbridge 150*25mm*5μm；mobile phase:[water(NH 4HCO 3)-ACN]；B％:28％-58％,8min，纯化后得到(2S,3S,4S)-3,4-二羟基-N-甲基-1-(6-甲基-4-(三氟甲基)吡啶-2-基)-5-氧亚基-N-(吡咯并[1,2-b]哒嗪-2-基)吡咯烷-2-甲酰胺(3.00mg，产率10.7％)。
1H NMR(400MHz,METHANOL-d 4)δ＝8.39(s,1H),8.05(s,1H),7.83(s,1H),7.27(s,1H),6.82-7.05(m,2H),6.67(s,1H),5.10-5.39,(m,1H),4.68(br s,1H),4.59(s,2H),4.35(d,J＝5.62Hz,1H),3.40(m,3H),2.59(s,3H).
实施例3
以下化合物的制备方法参考实施例1和2，
Figure PCTCN2022143548-appb-000062
Figure PCTCN2022143548-appb-000063
Figure PCTCN2022143548-appb-000064
在本发明测试例中，对照化合物I制备方法参考专利WO2021/028643A1，结构如下所示，
Figure PCTCN2022143548-appb-000065
对照化合物I
测试例1:化合物对Polθ聚合酶活性抑制试验
本测试所使用的重组Polθ蛋白聚合酶结构域(aa 1819-2590)是通过Invitrogen公司的Bac-to-Bac杆状病毒表达系统表达和纯化得到(Seki,M.et al.2003 Nucleic Acids Res.)。测量Polθ聚合酶活性所使用的检测方法为PicoGreen dsDNA定量检测。
反应体系由溶解于DMSO的化合物、纯化的重组Polθ(aa 1819-2590)蛋白、退火混合物及dNTPs组成。其中所有化合物先用DMSO配制成10mM储备液，使用前用实验缓冲液(25mM Tris HCl pH 7.5，12.5mM NaCl，0.5mM MgCl 2，5％甘油，0.01％Triton X-100,0.01％BGG和1mM DTT)进行梯度稀释；重组蛋白溶液为终浓度30nM的重组Polθ(aa 1819-2590)蛋白溶解于实验缓冲液中所得；退火混合物为终浓度150nM的引物(5'-GCG GCT GTC ATA AG-3')和终浓度150nM的模板(5'-GCT ACA TTG ACA ATG GCA TCA AAT CTC AGA TTG CGT CTT ATG ACA GCC)溶解于实验缓冲液中，加热至42℃ 3min后退火所得；dNTP溶液为终浓度为120μM的dNTP溶解于实验缓冲液中所得。
化合物筛选实验中，先在384孔板(Perkin Elmer-Proxiplate)中加入2μl/well的重组蛋白溶液，随后依次加入0.06μl/well的不同浓度化合物及阴性对照(DMSO)，最后加入2μl/well的退火混合物和2μl/well的dNTP。空白对照组仅含有退火混合物和dNTP。将此384孔板用铝箔封口膜密封后，置于37℃下孵育30min，然后通过向测试孔中加入4μl反应终止液(25mM Tris-HCl,10mM阳EDTA以及1:80PicoGreen)终止反应，并于常温避光孵育90min后，在酶标仪(PerkinElmer
Figure PCTCN2022143548-appb-000066
λex＝485nmλem＝520nm)上读取荧光值。抑制率如下计算:抑制率＝(1-(化合物组-空白组)/(阴性对照组-空白组))×100％,使用GraphPad Prism8软件计算各化合物的IC 50值。
表1.化合物对Polθ聚合酶活性抑制结果
测试化合物 IC 50(nM)
对照化合物I 30
I-1A 31
I-1B 6
I-2 48
实验结果表明：本发明化合物对Polθ蛋白聚合酶有良好的抑制作用。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (17)

  1. 一种如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药：
    Figure PCTCN2022143548-appb-100001
    其中，基团Q为
    Figure PCTCN2022143548-appb-100002
    环A为5或6元杂芳基，环B为5-8元杂环烷基或5或6元杂芳基；
    Y表示C；
    R 8、R 9、R 10和R 11各自独立地为氢、氘、卤素、羟基、氨基、氰基、C 1-C 6烷基、-O-C 1-C 6烷基或-NH-C 1-C 6烷基；
    任选地，所述R 8、R 9、R 10和R 11各自独立地被1、2、3或4个选自下列的取代基取代：氘、卤素、羟基、氨基、氰基和C 1-C 6烷基；当取代基为多个时，所述取代基相同或不同；
    m、n、f和g各自独立地为0、1、2或3；当取代基R 8、R 9、R 10和R 11为多个时，所述取代基R 8、R 9、R 10和R 11相同或不同；
    R 1、R 2和R 3各自独立地为氢、氘、卤素、C 1-C 6烷基、C 1-C 6卤代烷基、3-6元环烷基或4-8元杂环烷基；
    R 4、R 5和R 6各自独立地为氢、氘、卤素、羟基、氨基、
    Figure PCTCN2022143548-appb-100003
    C 1-C 6烷基或C 1-C 6卤代烷基；
    R 7为C 1-C 6烷基、C 1-C 6氘代烷基或C 1-C 6卤代烷基。
  2. 根据权利要求1中所述的如式I所示杂环化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药：
    Figure PCTCN2022143548-appb-100004
    Figure PCTCN2022143548-appb-100005
    其中，基团Q为
    Figure PCTCN2022143548-appb-100006
    环A为5或6元杂芳基，环B为5-8元杂环烷基或5或6元杂芳基；
    Y表示C；
    R 8、R 9、R 10和R 11各自独立地为氢、卤素、羟基、氨基、氰基、C 1-C 6烷基、-O-C 1-C 6烷基或-NH-C 1-C 6烷基；
    任选地，所述R 8、R 9、R 10和R 11各自独立地被1、2、3或4个选自下列的取代基取代：卤素、羟基、氨基、氰基和C 1-C 6烷基；当取代基为多个时，所述取代基相同或不同；
    m、n、f和g各自独立地为0、1、2或3；当取代基R 8、R 9、R 10和R 11为多个时，所述取代基R 8、R 9、R 10和R 11相同或不同；
    R 1、R 2和R 3各自独立地为氢、卤素、C 1-C 6烷基或C 1-C 6卤代烷基；
    R 4、R 5和R 6各自独立地为氢、卤素、羟基、氨基、
    Figure PCTCN2022143548-appb-100007
    C 1-C 6烷基或C 1-C 6卤代烷基；
    R 7为C 1-C 6烷基或C 1-C 6卤代烷基。
  3. 根据权利要求1中所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药：
    Figure PCTCN2022143548-appb-100008
    其中，基团Q为
    Figure PCTCN2022143548-appb-100009
    环A为5或6元杂芳基，环B为5-8元杂环烷基或5或6元杂芳基；
    Y表示C；
    R 8、R 9、R 10和R 11各自独立地为氢或卤素；
    m、n、f和g各自独立地为0、1或2；当取代基R 8、R 9、R 10和R 11为多个时，所述取代基R 8、R 9、R 10和R 11相同或不同；
    R 1、R 2和R 3各自独立地为氢或C 1-C 6烷基、C 1-C 6卤代烷基；
    R 4、R 5和R 6各自独立地为羟基或
    Figure PCTCN2022143548-appb-100010
    R 7为C 1-C 6烷基或C 1-C 6氘代烷基。
  4. 根据权利要求1-3中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，其满足以下条件中的一种或多种：
    (1)R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10和R 11中，所述卤素独立地为氟、氯、溴或碘，例如氟或氯；
    (2)R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10和R 11中，所述C 1-C 6烷基独立地为C 1-4烷基，例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，还例如为甲基；
    (3)R 1、R 2、R 3、R 4、R 5、R 6和R 7中，所述C 1-C 6卤代烷基中卤素独立地为氟、氯、溴或碘，例如氟；
    (4)R 8、R 9、R 10和R 11中，所述-O-C 1-C 6烷基或-NH-C 1-C 6烷基中C 1-C 6烷基独立地为C 1-4烷基，例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    (5)R 1、R 2、R 3、R 4、R 5、R 6和R 7中，所述C 1-C 6卤代烷基独立地为C 1-C 4卤代烷基，例如被1个、2个或3个F取代的C 1-C 4烷基，还例如，一氟甲基、二氟甲基或三氟甲基；
    (6)R 1、R 2和R 3中，所述3-6元环烷基独立地为丙基、环丁基、环戊基或环己基；
    (7)R 1、R 2和R 3中，所述4-8元杂环烷基中的杂原子数为1个；
    (8)R 1、R 2和R 3中，所述4-8元杂环烷基中的杂原子为N、O或S，例如N；
    (9)R 7中，所述C 1-C 6氘代烷基为C 1-C 4氘代烷基，例如被1个、2个或3个氘取代的C 1-C 4烷基，还例如
    Figure PCTCN2022143548-appb-100011
    (10)环A中，所述5或6元杂芳基中的杂原子数为1个；
    (11)环A中，所述5或6元杂芳基中的杂原子为N、O或S，例如N；
    (12)环B中，所述5-8元杂环烷基中的杂原子数为1个；
    (13)环B中，所述5-8元杂环烷基中的杂原子为N、O或S，例如N；
    (14)环B中，所述5或6元杂芳基中的杂原子数为1个；和
    (15)环B中，所述5或6元杂芳基中的杂原子为N、O或S，例如N。
  5. 根据权利要求1-3中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，其满足以下条件中的一种或多种：
    (1)R 1、R 2和R 3各自独立地为氢、C 1-C 6烷基或C 1-C 6卤代烷基；
    (2)R 4、R 5和R 6各自独立地为羟基或
    Figure PCTCN2022143548-appb-100012
    (3)R 7为C 1-C 6烷基或C 1-C 6氘代烷基；
    (4)R 8、R 9、R 10和R 11各自独立地为氢、氘、卤素、羟基、氨基、氰基、C 1-C 6烷基、-O-C 1-C 6烷基或-NH-C 1-C 6烷基；
    (5)m、n、f和g各自独立地为0、1或2；当取代基R 8、R 9、R 10和R 11为多个时，所述取代基R 8、R 9、R 10和R 11相同或不同；
    (6)环A、环B共同含有1、2或3个N杂原子；任选地还含有1个O或S杂原子；
    进一步地，
    (7)R 1为甲基或三氟甲基；
    (8)R 2为氢；
    (9)R 3为三氟甲基；
    (10)R 4为
    Figure PCTCN2022143548-appb-100013
    (11)R 5为羟基；
    (12)R 6为羟基；
    (13)R 7为甲基或氘代甲基；
    (14)R 8为氢或卤素；进一步地，R 8为氢、氟或氯；
    (15)R 9为氢；
    (16)R 10为氢；和
    (17)R 11为氢、氟或氯。
  6. 根据权利要求1-3中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，环A为5或6元杂芳基，环B为5或6元杂芳基，且环A和环B共同含有1、2或3个N杂原子。
  7. 根据权利要求1-3中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，环A为5或6元杂芳基，环B为5-8元杂环烷基；其中，环A、环B共同含有1或2个N杂原子；任选地，环B还含有1个O或S杂原子；进一步地，环A为5或6元杂芳基，优选环A为5或6元含N杂芳基，环B为5或6元杂环烷基。
  8. 根据权利要求1-3中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，其满足以下条件中的一种或多种：
    (1)R 2为氢；R 1、R 3各自独立地为氟、氯、C 1-C 3烷基、C 1-C 3氟代烷基或C 1-C 3氯代烷基；进一步地，R 1为甲基或三氟甲基，R 2为氢，R 3为三氟甲基；更进一步地，R 1为甲基，R 2为氢，R 3为三氟甲基；
    (2)R 4为
    Figure PCTCN2022143548-appb-100014
    R 5、R 6为羟基；
    (3)R 7为甲基、乙基、丙基或C 1-C 3氟代烷基；较佳地，R 7为甲基；
    (4)R 7为C 1-C 3氘代烷基；较佳地，R 7为氘代甲基；
    (5)R 1为甲基，R 2为氢，R 3为3-6元环烷基；较佳地，R 3为环丙基；
    (6)R 8、R 9、R 10、R 11各自独立地为氢、氟、氯、羟基、氨基、氰基、C 1-C 6烷基、-O-C 1-C 6烷基或-NH-C 1-C 6烷基；
    (7)R 8、R 9、R 10、R 11各自独立地被1、2、3或4个选自下列的取代基取代：氟、氯、C 1-C 6烷基；当取代基为多个时，所述取代基相同或不同；
    进一步地，
    (8)R 8、R 9、R 10、R 11各自独立地为氢、氟、氯、C 1-C 3烷基、C 1-C 3氟代烷基或C 1-C 3氯代烷基；较佳地，R 8、R 9、R 10、R 11各自独立地为氢、氟或氯。
  9. 根据权利要求1-3中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，具有结构Ia、Ib、Ic或Id；
    Figure PCTCN2022143548-appb-100015
    其中，基团Q的定义如权利要求1-3中任一项所述。
  10. 根据权利要求1-3中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，具有结构Ie、If或Ig；
    Figure PCTCN2022143548-appb-100016
    Figure PCTCN2022143548-appb-100017
    其中，基团Q的定义如权利要求1-3中任一项所述。
  11. 根据权利要求1-3中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，在基团
    Figure PCTCN2022143548-appb-100018
    中，基团
    Figure PCTCN2022143548-appb-100019
    选自：
    Figure PCTCN2022143548-appb-100020
    较佳地，基团
    Figure PCTCN2022143548-appb-100021
    选自：
    Figure PCTCN2022143548-appb-100022
    基团
    Figure PCTCN2022143548-appb-100023
    选自：
    Figure PCTCN2022143548-appb-100024
    Figure PCTCN2022143548-appb-100025
    基团
    Figure PCTCN2022143548-appb-100026
    选自：
    Figure PCTCN2022143548-appb-100027
    基团
    Figure PCTCN2022143548-appb-100028
    选自：
    Figure PCTCN2022143548-appb-100029
    基团
    Figure PCTCN2022143548-appb-100030
    选自：
    Figure PCTCN2022143548-appb-100031
    Figure PCTCN2022143548-appb-100032
    进一步地，
    基团
    Figure PCTCN2022143548-appb-100033
    选自：
    Figure PCTCN2022143548-appb-100034
    Figure PCTCN2022143548-appb-100035
    基团
    Figure PCTCN2022143548-appb-100036
    选自：
    Figure PCTCN2022143548-appb-100037
    Figure PCTCN2022143548-appb-100038
  12. 根据权利要求1-11中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药，其特征在于，
    Figure PCTCN2022143548-appb-100039
    Figure PCTCN2022143548-appb-100040
    具体地，
    Figure PCTCN2022143548-appb-100041
    Figure PCTCN2022143548-appb-100042
    Figure PCTCN2022143548-appb-100043
  13. 一种药物组合物，其特征在于，包括根据权利要求1-12中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药。
  14. 根据权利要求13中所述的药物组合物，其特征在于，包括根据权利要求1-12中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药和
    i)一种或多种活性药物；和/或
    ii)药学上可接受的载体。
  15. 根据权利要求1-12中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药或根据权利要求13-14中任一项所述的药物组合物的用途，其特征在于，包括：
    抑制Polθ活性；
    和/或，预防和/或治疗Polθ介导的疾病；
    和/或，制备用于抑制Polθ，和/或预防和/或治疗Polθ介导的疾病的药物、药物组合物或制剂。
  16. 根据权利要求15所述的用途，其特征在于，所述Polθ介导的疾病为细胞增殖性病症；较佳地，所述细胞增殖性病症为癌症。
  17. 根据权利要求1-12中任一项所述的如式I所示杂环化合物、其互变异构体、立体异构体、溶剂化物、药学上可接受的盐或前药或根据权利要求13-14中任一项所述的药物组合物在制备预防和/或治疗疾病的药物中的应用，所述的疾病为细胞增殖性病症；较佳地，所述细胞增殖性病症为癌症。
PCT/CN2022/143548 2021-12-29 2022-12-29 作为Polθ抑制剂的杂环化合物及其制备方法和用途 WO2023125841A1 (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202111639760 2021-12-29
CN202111639760.3 2021-12-29
CN202210983608 2022-08-16
CN202210983608.5 2022-08-16

Publications (1)

Publication Number Publication Date
WO2023125841A1 true WO2023125841A1 (zh) 2023-07-06

Family

ID=86905810

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/143548 WO2023125841A1 (zh) 2021-12-29 2022-12-29 作为Polθ抑制剂的杂环化合物及其制备方法和用途

Country Status (2)

Country Link
CN (1) CN116354926A (zh)
WO (1) WO2023125841A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024069592A1 (en) * 2022-09-29 2024-04-04 Repare Therapeutics Inc. N-(5-substituted-[(l,3,4-thiadiazolyl) or (l,3-thiazolyl)](substituted)carboxamide compounds, pharmaceutical compositions, and methods of preparing the amide compounds and of their use

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120142677A1 (en) * 2009-01-05 2012-06-07 Boehringer Ingelheim International Gmbh Pyrrolidine Compounds Which Modulate The CB2 Receptor
WO2021028643A1 (en) * 2019-08-09 2021-02-18 Artios Pharma Limited Heterocyclic compounds for use in the treatment of cancer
WO2021028670A1 (en) * 2019-08-09 2021-02-18 Artios Pharma Limited Deuterated compounds for use in the treatment of cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120142677A1 (en) * 2009-01-05 2012-06-07 Boehringer Ingelheim International Gmbh Pyrrolidine Compounds Which Modulate The CB2 Receptor
WO2021028643A1 (en) * 2019-08-09 2021-02-18 Artios Pharma Limited Heterocyclic compounds for use in the treatment of cancer
WO2021028670A1 (en) * 2019-08-09 2021-02-18 Artios Pharma Limited Deuterated compounds for use in the treatment of cancer

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024069592A1 (en) * 2022-09-29 2024-04-04 Repare Therapeutics Inc. N-(5-substituted-[(l,3,4-thiadiazolyl) or (l,3-thiazolyl)](substituted)carboxamide compounds, pharmaceutical compositions, and methods of preparing the amide compounds and of their use

Also Published As

Publication number Publication date
CN116354926A (zh) 2023-06-30

Similar Documents

Publication Publication Date Title
WO2021063346A1 (zh) Kras g12c抑制剂及其应用
CN112047948B (zh) Kras突变体抑制剂
CA3177261A1 (en) Benzothiazolyl biaryl compound, and preparation method and use
JP2024102236A (ja) Ｐｒｍｔ５阻害剤
JP6457623B2 (ja) ２，４−二置換７Ｈ−ピロロ［２，３−ｄ］ピリミジン誘導体、その製造方法および医薬における使用
WO2015127872A1 (zh) 2,4-二取代苯-1,5-二胺衍生物及其应用以及由其制备的药物组合物和药用组合物
WO2018118842A1 (en) Amine-substituted heterocyclic compounds as ehmt2 inhibitors and methods of use thereof
CN111499634B (zh) 一种喹唑啉化合物及其在医药上的应用
CN111171049B (zh) 酪氨酸激酶抑制剂及其用途
WO2022135432A1 (zh) 作为egfr抑制剂的大环杂环类化合物及其应用
WO2016173557A1 (zh) 一类具有激酶抑制活性的化合物、制备方法和用途
CN106749267B (zh) 新的表皮生长因子受体抑制剂及其应用
US11267815B2 (en) Class of amino-substituted nitrogen-containing fused ring compounds, preparation method therefor, and use thereof
WO2018028664A1 (zh) Fgfr4抑制剂及其制备方法和应用
CN111484481A (zh) 哒嗪酮类衍生物、其制备方法及其在医药上的用途
JP2024505732A (ja) ピリドピリミジノン系誘導体及びその製造方法と使用
WO2022193982A1 (zh) Krasg12c突变蛋白抑制剂的制备及其应用
WO2023125841A1 (zh) 作为Polθ抑制剂的杂环化合物及其制备方法和用途
CN115197221A (zh) 二氢吡唑并嘧啶酮类大环衍生物及其用途
CN111635373B (zh) 多环磺酰胺类RORγ调节剂
TW202341987A (zh) 一種Polθ抑制劑
WO2023134753A1 (zh) 微管蛋白-src双靶点抑制剂
WO2020156162A1 (zh) Mek抑制剂及其在医药上的应用
CN109761986A (zh) 三并环类衍生物抑制剂、其制备方法和应用
WO2023025136A1 (zh) 异吲哚啉酮化合物及其用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22915090

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE