WO2023051759A1 - 三环化合物及其制备方法 - Google Patents

三环化合物及其制备方法 Download PDF

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Publication number
WO2023051759A1
WO2023051759A1 PCT/CN2022/123111 CN2022123111W WO2023051759A1 WO 2023051759 A1 WO2023051759 A1 WO 2023051759A1 CN 2022123111 W CN2022123111 W CN 2022123111W WO 2023051759 A1 WO2023051759 A1 WO 2023051759A1
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membered
compound
pharmaceutically acceptable
alkyl
acceptable salt
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PCT/CN2022/123111
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English (en)
French (fr)
Inventor
李云飞
王艳辉
刘彪
贾云静
张瑱
林晓燕
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上海拓界生物医药科技有限公司
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Priority to CN202280060548.8A priority Critical patent/CN117999264A/zh
Publication of WO2023051759A1 publication Critical patent/WO2023051759A1/zh

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    • 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
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • the disclosure belongs to the field of medicine, and relates to a tricyclic compound and a preparation method thereof.
  • Mucosa-associated-lymphoid-tissuelymphoma-translocation1 is an important protein molecule in the upstream of NF- ⁇ B signaling pathway, which is similar to B-cell chronic lymphocytic leukemia/lymphoma protein (B-cell Chronic lymphocyticleukemia/lymphoma10, BCL10) and membrane-associated guanylate kinase 1 (caspase-recruitment domain (CARD) containing membrane-associated guanylatekinase protein 1, CARMA1) with caspase recruitment structure form a complex CBM, which integrates the proximal antigen receptor protein signal Delivered to I ⁇ B kinase (IKK), which in turn activates the NF- ⁇ B signaling pathway. Excessive activation of MALT1-NF- ⁇ B signaling pathway is closely related to inflammation and tumorigenesis.
  • the disclosure provides a compound shown in formula I or a pharmaceutically acceptable salt thereof
  • Z is selected from S, O or CR 7 ;
  • X is selected from C or N;
  • Y is selected from C or N;
  • R 1 and R 2 form 3-7 membered cycloalkyl, 5-8 membered heterocycloalkyl, 5-8 membered heteroaryl, phenyl with adjacent atoms;
  • R 3 , R 6 , R 7 or R 8 are independently selected from hydrogen, C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, -O-3-7 membered cycloalkyl , nitro, cyano, halogen, hydroxyl, amino, -CONH 2 , 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5 -6-membered heteroaryl, phenyl, benzyl, methanesulfonyl, wherein said C 1-6 alkyl, 3-6-membered cycloalkyl, -OC 1-6 alkyl, -O-3-7 Cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -O-3-6-membered heterocycloalkyl, -O-5-6-membered heteroaryl, phen
  • n is an integer selected from 0-5;
  • n is an integer selected from 1-3;
  • R 4 or R 5 are independently selected from hydrogen, C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, -O-3-7 membered cycloalkyl, nitro, cyano , halogen, hydroxyl, amino, -CONH 2 , 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 membered heteroaryl , oxo, phenyl, benzyl; said C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, -O-3-7 membered cycloalkyl, -CONH 2 , 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 membered heteroaryl, phenyl, benzyl are optionally
  • R 4 and R 5 form 3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, phenyl with adjacent atoms; said 3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, and phenyl are optionally substituted by one or more R 5a ;
  • R 9 , R 4a or R 5a are independently selected from oxo, nitro, cyano, halogen, hydroxyl, amino, C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, -O-3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 membered heteroaryl , aryl, benzyl; said C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, -O-3-7 membered cycloalkyl, 3-6 membered heterocycloalkane Base, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 membered heteroaryl, aryl, benzyl are optionally replaced by one or more selected from oxo,
  • X and Y are C atoms.
  • the present disclosure also provides a compound represented by formula I-a, I-b, I-c, I-d or a pharmaceutically acceptable salt thereof
  • R 1 and R 2 form a 3-7 membered cycloalkyl group with adjacent atoms.
  • R 1 and R 2 form a 5-8 membered heterocycloalkyl group with adjacent atoms.
  • R 1 and R 2 form a 5-8 membered heteroaryl group with adjacent atoms.
  • R and R form with adjacent atoms
  • R is selected from hydrogen, C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, -O-3-7-membered cycloalkyl, nitro, cyano, halogen, hydroxyl, amino, -CONH 2 , 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 membered heteroaryl, methanesulfonyl,; wherein said C 1-6 alkyl, 3-6 membered cycloalkyl, -OC 1 -6 alkyl, -O-3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5- 6-
  • R 3 is selected from C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1- 6 alkyl, -O-3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 Member heteroaryl; wherein said C 1-6 alkyl, 3-6 member cycloalkyl, -OC 1-6 alkyl, -O-3-7 member cycloalkyl, 3-6 member heterocycloalkane Base, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 membered heteroaryl are optionally substituted by 1-3 R 9 .
  • R 3 is selected from nitro, cyano, halogen, hydroxyl, amino, -CONH 2 , methylsulfonyl .
  • R is selected from hydrogen, C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, -O-3-7-membered cycloalkyl, nitro, cyano, halogen, hydroxyl, amino, -CONH 2 , 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 membered heteroaryl, methanesulfonyl,; wherein said C 1-6 alkyl, 3-6 membered cycloalkyl, -OC 1 -6 alkyl, -O-3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5- 6-
  • R 7 is selected from C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1- 6 alkyl, -O-3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 Member heteroaryl; wherein said C 1-6 alkyl, 3-6 member cycloalkyl, -OC 1-6 alkyl, -O-3-7 member cycloalkyl, 3-6 member heterocycloalkane Base, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 membered heteroaryl are optionally substituted by 1-3 R 9 .
  • R 7 is selected from nitro, cyano, halogen, hydroxyl, amino, -CONH 2 , methylsulfonyl .
  • R 7 is hydrogen
  • R is selected from hydrogen, C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, -O-3-7-membered cycloalkyl, nitro, cyano, halogen, hydroxyl, amino, -CONH 2 , 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 membered heteroaryl, methanesulfonyl, wherein said C 1-6 alkyl, 3-6 membered cycloalkyl, -OC 1- 6 alkyl, -O-3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 The membere
  • R 6 is selected from C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1- 6 alkyl, -O-3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 Member heteroaryl; wherein said C 1-6 alkyl, 3-6 member cycloalkyl, -OC 1-6 alkyl, -O-3-7 member cycloalkyl, 3-6 member heterocycloalkane Base, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 membered heteroaryl are optionally substituted by 1-3 R 9 .
  • R 6 is selected from hydrogen, nitro, cyano, halogen, hydroxyl, amino, -CONH 2 , formazan Sulfonyl; preferably R6 is selected from hydrogen.
  • R 4 and R 5 form 3-7 membered cycloalkyl, 3-6 membered Heterocycloalkyl; the 3-7 membered cycloalkyl and 3-6 membered heterocycloalkyl are optionally substituted by one or more R 5a .
  • R 4 or R 5 are independently selected from hydrogen, C 1-6 alkyl, 3-7 membered ring Alkyl, -OC 1-6 alkyl, -O-3-7 membered cycloalkyl, nitro, cyano, halogen, hydroxyl, amino, -CONH 2 , 3-6 membered heterocycloalkyl, 5-6 Heteroaryl, -O-3-6-membered heterocycloalkyl, -O-5-6-membered heteroaryl, oxo; the C 1-6 alkyl, 3-7-membered cycloalkyl, -OC 1-6- membered alkyl, -O-3-7-membered cycloalkyl, -CONH 2 , 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -O-3-6-membered heterocycloalkyl, nitro, cyano, halogen, hydroxyl, amino, -CONH 2 , 3-6 member
  • R 4 or R 5 are independently selected from hydrogen, nitro, cyano, halogen, hydroxyl, amino, Oxo, -CONH 2 .
  • R 4 or R 5 are independently selected from hydrogen, C 1-6 alkyl, 3-7 membered ring Alkyl, -OC 1-6 alkyl, -O-3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl , -O-5-6 membered heteroaryl; said C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, -O-3-7 membered cycloalkyl, 3- 6-membered heterocycloalkyl, 5-6-membered heteroaryl, -O-3-6-membered heterocycloalkyl, -O-5-6-membered heteroaryl are optionally substituted by 1-3 R 4a .
  • R 4 or R 5 are independently selected from C 1-6 alkyl, 3-7 membered cycloalkyl , -OC 1-6 alkyl, hydroxyl, 5-6 membered heteroaryl; said C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, 5-6 membered heteroaryl
  • the group is optionally substituted by 1-3 R 4a .
  • R in the compound represented by formula I, Ia, Ib, Ic, Id or a pharmaceutically acceptable salt thereof is independently selected from hydrogen, C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1-6- membered alkyl, -O-3-7-membered cycloalkyl, nitro, cyano, halogen, hydroxyl, amino, -CONH 2 , 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl Base, -O-3-6 membered heterocycloalkyl, -O-5-6 membered heteroaryl, methanesulfonyl, wherein said C 1-6 alkyl, 3-6 membered cycloalkyl, -OC 1-6 alkyl, -O-3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl,
  • R 8 is selected from C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1- 6 alkyl, -O-3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 Member heteroaryl; wherein said C 1-6 alkyl, 3-6 member cycloalkyl, -OC 1-6 alkyl, -O-3-7 member cycloalkyl, 3-6 member heterocycloalkane Base, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 membered heteroaryl are optionally substituted by 1-3 R 9 .
  • R 8 is selected from hydrogen, nitro, cyano, halogen, hydroxyl, amino, -CONH 2 , formazan Sulfonyl; preferably R is selected from hydrogen.
  • R9 is independently selected from oxo, nitro, cyano, halogen, hydroxyl, amino, C1 -6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, -O-3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, - O-3-6 membered heterocycloalkyl, -O-5-6 membered heteroaryl; said C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, -O- 3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 membered heteroaryl are optionally 1-3 selected from ox
  • R in the compound shown in formula I, Ia, Ib, Ic, Id or its pharmaceutically acceptable salt is independently selected from oxo, nitro, cyano, halogen, hydroxyl, amino; preferably R 9 is halogen.
  • R in the compound represented by formula I, Ia, Ib , Ic, Id or a pharmaceutically acceptable salt thereof is independently selected from C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, -O-3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5 -6-membered heteroaryl; the C 1-6- membered alkyl, 3-7-membered cycloalkyl, -OC 1-6- membered alkyl, -O-3-7-membered cycloalkyl, 3-6-membered heterocycloalkane Base, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 membered heteroaryl are optionally replaced by 1-3 members selected from oxo, nitro, cyano
  • R in the compound represented by formula I, Ia, Ib , Ic, Id or a pharmaceutically acceptable salt thereof is independently selected from C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, -O-3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5 -6 membered heteroaryl.
  • R 4a is independently selected from oxo, nitro, cyano, halogen, hydroxyl, amino, C 1 -6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, -O-3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, - O-3-6 membered heterocycloalkyl, -O-5-6 membered heteroaryl; said C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, -O- 3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 membered heteroaryl are optionally 1-3 selected from o
  • R in the compound shown in formula I, Ia, Ib, Ic, Id or its pharmaceutically acceptable salt is independently selected from oxo, nitro, cyano, halogen, hydroxyl, amino; preferably R 4a is halogen.
  • R 4a is independently selected from C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, -O-3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5 -6-membered heteroaryl; the C 1-6- membered alkyl, 3-7-membered cycloalkyl, -OC 1-6- membered alkyl, -O-3-7-membered cycloalkyl, 3-6-membered heterocycloalkane Base, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 membered heteroaryl are optionally replaced by 1-3 members selected from oxo, nitro, cyano
  • R 4a is independently selected from C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, -O-3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5 -6 membered heteroaryl.
  • R 5a is independently selected from oxo, nitro, cyano, halogen, hydroxyl, amino, C 1 -6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, -O-3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, - O-3-6 membered heterocycloalkyl, -O-5-6 membered heteroaryl; said C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, -O- 3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 membered heteroaryl are optionally 1-3 selected from oxo
  • R in the compound shown in formula I, Ia, Ib, Ic, Id or its pharmaceutically acceptable salt is independently selected from oxo, nitro, cyano, halogen, hydroxyl, amino; preferably R 5a is halogen.
  • R in the compound represented by formula I, Ia, Ib, Ic, Id or a pharmaceutically acceptable salt thereof is independently selected from C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, -O-3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5 -6-membered heteroaryl; the C 1-6- membered alkyl, 3-7-membered cycloalkyl, -OC 1-6- membered alkyl, -O-3-7-membered cycloalkyl, 3-6-membered heterocycloalkane Base, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5-6 membered heteroaryl are optionally replaced by 1-3 members selected from oxo, nitro, cyano,
  • R in the compound represented by formula I, Ia, Ib, Ic, Id or a pharmaceutically acceptable salt thereof is independently selected from C 1-6 alkyl, 3-7 membered cycloalkyl, -OC 1-6 alkyl, -O-3-7 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -O-3-6 membered heterocycloalkyl, -O-5 -6 membered heteroaryl.
  • R 3 is selected from cyano, fluorine, chlorine, methyl, difluoromethyl, -CH 2 CHF 2. Ethyl, -OCHF 2 , -CH 2 CF 3 , -CH(OH)CH 3 ; preferably R 3 is chlorine.
  • R 4 or R 5 are independently selected from hydrogen, methyl, methoxy, trifluoromethyl, Difluoromethyl, cyclopropyl, -CH 2 OCH 3 ; preferably R 4 is selected from methyl, R 4 is selected from trifluoromethyl.
  • the present disclosure also provides a compound structure as shown below or a pharmaceutically acceptable salt thereof
  • the present disclosure also provides a compound structure as shown below or a pharmaceutically acceptable salt thereof
  • the present disclosure also provides an isotope substitution of the compound shown in the first aspect to the fourth aspect, preferably, the isotope substitution is deuterium atom substitution.
  • the present disclosure also provides a pharmaceutical composition, including the compound or pharmaceutically acceptable salt thereof described in the first aspect to the fourth aspect, and a pharmaceutically acceptable excipient.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition contains 0.01%-99.99% of pharmaceutically acceptable excipients based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1%-99% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 2%-98% of pharmaceutically acceptable excipients.
  • the present disclosure also provides a method for preventing and/or treating patients with MALT1-related disorders, by administering to the patient a therapeutically effective amount of the compound as described in the first aspect to the fourth aspect or its druggable Use the salt, or the isotope substitution described in the fifth aspect, or the pharmaceutical composition described in the sixth aspect.
  • the relevant diseases include but are not limited to autoimmune diseases, inflammatory diseases, cancers, tumors, etc., such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus or vasculitic diseases, primary cancers of the hematopoietic system or Solid tumors, including chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas.
  • autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus or vasculitic diseases, primary cancers of the hematopoietic system or Solid tumors, including chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas.
  • the present disclosure provides a method for preventing and/or treating patients with autoimmune diseases, inflammatory diseases, cancers, and tumors, by administering a therapeutically effective amount of the compound described in the first to third or fourth aspects to the patient Or a pharmaceutically acceptable salt thereof, or the isotope substitution described in the fourth and fifth aspects, or the pharmaceutical composition described in the fifth and sixth aspects
  • Such diseases include, but are not limited to, autoimmune and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus or vasculitic diseases, primary cancers of the hematopoietic system or solid tumors, including chronic myeloid leukemia, myelogenous leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas.
  • autoimmune and inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus or vasculitic diseases, primary cancers of the hematopoietic system or solid tumors, including chronic myeloid leukemia, myelogenous leukemia, non-Hodgkin's lymphoma, and other B-cell lymphomas.
  • the present disclosure also provides the compounds described in the first aspect to the third aspect or their pharmaceutically acceptable salts, or the isotope substitutions described in the fourth aspect, or the pharmaceutical composition described in the fifth aspect in the preparation for preventing and/or Or use in medicines for the treatment of diseases associated with MALT1.
  • the present disclosure also provides the compounds described in the first aspect to the third aspect or their pharmaceutically acceptable salts, or the isotope substitutions described in the fourth aspect, or the pharmaceutical composition described in the fifth aspect in the preparation for preventing and/or Or use in medicines for treating autoimmune diseases, inflammatory diseases, cancers, and tumors.
  • the compounds of the present disclosure or their pharmaceutically acceptable salts or pharmaceutical compositions have a good inhibitory effect on MALT1, and the IC50 value of the MALT1 inhibitory activity is between 0.01 and 1000nM, and the IC50 value of the MALT1 inhibitory activity of some compounds is between 0.01 to 500nM, some compounds have an IC50 value of MALT1 inhibitory activity between 0.01 and 300nM, some compounds have an IC50 value of MALT1 enzyme inhibitory activity between 0.01 and 200nM, and some compounds have an IC50 value of MALT1 enzyme inhibitory activity between 0.01 and 500nM. 0.01 to 100nM, some compounds have an IC50 value of ⁇ 100nM for the inhibitory activity of the MALT1 enzyme, and some compounds have an IC50 value of ⁇ 50nM for the inhibitory activity of the MALT1 enzyme.
  • compositions described in the present disclosure may be selected from inorganic or organic salts.
  • Compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • the bond Indicates unassigned configuration, i.e. if chiral isomers exist in the chemical structure, the bond can be or both Two configurations.
  • the bond If the configuration is not specified, it can be Z configuration or E configuration, or both E and Z configurations are included.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • lactam-lactim isomerization
  • An example of a lactam-lactim equilibrium is between A and B as shown below.
  • the present disclosure also includes certain isotopically labeled compounds of the disclosure that are identical to those described herein, but wherein one or more atoms are replaced by an atom of an atomic mass or mass number different from that normally found in nature.
  • isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e., at least 10 % deuterium incorporation).
  • exemplary compounds having a natural abundance greater than deuterium can be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 5000 times more abundant deuterium, at least 6000 times more abundant deuterium, or more abundant deuterium.
  • the present disclosure also includes various deuterated forms of compounds of formula (I). Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
  • deuterated starting materials can be used in the preparation of deuterated forms of compounds of formula (I), or they can be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • Optionally or “optionally” means that the subsequently described event or circumstance may but need not occur, and the description includes occasions where the event or circumstance occurs or does not occur.
  • the C 1-6 alkyl” means that a halogen or a cyano group may but not necessarily exist, and this specification includes the case where the alkyl group is substituted by a halogen or a cyano group and the case where the alkyl group is not substituted by a halogen or a cyano group.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically acceptable carriers and excipients. Forming agent.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable excipients” include, but are not limited to, any adjuvants, carriers, glidants, sweeteners, diluents that have been approved by the U.S. Food and Drug Administration (FDA) to be acceptable for human or livestock use , preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic or emulsifying agent.
  • FDA Food and Drug Administration
  • an “effective amount” or “therapeutically effective amount” as used in the present disclosure includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition.
  • An effective amount also means an amount sufficient to permit or facilitate diagnosis.
  • Effective amounts for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects.
  • An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • Alkyl refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. An alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched isomers, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, 3 to 7 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, said alkyl, alkoxy, ring Alkyl or heterocycloalkyl is optionally substituted with halo, hydroxy, nitro, cyano or amino.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 7 carbon atoms.
  • monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.
  • multicyclic cycloalkyls include spiro Cycloalkyls of rings, parallel rings and bridged rings.
  • Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo , cyano, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, 3 to 7 membered cycloalkyl or 3 to 7 membered heterocycloalkyl, the alkyl, alkoxy, Cycloalkyl or heterocycloalkyl is optionally substituted with halo, hydroxy, nitro, nitro, cyano or amino.
  • heterocycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O ) m (where m is an integer from 0 to 2), excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • m is an integer from 0 to 2
  • it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably it contains 3 to 7 ring atoms; more preferably it contains 3 to 6 ring atoms.
  • Non-limiting examples of “heterocycloalkyl” include:
  • heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring bonded to the parent structure is a heterocycloalkyl, non-limiting examples of which include:
  • Heterocycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, 3 to 7 membered cycloalkyl or 3 to 7 membered heterocycloalkyl, the alkyl, alkoxy, cycloalkyl or heterocycloalkyl optionally Substituted by halogen, hydroxy, nitro, cyano or amino.
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy.
  • Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, cyano, amino, nitro , C 1-6 alkyl, C 1-6 alkoxy, 3 to 7 membered cycloalkyl or 3 to 7 membered heterocycloalkyl, said alkyl, alkoxy, cycloalkyl or heterocycloalkyl Optionally substituted by halo, hydroxy, nitro, cyano or amino.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 12 membered, having a conjugated pi-electron system, such as benzene base and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C1-6 Alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, 3-6 membered cycloalkoxy, 3-6 membered heterocycloalkoxy, C 3-8 Cycloalkenyloxy, 5 to 6-membered aryl or heteroaryl, the C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, 3 6-membered cycloalkoxy, 3-6 membered heterocycloalkoxy, 3-8 membered cycloalkenyloxy, 5-6 membered aryl or heteroaryl are optionally selected from one or more halogen, hydroxyl, cyano, amino, C 1-6 alkyl or C 1-6 al
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 6 to 12 membered, more preferably 5 or 6 membered.
  • Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl , Thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl, wait.
  • the heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from halogen, hydroxy, cyano, amino, C alkane group or C 1-6 alkoxy group (here needs to be adjusted according to the claims!).
  • spiro refers to a compound in which two rings share one atom.
  • spirocycloalkyl groups include:
  • merged ring refers to a compound formed by combining two or more rings by sharing two adjacent atoms.
  • cycloalkyl groups include:
  • bridged ring refers to a structure formed by two or more ring structures sharing two non-adjacent ring atoms with each other. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • hydroxyl refers to a -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • cyano refers to -CN.
  • amino refers to -NH2 .
  • nitro refers to -NO2 .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents.
  • two (2) hydrogens on the atom are replaced.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS was determined by Shimadzu 2010 Mass Spectrometer or Agilent 6110A MSD mass spectrometer.
  • HPLC uses Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent Agilent 1200 LC high pressure liquid chromatography (Ultimate XB-C18 3.0*150mm column or Xtimate C18 2.1*30mm column).
  • Chiralpak IC-3 100 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 150 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3um, Chiralpak AS-3 150 ⁇ 4.6mm were used for chiral HPLC analysis and determination I.D., 3um, Chiralpak AS-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OD-3 150 ⁇ 4.6mm I.D., 3um, Chiralcel OD-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OJ-H 150 ⁇ 4.6mm I.D., 5um, Chiralcel OJ-3 150 ⁇ 4.6mm I.D., 3um column;
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ⁇ 0.5mm.
  • the chiral preparative column uses DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).
  • the CombiFlash rapid preparation instrument uses Combiflash Rf150 (TELEDYNE ISCO).
  • the known starting materials of the present disclosure can be adopted or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui chemical companies.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation instrument and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation instrument.
  • the hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin-layer chromatography (TLC), the developing agent used in reaction, the eluent system of the eluent system of the column chromatography that purification compound adopts and the developing agent system of thin-layer chromatography, the volume of solvent
  • TLC thin-layer chromatography
  • the ratio is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • reaction solution was poured into 500 ml of water, extracted three times with dichloromethane (500 mL), the organic phase was washed three times with water (300 mL), then washed three times with saline (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated , the crude product was obtained, and then purified on a silica gel column with 0-15% ethyl acetate/petroleum ether to obtain the title compound 1b (54 g, yield: 84%).
  • Benzo[c][1,2,5]thiadiazole-5-carboxylic acid 2a (16.39 mg, 0.086 mmol) was dissolved in tetrahydrofuran (2 mL), and diphenylphosphoryl azide (23.78 mg, 0.086 mmol) was added , triethylamine (29.14mg, 0.288mmol), react at room temperature for 2 hours.
  • Compound 1k (20mg, 0.072mmol) was dissolved in 1,4-dioxane (2mL) and added to the above reaction solution, heated to 100°C, reacted for 2 hours, concentrated under reduced pressure, and purified by HPLC to obtain the title compound 2 (10 mg, yield: 31%).
  • In vitro assays include assays that determine cell morphology, protein expression and/or cytotoxicity, enzyme inhibitory activity, and/or subsequent functional consequences of treatment of cells with compounds of the invention. Alternatively or additionally to in vitro assays can be used to quantify the ability of an inhibitor to bind to a protein or nucleic acid molecule within a cell.
  • Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor/target molecule complex, and determining the amount of radiolabel bound. Alternatively or in addition, inhibitor binding can be determined by running competition experiments in which new inhibitors are incubated with purified proteins or nucleic acids bound to known radioligands. Detailed conditions of an exemplary system for assaying compounds of formula (I) of the present invention as inhibitors of MALT1 are set forth in the Biological Examples below.
  • Such assays are exemplary and not intended to limit the scope of the invention.
  • the skilled practitioner will understand that conventional assays can be modified to develop equivalent or other assays that can be used to equally assess activity or otherwise characterize compounds and/or compositions as described herein.
  • Test example 1 MALT1 biochemical protease assay
  • the composition of the final assay buffer was 5.625nM MALT1 protein, 2.5 ⁇ M Ac-LRSR-MCA, 20mM HEPES, 10mM KCl, 1.5mM MgCl 6H2O, 1mM 2Na(EDTA 2Na), 0.01% TritonX-100, 1M citric acid Trisodium Citrate Dihydrate, 10mM DTT.
  • Test compounds dissolved in 100% DMSO were added to a 384-well plate (Greiner-781086) at 200 nL per well using Echo. The highest concentration of each test compound was 10 ⁇ M or 1 ⁇ M, 3-fold serial dilution, and the tested concentration range was from 10 ⁇ M to 0.2 nM.
  • Control wells with assay buffer without enzyme were used as low controls (LC) and wells with vehicle (1% DMSO) treated with enzyme but no compound were used as high controls (HC).
  • Compounds were incubated with MALT1 enzyme and substrate for 15 hours at room temperature. Fluorescence was then measured using Envision at excitation 360 nm and emission 450 nm. XLfit was used to fit the inhibition curve and calculate the IC50 value.
  • 25,000 Jurkat cells were inoculated in each well of a 96-well cell culture plate (Gbo, 655090) with RPMI 1640 (Gibco, A1049101) medium supplemented with 10% fetal bovine serum (Gibco, 10099-141C). 100uL. Subsequently, the compound was added into each well with Multidrop Pico8, the compound was set at 9 concentration points, the highest concentration was 10 ⁇ M, and the compound was serially diluted 3 times (the final concentration of DMSO was 0.1%). DMSO control wells were used to determine maximum signal (HC).
  • the capture antibody was diluted to a working concentration of 4 ⁇ g/mL with PBS, and 100 ⁇ L of diluted capture antibody was immediately added to each well of a 96-well microplate, Incubate overnight at room temperature. The next day, wash 3 times with 200 ⁇ L of washing solution, add 300 ⁇ L of blocking buffer to each well, and after incubating at room temperature for 1 hour, add 100 ⁇ L of diluted Jurkat cell culture medium (50-fold dilution) treated with the compound to each well, Incubate at room temperature for 2 hours.
  • IL-2 detection antibody with a working concentration of 100ng/mL and incubate at room temperature for 2 hours; after washing the plate, add secondary antibody Streptavidin-HRP diluted 40 times according to the instructions; incubate at room temperature for 20 minutes in the dark. After washing the plate, add 100 ⁇ L of substrate to each well, incubate in the dark for 20 minutes, then terminate the color reaction, and use Envision to read the signal value at a wavelength of 450 nM.
  • the number of cells per well was detected according to the instructions of the CellTiter Glo detection kit (Promega, G7572), and the secretion of IL-2 was calibrated by the number of cells per well.
  • NF ⁇ B signaling regulates the secretion of various cytokines, including IL-6 and IL-10.
  • IL-10ELISA R&D VAL112
  • MALT1 inhibitors Inhibition of NF ⁇ B signaling by MALT1 inhibitors resulted in decreased IL-10 secretion.
  • OCI-LY10 cells were cultured in IMEM (Gibco 12440-053) medium supplemented with 20% fetal bovine serum (Gibco 10099-141C).
  • IMEM Gibco 12440-053 medium supplemented with 20% fetal bovine serum
  • IL-10 secretion assay 300,000 OCI-LY10 cells were seeded into each well of a 96-well plate (Corning #3599), and the test compound was added in 7 dilution gradients (1:3) with a maximum concentration of 10 ⁇ M ( The final concentration of DMSO was 0.1%). DMSO control wells were used to determine maximum signal (HC).

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Abstract

公开了三环化合物及其制备方法。具体而言，公开了一种如式I-d所示的三环化合物及其制备方法，以及其用于预防和/或治疗肿瘤或者癌症的的用途。

Description

三环化合物及其制备方法 技术领域
本公开属于医药领域，涉及一种三环化合物及其制备方法。
背景技术
黏膜相关组织淋巴瘤异位蛋白1(mucosa-associated-lymphoid-tissuelymphoma-translocation1，MALT1)是NF-κB信号通路上游一个重要的蛋白分子，同B细胞慢性淋巴细胞白血病/淋巴瘤蛋白(B-cell chronic lymphocyticleukemia/lymphoma10，BCL10)和含caspase募集结构的膜相关鸟苷酸激1(caspase-recruitment domain(CARD)containing membrane-associated guanylatekinase protein1，CARMA1)组成复合物CBM，将近端抗原受体蛋白信号传递给IκB激酶(IKK)，进而激活NF-κB信号通路。MALT1-NF-κB信号通路的过度活化与炎症及肿瘤的发生密切相关。
发明内容
第一方面，本公开(The disclosure)提供了式I所示化合物或其可药用的盐
Figure PCTCN2022123111-appb-000001
其中
每个
Figure PCTCN2022123111-appb-000002
独立地为单键或双键；
Z选自S、O或CR 7；
X选自C或N；
Y选自C或N；
且X、Y不同时为N；
R 1和R 2与相邻的原子形成3-7元环烷基、5-8元杂环烷基、5-8元杂芳基、苯基；
R 3、R 6、R 7或R 8独立地选自氢、C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、硝基、氰基、卤素、羟基、氨基、-CONH 2、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基、苯基、苄基、甲磺酰基，其中所述的C 1-6烷基、3-6元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基、苯基、苄基任选被一至多个R 9所取代；
m选自0-5的整数；
n选自1-3的整数；
R 4或R 5独立地选自氢、C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、硝基、氰基、卤素、羟基、氨基、-CONH 2、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基、氧代、苯基、苄基；所述C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、-CONH 2、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基、苯基、苄基任选被一至多个R 4a所取代；
或R 4和R 5与相邻的原子形成3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基；所述3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、苯基任选被一至多个R 5a所取代；
R 9、R 4a或R 5a独立地选自氧代、硝基、氰基、卤素、羟基、氨基、C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基、芳基、苄基；所述C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基、芳基、苄基任选被一至多个选自氧代、硝基、氰基、卤素、羟基、氨基、甲基、乙基、亚甲基环丙基、环丙基、丙基、甲氧基、乙氧基、环丙氧基的取代基所取代。
在某些实施方案，式I所示的化合物或其可药用盐中当Z选自O或S原子时，X、Y为C原子。
在某些实施方案，式I所示的化合物或其可药用盐中当Z选自CR 7时，X、Y其中仅有一个为N原子。
第二方面，本公开还提供了一种如式I-a、I-b、I-c、I-d所示的化合物或其可药用盐
Figure PCTCN2022123111-appb-000003
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 1和R 2与相邻的原子形成3-7元环烷基。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 1和R 2与相邻 的原子形成5-8元杂环烷基。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 1和R 2与相邻的原子形成5-8元杂芳基。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 1和R 2与相邻的原子形成
Figure PCTCN2022123111-appb-000004
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 3选自氢、C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、硝基、氰基、卤素、羟基、氨基、-CONH 2、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基、甲磺酰基、；其中所述的C 1-6烷基、3-6元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基任选被1-3个R 9所取代。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 3选自C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基；其中所述的C 1-6烷基、3-6元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基任选被1-3个R 9所取代。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 3选自硝基、氰基、卤素、羟基、氨基、-CONH 2、甲磺酰基。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 7选自氢、C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、硝基、氰基、卤素、羟基、氨基、-CONH 2、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基、甲磺酰基、；其中所述的C 1-6烷基、3-6元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基任选被1-3个R 9所取代。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 7选自C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基；其中所述的C 1-6烷基、3-6元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基任选被1-3个R 9所取代。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 7选自硝基、氰基、卤素、羟基、氨基、-CONH 2、甲磺酰基。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 7为氢。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 6选自氢、C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、硝基、氰基、卤素、羟基、氨基、-CONH 2、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基、甲磺酰基，其中所述的C 1-6烷基、3-6元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基任选被1-3个R 9所取代。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 6选自C 1-6烷基、 3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基；其中所述的C 1-6烷基、3-6元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基任选被1-3个R 9所取代。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 6选自氢、硝基、氰基、卤素、羟基、氨基、-CONH 2、甲磺酰基；优选R 6选自氢。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 4和R 5与相邻的原子形成3-7元环烷基、3-6元杂环烷基；所述3-7元环烷基、3-6元杂环烷基任选被一至多个R 5a所取代。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 4或R 5独立地选自氢、C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、硝基、氰基、卤素、羟基、氨基、-CONH 2、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基、氧代；所述C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、-CONH 2、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基任选被1-3个R 4a所取代。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 4或R 5独立地选自氢、硝基、氰基、卤素、羟基、氨基、氧代、-CONH 2。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 4或R 5独立地选自氢、C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基；所述C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基任选被1-3个R 4a所取代。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 4或R 5独立地选自C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、羟基、5-6元杂芳基；所述C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、5-6元杂芳基任选被1-3个R 4a所取代。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 8独立地选自氢、C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、硝基、氰基、卤素、羟基、氨基、-CONH 2、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基、甲磺酰基，其中所述的C 1-6烷基、3-6元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基任选被1-3个R 9所取代；
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 8选自C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基；其中所述的C 1-6烷基、3-6元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基任选被1-3个R 9所取代。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 8选自氢、硝基、氰基、卤素、羟基、氨基、-CONH 2、甲磺酰基；优选R 8选自氢。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 9独立地选自氧 代、硝基、氰基、卤素、羟基、氨基、C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基；所述C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基任选被1-3个选自氧代、硝基、氰基、卤素、羟基、氨基、甲基、乙基、亚甲基环丙基、环丙基、丙基、甲氧基、乙氧基、环丙氧基的取代基所取代。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 9独立地选自氧代、硝基、氰基、卤素、羟基、氨基；优选R 9为卤素。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 9独立地选自C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基；所述C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基任选被1-3个选自氧代、硝基、氰基、卤素、羟基、氨基、甲基、乙基、亚甲基环丙基、环丙基、丙基、甲氧基、乙氧基、环丙氧基的取代基所取代。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 9独立地选自C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 4a独立地选自氧代、硝基、氰基、卤素、羟基、氨基、C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基；所述C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基任选被1-3个选自氧代、硝基、氰基、卤素、羟基、氨基、甲基、乙基、亚甲基环丙基、环丙基、丙基、甲氧基、乙氧基、环丙氧基的取代基所取代。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 4a独立地选自氧代、硝基、氰基、卤素、羟基、氨基；优选R 4a为卤素。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 4a独立地选自C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基；所述C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基任选被1-3个选自氧代、硝基、氰基、卤素、羟基、氨基、甲基、乙基、亚甲基环丙基、环丙基、丙基、甲氧基、乙氧基、环丙氧基的取代基所取代。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 4a独立地选自C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 5a独立地选自氧代、硝基、氰基、卤素、羟基、氨基、C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷 基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基；所述C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基任选被1-3个选自氧代、硝基、氰基、卤素、羟基、氨基、甲基、乙基、亚甲基环丙基、环丙基、丙基、甲氧基、乙氧基、环丙氧基的取代基所取代。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 5a独立地选自氧代、硝基、氰基、卤素、羟基、氨基；优选R 5a为卤素。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 5a独立地选自C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基；所述C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基任选被1-3个选自氧代、硝基、氰基、卤素、羟基、氨基、甲基、乙基、亚甲基环丙基、环丙基、丙基、甲氧基、乙氧基、环丙氧基的取代基所取代。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 5a独立地选自C 1-6烷基、3-7元环烷基、-O-C 1-6烷基、-O-3-7元环烷基、3-6元杂环烷基、5-6元杂芳基、-O-3-6元杂环烷基、-O-5-6元杂芳基。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 3选自氰基、氟、氯、甲基、二氟甲基、-CH 2CHF 2、乙基、-OCHF 2、-CH 2CF 3、-CH(OH)CH 3；优选R 3为氯。
在某些实施方案，式I、I-a、I-b、I-c、I-d所示的化合物或其可药用盐中R 4或R 5独立地选自氢、甲基、甲氧基、三氟甲基、二氟甲基、环丙基、-CH 2OCH 3；优选R 4选自甲基，R 4选自三氟甲基。
第三方面，本公开还提供一种如下所示的化合物结构或其可药用盐
Figure PCTCN2022123111-appb-000005
第四方面，本公开还提供一种如下所示的化合物结构或其可药用盐
Figure PCTCN2022123111-appb-000006
Figure PCTCN2022123111-appb-000007
第五方面，本公开还提供一种如第一方面至第四方面所示的化合物的同位素取代物，优选地，所述的同位素取代为氘原子取代。
第六方面，本公开还提供一种药物组合物，包括第一方面至第四方面所述的化合物或其可药用盐和可药用赋形剂。
在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的前述化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有1％-99％的前述化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有2％-98％的前述化合物或其可药用的盐。
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有2％-98％的药学上可接受的赋形剂。
第七方面，本公开还提供一种预防和/或治疗与MALT1相关病症患者的方法，其通过向所述患者施用治疗有效量的如第一方面至第四方面所述的化合物或其可药用盐、或第五方面所述的同位素取代物、或第六方面所述的药物组合物。
所述相关病症包括但不限于自身免疫性疾病、炎性疾病、癌症、肿瘤等，例如类风湿性关节炎、多重硬化症、系统性红斑狼疮或血管炎性疾病、造血系统原发性癌症或实体瘤，包括慢性髓性白血病、髓性白血病、非霍奇金淋巴瘤和其它B细胞淋巴瘤。
本公开提供一种预防和/或治疗自身免疫性疾病、炎性疾病、癌症、肿瘤患者的方法，其通过向所述患者施用治疗有效量的如第一方面至第三四方面所述的化合物或其可药用盐、或第四五方面所述的同位素取代物、或第五六方面所述的药物组合物
所述疾病包括但不限于自身免疫性疾病和炎性疾病，例如类风湿性关节炎、多重硬化症、系统性红斑狼疮或血管炎性疾病、造血系统原发性癌症或实体瘤，包括慢性髓性白血病、髓性白血病、非霍奇金淋巴瘤和其它B细胞淋巴瘤。
本公开还提供第一方面至第三方面所述的化合物或其可药用盐、或第四方面所述的同位素取代物、或第五方面所述的药物组合物在制备用于预防和/或治疗与MALT1相关病症的药物中的用途。
本公开还提供第一方面至第三方面所述的化合物或其可药用盐、或第四方面所述的同位素 取代物、或第五方面所述的药物组合物在制备用于预防和/或治疗自身免疫性疾病、炎性疾病、癌症、肿瘤的药物中的用途。
本公开所述的化合物或其可药用盐或药物组合物对MALT1具有很好的抑制作用，对MALT1的抑制活性的IC50值在0.01至1000nM，某些化合物对MALT1的抑制活性的IC50值在0.01至500nM，某些化合物对MALT1的抑制活性的IC50值在0.01至300nM，某些化合物对MALT1酶的抑制活性的IC50值在0.01至200nM，某些化合物对MALT1酶的抑制活性的IC50值在0.01至100nM，某些化合物对MALT1酶的抑制活性的IC50值<100nM，某些化合物对MALT1酶的抑制活性的IC50值<50nM。
本公开中所述化合物可药用盐可选自无机盐或有机盐。
本公开化合物可以存在特定的几何或立体异构体形式。本公开设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本公开的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本公开的范围之内。本公开的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本公开某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明所述化合物的化学结构中，键
Figure PCTCN2022123111-appb-000008
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2022123111-appb-000009
可以为
Figure PCTCN2022123111-appb-000010
或者同时包含
Figure PCTCN2022123111-appb-000011
两种构型。本公开所述化合物的化学结构中，键
Figure PCTCN2022123111-appb-000012
并未指定构型，即可以为Z构型或E构型，或者同时包含E和Z两种构型。
本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺、内酰胺-内酰亚胺异构化。内酰胺-内酰亚胺平衡实例是在如下所示的A和B之间。
Figure PCTCN2022123111-appb-000013
本发明中的所有化合物可以被画成A型或B型。所有的互变异构形式在本发明的范围内。化合物的命名不排除任何互变异构体。
本公开还包括一些与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即，至少10％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘、至少2000倍的丰度的氘、至少3000倍的丰度的氘、至少4000倍的丰度的氘、至少5000倍的丰度的氘、至少6000倍的丰度的氘或更高丰度的氘。本公开还包括各种氘化形式的式(I)化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的式(I)化合物。在制备氘代形式的式(I)化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。
任选地”或“任选”是指意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如“任选的被卤素或者氰基取代的C 1-6烷基”是指卤素或者氰基可以但不必须存在，该说明包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。
术语解释：
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用赋形剂”包括但不限于任何已经被美国食品和药物管理局(FDA)批准对于人类或家畜动物使用可接受的任何助剂、载体、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂或乳化剂。
本公开中所述“有效量”或“有效治疗量”包含足以改善或预防医学病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
“烷基”指饱和的脂族烃基团，包括1至20个碳原子的直链和支链基团。含有1至6个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基及其各种支链异构体等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自卤素、羟基、氧代、氰基、氨基、硝基、C 1-6烷基、C 1-6烷氧基、3至7元环烷基或3至6元杂环烷基，所述烷基、烷氧基、环烷基或杂环烷基任选被卤素、羟基、硝基、氰基或氨基所取代。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至7个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基等；多环环烷基包括螺环、并环和桥环的环烷基。环烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自卤素、羟基、氧代、氰基、氨基、硝基、C 1-6烷基、C 1-6烷氧基、3至7元环烷基或3至7元杂环烷基，所述烷基、烷氧基、环烷基或杂环烷基任选被卤素、羟基、硝基、硝基、氰基或氨基所取代。
术语“杂环烷基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至7个环原子；更优选包含3至6个环原子。“杂环烷基”非限制性实例包括：
Figure PCTCN2022123111-appb-000014
所述杂环烷基环可以稠合于芳基或杂芳基环上，其中与母体结构连接在一起的环为杂环烷基，其非限制性实例包括：
Figure PCTCN2022123111-appb-000015
等。
杂环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、羟基、氧代、氰基、氨基、C 1-6烷基、C 1-6烷氧基、3至7元环烷基或3至7元杂环烷基，所述烷基、烷氧基、环烷基或杂环烷基任选被卤素、羟基、硝基、氰基或氨基所取代。
术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、羟基、氧代、氰基、氨基、硝基、C 1-6烷基、C 1-6烷氧基、3至7元环烷基或3至7元杂环烷基，所述烷基、烷氧基、环烷基或杂环烷基任选被卤素、羟基、硝基、氰基或氨基所取代。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至12元，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2022123111-appb-000016
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、羟基、氧代、硝基、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、3至6元环烷氧基、3至6元杂环烷氧基、C 3-8环烯氧基、5至6元芳基或杂芳基，所述C 1-6烷基、C 1-6烷氧基、C 2-6烯氧基、C 2-6炔氧基、3至6元环烷氧基、3至6元杂环烷氧基、3至8元环烯氧基、5至6元芳基或杂芳基任选被一个或多个选自卤素、羟基、氰基、氨基、C 1-6烷基或C 1-6烷氧基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为6至12元，更优选为5元或6元。例如。其非限制性实例包括：咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基(oxazolyl)、异噁唑基(isoxazolyl)、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基、三唑基、吲唑基、苯并咪唑基、
Figure PCTCN2022123111-appb-000017
Figure PCTCN2022123111-appb-000018
等。
所述杂芳基环可以稠合于芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环 为杂芳基环，其非限制性实例包括：
Figure PCTCN2022123111-appb-000019
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自卤素、羟基、氰基、氨基、C 1-6烷基或C 1-6烷氧基(此处需要根据权利要求调整！)。
术语“螺环”指两环共用一个原子的化合物。螺环烷基的非限制性实例包括：
Figure PCTCN2022123111-appb-000020
术语“并环”指两个或两个以上环通过共用两个相邻的原子并合而成的化合物。并环烷基的非限制性实例包括：
Figure PCTCN2022123111-appb-000021
术语“桥环”指两个或两个以上环状结构彼此共用两个非相邻的环原子所形成的结构。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2022123111-appb-000022
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氰基”指-CN。
术语“氨基”指-NH 2。
术语“硝基”指-NO 2。
术语“氧代”指＝O取代基。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼 此独立地被相应数目的取代基取代。当取代基是酮或氧代(即，＝O)时，则原子上有两个(2个)氢被替代。
具体实施方式
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。
实施例
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Shimadzu 2010 Mass Spectrometer或Agilent 6110A MSD质谱仪。
HPLC的测定使用Shimadzu LC-20A systems、Shimadzu LC-2010HT series或安捷伦Agilent 1200 LC高压液相色谱仪(Ultimate XB-C18 3.0*150mm色谱柱或Xtimate C18 2.1*30mm色谱柱)。
手性HPLC分析测定使用Chiralpak IC-3 100×4.6mm I.D.,3um、Chiralpak AD-3 150×4.6mm I.D.,3um、Chiralpak AD-3 50×4.6mm I.D.,3um、Chiralpak AS-3 150×4.6mm I.D.,3um、Chiralpak AS-3 100×4.6mm I.D.,3μm、ChiralCel OD-3 150×4.6mm I.D.,3um、Chiralcel OD-3 100×4.6mm I.D.,3μm、ChiralCel OJ-H 150×4.6mm I.D.,5um、Chiralcel OJ-3 150×4.6mm I.D.,3um色谱柱；
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶100～200目、200～300目或300～400目硅胶为载体。
手性制备柱使用DAICEL CHIRALPAK IC(250mm*30mm,10um)或Phenomenex-Amylose-1(250mm*30mm,5um)。
CombiFlash快速制备仪使用Combiflash Rf150(TELEDYNE ISCO)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1
N-(苯并[c][1,2,5]恶二唑-5-基)-2-氯-8-甲基-8-(三氟甲基)-7,8-二氢-6H-吡唑并[1,5-a]吡咯[2,3-e]嘧啶-6-羧酰胺1
Figure PCTCN2022123111-appb-000023
第一步
N-苄基-N-丙酰甘氨酸乙酯1b
将2-(苄基氨基)乙酸乙酯(50g，258.73mmol)溶于氯仿(500mL)，再加入N，N-二乙基乙胺(85.5mL，517.46mmol)。将丙酰氯(26g,284.6mmol)在氯仿(80mL)中于0℃下滴加。在25℃下搅拌1小时。反应完后将反应液倒入500毫升水中，用二氯甲烷(500mL)萃取三次,有机相用水(300mL)洗三次，再用食盐水(300mL)洗三次，无水硫酸钠干燥，过滤，浓缩，得到粗品，然后在硅胶柱上用0～15％乙酸乙酯/石油醚洗脱纯化，得到标题化合物1b(54g,产率：84％)。
1H NMR(400MHz,CDCl 3)：7.42-7.16(m,5H),4.70-4.61(m,2H),4.23-4.12(m,2H),4.09-3.91(m,2H),2.53-2.29(m,2H),1.30-1.23(m,3H),1.22-1.14(m,3H).
第二步
1-苄基-3-甲基吡咯烷-2,4-二酮1c
将氢化钠(5.78g,144.40mmol,60％)溶于四氢呋喃(500mL)中，将化合物1b(30g,120.33mmol)溶于四氢呋喃(300mL)中，在75℃滴加到反应液中。反应在75℃下反应12小时。反应完后，向反应液中加入10mL水，浓缩干后，在硅胶柱上用0～10％甲醇/二氯甲烷洗脱纯化，得到标题化合物1c(14.5g,产率：59％)。
1H NMR(400MHz,DMSO-d 6)：10.64(s,1H),7.36-7.30(m,2H),7.28-7.22(m,1H),7.17(d,J＝7.2Hz,2H),4.46(s,2H),3.63(s,2H),1.58(s,3H).
第三步
1-苄基-3-甲基-3-(三氟甲基)吡咯烷-2,4-二酮1d
将化合物1c(5g,24.60mmol)溶于N，N-二甲基甲酰胺(50mL)中，加入钠氢(0.98g,24.60mmol)，反应在25℃反应半小时。将反应降至-55℃下，加入5-(三氟甲基)二苯并噻吩-5-鎓三氟甲磺酸盐(9.90g,24.60mmol)，并在-55℃下反应1小时。再在室温下反应一小时。反应完后，用15毫升饱和氯化铵溶液淬灭，用乙酸乙酯(50mL)萃取三次。有机相用水(30mL)洗涤三次，食盐水(50mL)洗涤三次，无水硫酸钠干燥，浓缩干后，在硅胶柱上用25％乙酸乙酯/石油醚洗脱纯化，得到标题化合物1d(5g,产率：75％)。
MS(ESI):m/z＝271.9[M+H] +
1H NMR(400MHz,DMSO-d 6)：7.42-7.23(m,5H),4.83(d,J＝15.0Hz,1H),4.44(d,J＝15.1Hz,1H),4.04(s,2H),1.47(s,3H).
第四步
1-苄基-4-甲基-4-(三氟甲基)吡咯烷-3-醇1e
将化合物1d(1g,3.69mmol)溶于四氢呋喃(15mL)中，0℃下加入四氢铝锂(0.98g,25.80mmol)，反应在80℃反应12小时。将反应降至0℃下，依次加入水(280mg)，10％氢氧化钠溶液(280mg)和水(280mg)，室温搅拌10分钟后过滤。滤液浓缩干后，在硅胶柱上用5％甲醇/二氯甲烷洗脱纯化，得到标题化合物1e(467mg,产率：49％)。
MS(ESI):m/z＝260.1[M+H] +
1H NMR(400MHz,DMSO-d 6)δ7.36-7.21(m,5H),5.31(d,J＝5.9Hz,1H),3.98-3.90(m,1H),3.67-3.49(m,2H),3.04(dd,J＝6.5,9.1Hz,1H),2.66(d,J＝9.4Hz,1H),2.31-2.24(m,1H),1.23(s,3H).
第五步
4-甲基-4-(三氟甲基)吡咯烷-3-醇盐酸盐1f
将化合物1e(2g,7.71mmol)溶于乙醇(40mL)中，加入盐酸(1M,8.5mL)和Pd/C(500mg,10％)。用氢气置换三次，并在氢气球的保护下室温反应12小时。反应完后，向反应加入盐酸(1M,8.5mL)搅拌15分钟。过滤，浓缩，得到标题化合物1f(1.6g,粗品)，直接用于下一步反应。
MS(ESI):m/z＝170.2[M+H] +
第六步
4-羟基-3-甲基-3-(三氟甲基)吡咯烷-1-羧酸叔丁酯1g
将化合物1f(1.6g,7.78mmol)溶于四氢呋喃(40mL)中，加入二碳酸二叔丁酯(2.55g,11.67mmol)和N,N-二乙基乙胺(4g,31.13mmol)。在室温反应2小时。反应完后，减压浓缩，粗品在硅胶柱上用25％乙酸乙酯/石油醚洗脱纯化，得到标题化合物1g(1.4g,产率：67％)
MS(ESI):m/z＝270.2[M+H] +
第七步
3-甲基-4-氧代-3-(三氟甲基)吡咯烷-1-羧酸叔丁酯1h
将化合物1g(800mg,2.97mmol)溶于二氯甲烷(30mL)中，加入氯铬酸吡啶鎓盐(3.2g,14.86mmol)和硅胶(1.6g)。在40℃反应12小时，反应完后，浓缩干，粗品在硅胶柱上用10％乙酸乙酯/石油醚洗脱纯化，得到标题化合物1h(340mg,产率：43％)
MS(ESI):m/z＝268.3[M+H] +
第八步
3-甲基-4-氧代-3-(三氟甲基)吡咯烷-1-羧酸叔丁酯1i
将化合物1h(340mg,1.27mmol)溶于N,N-二甲基甲酰胺(3mL)中，加入N,N-二甲基甲酰胺二甲缩醛(3mL)。在35℃下反应1小时。反应完后，浓缩干，得到标题化合物1i(450mg,产率：粗品)，不用进一步纯化，直接用于下一步。
MS(ESI):m/z＝323.2[M+H] +
第九步
2-氯-8-甲基-8-(三氟甲基)-7,8-二氢-6H-吡唑并[1,5-a]吡咯并[2,3-e]嘧啶-6-羧酸的叔丁酯1j
将化合物1i(450mg，1.40mmol)溶于甲苯(10mL)和醋酸(1mL)中，在95℃下反应15小时。反应完后，加入饱和碳酸氢钠溶液(10mL)，再用乙酸乙酯(20mL)萃取2次，有机相干燥浓缩后，粗品在硅胶柱上用30％乙酸乙酯/石油醚洗脱纯化，得到标题化合物1j(140mg,产率：26％)。
MS(ESI):m/z＝377.3[M+H] +
第十步
2-氯-8-甲基-8-(三氟甲基)-7,8-二氢-6H-吡唑并[1,5-a]吡咯并[2,3-e]嘧啶1k
将化合物1j(140mg，0.37mmol)溶于二氯甲烷(5mL)和三氟乙酸(1mL)中，在室温下反应15小时。反应完后，浓缩干，加入15毫升饱和碳酸氢钠溶液，再用乙酸乙酯(30mL)萃取2次，有机相干燥浓缩后，在硅胶柱上用0～20％甲醇/二氯甲烷洗脱纯化，得到标题化合物1k(60mg,产率：58％)。
MS(ESI):m/z＝277.3[M+H] +
第十一步
N-(苯并[c][1,2,5]恶二唑-5-基)-2-氯-8-甲基-8-(三氟甲基)-7,8-二氢-6H-吡唑并[1,5-a]吡咯[2,3-e] 嘧啶-6-羧酰胺1
将2,1,3-苯并噁二唑-5-羧酸(18mg，0.11mmol)溶于四氢呋喃(2mL)，加入叠氮磷酸二苯酯(34mg，0.13mmol)，在室温下反应5小时。将化合物1k(30mg，0.11mmol)溶于2毫升二氧六环中，加入上面反应液中，加热到100℃反应2小时，冷却到室温后，减压浓缩，粗品通过制备HPLC纯化，得到标题化合物1(8mg,产率：17％)。
MS(ESI):m/z＝438.2[M+H] +
1H NMR(400MHz,CDCl 3)：9.43(s,1H),8.12(s,1H),7.92-7.84(m,1H),7.52-7.44(m,1H),6.88(s,1H),6.80(s,1H),4.67-4.58(m,2H),2.11(s,3H).
实施例2
N-(苯并[c][1,2,5]噻二唑-5-基)-2-氯-8-甲基-8-(三氟甲基)-7,8-二氢-6H-吡唑并[1,5-a]吡咯[2,3-e]嘧啶-6-羧酰胺
Figure PCTCN2022123111-appb-000024
将苯并[c][1,2,5]噻二唑-5-羧酸2a(16.39mg,0.086mmol)溶于四氢呋喃(2mL),加入叠氮磷酸二苯酯(23.78mg,0.086mmol)，三乙胺(29.14mg,0.288mmol)，在室温下反应2小时。将化合物1k(20mg,0.072mmol)溶于1,4-二氧六环(2mL)加入上述反应液中，加热至100℃后，反应2小时，减压浓缩，通过HPLC纯化，得到标题化合物2(10mg,产率：31％)。
MS(ESI):m/z＝454.2[M+H] +
1H NMR(400MHz,CDCl 3):9.45(s,1H),8.22-8.21(m,1H),8.01-7.99(m,1H),7.69-7.66(m,1H),6.77(s,1H),6.58(s,1H),4.61-4.59(m,1H),4.11-4.08(m,1H),2.10(s,3H).
实施例3
2-氯-N-(3-氯-4-甲氧基苯基)-8-甲基-8-(三氟甲基)-7,8-二氢-6H-吡唑并[1,5-a]吡咯并[2,3-e]嘧啶-6-羧酰胺
Figure PCTCN2022123111-appb-000025
将3-氯-4-甲氧基苯胺(16.12mg,0.086mmol)溶于四氢呋喃(2mL),加入叠氮磷酸二苯酯(23.78mg,0.086mmol)，三乙胺(29.14mg,0.288mmol)，在室温下反应2小时。将化合物1k(20mg,0.072mmol)溶于二氧六环(2mL),加入上述反应液中，加热至100℃后，反应2小时，浓缩干，通过HPLC纯化，得到标题化合物3(10mg,产率：45％)。
MS(ESI):m/z＝460.2[M+H] +
1H NMR(400MHz,CDCl 3):9.40(s,1H),7.50-7.49(m,1H),7.32-7.29(m,1H),6.95-6.92(m,1H),6.74(s,1H),6.24(s,1H),4.51-4.48(m,1H),4.00-3.98(m,1H),3.91(s,3H),2.06(s,3H).
生物学测试
体外测定法包括确定细胞形态、蛋白质表达和/或细胞毒性、酶抑制活性和/或用本发明化合物处理细胞的后续功能后果的测定法。体外测定法的替代或附加可用于定量抑制剂在细胞内结合至蛋白质或核酸分子的能力。
抑制剂结合可通过在结合之前放射性标记抑制剂、分离抑制剂/靶标分子复合物并确定放射性标记结合的量来测量。可选地或除此之外，抑制剂结合可通过运行竞争实验来确定，其中新抑制剂与经纯化的蛋白质或结合到已知放射性配体的核酸一起培养。用于测定本发明的作为MALT1抑制剂的式(I)化合物的示例性系统的详细条件在下文的生物学实施例中陈述。
此类测定是示例性的，并非旨在限制本发明的范围。熟练的从业人员能够理解，可以对传统的测定方法进行修改以开发等效的或其他的测定方法，其可用于同等的评估活性或以其他方式表征如本文所述的化合物和/或组合物。
测试例1MALT1生物化学蛋白酶测定
使用作为底物的四肽(Ac-LRSR-MCA,PEPTIDE INSTITUTE)以及从哺乳动物细胞HEK293T纯化的全长MALT1蛋白(Strep-MALT1(1-824)-Myc/DDK,ORIGENE TP314639)，在 体外测定中评估MALT1蛋白酶活性。四肽LRSR与AMC(7-氨基-4-甲基香豆素)偶联，并为MALT1蛋白酶提供淬灭的荧光底物。从精氨酸残基上切割AMC导致在450nm处测量的香豆素荧光增大(激发360nm)。最终的检测缓冲液的组成为5.625nM MALT1蛋白、2.5μM Ac-LRSR-MCA、20mM HEPES、10mM KCl、1.5mM MgCl·6H2O、1mM 2Na(EDTA·2Na)、0.01％TritonX-100、1M柠檬酸三钠二水合物Trisodium Citrate Dihydrate、10mM DTT。使用Echo将溶于100％DMSO的测试化合物以每孔200nL的量添加到384-孔板(Greiner-781086)中。每个测试化合物的最高浓度为10μM或1μM，3倍梯度稀释，测试的浓度范围为10μM至0.2nM。不含酶的检测缓冲液的对照孔用作低对照(LC)，利用与酶反应但不加化合物处理的溶媒(1％DMSO)孔作为高对照(HC)。将化合物与MALT1酶以及底物在室温下温育15小时。随后使用Envision中在激发360nm和发射450nm处测量荧光。使用XLfit进行抑制曲线的拟合并计算IC 50值。
使用下式计算IC 50值(Z prime>0.5)：
LC＝低对照值的中值
低对照：无MALT1酶的反应
HC＝高对照值的中值
高对照：没有化合物的溶媒对照
抑制％＝100-[(样品-LC)/(HC-LC)×100]
曲线拟合公式：fit＝(A+((B-A)/(1+((C/x)^D))))
A：Min(Bottom)，B：Max(Top)，C：IC 50(拐点)，D：斜率(Hill值)
表1
化合物编号 MALT1抑制IC 50(nM)
1 34
WO2021134004A 实施例27 17
测试例2
Jurkat细胞中PMA诱导的IL-2检测
将25000个Jurkat细胞用添加了10％胎牛血清(Gibco,10099-141C)的RPMI 1640(Gibco,A1049101)培养基接种在96孔细胞培养板(Gbo,655090)的每个孔，培养基体积为100uL。随后，用Multidrop Pico8将化合物加入每个孔中，化合物设置9个浓度点，最高浓度为10μM，3倍梯度稀释(DMSO的终浓度为0.1％)。DMSO对照孔用于确定最大信号(HC)。将化合物和细胞于37℃，5％CO 2条件下孵育30分钟后，每孔中加入100μL稀释于添加了10％胎牛血清的RPMI 1640培养基的2X eBioscience TM(细胞刺激混合物，佛波醇12-豆蔻酸13-乙酸酯(PMA)和离子霉素，Invitrogen,00-4970-93)；继续在37℃，5％CO2条件下孵育20小时。第二天收集100μL细胞培养液用于IL-2ELISA检测，剩余100μL用于CTG检测。
按照IL-2ELISA检测试剂盒(R&D Systems,DY202，DY008)的说明书，用PBS将捕获抗体稀释到工作浓度4μg/mL，并立即在96孔的微孔板中每孔添加100μL的稀释捕获抗体，室温下孵育过夜。第二天用200μL洗涤液洗涤3次，在每个孔中加入300μL的封闭缓冲液，室温下孵育1小时后，每孔加入100μL稀释的经化合物处理的Jurkat细胞培养液(50倍稀释)，室温孵育2小时。加入工作浓度为100ng/mL的IL-2检测抗体,室温孵育2小时；洗板后，按照说明书加入稀释40倍的二抗Streptavidin-HRP；室温避光孵育20分钟。洗板后，每孔加入100μL底物，避光孵育20分钟后终止显色反应，使用Envision在450nM波长读取信号值。
根据CellTiter Glo检测试剂盒(Promega,G7572)的说明书检测每孔的细胞数量，采用每孔的细胞数对IL-2的分泌量进行校准。使用XLfit对校准后的IL-2浓度进行抑制曲线的拟合并计算IC 50值，计算公式同测试例1
表2
化合物编号 IL-2抑制IC 50(nM)
1 58
2 108
3 335
WO2021134004A 实施例27 86
测试例3
OCI-Ly10细胞中IL-10ELISA测定
NFκB信号传导调节多种细胞因子,包括IL-6和IL-10的分泌。本测试例使用IL-10ELISA(R&D VAL112)试剂盒来检测ABC-DLBCL细胞OCI-LY10的细胞因子IL-10分泌情况。MALT1抑制剂对NFκB信号传导的抑制导致IL-10分泌减少。
OCI-LY10细胞在补充有20％胎牛血清(Gibco 10099-141C)的IMEM(Gibco 12440-053)培养基中培养。对于IL-10分泌测定，将300,000个OCI-LY10细胞接种到96孔板(Corning#3599)的每个孔中，并且以7个稀释梯度(1:3)添加测试化合物，最大浓度为10μM(DMSO的终浓度为0.1％)。DMSO对照孔用于确定最大信号(HC)。将化合物和细胞在37℃和5％CO 2下温育24小时后，取15μL细胞培养，稀释20倍，并转移200μL到ELISA检测板中，在室温下温育2小时。温育之后，每孔加入200μL人IL-10检测抗体，按照试剂盒的说明书检测IL-10的浓度，使用Envision在450nM波长读取信号值。使用GraphPad Prism进行抑制曲线的拟合并计算IC 50值，计算公式同测试例1。
表3
化合物编号 IL-10抑制IC 50(nM)
1 67
3 134
WO2021134004A 实施例27 142

Claims (8)

  1. 如式I-d所述的化合物或其可药用盐，
    Figure PCTCN2022123111-appb-100001
    R 1和R 2与相邻的原子形成5-8元杂芳基；
    R 3选自硝基、氰基、卤素、羟基、氨基、-CONH 2、甲磺酰基；
    R 7选自硝基、氰基、卤素、羟基、氨基、-CONH 2、甲磺酰基；优选R 7为氢；
    R 6选自氢、硝基、氰基、卤素、羟基、氨基、-CONH 2、甲磺酰基，优选R 6选自氢；
    R 4或R 5独立地选自氢、甲基、甲氧基、三氟甲基、二氟甲基、环丙基、-CH 2OCH 3；优选R 4选自甲基，R 4选自三氟甲基；
    R 8选自氢、硝基、氰基、卤素、羟基、氨基、-CONH 2、甲磺酰基；优选R 8选自氢；
    n选自1-3的整数；优选n选自1-2的整数；更优选n为1；
    m选自0-5的整数；优选m选自0-3的整数；更优选m为0。
  2. 如权利要求1所述的化合物或其可药用盐，其中
    R 1和R 2与相邻的原子形成
    Figure PCTCN2022123111-appb-100002
  3. 如权利要求1所述的化合物或其可药用盐，其为下述式所示化合物或其可药用盐：
    Figure PCTCN2022123111-appb-100003
  4. 如权利要求1所述的化合物或其可药用盐，其为下述式所示化合物或其可药用盐：
    Figure PCTCN2022123111-appb-100004
  5. 一种如权利要求1-4中任一项所示的化合物的同位素取代物，优选地，所述的同位素取代为氘原子取代。
  6. 一种药物组合物，包括权利要求1-4中任一项的所述的化合物或其可药用盐、或权利要求5所述的同位素取代物和可药用赋形剂。
  7. 权利要求1-4任一项所述的化合物或其可药用盐、权利要求5所述的同位素取代物或权利要求46所述的药物组合物在制备用于预防和/或治疗与MALT1相关病症的药物中的用途。
  8. 权利要求1-4任一项所述的化合物或其可药用盐、权利要求5所述的同位素取代物或权利要求6所述的药物组合物在制备用于预防和/或治疗自身免疫性疾病、炎性疾病、癌症、肿瘤的药物中的用途。
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