WO2023217233A1 - 驱动蛋白kif18a抑制剂及其应用 - Google Patents

驱动蛋白kif18a抑制剂及其应用 Download PDF

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WO2023217233A1
WO2023217233A1 PCT/CN2023/093541 CN2023093541W WO2023217233A1 WO 2023217233 A1 WO2023217233 A1 WO 2023217233A1 CN 2023093541 W CN2023093541 W CN 2023093541W WO 2023217233 A1 WO2023217233 A1 WO 2023217233A1
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alkyl
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group
halogenated
pharmaceutically acceptable
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French (fr)
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肖贻崧
谷晓辉
赖焜民
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上海湃隆生物科技有限公司
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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    • A61K31/4965—Non-condensed pyrazines
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • 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
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    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
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    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • 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
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    • 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
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    • 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
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Definitions

  • the invention belongs to the field of medicine and relates to a type of kinesin KIF18A inhibitor and its use for inhibiting the proliferation of cancer cells and treating cancer.
  • KIF18A is a member of the kinesin-8 family. In cells, it can rely on the energy released by hydrolyzing ATP to move in the positive direction using microtubules as tracks. At the same time, KIF18A is located at the anode end of microtubules, can regulate the dynamic instability of microtubules, and exerts an activity similar to microtubule depolymerase. During mitosis, KIF18A can regulate spindle microtubule dynamics and chromosome amplitude, playing a key role in completing chromosome alignment in time during mitosis, maintaining genome stability, and successfully completing mitosis.
  • the KIF18A gene belongs to the kinesin-8 subfamily and is a plus-end-directed motor. KIF18A is thought to influence the dynamics of the plus ends of centromeric microtubules to control correct chromosome positioning and spindle tension. Depletion of human KIF18A results in longer spindles, increased chromosome oscillation during metaphase, and activation of the mitotic spindle assembly checkpoint in HeLa cervical cancer cells (MI Mayr et al., Current Biology) 17,488–98,2007). KIF18A appears to be a viable target for cancer therapy.
  • KIF18A is overexpressed in multiple types of cancer, including but not limited to colon, breast, lung, pancreatic, prostate, bladder, head, neck, cervix, and ovarian cancers. Furthermore, in cancer cell lines, gene deletion or knockout or KIF18A inhibition affects the mitotic spindle apparatus. In particular, inhibition of KIF18A has been found to induce mitotic cell arrest, a known vulnerability that can drive lethality or mitotic slippage in interphase through apoptosis, mitotic catastrophe, or polyphasics. Postapoplexy death to promote mitotic cell death. Therefore, there is strong interest in finding inhibitors of KIF18A protein. Therefore, inhibition of KIF18A ATPase activity is a promising approach to develop new anticancer agents.
  • the invention belongs to the field of medicine and relates to a class of kinesin KIF18A inhibitors, specifically to the compound or its stereoisomer, tautomer, meso, racemate, enantiomer, non- Enantiomers or mixtures thereof or their pharmaceutically acceptable salts, co-crystals, metabolites, solvates, prodrugs or isotopic labels, methods for their preparation and pharmaceutical combinations containing such compounds and their use as therapeutic agents, Especially used to inhibit cancer cell proliferation and treat cancer.
  • the present invention provides a novel class of compounds for modulating KIF18A protein alone or in bound complexes with microtubules for the treatment of KIF18A-mediated disorders and/or diseases, including cancer, inflammation or ciliopathies.
  • Neo-Confucianism a novel class of compounds for modulating KIF18A protein alone or in bound complexes with microtubules for the treatment of KIF18A-mediated disorders and/or diseases, including cancer, inflammation or ciliopathies.
  • the compounds provided by the present invention have MT-based KIF18A regulatory activity, and in particular, have KIF18A inhibitory activity.
  • the present invention also provides the preparation and manufacture of medicaments for the therapeutic, preventive, acute or chronic treatment of KIF18A-mediated diseases and disorders (including but not limited to cancer) of these compounds and pharmaceutically acceptable salts thereof. Use in compositions or pharmaceuticals.
  • the present invention provides a technical solution: a compound having the structure of formula (I) or its pharmaceutically acceptable salt, stereoisomer, isotope isomer, prodrug, hydrate or solvate:
  • W 1 represents CR W1 or N;
  • W 2 represents CR W2 or N;
  • W 3 means CR W3 or N;
  • Z represents -CR T R T ' or -NR S R S ';
  • R T and R T ' together with the C atom to which they are commonly attached form a ring having a structure selected from the following:
  • R S and R S ' together with the N atom to which they are co-attached form a ring having a structure selected from the following:
  • Y 1 , Y 2 , and Y 3 each independently represent -(CR a R b ) o -(NR a ) p -(CR a 'R b ') q -;
  • a and B each independently represent -(CR a R b ) m -;
  • L 1 represents -C(O)NH-, -HNC(O)-, 5-6 membered heteroaryl,
  • L 2 represents absence, -C 1 -C 6 alkylene-, -NR a -, -NR a (C 1 -C 6 alkylene)-, -C(O)NR a (C 1 - C 6 alkylene)-, -O-, -O-(C 1 -C 6 alkylene), -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR a -or-S(O)(NR a )-;
  • R 1 represents L 3 -R 3 ;
  • R 3 represents absence, hydrogen or C substituted by 0-3 groups selected from halogen, -OR a , -NR a R b , cyano and -O-halogenated C 1 -C 6 alkyl. 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
  • R W1 , R W2 and R W3 each independently represent hydrogen, halogen, cyano group, nitro group, hydroxyl C 1 -C 6 alkyl group, C 1 -C 6 alkyl group, C 3 -C 8 cycloalkyl group, Halogenated C 1 -C 6 alkyl, -OR a , -SO 3 R a , -S(O)R a , -O-halogenated C 1 -C 6 alkyl, -SR a , -SF 5 or - NR a R b ;
  • Cy 1 represents a 6-12-membered aryl group or a 5-12-membered heteroaryl group; and the Cy 1 can also be optionally substituted by 0-3 groups selected from the following substituents: halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, hydroxyl C 1 -C 6 alkyl, OR a , -O-halogenated C 1 -C 6 alkyl, 5-6 membered heteroaryl, benzene Group, -SR a , -SF 5 , cyano group, nitro group, -NR a R b , -NR a C(O)R b , -C(O)NR a R b , -OC(O)R a , -C(O)R a , -P(O)R a R b , -C(O)OR a , -S(O)R a , -S(O
  • Cy 2 represents a 3-12 membered saturated or unsaturated monocyclic or bicyclic ring.
  • the ring can optionally contain 0-3 heteroatoms selected from O, N and S, and the Cy 2 can also be optionally Ground is substituted by 0-3 groups selected from the following substituents: halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, -OR a , -O-halogenated C 1 -C 6 alkyl, -SR a , -SF 5 , cyano group, nitro, -NR a R b , -NR a C(O)R b , -C(O)NR a R b , -OC(O)R a , -C(O)OR a , -S(O)R a , -S(O) 2 R a and -S(O) 2 NR a R
  • Ring A represents a saturated or unsaturated 4-12-membered ring, preferably a 5-12-membered ring; and the ring may optionally contain 0-3 heteroatoms selected from O, N and S, and the Ring A of can also be optionally substituted by 0-3 groups selected from the following substituents: halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, hydroxyl C 1 -C 6 alkyl Group, -OR a , -O-halogenated C 1 -C 6 alkyl group, -SR a , -SF 5 , cyano group, nitro group, -NR a R b , -NR a C(O)R b , - C(O)NR a R b , -OC(O)R a , -C(O)OR a , -S(O)R a , -S(O) 2 R a and -
  • R a , R b , R a ', and R b ' each independently represent hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogenated C 1 -C 6 alkyl or Hydroxy C 1 -C 6 alkyl; or R a and R b together with the atoms connected to them form 3-6 A one-membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S and N; or R a' and R b' together with the atoms connected to them form a 3-6 membered saturated ring Or an unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S and N;
  • n, o, p, q represent integers from 0 to 3.
  • the present invention provides a compound having the structure of formula (II) or a pharmaceutically acceptable salt, stereoisomer, isotopomer, prodrug, hydrate or solvate thereof:
  • W 1 represents CR W1 or N;
  • W 2 represents CR W2 or N;
  • Z represents -CR T R T' or -NR S R S' ;
  • R T and R T' together with the C atom to which they are commonly attached form a ring having a structure selected from the following:
  • R S and R S' together with the N atom to which they are commonly attached form a ring having a structure selected from the following:
  • Y 1 , Y 2 , and Y 3 each independently represent -(CR a R b ) o -(NR a ) p -(CR a' R b' ) q -;
  • a and B each independently represent -(CR a R b ) m -;
  • L 1 represents -C(O)NH-, -HNC(O)-, 5-6 membered heteroaryl,
  • L 2 represents absence, -C 1 -C 6 alkylene-, -NR a -, -NR a (C 1 -C 6 alkylene)-, -C(O)NR a (C 1 - C 6 alkylene)-, -O-, -O-(C 1 -C 6 alkylene), -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR a -or-S(O)(NR a )-;
  • R 1 represents L 3 -R 3 ;
  • R 3 represents absence, hydrogen or C substituted by 0-3 groups selected from halogen, -OR a , -NR a R b , cyano and -O-halogenated C 1 -C 6 alkyl. 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;
  • R W1 and R W2 each independently represent hydrogen, halogen, cyano group, nitro group, hydroxyl C 1 -C 6 alkyl group, C 1 -C 6 alkyl group, C 3 -C 8 cycloalkyl group, halogenated C 1 -C 6 alkyl, -OR a , -SO 3 R a , -S(O)R a , -O-halogenated C 1 -C 6 alkyl, -SR a , -SF 5 or -NR a R b ;
  • Cy 1 represents a 6-12-membered aryl group or a 5-12-membered heteroaryl group; and the Cy 1 can also be optionally substituted by 0-3 groups selected from the following substituents: halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, hydroxyl C 1 -C 6 alkyl, OR a , -O-halogenated C 1 -C 6 alkyl, 5-6 membered heteroaryl, benzene Group, -SR a , -SF 5 , cyano group, nitro group, -NR a R b , -NR a C(O)R b , -C(O)NR a R b , -OC(O)R a , -C(O)R a , -P(O)R a R b , -C(O)OR a , -S(O)R a , -S(O
  • Cy 2 represents a 3-12 membered saturated or unsaturated monocyclic or bicyclic ring.
  • the ring can optionally contain 0-3 heteroatoms selected from O, N and S, and the Cy 2 can also be optionally Ground is substituted by 0-3 groups selected from the following substituents: halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, -OR a , -O-halogenated C 1 -C 6 alkyl, -SR a , -SF 5 , cyano group, nitro, -NR a R b , -NR a C(O)R b , -C(O)NR a R b , -OC(O)R a , -C(O)OR a , -S(O)R a , -S(O) 2 R a and -S(O) 2 NR a R
  • Ring A represents a saturated or unsaturated 4-12-membered ring, preferably a 5-12-membered ring; and the ring may optionally contain 0-3 heteroatoms selected from O, N and S, and the Ring A of can also be optionally substituted by 0-3 groups selected from the following substituents: halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, hydroxyl C 1 -C 6 alkyl Group, -OR a , -O-halogenated C 1 -C 6 alkyl group, -SR a , -SF 5 , cyano group, nitro group, -NR a R b , -NR a C(O)R b , - C(O)NR a R b , -OC(O)R a , -C(O)OR a , -S(O)R a , -S(O) 2 R a and -
  • R a , R b , R a' and R b' each independently represent hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogenated C 1 -C 6 alkyl or Hydroxy C 1 -C 6 alkyl; or R a and R b together with the atoms connected to them form a 3-6 membered saturated or unsaturated ring, which ring can optionally contain 0-2 atoms selected from O, S and N heteroatoms; or R a' and R b' together with the atoms connected to them form a 3-6 membered saturated or unsaturated ring, which ring can optionally contain 0-2 selected from O, S and N heteroatoms;
  • n, o, p, q represent integers from 0 to 3.
  • W 1 represents CH or N.
  • W 2 represents CH or N.
  • L 3 represents -NR a SO 2 -.
  • R 3 represents hydrogen or is 0-3 selected from halogen, -OR a , -NR a R b , cyano group and -O-halogenated C 1 -C 6 alkyl group. C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl substituted by the group.
  • R 3 represents a radical substituted by 0-3 selected from halogen, -OR a , -NR a R b , cyano group and -O-halogenated C 1 -C 6 alkyl group. Group-substituted C 1 -C 6 alkyl.
  • Z represents -NR S RS ' .
  • Z represents:
  • R a and R b each independently represent hydrogen, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, halogenated C 1 -C 6 alkyl group or hydroxyl C 1 -C 6 alkyl group; or R a and R b together with the atoms connected thereto form a 3-6 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S and N.
  • Z represents: Wherein, R a and R b each independently represent hydrogen, C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, halogenated C 1 -C 6 alkyl group or hydroxyl C 1 -C 6 alkyl group; or R a and R b together with the atoms connected thereto form a 3-6 membered saturated or unsaturated ring, which may optionally contain 0-2 heteroatoms selected from O, S and N.
  • Z represents:
  • L 1 represents -C(O)NH-, -HNC(O)-, 5-6 membered heteroaryl
  • L 1 represents -C(O)NH-.
  • L 1 represents: -C(O)NH-, -HNC(O)-, 5-6 membered heteroaryl,
  • L 1 represents any one of the following groups:
  • Cy 1 represents 0-3 substituents selected from the following: halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, hydroxyl C 1 -C 6 alkyl, OR a , -O-halogenated C 1 -C 6 alkyl, 5-6 membered heteroaryl, phenyl, -SR a , -SF 5 , cyano group, nitro, -NR a R b , -NR a C(O)R b , -C(O)NR a R b , -OC(O)R a , -C(O)R a , -P(O)R a R b , -C( One of the following groups substituted by O)OR a , -S(O)R a , -S(O) 2 R a and -S(O) 2 NR a R b :
  • Cy 1 represents 0-3 substituents selected from the following: halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, hydroxyl C 1 -C 6 alkyl, OR a , -O-halogenated C 1 -C 6 alkyl, 5-6 membered heteroaryl, phenyl, -SR a , -SF 5 , cyano group, nitro, -NR a R b , -NR a C(O)R b , -C(O)NR a R b , -OC(O)R a , -C(O)R a , -P(O)R a R b , -C( O)OR a , -S(O)R a , -S(O) 2 R a and -S(O) 2 NR a R b Substituted by any of the following groups:
  • Cy 1 represents 0-3 substituents selected from the following: halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, hydroxyl C 1 -C 6 alkyl, OR a , -O-halogenated C 1 -C 6 alkyl, 5-6 membered heteroaryl, phenyl, -SR a , -SF 5 , cyano group, nitro, -NR a R b , -NR a C(O)R b , -C(O)NR a R b , -OC(O)R a , -C(O)R a , -P(O)R a R b , -C( O)OR a , -S(O)R a , -S(O) 2 R a and -S(O) 2 NR a R b substituted
  • Cy 1 represents substituted by phenyl, pyridyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, N-methylpyrazolyl
  • Cy 1 represents the following group:
  • Cy 1 represents 0-3 substituents selected from the following: halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, hydroxyl C 1 -C 6 alkyl, OR a , -O-halogenated C 1 -C 6 alkyl, 5-6 membered heteroaryl, phenyl, -SR a , -SF 5 , cyano group, nitro, -NR a R b , -NR a C(O)R b , -C(O)NR a R b , -OC(O)R a , -C(O)R a , -P(O)R a R b , -C( O)OR a , -S(O)R a , -S(O) 2 R a and -S(O) 2 NR a R b substituted
  • L 2 represents absence, -C 1 -C 6 alkylene- or -NH-.
  • L 2 represents absence
  • Cy 2 represents 0-3 substituents selected from the following: halogen, cyano, nitro, hydroxyl C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, halogenated C 1 -C 6 alkyl, -OR a , -SO 3 R a , -S(O)R a , -O halogenated C 1 -C 6 alkyl, - SR a , -SF 5 or NR a R b substituted morpholinyl, piperidinyl, azetidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperazinyl Or tetrahydrofuranyl, wherein R a and R b each independently represent hydrogen, halogen, C 1 -C 6 alkyl, C 3
  • ring A represents a benzene ring or
  • W 1 represents CH or N
  • the dotted line represents a single bond or a double bond
  • And ring A can also be optionally substituted by 0-3 groups selected from the following substituents: halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, hydroxyl C 1 -C 6 alkyl Group, -OR a , -O-halogenated C 1 -C 6 alkyl group, -SR a , -SF 5 , cyano group, nitro group, -NR a R b , -NR a C(O)R b , - C(O)NR a R b , -OC(O)R a , -C(O)OR a , -S(O)R a , -S(O) 2 R a and -S(O) 2 NR a R b .
  • Ring A represents
  • W 1 represents CH or N
  • And ring A can also be optionally substituted by 0-3 groups selected from the following substituents: halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, hydroxyl C 1 -C 6 alkyl Group, -OR a , -O-halogenated C 1 -C 6 alkyl group, -SR a , -SF 5 , cyano group, nitro group, -NR a R b , -NR a C(O)R b , - C(O)NR a R b , -OC(O)R a , -C(O)OR a , -S(O)R a , -S(O) 2 R a and -S(O) 2 NR a R b .
  • Ring A represents: benzene ring, pyridine ring, pyrazine ring, cyclobutane ring, cyclopentane ring, tetrahydrofuran ring, oxazole ring, thiazole ring, thiophene ring, pyrazole ring, imidazole ring, piperidine ring, hexahydropyran ring, cyclohexane ring;
  • And ring A can also be optionally substituted by 0-3 groups selected from the following substituents: halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, hydroxyl C 1 -C 6 alkyl Group, -OR a , -O-halogenated C 1 -C 6 alkyl group, -SR a , -SF 5 , cyano group, nitro group, -NR a R b , -NR a C(O)R b , - C(O)NR a R b , -OC(O)R a , -C(O)OR a , -S(O)R a , -S(O) 2 R a and -S(O) 2 NR a R b .
  • And ring A can also be optionally substituted by 0-3 groups selected from the following substituents: halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, hydroxyl C 1 -C 6 alkyl Group, -OR a , -O-halogenated C 1 -C 6 alkyl group, -SR a , -SF 5 , cyano group, nitro group, -NR a R b , -NR a C(O)R b , - C(O)NR a R b , -OC(O)R a , -C(O)OR a , -S(O)R a , -S(O) 2 R a and -S(O) 2 NR a R b .
  • the invention provides a compound having the following structure:
  • the present invention also provides a pharmaceutical composition, which contains any compound in the technical solution of the present invention or its pharmaceutically acceptable salt, stereoisomer, isotopic isomer, prodrug, hydrated compounds or solvates, and pharmaceutically acceptable carriers thereof.
  • the present invention also provides a method for treating tumors by inhibiting KIF18A, including administering any compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, or isotope thereof to an individual in need Isomers, prodrugs, hydrates or solvates.
  • the compound of the present invention can also be extended to include pharmaceutically acceptable salts of the compound, its stereoisomers, isotopic isomers (such as deuterated compounds), solvents Compounds, hydrates, prodrugs, and metabolites, that is, pharmaceutically acceptable salts of the compound, and its stereoisomers, isotopomers, solvates, hydrates, prodrugs, and metabolites also fall into Compound scope of protection.
  • alkyl refers to a saturated aliphatic hydrocarbon group or linker containing 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, or 1 to 6 carbon atoms , or straight and branched chain groups of 1 to 4 carbon atoms.
  • “Lower alkyl” refers in particular to alkyl groups having 1 to 4 carbon atoms. Examples of alkyl groups include -( CH2 ) 3- , methyl, trifluoromethyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, and the like.
  • Alkyl groups may be substituted or unsubstituted.
  • Typical substituents include cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, Thiocarbonyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-amide, C-carboxyl, O-carboxyl, Nitro , silyl, amino and -NR Combined 5- or 6-membered heterocyclyl rings.
  • alkenyl refers to a straight or branched hydrocarbon radical containing one or more double bonds and usually having a length of 2 to 20 carbon atoms.
  • C 2 -C 6 alkenyl contains two to six carbon atoms.
  • Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
  • alkynyl refers to a straight or branched hydrocarbon radical containing one or more triple bonds and typically having a length of 2 to 20 carbon atoms.
  • C2-C6 alkynyl contains two to six carbon atoms.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, and the like.
  • alkoxy refers to -O-alkyl.
  • C1-C6 alkoxy (or alkyloxy) is intended to include C1, C2, C3, C4, C5, C6 alkoxy.
  • alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (eg, n-propoxy and isopropoxy), and tert-butoxy.
  • alkylthio or “thioalkoxy” means a sulfur-bridged alkyl group as defined above having the specified number of carbon atoms; for example, methyl-S- and ethyl-S-.
  • cycloalkyl refers to a 3 to 8-membered all-carbon monocyclic ring or bicyclic structure, an all-carbon 5-membered/6-membered or 6-membered/6-membered fused bicyclic ring, or Polycyclic fused rings
  • fused ring systems refer to systems in which Each ring system in this system shares at least one adjacent carbon atom) group with the other rings in the system.
  • One or more of the rings may contain one or more double bonds, but no such ring has complete conjugation.
  • ⁇ -electron systems, or bicyclic rings that share a carbon to form a spiro ring are examples of the rings that share a carbon to form a spiro ring.
  • cycloalkyl groups are, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene, and the like.
  • Bicyclic cyclic alkyl groups include bridged, spiro or fused ring cycloalkyl groups.
  • Illustrative examples of cycloalkyl groups are derived from, but are not limited to, the following:
  • Aryl refers to an all-carbon monocyclic or fused-ring polycyclic group of 6 to 12 carbon atoms, with a complete conjugated ⁇ -electron system. Examples of aryl groups are, but are not limited to, phenyl, naphthyl, and anthracenyl. Aryl groups may be substituted or unsubstituted.
  • Typical substituents include halo, trihalomethyl, alkyl, hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, nitro, carbonyl, thiocarbonyl, C-carboxyl, O-carbamoyl, N-carbamoyl, O-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-amide, sulfinyl, sulfonyl, amino and -NR a R b , where R a and R b are as defined above.
  • Aryl fused saturated or unsaturated cycloalkyl/saturated or unsaturated heterocycloalkyl can be regarded as a special substituent of aryl. Typical examples include but are not limited to:
  • Heteroaryl refers to a monocyclic or fused ring of 5 to 12 ring atoms, containing one, two, three or four ring heteroatoms selected from N, O and S, the remaining ring atoms are C, and In addition, it has a complete conjugated ⁇ -electron system.
  • heteroaryl groups are, but are not limited to, acridinyl, azetidinyl, azecinyl, benzimidazolyl, benzofuryl, benzothiofuranyl, benzothienyl, benzo Oxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl , 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2 ,3-b]Tetrahydrofuryl, furanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-
  • heteroaryl may also include a biaryl structure formed by the above-defined “aryl” and a monocyclic “heteroaryl”, such as but not limited to "-phenylbipyridyl-", “- "Phenylbipyrimidinyl”, “-pyridylbiphenyl”, “-pyridylbipyrimidinyl-", “-pyrimidinylbiphenyl-”; wherein the present invention also includes fused rings containing, for example, the above-mentioned heterocyclic rings and Spirocyclic compounds.
  • a pharmaceutically acceptable heteroaryl group is sufficiently stable to be linked to a compound of the invention, formulated into a pharmaceutical composition, and subsequently administered to a patient in need thereof.
  • substituents in the present invention are independent and not interrelated.
  • R a (or R b ) in a substituent they are independent in the definitions of different substituents.
  • R a (or R b ) in one substituent it does not mean that R a (or R b ) has the same definition in other substituents.
  • NR a R b when the definition of R a (or R b ) is selected from hydrogen, it does not mean that in -C(O)-NR a R R a (or R b ) in b must be hydrogen.
  • Halo or halogen includes fluorine, chlorine, bromine and iodine.
  • Haloalkyl is intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more halogens.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoroethyl Propyl and heptachloropropyl.
  • haloalkyl groups also include "fluoroalkyl groups” which are intended to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms substituted with one or more fluorine atoms.
  • Haloalkoxy or "haloalkyloxy” means a haloalkyl group as defined above having the specified number of carbon atoms linked via an oxygen bridge.
  • C 1 -C 6 haloalkoxy is intended to include C1, C2, C3, C4, C5, C6 haloalkoxy.
  • Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluoroethoxy.
  • haloalkylthio or “thiohaloalkoxy” means a sulfur-bridged haloalkyl group as defined above having the specified number of carbon atoms; for example, trifluoromethyl-S- and pentafluoroethyl -S-.
  • Cx1-Cx2 is used when referring to some substituent groups, which means that the number of carbon atoms in the substituent group may be x1 to x2.
  • C0-C8 means that the group contains 0, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • C1-C8 means that the group contains 1, 2, 3, 4, 5 ,6, 7 or 8 carbon atoms
  • C2-C8 means that the group contains 2, 3, 4, 5, 6, 7 or 8 carbon atoms
  • C3-C8 means that the group contains 3, 4, 5, 6, 7 or 8 carbon atoms
  • C4-C8 means that the group contains 4, 5, 6, 7 or 8 carbon atoms
  • C0-C6 means that the group contains 0, 1, 2, 3, 4, 5 or 6 carbon atoms
  • C1-C6 means the group contains 1, 2, 3, 4, 5 or 6 carbon atoms
  • C2-C6 means the group contains 2, 3, 4, 5 or 6 carbon atoms
  • C3-C6 means that the group contains 3, 4, 5 or 6 carbon atoms.
  • x1-x2 membered ring is used when referring to cyclic groups (such as aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), which means that the ring atoms of the group The number can be x1 to x2.
  • the 3-12-membered cyclic group can be a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12-membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • 3-6 membered ring means that the cyclic group can be a 3, 4, 5 or 6 membered ring, and the number of ring atoms can be 3, 4, 5 or 6 ;
  • 3-8 membered ring means that the cyclic group can be 3, 4, 5, 6, 7 or 8 membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7 or 8; 3-9
  • the membered ring means that the cyclic group can be a 3, 4, 5, 6, 7, 8 or 9-membered ring, and the number of ring atoms can be 3, 4, 5, 6, 7, 8 or 9; 4-7
  • the membered ring means that the cyclic group can be a 4, 5, 6 or 7-membered ring, and the number of ring atoms can be
  • the ring atoms may be carbon atoms or heteroatoms, such as heteroatoms selected from N, O and S.
  • the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more ring heteroatoms, for example selected from N, O and S of heteroatoms.
  • one or more halogens may be each independently selected from fluorine, chlorine, bromine and iodine.
  • substituted means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valency is maintained and that the substitution results in a stable compound.
  • nitrogen atoms e.g. amines
  • these nitrogen atoms can be converted into N-oxides by treatment with oxidizing agents (e.g. mCPBA and/or hydrogen peroxide) to obtain other compounds of the invention.
  • oxidizing agents e.g. mCPBA and/or hydrogen peroxide
  • the nitrogen atoms shown and claimed are deemed to encompass the nitrogen atoms shown and their N-oxides to obtain the derivatives of the invention.
  • any variable occurs more than once in any composition or formula of a compound, its definition on each occurrence is independent of its definition on every other occurrence.
  • the group may be optionally substituted with up to three R groups, with R on each occurrence being independently selected from the definition of R.
  • substituents and/or variables are permitted only if such combinations result in stable compounds.
  • patient refers to an organism to be treated by the methods of the present invention.
  • organisms preferably include, but are not limited to, mammals (eg, rodents, apes/monkeys, horses, cattle, pigs, dogs, cats, etc.) and most preferably refer to humans.
  • the term "effective amount” means an amount of a drug or agent (i.e., a compound of the invention) that will elicit the biological or medical response in a tissue, system, animal, or human, for example, that is sought by a researcher or clinician.
  • therapeutically effective amount means an amount that results in improved treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or a reduction in the risk of a disease, disorder, or side effect as compared to a corresponding subject that does not receive such amount. or the rate at which the condition progresses.
  • An effective amount may be administered in one or more administrations, administrations or doses and is not intended to be limited to a particular formulation or route of administration. The term also includes within its scope an amount effective to enhance normal physiological functions.
  • treatment is used herein in its broadest sense and encompasses therapeutic and/or prophylactic treatment of a subject.
  • treatment includes any treatment that results in the alleviation, suppression, elimination and amelioration and/or prevention of a condition, disease, disorder, etc., such as alleviation, reduction, regulation, amelioration, elimination, prevention, prevention or amelioration thereof.
  • the therapeutic treatment includes alleviating, inhibiting or ameliorating the symptoms or condition of the disease; inhibiting the occurrence of complications; improving the underlying metabolic syndrome; inhibiting the occurrence of the disease or symptoms, such as controlling the development of the disease or condition; alleviating the disease or symptoms; Reduction of disease or symptoms; reduction of complications caused by disease or symptoms, or treatment of symptoms caused by disease or symptoms.
  • Preventative treatment includes prior treatment to prevent, block or delay, slow the onset or progression of a disease or condition or reduce the severity of a disease or condition.
  • therapeutic agent also includes agents or agents that have therapeutic and/or prophylactic treatment in a subject.
  • pharmaceutically useful or “pharmaceutically acceptable” is used herein to refer to those compounds, substances, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for contact with human and animal tissue. Used without undue toxicity, irritation, allergic reactions and/or other problems or complications and commensurate with a reasonable benefit/risk ratio.
  • cancer refers to an abnormal growth of cells that is uncontrollable and, under certain conditions, capable of metastasis (spread).
  • This type of cancer includes, but is not limited to, solid tumors (such as bladder, bowel, brain, chest, uterus, heart, kidney, lung, lymphoid tissue (lymphoma), ovaries, pancreas or other endocrine organs (such as thyroid), prostate , skin (melanoma) or blood tumors (such as non-leukemic leukemia).
  • coadministration refers to the administration of several selected therapeutic agents to a patient, in the same or different modes of administration and at the same or different times.
  • enhancement means that the desired outcome is increased or prolonged, either in potency or duration.
  • enhancing refers to the ability of a drug to increase or prolong its potency or duration in the system.
  • enhancement value refers to the ability to maximize the enhancement of another therapeutic drug in an ideal system.
  • immune disease refers to a disease or condition resulting from an adverse or harmful response to endogenous or exogenous antigens. The result is usually dysfunction of cells, or damage to organs or tissues that may produce immune symptoms.
  • subject include mammals and non-mammals.
  • Mammals include, but are not limited to, mammals: humans, non-human primates such as orangutans, apes and monkeys; agricultural animals such as cattle, horses, Goats, sheep, pigs; domestic animals such as rabbits and dogs; experimental animals include rodents, such as rats, mice and guinea pigs.
  • Non-mammals include, but are not limited to, birds, fish, etc.
  • the selected mammal is a human.
  • a compound or pharmaceutical composition when administered, can ameliorate a disease, symptom or condition, especially its severity, delay its onset, slow down its progression, or reduce its duration. Circumstances that may be attributed to or related to the administration, whether fixed or temporary, continuous or intermittent.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transdermal, vaginal, and ear canal administration. , nasal administration and topical administration.
  • parenteral administration includes intramuscular injection, subcutaneous injection, intravenous injection, intramedullary injection, ventricular injection, intraperitoneal injection, intralymphatic injection, and intranasal injection.
  • the administration of the compounds of the present invention may be topical administration.
  • long-acting formulations are administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection.
  • the drug is administered via a targeted drug delivery system.
  • liposomes coated with organ-specific antibodies In this specific embodiment, the liposomes are selectively targeted to specific organs for uptake.
  • compositions and dosages are provided.
  • pharmaceutically acceptable carrier means a pharmaceutical substance, composition or vehicle such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate , calcium stearate or zinc stearate or stearic acid) or solvent encapsulated substances which involve carrying or transporting the subject compound from one organ or part of the body to another.
  • manufacturing aid e.g., lubricant, talc, magnesium stearate , calcium stearate or zinc stearate or stearic acid
  • solvent encapsulated substances which involve carrying or transporting the subject compound from one organ or part of the body to another.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
  • composition means a composition comprising a compound of the invention and optionally other pharmaceutically acceptable carriers.
  • “Pharmaceutically acceptable carrier” refers to a medium generally accepted in the art for delivering a biologically active agent to an animal, particularly a mammal, including (i.e.) an adjuvant, excipient or vehicle such as a diluent, preservative agents, fillers, flow control agents, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatics, antibacterial agents, antifungal agents, lubricants and dispersants, depending on on the mode of administration and the nature of the dosage form.
  • an adjuvant, excipient or vehicle such as a diluent, preservative agents, fillers, flow control agents, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatics, antibacterial agents, antifungal agents, lubricants and dispersants, depending on on the mode of
  • compositions of the invention may comprise a therapeutically effective amount of one or more compounds of the invention formulated together with optionally one or more pharmaceutically acceptable carriers (additives) and/or diluents, and optionally one or more other therapeutic agents.
  • the compounds of the invention for any of the above uses may be administered by any suitable means, for example orally, such as tablets, pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g.
  • nasally including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in the form of a suppository; or intratumoral injection.
  • nasally including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in the form of a suppository; or intratumoral injection.
  • nasally including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in the form of a suppository; or intratumoral injection.
  • nasally including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally, such as in the form of a suppository; or intratumoral injection.
  • nasally
  • Formulating pharmaceutically acceptable carriers will depend on a number of factors within the scope of those skilled in the art. These factors include, but are not limited to: the type and nature of the active agent formulated; the subject to whom the composition containing the active agent is to be administered; The intended route of administration of the composition; and the therapeutic indication targeted.
  • Pharmaceutical carriers include aqueous and non-aqueous liquid media and various solid and semi-solid dosage forms.
  • the carriers described above may include many different ingredients and additives in addition to the active agent, which other ingredients are included in the formulation for various reasons known to those skilled in the art, such as stabilizing the active agent, binders, etc.
  • suitable pharmaceutical carriers and factors involved in carrier selection can be found in several readily available sources, such as Allen L.V. Jr. et al. Remington: The Science and Practice of Pharmacy (2Volumes), 22nd Edition (2012) ,Pharmaceutical Press.
  • Dosage regimens for the compounds of the invention will, of course, vary depending on known factors such as the pharmacodynamic properties of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition and weight of the recipient ; Nature and extent of symptoms; type of concurrent treatment; frequency of treatment; route of administration, patient's renal and hepatic function, and expected effects.
  • the daily oral dosage of each active ingredient should be from about 0.001 mg/day to about 10-5000 mg/day, preferably from about 0.01 mg/day to about 1000 mg/day, and most preferably The range is about 0.1 mg/day to about 250 mg/day.
  • the most preferred intravenous dose should be from about 0.01 mg/kg/minute to about 10 mg/kg/minute.
  • the compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses of two, three or four times daily.
  • the compounds are typically formulated with a suitable pharmaceutical diluent, excipient or carrier (herein (collectively referred to as pharmaceutical carriers) are administered in the form of a mixture.
  • a suitable pharmaceutical diluent, excipient or carrier herein (collectively referred to as pharmaceutical carriers) are administered in the form of a mixture.
  • Dosage forms suitable for administration may contain from about 1 mg to about 2000 mg of active ingredient per dosage unit.
  • the active ingredient will generally be present in an amount of about 0.1 to 95% by weight, based on the total weight of the composition.
  • compositions comprising as active ingredient a therapeutically effective amount of at least one compound of the invention, alone or in combination with a pharmaceutically acceptable carrier.
  • the compounds of the invention may be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agents (eg, anticancer agents or other pharmaceutically active substances).
  • the compounds of the invention (which may be used in a suitably hydrated form) and/or the pharmaceutical compositions of the invention are formulated into pharmaceutical dosage forms by conventional methods known to those skilled in the art.
  • the actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention can be varied to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response, composition, and mode of administration for a particular patient without being toxic to the patient.
  • the dosage level selected will depend on a variety of factors, including the activity of the particular compound of the invention employed, or its ester, salt or amide; the route of administration; the time of administration; the rate of excretion of the particular compound employed; the rate and extent of absorption. ;The duration of treatment; other drugs, compounds and/or substances used in combination with the specific compound used; factors well known in the medical field such as age, sex, weight, condition, general health and previous medical history of the patient being treated.
  • a physician or veterinarian of ordinary skill in the art can readily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, to achieve a desired therapeutic effect, a physician or veterinarian may initiate a trial of a compound of the invention used in a pharmaceutical composition at a level lower than required and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be the lowest dose of compound effective to produce a therapeutic effect. Such effective doses will generally depend on the factors noted above.
  • oral, intravenous, intracerebroventricular, and subcutaneous dosages of a compound of the invention for use in a patient range from about 0.01 to about 50 mg/kg body weight/day.
  • an effective daily dose of active compound may be administered separately in two, three, four, five, six or more sub-doses at appropriate intervals throughout the day, optionally in unit dosage form. In certain aspects of the invention, administration is once daily.
  • compositions can be administered alone, it is preferred to administer the compounds in the form of pharmaceutical preparations (compositions).
  • kits can be composed of a conveyor, a drug pack or a container box, which can be divided into multiple compartments to accommodate one or more containers, such as vials, test tubes and the like, each container containing all a single ingredient in the method described.
  • Suitable containers include bottles, vials, syringes and test tubes.
  • Containers are made of acceptable materials such as glass or plastic.
  • the container may contain one or more compounds described herein, either as a pharmaceutical component or in a mixture with other ingredients described herein.
  • the container may have a sterile outlet (for example, the container may be an IV bag or bottle, and the stopper may be pierced by a hypodermic needle).
  • kits may contain a compound and instructions, labels, or instructions for use as described herein.
  • a typical kit may include one or more containers, each containing one or more materials (such as reagents, or concentrated stock solutions, and/ or equipment). These materials include, but are not limited to, buffers, diluents, filters, needles, syringes, delivery devices, bags, containers, bottles and/or test tubes, accompanied by a list of contents and/or instructions for use, as may the built-in packaging. The entire set of instructions must be included.
  • Labels can appear on the container or be closely associated with the container. When a label appears on a container, it means that the label's letters, numbers, or other features are pasted, molded, or engraved on the container; the label may also appear inside a container box or shipping box containing a variety of containers, such as in a product insert. A label may be used to indicate a specific therapeutic use of the contents. The label may also indicate instructions for use of the contents, such as described in the method above.
  • the unit of weight-volume percentage in the present invention is well known to those skilled in the art, for example, it refers to the weight of the solute in 100 ml of solution. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as familiar to one skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the method of the present invention. The preferred implementation methods and materials described in this article are for demonstration purposes only.
  • HPLC analysis used SHIMADZU 20A high performance liquid chromatograph.
  • Preparative HPLC separation uses Shimadzu LC-20AP pump, Shimadzu LH-40 Liquid Handler, Shimadzu SPD-20A Detector, Gilson GX-281 Liquid Handler, Gilson 322 pump, Gilson 156 UV Detector preparative chromatograph.
  • SFC separation uses The Berger MG II, MG III, Sepiatec's Prep SFC 100 system, Waters Prep 80Q SFC SYSTEM, Prep 150 AP SFC SYSTEM, Prep 200 SFC SYSTEM, Prep 350 SFC SYSTEM.
  • the thin layer chromatography silica gel plate uses the GF254 acrylic adhesive silica gel plate of Anhui Liangchen Silicon Source Materials Co., Ltd.
  • the specification of the silica gel plate used in thin layer chromatography (TLC) is 0.25mm, and the thin layer chromatography separation and purification products use silica gel plate.
  • the specification is 0.5mm.
  • Microwave reaction uses Biotage Initiator+ microwave synthesizer.
  • the glove box uses DELLIX custom-made glove box.
  • Step 2 Add N,N-diisopropylethylamine (11.6g) to a solution of methyl 2-amino-4,6-dihydroxynicotine ester (5.50g, 29.9mmol) in phosphorus oxychloride (50mL) , 89.6 mmol), and the reaction mixture was stirred at 25°C for 6 hours.
  • the reaction solution was concentrated and spun to dryness, water (100 mL) was added to the reaction mixture, and extracted with ethyl acetate (100 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin the filtrate to dryness to obtain a residue.
  • Step 3 Add methyl 2-amino-4,6-dichloronicotine ester (2.30g, 10.4mmol) and 6-azaspiro[2.5]octane hydrochloride (1.54g, 10.4mmol) to dimethyl
  • potassium carbonate 3.74 g, 27.1 mmol
  • Water 50 mL was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin the filtrate to dryness to obtain a residue.
  • Step 4 Add methyl 2-amino-6-chloro-4-(6-azaspiro[2.5]octane-6-yl)nicotine ester (1.40g, 4.73mmol) and sodium bicarbonate (0.80g, To a solution of 9.47 mmol) in methanol (12 mL) and water (6 mL) was added 2-chloroacetaldehyde (2.79 g, 14.2 mmol). The mixture was heated to 80°C and stirred for 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3).
  • Step 5 Add methyl 5-chloro-7-(6-azaspiro[2.5]octane-6-yl)imidazo[1,2-a]pyridine-8- at a temperature of 5-10°C.
  • methyl formate (1.00g, 3.13mmol) in tetrahydrofuran (20mL)
  • trimethylaluminum 4.69mL, 2M, 9.38mmol
  • 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (1.07g, 4.69mmol) was added to the reaction solution.
  • Step 6 To 5-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-7-(6-azaspiro[2.5 ] Octan-6-yl)imidazo[1,2-a]pyridine-8-carboxamide (300mg, 0.58mmol), 2-hydroxyethanesulfonamide (94.6mg, 0.76mmol), potassium phosphate (500mg, 2.33 mmol) and 2-di-tert-butylphosphine-2′,4′,6′-triisopropylbiphenyl (49.4 mg, 0.12 mmol) in dioxane (10 mL) was added tris(dibenzylidene) Acetone) dipalladium (54.3 mg, 0.06 mmol).
  • Step 1 Slowly add sodium hydride (3.51g, 87.6mmol, purity 60%) to a solution of 2,2-dimethoxyethanol (8.88g, 83.6mmol) in tetrahydrofuran (400mL) at 0°C. The mixture was stirred at 25°C for 1 hour, then methyl 4-bromo-2,6-difluorobenzoate (20.0 g, 79.6 mmol) was added to the mixture, and the mixture was stirred at 25°C for 2 hours.
  • Step 2 Stir the solution of polyphosphoric acid (52.0g, 113mmol) in toluene (400mL) at 60°C for 30 minutes. Then methyl 4-bromo-2-(2,2-dimethoxyethoxy)-6-fluorobenzoate (19.0 g, 56.4 mmol) was added to the mixture, and the mixture was stirred at 60°C for 4 hours. . Water (200 mL) was added to the reaction mixture, and extracted with ethyl acetate (200 mL x 2). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin the filtrate to dryness to obtain a residue.
  • Step 3 Add methyl 4-bromo-6-fluorobenzofuran-7-carboxylate (3.00g, 11.0mmol) and triethylamine (3.33g, 32.9mmol) in dimethyl sulfoxide (30mL) 6-Azaspiro[2.5]octane hydrochloride (1.78g, 12.1mmol) was added to the solution. The mixture was stirred at 130°C for 16 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin the filtrate to dryness to obtain a residue.
  • Step 4 Add 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (1.13g, 4.94mmol) to trimethylaluminum (9.90mL) at 0°C. , 2M) toluene solution was added with methyl 4-bromo-6-(6-azaspiro[2.5]octane-6-yl)benzofuran-7-carboxylate (1.20g, 3.29mmol). The mixture was heated to 120°C and stirred for 16 hours. The mixture was cooled to room temperature, then slowly poured into ice water (30 mL), and extracted with ethyl acetate (30 mL x 3).
  • Step 5 Add N,N-dimethyl to 2-hydroxyethanesulfonamide (174mg, 1.39mmol), 2-(methylamino)acetic acid (95.4mg, 1.07mmol), potassium phosphate (927mg, 4.28mmol) Cuprous iodide (104 mg, 0.54 mmol) was added to the formamide (12 mL) solution. The mixture was stirred at 50°C for 5 minutes.
  • the first step to N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-4-(2-hydroxyethylsulfonylamino)-6 -
  • methanol 2 mL
  • palladium on carbon 20 mg, purity 10%
  • the mixture was stirred at 25°C for 16 hours under a hydrogen pressure of 50 Psi.
  • the mixture was filtered through Celite, and the filtrate was concentrated and spun to dryness.
  • Step 1 Dissolve 4-bromonaphthyl-1-amine (30.0g, 135mmol) in tetrahydrofuran (300mL), add N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (51.1g, 162mmol), 25 °C and stirred for 12 hours.
  • Step 2 Place boron trifluoride ether (8.87g, 62.5mmol) in a three-necked flask and cool it to -15°C. Add dropwise 4-bromo-2-dissolved in N,N-dimethylacetamide (100mL). Fluoronaphthyl-1-amine (10.0g, 41.6mmol), Add tert-butyl nitrite (5.70g, 54.1mmol) dissolved in N,N-dimethylacetamide (100mL) dropwise, and stir at –15°C for 1 hour.
  • Step 3 Add 4-bromo-2-fluoro-1-naphthalenenitrile (4.90g, 19.6mmol) to sulfuric acid (100mL, 70%), and stir at 80°C for 16 hours. Add sodium nitrite (1.94g, 28.1mmol) at 80°C and stir at 80°C for 1 hour.
  • Step 4 Dissolve 4-bromo-2-fluoro-1-naphthoic acid (2.00g, 7.43mmol) and N,N carbonyldiimidazole (7.23g, 44.6mmol) in N,N-dimethylformamide ( 40.0 mL), heated to 60°C and stirred for 4 hours.
  • 2-(4,4-Difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (2.04g, 8.92mmol) was dissolved in N,N-dimethylformamide (40mL), 0°C Add sodium hydrogen (0.89g, 22.3mmol, 60% mass fraction), stir at 25°C for 30 minutes, add the above solution to the reaction system, and stir at 25°C for 16 hours.
  • reaction solution was quenched by adding water (200 mL), extracted with ethyl acetate (200 mL x 2), and the organic phase was dried, filtered, and concentrated to obtain a residue.
  • the residue was purified by flash column chromatography (silica gel, 0-7% gradient of tetrahydrofuran/petroleum ether) to give 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6- as a yellow solid Methylpyrimidin-4-yl)-2-fluoro-1-naphthylamide (1.10g, 2.19mmol, yield 20%).
  • Step 5 Combine 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-fluoro-1-naphthylamide (1.10 g, 93%) and 6-azaspiro[2.5]octane hydrochloride (0.44g, 2.98mmol) were dissolved in dimethyl sulfoxide (40.0mL), and potassium carbonate (0.95g, 6.89mmol) was added. Stir at 120°C for 16 hours.
  • reaction solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL x 2), the organic phase was dried, filtered and concentrated, and the residue was purified by flash column chromatography (silica gel, 0-7% gradient of tetrahydrofuran/petroleum ether) to obtain a yellow solid 4-Bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octane-6 -yl)-1-naphthylamide (0.36g, 0.71mmol, yield 31%).
  • Step 6 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-2-(6-azaspiro[2.5 ] Octan-6-yl)-1-naphthylamide (200mg, 0.35mmol) and 2-hydroxyethanesulfonamide (57.0mg, 0.46mmol) were dissolved in dioxane (10.0mL), and potassium phosphate (297mg ,1.40mmol), 2-di-tert-butylphosphine-2′,4′,6′-triisopropylbiphenyl (29.8mg, 0.07mmol), tris(dibenzylidene) acetone) dipalladium (32.1 mg, 0.04 mmol).
  • Step 1 Add iron powder (8.55g, 151.51mmol), 4-bromo-2-fluoro-5-nitrobenzoic acid (8.00) to a mixed solution of ethanol (40mL), water (10mL) and tetrahydrofuran (40mL) g, 30.30mmol) and ammonium chloride (2.45g, 45.45mmol), the mixture was heated to 90°C and stirred for 3 hours. After the mixture was cooled to 40°C, it was poured into a diatomite sand core funnel while hot and filtered.
  • Step 2 Add glycerol (5.96g, 64.10mmol) to a mixed solution of concentrated sulfuric acid (20mL) and water (5mL), heat the mixture to 100°C and stir for 15 minutes. After the mixture was cooled to 40°C, 5-amino-4-bromo-2-fluorobenzoic acid (5.00g, 21.36mmol) and 3-nitrobenzene sulfonate sodium salt (4.85g, 21.36mmol) were added to the mixture. ), the mixture was heated to 100°C and stirred for 15 hours. After the reaction was completed, water (100 mL) was added to the reaction mixture, and extracted with ethyl acetate (100 mL x 3).
  • Step 4 Add 2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-amine (758 mg, 3.32 mmol) and 8-bromo-6-(6-azaspiro To a solution of [2.5]octane-6-yl)quinoline-5-carboxylic acid (1.00g, 1.30mmol) in dichloromethane (10.0mL) was added N,N,N′,N′-tetramethyl- The mixture was stirred at 100°C for 24 hours. After the reaction was completed, water (10 mL) was added to the reaction mixture, and extracted with dichloromethane (20 mL x 3).
  • Step 5 Under nitrogen atmosphere, combine 2-hydroxyethanesulfonamide (67mg, 1.40mmol), tris(dibenzylideneacetone)dipalladium (33mg, 0.03mmol), potassium phosphate (303mg, 1.40mmol) and 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (30 mg, 0.06 mmol) was put into the bottle, 1,4-dioxane (4 mL) was added into the reaction bottle, and the mixture was Stir for 0.5 hours at 50°C, and then add 8-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-6-(6-nitrogen Heterospiro[2.5]octane-6-yl)quinoline-5-carboxamide (200 mg, 0.35 mmol) was added to the vial.
  • Step 1 8-(4,4-difluoropiperidin-1-yl)-7-fluoroquinolin-6-amine (171 mg, 0.61 mmol) and 2- ⁇ 6-azaspiro[2.5]octane
  • -6-yl ⁇ -4-bromonaphthalene-1-carbonyl chloride 230 mg, 0.61 mmol
  • N,N-diisopropylethylamine 240 mg, 1.82 mmol
  • the second step 2- ⁇ 6-azaspiro[2.5]octane-6-yl ⁇ -4-bromo-N-[8-(4,4-difluoropiperidin-1-yl)-7- Fluoroquinolin-6-yl]naphthalene-1-carboxamide (210mg, 0.33mmol) and 2-hydroxyethanesulfonamide (84.3mg, 0.67mmol) were dissolved in dioxane (4mL), and potassium phosphate (214mg ,1.01mmol), 2-di-tert-butylphosphine-2′,4′,6′-triisopropylbiphenyl (14.3mg, 0.03mmol), tris(dibenzylideneacetone)dipalladium (31.4mg, 0.03mmol).
  • Step 1 Add 4-chloro-2-(4,4-difluoropiperidin-1-yl)-6-methoxypyrimidine (5.00g, 18.9mmol) in dioxane (100mL) Benzophenone imine (5.16g, 28.5mmol), cesium carbonate (18.9g, 56.9mmol), 4,5-bis(diphenylphosphorus)-9,9-dimethylxanthene (1.12g, 1.90mmol) and tris(dibenzylideneacetone)dipalladium (1.77g, 1.90mmol). The reaction solution was replaced with nitrogen three times, heated to 100°C under a nitrogen atmosphere, and stirred for 12 hours.
  • reaction solution was cooled to room temperature, extracted with water (200 mL) and ethyl acetate (200 mL x 3), the organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spun dry to obtain The residue.
  • the residue was slurried with ethyl acetate to obtain yellow solid N-[2-(4,4-difluoropiperidin-1-yl)-6-methoxypyrimidin-4-yl]-1,1-diphenylmethyl Imine (5.90g, 14.4mmol, yield 76%).
  • Step 2 To N-[2-(4,4-difluoropiperidin-1-yl)-6-methoxypyrimidin-4-yl]-1,1-diphenylmethimine (1.00g , 2.45mmol) in methanol (10mL), sodium acetate (0.60g, 7.34mmol) and hydroxylamine hydrochloride (0.34g, 4.90mmol) were added. The mixture was stirred at 25°C for 1 hour. Pour the reaction solution into ice water (20 mL), and extract with ethyl acetate (20 mL x 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin the filtrate to dryness to obtain a residue.
  • Step 3 Add 4-bromo-2-fluoronaphthalene-1-carboxylic acid (2.00g, 7.43mmol) and 6-azaspiro[2.5]octyl hydrochloride (1.65g, 11.1mmol) in dimethyl sulfoxide ( Potassium carbonate (3.14g, 22.3mmol) was added to the solution. The mixture was heated to 120°C and stirred for 72 hours. Water (50 mL) was added to the reaction mixture, the pH was adjusted to 4 with 3M dilute hydrochloric acid, and extracted with ethyl acetate (50 mL x 2). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin the filtrate to dryness to obtain a residue.
  • Potassium carbonate 3.14g, 22.3mmol
  • Step 4 To 2- ⁇ 6-azaspiro[2.5]octane-6-yl ⁇ -4-bromonaphthalene-1-carboxylic acid (250 mg, 0.69 mmol) in dichloromethane (5 mL) was added oxalyl chloride (107 mg, 0.83 mmol), then N.N-dimethylformamide (5.07 mg, 0.07 mmol) was added dropwise to the reaction solution, and the mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated and spun to dryness to obtain a crude yellow solid 2- ⁇ 6-azaspiro[2.5]octane-6-yl ⁇ -4-bromonaphthalene-1-carbonyl chloride (250 mg, crude product).
  • Step 5 2-(4,4-difluoropiperidin-1-yl)-6-methoxypyrimidin-4-amine (193 mg, 0.79 mmol) and 2- ⁇ 6-azaspiro[2.5]octane
  • N,N-diisopropylethylamine 313 mg, 2.37 mmol
  • the mixture was stirred at 50°C for 16 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3).
  • Step 6 2- ⁇ 6-azaspiro[2.5]octane-6-yl ⁇ -4-bromo-N-[2-(4,4-difluoropiperidin-1-yl)-6- Methoxypyrimidin-4-yl]naphthalene-1-carboxamide (80 mg, 0.13 mmol) and 2-hydroxyethanesulfonamide (34.1 mg, 0.27 mmol) were dissolved in dioxane (4 mL), and potassium phosphate ( 86.8mg, 0.41mmol), 2-di-tert-butylphosphine-2′,4′,6′-triisopropylbiphenyl (5.79mg, 0.01mmol), tris(dibenzylideneacetone)dipalladium (12.7 mg, 0.01mmol).
  • Step 1 At 20°C, mix a solution of glycerol (1.13g, 12.09mmol) and sodium 3-nitrobenzene sulfonate (1.00g, 4.43mmol) in sulfuric acid (4.00mL)/water (2.00mL). Stir at 120°C for 30 minutes. The reaction system was cooled to 40°C. Methyl 2-amino-4-bromo-6-fluorobenzoate (1.00 g, 4.03 mmol) was added to the reaction mixture, and the mixture was stirred at 120°C for 4 hours. The reaction mixture was poured into ice water (50 mL), the mixture was filtered, and the filter cake was washed with ethyl acetate (30 mL).
  • the organic phases were combined, dried, filtered, and concentrated to obtain 5-bromo-7-fluoroquinoline-8-carboxylic acid (200 mg, 0.74 mmol, yield 16.7%) as a gray solid.
  • Step 2 At 20°C, add 5-bromo-7-fluoroquinoline-8-carboxylic acid (1.00g, 3.70mmol), 6-azaspiro[2.5]octane hydrochloride (0.83g, 5.55 mmol) in dimethyl sulfoxide (13.00 mL) was added potassium carbonate (1.56 g, 11.10 mmol). The resulting reaction mixture was stirred at 120°C for 16 hours.
  • Step 3 Add 7-(6-azaspiro[2.5]octane-6-yl)-5-bromoquinoline-8-carboxylic acid (0.53g, 1.47mmol) to dichloromethane at 20°C. (3.00mL) solution was added thionyl chloride (100uL). The reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was concentrated to dryness without purification to obtain 7-(6-azaspiro[2.5]octane-6-yl)-5-bromoquinoline-8-carboxylic acid chloride (550 mg, 1.45 mmol, yield 98.7% ), as an orange solid.
  • LCMS(ESI):[M+H] + 377.1
  • Step 4 At 20°C, add tert. Potassium butoxide (328mg, 2.90mmol). The reaction mixture was stirred at 20°C for 5 minutes, and 7-(6-azaspiro[2.5]octane-6-yl)-5-bromoquinoline-8-carboxylic acid chloride (550 mg, 1.45 mmol) was added. The reaction mixture was stirred at 20°C for 16 hours. Water (20 mL) was added to the reaction mixture, and extracted with ethyl acetate (10 mL x 3).
  • Step 5 At 20°C, react with [7-(6-azaspiro[2.5]octane-6-yl)-5-bromo(8-quinoline)]-N-[2-(4,4 -Difluoropiperidinyl)-6-methylpyrimidin-4-yl]carboxamide (150 mg, 0.26 mmol), 2-hydroxyethylsulfonamide (98 mg, 0.79 mmol), potassium phosphate (170 mg, 0.79 mmol), Add 1, 4-Dioxane (7.00 mL), the resulting reaction mixture was sparged with nitrogen for 2 minutes and stirred at 60°C for 5 hours.
  • the first step contains 4-bromo-2-fluoro-6-methylbenzoic acid methyl ester (25.0g, 101.19mmol), N-bromosuccinimide (21.6g, 121.43mmol), azobisiso
  • a mixed solution of butyronitrile (8.5g, 50.60mmol) and acetonitrile (250mL) was stirred at 70°C for 3 hours.
  • the reaction solution was poured into water (50mL) and extracted with ethyl acetate (50mL x 3).
  • Step 2 Contains 4-bromo-2-(bromomethyl)-6-fluorobenzoic acid methyl ester (18g, 55.22mmol), tert-butyl ethyl malonate (11.4g, 60.74mmol), cesium carbonate ( A mixed solution of 36.7 g, 110.44 mmol) and N,N-dimethylformamide (200 mL) was stirred at 20°C for 2 hours.
  • reaction solution was poured into water (300mL) and extracted with ethyl acetate (100mL Petroleum ether) was purified to obtain compound 1-(tert-butyl)3-ethyl-2-(5-bromo-3-fluoro-2-(methoxycarbonyl)benzyl)malonic acid (15.4g, crude product), It is colorless oil.
  • Step 3 Contains 1-(tert-butyl)3-ethyl-2-(5-bromo-3-fluoro-2-(methoxycarbonyl)benzyl)malonic acid (15g, 34.62mmol) and trifluoro
  • acetic acid 60 mL was stirred at 20°C for 1 hour.
  • the reaction solution was concentrated to remove trifluoroacetic acid, then toluene (60 mL) and triethylamine (35.75g, 346.21mmol) were added, and stirring was continued at 120°C for 3 hours.
  • Step 4 Contains 4-bromo-2-(3-ethoxy-3-oxypropyl)-6-fluorobenzoic acid methyl ester (6.8g, 20.41mmol), lithium hydroxide monohydrate (4.9g, 204.11 mmol), a mixed solution of tetrahydrofuran (40 mL), methanol (40 mL) and water (40 mL) was stirred at 20°C for 4 hours.
  • the reaction solution was concentrated to remove tetrahydrofuran and methanol, 4M hydrochloric acid ethyl acetate solution (100 mL) was added to adjust the pH to close to 5, and then extracted with ethyl acetate (20 mL x 3).
  • Step 5 Add oxalyl chloride (15.3g, 120.25mmol) to a solution containing 4-bromo-2-(2-carboxyethyl)-6-fluorobenzoic acid (5.0g, 17.18mmol) and dichloromethane (50mL) into the mixed solution, and the resulting mixture was stirred at 20°C for 1 hour. The reaction solution was concentrated to obtain compound 4-bromo-2-(3-chloro-3-oxypropyl)-6-fluorobenzoyl chloride (5.7 g, crude product) as a yellow oil.
  • LCMS (ESI): [M+H] + 319.0 (corresponding methyl ester).
  • Step 6 Dissolve 4-bromo-2-(3-chloro-3-oxypropyl)-6-fluorobenzoyl chloride (5.0g, 15.25mmol) in dichloromethane (50mL), and add dropwise at 0°C into a solution containing aluminum trichloride (8.1g, 60.98mmol) and dichloromethane (50mL). The reaction solution was stirred at 40°C for 16 hours. The reaction mixture was poured into water (30mL) and washed with dichloromethane (30mL).
  • Step 7 Contains 7-bromo-5-fluoro-1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid (3.3g, 12.09mmol), 6-azaspiro[2.5]octane A mixed solution of alkyl hydrochloride (2.7g, 18.13mmol), potassium carbonate (6.0g, 42.30mmol) and dimethyl sulfoxide (30mL) was stirred at 100°C for 12 hours, and the reaction solution was poured into water (30mL).
  • Step 8 Contains 7-bromo-1-oxo-5-(6-azaspiro[2.5]oct-6-yl)-2,3-dihydro-1H-indane-4-carboxylic acid (1g, A mixed solution of triethylsilane (3.2g, 27.45mmol) and trifluoroacetic acid (10mL) was stirred at 80°C for 12 hours. After the reaction solution was concentrated, sodium bicarbonate aqueous solution (50mL) was added, and then 4M hydrochloric acid was added.
  • Step 9 Add oxalyl chloride (518 mg, 4.00 mmol) to the solution containing 7-bromo-5-(6-azaspiro[2.5]oct-6-yl)-2,3-dihydro-1H-indene-4 -
  • carboxylic acid chlorinated phthalic acid 700 mg, 2.00 mmol
  • dichloromethane 10 mL
  • the resulting mixture was stirred at 20°C for 30 minutes, and the reaction mixture was concentrated to obtain compound 7-bromo-5 -(6-Azaspiro[2.5]oct-6-yl)-2,3-dihydro-1H-indene-4-carbonyl chloride (760 mg, crude product), as a yellow oil.
  • LCMS(ESI): [M+H] + 364.2. (corresponding methyl ester)
  • Step 10 Contains 2-(4,4-difluoropropylpiperidinyl)-6-methylpyrimidin-4-amine (650mg, 2.85mmol), N,N-diisopropylethylamine (2.5g , 18.99mmol), a mixed solution of potassium tert-butoxide (323mg, 2.85mmol) and tetrahydrofuran (10mL) was stirred at 20°C for 30 minutes, and then 7-bromo-5-(6-azaspiro[2.5]octane- 6-yl)-2,3-dihydro-1H-indene-4-carbonyl chloride (700mg, 1.90mmol), pour the reaction solution into water (30mL) and extract with ethyl acetate (30mL x 3), and use the organic phase Dry over anhydrous sodium sulfate, filter and concentrate, and then purify by column chromatography (silica gel, 0-50% gradient of ethyl acetate/petrol
  • Step 11 Under nitrogen atmosphere, containing 7-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-(6- Azaspiro[2.5]oct-6-yl)-2,3-dihydro-1H-indene-4-carboxamide (300 mg, 0.54 mmol), 2-hydroxyethanesulfonamide (137 mg, 1.07 mmol), potassium phosphate (348mg, 1.61mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (23mg, 0.054mmol), tris(dibenzylideneacetone)dipalladium (50mg, 0.054 The reaction solution of mmol) and dioxane (5mL) was stirred at 100°C for 8 hours.
  • reaction solution was poured into water (30mL) and extracted with ethyl acetate (30mL x 3). The organic phase was dried over anhydrous sodium sulfate and filtered. After concentration, column chromatography (silica gel, 0-100% gradient of ethyl acetate/petroleum ether) was performed to obtain compound N-(2-(4,4-difluoropiperidin-1-yl)-6-methyl Pyrimidin-4-yl)-7-((2-hydroxyethyl)sulfonamide)-5-(6-azaspiro[2.5]oct-6-yl)-2,3-dihydro-1H-indene -4-Carboxamide (149.0 mg, 0.25 mmol, yield: 46.0%), is a white solid.
  • Step 1 tert-Butyl N-[6-amino-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-2-yl]-N -[(tert-butoxy)carbonyl]carbamomethyl ester (120 mg, 0.30 mmol) and 2- ⁇ 6-azaspiro[2.5]octane-6-yl ⁇ -4-bromonaphthalene-1-carbonyl chloride To a solution of N,N-diisopropylethylamine (418 mg, 3.17 mmol) in tetrahydrofuran (8.00 mL) was added. The mixture was stirred at 25°C for 16 hours.
  • Step 2 Add tert-butyl N-[6-(2- ⁇ 6-azaspiro[2.5]octane-6) to the mixed solution of trifluoroacetic acid (0.50mL) and dichloromethane (1.50mL) -yl ⁇ -4-bromonaphthyl-1-acylamino)-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-2-yl]-N -[(tert-butoxy)carbonyl]carbamomethyl ester (400 mg, 0.47 mmol). The mixture was stirred at 25°C for 4 hours.
  • Step 3 At 25°C, add to N-[2-amino-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-6-yl] -To a solution of 2- ⁇ 6-azaspiro[2.5]octane-6-yl ⁇ -4-bromonaphthalene-1-carboxamide (360 mg, 0.56 mmol) in dioxane (2 mL) was added ethyl 2- Sulfamoylpropyl ester (101mg, 0.56mmol), potassium phosphate (363mg, 1.68mmol), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane ( 23.7 mg, 0.06 mmol) and tris(dibenzylideneacetone)dipalladium (52.2 mg, 0.06 mmol).
  • Step 4 Ethyl 2-[(4- ⁇ [2-amino-4-(4,4-difluoropiperidin-1-yl)-5-fluoro-1,3-benzothiazol-6-yl ]Aminocarbonyl ⁇ -3- ⁇ 6-azaspiro[2.5]octane-6-yl ⁇ naphth-1-yl)sulfamoyl]propyl ester (300 mg, 0.40 mmol) was added to the tetrahydrofuran (14 mL) solution. Lithium aluminum tetrahydride (21.6 mg, 0.60 mmol) was added in portions at 25°C, and the mixture was stirred at 25°C for 1 hour.
  • the diluted solution was purified by preparative HPLC (C18, 28-68% gradient water (formic acid)/acetonitrile) to obtain the white solid compound N-[2-amino-4-(4,4-difluoropiperidin-1-yl) )-5-fluoro-1,3-benzothiazol-6-yl]-2- ⁇ 6-azaspiro[2.5]octane-6-yl ⁇ -4-(1-hydroxypropane-2-sulfonyl Amino)naphthalene-1-carboxamide (37.9 mg, 0.052 mmol, yield 13%).
  • Step 1 Under nitrogen atmosphere, containing 7-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-6-methylpyrimidin-4-yl)-5-(6-nitrogen Heterospiro[2.5]oct-6-yl)-2,3-dihydro-1H-indene-4-carboxamide (300 mg, 0.54 mmol), ethyl 2-methyl-2-sulfamic acid propionate (209 mg , 1.07mmol), potassium phosphate (348mg, 1.61mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (23mg, 0.054mmol), tris(dibenzylideneacetone) )
  • the reaction solution of dipalladium (50mg, 0.054mmol) and dioxane (5mL) was stirred at 100°C for 8 hours.
  • Step 2 Add lithium aluminum tetrahydride (40 mg, 1.11 mmol) in batches containing 2-(N-(7-((2-(4,4-difluoropiperidin-1-yl)-6-methyl) Pyrimidin-4-yl)carbamoyl)-6-(6-azaspiro[2.5]oct-6-yl)-2,3-dihydro-1H-inden-4-yl)sulfamoyl)-2 -In a mixed solution of ethyl methylpropionate (250 mg, 0.37 mmol) and tetrahydrofuran (5 mL), the reaction solution was stirred at 20°C for 1 hour, saturated aqueous ammonium chloride solution (20 mL) was added to quench the reaction, and then ethyl acetate was added (30mL and C18 (0-100% gradient acetonitrile/water) to obtain compound N-(2-(4,4-difluoropiperidin-1-yl)-6-
  • Enzyme activity detection Use DMSO to dissolve the compound powder into a 10mM stock solution; perform gradient dilution of the compound in a microplate to a final concentration of 0-10 ⁇ M. Then add 2.5 ⁇ L each of tubulin, compound, ATP, and KIF18A protein to the microwell plate in sequence, and react at room temperature for 120 minutes. The final concentration of the enzyme reaction was 60 ⁇ g/mL for microtubules, 25 ⁇ M for ATP, and 2.5 nM for KIF18A protein. After the enzyme reaction is completed, add 10 ⁇ l ADP-GLO reaction reagent to each well and incubate at room temperature for 30 minutes. Afterwards, add 20 ⁇ l of detection reagent to each well and incubate at room temperature in the dark for 30 minutes. Finally, PerkinElmer Envision was used for chemiluminescence detection.
  • Table 1 Biological data of enzymatic activity of the compounds of the present invention
  • OVCAR3 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd.
  • RPMI-1640 culture medium, fetal calf serum, and CyQUANT Direct Cell Proliferation Assay kit were purchased from Thermo Fisher Scientific in the United States;
  • 96-well cell culture plates were purchased from Corning Company in the United States.
  • OVCAR3 cells were cultured in RPMI-1640 culture medium containing 10% fetal bovine serum and placed in an incubator at 37°C and 5% CO2 . Cells in the logarithmic growth phase can be used for experiments.
  • OVCAR3 cells were seeded into a 96-well cell culture plate, 90 ⁇ l per well, and cultured overnight in a 37°C, 5% CO2 incubator. Dissolve the compound powder into a 10mM stock solution using DMSO; perform a gradient dilution of the compound in a microplate to a final concentration of 0-10 ⁇ M. Add 10 ⁇ L of compound-containing cell culture fluid to each well to give a final DMSO content of 0.2%. The cell plate was cultured in an incubator at 37°C and 5% CO2 for 3 days. Add 100 ⁇ l of CyQUANT detection reagent to each well, react at 37°C for 60 minutes, and use Envision from PerkinElmer for fluorescence detection.
  • Table 2 OVCAR-3 cell activity biological data of compounds of the present invention
  • HT29 cells were purchased from Nanjing Kebai Biotechnology; RPMI-1640 culture medium was purchased from ThermoFisher Company (USA); fetal bovine serum was purchased from ThermoFisher Company (USA); Trypsin-EDTA (0.25%) was purchased from ThermoFisher Company (USA) ); DMSO was purchased from SIGMA Company (USA); 96-well plate was purchased from ThermoFisher Company (USA); CyQuant reagent was purchased from ThermoFisher Company (USA).
  • HT29 cells were cultured in RPMI-1640 containing 10% fetal calf serum at 37°C and 5% CO2 . Cells in the logarithmic growth phase can be used for experiments.
  • CyQuant reagent was used to detect the proliferation inhibitory activity of compounds on HT29 cells. Adjust the cell density, inoculate 100 ⁇ l per well into a 96-well plate (2000/well for HT29), and culture overnight at 37°C and 5% CO2 . Add each target concentration compound (initial concentration 3000 nM, 3-fold dilution, 9 concentration gradients), and the DMSO content is 0.2%. The cell plate was incubated at 37°C and 5% CO for 3 days. Add CyQuant reagent and incubate for 1 hour, read the plate with Envision, and calculate IC 50 using XLFIT.
  • Table 3 HT-29 cell activity biological data of the compounds of the present invention
  • Hepatocytes from other races may be used, and specific information will be reflected in the trial report.
  • hepatocyte tubule (1 mL, approximately 5 ⁇ 10 6 cells) into a 50 mL centrifuge tube containing 50 mL of recovery medium, and centrifuge it at 100 g for 10 minutes. After centrifugation, aspirate the recovery medium and add sufficient inoculation medium to obtain a cell density of approximately 1.0 ⁇ 10 6 cells/mL of cell suspension.
  • use Use a cell counter to count liver cells and determine viable cell density. The survival rate of liver cells must be greater than 80%.
  • Use inoculation medium to adjust the cell density to 0.2 ⁇ 10 6 cells/mL and inoculate it into a collagen I-coated 96-well plate. Medium, 100 ⁇ L per well. Place the culture plate in a 5% CO2 incubator, 95% relative humidity, and incubate at 37°C for 4–6 hours.
  • the survival rate of the test compound can be calculated using the following formula:
  • liver cells 1) Take a tube of ultra-low-temperature-preserved liver cells and ensure that the liver cells are in a low-temperature frozen state before recovery.
  • the hepatocytes were quickly placed in a 37°C water bath and gently shaken until all ice crystals dispersed, sprayed with 70% ethanol and transferred to a biological safety cabinet.
  • Use Cellometer Vision to count liver cells and determine viable cell density. The survival rate of liver cells must be greater than 80%.
  • Use inoculation medium to adjust the cell density to 4000 cells/well, and inoculate 100 ⁇ L per well.

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Abstract

提供一种具有式（I）结构的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物。所述化合物能够调节KIF18A蛋白，从而影响细胞周期和细胞增殖过程以治疗癌症和癌症相关疾病。还提供所述化合物的合成方法、包含所述化合物的药物组合物以及用于治疗与KIF18A活性相关的病况的方法。

Description

驱动蛋白KIF18A抑制剂及其应用
本申请要求以下申请的优先权：
1)于2022年05月13日提交到中国国家知识产权局、申请号为202210520744.0、发明名称为“驱动蛋白KIF18A抑制剂及其应用”的中国专利申请；
2)于2022年07月25日提交到中国国家知识产权局、申请号为202210878192.0、发明名称为“驱动蛋白KIF18A抑制剂及其应用”的中国专利申请；
3)于2022年09月27日提交到中国国家知识产权局、申请号为202211183092.2、发明名称为“驱动蛋白KIF18A抑制剂及其应用”的中国专利申请；
4)于2022年12月02日提交到中国国家知识产权局、申请号为202211537992.2、发明名称为“驱动蛋白KIF18A抑制剂及其应用”的中国专利申请；
5)于2023年01月16日提交到中国国家知识产权局、申请号为202310071265.X、发明名称为“驱动蛋白KIF18A抑制剂及其应用”的中国专利申请；
6)于2023年03月22日提交到中国国家知识产权局、申请号为202310288871.7、发明名称为“驱动蛋白KIF18A抑制剂及其应用”的中国专利申请；
7)于2023年04月27日提交到中国国家知识产权局、申请号为202310475180.8、发明名称为“驱动蛋白KIF18A抑制剂及其应用”的中国专利申请，其全部内容均通过引用结合在本申请中。
技术领域
本发明属于医药领域，涉及一类驱动蛋白KIF18A抑制剂及其作为抑制癌细胞增殖和治疗癌症的用途。
背景技术
KIF18A是驱动蛋白kinesin-8家族中的一员,在细胞内能够依靠水解ATP释放的能量,以微管为轨道向正极方向运动。同时,KIF18A定位在微管正极末端,可调控微管的动态不稳定性,发挥类似于微管解聚酶的活性。在有丝分裂过程中,KIF18A能够调控纺锤体微管动力学和染色体振幅,对有丝分裂期染色体及时完成整列、维持基因组稳定和顺利完成有丝分裂具有关键作用。
KIF18A基因属于驱动蛋白kinesin-8亚家族并且是一个正端定向马达。KIF18A被认为影响着丝粒微管的正端的动力学以控制正确的染色体定位和纺锤体张力。人KIF18A的耗尽在HeLa宫颈癌细胞中导致更长的纺锤体，在中期增加的染色体振荡(chromosome oscillation)以及有丝分裂纺锤体组装检查点的激活(MI Mayr等人，Current Biology[当代生物学]17,488–98,2007)。KIF18A似乎是癌症治疗的可行靶标。KIF18A在多种类型的癌症中过表达，包括但不限于结肠癌、乳腺癌、肺癌、胰腺癌、前列腺癌、膀胱癌、头癌、颈癌、子宫颈癌和卵巢癌。此外，在癌细胞系中，基因缺失或敲除或KIF18A抑制影响有丝分裂纺锤体装置。特别地，已发现抑制KIF18A来诱导有丝分裂细胞停滞，这是一种已知的弱点，其可以通过凋亡、有丝分裂灾变或多相驱动致死性或分裂间期中有丝分裂滑 脱后的死亡来促进有丝分裂细胞死亡。因此，对寻找KIF18A蛋白的抑制剂存在着强烈的兴趣。因此，KIF18A ATP酶活性的抑制是一种有前途的开发新的抗癌剂的方法。
发明内容
本发明属于医药领域，涉及一类驱动蛋白KIF18A抑制剂，具体涉及所述化合物或其立体异构体，互变异构体，内消旋体，外消旋体，对映异构体，非对映异构体或其混合物形式或其可药用的盐，共晶，代谢产物，溶剂化物，前药或同位素标记物，其制备方法及含有该类化合物的药物组合及其作为治疗剂，尤其作为抑制癌细胞增殖和治疗癌症的用途。
本发明提供了一类新的化合物，所述化合物单独或在与微管的结合复合物中用于调节KIF18A蛋白，用以治疗KIF18A介导的病症和/或疾病，包括癌症、炎症或纤毛病理学。
本发明提供的化合物具有基于MT的KIF18A调节活性，特别地，具有KIF18A抑制活性。为此，本发明还提供了这些化合物及其药学上可接受的盐在制备和制造用于治疗性、预防性、急性或慢性治疗KIF18A介导的疾病和障碍(包括但不限于癌症)的药物组合物或药物中的用途。
本发明提供了技术方案：具有式(I)结构的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物：
其中，W1表示CRW1或N；
其中，W2表示CRW2或N；
其中，W3表示CRW3或N；
其中，Z表示-CRTRT'或-NRSRS'；
其中，RT和RT'与与之共同相连的C原子一起形成具有选自以下结构的环：
其中，RS和RS'与与之共同相连的N原子一起形成具有选自以下结构的环：
其中，Y1、Y2、Y3各自独立地表示-(CRaRb)o-(NRa)p-(CRa'Rb')q-；
其中，A、B各自独立地表示-(CRaRb)m-；
其中，L1表示表示-C(O)NH-、-HNC(O)-、5-6元杂芳基、
其中，L2表示不存在、-C1-C6亚烷基-、-NRa-、-NRa(C1-C6亚烷基)-、-C(O)NRa(C1-C6亚烷基)-、-O-、-O-(C1-C6亚烷基)、-S-、-S(O)-、-S(O)2-、-S(O)2NRa-或者-S(O)(NRa)-；
其中，R1表示L3-R3；
其中，L3表示不存在、C1-C6亚烷基、-NRa-、-NRaSO2-、-SO2NRa-、-S(＝O)(NRa)-、-P(O)(ORa)2、-NRaP(O)(ORa)2或-NRaP(O)(Ra)2；
其中，R3表示不存在、氢或者被0-3个选自卤素、-ORa、-NRaRb、氰基和-O-卤代C1-C6烷基之基团取代的C1-C6烷基或C3-C6环烷基；
其中，RW1、RW2和RW3各自独立地表示氢、卤素、氰基、硝基、羟基C1-C6烷基、C1-C6烷基、C3-C8环烷基、卤代C1-C6烷基、-ORa、-SO3Ra、-S(O)Ra、-O-卤代C1-C6烷基、-SRa、-SF5或-NRaRb；
其中，Cy1表示6-12元芳基或者5-12元杂芳基；并且所述的Cy1还可以任意地被0-3个选自以下取代基的基团所取代：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、ORa、-O-卤代C1-C6烷基、5-6元杂芳基、苯基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)Ra、-P(O)RaRb、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb；
其中，Cy2表示3-12元饱和或不饱和的单环或者双环，该环中可以任意地含有0-3个选自O、N和S的杂原子，并且所述的Cy2还可以任意地被0-3个选自以下取代基的基团所取代：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、-ORa、-O-卤代C1-C6烷基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb；
其中，环A表示饱和或者不饱和的4-12元环，优选为5-12元环；并且该环中可以任意地含有0-3个选自O、N和S的杂原子，并且所述的环A还可以任意地被0-3个选自以下取代基的基团所取代：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、-ORa、-O-卤代C1-C6烷基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb；
其中，Ra、Rb、Ra'、Rb'各自独立地表示氢、卤素、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基或羟基C1-C6烷基；或者Ra、Rb一起与与之相连的原子形成3-6 元饱和或不饱和环，该环中可以任意地含有0-2个选自O、S和N的杂原子；或者Ra'、Rb'一起与与之相连的原子形成3-6元饱和或不饱和环，该环中可以任意地含有0-2个选自O、S和N的杂原子；
其中，m、o、p、q表示0-3的整数。
除此之外，本发明提供了一种具有式(II)结构的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物：
其中，W1表示CRW1或N；
其中，W2表示CRW2或N；
其中，Z表示-CRTRT'或-NRSRS'；
其中，RT和RT'与与之共同相连的C原子一起形成具有选自以下结构的环：
其中，RS和RS'与与之共同相连的N原子一起形成具有选自以下结构的环：
其中，Y1、Y2、Y3各自独立地表示-(CRaRb)o-(NRa)p-(CRa'Rb')q-；
其中，A、B各自独立地表示-(CRaRb)m-；
其中，L1表示表示-C(O)NH-、-HNC(O)-、5-6元杂芳基、
其中，L2表示不存在、-C1-C6亚烷基-、-NRa-、-NRa(C1-C6亚烷基)-、-C(O)NRa(C1-C6亚烷基)-、-O-、-O-(C1-C6亚烷基)、-S-、-S(O)-、-S(O)2-、-S(O)2NRa-或者-S(O)(NRa)-；
其中，R1表示L3-R3；
其中，L3表示不存在、C1-C6亚烷基、-NRa-、-NRaSO2-、-SO2NRa-、-S(＝O)(NRa)-、-P(O)(ORa)2、-NRaP(O)(ORa)2或-NRaP(O)(Ra)2；
其中，R3表示不存在、氢或者被0-3个选自卤素、-ORa、-NRaRb、氰基和-O-卤代C1-C6烷基之基团取代的C1-C6烷基或C3-C6环烷基；
其中，RW1和RW2各自独立地表示氢、卤素、氰基、硝基、羟基C1-C6烷基、C1-C6烷基、C3-C8环烷基、卤代C1-C6烷基、-ORa、-SO3Ra、-S(O)Ra、-O-卤代C1-C6烷基、-SRa、-SF5或-NRaRb；
其中，Cy1表示6-12元芳基或者5-12元杂芳基；并且所述的Cy1还可以任意地被0-3个选自以下取代基的基团所取代：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、ORa、-O-卤代C1-C6烷基、5-6元杂芳基、苯基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)Ra、-P(O)RaRb、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb；
其中，Cy2表示3-12元饱和或不饱和的单环或者双环，该环中可以任意地含有0-3个选自O、N和S的杂原子，并且所述的Cy2还可以任意地被0-3个选自以下取代基的基团所取代：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、-ORa、-O-卤代C1-C6烷基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb；
其中，环A表示饱和或者不饱和的4-12元环，优选为5-12元环；并且该环中可以任意地含有0-3个选自O、N和S的杂原子，并且所述的环A还可以任意地被0-3个选自以下取代基的基团所取代：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、-ORa、-O-卤代C1-C6烷基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb；
其中，Ra、Rb、Ra'、Rb'各自独立地表示氢、卤素、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基或羟基C1-C6烷基；或者Ra、Rb一起与与之相连的原子形成3-6元饱和或不饱和环，该环中可以任意地含有0-2个选自O、S和N的杂原子；或者Ra'、Rb'一起与与之相连的原子形成3-6元饱和或不饱和环，该环中可以任意地含有0-2个选自O、S和N的杂原子；
其中，m、o、p、q表示0-3的整数。
在本发明的优选技术方案中，其中，W1表示CH或N。
在本发明的优选技术方案中，其中，W2表示CH或N。
在本发明的优选技术方案中，其中，L3表示-NRaSO2-、-SO2NRa-或-S(＝O)(NRa)-。
在本发明的优选技术方案中，其中，L3表示-NRaSO2-。
在本发明的优选技术方案中，其中，R3表示氢或者被0-3个选自卤素、-ORa、-NRaRb、氰基和-O-卤代C1-C6烷基之基团取代的C1-C6烷基或C3-C6环烷基。
在本发明的优选技术方案中，其中，R3表示被0-3个选自卤素、-ORa、-NRaRb、氰基和-O-卤代C1-C6烷基之基团取代的C1-C6烷基。
在本发明的优选技术方案中，其中，Z表示-NRSRS'。
在本发明的优选技术方案中，其中，Z表示：
其中，Ra、Rb各自独立地表示氢、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基或羟基C1-C6烷基；或者Ra、Rb一起与与之相连的原子形成3-6元饱和或不饱和环，该环中可以任意地含有0-2个选自O、S和N的杂原子。
在本发明的优选技术方案中，其中，Z表示：其中，Ra、Rb各自独立地表示氢、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基或羟基C1-C6烷基；或者Ra、Rb一起与与之相连的原子形成3-6元饱和或不饱和环，该环中可以任意地含有0-2个选自O、S和N的杂原子。
在本发明的优选技术方案中，其中，Z表示：
在本发明的优选技术方案中，其中，L1表示-C(O)NH-、-HNC(O)-、5-6元杂芳基、
在本发明的优选技术方案中，其中，L1表示-C(O)NH-。
在本发明的优选技术方案中，其中，L1表示：-C(O)NH-、-HNC(O)-、5-6元杂芳基、
在本发明的优选技术方案中，L1表示以下任意基团之一：
在本发明的优选技术方案中，其中，Cy1表示被0-3个选自以下取代基：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、ORa、-O-卤代C1-C6烷基、5-6元杂芳基、苯基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)Ra、-P(O)RaRb、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb取代的以下任意基团之一：






例如：




在本发明的优选技术方案中，其中，Cy1表示被0-3个选自以下取代基：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、ORa、-O-卤代C1-C6烷基、5-6元杂芳基、苯基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)Ra、-P(O)RaRb、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb 取代的以下任意基团之一：
在本发明的优选技术方案中，其中，Cy1表示被0-3个选自以下取代基：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、ORa、-O-卤代C1-C6烷基、5-6元杂芳基、苯基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)Ra、-P(O)RaRb、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb取代的
在本发明的优选技术方案中，其中，Cy1表示被苯基、吡啶基、噻唑基、噁唑基、吡唑基、咪唑基、N-甲基吡唑基取代的
在本发明的优选技术方案中，其中，Cy1表示以下基团：

在本发明的优选技术方案中，其中，Cy1表示被0-3个选自以下取代基：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、ORa、-O-卤代C1-C6烷基、5-6元杂芳基、苯基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)Ra、-P(O)RaRb、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb取代的
在本发明的优选技术方案中，其中，L2表示不存在、-C1-C6亚烷基-或-NH-。
在本发明的优选技术方案中，其中，L2表示不存在。
在本发明的优选技术方案中，其中，Cy2表示被0-3个选自以下取代基：卤素、氰基、硝基、羟基C1-C6烷基、C1-C6烷基、C3-C8环烷基、卤代C1-C6烷基、-ORa、-SO3Ra、-S(O)Ra、-O卤代C1-C6烷基、-SRa、-SF5或NRaRb取代的吗啉基、哌啶基、氮杂环丁烷基、吡咯烷基、环丙基、环丁基、环戊基、环己基、哌嗪基或四氢呋喃基，其中，Ra、Rb各自独立地表示氢、卤素、C1-C6烷基、C3-C8环烷基、卤代C1-C6烷基或羟基C1-C6烷基；或者R1a、R1b一起与与之相连的原子形成3-6元环，该环中含有0-2个选自O、N和S的杂原子。
在本发明的优选技术方案中，其中，Cy2表示
在本发明的优选技术方案中，其中，环A表示苯环或者
其中，W1表示CH或N，
其中，虚线表示单键或者双键；
并且环A还可以任意地被0-3个选自以下取代基的基团所取代：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、-ORa、-O-卤代C1-C6烷基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb。
在本发明的优选技术方案中，其中，环A表示
其中，W1表示CH或N；
并且环A还可以任意地被0-3个选自以下取代基的基团所取代：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、-ORa、-O-卤代C1-C6烷基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb。
在本发明的优选技术方案中，其中，环A表示：苯环、吡啶环、吡嗪环、环丁烷环、环戊烷环、四氢呋喃环、噁唑环、噻唑环、噻吩环、吡唑环、咪唑环、哌啶环、六氢吡喃环、环己烷环；
并且环A还可以任意地被0-3个选自以下取代基的基团所取代：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、-ORa、-O-卤代C1-C6烷基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb。
在本发明的优选技术方案中，其中，环A与其相稠合的环一起形成如下结构：

并且环A还可以任意地被0-3个选自以下取代基的基团所取代：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、-ORa、-O-卤代C1-C6烷基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb。
在本发明的优选技术方案中，其中，环A与其相稠合的环一起形成如下结构：

具体地，本发明提供了一种化合物，具有以下结构：



除此之外，本发明还提供了一种药物组合物，其含有本发明技术方案中任意一种化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，以及其药学上可接受的载体。
除此之外，本发明还提供了一种通过抑制KIF18A来治疗肿瘤的方法，包括向有需要的个体施用本发明中任意一种化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物。
定义
如无相反指示，本发明的化合物除化合物具体结构之外，还可以被延伸解读还包括该化合物药学上可接受的盐，其立体异构体、同位素异构体(例如氘代化物)、溶剂合物、水合物、前药、代谢产物，也即是该化合物药学上可接受的盐，其立体异构体、同位素异构体、溶剂合物、水合物、前药、代谢产物也落入化合物的保护范围。
除非另有述及，否则于本专利说明书与权利请求中使用的下述术语具有下文所讨论的意义。再者，此处定义的许多基团可选择性地被取代。在此定义部分中典型取代基的清单是作为举例，并非意欲限制本专利说明书与权利要求书中别处所定义的取代基。
术语“烷基”是指饱和脂族烃基团或连接臂，包括1至20个碳原子，优选为1至12个碳原子，更优选为1至8个碳原子，或1至6个碳原子，或1至4个碳原子的直链与支链基团。“低级烷基”特别指具有1至4个碳原子的烷基。烷基的实例包括-(CH2)3-，甲基、三氟甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、戊基等。烷基可为被取代或未被取代。典型取代基包括环烷基、芳基、杂芳基、杂环烷基、羟基、烷氧基、芳氧基、巯基、烷硫基、芳基硫基、氰基、卤代基、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰胺基、C-羧基、O-羧基、硝基、硅烷基、氨基及-NRxRy，其中Rx与Ry独立选自包括氢、烷基、环烷基、芳基、羰基、乙酰基、磺酰基、三氟甲烷磺酰基及合并的5-或6-元杂环基环。
术语“烯基”表示含一个或更多个双键且通常长度为2至20个碳原子的直链或支链的烃基。例如，“C2-C6烯基”含有两个至六个碳原子。烯基包括但不限于例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基等。
术语“炔基”表示含一个或更多个三键且通常长度为2至20个碳原子的直链或支链的烃基。例如，“C2-C6炔基”含有两个至六个碳原子。代表性炔基包括但不限于例如乙炔基、1-丙炔基、1-丁炔基等。
术语“烷氧基”或“烷基氧基”是指-O-烷基。“C1-C6烷氧基”(或烷基氧基)意欲包括C1、C2、C3、C4、C5、C6烷氧基。烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(例如正丙氧基和异丙氧基)和叔丁氧基。类似地，“烷基硫基”或“硫代烷氧基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的烷基；例如甲基-S-和乙基-S-。
术语“环烷基”是指3至8元全碳单环状环或二环结构，全碳5-元/6-元或6-元/6-元经稠合的双环状环，或多环状稠合环(“经稠合”环系统是指在此系统 中的每一个环系与此系统中的其它环至少共有一个相邻碳原子)基团，其中一或多个环可含有一或多个双键，但这样的环均不具有完整的共轭π-电子系统，亦或双环通过共用一个碳形成螺环。环烷基的实例是(但不限于)环丙烷、环丁烷、环戊烷、环戊烯、环己烷、环己二烯、金刚烷、环庚烷、环庚三烯等。二环的环状烷基包括桥环、螺环或融合环的环烷基。环烷基的说明性实例衍生自(但不限于)下列:
“芳基”是指6至12个碳原子的全碳单环状或稠合环多环基团，具有完整共扼π-电子系统。芳基的实例是但不限于苯基、萘基及蒽基。芳基可为被取代或未被取代。典型取代基包括卤代基、三卤代甲基、烷基、羟基、烷氧基、芳氧基、巯基、烷硫基、芳基硫基、氰基、硝基、羰基、硫代羰基、C-羧基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰胺基、亚磺酰基、磺酰基、氨基及-NRaRb，其中Ra与Rb系如上文定义。芳基稠合饱和或不饱和环烷基/饱和或不饱和杂环烷基可看作为芳基的特殊取代基，典型的实例包括但不限于:
“杂芳基”是指5至12个环原子的单环状或稠合环，含有一、二、三或四个选自N,O及S的环杂原子，其余环原子为C，且此外，具有完整共扼π-电子系统。典型的杂芳基的实例是但不限于吖啶基、氮杂环丁基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色满基、色烯基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、咪唑并吡啶基、假吲哚基(indolenyl)、二氢吲哚基、吲嗪基、吲哚基、3H-吲哚基、靛红酰基(isatinoyl)、异苯并呋喃基、异色满基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异噻唑并吡啶基、异噁唑基、异噁唑并吡啶基、亚甲基二氧基苯基、吗啉基、二氮杂萘基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5- 噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑并吡啶基、噁唑烷基、萘嵌间二氮杂苯基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑并吡啶基、吡唑基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四唑基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑并吡啶基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基、喹啉基、异喹啉基、酞嗪基、喹唑啉基、吲哚基、异吲哚基、二氢吲哚基、1H-吲唑基、苯并咪唑基、1,2,3,4-四氢喹啉基、1,2,3,4-四氢异喹啉基、5,6,7,8-四氢-喹啉基、2,3-二氢-苯并呋喃基、色满基、1,2,3,4-四氢-喹喔啉基和1,2,3,4-四氢-喹唑啉基。术语“杂芳基”还可以包括由上述所定义的“芳基”与单环“杂芳基”所形成的联芳基结构，例如但不限于“-苯基联吡啶基-”、“-苯基联嘧啶基”、“-吡啶基联苯基”、“-吡啶基联嘧啶基-”、“-嘧啶基联苯基-”；其中本发明还包括含有例如上述杂环的稠环和螺环化合物。
药学上可接受的杂芳基是足够稳定以被连接至本发明的化合物被配制成药物组合物，及随后被施用有需要的病患者。
除非另有定义，本发明的取代基的定义是各自独立而非互相关联的，例如对于取代基中Ra(或者Rb)而言，其在不同的取代基的定义中是各自独立的。具体而言，对于Ra(或者Rb)在一种取代基中选择一种定义时，并不意味着该Ra(或者Rb)在其他取代基中都具有该相同的定义。更具体而言，例如(仅列举非穷举)对于NRaRb中，当Ra(或者Rb)的定义选自氢时，其并不意味着在-C(O)-NRaRb中Ra(或者Rb)必然为氢。
“卤代”或“卤素”包括氟、氯、溴和碘。“卤代烷基”意欲包括具有指定碳原子数且取代有1个或多个卤素的支链和直链饱和脂族烃基团。卤代烷基的实例包括但不限于氟甲基、二氟甲基、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。卤代烷基的实例还包括意欲包括具有指定碳原子数且取代有1个或多个氟原子的支链和直链饱和脂族烃基团的“氟烷基”。
“卤代烷氧基”或“卤代烷基氧基”表示具有指定数量碳原子的经氧桥连接的如上文所定义的卤代烷基。例如，“C1-C6卤代烷氧基”意欲包括C1、C2、C3、C4、C5、C6卤代烷氧基。卤代烷氧基的实例包括但不限于三氟甲氧基、2,2,2-三氟乙氧基和五氟乙氧基。类似地，“卤代烷基硫基”或“硫代卤代烷氧基”表示具有指定数量碳原子的经硫桥连接的如上文所定义的卤代烷基；例如三氟甲基-S-和五氟乙基-S-。
本公开内容中，当提到一些取代基团时使用Cx1-Cx2的表述，这表示所述取代基团中的碳原子数可以是x1至x2个。例如，C0-C8表示所述基团含有0、1、2、3、4、5、6、7或8个碳原子，C1-C8表示所述基团含有1、2、3、4、5、6、 7或8个碳原子，C2-C8表示所述基团含有2、3、4、5、6、7或8个碳原子，C3-C8表示所述基团含有3、4、5、6、7或8个碳原子，C4-C8表示所述基团含有4、5、6、7或8个碳原子，C0-C6表示所述基团含有0、1、2、3、4、5或6个碳原子，C1-C6表示所述基团含有1、2、3、4、5或6个碳原子，C2-C6表示所述基团含有2、3、4、5或6个碳原子，C3-C6表示所述基团含有3、4、5或6个碳原子。
本公开内容中，当提到环状基团(例如芳基、杂芳基、环烷基和杂环烷基)时使用“x1-x2元环”的表述，这表示该基团的环原子数可以是x1至x2个。例如，所述3-12元环状基团可以是3、4、5、6、7、8、9、10、11或12元环，其环原子数可以是3、4、5、6、7、8、9、10、11或12个；3-6元环表示该环状基团可以是3、4、5或6元环，其环原子数可以是3、4、5或6个；3-8元环表示该环状基团可以是3、4、5、6、7或8元环，其环原子数可以是3、4、5、6、7或8个；3-9元环表示该环状基团可以是3、4、5、6、7、8或9元环，其环原子数可以是3、4、5、6、7、8或9个；4-7元环表示该环状基团可以是4、5、6或7元环，其环原子数可以是4、5、6或7个；5-8元环表示该环状基团可以是5、6、7或8元环，其环原子数可以是5、6、7或8个；5-12元环表示该环状基团可以是5、6、7、8、9、10、11或12元环，其环原子数可以是5、6、7、8、9、10、11或12个；6-12元环表示该环状基团可以是6、7、8、9、10、11或12元环，其环原子数可以是6、7、8、9、10、11或12个。所述环原子可以是碳原子或杂原子，例如选自N、O和S的杂原子。当所述环是杂环时，所述杂环可以含有1、2、3、4、5、6、7、8、9、10或更多个环杂原子，例如选自N、O和S的杂原子。
本发明内容中，一个或更多个卤素可以各自独立地选自氟、氯、溴和碘。
本文中所用的术语“取代”意指至少一个氢原子被非氢基团替代，条件是维持正常化合价且所述取代得到稳定的化合物。本文所用的环双键为在两个相邻环原子之间形成的双键(例如C＝C、C＝N或N＝N)。
在本发明化合物上存在氮原子(例如胺)的情形下，可通过使用氧化剂(例如mCPBA和/或过氧化氢)进行处理来将这些氮原子转化成N-氧化物以获得本发明的其它化合物。因此，所显示和要求保护的氮原子视为均涵盖所显示氮及其N-氧化物以获得本发明衍生物。
当任何变量在化合物的任何组成或式中出现一次以上时，其每次出现时的定义均独立于其在其它每种情况下出现时的定义。因此，例如如果显示基团取代有0-3个R，则所述基团可任选地取代有至多三个R基团，且在每次出现时R独立地选自R的定义。此外，取代基和/或变量的组合仅在上述组合可产生稳定的化合物时才容许存在。
本文使用的术语“患者”是指通过本发明的方法进行治疗的有机体。这类有机体优选包括但不限于哺乳动物(例如鼠类、猿/猴、马、牛、猪、犬、猫等)且最优选是指人类。
本文使用的术语“有效量”意指将会引起例如研究人员或临床医师所寻求的组织、系统、动物或人的生物学或医学响应的药物或药剂(即本发明化合物)的量。 此外，术语“治疗有效量”意指这样的量：与未接受上述量的相应受试者相比，所述量导致改善的治疗、治愈、预防或减轻疾病、病症或副作用，或降低在疾病或病症的进展速度。有效量可以一个或更多个给药、施用或剂量给予且不意欲被特定的制剂或给药途径限制。该术语还包括在其范围内的增强正常生理机能的有效量。
本文使用的术语“治疗”包括其广义上的含义，涵盖对对象的治疗性处理和/或预防性处理。具体而言，所述“治疗”包括导致病症、疾病、障碍等的缓和、抑制、消除和改善和/或预防的任何处理，例如减轻、减少、调节、改善、消除、预防、防止或改善其症状。所述治疗性处理包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善潜在代谢综合征；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或治疗由疾病或症状引起的征兆。所述预防性处理包括事先处理以防止、阻断或延迟、减缓疾病或病症的发生或发展或者减弱疾病或病症的严重程度。
同样，“治疗剂”也包括对对象具有治疗性处理和/或预防性处理的药剂或试剂。
术语“药用”或“药学上可接受的”在本文中用于指如下那些化合物、物质、组合物和/或剂型：在合理医学判断的范围内，其适于与人类和动物的组织接触使用而无过高毒性、刺激性、过敏反应和/或其它问题或并发症，并与合理的益处/风险比相称。
特定药学及医学术语
术语“癌症”，如本文所用，指一种不能控制的细胞的异常生长，并且在某种条件下能够转移(传播)。这种类型的癌症包括但不限于，实体肿瘤(如膀胱、肠、脑、胸、子宫、心脏、肾、肺、淋巴组织(淋巴瘤)、卵巢、胰腺或其它内分泌器官(如甲状腺)、前列腺、皮肤(黑色素瘤)或血液瘤(如非白血性白血病)。
术语“联合给药”或其类似术语，如本文所用，指将几种所选的治疗药物给一个病人用药，以相同或不同的给药方式在相同或不同的时间给药。
术语“增强”或“能增强”，如本文所用，指预期的结果能够在效价或是持续时间方面都有增加或延长。因此，在增强药物的治疗效果方面，术语“能增强”指药物在系统中有提高或延长效价或持续时间的能力。本文所用的“增效值”，指在理想的系统中，能够最大限度地的增强另外一个治疗药物的能力。
术语“免疫性疾病”指对内源性或外源性抗原产生的不良或有害反应的疾病或症状。结果通常会造成细胞的功能障碍、或因此而破坏并造成机能障碍、或破坏可能产生免疫症状的器官或组织。
术语“试剂盒”与“产品包装”是同义词。
术语“对象”、“受试者”或“病人”包括哺乳动物和非哺乳动物。哺乳动物包括但不限于，哺乳类：人、非人灵长类如猩猩、猿及猴类；农业动物如牛、马、 山羊、绵羊、猪；家畜如兔、狗；实验动物包括啮齿类，如大鼠、小鼠及豚鼠等。非哺乳类动物包括但不限于，鸟、鱼等。在一优选例中，所选哺乳动物是人。
如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或断续给药，可以归因于或与给药有关的情况。
给药途径
适合的给药途径包括但不限于，口服、静脉注射、直肠、气雾剂、非肠道给药、眼部给药、肺部给药、经皮给药、阴道给药、耳道给药、鼻腔给药及局部给药。此外，仅作举例说明，肠道外给药，包括肌肉注射、皮下注射、静脉注射、髓内注射、心室注射、腹膜内注射、淋巴管内注射、及鼻内注射。
本发明化合物给药方式可以是局部的给药方式。在特定的具体实施例中，长效制剂通过植入给药(例如皮下或肌肉)或通过肌肉注射。此外，在另一具体化实施例中，药物通过靶向药物给药系统来给药。例如，由器官特异性抗体包裹的脂质体。在这种具体实施例中，所述脂质体被选择性的导向特定器官并吸收。
药物组合物和剂量
本文使用的短语“可药用载体”意指药用物质、组合物或媒介物，诸如液体或固体填充剂、稀释剂、赋形剂、制造助剂(例如润滑剂、滑石、硬脂酸镁、硬脂酸钙或硬脂酸锌或硬脂酸)或溶剂包囊物质，其涉及将主题化合物从一个器官或身体的部分携带或运送至另一个器官或身体的部分。每种载体在与制剂的其它成分相容和对患者无害的意义上必须是“可接受的”。
术语“药物组合物”意指包含本发明化合物与任选的其它可药用载体的组合物。“可药用载体”是指本领域中通常接受用于将生物活性剂递送至动物(具体为哺乳动物)的介质，包括(即)佐剂、赋形剂或媒介物，诸如稀释剂、防腐剂、填充剂、流动调控剂、崩解剂、润湿剂、乳化剂、悬浮剂、增甜剂、矫味剂、芳香剂、抗细菌剂、抗真菌剂、润滑剂和分散剂，这取决于给药模式和剂型的性质。
本发明的药用组合物可包含治疗有效量的与任选的一种或多种可药用载体(添加剂)和/或稀释剂一起配制的一种或多种本发明的化合物，以及任选的一种或多种其它治疗剂。可通过任意合适方式给予本发明化合物以用于任意上述用途，例如口服，诸如片剂、丸剂、粉剂、颗粒剂、酏剂、酊剂、悬浮液(包括纳米悬浮液、微悬浮液、喷雾干燥的分散液)、糖浆和乳液；经舌下；含服；经肠胃外，诸如通过皮下、静脉内、肌内或胸骨内注射或输注技术(例如以无菌可注射水性或非水性溶液或悬浮液形式)；经鼻，包括向鼻膜给药，诸如通过吸入喷雾；局部，诸如以乳膏剂或软膏剂形式；或经直肠，诸如以栓剂形式；或经瘤内注射。它们可单独给药，但通常使用基于所选给药途径和标准药学实践选择的药物载体给药。
根据本领域技术人员认识范围内的诸多因素来调配可药用载体。这些因素包括，但不限于：所调配活性剂的类型和性质；含有活性剂的组合物所要给药的受试者； 组合物的预期给药途径；及所靶向的治疗适应症。药用载体包括水性和非水性液体介质及各种固体和半固体剂型。
上述载体可包括除活性剂外的诸多不同成分和添加剂，上述其它成分出于本领域技术人员公知的各种原因包括于制剂中，例如稳定活性剂、粘合剂等。关于合适的药用载体和载体选择中所涉及的因素的描述可参见多个容易获得的来源，例如Allen L.V.Jr.et al.Remington:The Science and Practice of Pharmacy(2Volumes),22nd Edition(2012),Pharmaceutical Press。
当然，本发明化合物的剂量方案取决于已知因素而有所变化，诸如具体药剂的药效学特性及其给药模式和途径；接受者的物种、年龄、性别、健康状况、医学病状和重量；症状的性质和程度；同时治疗的种类；治疗频率；给药途径、患者的肾和肝功能及期望效应。根据一般指导，当用于指定效应时，各活性成分的日口服剂量应为约0.001mg/天至约10-5000mg/天，优选地为约0.01mg/天至约1000mg/天，且最优选地为约0.1mg/天至约250mg/天。在恒速输注期间，静脉内最优选剂量应为约0.01mg/kg/分钟至约10mg/kg/分钟。本发明化合物可以单一日剂量给药，或可以每日两次、三次或四次的分开剂量给药总日剂量。
所述化合物通常以与根据预期给药形式(例如口服片剂、胶囊剂、酏剂和糖浆剂)适当地选择且与常规药学实践相符合的合适药物稀释剂、赋形剂或载体(在本文中统称为药物载体)的混合物形式进行给药。
适于给药的剂型(药物组合物)可含有约1毫克至约2000毫克活性成分/剂量单位。在这些医药组合物中，以组合物的总重量计，活性成分通常将以约0.1-95重量％的量存在。
本发明范围包括(单独或与可药物载体组合)包含治疗有效量的至少一种本发明化合物作为活性成分的药物组合物。任选地，本发明化合物可单独使用、与本发明其它化合物组合使用或与一种或多种其它治疗剂(例如抗癌剂或其它药学活性物质)组合使用。
不考虑所选择的给药路径，通过本领域技术人员已知的常规方法来将本发的化合物(其可以合适的水合形式使用)和/或本发明的药物组合物配制成药用剂量形式。
可改变活性成分在本发明的药物组合物中的实际剂量水平，从而获得对于实现特定患者的期望的治疗响应、组成和给药模式有效的而对患者无毒的活性成分量。
选定的剂量水平会取决于多种因素，包括所用的本发明的特定化合物或其酯、盐或酰胺的活性；给药路径；给药时间；所用的特定化合物的排泄速率；吸收速率和程度；治疗的持续时间；与所用的特定化合物组合使用的其它药物、化合物和/或物质；所治疗的患者的年龄、性别、重量、状况、一般健康和先前的医学史等医学领域公知的因素。
具有本领域普通技术的医生或兽医可容易地确定并开出有效量的所需药物组合物。例如，为了达到所期望的治疗效果，医师或兽医可在低于所需的水平开始药物组合物中所用的本发明化合物的较量，并逐步增加剂量直至实现所期望的效果。 通常，合适日剂量的本发明化合物将是有效产生治疗效果的最低剂量的化合物的量。此种有效剂量通常取决于上述因素。通常，口服、静脉内、脑室内和皮下剂量的用于患者的本发明化合物的范围为约0.01至约50mg/kg体重/天。如果需要的话，有效日剂量的活性化合物可以两个、三个、四个、五个、六个或更多个亚剂量在一天当中的适当的间隔分别给药，任选地呈单位剂型形式。在本发明的某些方面中，服药为每天一次给药。
虽然本发明化合物可单独给药，但优选以药物制剂(组合物)形式给予化合物。
试剂盒/产品包装
为了用于上述适应症的治疗，试剂盒/产品包装也在此进行描述。这些试剂盒可以由输送器、药包或容器盒组成，容器盒可被划分成多格，以容纳一种或多种容器，如管形瓶、试管及类似物等，每个容器中包含所述方法中的单独一种成分。合适的容器包括瓶子，管形瓶，注射器和试管等。容器由可接受的玻璃或塑料等材料制作而成。
举例来讲，容器可装有一种或多种在此所述的化合物，化合物可能以药物组分形式存在，也可能与在本文中所述的其它成分组成混合物体存在。容器可有一个无菌输出口(例如容器可为静脉输液包或瓶，瓶塞可被皮下注射器针头刺破)。这样的试剂盒可带有一种化合物，及本文中所述的使用方法的说明、标签或操作说明。
一个典型的试剂盒可包括一种或多种容器，为适应商业推广和使用者对化合物使用的需求，每个容器装有一种或多种材料(如试剂，也可以是浓缩的母液，和/或器械)。这些材料包括但不局限于缓冲液，稀释液，滤器，针头，注射器，输送器，包，容器，瓶和/或试管，附有内容清单和/或使用说明书，内置包装也附有说明书。整套的说明都要包括在内。
标签可显示在容器上或与容器紧密相关。标签出现在容器上即指标签字母、数字或其它特征被粘贴、铸模、刻在容器上；标签也可出现在装有多种容器的容器盒或运输盒内，如在产品插页中。一个标签可用来提示内容物的某种特定治疗用途。标签也可标示内容物使用说明，诸如在上述方法中描述的。
在本说明书中被描述的所有特征(包括任何所述的权利要求、摘要和图),和/或任何方法或过程中涉及的所有步骤，均有可能以任意一种组合存在，除非某些特征或步骤在同一组合中是相互排斥的。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。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。除非另外说明，否则所有的百分数、比率、比例、或份数按重量计。
本发明中的重量体积百分比中的单位是本领域技术人员所熟知的，例如是指在100毫升的溶液中溶质的重量。除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
NMR的测定是用Bruker AVANCE-400核磁仪。测定溶剂在谱图解析中注明。
MS的测定用Agilent 1200-G1956A/1200-6110A/1200-6140A/1260-6125B/Prime-6125B/1260-6120液质联用仪，SHIMADZU 20A-2010/20A-2020液质联用仪，Waters ACQ-QDA液质联用仪。
HPLC分析使用SHIMADZU 20A高效液相色谱仪。
SFC分析测定使用Waters UPCC with PDA Detector and QDa Detector超高效合相色谱仪，Waters UPC2with PDA detector超高效合相色谱仪，Agilent1260with DAD detector高效液相色谱仪，Shimadzu LC-20AB with PDA detector高效液相色谱仪，Shimadzu LC-20AD with PDA detector高效液相色谱仪。
制备型HPLC分离使用Shimadzu LC-20AP pump,Shimadzu LH-40 Liquid Handler,Shimadzu SPD-20A Detector，Gilson GX-281Liquid Handler,Gilson 322 pump,Gilson 156 UV Detector制备型色谱仪。
SFC分离使用The Berger MG II、MG III，Sepiatec's Prep SFC 100 system，Waters Prep 80Q SFC SYSTEM、Prep 150 AP SFC SYSTEM、Prep 200 SFC SYSTEM、Prep 350 SFC SYSTEM。
快速柱色谱分离使用Biotage IsoleraOne快速制备色谱仪。
薄层层析硅胶板使用安徽良臣硅源材料有限公司的GF254丙烯酸粘合剂硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.25mm，薄层层析分离纯化产品采用的规格是0.5mm。
加压氢化反应氢化瓶和氢气钢瓶。
微波反应使用Biotage Initiator+微波合成仪。
手套箱使用德力斯DELLIX定制手套箱。
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1:N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-(2-羟基乙基磺酰氨基)-7-(6-氮杂螺[2.5]辛烷-6-基)咪唑并[1,2-a]吡啶-8-甲酰胺
第一步:向二甲基3-氧亚基戊二酯(20.0g,114mmol)和氨基腈(7.24g,172mmol)的二氧六环(100mL)的溶液中加入乙酰丙酮化镍(2.95g,11.5mmol)，将混合物加热至100℃搅拌16小时，大量黄色固体析出。将析出的固体过滤旋干得到黄色固体甲基2-氨基-4,6-二羟基尼古丁酯(7.50g,40.2mmol，收率35％)。LCMS(ESI):[M+H]+＝184.9.
第二步:向甲基2-氨基-4,6-二羟基尼古丁酯(5.50g,29.9mmol)的三氯氧磷(50mL)溶液中加入N,N-二异丙基乙胺(11.6g,89.6mmol),将反应混合物在25℃搅拌6小时。将反应液浓缩旋干，向反应混合物中加入水(100mL)，用乙酸乙酯(100mL x 3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液旋干得残余物。残留物用快速柱色谱纯化(硅胶，0-15％梯度的乙酸乙酯/石油醚)得到黄色固体甲基2-氨基-4,6-二氯尼古丁酯(2.30g,10.4mmol，收率35％)。LCMS(ESI):[M+H]+＝221.0.
第三步:向甲基2-氨基-4,6-二氯尼古丁酯(2.30g,10.4mmol)和6-氮杂螺[2.5]辛烷盐酸盐(1.54g,10.4mmol)的二甲基亚砜(23mL)的溶液中加入碳酸钾(3.74g,27.1mmol)。将混合物加热至110℃搅拌16小时。向反应液中加入水(50mL)，用乙酸乙酯(50mL x 3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液旋干得残余物。残留物用快速柱色谱纯化(硅胶，0-15％梯度的乙酸乙酯/石油醚)得到黄色固体甲基2-氨基-6-氯-4-(6-氮杂螺[2.5]辛烷-6-基)尼古丁酯(1.40g,4.68mmol,收率45％)。LCMS(ESI):[M+H]+＝296.0。1H NMR(400MHz,DMSO-d6)δppm 6.74-6.57(m,2H),6.30-6.13(m,1H),3.86-3.69(m,3H),3.21-3.07(m,4H),1.49-1.33(m,4H),0.37-0.31(m,4H)
第四步:向甲基2-氨基-6-氯-4-(6-氮杂螺[2.5]辛烷-6-基)尼古丁酯(1.40g,4.73mmol)和碳酸氢钠(0.80g,9.47mmol)的甲醇(12mL)和水(6mL)的溶液中加入2-氯乙醛(2.79g,14.2mmol)。将混合物加热至80℃搅拌16小时。向反应液中加入水(20mL)，用乙酸乙酯(20mL x 3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液旋干得残余物。残留物用快速柱色谱纯化(硅胶，0-20％梯度的乙酸乙酯/石油醚)得到黄色固体甲基5-氯-7-(6-氮杂螺[2.5]辛烷-6-基)咪唑并[1,2-a]吡啶-8-甲酸基酯(1.20g,3.40mmol,收率72％)。LCMS(ESI):[M+H]+＝319.9.
第五步:在5-10℃的温度下向甲基5-氯-7-(6-氮杂螺[2.5]辛烷-6-基)咪唑并[1,2-a]吡啶-8-甲酸基酯(1.00g,3.13mmol)的四氢呋喃(20mL)溶液中缓慢滴加三甲基铝(4.69mL，2M,9.38mmol)的甲苯溶液。将混合物在15℃搅拌0.5小时，将2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-胺(1.07g,4.69mmol)加入到反应液中，将混合物加热至90℃搅拌4小时。将反应液冷却到25℃ 并且倒入到冰水(20mL)中淬灭。用乙酸乙酯(20mL x 3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液旋干得残余物。残留物用快速柱色谱纯化(硅胶，0-10％梯度的乙酸乙酯/石油醚)得到黄色固体5-氯-N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-7-(6-氮杂螺[2.5]辛烷-6-基)咪唑并[1,2-a]吡啶-8-甲酰胺(0.30g,0.59mmol，收率19％)。LCMS(ESI):[M+H]+＝516.1.
第六步:向5-氯-N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-7-(6-氮杂螺[2.5]辛烷-6-基)咪唑并[1,2-a]吡啶-8-甲酰胺(300mg,0.58mmol)，2-羟基乙磺酰胺(94.6mg,0.76mmol)，磷酸钾(500mg,2.33mmol)和2-二叔丁基膦-2′,4′,6′-三异丙基联苯(49.4mg,0.12mmol)的二氧六环(10mL)溶液中加入三(二亚苄基丙酮)二钯(54.3mg,0.06mmol)。在氮气的保护下将混合物加热至90℃搅拌16小时。向反应液中加入水(10mL)，用乙酸乙酯(10mL x 3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液旋干得残余物。残留物用制备型HPLC(C18，20-60％梯度的乙腈/水)纯化，得到黄色固体化合物N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-(2-羟基乙基磺酰氨基)-7-(6-氮杂螺[2.5]辛烷-6-基)咪唑并[1,2-a]吡啶-8-甲酰胺(122mg,0.04mmol，收率35％)。LCMS(ESI):[M+H]+＝605.1。1H NMR(400MHz,DMSO-d6)δppm 13.08-12.87(m,1H),12.83-12.58(m,1H),7.93-7.79(m,1H),7.71-7.63(m,1H),7.49-7.41(m,1H),6.87-6.78(m,1H),3.99-3.88(m,4H),3.85-3.77(m,2H),3.28-3.20(m,2H),3.11-3.01(m,4H),2.39-2.32(m,3H),2.11-1.96(m,4H),1.87-1.61(m,4H),0.45-0.33(m,4H)。
实施例2：N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(2-羟基乙基磺酰氨基)-6-(6-氮杂螺[2.5]辛烷-6-基)苯并呋喃-7-甲酰胺
第一步:在0℃时向2,2-二甲氧基乙醇(8.88g,83.6mmol)的四氢呋喃(400mL)溶液中缓慢加入氢化钠(3.51g,87.6mmol，纯度60％)。将混合物在25℃搅拌1小时，然后将甲基4-溴-2,6-二氟苯酸盐(20.0g,79.6mmol)加入到混合物中，将混合物在25℃搅拌2小时。向反应混合物中加入水(200mL)，用乙酸乙酯(200mL x 2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液旋干得残余物。残留物用快速柱色谱纯化(硅胶，0-10％梯度的乙酸乙酯/石油醚)得到黄色固体甲基4-溴-2-(2,2-二甲氧基乙氧基)-6-氟苯酸盐(17.0g,50.2mmol，收率63％)。1H NMR(400MHz,DMSO-d6)δppm 7.34-7.27(m,2H),4.61(dd,J＝4.8 5.6Hz,1H),4.11(d,J＝5.2Hz,2H),3.82(s,3H),3.34 (s,6H)
第二步:将多聚磷酸(52.0g,113mmol)的甲苯(400mL)溶液在60℃搅拌30分钟。然后将甲基4-溴-2-(2,2-二甲氧基乙氧基)-6-氟苯酸盐(19.0g,56.4mmol)加入到混合物中，将混合物在60℃搅拌4小时。向反应混合物中加入水(200mL)，用乙酸乙酯(200mL x 2)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液旋干得残余物。残留物用快速柱色谱纯化(硅胶，0-10％梯度的乙酸乙酯/石油醚)得到黄色固体甲基4-溴-6-氟苯并呋喃-7-甲酸基酯(9.70g,35.5mmol，收率63％)。LCMS(ESI):[M+H]+＝274.8。1H-NMR(400MHz,DMSO-d6)δppm 8.26(d,J＝1.0Hz,1H),7.70(d,J＝10.8Hz,1H),7.04(d,J＝1.0Hz,1H),3.93(s,3H)
第三步:向甲基4-溴-6-氟苯并呋喃-7-甲酸基酯(3.00g,11.0mmol)和三乙胺(3.33g,32.9mmol)的二甲基亚砜(30mL)的溶液中加入6-氮杂螺[2.5]辛盐酸(1.78g,12.1mmol)。将混合物在130℃搅拌16小时。向反应液中加入水(30mL)，用乙酸乙酯(30mL x 3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液旋干得残余物。残留物用快速柱色谱纯化(硅胶，0-8％梯度的四氢呋喃/石油醚)得到黄色固体甲基4-溴-6-(6-氮杂螺[2.5]辛烷-6-基)苯并呋喃-7-甲酸基酯(1.20g,0.30mmol,收率30％)。LCMS(ESI):[M+H]+＝363.8。1H-NMR(400MHz,DMSO-d6)δppm 8.04(d,J＝2.4Hz,1H),7.27(s,1H),6.87(d,J＝2.0Hz,1H),3.89(s,3H),2.94-2.87(m,4H),1.35-1.27(m,4H),0.31(s,4H)
第四步:在0℃时向2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-胺(1.13g,4.94mmol)的三甲基铝(9.90mL，2M)的甲苯溶液中加入甲基4-溴-6-(6-氮杂螺[2.5]辛烷-6-基)苯并呋喃-7-甲酸基酯(1.20g,3.29mmol)。将混合物加热至120℃搅拌16小时。将混合物冷却至室温，然后缓慢倒入冰水(30mL)中，用乙酸乙酯(30mL x 3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液旋干得残余物。残留物用快速柱色谱纯化(硅胶，0-8％梯度的四氢呋喃/石油醚)得到黄色固体4-溴-N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-6-(6-氮杂螺[2.5]辛烷-6-基)苯并呋喃-7-甲酰胺(0.65g,1.15mmol,收率35％)。LCMS(ESI):[M+H]+＝562.0.
第五步:向2-羟基乙磺酰胺(174mg,1.39mmol)，2-(甲基氨基)乙酸(95.4mg,1.07mmol)，磷酸钾(927mg,4.28mmol)的N,N-二甲基甲酰胺(12mL)溶液中加入碘化亚铜(104mg,0.54mmol)。将混合物在50℃搅拌5分钟。然后将4-溴-N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-6-(6-氮杂螺[2.5]辛烷-6-基)苯并呋喃-7-甲酰胺(600mg,1.07mmol)在50℃加入到反应混合物中，将混合物在氮气的保护下加热至100℃搅拌16小时。向反应液中加入水(10mL)，用乙酸乙酯(10mL x 2)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液旋干得残余物。残留物用制备型HPLC(C18，38-78％梯度的水(甲酸)/乙腈)纯化，得到白色固体化合物N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(2-羟基乙基磺酰氨基)-6-(6-氮杂螺[2.5]辛烷-6-基)苯并呋喃-7-甲酰胺(260mg,0.40mmol，收率38％)。LCMS(ESI):[M+H]+＝605.5。1H-NMR(400MHz,DMSO-d6)δppm 12.87(s,1H),10.31(s,1H),8.01(d,J＝2.0Hz,1H),7.51-7.23(m,3H),4.94(m,1H),4.09-3.81(m,4H),3.81-3.70(m,2H),3.44-3.36(m,2H),3.09-2.94(m,4H),2.32(s,3H),2.08-1.90(m,4H),1.79-1.57(m,4H),0.38(s,4H)
实施例3：N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(2-羟基乙基磺酰氨基)-6-(6-氮杂螺[2.5]辛烷-6-基)-2,3-二氢苯并呋喃-7-甲酰胺
第一步:向N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(2-羟基乙基磺酰氨基)-6-(6-氮杂螺[2.5]辛烷-6-基)苯并呋喃-7-甲酰胺(100mg,0.17mmol)的甲醇(2mL)溶液中加入钯/碳(20mg,纯度10％)。将混合物在50Psi的氢气压力下在25℃搅拌16小时。将混合物用硅藻土过滤，滤液浓缩旋干。残留物用制备型HPLC(C18，24-64％梯度的水(甲酸)/乙腈)纯化，得到白色固体化合物N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(2-羟基乙基磺酰氨基)-6-(6-氮杂螺[2.5]辛烷-6-基)-2,3-二氢苯并呋喃-7-甲酰胺(40.0mg,0.07mmol,收率40％)。LCMS(ESI):[M+H]+＝607.5。1H-NMR(400MHz,DMSO-d6)δppm 11.88(s,1H),9.58(s,1H),7.31(s,1H),6.82(s,1H),5.01(br s,1H),4.56(t,J＝1.0Hz,2H),3.99-3.81(m,4H),3.76(t,J＝1.0Hz,2H),3.32-3.30(m,2H),3.13(t,J＝1.0Hz,2H),2.98-2.84(m,4H),2.26(s,3H),2.03-1.91(m,4H),1.64-1.45(m,4H),0.32(s,4H)
实施例4：N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(2-羟基乙基磺酰氨基)-2-(6-氮杂螺[2.5]辛烷-6-基)-1-萘酰胺
第一步：将4-溴萘-1-胺(30.0g,135mmol)溶于四氢呋喃(300mL)中，加入N-氟-N-(苯磺酰)苯磺酰胺(51.1g,162mmol)，25℃搅拌12小时。反应液加入水(500mL)稀释，使用乙酸乙酯(300mL x 3)萃取，有机相干燥过滤浓缩，残留物用快速柱色谱纯化(硅胶，0-5％梯度的乙酸乙酯/石油醚)得棕色固体4-溴-2-氟萘-1-胺(12.8g,52.7mmol,收率39％)，LCMS(ESI):[M+H]+＝239.9。
第二步：三氟化硼乙醚(8.87g,62.5mmol)置于三口烧瓶中降温至-15℃，滴加溶于N,N-二甲基乙酰胺(100mL)的4-溴-2-氟萘-1-胺(10.0g,41.6mmol)， 滴加溶于N,N-二甲基乙酰胺(100mL)的亚硝酸叔丁酯(5.70g,54.1mmol)，–15℃搅拌1小时。温度升至5℃，加入正戊烷(200mL)，过滤并用正戊烷(200mL)洗涤后得到棕色固体，将过滤后的棕色固体溶于乙腈(180mL)中。将氰化钾(7.52g,115.47mmol)和氰化亚铜(4.00g,43.7mmol)溶于乙腈(90mL)和纯水(30mL)中，然后将溶于乙腈的棕色固体加入到该反应液中，加热到80℃搅拌2小时。反应液使用饱和碳酸钠溶液(500mL)淬灭，使用乙酸乙酯(400mL x 2)萃取，有机相干燥过滤浓缩，残留物用快速柱色谱纯化(硅胶，0-5％梯度的四氢呋喃/石油醚)得棕色固体4-溴-2-氟-1-萘腈(4.90g,14.99mmol,收率36％)。1H NMR(400MHz,DMSO-d6)δppm 8.33-8.25(m,2H),8.15-8.08(m,1H),7.96-7.84(m,2H)
第三步：将4-溴-2-氟-1-萘腈(4.90g,19.6mmol)加入到硫酸(100mL,70％)中，80℃搅拌16小时。80℃加入亚硝酸钠(1.94g,28.1mmol)，80℃搅拌1小时。反应液加入水(50mL)稀释，使用乙酸乙酯200mL(100mL x 3)萃取，有机相干燥过滤浓缩，残留物使用二氯甲烷(80mL)在25℃搅拌16小时打浆纯化，得到棕色固体4-溴-2-氟-1-萘酸(4.00g,14.9mmol，收率76％)。1H NMR(400MHz,DMSO-d6)δppm 8.25-8.19(m,1H),8.07(d,J＝9.2Hz,2H),7.79-7.72(m,2H)
第四步：将4-溴-2-氟-1-萘酸(2.00g,7.43mmol)和N,N羰基二咪唑(7.23g,44.6mmol)溶于N,N-二甲基甲酰胺(40.0mL)中，加热到60℃搅拌4小时。2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-胺(2.04g,8.92mmol)溶于N,N-二甲基甲酰胺(40mL)，0℃加入钠氢(0.89g,22.3mmol,60％质量分数)，25℃搅拌30分钟，将上述溶液加入到该反应体系中，25℃搅拌16小时。反应液加入水(200mL)淬灭，使用乙酸乙酯(200mL x 2)萃取，有机相干燥过滤浓缩，得到残留物。残留物用快速柱色谱纯化(硅胶，0-7％梯度的四氢呋喃/石油醚)得到黄色固体4-溴-N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-氟-1-萘酰胺(1.10g,2.19mmol,收率20％)。LCMS(ESI):[M+H]+＝480.9，1H NMR(400MHz,DMSO-d6)δppm 11.29(br s,1H),8.26-8.21(m,1H),8.10(d,J＝8.8Hz,1H),7.87(br d,J＝2.0Hz,1H),7.76-7.71(m,2H),7.47(br s,1H),3.86(br s,4H),2.36(br s,3H),1.97(br s,4H)
第五步：将4-溴-N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-氟-1-萘酰胺(1.10g,93％)和6-氮杂螺[2.5]辛烷盐酸盐(0.44g,2.98mmol)溶于二甲基亚砜(40.0mL)中，加入碳酸钾(0.95g,6.89mmol)，120℃搅拌16小时。反应液加入水(100mL)稀释，使用乙酸乙酯(100mL x 2)萃取，有机相干燥过滤浓缩，残留物用快速柱色谱纯化(硅胶，0-7％梯度的四氢呋喃/石油醚)得到黄色固体4-溴-N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮杂螺[2.5]辛烷-6-基)-1-萘酰胺(0.36g,0.71mmol,收率31％)。LCMS(ESI):[M+H]+＝572.2，1H NMR(400MHz,DMSO-d6)δppm 10.75(br s,1H),8.18-8.08(m,1H),7.91-7.78(m,2H),7.63-7.57(m,2H),7.49(br s,1H),3.87(br s,4H),3.11(br s,4H),2.36(br s,3H),2.12-1.94(m,4H),1.42-1.35(m,4H),0.28(s,4H)
第六步:将4-溴-N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮杂螺[2.5]辛烷-6-基)-1-萘酰胺(200mg,0.35mmol)和2-羟基乙磺酰胺(57.0mg,0.46mmol)溶于二氧六环(10.0mL)中，加入磷酸钾(297mg,1.40mmol),2-二叔丁基膦-2′,4′,6′-三异丙基联苯(29.8mg,0.07mmol)，三(二亚苄 基丙酮)二钯(32.1mg,0.04mmol)。氮气氛围下60℃搅拌16小时。反应液过滤稀释后用制备型HPLC(C18，28-68％梯度的水(氨水+碳酸氢铵)/乙腈)纯化，得到白色固体N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(2-羟基乙基磺酰氨基)-2-(6-氮杂螺[2.5]辛烷-6-基)-1-萘酰胺(27.7mg,0.05mmol,收率13％)。LCMS(ESI):[M+H]+＝615.2，1H NMR(400MHz,DMSO-d6)δppm 10.74(br s,1H),9.90(br s,1H),8.25(d,J＝8.4Hz,1H),7.90(br d,J＝7.6Hz,1H),7.62-7.37(m,4H),5.02(s,1H),3.97-3.71(m,6H),3.32-3.28(m,2H),3.09(br s,4H),2.40-2.29(m,3H),2.02-1.90(m,4H),1.44–1.36(m,4H),0.29(s,4H)
实施例5：N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-8-(2-羟乙基磺酰胺)-6-(6-氮杂螺[2.5]辛烷-6-基)喹啉-5-甲酰胺
第一步：向乙醇(40mL)，水(10mL)和四氢呋喃(40mL)的混合溶液中加入铁粉(8.55g,151.51mmol)，4-溴-2-氟-5-硝基苯甲酸(8.00g,30.30mmol)和氯化铵(2.45g,45.45mmol)，将混合物加热至90℃搅拌3小时。将混合物冷却到40℃后，趁热倒入硅藻土砂芯漏斗中过滤，将滤液浓缩蒸干得到黄色固体5-氨基-4-溴-2-氟苯甲酸(6.00g，25.63mmol，收率:84.6％)。LCMS(ESI):[M+H]+＝234.1
第二步：向浓硫酸(20mL)和水(5mL)的混合溶液中加入甘油(5.96g，64.10mmol)，将混合物加热至100℃搅拌15分钟。将混合物冷却到40℃后，向该混合液中加入5-氨基-4-溴-2-氟苯甲酸(5.00g,21.36mmol)和3-硝基苯磺酸钠盐(4.85g，21.36mmol)，将混合物加热至100℃搅拌15小时。待反应结束后将反应混合物加入水(100mL)，用乙酸乙酯(100mL x 3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液旋干得残余物。残留物用快速柱色谱纯化(硅胶，0-20％梯度的甲醇/二氯甲烷)得到黄色固体8-溴-6-氟喹啉-5-羧酸(3.30g，12.21mmol，收率:57.3％)。LCMS(ESI):[M+H]+＝270.0；1HNMR(400MHz,DMSO)δ9.06(dd,J＝4.1,1.6Hz,1H),8.60(dd,J＝8.6,1.6Hz,1H),8.33(d,J＝9.4Hz,1H),7.77(dd,J＝8.6,4.1Hz,1H).
第三步:向8-溴-6-氟喹啉-5-羧酸(2.00g,7.41mmol)的二甲基亚砜(20mL)的溶液中加入6-氮杂螺[2.5]辛烷盐酸盐(1.66g,11.10mmol)和碳酸钾(3.13g,22.2mmol)，将混合物加热至120℃搅拌36小时。待反应完成后， 然后用饱和碳酸氢钠水溶液(20mL)将水层调节至pH＝6，并用乙酸乙酯(50mL x 3)萃取，合并有机相，饱和氯化钠水溶液(50mL)洗涤有机层，无水硫酸钠干燥，减压浓缩，粗品用快速柱色谱纯化(硅胶，0-20％梯度的甲醇/二氯甲烷得到黄色固体8-溴-6-(6-氮杂螺[2.5]辛烷-6-基)喹啉-5-羧酸(1.50g,4.15mmol，收率：56.2％)。LCMS(ESI):[M+H]+＝361.2
第四步：向2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-胺(758mg,3.32mmol)和8-溴-6-(6-氮杂螺[2.5]辛烷-6-基)喹啉-5-羧酸(1.00g,1.30mmol)的二氯甲烷(10.0mL)的溶液中加入N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(1.61g,4.15mmol)和叔丁醇钾(941mg,8.30mmol)，混合物于100℃搅拌24小时。待反应完成后，向反应混合物中加入水(10mL)，用二氯甲烷(20mL x 3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液旋干得残余物。残留物用快速柱色谱纯化(硅胶，0-50％梯度的乙酸乙酯/石油醚)得到黄色固体8-溴-N-(2-(4，4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-6-(6-氮杂螺[2.5]辛烷-6-基)喹啉-5-甲酰胺(200mg，0.35mmol，收率：12.6％)。LCMS(ESI):[M+H]+＝571.3
第五步：在氮气气氛下，将2-羟乙烷磺酰胺(67mg，1.40mmol),三(二亚苄基丙酮)二钯(33mg，0.03mmol)，磷酸钾(303mg，1.40mmol)和2-二-叔丁膦基-2',4',6'-三异丙基联苯(30mg，0.06mmol)放入瓶中，1,4-二氧六环(4mL)加入反应瓶，混合物在50℃下搅拌0.5小时，再将8-溴-N-(2-(4，4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-6-(6-氮杂螺[2.5]辛烷-6-基)喹啉-5-甲酰胺(200mg，0.35mmol)加入瓶中。将反应体系升高温度至120℃搅拌5小时.反应结束后将体系降温室后，将体系倒入水(10mL)中，用二氯甲烷(30mL×3)萃取，有机相用无水硫酸钠干燥，过滤并浓缩后制备HPLC纯化(C18，0-100％梯度的乙腈/水)，得到化合物固体N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-8-(2-羟乙基磺酰胺)-6-(6-氮杂螺[2.5]辛烷-6-基)喹啉-5-甲酰胺(20mg，0.032mmol，收率：9.3％)，为黄色固体。LCMS(ESI)m/z:[M+H]+＝616.4；1H NMR(400MHz,DMSO)δ10.98(s,1H),10.06–9.08(m,1H),8.80(d,J＝3.9Hz,1H),8.60(s,1H),8.00–7.39(m,3H),5.14(s,1H),4.02–3.75(m,6H),3.50(q,J＝4.9Hz,2H),3.16(s,4H),2.37(s,3H),1.96(d,J＝20.8Hz,4H),1.49(s,4H),0.33(d,J＝2.7Hz,4H).
实施例6：2-{6-氮杂螺[2.5]辛烷-6-基}-N-[8-(4,4-二氟哌啶-1-基)-7-氟喹啉-6-基]-4-(2-羟基乙磺酰氨基)萘-1-甲酰胺
第一步:8-(4,4-二氟哌啶-1-基)-7-氟喹啉-6-胺(171mg,0.61mmol)和2-{6-氮杂螺[2.5]辛烷-6-基}-4-溴萘-1-羰基氯化(230mg,0.61mmol)的四氢呋喃(6mL)溶液中加入N,N-二异丙基乙胺(240mg,1.82mmol)。将混合物在25° C搅拌16小时。向反应液中加入水(20mL)，用乙酸乙酯(20mL x 3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液旋干得残余物。残留物用快速柱色谱纯化(硅胶，0-10％梯度的四氢呋喃/石油醚)得到黄色固体2-{6-氮杂螺[2.5]辛烷-6-基}-4-溴-N-[8-(4,4-二氟哌啶-1-基)-7-氟喹啉-6-基]萘-1-甲酰胺(250mg,0.40mmol,收率66％)。LCMS(ESI):[M+H]+＝625.1；1H NMR(400MHz,DMSO-d6)δppm 0.45(s,1H),8.88(dd,J＝1.2,4.4Hz,1H),8.47-8.36(m,2H),8.23-8.11(m,1H),7.97(d,J＝8.0Hz,1H),7.88(s,1H),7.70-7.58(m,2H),7.53(dd,J＝4.0,8.4Hz,1H),3.56(br t,J＝4.8Hz,4H),3.20-3.15(m,4H),2.26-2.12(m,4H),1.49-1.39(m,4H),0.29(s,4H)
第二步:将2-{6-氮杂螺[2.5]辛烷-6-基}-4-溴-N-[8-(4,4-二氟哌啶-1-基)-7-氟喹啉-6-基]萘-1-甲酰胺(210mg,0.33mmol)和2-羟基乙磺酰胺(84.3mg,0.67mmol)溶于二氧六环(4mL)中，加入磷酸钾(214mg,1.01mmol),2-二叔丁基膦-2′,4′,6′-三异丙基联苯(14.3mg,0.03mmol)，三(二亚苄基丙酮)二钯(31.4mg,0.03mmol)。氮气氛围下60℃搅拌16小时。反应液过滤稀释后用制备型HPLC(C18，34-74％梯度的水(甲酸)/乙腈)纯化，得到黄色固体2-{6-氮杂螺[2.5]辛烷-6-基}-N-[8-(4,4-二氟哌啶-1-基)-7-氟喹啉-6-基]-4-(2-羟基乙磺酰氨基)萘-1-甲酰胺(56mg,0.08mmol,收率25％)。LCMS(ESI):[M+H]+＝668.3；1H NMR(400MHz,DMSO-d6)δppm 10.45(s,1H),10.16-9.47(m,1H),8.87(dd,J＝1.6,4.0Hz,1H),8.42(d,J＝8.0Hz,2H),8.28(d,J＝8.4Hz,1H),7.99(d,J＝8.4Hz,1H),7.62-7.45(m,4H),5.31-4.83(m,1H),3.83(t,J＝6.4Hz,2H),3.55(br d,J＝4.8Hz,4H),3.32-3.30(m,2H),3.18-3.11(m,4H),2.26-2.12(m,4H),1.43(br s,4H),0.30(s,4H)
实施例7：2-{6-氮杂螺[2.5]辛烷-6-基}-N-[2-(4,4-二氟哌啶-1-基)-6-甲氧基嘧啶-4-基]-4-(2-羟基乙磺酰氨基)萘-1-甲酰胺
第一步：向4-氯-2-(4,4-二氟哌啶-1-基)-6-甲氧基嘧啶(5.00g,18.9mmol)的二氧六环(100mL)溶液中加入二苯甲酮亚胺(5.16g,28.5mmol)，碳酸铯(18.9g,56.9mmol)，4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(1.12g,1.90mmol)和三(二亚苄基丙酮)二钯(1.77g,1.90mmol)。反应液用氮气置换三次，并在氮气氛围下加热至100℃搅拌12小时。将反应液冷却至室温，用水(200mL)和乙酸乙酯(200mL x 3)进行萃取，合并有机相，用饱和食盐水(200mL)洗涤，再用无水硫酸钠干燥，过滤，滤液旋干得残余物。残留物用乙酸乙酯打浆得到黄色固体N-[2-(4,4-二氟哌啶-1-基)-6-甲氧基嘧啶-4-基]-1,1-二苯基甲亚胺(5.90g,14.4mmol，收率76％)。LCMS(ESI):[M+H]+＝409.2；1H NMR(400MHz,DMSO-d6)δppm 7.81-7.13(m,10H),5.50(s,1H),3.77-3.70(m,7H),1.95-1.75(m,4H)
第二步：向N-[2-(4,4-二氟哌啶-1-基)-6-甲氧基嘧啶-4-基]-1,1-二苯基甲亚胺(1.00g,2.45mmol)的甲醇(10mL)溶液中加入乙酸钠(0.60g,7.34mmol)和盐酸羟胺(0.34g,4.90mmol)。将混合物在25℃下搅拌1小时。将反应液倒入冰水(20mL)中，用乙酸乙酯(20mL x 3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液旋干得残余物。残留物用快速柱色谱纯化(硅胶，0-50％梯度的四氢呋喃/石油醚)得到黄色固体2-(4,4-二氟哌啶-1-基)-6-甲氧基嘧啶-4-胺(0.60mg,2.44mmol，收率100％)。LCMS(ESI):[M+H]+＝245.1
第三步:向4-溴-2-氟萘-1-羧酸(2.00g,7.43mmol)和6-氮杂螺[2.5]辛盐酸(1.65g,11.1mmol)的二甲基亚砜(40mL)溶液中加入碳酸钾(3.14g,22.3mmol)。将混合物加热至120℃搅拌72小时。向反应混合物中加入水(50mL)，用3M稀盐酸调节PH至4，用乙酸乙酯(50mL x 2)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液旋干得残余物。残留物用快速柱色谱纯化(硅胶，0-15％梯度的乙酸乙酯/石油醚)得到黄色油状物2-{6-氮杂螺[2.5]辛烷-6-基}-4-溴萘-1-羧酸(0.65g,1.80mmol,收率24％)。LCMS(ESI):[M+H]+＝361.9.
第四步:向2-{6-氮杂螺[2.5]辛烷-6-基}-4-溴萘-1-羧酸(250mg,0.69mmol)的二氯甲烷(5mL)中加入草酰氯(107mg,0.83mmol)，随后向反应液中滴加N.N-二甲基甲酰胺(5.07mg,0.07mmol)，将混合物在25℃搅拌1小时。将反应液浓缩旋干得到粗品黄色固体2-{6-氮杂螺[2.5]辛烷-6-基}-4-溴萘-1-羰基氯化(250mg,粗品)。LCMS(ESI):376.0.(甲醇送样，出甲酯的mass)
第五步:2-(4,4-二氟哌啶-1-基)-6-甲氧基嘧啶-4-胺(193mg,0.79mmol)和2-{6-氮杂螺[2.5]辛烷-6-基}-4-溴萘-1-羰基氯化(300mg,0.79mmol)的四氢呋喃(6mL)溶液中加入N,N-二异丙基乙胺(313mg,2.37mmol)。将混合物在50℃搅拌16小时。向反应液中加入水(20mL)，用乙酸乙酯(20mL x 3)萃取。合并有机相，用无水硫酸钠干燥，过滤，滤液旋干得残余物。残留物用快速柱色谱纯化(硅胶，0-10％梯度的四氢呋喃/石油醚)得到黄色固体2-{6-氮杂螺[2.5]辛烷-6-基}-4-溴-N-[2-(4,4-二氟哌啶-1-基)-6-甲氧基嘧啶-4-基]萘-1-甲酰胺(80mg,0.13mmol,收率17.2％)。LCMS(ESI):[M+H]+＝588.0.
第六步:将2-{6-氮杂螺[2.5]辛烷-6-基}-4-溴-N-[2-(4,4-二氟哌啶-1-基)-6-甲氧基嘧啶-4-基]萘-1-甲酰胺(80mg,0.13mmol)和2-羟基乙磺酰胺(34.1mg,0.27mmol)溶于二氧六环(4mL)中，加入磷酸钾(86.8mg,0.41mmol),2-二叔丁基膦-2′,4′,6′-三异丙基联苯(5.79mg,0.01mmol)，三(二亚苄基丙酮)二钯(12.7mg,0.01mmol)。氮气氛围下60℃搅拌16小时。反应液过滤稀释后用制备型HPLC(C18，50-90％梯度的水(甲酸)/乙腈)纯化，得到白色固体2-{6-氮杂螺[2.5]辛烷-6-基}-N-[2-(4,4-二氟哌啶-1-基)-6-甲氧基嘧啶-4-基]-4-(2-羟基乙磺酰氨基)萘-1-甲酰胺(9.3mg,0.01mmol，收率11％)。LCMS(ESI):[M+H]+＝631.5；1H NMR(400MHz,DMSO-d6)δppm 10.70(br s,1H),10.02-9.64(m,1H),8.25(br d,J＝8.4Hz,1H),7.90(br dd,J＝2.0,4.8Hz,1H),7.63-7.39(m,3H),7.00(br s,1H),5.20-4.82(m,1H),4.01-3.77(m,9H),3.46-3.38(m,2H),3.09(br s,4H),1.98(br s,4H),1.40(br s,4H),0.30(s,4H)
实施例8：N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-((2-羟乙基)磺酰胺基)-7-(6-氮杂螺环[2.5]辛烷-6-基)喹啉-8-羧酰胺
第一步：20℃下，将丙三醇(1.13g,12.09mmol)和3-硝基苯磺酸钠(1.00g,4.43mmol)的硫酸(4.00mL)/水(2.00mL)混合溶液在120℃下搅拌30分钟。将反应体系降温至40℃。向反应混合液中加入甲基2-胺基-4-溴-6-氟苯甲酸酯(1.00g,4.03mmol)，在120℃下搅拌4小时。将反应混合物倒入到冰水(50mL)中，混合物经过滤，滤饼用乙酸乙酯(30mL)洗。有机相弃去，水相用碳酸钾溶液调至pH＝9，用乙酸乙酯(15mL x 2)萃取。有机相弃去，水相用稀盐酸(1M)调至pH＝4，用乙酸乙酯(15mL x 3)萃取。合并有机相、干燥、过滤、浓缩得5-溴-7-氟喹啉-8-羧酸(200mg，0.74mmol，收率16.7％)，为灰色固体。LCMS(ESI):[M+H]+＝270.0；1H NMR(400MHz,DMSO)δ14.02(s,1H),9.07(dd,J＝4.3,1.6Hz,1H),8.60(dd,J＝8.5,1.6Hz,1H),8.21(d,J＝9.0Hz,1H),7.85–7.74(m,1H).
第二步：20℃下，向5-溴-7-氟喹啉-8-羧酸(1.00g,3.70mmol),6-氮杂螺环[2.5]辛烷盐酸盐(0.83g,5.55mmol)的二甲基亚砜(13.00mL)溶液中加入碳酸钾(1.56g,11.10mmol)。所得反应混合物在120℃下搅拌16小时。将反应混合物过滤，滤饼在水(20mL)中搅拌5分钟，再次过滤，滤饼经干燥得7-(6-氮杂螺环[2.5]辛烷-6-基)-5-溴喹啉-8-羧酸(900mg，2.49mmol，收率67.4％)，为黄色固体。LCMS(ESI):[M+H]+＝361.1；1H NMR(400MHz,CD3OD)δ8.78(dd,J＝4.3,1.7Hz,1H),8.42(dd,J＝8.4,1.7Hz,1H),7.71(d,J＝1.6Hz,1H),7.40(ddd,J＝8.5,4.3,1.5Hz,1H),3.35(t,J＝5.4Hz,4H),1.57(t,J＝5.3Hz,4H),0.36(d,J＝1.6Hz,4H).
第三步：20℃下，向7-(6-氮杂螺环[2.5]辛烷-6-基)-5-溴喹啉-8-羧酸(0.53g,1.47mmol)的二氯甲烷(3.00mL)溶液中加入氯化亚砜(100uL)。反应混合物在50℃下搅拌1小时。将反应混合物浓缩干不需纯化，得7-(6-氮杂螺环[2.5]辛烷-6-基)-5-溴喹啉-8-羧酰氯(550mg,1.45mmol，收率98.7％)，为橘黄色固体。LCMS(ESI):[M+H]+＝377.1
第四步：20℃下，向2-(4,4-二氟哌啶基)-6-甲基嘧啶-4-基胺(330.63mg,1.45mmol)的四氢呋喃(10.00mL)溶液中加入叔丁醇钾(328mg,2.90mmol)。反应混合物在20℃下搅拌5分钟，加入7-(6-氮杂螺环[2.5]辛烷-6-基)-5-溴喹啉-8-羧酰氯(550mg,1.45mmol)。反应混合物在20℃下搅拌16小时。向反应混合物中加入水(20mL)，用乙酸乙酯(10mL x 3)萃取。有机相用饱和氯化钠溶液(20mL x 2)洗涤，经干燥、过滤、浓缩得残余物经快速柱层析(二氧化硅，0-20％乙酸乙酯/石油醚)纯化得[7-(6-氮杂螺环[2.5]辛烷-6-基)-5-溴(8-喹啉)]-N-[2-(4,4-二氟哌啶基)-6-甲基嘧啶-4-基]羧酰胺(250mg，0.44mmol，收率30％)，LCMS(ESI):[M+H]+＝573.3
第五步：20℃下，向[7-(6-氮杂螺环[2.5]辛烷-6-基)-5-溴(8-喹啉)]-N-[2-(4,4-二氟哌啶基)-6-甲基嘧啶-4-基]羧酰胺(150mg,0.26mmol)，2-羟乙基磺酰胺(98mg,0.79mmol)，磷酸钾(170mg,0.79mmol)，三(二亚苄基丙酮)二钯(24mg,0.03mmol)，2-二叔丁基膦-2',4',6'-三异丙基联苯(22mg,0.052mmol)中加入1,4-二氧六环(7.00mL)，所得反应混合物用氮气鼓气2分钟，在60℃下搅拌5小时。向反应混合物中加入乙酸乙酯(20mL)，将混合物过滤，滤液用饱和氯化钠溶液(10mL x 3)洗涤。有机相经干燥、过滤、浓缩得残余物，经快速柱层析纯化(二氧化硅，0-5％梯度的甲醇/二氯甲烷)得产物100 mg，进一步经制备级HPLC纯化(C18,70-90％梯度的乙腈/水)，得N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-((2-羟乙基)磺酰胺基)-7-(6-氮杂螺环[2.5]辛烷-6-基)喹啉-8-羧酰胺(61mg,0.10mmol，收率38％)，为橘黄色固体。LCMS(ESI):[M+H]+＝616.4；1H NMR(400MHz,DMSO)δ10.60(s,1H),9.95(s,1H),8.81(s,1H),8.58(d,J＝8.6Hz,1H),7.53–7.43(m,3H),5.03(s,1H),3.83(d,J＝14.7Hz,6H),3.31(s,2H),3.21(s,4H),2.34(s,3H),1.95(s,4H),1.40(s,4H),0.31(s,4H).
实施例9：N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-7-((2-羟乙基)磺酰胺基)-5-(6-氮杂螺[2.5]辛-6-基)-2,3-二氢-1H-茚-4-甲酰胺
第一步：含有4-溴-2-氟-6-甲基苯甲酸甲酯(25.0g，101.19mmol)、N-溴代丁二酰亚胺(21.6g，121.43mmol)，偶氮二异丁腈(8.5g，50.60mmol)和乙腈(250mL)的混合溶液在70℃下搅拌3小时，将反应液倒入水中(50mL)并用乙酸乙酯(50mL x 3)萃取，有机相用无水硫酸钠干燥，过滤并浓缩后经柱层析(硅胶，0-10％梯度的乙酸乙酯/石油醚)纯化,得到化合物4-溴-2-(溴甲基)-6-氟苯甲酸甲酯(18.1g,55.53mmol,收率:54.9％),为无色油状。LCMS(ESI):[M+H]+＝326.9；1H NMR(400MHz,DMSO)δ7.73(m,2H),4.77(s,2H),3.91(s,3H).
第二步：含有4-溴-2-(溴甲基)-6-氟苯甲酸甲酯(18g，55.22mmol)、丙二酸叔丁基乙酯(11.4g，60.74mmol)，碳酸铯(36.7g，110.44mmol)和N,N-二甲基甲酰胺(200mL)的混合溶液在20℃下搅拌2小时。将反应液倒入水中(300mL)并用乙酸乙酯(100mL x 3)萃取，有机相用无水硫酸钠干燥，过滤并浓缩后经柱层析(硅胶，0-10％梯度的乙酸乙酯/石油醚)纯化,得到化合物1-(叔丁基)3-乙基-2-(5-溴-3-氟-2-(甲氧羰基)苄基)丙二酸(15.4g,粗品),为无色油状。LCMS(ESI):[M+Na]+＝455.3；1H NMR(400MHz,DMSO)δ7.64(dd,J＝9.6,2.0Hz,1H),7.47–7.44(m,1H),4.17-4.08(m,2H),3.88(s,3H),3.70(t,J＝8.0Hz,1H),3.18–3.04(m,2H),1.35(s,9H),1.15(t,J＝7.2Hz,3H).
第三步：含有1-(叔丁基)3-乙基-2-(5-溴-3-氟-2-(甲氧羰基)苄基)丙二酸(15g，34.62mmol)和三氟乙酸(60mL)的溶液在20℃下搅拌1小时，反应液浓缩去除三氟乙酸，然后加入甲苯(60mL)和三乙胺(35.75g，346.21mmol)，在120℃继续搅拌3小时。浓缩反应液，加入饱和碳酸氢钠水溶液将pH调节至接近8，然后用乙酸乙酯(50mL x 3)萃取，有机相用无水硫酸钠干燥，过滤并浓缩后经柱层析(硅胶，0-10％梯度的乙酸乙酯/石油醚)纯化,得到化合物4-溴-2-(3-乙氧基-3-氧丙基)-6-氟苯甲酸甲酯(6.8g,20.41mmol,收率：59.0％)。LCMS(ESI):[M+H]+＝333.0。
第四步：含有4-溴-2-(3-乙氧基-3-氧丙基)-6-氟苯甲酸甲酯(6.8g，20.41mmol)、一水合氢氧化锂(4.9g，204.11mmol)，四氢呋喃(40mL)、甲醇(40mL)和水(40mL)的混合溶液在20℃下搅拌4小时。将反应液浓缩去除四氢呋喃和甲醇，加入4M盐酸乙酸乙酯溶液(100mL)将pH调节至接近5，然后用乙酸乙酯(20mL x 3)萃取，有机相用无水硫酸钠干燥，过滤并浓缩后得到化合物4-溴-2-(2-羧乙基)-6-氟苯甲酸(5.1g,17.52mmol,收率：85.8％)，为白色固体。LCMS(ESI):[M+Na]+＝313.0；1H NMR(400MHz,DMSO)δ12.95(s,2H),7.58(dd,J＝9.2,2.0Hz,1H),7.49(d,J＝2.0Hz,1H),2.94(dd,J＝8.4,7.2Hz,2H),2.60(dd,J＝8.4,7.2Hz,2H).
第五步：将草酰氯(15.3g,120.25mmol)加入到含有4-溴-2-(2-羧乙基)-6-氟苯甲酸(5.0g，17.18mmol)和二氯甲烷(50mL)的混合溶液中，将所得混合物在20℃下搅拌1小时。将反应液浓缩，得到化合物4-溴-2-(3-氯-3-氧丙基)-6-氟苯甲酰氯(5.7g，粗品)，为黄色油状。LCMS(ESI):[M+H]+＝319.0(对应的甲酯)。
第六步：将4-溴-2-(3-氯-3-氧丙基)-6-氟苯甲酰氯(5.0g，15.25mmol)溶于二氯甲烷(50mL)，0℃下滴加到含有三氯化铝(8.1g，60.98mmol)和二氯甲烷(50mL)的溶液中，反应液在40℃下搅拌16小时，将反应混合物倒入水(30mL)中并用二氯甲烷(30mL x 3)萃取，有机相用无水硫酸钠干燥，过滤并浓缩后经柱层析(硅胶，0-100％梯度的乙酸乙酯/石油醚)纯化,得到化合物7-溴-5-氟-1-氧代-2,3-二氢-1H-茚-4-羧酸(3.4g,12.45mmol,收率：81.7％)，为棕色固体，LCMS(ESI):[M+H]+＝273.0。
第七步：含有7-溴-5-氟-1-氧代-2,3-二氢-1H-茚-4-羧酸(3.3g，12.09mmol)、6-氮杂螺[2.5]辛烷盐酸盐(2.7g，18.13mmol)，碳酸钾(6.0g，42.30mmol)和二甲基亚砜(30mL)的混合溶液在100℃下搅拌12小时，将反应液倒入水中(30mL)并用乙酸乙酯(30mL x 3)萃取，有机相用无水硫酸钠干燥，过滤并浓缩后经柱层析(硅胶，0-100％梯度的乙酸乙酯/石油醚)纯化,得到化合物7-溴-1-氧代-5-(6-氮杂螺[2.5]辛-6-基)-2,3-二氢-1H-茚-4-羧酸(2.5g，6.86mmol,收率：56.8％)，为灰色固体，LCMS(ESI):[M+H]+＝364.4。
第八步：含有7-溴-1-氧代-5-(6-氮杂螺[2.5]辛-6-基)-2,3-二氢-1H-茚-4-羧酸(1g，2.75mmol)、三乙基硅烷(3.2g，27.45mmol)和三氟乙酸(10mL)的混合溶液在80℃下搅拌12小时，反应液浓缩后加入碳酸氢钠水溶液(50mL)，然后加入4M盐酸乙酸乙酯溶液(40mL)将pH调节至接近4，并用乙酸乙酯(30mL x 3)萃取，有机层用无水硫酸钠干燥，过滤并浓缩后经柱层析(硅胶，0-100％梯度的乙酸乙酯/石油醚)纯化,得到化合物7-溴-5-(6- 氮杂螺[2.5]辛-6-基)-2,3-二氢-1H-茚-4-羧酸(700mg,2.00mmol,收率：72.8％)，为白色固体。LCMS(ESI):[M+H]+＝350.2。
第九步：将草酰氯(518mg，4.00mmol)加入到含有7-溴-5-(6-氮杂螺[2.5]辛-6-基)-2,3-二氢-1H-茚-4-羧酸氯化邻苯二甲酸(700mg，2.00mmol)和二氯甲烷(10mL)的混合溶液中，将所得混合物在20℃下搅拌30分钟，将反应混合物浓缩，得到化合物7-溴-5-(6-氮杂螺[2.5]辛-6-基)-2,3-二氢-1H-茚-4-羰基氯(760mg，粗品)，为黄色油状。LCMS(ESI):[M+H]+＝364.2。(相应的甲酯)
第十步：含有2-(4,4-二氟丙哌啶基)-6-甲基吡嘧啶-4-胺(650mg，2.85mmol)、N,N-二异丙基乙胺(2.5g，18.99mmol)，叔丁醇钾(323mg，2.85mmol)和四氢呋喃(10mL)的混合溶液在20℃下搅拌30分钟，然后加入7-溴-5-(6-氮杂螺[2.5]辛-6-基)-2,3-二氢-1H-茚-4-羰基氯(700mg，1.90mmol)，将反应液倒入水中(30mL)并用乙酸乙酯(30mL x 3)提取，有机相用无水硫酸钠干燥，过滤并浓缩后经柱层析(硅胶，0-50％梯度的乙酸乙酯/石油醚)纯化,得到化合物7-溴-N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-(6-氮杂螺[2.5]辛-6-基)-2,3-二氢-1H-茚-4-甲酰胺(630mg,1.12mmol,收率：59.2％)，为灰色固体。LCMS(ESI):[M+H]+＝560.3。
第十一步：氮气氛围下,含有7-溴-N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-(6-氮杂螺[2.5]辛-6-基)-2,3-二氢-1H-茚-4-甲酰胺(300mg,0.54mmol)、2-羟基乙磺酰胺(137mg，1.07mmol)，磷酸钾(348mg,1.61mmol),2-二-叔丁膦基-2',4',6'-三异丙基联苯(23mg,0.054mmol),三(二亚苄基丙酮)二钯(50mg，0.054mmol)和二氧六环(5mL)的反应液在100℃搅拌8小时,将反应液倒入水中(30mL)并用乙酸乙酯(30mL x 3)萃取，有机相用无水硫酸钠干燥，过滤并浓缩后经柱层析(硅胶，0-100％梯度的乙酸乙酯/石油醚)，得到化合物N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-7-((2-羟乙基)磺酰胺基)-5-(6-氮杂螺[2.5]辛-6-基)-2,3-二氢-1H-茚-4-甲酰胺(149.0mg,0.25mmol,收率：46.0％)，为白色固体。LCMS(ESI):[M+H]+＝605.40；1H NMR(400MHz,CDCl3)δ12.79(s,1H),7.46(s,1H),7.39(s,1H),6.61(s,1H),4.12(q,J＝5.2Hz,2H),3.98(t,J＝5.6Hz,4H),3.45–3.37(m,4H),3.04(t,J＝5.2Hz,4H),2.79(t,J＝7.6Hz,2H),2.48(t,J＝5.6Hz,1H),2.37(s,3H),2.13(q,J＝7.6Hz,2H),2.03-1.92(m,4H),1.79-1.56(m,4H),0.38(s,4H).
实施例10：N-[2-氨基-4-(4,4-二氟哌啶-1-基)-5-氟-1,3-苯并噻唑-6-基]-2-{6-氮杂螺[2.5]辛烷-6-基}-4-(1-羟基丙烷-2-磺酰氨基)萘-1-甲酰胺
第一步：叔-丁基N-[6-氨基-4-(4,4-二氟哌啶-1-基)-5-氟-1,3-苯并噻唑-2-基]-N-[(叔-丁氧基)羰基]氨基甲酯(120mg,0.30mmol)和2-{6-氮杂螺[2.5]辛烷-6-基}-4-溴萘-1-羰基氯化(716mg,1.43mmol)的四氢呋喃(8.00mL)溶液中加入N,N-二异丙基乙胺(418mg,3.17mmol).将混合物在25℃下搅拌16小时。反应液用水(5mL)稀释，用二氯甲烷(15mL x 2)萃取，有机层用饱和食盐水(20mL)洗涤，用硫酸镁干燥，过滤，减压浓缩。残留物用快速柱色谱纯化(硅胶，0-20％梯度的乙酸乙酯/石油醚)得得到黄色固体叔-丁基N-[6-(2-{6-氮杂螺[2.5]辛烷-6-基}-4-溴萘-1-酰氨基)-4-(4,4-二氟哌啶-1-基)-5-氟-1,3-苯并噻唑-2-基]-N-[(叔-丁氧基)羰基]氨基甲酯(650mg,0.77mmol,收率72.8％)。LCMS(ESI):[M+H]+＝846.1
第二步：向三氟乙酸(0.50mL)和二氯甲烷(1.50mL)的混合溶液中加入叔-丁基N-[6-(2-{6-氮杂螺[2.5]辛烷-6-基}-4-溴萘-1-酰氨基)-4-(4,4-二氟哌啶-1-基)-5-氟-1,3-苯并噻唑-2-基]-N-[(叔-丁氧基)羰基]氨基甲酯(400mg,0.47mmol)。将混合液在25℃下搅拌4小时。向反应液中加入饱和的碳酸氢钠水溶液(20mL)，用二氯甲烷(20mL x 2)萃取。合并有机相，用无水硫酸镁干燥，过滤，滤液旋干得到白色固体N-[2-氨基-4-(4,4-二氟哌啶-1-基)-5-氟-1,3-苯并噻唑-6-基]-2-{6-氮杂螺[2.5]辛烷-6-基}-4-溴萘-1-甲酰胺(300mg,0.464mmol，收率98.3％)。LCMS(ESI):[M+H]+＝645.8
第三步：在25℃下，向N-[2-氨基-4-(4,4-二氟哌啶-1-基)-5-氟-1,3-苯并噻唑-6-基]-2-{6-氮杂螺[2.5]辛烷-6-基}-4-溴萘-1-甲酰胺(360mg,0.56mmol)的二氧六环(2mL)溶液中加入乙基2-氨磺酰丙酯(101mg,0.56mmol)，磷酸钾(363mg,1.68mmol)，二叔-丁基-[2-(2,4,6-三异丙基苯基)苯基]磷烷(23.7mg,0.06mmol)和三(二亚苄基丙酮)二钯(52.2mg,0.06mmol)，反应混合物在氮气的保护下加热到90℃搅拌4小时。将反应混合物减压浓缩，滤液旋干得残余物。残留物用快速柱色谱纯化(硅胶，0-30％梯度的四氢呋喃/石油醚)得到白色固体化合物乙基2-[(4-{[2-氨基-4-(4,4-二氟哌啶-1-基)-5-氟-1,3-苯并噻唑-6-基]氨基羰基}-3-{6-氮杂螺[2.5]辛烷-6-基}萘-1-基)氨磺酰]丙酯(300mg,0.463mmol，收率83％)。LCMS(ESI):[M+H]+＝745.2
第四步：乙基2-[(4-{[2-氨基-4-(4,4-二氟哌啶-1-基)-5-氟-1,3-苯并噻唑-6-基]氨基羰基}-3-{6-氮杂螺[2.5]辛烷-6-基}萘-1-基)氨磺酰]丙酯(300mg,0.40mmol)加入至四氢呋喃(14mL)溶液中，在25℃下分批加入四氢铝锂(21.6mg,0.60mmol)，混合物在25℃搅拌1小时。向反应液中依次加入水(0.05mL)，15％氢氧化钠水溶液(0.05mL)淬灭和水(0.1mL)过滤，滤液旋干得残余物。用N,N-二甲基甲酰胺(5mL)稀释残渣。稀释液用制备型HPLC(C18，28-68％梯度的水(甲酸)/乙腈)纯化，得到白色固体化合物N-[2-氨基-4-(4,4-二氟哌啶-1-基)-5-氟-1,3-苯并噻唑-6-基]-2-{6-氮杂螺[2.5]辛烷-6-基}-4-(1-羟基丙烷-2-磺酰氨基)萘-1-甲酰胺(37.9mg,0.052mmol，收率13％)。LCMS(ESI):[M+H]+＝703.1；1H NMR(400MHz,DMSO-d6)δppm 10.01(s,1H),9.95-9.61(m,1H),8.27(d,J＝8.4Hz,1H),7.94(d,J＝8.4Hz,1H),7.84(d,J＝6.4Hz,1H),7.62-7.44(m,5H),5.32-4.83(m,1H),3.92(dd,J＝4.4,11.2Hz,1H),3.50(dd,J＝8.0,11.2Hz,1H),3.40(br t,J＝5.2Hz,4H),3.27-3.20(m,1H),3.13(br t,J＝5.2Hz,4H),2.21-2.03(m,4H),1.46(br s,4H),1.34(d,J＝7.2Hz,3H),0.33(s,4H)
实施例11：N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-7-((2-羟基-1,1-二甲基乙基)磺酰胺基)-5-(6-氮杂螺[2.5]辛-6-基)-2,3-二氢-1H-茚-4-甲酰胺
第一步：氮气氛围下,含有7-溴-N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-(6-氮杂螺[2.5]辛-6-基)-2,3-二氢-1H-茚-4-甲酰胺(300mg,0.54mmol)、2-甲基-2-氨磺基丙酸乙酯(209mg，1.07mmol)，磷酸钾(348mg,1.61mmol),2-二-叔丁膦基-2',4',6'-三异丙基联苯(23mg,0.054mmol),三(二亚苄基丙酮)二钯(50mg，0.054mmol)和二氧六环(5mL)的反应液在100℃搅拌8小时,将反应液倒入水中(30mL)并用乙酸乙酯(30mL x 3)萃取，有机相用无水硫酸钠干燥，过滤并浓缩后经柱层析(硅胶，0-30％梯度的乙酸乙酯/石油醚)，得到化合物2-(N-(7-((2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)氨基甲酰基)-6-(6-氮杂螺[2.5]辛-6-基)-2,3-二氢-1H-茚-4-基)氨磺酰基)-2-甲基丙酸乙酯(270mg,0.40mmol,收率：76.2％)，为淡黄色固体。LCMS(ESI):[M+H]+＝675.5.
第二步：将四氢铝锂(40mg,1.11mmol)分批加入含有2-(N-(7-((2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)氨基甲酰基)-6-(6-氮杂螺[2.5]辛-6-基)-2,3-二氢-1H-茚-4-基)氨磺酰基)-2-甲基丙酸乙酯(250mg,0.37mmol)和四氢呋喃(5mL)的混合溶液中，反应液在20℃搅拌1小时，加入饱和氯化铵水溶液(20mL)淬灭反应，然后用乙酸乙酯(30mL x 3)萃取，有机相用无水硫酸钠干燥，过滤并浓缩后经柱层析(硅胶，0-100％梯度的乙酸乙酯/石油醚) 和C18(0-100％梯度的乙腈/水)，得到化合物N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-7-((2-羟基-1,1-二甲基乙基)磺酰胺基)-5-(6-氮杂螺[2.5]辛-6-基)-2,3-二氢-1H-茚-4-甲酰胺(40.25mg,0.064mmol,收率:17.2％),为白色固体。LCMS(ESI):[M+H]+＝633.40；1H NMR(400MHz,DMSO)δ13.05(s,1H),9.17(s,1H),7.46(s,1H),7.38(s,1H),5.22(s,1H),3.90(t,J＝5.6Hz,4H),3.55(s,2H),3.23(t,J＝7.6Hz,2H),2.94-2.85(m,6H),2.30(s,3H),2.02-1.91(m,6H),1.66(s,4H),1.23(s,6H),0.36(s,4H).
效果实施例1：酶学活性检测实验
材料：人源KIF18A(氨基酸序列1-417)，购于上海维亚生物科技有限公司；ADP-GloTM蛋白激酶试剂盒购自美国普洛麦格公司；微管蛋白购自美国Cytoskeleton公司；384孔检测板以及多功能酶标仪Envision购自美国珀金埃尔默公司。
酶学活性检测：使用DMSO将化合物粉末溶解成10mM的储存液；在微孔板中对化合物进行梯度稀释，并使其最终浓度为0-10μM之间。然后依次在微孔板中加入微管蛋白，化合物，ATP，以及KIF18A蛋白各2.5μL，并在室温反应120分钟。酶反应终浓度为微管60μg/mL，ATP 25μM,KIF18A蛋白2.5nM。酶反应结束后，每孔加入10μl ADP-GLO反应试剂，常温孵育30分钟。之后，每孔再加入20μl检测试剂，常温避光孵育30分钟。最后使用珀金埃尔默Envision进行化学发光检测。
表1：本发明化合物的酶学活性生物数据
NT表示没有测试
效果实施例2：细胞増殖活性检测实验
材料与细胞：OVCAR3细胞购于南京科佰生物科技有限公司。RPMI-1640培养基，胎牛血清，CyQUANT Direct Cell Proliferation Assay试剂盒购于美国赛默飞公司；96孔细胞培养板购于美国康宁公司。
细胞培养：用含10％胎牛血清的RPMI-1640培养液对OVCAR3细胞进行培养，并放置在37℃、5％CO2的培养箱中。处于对数生长期细胞方可用于实验。
细胞増殖活性检测：
将OVCAR3细胞接种于96孔细胞培养板，每孔90μl，置于37℃、5％CO2的培养箱中培养过夜。使用DMSO将化合物粉末溶解成10mM的储存液；在微孔板中对化合物进行梯度稀释，并使其最终浓度为0-10μM之间。每孔加入10μL含化合物的细胞培养液，使最终的DMSO含量为0.2％。细胞板置于37℃、5％CO2的培养箱中培养3天。每孔加入100μl的CyQUANT检测试剂，37℃反应60分钟，并使用珀金埃尔默公司的Envision进行荧光检测。
表2：本发明化合物的OVCAR-3细胞活性生物数据
NT表示没有测试
效果实施例3：CyQuant细胞増殖活性检测实验
材料与细胞：HT29细胞购于南京科佰生物；RPMI-1640培养基购于ThermoFisher公司(美国)；胎牛血清购于ThermoFisher公司(美国)；Trypsin-EDTA(0.25％)购于ThermoFisher公司(美国)；DMSO购于SIGMA公司(美国)；96孔板购于ThermoFisher公司(美国)；CyQuant试剂购于ThermoFisher公司(美国)。
细胞培养：HT29细胞用含10％胎牛血清的RPMI-1640培养基于37℃、5％CO2条件下培养。处于对数生长期细胞方可用于实验。
细胞増殖活性检测：利用CyQuant试剂检测化合物对HT29细胞的增殖抑制活性。调整细胞密度，每孔100μl接种96孔板(HT29为2000/孔)，置于37℃、5％CO2条件下培养过夜。加入各目的浓度化合物(起始浓度3000nΜ，3倍稀释，9个浓度梯度)，DMSO含量为0.2％。细胞板置于37℃、5％CO2条件下孵育3天。加入CyQuant试剂孵育1小时，Envision读板，利用XLFIT计算IC50。
表3：本发明化合物的HT-29细胞活性生物数据
NT表示没有测试
效果实施例4：人原代肝细胞的细胞毒性实验测试。
材料：一个供体将用于细胞毒性测试，人原代肝细胞的信息见下表。
注：可能使用其他人种的肝细胞，具体信息将在试验报告中体现。
1)CellTiter-Glo Luminescent Cell Viability Assay System发光细胞活力测定系统购自Promega(Madison,WI).
仪器：
实验设计：
将以下介质在水浴中加热至37℃:根据下表配制肝细胞复苏培养基、接种培养 基和孵育培养基。
复苏培养基
接种培养基
孵育培养基
1)取一管超低温保存的肝细胞，确保肝细胞在复苏之前仍处于低温冰冻状态。将肝细胞迅速置于37℃水浴中并轻摇直至所有冰晶全部分散，喷洒75％乙醇后转移至生物安全柜中
2)将肝细胞小管的内容物(1mL，约5×106个细胞)倾入盛有50mL复苏培养基的50mL离心管中，将其于100g离心10分钟。离心后，吸出复苏培养基并加入足量接种培养基得到细胞密度约1.0×106 cells/mL的细胞混悬液。用细胞计数仪对肝细胞进行计数及确定活细胞密度，肝细胞成活率必须大于80％，用接种培养基将细胞密度调整为0.2×106cells/mL，接种于collagen I包被的96孔板中，每孔100μL。将培养板置于5％的CO2培养箱中，95％相对湿度，37℃培养4–6小时。
3)在DMSO中配制200X的试验化合物原液(可根据溶解度降低试验化合物的原液浓度)。DMSO终浓度为0.5％
4)将2.5μL待测化合物原液加入497.5μL的肝细胞培养培养基中，在无菌的96孔板上配制工作液。
5)将肝细胞培养液从细胞板上取下，在相应的孔中加入125μL的工作液，每孔重复三次。在37℃,5％CO2下孵育板72小时。每处理24小时后，用肝细胞培养基新稀释的试验化合物和阳性对照化合物更换细胞板中的培养基。将细胞板放回培养箱直接向96孔板中每个孔加入50μL的CellTiter-Glo试剂。在室温下用摇板器摇10分钟。10分钟后，取100μL以上孵育液至新的白色平底不透明96孔板上，记录荧光。
数据分析:
所有计算均使用Microsoft Excel进行.
测试化合物的存活率可以用下式计算:
将％Vehicle与被试化合物的浓度进行拟合，然后使用GraphPad Prism5.0将数据拟合为变斜率的s型剂量-响应曲线。根据曲线计算该化合物的IC50，公式如下
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
效果实施例5：人原代肝细胞微球模型实验测试
细胞：供体信息：男性，高加索人，36岁(Lot No.NFX,BioIVT)
仪器：

细胞接种和培养:
1)取一管超低温保存的肝细胞，确保肝细胞在复苏之前处于低温冰冻状态。将肝细胞迅速置于37℃水浴中并轻摇直至所有的冰晶全部散开，喷洒70％乙醇后转移至生物安全柜中。
2)将肝细胞小管的内容物倾入盛有50mL复苏培养基的50mL离心管中，将其于100g离心3分钟。离心后，吸出复苏培养基并加入足量孵育培养基得到细胞密度约为1.0x106cells/mL细胞混悬液。
3)用Cellometer Vision对肝细胞进行计数及确定活细胞密度，肝细胞成活率必须大于80％，用接种培养基将细胞密度调整为4000个/孔，每孔接种100μL。
4)放入细胞培养箱中，恒温37℃孵育7-9天直至微球形成。
化合物的准备及给药:
1)使用细胞培养基对化合物，按照三倍稀释法进行稀释，稀释梯度如下表。对照化合物的最大浓度是200μM，测试化合物最大浓度(依据客户要求)为5μM，DMSO的最终浓度为0.1％。
2)在微球形成后，进行给药。每次给药前需将细胞培养板孔中的培养基吸干，并加入100μL的化合物工作液。每三天给药一次，直至成球后的第十四天。
试验指标检测:
1)培养14天后，从培养箱中取出细胞培养板，取80μL上清检测白蛋白和乳酸脱氢酶的含量。
2)CellTiter-FluorTM Cell Viability试剂盒室温下解冻，将10μL GF-AFC底物加入到10mL2×工作液中，并补充等体积的PBS稀释成1×工作液。
3)细胞培养板每孔中加入100μL工作液,并在37℃孵育30min后，吸取上清80μL至96孔黑板中，于激发波长400nm和发射波长505nm处检测吸光度。
数据分析:
1)细胞存活百分比(％Vehicle)使用以下公式进行计算：
2)使用GraphPad Prism 8.0.2计算IC50，软件运算公式如下：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))

Claims (32)

  1. 具有式(I)结构的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物：
    其中，W1表示CRW1或N；
    其中，W2表示CRW2或N；
    其中，W3表示CRW3或N；
    其中，Z表示-CRTRT'或-NRSRS'；
    其中，RT和RT'与与之共同相连的C原子一起形成具有选自以下结构的环：
    其中，RS和RS'与与之共同相连的N原子一起形成具有选自以下结构的环：
    其中，Y1、Y2、Y3各自独立地表示-(CRaRb)o-(NRa)p-(CRa'Rb')q-；
    其中，A、B各自独立地表示-(CRaRb)m-；
    其中，L1表示表示-C(O)NH-、-HNC(O)-、5-6元杂芳基、
    其中，L2表示不存在、-C1-C6亚烷基-、-NRa-、-NRa(C1-C6亚烷基)-、-C(O)NRa(C1-C6亚烷基)-、-O-、-O-(C1-C6亚烷基)、-S-、-S(O)-、-S(O)2-、-S(O)2NRa-或者-S(O)(NRa)-；
    其中，R1表示L3-R3；
    其中，L3表示不存在、C1-C6亚烷基、-NRa-、-NRaSO2-、-SO2NRa-、-S(＝O)(NRa)-、-P(O)(ORa)2、-NRaP(O)(ORa)2或-NRaP(O)(Ra)2；
    其中，R3表示不存在、氢或者被0-3个选自卤素、-ORa、-NRaRb、氰基和-O-卤代C1-C6烷基之基团取代的C1-C6烷基或C3-C6环烷基；
    其中，RW1、RW2和RW3各自独立地表示氢、卤素、氰基、硝基、羟基C1-C6烷基、C1-C6烷基、C3-C8环烷基、卤代C1-C6烷基、-ORa、-SO3Ra、-S(O)Ra、-O-卤代C1-C6烷基、-SRa、-SF5或-NRaRb；
    其中，Cy1表示6-12元芳基或者5-12元杂芳基；并且所述的Cy1还可以任意地被0-3个选自以下取代基的基团所取代：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、ORa、-O-卤代C1-C6烷基、5-6元杂芳基、苯基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)Ra、-P(O)RaRb、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb；
    其中，Cy2表示3-12元饱和或不饱和的单环或者双环，该环中可以任意地含有0-3个选自O、N和S的杂原子，并且所述的Cy2还可以任意地被0-3个选自以下取代基的基团所取代：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、-ORa、-O-卤代C1-C6烷基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb；
    其中，环A表示饱和或者不饱和的4-12元环，优选为5-12元环；并且该环中可以任意地含有0-3个选自O、N和S的杂原子，并且所述的环A还可以任意地被0-3个选自以下取代基的基团所取代：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、-ORa、-O-卤代C1-C6烷基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb；
    其中，Ra、Rb、Ra'、Rb'各自独立地表示氢、卤素、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基或羟基C1-C6烷基；或者Ra、Rb一起与与之相连的原子形成3-6元饱和或不饱和环，该环中可以任意地含有0-2个选自O、S和N的杂原子；或者Ra'、Rb'一起与与之相连的原子形成3-6元饱和或不饱和环，该环中可以任意地含有0-2个选自O、S和N的杂原子；
    其中，m、o、p、q表示0-3的整数。
  2. 具有式(II)结构的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物：
    其中，W1表示CRW1或N；
    其中，W2表示CRW2或N；
    其中，Z表示-CRTRT'或-NRSRS'；
    其中，RT和RT'与与之共同相连的C原子一起形成具有选自以下结构的环：
    其中，RS和RS'与与之共同相连的N原子一起形成具有选自以下结构的环：
    其中，Y1、Y2、Y3各自独立地表示-(CRaRb)o-(NRa)p-(CRa'Rb')q-；
    其中，A、B各自独立地表示-(CRaRb)m-；
    其中，L1表示表示-C(O)NH-、-HNC(O)-、5-6元杂芳基、
    其中，L2表示不存在、-C1-C6亚烷基-、-NRa-、-NRa(C1-C6亚烷基)-、-C(O)NRa(C1-C6亚烷基)-、-O-、-O-(C1-C6亚烷基)、-S-、-S(O)-、-S(O)2-、-S(O)2NRa-或者-S(O)(NRa)-；
    其中，R1表示L3-R3；
    其中，L3表示不存在、C1-C6亚烷基、-NRa-、-NRaSO2-、-SO2NRa-、-S(＝O)(NRa)-、-P(O)(ORa)2、-NRaP(O)(ORa)2或-NRaP(O)(Ra)2；
    其中，R3表示不存在、氢或者被0-3个选自卤素、-ORa、-NRaRb、氰基和-O-卤代C1-C6烷基之基团取代的C1-C6烷基或C3-C6环烷基；
    其中，RW1和RW2各自独立地表示氢、卤素、氰基、硝基、羟基C1-C6烷基、C1-C6烷基、C3-C8环烷基、卤代C1-C6烷基、-ORa、-SO3Ra、-S(O)Ra、-O-卤代C1-C6烷基、-SRa、-SF5或-NRaRb；
    其中，Cy1表示6-12元芳基或者5-12元杂芳基；并且所述的Cy1还可以任意地被0-3个选自以下取代基的基团所取代：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、ORa、-O-卤代C1-C6烷基、5-6元杂芳基、苯基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)Ra、-P(O)RaRb、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb；
    其中，Cy2表示3-12元饱和或不饱和的单环或者双环，该环中可以任意地含 有0-3个选自O、N和S的杂原子，并且所述的Cy2还可以任意地被0-3个选自以下取代基的基团所取代：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、-ORa、-O-卤代C1-C6烷基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb；
    其中，环A表示饱和或者不饱和的4-12元环，优选为5-12元环；并且该环中可以任意地含有0-3个选自O、N和S的杂原子，并且所述的环A还可以任意地被0-3个选自以下取代基的基团所取代：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、-ORa、-O-卤代C1-C6烷基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb；
    其中，Ra、Rb、Ra'、Rb'各自独立地表示氢、卤素、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基或羟基C1-C6烷基；或者Ra、Rb一起与与之相连的原子形成3-6元饱和或不饱和环，该环中可以任意地含有0-2个选自O、S和N的杂原子；或者Ra'、Rb'一起与与之相连的原子形成3-6元饱和或不饱和环，该环中可以任意地含有0-2个选自O、S和N的杂原子；
    其中，m、o、p、q表示0-3的整数。
  3. 根据权利要求1所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，W1表示CH或N。
  4. 根据权利要求1-3任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，W2表示CH或N。
  5. 根据权利要求1-4任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，L3表示-NRaSO2-、-SO2NRa-或-S(＝O)(NRa)-。
  6. 根据权利要求1-5任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，L3表示-NRaSO2-。
  7. 根据权利要求1-6任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，R3表示氢或者被0-3个选自卤素、-ORa、-NRaRb、氰基和-O-卤代C1-C6烷基之基团取代的C1-C6烷基或C3-C6环烷基。
  8. 根据权利要求1-7任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，R3表示被0-3个选自卤素、-ORa、-NRaRb、氰基和-O-卤代C1-C6烷基之基团取代的C1-C6烷基。
  9. 根据权利要求1-8任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，Z表示-NRSRS'。
  10. 根据权利要求1-9任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，Z表示：
    其中，Ra、Rb各自独立地表示氢、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基或羟基C1-C6烷基；或者Ra、Rb一起与与之相连的原子形成3-6元饱和或不饱和环，该环中可以任意地含有0-2个选自O、S和N的杂原子。
  11. 根据权利要求1-10任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，Z表示：其中，Ra、Rb各自独立地表示氢、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基或羟基C1-C6烷基；或者Ra、Rb一起与与之相连的原子形成3-6元饱和或不饱和环，该环中可以任意地含有0-2个选自O、S和N的杂原子。
  12. 根据权利要求1-11任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，Z表示：
  13. 根据权利要求1-12任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，L1表示-C(O)NH-、-HNC(O)-、5-6元杂芳基、
  14. 根据权利要求1-13任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，L1表示-C(O)NH-。
  15. 根据权利要求1-14任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，L1表示：-C(O)NH-、-HNC(O)-、5-6元杂芳基、
  16. 根据权利要求15所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，L1表示以下任意基团之一：
  17. 根据权利要求1-16任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，Cy1表示被0-3个选自以下取代基：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、ORa、-O-卤代C1-C6烷基、5-6元杂芳基、苯基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)Ra、-P(O)RaRb、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb取代的以下任意基团之一：





    例如：




  18. 根据权利要求17所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，Cy1表示被0-3个选自以下取代基：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、ORa、-O-卤代C1-C6烷基、5-6元杂芳基、苯基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、 -C(O)NRaRb、-OC(O)Ra、-C(O)Ra、-P(O)RaRb、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb取代的以下任意基团之一：
  19. 根据权利要求18所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，Cy1表示被0-3个选自以下取代基：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、ORa、-O-卤代C1-C6烷基、5-6元杂芳基、苯基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)Ra、-P(O)RaRb、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb取代的
  20. 根据权利要求18所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，Cy1表示被苯基、吡啶基、噻唑基、噁唑基、吡唑基、咪唑基、N-甲基吡唑基取代的
  21. 根据权利要求19所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，Cy1表示以下基团：

  22. 根据权利要求18所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，Cy1表示被0-3个选自以下取代基：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、ORa、-O-卤代C1-C6烷基、5-6元杂芳基、苯基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)Ra、-P(O)RaRb、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb取代的
  23. 根据权利要求1-20任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，L2表示不存在、-C1-C6亚烷基-或-NH-。
  24. 根据权利要求1-21任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，L2表示不存在。
  25. 根据权利要求1-22任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，Cy2表示被0-3个选自以下取代基：卤素、氰基、硝基、羟基C1-C6烷基、C1-C6烷基、C3-C8环烷基、卤代C1-C6烷基、-ORa、-SO3Ra、-S(O)Ra、-O卤代C1-C6烷基、-SRa、-SF5或NRaRb取代的吗啉基、哌啶基、氮杂环丁烷基、吡咯烷基、环丙基、环丁基、环戊基、环己基、哌嗪基或四氢呋喃基，其中，Ra、Rb各自独立地表示氢、卤素、C1-C6烷基、C3-C8环烷基、卤代C1-C6烷基或羟基C1-C6烷基；或者R1a、R1b一起与与之相连的原子形成3-6元环，该环中含有0-2个选自O、N和S的杂原子。
  26. 根据权利要求1-23任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，Cy2表示
  27. 根据权利要求1-24任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，环A表示苯环或者
    其中，W1表示CH或N，
    其中，虚线表示单键或者双键；
    并且环A还可以任意地被0-3个选自以下取代基的基团所取代：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、-ORa、-O-卤代C1-C6烷基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb。
  28. 根据权利要求1-25任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，环A表示
    其中，W1表示CH或N；
    并且环A还可以任意地被0-3个选自以下取代基的基团所取代：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、-ORa、-O-卤代C1-C6烷基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb。
  29. 根据权利要求1-25任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，环A表示：苯环、吡啶环、吡嗪环、环丁烷环、环戊烷环、四氢呋喃环、噁唑环、噻唑环、噻吩环、吡唑环、咪唑环、哌啶环、六氢吡喃环、环己烷环；
    并且环A还可以任意地被0-3个选自以下取代基的基团所取代：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、-ORa、-O-卤代C1-C6烷基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb。
  30. 根据权利要求1-25任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，环A与其相稠合的环一起形成如下结构：

    并且环A还可以任意地被0-3个选自以下取代基的基团所取代：卤素、C1-C6烷基、卤代C1-C6烷基、羟基C1-C6烷基、-ORa、-O-卤代C1-C6烷基、-SRa、-SF5、氰基、硝基、-NRaRb、-NRaC(O)Rb、-C(O)NRaRb、-OC(O)Ra、-C(O)ORa、-S(O)Ra、-S(O)2Ra和-S(O)2NRaRb。
  31. 根据权利要求1-25任意一项所述的化合物或其药学上可接受的盐、立体异构体、同位素异构体、前药、水合物或溶剂合物，其中，环A与其相稠合的环一起形成如下结构：

  32. 化合物，具有以下结构：



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