WO2022161461A1 - Sos1抑制剂及其制备方法和应用 - Google Patents

Sos1抑制剂及其制备方法和应用 Download PDF

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WO2022161461A1
WO2022161461A1 PCT/CN2022/074591 CN2022074591W WO2022161461A1 WO 2022161461 A1 WO2022161461 A1 WO 2022161461A1 CN 2022074591 W CN2022074591 W CN 2022074591W WO 2022161461 A1 WO2022161461 A1 WO 2022161461A1
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alkyl
cycloalkyl
amino
pharmaceutically acceptable
acceptable salt
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PCT/CN2022/074591
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English (en)
French (fr)
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张雁
杨圣伟
庞司林
赵春艳
王峰
唐锋
彭少平
任晋生
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江苏先声药业有限公司
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Priority to CN202280011875.4A priority Critical patent/CN117279914A/zh
Publication of WO2022161461A1 publication Critical patent/WO2022161461A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the technical field of medicine, and relates to SOS1 inhibitor compounds or optical isomers, pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them and their use as SOS1 inhibitors.
  • RAS family proteins include KRAS (V-Ki-ras2 Kirsten rat sarcoma virus oncogene homolog), NRAS (neuroblastoma RAS virus oncogene homolog) and HRAS (Harvey murine sarcoma virus oncogene), etc.
  • Small GTPases present in cells in either a GTP-bound state or a GDP-bound state (McCormick et al, J. Mol. Med. (Berl)., 2016, 94(3): 253-8; Nimnual et al, Sci. STKE ., 2002, 2002(145):pe36).
  • RAS family proteins play an important role in human cancer. Tumors caused by mutations in RAS proteins account for 20-30% of all tumors in humans and are thought to be tumorigenic drivers, especially in lung, colorectal, and pancreatic cancer (Malumbres & Barbacid 2002 Nature Reviews Cancer, Pylayeva-Gupta et al., 2011 Nature Reviews Cancer).
  • SOS1 (son of sevenless homolog 1) protein is a regulatory protein widely expressed in cells. As a kind of guanine nucleotide exchange factor of RAS and RAC proteins, it plays a role in the signal transduction pathway of RAS and RAC in cells. important regulatory role. SOS1 has two binding sites for RAS family proteins: a catalytic site, which binds GDP-bound RAS family proteins to facilitate guanine nucleotide exchange; and an allosteric site, which binds GTP-bound RAS family protein, which leads to a further increase in the catalytic GEF function of SOS1 (Freedman et al., Proc. Natl. Acad. Sci.
  • SOS1 small molecule inhibitors have also been reported in the existing literature (such as patent documents WO2018/115380A1 and WO2018/172250A1), there are still a large number of patients who cannot obtain satisfactory clinical therapeutic effects, so there is still a need to develop them with good activity. And SOS1 inhibitor with good selectivity and low toxicity.
  • the present invention provides compounds represented by formula (I) and pharmaceutically acceptable salts thereof. These compounds can inhibit the activity of SOS1, thereby affecting biological function.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • X is selected from CH or N;
  • Y is selected from CH or N;
  • Z is selected from CH or N
  • R 1 is selected from H, CN, C 1-6 alkyl or C 3-6 cycloalkyl;
  • Ring A is selected from C 6-10 aryl, benzo 5-7 membered heterocyclyl or benzo 5-7 membered heteroaryl;
  • L is selected from chemical bonds or O;
  • R 2 is selected from C 3-10 cycloalkyl, C 6-10 aryl, 3-10-membered heterocyclyl or 5-10 -membered heteroaryl, the C 3-10 cycloalkyl, C 6-10 aryl group, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R 2b and/or R 2c ;
  • R 2b is selected from -OR 2c , -N(R 2c ) 2 , halogen, hydroxy, cyano, amino, -C(O)R 2c , -C(O)NHR 2c , -C(O)NH 2 , - NHR 2c , -C(O)H, -C(O)OH, -S(O) 2 NHR 2c , -NHC(O)H, -N(C 1-4 alkyl)C(O)H, - C(O)N(R 2c ) 2 , -C(O)OR 2c , -S(O) 2 R 2c , -S(O) 2 N(R 2c ) 2 , -NHC(O)R 2c or - N(C 1-4 alkyl)C(O)R 2c ;
  • R 2c is independently selected from C 1-6 alkyl, C 1-3 deuterated alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heterocyclyl Aryl, the C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10-membered heterocyclyl, 5-10-membered heteroaryl are optionally substituted by R 2d ;
  • R 2d is selected from halogen, hydroxyl, cyano, amino, -C(O)R 2f , -C(O)N(R 2f ) 2 , -C(O)OR 2f , -S(O) 2 R 2f , -S(O) 2 N(R 2f ) 2 , -N(C 1-4 alkyl)R 2f , -NHC(O)R 2f or -N(C 1-4 alkyl)C(O)R 2f ;
  • R 2f is independently selected from H or C 1-6 alkyl
  • R 3 is selected from H, halogen, hydroxyl, cyano, amino, -NH-C 3-6 cycloalkyl, C 1-3 deuterated alkyl, -OC 1-3 deuterated alkyl, C 1-6 alkane base, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -O-(3-8 membered heterocyclyl), 5- 10-membered heteroaryl, -C(O)R 3a , -C(O)N(R 3a ) 2 , -C(O)OR 3a , -S(O) 2 R 3a , -S(O) 2 N (R 3a ) 2 , -NHC(O)R 3a or -N(C 1-4 alkyl)C(O)R 3a , the -NH-C 3-6 cycloalkyl, C 1-6 alkyl , C 3-6
  • the R 3a is independently selected from H or C 1-6 alkyl
  • the R 3b is independently selected from halogen, hydroxyl, cyano, amino, 3-8 membered heterocyclyl or C 1-6 alkyl;
  • R 4 is selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -O-(3 -8-membered heterocyclyl), 3-8 membered heterocyclyl, 5-10 membered heteroaryl or -S(O) 2 -C 1-4 alkyl, said C 1-6 alkyl, C 3- 6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -O-(3-8 membered heterocyclyl), 3-8 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R4a ; said R4a is selected from halogen, hydroxy, cyano or amino;
  • R 5 is selected from C 1-3 deuterated alkyl, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 6 is selected from H, deuterium, C 1-3 deuterated alkyl, C 1-6 alkyl or C 1-6 haloalkyl;
  • n is selected from 0, 1, 2, 3 or 4;
  • R 1 is selected from CN, C 1-6 alkyl or C 3-6 cycloalkyl
  • R 3 is selected from hydroxyl, cyano, amino, C 1-3 deuterated alkyl, -OC 1-3 deuterated alkyl, C 1-6 alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -O-(3-8 membered heterocyclyl), 5-10 membered heteroaryl, -C(O)R 3a , -C(O)N(R 3a ) 2 , -C(O)OR 3a , -S(O) 2 R 3a , -S(O) 2 N(R 3a ) 2 , -NHC(O)R 3a or -N(C 1-4 alkyl)C(O)R 3a , the C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, -OC 1-6 alkyl, -
  • X, Z are independently selected from N, Y is selected from CH, and R 1 is selected from CN, C 1-6 alkyl or C 3-6 cycloalkyl, R 2 is selected from optionally The following groups substituted by R 2b and/or R 2c :
  • X, Z are independently selected from N, Y is selected from CH, and R 1 is selected from CN, C 1-6 alkyl or C 3-6 cycloalkyl, R 2 is selected from optionally The following groups substituted by R 2b and/or R 2c :
  • X, Z are independently selected from N, Y is selected from CH, and R 1 is selected from CN, C 1-6 alkyl or C 3-6 cycloalkyl, and R 2 is selected from the following groups:
  • X, Z are independently selected from N, Y is selected from CH, and R 1 is selected from CN, C 1-6 alkyl or C 3-6 cycloalkyl, R 2 is selected from optionally The following groups substituted by R 2b and/or R 2c : , R 3 is selected from -O-CH 2 CHF 2 or -NH-C 3-6 cycloalkyl.
  • X, Z are independently selected from N, Y is selected from CH, and R 1 is selected from CN, C 1-6 alkyl or C 3-6 cycloalkyl, R 2 is selected from optionally The following groups substituted by R 2b and/or R 2c : , R 3 is selected from -O-CH 2 CHF 2 .
  • X, Z are independently selected from N, Y is selected from CH, and R 1 is selected from CN, C 1-6 alkyl or C 3-6 cycloalkyl, R 2 is selected from optionally The following groups substituted by R 2b and/or R 2c : , R 3 is selected from -O-CH 3 .
  • X, Y, Z are independently selected from CH, and R is selected from hydroxy, cyano, amino, C 1-3 deuterated alkyl, -OC 1-3 deuterated alkyl, C 1 -6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -O-(3-8 membered heterocyclyl) , 5-10-membered heteroaryl, -C(O)R 3a , -C(O)N(R 3a ) 2 , -C(O)OR 3a , -S(O) 2 R 3a , -S(O ) 2 N(R 3a ) 2 , -NHC(O)R 3a or -N(C 1-4 alkyl)C(O)R 3a , the C 1-6 alkyl, C 3-6 cycloalkyl , 3-8 membered heterocycl
  • X, Y, Z are independently selected from CH, and R 3 is selected from -C(O)R 3a , -C(O)OR 3a , C 1-6 alkyl, -OC 1-6 Alkyl or 5-10 membered heteroaryl, said C 1-6 alkyl, -OC 1-6 alkyl or 5-10 membered heteroaryl optionally substituted with R 3b .
  • Ring A is selected from phenyl, indanyl, indenyl, tetralinyl, dihydronaphthyl, or naphthyl.
  • Ring A is selected from phenyl.
  • R1 is selected from H, CN, methyl, or cyclopropyl.
  • R 1 is selected from C 1-6 alkyl.
  • R1 is selected from CH3 .
  • R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, the C 3-10 cycloalkyl, 3-10 membered heterocycle or 5-10 membered heteroaryl optionally substituted with R 2b and/or R 2c .
  • R 2 is selected from 3-10 membered heterocyclyl or 5-10 membered heteroaryl, which is optionally surrounded by R 2b and / or R 2c substituted.
  • R 2 is selected from 4-8 membered heterocyclyl or 5-6 membered heteroaryl, said 4-8 membered heterocyclyl or 5-6 membered heteroaryl optionally being replaced by R 2b and / or R 2c substituted.
  • R 2 is selected from the following groups optionally substituted with R 2b and/or R 2c :
  • R 2 is selected from the following groups optionally substituted with R 2b and/or R 2c :
  • R 2 is selected from the following groups optionally substituted with R 2b and/or R 2c :
  • R 2 is selected from the following groups optionally substituted with R 2b and/or R 2c : , R 3 is selected from -O-CH 2 CHF 2 or -NH-C 3-6 cycloalkyl.
  • R 2 is selected from the following groups optionally substituted with R 2b and/or R 2c : , R 3 is selected from -O-CH 2 CHF 2 .
  • R 2 is selected from the following groups optionally substituted with R 2b and/or R 2c : , R 3 is selected from -O-CH 3 .
  • R 2b is selected from -OR 2c , -N(R 2c ) 2 , halogen, hydroxy, cyano, amino, -C(O)R 2c , -C(O)NHR 2c , -C( O)N(R 2c ) 2 , -C(O)OR 2c , -S(O) 2 R 2c , -S(O) 2 N(R 2c ) 2 , -NHC(O)R 2c or -N( C 1-4 alkyl)C(O)R 2c .
  • R 2b is selected from -OR 2c , -N(R 2c ) 2 , halogen, hydroxy, cyano, amino, -C(O)R 2c , -C(O)N(R 2c ) 2 , -C(O)OR 2c , -S(O) 2 R 2c , -S(O) 2 N(R 2c ) 2 , -NHC(O)R 2c or -N(C 1-4 alkyl)C (O)R 2c .
  • R 2b is selected from -OR 2c , halogen, hydroxy, cyano, amino, -C(O)R 2c , -C(O)OR 2c , -S(O) 2 R 2c , -C (O)NHR 2c or -NHC(O)R 2c .
  • R 2b is selected from -OR 2c , halogen, hydroxy, cyano, amino, -C(O)R 2c , -C(O)OR 2c , -S(O) 2 R 2c or -C (O)NHR 2c .
  • R 2b is selected from -OR 2c , halogen, hydroxy, cyano, -C(O)R 2c , -C(O)OR 2c , -S(O) 2 R 2c or -C(O ) NHR 2c .
  • R 2b is selected from -OR 2c , halo, hydroxy, cyano, -C(O)R 2c , -C(O)OR 2c or -S(O) 2 R 2c .
  • R 2b is selected from halogen, hydroxy, cyano, amino, -C(O)R 2c , -S(O) 2 R 2c or -C(O)NHR 2c .
  • R 2b is selected from halogen, hydroxy, cyano, -C(O)R 2c , -S(O) 2 R 2c or -C(O)NHR 2c .
  • R 2b is selected from halogen, hydroxy, cyano, -C(O)R 2c or -S(O) 2 R 2c .
  • R 2c is independently selected from C 1-6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl,
  • the C 1-6 alkyl group, C 3-10 cycloalkyl group, C 6-10 aryl group, 3-10 membered heterocyclic group, 5-10 membered heteroaryl group are optionally substituted by R 2d .
  • R 2c is selected from C 1-6 alkyl, C 1-3 deuterated alkyl, C 3-10 cycloalkyl, or 3-10 membered heterocyclyl, said C 1-6 alkyl , C 3-10 cycloalkyl or 3-10 membered heterocyclyl optionally substituted with R 2d .
  • R 2c is selected from C 1-6 alkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, said C 1-6 alkyl, C 3-10 cycloalkyl or The 3-10 membered heterocyclyl is optionally substituted with R 2d .
  • R 2c is selected from C 1-4 alkyl, C 3-6 cycloalkyl, or 4-6 membered heterocyclyl, said C 1-4 alkyl, C 3-6 cycloalkyl or The 4-6 membered heterocyclyl is optionally substituted with R 2d .
  • R 2d is selected from halo, hydroxy, cyano, or amino.
  • R 4 is selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 3-6 cycloalkyl or 3-8 membered heterocyclyl, the C 1-6 alkyl , C 3-6 cycloalkyl or 3-8 membered heterocyclyl optionally substituted with R 4a .
  • R 4 is selected from halo, hydroxy, cyano, amino, or C 1-4 alkyl optionally substituted with R 4a .
  • R 4 is selected from halo, amino, or C 1-4 alkyl optionally substituted with R 4a .
  • R 3 is selected from H, halogen, hydroxy, cyano, amino, C 1-3 deuterated alkyl, -OC 1-3 deuterated alkyl, C 1-6 alkyl, C 3- 6 -cycloalkyl, 3-8-membered heterocyclyl, -OC 1-6 alkyl, -OC 3-6 -cycloalkyl, -O-(3-8-membered heterocyclyl), 5-10-membered heteroaryl , -C(O)R 3a , -C(O)N(R 3a ) 2 , -C(O)OR 3a , -S(O) 2 R 3a , -S(O) 2 N(R 3a ) 2 , -NHC(O)R 3a or -N(C 1-4 alkyl)C(O)R 3a , the C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl , -OC
  • R 3 is selected from H, halogen, hydroxy, cyano, amino, -NH-C 3-6 cycloalkyl, C 1-3 deuterated alkyl, -OC 1-3 deuterated alkyl , C 1-6 alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -C(O)R 3a , -C(O)OR 3a , - S(O) 2 -C 1-4 alkyl or 5-10 membered heteroaryl, the -NH-C 3-6 cycloalkyl, C 1-6 alkyl, C 3-6 cycloalkyl, - OC 1-6 alkyl, -OC 3-6 cycloalkyl or 5-10 membered heteroaryl is optionally substituted with R 3b .
  • R 3 is selected from H, halogen, hydroxy, cyano, amino, C 1-3 deuterated alkyl, -OC 1-3 deuterated alkyl, C 1-6 alkyl, C 3- 6 -cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -S(O) 2 -C 1-4 alkyl or 5-10-membered heteroaryl, the C 1-6 Alkyl, C 3-6 cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl or 5-10 membered heteroaryl are optionally substituted with R 3b .
  • R 3 is selected from H, halogen, hydroxy, cyano, amino, C 1-3 deuterated alkyl, -OC 1-3 deuterated alkyl, C 1-6 alkyl, C 3- 6 -cycloalkyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl or -S(O) 2 -C 1-4 alkyl, the C 1-6 alkyl, C 3-6 ring Alkyl, -OC 1-6 alkyl or -OC 3-6 cycloalkyl is optionally substituted with R 3b .
  • R 3 is selected from H, halogen, hydroxy, cyano, amino, -NH-C 3-6 cycloalkyl, C 1-3 deuterated alkyl, -OC 1-3 deuterated alkyl , C 1-6 alkyl, -OC 1-6 alkyl, -C(O)R 3a , -C(O)OR 3a , -S(O) 2 -C 1-4 alkyl or 5-10 yuan Heteroaryl, the -NH-C 3-6 cycloalkyl, C 1-6 alkyl, -OC 1-6 alkyl or 5-10 membered heteroaryl is optionally substituted with R 3b .
  • R 3 is selected from H, halogen, hydroxy, cyano, amino, C 1-3 deuterated alkyl, -OC 1-3 deuterated alkyl, C 1-6 alkyl, -OC 1 -6 alkyl, -S(O) 2 -C 1-4 alkyl or 5-10 membered heteroaryl, the C 1-6 alkyl, -OC 1-6 alkyl or 5-10 membered heteroaryl group is optionally substituted with R 3b .
  • R 3 is selected from H, halogen, hydroxy, cyano, amino, C 1-3 deuterated alkyl, -OC 1-3 deuterated alkyl, C 1-6 alkyl, -OC 1 -6 alkyl or -S(O) 2 -C 1-4 alkyl optionally substituted with R 3b .
  • R 3 is selected from H, C 1-3 deuterated alkyl, -OC 1-3 deuterated alkyl, C 1-6 alkyl, -OC 1-6 alkyl, -S(O ) 2 -C 1-4 alkyl or 5-10 membered heteroaryl, said C 1-6 alkyl, -OC 1-6 alkyl or 5-10 membered heteroaryl optionally substituted by R 3b .
  • R is selected from H, C 1-3 deuterated alkyl, -OC 1-3 deuterated alkyl, C 1-6 alkyl, -OC 1-6 alkyl, or -S(O ) 2 -C 1-4 alkyl, the C 1-6 alkyl or -OC 1-6 alkyl is optionally substituted with R 3b .
  • R 3 is selected from H, C 1-3 deuterated alkyl, -OC 1-3 deuterated alkyl, C 1-6 alkyl or -OC 1-6 alkyl, the C 1 -6 alkyl or -OC 1-6 alkyl is optionally substituted with R 3b .
  • R 3 is selected from H, amino, -NH-C 3-6 cycloalkyl, -C(O)R 3a , -C(O)OR 3a , C 1-6 alkyl, -OC 1-6 alkyl or 5-10 membered heteroaryl, the -NH-C 3-6 cycloalkyl, C 1-6 alkyl, -OC 1-6 alkyl or 5-10 membered heteroaryl is any optionally substituted with R 3b .
  • R 3 is selected from H, amino, -NH-cyclobutyl, -C(O)R 3a , -C(O)OR 3a , C 1-3 alkyl, -OC 1-3 alkane or pyrazolyl, the -NH-cyclobutyl, C 1-3 alkyl, -OC 1-3 alkyl or pyrazolyl is optionally substituted with R 3b .
  • R3 is selected from H, amino, -O- CH3 , CF3 , -O - CH2CHF2 , -O- CF2H , -C(O) CH3 , C(O) OH,
  • R 3 is selected from H, C 1-6 alkyl, -OC 1-6 alkyl or 5-10 membered heteroaryl, the C 1-6 alkyl, -OC 1-6 alkane or 5-10 membered heteroaryl optionally substituted with R 3b .
  • R 3 is selected from H, C 1-6 alkyl or -OC 1-6 alkyl optionally substituted with R 3b .
  • R 3 is selected from -C(O)R 3a , -C(O)OR 3a , C 1-6 alkyl, -OC 1-6 alkyl or 5-10 membered heteroaryl, wherein Said C 1-6 alkyl, -OC 1-6 alkyl or 5-10 membered heteroaryl is optionally substituted with R 3b .
  • R3 is selected from -O- CH3 , -O - CH2CHF2 , -O- CF2H , -C(O) CH3 , C(O)OH or In some embodiments, R 3a is selected from H or CH 3 .
  • R 3b is independently selected from halo, hydroxy, cyano, amino, or 3-8 membered heterocyclyl.
  • R 3b is independently selected from halogen or C 1-6 alkyl.
  • R 3b is independently selected from F or CH 3 .
  • R 3b is independently selected from halogen or C 1-6 alkyl.
  • R 3b is independently selected from halogen.
  • R 2 is selected from the following groups:
  • R 5 is selected from C 1-3 deuterated alkyl, C 1-3 alkyl, or C 1-3 haloalkyl.
  • R5 is selected from CH3 , CD3 , CF3 , CHF2 , or CH2F .
  • R 6 is selected from H, deuterium, C 1-3 deuterated alkyl, C 1-3 alkyl, or C 1-3 haloalkyl.
  • R 6 is selected from H, deuterium, CH 3 or CD 3 .
  • n is selected from 0, 1 or 2.
  • n is 2.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • R 3 is selected from hydroxyl, cyano, amino, C 1-3 deuterated alkyl, -OC 1 -3 Deuterated alkyl, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, -OC 1-6 alkyl, -OC 3-6 cycloalkyl, -O- (3-8 membered heterocyclyl), 5-10 membered heteroaryl, -C(O)R 3a , -C(O)N(R 3a ) 2 , -C(O)OR 3a , -S(O ) 2 R 3a , -S(O) 2 N(R 3a ) 2 , -NHC(O)R 3a or -N(C 1-4 alkyl)C(O)R 3a , the C 1-6 alkane base, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, -OC 1-6 alkyl, -OC 3-6 cyclo
  • R 3 is selected from hydroxy, cyano, amino, C 1-3 deuterated alkyl, -OC 1-3 deuterated alkyl, C 1-6 alkyl, -OC 1-6 alkyl , -C(O)R 3a , -C(O)OR 3a , -S(O) 2 -C 1-4 alkyl or 5-10 membered heteroaryl, the C 1-6 alkyl, -OC 1-6 alkyl or 5-10 membered heteroaryl optionally substituted with R 3b .
  • R 3 is selected from hydroxy, cyano, amino, C 1-3 deuterated alkyl, -OC 1-3 deuterated alkyl, C 1-6 alkyl, -OC 1-6 alkyl , -S(O) 2 -C 1-4 alkyl or 5-10 membered heteroaryl, the C 1-6 alkyl, -OC 1-6 alkyl or 5-10 membered heteroaryl optionally Substituted by R 3b .
  • R 3 is selected from hydroxy, cyano, amino, C 1-3 deuterated alkyl, -OC 1-3 deuterated alkyl, C 1-6 alkyl, -OC 1-6 alkyl or -S(O) 2 -C 1-4 alkyl, said C 1-6 alkyl or -OC 1-6 alkyl optionally substituted with R 3b .
  • R 3 is selected from C 1-3 deuterated alkyl, -OC 1-3 deuterated alkyl, C 1-6 alkyl, -OC 1-6 alkyl, -C(O)R 3a , -C(O)OR 3a , -S(O) 2 -C 1-4 alkyl or 5-10-membered heteroaryl, the C 1-6 alkyl, -OC 1-6 alkyl or 5 -10 membered heteroaryl optionally substituted with R 3b .
  • R 3 is selected from C 1-3 deuterated alkyl, -OC 1-3 deuterated alkyl, C 1-6 alkyl, -OC 1-6 alkyl, -S(O) 2 -C 1-4 alkyl or 5-10 membered heteroaryl optionally substituted with R 3b .
  • R 3 is selected from C 1-3 deuterated alkyl, -OC 1-3 deuterated alkyl, C 1-6 alkyl, -OC 1-6 alkyl, or -S(O) 2 -C 1-4 alkyl, said C 1-6 alkyl or -OC 1-6 alkyl is optionally substituted with R 3b .
  • R 3 is selected from H, -C(O)R 3a , -C(O)OR 3a , C 1-6 alkyl, -OC 1-6 alkyl, or 5-10 membered heteroaryl , the C 1-6 alkyl, -OC 1-6 alkyl or 5-10-membered heteroaryl is optionally substituted by R 3b .
  • R 3 is selected from -C(O)R 3a , -C(O)OR 3a , C 1-6 alkyl, -OC 1-6 alkyl or 5-10 membered heteroaryl, wherein Said C 1-6 alkyl, -OC 1-6 alkyl or 5-10 membered heteroaryl is optionally substituted with R 3b .
  • R 3 is selected from H, C 1-6 alkyl, -OC 1-6 alkyl or 5-10 membered heteroaryl, the C 1-6 alkyl, -OC 1-6 alkane or 5-10 membered heteroaryl optionally substituted with R 3b .
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from cyano, C 1-6 alkyl or C 3-6 cycloalkyl
  • R 2 is selected from From the following groups optionally substituted by R 2b and/or R 2c :
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from cyano, C 1-6 alkyl or C 3-6 cycloalkyl
  • R 2 is selected from From the following groups optionally substituted with R 2b and/or R 2c :
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (V) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from cyano, C 1-6 alkyl or C 3-6 cycloalkyl
  • R 2 is selected from From the following groups optionally substituted by R 2b and/or R 2c :
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof,
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
  • the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating diseases related to SOS1.
  • the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of diseases related to SOS1.
  • the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating SOS1-related diseases.
  • the present invention also relates to a method for preventing or treating SOS1-related diseases, the method comprising administering to a patient a therapeutically effective dose of a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present invention. Further, the SOS1-related disease is selected from cancer.
  • the present invention provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating cancer.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of cancer.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating cancer.
  • the present invention provides a method of preventing or treating cancer comprising therapeutically administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • pharmaceutically acceptable salts refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • stereoisomer refers to isomers resulting from different arrangements of atoms in a molecule in space, and includes cis-trans isomers, enantiomers, diastereomers and conformers.
  • tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist as two or more interconvertible species.
  • Proton tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms.
  • Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually result in a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the ketone form predominates; in phenols, the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • composition means a mixture of one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, so long as the valence of the specified atom is normal and the compound after substitution is stable.
  • an ethyl group “optionally” substituted with halogen means that the ethyl group can be unsubstituted ( CH2CH3 ) , monosubstituted (eg CH2CH2F ) , polysubstituted (eg CHFCH2F , CH 2 CHF 2 etc.) or fully substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is sterically impossible and/or cannot be synthesized.
  • C 1-6 alkyl is understood to mean a linear or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl , 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,
  • halogen refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
  • C 3-10 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms.
  • Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic hydrocarbon groups such as decalin ring.
  • the bicyclic hydrocarbon ring includes a bridged ring, a spirocyclic ring or a paracyclic ring structure.
  • C3-8cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 8 atoms.
  • C 3-6 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 atoms.
  • C 6-10 aryl is to be understood as a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10 carbon atoms, in particular having 6 A ring of carbon atoms (“C 6 aryl”), such as phenyl; or a ring of 9 carbon atoms (“C 9 aryl”), such as indanyl or indenyl, or a ring of 10 carbon atoms (“C 10 aryl”), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl.
  • heterocyclyl is to be understood as a saturated or partially unsaturated monovalent monocyclic or bicyclic ring having 3 to 10 ring atoms.
  • the bicyclic rings include bridged rings, spiro rings, and fused rings.
  • the heterocyclyl group may be monocyclic, including but not limited to: 4-membered ring, such as azetidinyl, oxetanyl; 5-membered ring, such as tetrahydrofuranyl, dioxane Pentenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholine base, 1,1-dioxothiomorpholinyl, piperazinyl, trithianyl, or a 7-membered ring such as diazepanyl or
  • the heterocyclyl group may be bicyclic, such as, but not limited to, a 5,5 membered ring, such as a hexahydrocyclopento[c]pyrrol-2(1H)-y
  • the ring may be partially unsaturated, i.e. it may contain one or more double bonds such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazine group, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl or Alternatively, it can be benzo-fused, such as, but not limited to, dihydroisoquinolinyl.
  • 3-8 membered heterocyclyl is to be understood as a saturated or partially unsaturated monovalent monocyclic or bicyclic ring having 3 to 8 ring atoms.
  • the term "3-6 membered heterocyclyl” is to be understood as a saturated or partially unsaturated monovalent monocyclic or bicyclic ring having 3-6 ring atoms.
  • benzo 5-7 membered heterocyclic group may include, but is not limited to, benzotetrahydrofuranyl, benzotetrahydropyrrolyl, benzotetrahydropyridyl, and the like.
  • heteroaryl is to be understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems, in particular 5 or 6 or 9 or 10 ring atoms, and in each case additionally Can be benzo-fused.
  • heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl Diazolyl and the like and their benzo derivatives such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinoline oxazolinyl, isoquinolinyl, etc; Naph
  • benzo 5-7 membered heteroaryl should be understood to include a bicyclic ring formed by an unsaturated heterocyclic ring of 5-7 ring atoms, said bicyclic ring being a fused ring, said benzo 5-7 membered heteroaryl group
  • benzo 5-7 membered heteroaryl groups may include, but are not limited to: benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, quinolinyl, Quinazolinyl, isoquinolinyl, etc.
  • treating means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • terapéuticaally effective amount means (i) treating a particular disease, condition or disease, (ii) reducing, ameliorating or eliminating one or more symptoms of a particular disease, condition or disease, or (iii) delaying the described herein
  • the amount of a compound of the present invention for the onset of one or more symptoms of a particular disease, condition, or disease will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art according to its own knowledge and the present disclosure.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • classes of the term “excipient” include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flowability and/or stickiness.
  • typical "pharmaceutically acceptable carriers” suitable for the above-mentioned preparations are: carbohydrates, starches, cellulose and their derivatives and other commonly used adjuvants in pharmaceutical preparations.
  • pharmaceutically acceptable excipients refers to those excipients which are not significantly irritating to the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • the words “comprise”, “comprise” or “comprise” and their English variants such as comprises or comprising are to be understood in an open, non-exclusive sense, ie, "including but not limited to”.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolving method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by admixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, gels, slurries, suspensions, etc., for oral administration to patients.
  • Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets or icing core.
  • Suitable adjuvants include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
  • the doses administered per day range from 0.01 mg/kg body weight to 200 mg/kg body weight.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the units of NMR shifts are 10 ⁇ 6 (ppm).
  • the solvents for NMR determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); “IC 50 ” refers to the half inhibitory concentration, which refers to the half of the maximum inhibitory effect. concentration.
  • Et 3 N and TEA triethylamine; ACN: acetonitrile; DIPEA and DIEA: N,N-diisopropylethylamine; dioxane: 1,4-dioxane; DMF: N,N-dimethylmethane amide; AcOH: acetic acid; Ac 2 O: acetic anhydride; Cs 2 CO 3 : cesium carbonate; THF: tetrahydrofuran; DMSO: dimethyl sulfoxide; DCM: dichloromethane; DMAP: 4-dimethylaminopyridine; TFA: Trifluoroacetic acid; Pd(dppf)Cl 2 : 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride; Pd 2 (dba) 3 : tris(benzylideneacetone)dipalladium; X- Phos: 2-dicyclohexylphosphorus-2',4'
  • Step 1 Synthesis of (R)-6-bromo-7-methoxy-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinolin-4-amine
  • 6-Bromo-4-chloro-7-methoxyquinoline 150 mg, 0.55 mmol
  • (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethane-1 -Amine 155mg, 0.66mmol
  • N,N-diisopropylethylamine 129mg, 1.00mmol
  • reaction solution was added to 30 mL of saturated aqueous sodium chloride solution, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the organic layer was concentrated, and the obtained residue was subjected to column chromatography (petroleum ether/ethyl acetate gradient) elution) to give the title compound.
  • Step 3 (R)-N-(1-(3-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-6-morpholinoquinoline-4 -Synthesis of amines
  • Iron powder 25.8 mg, 0.46 mmol
  • ammonium chloride (1.23 mg, 0.02 mmol) were dissolved in 2 mL of water, heated to 100 °C and refluxed for half an hour; (R)-7-methoxy-6-morpholino -N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinolin-4-amine (55.0 mg, 0.11 mmol) in ethanol (2 mL) was added to the reaction system, The reaction was completed after stirring at 100°C for 4 hours.
  • Step 1 Synthesis of (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxyquinolin-4-amine
  • reaction solution was added to 40 mL of saturated aqueous sodium chloride solution, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the organic layer was concentrated, and the obtained residue was subjected to column chromatography (petroleum ether/ethyl acetate gradient) elution) to give the title compound.
  • Step 2 (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-6-morpholinoquinolin-4-amine synthesis
  • the difference is that the morpholine in step 2 is replaced with 2-oxa-6-aza-spiro[3,3]heptane, and the title compound is prepared in the same way.
  • Example 3 Refer to the preparation method of Example 3, except that 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxo Boron-2-yl)-1H-pyrazole was replaced by 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-1H-pyrazole, the title compound was obtained by the same method.
  • the difference is that the morpholine in step 2 is replaced with thiomorpholine-1,1-dioxide, and the title compound is prepared in the same way.
  • 6-Bromo-2-methyl-3H-pyrido[2,3-d]pyrimidin-4-one 500 mg, 2.08 mmol was added to the reaction flask, phosphorus oxychloride (5 mL) and N,N were added -Diisopropylethylamine (404mg, 3.12mmol), the reaction solution was heated and stirred at 100°C, and the reaction was completed after 1 hour. The reaction solution was concentrated under reduced pressure to remove most of phosphorus oxychloride, then a small amount of dichloromethane was added, the mixture was poured into ice, and when the ice was completely melted, the pH of the system was adjusted to 7-8 with saturated sodium bicarbonate, and then acetic acid was used. Extract with ethyl ester (60 mL ⁇ 3), combine the organic layers, wash with saturated brine, fully dry with anhydrous sodium sulfate, then filter, and concentrate the filtrate under reduced pressure to obtain the title compound.
  • reaction solution was cooled and poured into water, then extracted with ethyl acetate (50 mL ⁇ 3), the organic layers were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Column chromatography (petroleum ether/ethyl acetate gradient elution) was used for separation and purification to obtain the title compound.
  • Step 3 (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(1-(tetrahydro-2H-pyran) Synthesis of -4-yl)-1H-pyrazol-4-yl)pyrido[2,3-d]pyrimidin-4amine
  • Example 13 N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(((2S,6R)-2,6-dimethyl morpholinyl)-2-methylpyrido[2,3-d]pyrimidin-4-amine
  • 3-Amino-6-chloro-5-methoxypyrazine-2-carboxylate methyl ester (5.50 g, 25.2 mmol) was added to 50 mL of methanol, and a 15 mL aqueous solution of sodium hydroxide (4.00 g, 0.10 mmol) was added , and the reaction was completed by heating and stirring at 90 °C for 30 min.
  • the reaction solution was concentrated, water was added, the pH was adjusted to 3-5, and a solid was precipitated. After suction filtration, the filter cake was dried to obtain the title compound.
  • 6-Chloro-7-methoxy-2-methyl-4H-pyrazino[2,3-d][1,3]oxazin-4-one (2.00 g, 8.80 mmol) was added to 10 mL of ammonia In methanol solution, the reaction was carried out at 40°C for 5 hours, and the reaction solution was concentrated to obtain the title compound.
  • Step 6 (S)-7-Methoxy-2-methyl-6-((tetrahydrofuran-3-yl)oxy)pteridin-4-yl-2,4,6-triisopropylbenzenesulfone acid ester
  • Step 7 7-Methoxy-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(((S )-tetrahydrofuran-3-yl)oxy)pteridine-4-amine
  • Step 8 N-((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(((S) -Tetrahydrofuran-3-yl)oxy)pteridine-4-amine
  • Example 3 Refer to the preparation method of Example 3, except that 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxo Boron-2-yl)-1H-pyrazole was replaced by 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron cyclopentan-2-yl)-1H-pyrazole, the title compound was obtained by the same method.
  • reaction solution was concentrated, 20 mL of ethyl acetate was added, the pH was adjusted to 7-9 with saturated aqueous sodium bicarbonate solution, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound.
  • Example 18 With reference to the preparation method of Example 18, the difference is that methanesulfonic anhydride is replaced with trifluoroacetic anhydride, and (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethane is prepared in the same way base)-7-methoxy-6-(1-(trifluoroacetyl)-1,2,3,6-tetrahydropyridin-4-yl)quinolin-4-amine, further refer to Example 19 , the title compound was prepared in the same way.
  • the difference is that the morpholine in step 2 is replaced by 4,4-difluoropiperidine, and the title compound is prepared by the same method.
  • Example 2 With reference to the preparation method of Example 2, the difference is that the morpholine in step 2 is replaced with 3-acetonitrile cyclobutanamine hydrochloride, and the title compound is prepared by the same method.
  • Example 3 Refer to the preparation method of Example 3, except that 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxo Boran-2-yl)-1H-pyrazole was replaced with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-3 , 6-Dihydro-2H-thiopyran 1,1-dioxide, the title compound was prepared in the same way.
  • the difference is that the morpholine in step 2 is replaced by 3-(R)-3-methylmorpholine, and the title compound is prepared in the same way.
  • the difference is that the morpholine in step 2 is replaced by 1-thiomorpholine oxide, and the title compound is prepared by the same method.
  • Step 1 Synthesis of (R)-4-(((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxyquinolin-6-ol
  • Step 2 N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-6-(((S-tetrahydrofuran-3- Synthesis of yl)oxy)quinolin-4-amine
  • reaction solution was added to 30 mL of water, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the organic layer was concentrated, and the obtained residue was separated by column chromatography (petroleum ether/ethyl acetate gradient elution), to obtain the title compound.
  • Step 2 (R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxyquinolin-6-yl) Synthesis of -4-methylpiperidin-4-ol
  • Step 1 Synthesis of 3-(4-Chloro-7-methoxyquinolin-6-yl)-3-hydroxyazetidine-1-carboxylate tert-butyl ester
  • 6-Bromo-4-chloro-7-methoxyquinoline 200 mg was dissolved in 5 mL of tetrahydrofuran, then the temperature was lowered to -78°C under the protection of an inert gas, and a hexane solution of n-butyllithium ( 1.6M, 0.64mL), after dripping and continuing to react for 1 hour at this temperature, 3-oxazetidine-1-carboxylate tert-butyl ester (138mg) was added thereto, and the reaction was continued at this temperature After 30 minutes, it was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, the organic phase was dried over anhydrous ammonium sulfate, filtered, concentrated, and the resulting residue was separated by column chromatography (petroleum ether/ethyl acetate gradient elution) , the title compound was obtained.
  • Step 2 (R)-3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxyquinolin-6-yl) Synthesis of -3-hydroxyazetidine-1-carboxylate tert-butyl ester
  • Step 4 (R)-1-(3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxyquinoline-6 Synthesis of -yl)-3-hydroxyazetidine-1-yl)ethane-1-one
  • 6-Bromo-4-chloro-7-methoxyquinoline 200 mg was dissolved in 4 mL of THF, then the temperature was lowered to -78°C under the protection of inert gas, and a hexane solution of n-butyllithium was added dropwise thereto.
  • the reaction solution was cooled to room temperature, diluted with ethyl acetate, filtered, and the filtrate was concentrated. The obtained residue was separated and purified by column chromatography (dichloromethane/methanol gradient elution). The title compound was obtained.
  • Step 1 Synthesis of ethyl 3-((4-bromo-3-methoxyphenyl)imino)-3-cyclopropylpropanoate
  • 6-Bromo-2-cyclopropyl-7-methoxyquinolin-4-ol (0.60 g) was added to 5 mL of phosphorus oxychloride, and the reaction was completed at 90° C. for 2 hours.
  • the reaction solution was concentrated to dryness, quenched by adding ice water, and adjusted to pH 9 with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated.
  • Column chromatography (petroleum ether/ethyl acetate gradient elution) gave the title compound.
  • reaction solution was added to 30 mL of saturated aqueous sodium chloride solution, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the organic layer was concentrated, and the obtained residue was subjected to column chromatography (petroleum ether/ethyl acetate gradient) elution) to give the title compound.
  • reaction solution was poured into water, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the organic layer was concentrated, and the obtained residue was separated by column chromatography (dichloromethane/methanol gradient elution) to obtain the title compound.
  • 6-Bromo-4-chloro-7-methoxy-2-methylquinoline (0.80g) and selenium dioxide (0.62g) were added to 8mL of dioxane solution, and the reaction was completed at 100°C for 3 hours. .
  • the reaction solution was poured into water, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the organic layer was concentrated, and the obtained residue was separated by column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain title compound.
  • Step 2 Synthesis of 6-bromo-4-chloro-7-methoxyquinoline-2-carbaldehyde oxime
  • 6-Bromo-4-chloro-7-methoxyquinoline-2-carbaldehyde oxime (0.17g) and trifluoromethanesulfonic anhydride (0.30g) were added to 3mL of dichloromethane, and then triethylamine was slowly added (0.27g), the reaction was completed at 0°C for 2 hours.
  • the reaction solution was poured into water, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the organic layer was concentrated, and the obtained residue was separated by column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain title compound.
  • reaction solution was added to 30 mL of saturated aqueous sodium chloride solution, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the organic layer was concentrated, and the obtained residue was subjected to column chromatography (petroleum ether/ethyl acetate gradient) elution) to give the title compound.
  • Step 5 (R)-4-(((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-6-morpholinoquinoline- 2-carbonitrile
  • reaction solution was poured into water, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the organic layer was concentrated, and the obtained residue was separated by column chromatography (dichloromethane/methanol gradient elution) to obtain the title compound.
  • Example 40 Referring to the synthesis method of Example 40, the difference is that the tetrahydropyran-4-one in step 1 is replaced by 3-oxetanone, and the title compound is obtained by the same method.
  • Step 1 (R)-6-Bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methylquinoline-4 -Synthesis of amines
  • reaction solution was added to 40 mL of saturated aqueous sodium chloride solution, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the organic layer was concentrated, and the obtained residue was subjected to column chromatography (petroleum ether/ethyl acetate gradient) elution) to give the title compound.
  • Step 2 (R)-6-Cyclopropyl-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methylquinoline Synthesis of -4-amine
  • Step 1 (R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxyquinolin-6-yl) Synthesis of -3-methylazetidine-3-carboxylate methyl ester
  • Step 2 (R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxyquinolin-6-yl) Synthesis of -3-methylazetidine-3-carboxylic acid
  • Step 3 (R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxyquinolin-6-yl) Synthesis of -N,3-dimethylazetidine-3-carboxamide
  • Acetamidine hydrochloride 250mg, 2.65mmol
  • 2,5,6-trichloronicotinic acid 500mg
  • cuprous iodide 42.0mg
  • cesium carbonate 719mg
  • 6-Chloro-7-(2,2-difluoroethoxy)-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one (65.0 mg) was dissolved in 2 ml of acetonitrile and added Phosphine trichloride (72.3 mg) and N,N-diisopropylethylamine (76.2 mg), under argon protection, stirred at 80°C for 1 hour. After the reaction was completed, the reaction solution was spin-dried to obtain the crude product of the title compound, which was directly used in the next reaction.
  • Step 4 (R)-6-Chloro-7-(2,2-difluoroethoxy)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)- 2-Methylpyrido[2,3-d]pyrimidin-4-amine
  • Step 5 (R)-7-(2,2-Difluoroethoxy)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl -6-Morpholinopyrido[2,3-d]pyrimidin-4-amine
  • Step 1 Synthesis of 3-(4-Chloro-7-methoxy-2-methylquinolin-6-yl)-3-hydroxyazetidine-1-carboxylate tert-butyl ester
  • 6-Bromo-4-chloro-7-methoxy-2-methylquinoline 200 mg was dissolved in 5 mL of tetrahydrofuran, then it was warmed to -78°C under the protection of inert gas, and n-butyllithium was added dropwise thereto.
  • 3-oxoazetidine-1-carboxylate tert-butyl ester 138 mg was added thereto, and the reaction was continued at this temperature for 1 hour.
  • Step 2 (R)-3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylquinoline Synthesis of -6-yl)-3-hydroxyazetidine-1-carboxylate tert-butyl ester
  • Step 3 (R)-3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylquinoline Synthesis of -6-yl)azetidinol
  • Step 4 (R)-1-(3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methyl Synthesis of quinolin-6-yl)-3-hydroxyazetidine-1-yl)ethan-1-one
  • reaction solution was diluted with ethyl acetate, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and the residue obtained after concentration was separated by column chromatography (dichloromethane/methanol gradient elution) to obtain the title compound.
  • Example 46 Refer to the preparation method of Example 46, except that (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7 in step 1 -Methoxyquinolin-4-amine was replaced with (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy -2-Methylquinolin-4-amine, the title compound was obtained by the same method.
  • Example 47 With reference to the preparation method of Example 47, the difference is that the morpholine in step 5 is replaced with 4-methylpiperidin-4-ol, and the title compound is prepared in the same manner.
  • 6-Bromo-4-chloro-7-methoxy-2-methylquinoline (5.00g) was added to the reaction flask, fitted with an argon balloon, the gas was replaced three times, and anhydrous 1,2- Dichloroethane (100 mL) was then placed in an ice bath to cool to 0°C, then boron tribromide in dichloromethane (2M, 26.2 mL) was added. The reaction solution was stirred in an ice bath for 30 minutes, and then placed in an oil bath at 50°C for overnight reaction.
  • 6-Bromo-4-chloro-2-methylquinolin-7-ol (1.50 g) was added to the reaction flask, dichloromethane (20 mL) and tetrahydrofuran (20 mL) were added, and then an argon balloon was installed to replace the gas Three times, cooled to -20° C. under gas protection, anhydrous pyridine (522 mg) was added, and trifluoromethanesulfonic anhydride (3.11 g) was slowly added dropwise with stirring. After the dropwise addition was completed, the reaction was carried out at room temperature for 3 hours.
  • reaction solution was poured into ice water, extracted with ethyl acetate (50 mL ⁇ 3), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to column chromatography ( Petroleum ether/ethyl acetate gradient elution) was separated and purified to obtain the title compound.
  • 6-Bromo-4-chloro-2-methylquinolin-7-yl trifluoromethanesulfonate 200 mg
  • 1-methyl-1H-pyrazole-3-boronic acid pinacol ester 108 mg
  • Cesium carbonate 322 mg
  • [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium 36.2 mg
  • anhydrous 1,4-dioxane 3.2 mL
  • Step 4 4-Chloro-6-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-7-(1-methyl-1H-pyrazol-3-yl)quinoline Synthesis of morpholino
  • Step 5 (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl Synthesis of )-2-methyl-7-(1-methyl-1H-pyrazol-3-yl)quinolin-4-amine
  • 6-Bromo-4-chloro-2-methylquinolin-7-ol (700 mg) was dissolved in 5 mL of DMF, followed by the addition of 1,1-difluoro-2-iodoethane (493 mg) and potassium carbonate ( 708 mg), the reaction system was reacted at 50 °C overnight, diluted with ethyl acetate, washed with saturated brine, and then separated, the organic phase was dried with anhydrous sodium sulfate, concentrated, and the resulting residue was subjected to column chromatography ( Petroleum ether/ethyl acetate gradient) to obtain the title compound.
  • Step 2 Synthesis of 3-(4-Chloro-7-(2,2-difluoroethoxy)-2-methyl-6-quinolinyl)oxetan-3-ol
  • 6-Bromo-4-chloro-7-(2,2-difluoroethoxy)-2-methylquinoline 200 mg was dissolved in 10 mL of ultra-dry tetrahydrofuran and then warmed to - After 10°C, a solution of isopropylmagnesium chloride lithium chloride complex in tetrahydrofuran (1.3M, 1.83mL) was added dropwise to it, and the reaction was continued for 1 h at this temperature, and 3-oxetanone was added thereto.
  • Step 3 (R)-3-(7-(2,2-Difluoroethoxy)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino Synthesis of )-2-methylquinolin-6-yl)oxetan-3-ol
  • Step 1 (R)-6-Bromo-N-(1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methylquinoline olin-4-amine
  • Example 56 ((R)-1-(4-(7-(2,2-difluoroethoxy)-4-((1-(3-(difluoromethyl)-2-fluorophenyl) )ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethan-1-one
  • 6-Bromo-7-chloro-2-methyl-3H-pyrido[2,3-d]pyrimidin-4-one (550mg) was dissolved in 2ml 2,2-difluoroethanol, sodium hydride (90.0mg) was added ), under argon protection, and stirred at 70°C for 3 hours. After the reaction was completed, ethyl acetate was added to dilute, washed with water, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained residue was separated by column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain the title compound.
  • Step 5 (R)-6-Bromo-7-(2,2-difluoroethoxy)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)- Synthesis of 2-Methylpyrido[2,3-d]pyrimidin-4-amine
  • Step 7 ((R)-1-(4-(7-(2,2-difluoroethoxy)-4-((1-(3-(difluoromethyl)-2-fluorophenyl) Synthesis of ethyl)amino)-2-methylpyridyl[2,3-d]pyrimidin-6-yl)piperidin-1-yl)ethan-1-one
  • Step 1 (R)-1-(7-(2,2-Difluoroethoxy)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino )-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3-methylazetidine-3-carboxylate methyl ester
  • Step 2 (R)-1-(7-(2,2-Difluoroethoxy)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino )-2-methylpyrido[2,3-d]pyrimidin-6-yl)-N,3-dimethylazetidine-3-carboxamide synthesis
  • 2-Amino-6-(trifluoromethyl)nicotinic acid 500 mg was dissolved in N,N-dimethylformamide (10 mL), stirred, and the light yellow clear liquid was dissolved in N-bromosuccinimide.
  • Amine (604 mg) was added to the reaction system, and the temperature was increased to 70° C. to react for half an hour.
  • the reaction solution was slowly added dropwise to 40 ml of water, stirred and dispersed for half an hour, filtered with suction, and the filter cake was dried to obtain the title compound.
  • 6-Bromo-2-methyl-7-(trifluoromethyl)-pyrido[2,3-d][1,3]oxazin-4-one (700 mg) was dissolved in tetrahydrofuran (20 mL), Argon was replaced three times, ammonia methanol (10 mL) was added dropwise, a white solid was precipitated, and the reaction was overnight at room temperature. The solvent was removed under reduced pressure, and part of the solvent was removed. 4N hydrochloric acid was added to the system to adjust pH ⁇ 3, and then saturated sodium bicarbonate solution was added. , adjusted pH ⁇ 7, a large amount of solid was precipitated, suction filtered, the filter cake was washed with water, and dried to obtain the title compound.
  • the water bath was about 10 degrees Celsius, the system was slowly poured into 15 mL of water, a large amount of yellow solid was precipitated, stirred and dispersed for half an hour, suction filtered, and the filter cake was purified by column chromatography (petroleum ether/ethyl acetate gradient elution) and separated to obtain the title compound .
  • Step 5 (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-morpholino-7-(trifluoromethyl) ) Synthesis of pyrido[2,3-d]pyrimidin-4-amine
  • Step 1 (R)-(1-(7-(2,2-Difluoroethoxy)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) Synthesis of tert-butyl amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-4-methylpiperidin-4-yl)carbamate
  • Step 2 (R)-6-(4-Amino-4-methylpiperidin-1-yl)-7-(2,2-difluoroethoxy)-N-(1-(3-(difluoroethoxy)- Synthesis of fluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidin-4-amine
  • reaction solution was concentrated under reduced pressure, then a small amount of dichloromethane and water were added to dissolve and dilute, the pH was adjusted to 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, purified by prep-HPLC (Triart C18 ExRS, acetonitrile/water gradient elution), and lyophilized to obtain the title compound.
  • prep-HPLC Triart C18 ExRS, acetonitrile/water gradient elution
  • Step 1 (R)-3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylquinoline Synthesis of -6-yl)-3-hydroxyazetidine-1-carboxylic acid tert-butyl ester
  • Step 2 (R)-3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylquinoline Synthesis of -6-yl)-3-fluoroazetidine-1-carboxylate tert-butyl ester
  • reaction solution was moved to room temperature to continue the reaction for 2 hours, quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried, concentrated and filtered through a column Chromatography (petroleum ether/ethyl acetate gradient) afforded the title compound.
  • Step 3 (R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-6-(3-fluoroazetidin-3-yl)-7 -Synthesis of -methoxy-2-methylquinolin-4-amine
  • Step 4 (R)-1-(3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methyl Synthesis of quinolin-6-yl)-3-fluoroazetidine-1-yl)ethan-1-one-2,2,2-D3
  • Step 1 Synthesis of 3-(4-Chloro-7-methoxyquinolin-6-yl)-3-methoxyazetidine-1-carboxylate tert-butyl ester
  • reaction solution was poured into 5 mL of ice water, followed by extraction with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated, and the obtained residue was subjected to column chromatography (petroleum ether/ethyl acetate gradient elution) Isolated to yield the title compound.
  • Step 2 (R)-3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxyquinolin-6-yl) Synthesis of -3-methoxyazetidine-1-carboxylate tert-butyl ester
  • Step 3 (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-6-(3-methoxyazetidine Synthesis of Alk-3-yl)quinolin-4-amine
  • Step 4 (R)-1-(3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxyquinoline-6 Synthesis of -yl)-3-methoxyazetidine-1-yl)ethan-1-one
  • Step 1 (R)-3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxyquinolin-6-yl) Synthesis of -3-hydroxyazetidine-1-carboxylate tert-butyl ester
  • Step 2 (R)-3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxyquinolin-6-yl) -Synthesis of tert-butyl 3-fluoroazetidine-1-carboxylate
  • Step 3 (R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-6-(3-fluoroazetidin-3-yl)-7 -Synthesis of methoxyquinolin-4-amine
  • Step 4 (R)-1-(3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxyquinoline-6 Synthesis of -yl)-3-fluoroazetidine-1-yl)ethan-1-one
  • Step 5 (R)-1-(3-Amino-3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy Synthesis of quinolin-6-yl)azetidine-1-yl)ethan-1-one
  • Step 1 (R)-6-bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinolin-7-ol synthesis
  • 6-Bromo-4-chloro-2-methylquinolin-7-ol 500 mg was dissolved in 5 mL of ultra-dry N-methylpyrrolidone, to which was then added (R)-1-(3-(bis Fluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride (478 mg) and potassium carbonate (976 mg) were reacted at 150° C.
  • Step 3 (R)-1-(7-(difluoromethoxy)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- Synthesis of Methylquinolin-6-yl)-4-methylpiperidin-4-ol
  • Example 68 (R)-1-(3-(7-(2,2-difluoroethoxy)-4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl yl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3-hydroxyazetidin-1-yl)ethan-1-one
  • Example 70 (R)-1-(3-(7-(2,2-difluoroethoxy)-4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl yl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3-methoxyazetidin-1-yl)ethan-1-one
  • the title compound was prepared in the same manner as in the preparation method of Example 59, except that tert-butyl N-(4-methyl-4-piperidinyl)carbamate was replaced by 1-acetylpiperazine.
  • Example 72 N-7-(3,3-Difluorocyclobutyl)-N-4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) -2-Methyl-6-(2-methyloxetan-2-yl)pyrido[2,3-d]pyrimidine-4,7-diamine
  • Step 1 Synthesis of 6-bromo-7-((3,3-difluorocyclobutyl)amino)-2-methyl-pyrido[2,3-d]pyrimidin-4-ol
  • 6-Bromo-7-chloro-2-methylpyrido[2,3-d]pyrimidin-4-ol 500 mg was dissolved in 5 mL of DMF, followed by the addition of 3,3-difluorocyclobutanamine (234mg) and N,N-diisopropylethylamine (470mg) were then heated to 80°C and reacted for 2 hours, the reaction solution was concentrated and separated by column chromatography (petroleum ether/ethyl acetate gradient elution) to obtain title compound.
  • Step 2 6-Bromo-N-7-(3,3-difluorocyclobutyl)-N-4-((1R)-1-(3-(difluoromethyl)-2-fluoro-phenyl )ethyl)-2-methyl-pyrido[2,3-d]pyrimidine-4,7-diamine synthesis
  • 6-Bromo-7-((3,3-difluorocyclobutyl)amino)-2-methyl-pyrido[2,3-d]pyrimidin-4-ol 500 mg was dissolved in 10 mL of DMF , to which were added (1R)-1-(3-(difluoromethyl)-2-fluoro-phenyl)ethanamine (392 mg) and (3H-1,2,3-triazolo(4,5- B) Pyridin-3-oxy) tris-1-pyrrolidinyl hexafluorophosphate (1.13g), and finally DBU (661mg) was added to it, and the temperature was raised to 60° C.
  • reaction was completed, and the reaction solution was cooled to At room temperature, diluted with ethyl acetate, washed with saturated brine, dried with anhydrous sodium sulfate, the organic phase was concentrated and separated by column chromatography (gradient elution of petroleum ether/ethyl acetate) to obtain the title compound.
  • Step 3 1-(7-((3,3-Difluorocyclobutyl)amino)-4-(((1R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane Synthesis of yl)amino)-2-methyl-pyrido[2,3-d]pyrimidin-6-yl)ethanone
  • Step 4 N-7-(3,3-Difluorocyclobutyl)-N-4-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)- Synthesis of 2-methyl-6-(2-methyloxetan-2-yl)pyrido[2,3-d]pyrimidine-4,7-diamine
  • Trimethylsulfoxide (22.9 mg) was dissolved in 1 mL of tert-butanol, and potassium tert-butoxide (11.7 mg) was added thereto.
  • the reaction solution was reacted at 50° C. for 30 minutes, and then 1-( 7-((3,3-Difluorocyclobutyl)amino)-4-(((1R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2 -Methyl-pyrido[2,3-d)pyrimidin-6-yl)ethanone (10.0 mg), after the reaction was continued for 6 hours at this temperature, the reaction solution was diluted with ethyl acetate, then filtered, and the filtrate was After concentration, separation by preparative HPLC (Triart C18 ExRS, mobile phase: acetonitrile/water) gave the title compound.
  • Example 62 With reference to the preparation method of Example 62, the difference is that the 3-(4-chloro-7-methoxyquinolin-6-yl)-3-hydroxyazetidine-1-carboxylic acid tertiary The butyl ester was replaced with 3-(4-chloro-7-methoxy-2-methylquinolin-6-yl)-3-hydroxyazetidine-1-carboxylate tert-butyl ester, the title was prepared in the same way compound.
  • step 1 substituting tert-butyl 3-oxoazetidine-1-carboxylate with N-tert-butoxycarbonyl-4-piperidone to prepare 4-(4-chloro-7 -Methoxy-2-methylquinolin-6-yl)-4-hydroxypiperidine-1-carboxylate tert-butyl ester.
  • Example 62 With reference to the preparation method of Example 62, the difference is that the 3-(4-chloro-7-methoxyquinolin-6-yl)-3-hydroxyazetidine-1-carboxylic acid tertiary
  • the butyl ester was replaced with 4-(4-chloro-7-methoxy-2-methylquinolin-6-yl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester, and the title compound was obtained by the same method.
  • Step 3 Synthesis of tert-butyl 4-(4-chloro-7-((4-methoxybenzyl)oxy)quinolin-6-yl)-4-hydroxypiperidine-1-carboxylate
  • Step 4 Synthesis of tert-butyl 4-(4-chloro-7-((4-methoxybenzyl)oxy)quinolin-6-yl)-4-methoxypiperidine-1-carboxylate
  • Step 5 (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-((4-methoxybenzyl) Synthesis of tert-butyl oxy)quinolin-6-yl)-4-methoxypiperidine-1-carboxylate
  • Step 6 (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-hydroxyquinolin-6-yl)-4 -Synthesis of tert-butyl methoxypiperidine-1-carboxylate
  • Step 7 (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-((((trifluoromethyl)sulfone Synthesis of acyl)oxy)quinolin-6-yl)-4-methoxypiperidine-1-carboxylic acid tert-butyl ester
  • Step 8 (R)-4-(7-Acetyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)quinolin-6-yl)- Synthesis of 4-Methoxypiperidine-1-carboxylate tert-butyl ester
  • Step 9 (R)-1-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(4-methoxypiperidine-4 Synthesis of -yl)quinolin-7-yl)ethane-1-one hydrochloride
  • Step 10 (R)-1-(4-(7-Acetyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)quinoline-6- Synthesis of yl)-4-methoxypiperidin-1-yl)ethan-1-one
  • Step 1 (R)-6-(1-(tert-Butoxycarbonyl)-4-methoxypiperidin-4-yl)-4-((1-(3-(difluoromethyl)-2 - Synthesis of methyl fluorophenyl)ethyl)amino)quinoline-7-carboxylate
  • Step 3 (R)-6-(1-Acetyl-4-methoxypiperidin-4-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl) Synthesis of methyl ethyl)amino)quinoline-7-carboxylate
  • Step 4 (R)-6-(1-Acetyl-4-methoxypiperidin-4-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl) Synthesis of ethyl)amino)quinoline-7-carboxylic acid
  • Positive control BAY-293 and test compounds (10 mM stock) were diluted 5-fold to 0.1 mM in 100% DMSO and 11 equal dilutions were performed 1:3 in 384-well dilution plates.
  • the IC50 50% inhibitory concentration of the compound was obtained using the following nonlinear fitting formula:
  • test results Under the experimental conditions, the test compounds have good inhibitory activity on the binding of KRASG12D::SOS1. The corresponding activity test results of the test compounds are shown in Table 1.
  • H358 cells (ATCC, CRL-5807) were cultured in RPMI1640 (Hyclone, SH30256.01) complete medium containing 10% FBS (Gibco, 10100147) and 100 U/mL penicillin-streptomycin (Gibco, 15140163), when When the cell growth reached 80-90%, the cells were digested and blown away and seeded in a 96-well plate (Corning, 4515), with 3000 cells per well (180 ⁇ l RPMI1640 complete medium), and then the 96-well plate was placed at 37°C, 5% Incubate overnight in a CO 2 incubator.
  • the percent inhibition of H358 cell proliferation by a compound can be calculated using the following formula:
  • Inhibition percentage 100*(signal value in 0% inhibition group-signal value at a specific concentration of the compound to be tested)/(signal value in 0% inhibition group-signal value in 100% inhibition group).
  • Y is the percentage of inhibition
  • X is the logarithm of the concentration of the compound to be tested
  • Bottom is the minimum percentage of inhibition
  • Top is the maximum percentage of inhibition
  • slope factor is the slope coefficient of the curve.
  • test results Under the experimental conditions, the examples of the present invention have good proliferation inhibitory activity on H358 cells. The corresponding activity test results of the test compounds are shown in Table 2.
  • Example IC50 (nM) 1 30.3 2 24.6 3 48.1 4 126.2 5 85.6 6 10.7 8 6.1 9 61.1 10 79.2 11 140.5 12 29.8
  • mice Healthy adult BALB/c mice, female, divided into equal groups, 3 mice in each group, 3 mice were intragastrically administered, and 3 mice were intravenously.
  • the mice were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., animal production license number: SCXK ( Zhejiang) 2019-0001.
  • a certain amount of the compound of the present invention was weighed, dissolved in DMSO 5% + PG 20% + anhydrous ethanol 5% + solutol 10% + water 60%, and formulated into 10 mg/mL for gavage.
  • a certain amount of the compound of the present invention was weighed, dissolved in DMSO 1% + PG 4% + anhydrous ethanol 1% + solutol 2% + water 92%, and formulated into 3 mg/mL or 2 mg/mL for intravenous injection.
  • Gavage group BALB/c mice were fasted overnight and then administered by gavage at a dose of 10 mg/kg and an administration volume of 1 mL/kg.
  • Intravenous group BALB/c mice were fasted overnight and administered intravenously, with a dose of 3 mg/kg and an administration volume of 1 mL/kg.
  • mice After the mice were given intragastrically or intravenously, 40 ⁇ L of blood was collected from the orbit at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, and 6 h after administration, and 5 ⁇ L of EDTA-K2 was anticoagulated, and the plasma was separated by centrifugation at 12000 rpm, 4 °C, 5 min. , and stored at -20°C.
  • Determination of the content of the test compound in mouse plasma after intragastric or intravenous administration of different concentrations of drugs take the sample to dissolve at room temperature, and vortex for 1 min; quantitatively transfer 15 ⁇ L to a 2 mL 96-well plate, add 150 ⁇ L of internal standard precipitant, and shake (1200 rpm). *3min); centrifuge (4000rpm*15min), transfer 100 ⁇ L of supernatant to a 1mL 96-well plate; dry with nitrogen, add 100 ⁇ L of reconstituted solution (acetonitrile water 1:9), shake well (900rpm*3min), and inject 20 ⁇ L analyze.
  • LC/MS/MS conditions mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: 0.1% formic acid acetonitrile, chromatographic column: ACE C18 5 ⁇ m (3.0mm*50mm), column temperature: 35°C, flow rate 0.5mL/min.
  • test compounds showed good pharmacokinetic properties, and the results are shown in Table 3 and Table 4 for details.
  • Example C 0 (ng/mL) T 1/2 (hr) AUClast(hr*ng/mL) Vss(L/Kg) 1* 463.4 1.1 228.2 8.1 2 900.0 1.1 473.3 6.1 3 1064.7 0.9 499.1 3.8 4 1001.1 1.1 449.5 4.4 12 2579.4 0.3 491.3 1.3 47 5251.7 0.5 1509.2 0.7
  • the experimental method is outlined as follows:
  • H358 cells (ATCC, CRL-5807) were cultured in RPMI1640 (ThermoFisher, A1049101) complete medium containing 10% FBS (Gibco, 10100147) and 100 U/mL penicillin-streptomycin (Gibco, 15140163)
  • RPMI1640 ThermoFisher, A1049101
  • FBS FBS
  • penicillin-streptomycin Gabco, 15140163
  • the coverage rate in the culture vessel reaches 80-90%, the cells are blown off and then planted in a 96-well plate (Corning, 3599), with 50,000 cells per well (90 ⁇ l RPMI1640 complete medium), and then placed at 37° C., Incubate for 6 h in a 5% CO 2 incubator and replace with serum-free RPMI1640 starvation overnight.
  • the percent inhibition of the p-ERK pathway in H358 cells by a compound can be calculated using the following formula:
  • Inhibition percentage 100*(signal value in 0% inhibition group-signal value at a specific concentration of the compound to be tested)/(signal value in 0% inhibition group-signal value in 100% inhibition group).
  • Y is the percentage of inhibition
  • X is the logarithm of the concentration of the test compound
  • Bottom is the minimum percentage of inhibition
  • Top is the maximum percentage of inhibition
  • slope factor is the slope coefficient of the curve. The default fit curve was used to fit the slope of the sigmoid curve to determine IC50 values.

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Abstract

一类SOS1抑制剂的系列化合物，具体公开了式(I)所示化合物、其药学上可接受的盐，包含它们的药物组合物以及它们在制备治疗癌症药物中的应用。

Description

SOS1抑制剂及其制备方法和应用
本申请要求以下五件在先申请的优先权，以下在先申请的全文通过引用的方式结合于本申请中：
2021年1月29日向中国国家知识产权局提交的，专利申请号为202110134521.6，发明名称为“SOS1抑制剂及其制备方法和应用”的在先申请；
2021年3月19日向中国国家知识产权局提交的，专利申请号为202110296210.X，发明名称为“SOS1抑制剂及其制备方法和应用”的在先申请；
2021年4月27日向中国国家知识产权局提交的，专利申请号为202110465173.0，发明名称为“SOS1抑制剂及其制备方法和应用”的在先申请；
2021年5月21日向中国国家知识产权局提交的，专利申请号为202110561063.4，发明名称为“SOS1抑制剂及其制备方法和应用”的在先申请；以及
2021年9月29日向中国国家知识产权局提交的，专利申请号为202111167826.3，发明名称为“SOS1抑制剂及其制备方法和应用”的在先申请。
技术领域
本发明属于医药技术领域，涉及SOS1抑制剂化合物或其光学异构体、药学上可接受的盐，含有它们的药物组合物以及作为SOS1抑制剂的用途。
背景技术
RAS家族蛋白包括KRAS(V-Ki-ras2 Kirsten大鼠肉瘤病毒致癌基因同源物)、NRAS(神经母细胞瘤RAS病毒致癌基因同源物)和HRAS(Harvey鼠肉瘤病毒致癌基因)等，是存在于细胞中处于GTP结合状态或GDP结合状态的小GTP酶(McCormick等人,J.Mol.Med.(Berl).,2016,94(3):253-8；Nimnual等人,Sci.STKE.,2002,2002(145):pe36)。
RAS家族蛋白在人类癌症中起着重要作用。RAS蛋白突变引起的肿瘤占人类所有肿瘤的20-30％，并且被认为是致瘤驱动因素，特别是在肺癌，结直肠癌和胰腺癌中(Malumbres&Barbacid 2002 Nature Reviews Cancer，Pylayeva-Gupta等人，2011 Nature Reviews Cancer)。
SOS1(son of sevenless homolog 1)蛋白是一种在细胞中广泛表达的调控蛋白，作为RAS、RAC蛋白的一类鸟嘌呤核苷酸交换因子，在细胞内RAS、RAC信号转导通路中起着重要的调控作用。SOS1具有两个针对RAS家族蛋白的结合位点：催化位点，所述催化位点结合GDP结合的RAS家族蛋白以促进鸟嘌呤核苷酸交换；变构位点，所述变构位点结合GTP结合的RAS家族蛋白，这导致SOS1的催化GEF功能进一步增加(Freedman等人，Proc.Natl.Acad.Sci.USA.,2006,103(4 5):16692-7；Pierre等人,Biochem.Pharmacol.,2011,82(9):1049-56)。公开数据表明SOS1参与在癌症中的突变KRAS活化和致癌信号传导(Jeng等人,Nat.Commun.,2012,3:1168)。消耗SOS1水平会降低携带KRAS突变的肿瘤细胞的增殖率和存活，而在KRAS野生型细胞系中没有观察到。SOS1丧失的影响无法通过引入催化位点突变的SOS1弥补，进一步证明了SOS1GEF活性在KRAS突变癌细胞中的重要作用。
在近几十年中，RAS家族蛋白-SOS1蛋白相互作用已进行了越来越多的研究。已鉴别出小的激活分子，其结合至紧密靠近RAS结合位点的SOS1的亲脂性口袋(Burns等人，Proc.Natl.Acad.Sci.2014,111(9):3401-6)。然而，这些分子的结合似乎导致核苷酸交换增加，从而激活RAS而非使其失活。
虽然现有文献中也报道了一些SOS1小分子抑制剂(如专利文献WO2018/115380A1及WO2018/172250A1)，但仍有大量的患者无法得到满意的临床治疗效果，因此目前仍然需要开发具有良好活性，且选择性好、毒副作用低的SOS1抑制剂。
发明内容
本发明提供式(I)所示化合物及其药学上可接受的盐。这些化合物可以抑制SOS1的活性，从而影响生物学功能。
本发明提供了一种式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2022074591-appb-000001
其中，
X选自CH或N；
Y选自CH或N；
Z选自CH或N；
R 1选自H、CN、C 1-6烷基或C 3-6环烷基；
环A选自C 6-10芳基、苯并5-7元杂环基或苯并5-7元杂芳基；
L选自化学键或O；
R 2选自C 3-10环烷基、C 6-10芳基、3-10元杂环基或5-10元杂芳基，所述C 3-10环烷基、C 6- 10芳基、3-10元杂环基或5-10元杂芳基任选地被R 2b和/或R 2c取代；
R 2b选自-OR 2c、-N(R 2c) 2、卤素、羟基、氰基、氨基、-C(O)R 2c、-C(O)NHR 2c、-C(O)NH 2、-NHR 2c、-C(O)H、-C(O)OH、-S(O) 2NHR 2c、-NHC(O)H、-N(C 1-4烷基)C(O)H、-C(O)N(R 2c) 2、-C(O)OR 2c、-S(O) 2R 2c、-S(O) 2N(R 2c) 2、-NHC(O)R 2c或-N(C 1-4烷基)C(O)R 2c；
R 2c独立地选自C 1-6烷基、C 1-3氘代烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基或5-10元杂芳基，所述C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基、5-10元杂芳基任选地被R 2d取代；
R 2d选自卤素、羟基、氰基、氨基、-C(O)R 2f、-C(O)N(R 2f) 2、-C(O)OR 2f、-S(O) 2R 2f、-S(O) 2N(R 2f) 2、-N(C 1-4烷基)R 2f、-NHC(O)R 2f或-N(C 1-4烷基)C(O)R 2f；
R 2f独立地选自H或C 1-6烷基；
R 3选自H、卤素、羟基、氰基、氨基、-NH-C 3-6环烷基、C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、C 3-6环烷基、3-8元杂环基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、5-10元杂芳基、-C(O)R 3a、-C(O)N(R 3a) 2、-C(O)OR 3a、-S(O) 2R 3a、-S(O) 2N(R 3a) 2、-NHC(O)R 3a或-N(C 1-4烷基)C(O)R 3a，所述-NH-C 3-6环烷基、C 1-6烷基、C 3-6环烷基、3-8元杂环基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)或5-10元杂芳基任选地被R 3b取代；
所述R 3a独立地选自H或C 1-6烷基；
所述R 3b独立地选自卤素、羟基、氰基、氨基、3-8元杂环基或C 1-6烷基；
R 4选自卤素、羟基、氰基、氨基、C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、3-8元杂环基、5-10元杂芳基或-S(O) 2-C 1-4烷基，所述C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、3-8元杂环基或5-10元杂芳基任选地被R 4a取代；所述R 4a选自卤素、羟基、氰基或氨基；
R 5选自C 1-3氘代烷基、C 1-6烷基或C 1-6卤代烷基；
R 6选自H、氘、C 1-3氘代烷基、C 1-6烷基或C 1-6卤代烷基；
n选自0、1、2、3或4；
其中，当X选自N，Z选自CH时，R 1选自CN或C 3-6环烷基；
当X、Z选自N时，R 1选自CN、C 1-6烷基或C 3-6环烷基；
当X、Z选自CH时，R 3选自羟基、氰基、氨基、C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、C 3-6环烷基、3-8元杂环基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、5-10元杂芳基、-C(O)R 3a、-C(O)N(R 3a) 2、-C(O)OR 3a、-S(O) 2R 3a、-S(O) 2N(R 3a) 2、-NHC(O)R 3a或-N(C 1-4烷基)C(O)R 3a，所述C 1-6烷基、C 3-6环烷基、3-8元杂环基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)或5-10元杂芳基任选地被R 3b取代。
在一些实施方案中，X、Z独立地选自N,Y选自CH，且R 1选自CN、C 1-6烷基或C 3-6环烷基，R 2选自任选地被R 2b和/或R 2c取代的以下基团：
Figure PCTCN2022074591-appb-000002
Figure PCTCN2022074591-appb-000003
在一些实施方案中，X、Z独立地选自N,Y选自CH，且R 1选自CN、C 1-6烷基或C 3-6环烷基，R 2选自任选地被R 2b和/或R 2c取代的以下基团：
Figure PCTCN2022074591-appb-000004
Figure PCTCN2022074591-appb-000005
在一些实施方案中，X、Z独立地选自N,Y选自CH，且R 1选自CN、C 1-6烷基或C 3-6环烷基，R 2选自以下基团：
Figure PCTCN2022074591-appb-000006
在一些实施方案中，X、Z独立地选自N,Y选自CH，且R 1选自CN、C 1-6烷基或C 3-6环烷基，R 2选自任选地被R 2b和/或R 2c取代的以下基团：
Figure PCTCN2022074591-appb-000007
时，R 3选自-O-CH 2CHF 2或-NH-C 3-6环烷基。
在一些实施方案中，X、Z独立地选自N,Y选自CH，且R 1选自CN、C 1-6烷基或C 3-6环烷基，R 2选自任选地被R 2b和/或R 2c取代的以下基团：
Figure PCTCN2022074591-appb-000008
时，R 3选自-O-CH 2CHF 2。
在一些实施方案中，X、Z独立地选自N,Y选自CH，且R 1选自CN、C 1-6烷基或C 3-6环烷基，R 2选自任选地被R 2b和/或R 2c取代的以下基团：
Figure PCTCN2022074591-appb-000009
时，R 3选自-O-CH 3。
在一些实施方案中，X、Y、Z独立地选自CH，且R 3选自羟基、氰基、氨基、C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、C 3-6环烷基、3-8元杂环基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、5-10元杂芳基、-C(O)R 3a、-C(O)N(R 3a) 2、-C(O)OR 3a、-S(O) 2R 3a、-S(O) 2N(R 3a) 2、 -NHC(O)R 3a或-N(C 1-4烷基)C(O)R 3a，所述C 1-6烷基、C 3-6环烷基、3-8元杂环基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)或5-10元杂芳基任选地被R 3b取代。在一些实施方案中，X、Y、Z独立地选自CH，且R 3选自-C(O)R 3a、-C(O)OR 3a、C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基，所述C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基任选地被R 3b取代。
在一些实施方案中，环A选自苯基、茚满基、茚基、四氢化萘基、二氢萘基或萘基。
在一些实施方案中，环A选自苯基。
在一些实施方案中，R 1选自H、CN、甲基或环丙基。
在一些实施方案中，R 1选自C 1-6烷基。
在一些实施方案中，R 1选自CH 3。
在一些实施方案中，R 2选自C 3-10环烷基、3-10元杂环基或5-10元杂芳基，所述C 3-10环烷基、3-10元杂环基或5-10元杂芳基任选地被R 2b和/或R 2c取代。
在一些实施方案中，R 2选自3-10元杂环基或5-10元杂芳基，所述3-10元杂环基或5-10元杂芳基任选地被R 2b和/或R 2c取代。
在一些实施方案中，R 2选自4-8元杂环基或5-6元杂芳基，所述4-8元杂环基或5-6元杂芳基任选地被R 2b和/或R 2c取代。
在一些实施方案中，R 2选自任选地被R 2b和/或R 2c取代的以下基团：
Figure PCTCN2022074591-appb-000010
在一些实施方案中，R 2选自任选地被R 2b和/或R 2c取代的以下基团：
Figure PCTCN2022074591-appb-000011
Figure PCTCN2022074591-appb-000012
在一些实施方案中，R 2选自任选地被R 2b和/或R 2c取代的以下基团：
Figure PCTCN2022074591-appb-000013
Figure PCTCN2022074591-appb-000014
在一些实施方案中，R 2选自任选地被R 2b和/或R 2c取代的以下基团：
Figure PCTCN2022074591-appb-000015
时，R 3选自-O-CH 2CHF 2或-NH-C 3-6环烷基。
在一些实施方案中，R 2选自任选地被R 2b和/或R 2c取代的以下基团：
Figure PCTCN2022074591-appb-000016
时，R 3选自-O-CH 2CHF 2。
在一些实施方案中，R 2选自任选地被R 2b和/或R 2c取代的以下基团：
Figure PCTCN2022074591-appb-000017
时，R 3选自-O-CH 3。
在一些实施方案中，R 2b选自-OR 2c、-N(R 2c) 2、卤素、羟基、氰基、氨基、-C(O)R 2c、-C(O)NHR 2c、-C(O)N(R 2c) 2、-C(O)OR 2c、-S(O) 2R 2c、-S(O) 2N(R 2c) 2、-NHC(O)R 2c或-N(C 1-4烷基)C(O)R 2c。
在一些实施方案中，R 2b选自-OR 2c、-N(R 2c) 2、卤素、羟基、氰基、氨基、-C(O)R 2c、-C(O)N(R 2c) 2、-C(O)OR 2c、-S(O) 2R 2c、-S(O) 2N(R 2c) 2、-NHC(O)R 2c或-N(C 1-4烷基)C(O)R 2c。
在一些实施方案中，R 2b选自-OR 2c、卤素、羟基、氰基、氨基、-C(O)R 2c、-C(O)OR 2c、-S(O) 2R 2c、-C(O)NHR 2c或-NHC(O)R 2c。
在一些实施方案中，R 2b选自-OR 2c、卤素、羟基、氰基、氨基、-C(O)R 2c、-C(O)OR 2c、-S(O) 2R 2c或-C(O)NHR 2c。
在一些实施方案中，R 2b选自-OR 2c、卤素、羟基、氰基、-C(O)R 2c、-C(O)OR 2c、-S(O) 2R 2c或-C(O)NHR 2c。
在一些实施方案中，R 2b选自-OR 2c、卤素、羟基、氰基、-C(O)R 2c、-C(O)OR 2c或-S(O) 2R 2c。
在一些实施方案中，R 2b选自卤素、羟基、氰基、氨基、-C(O)R 2c、-S(O) 2R 2c或-C(O)NHR 2c。
在一些实施方案中，R 2b选自卤素、羟基、氰基、-C(O)R 2c、-S(O) 2R 2c或-C(O)NHR 2c。
在一些实施方案中，R 2b选自卤素、羟基、氰基、-C(O)R 2c或-S(O) 2R 2c。
在一些实施方案中，R 2c独立地选自C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基或5-10元杂芳基，所述C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基、5-10元杂芳基任选地被R 2d取代。
在一些实施方案中，R 2c选自C 1-6烷基、C 1-3氘代烷基、C 3-10环烷基或3-10元杂环基，所述C 1-6烷基、C 3-10环烷基或3-10元杂环基任选地被R 2d取代。
在一些实施方案中，R 2c选自C 1-6烷基、C 3-10环烷基或3-10元杂环基，所述C 1-6烷基、C 3- 10环烷基或3-10元杂环基任选地被R 2d取代。
在一些实施方案中，R 2c选自C 1-4烷基、C 3-6环烷基或4-6元杂环基，所述C 1-4烷基、C 3-6环烷基或4-6元杂环基任选地被R 2d取代。
在一些实施方案中，R 2d选自卤素、羟基、氰基或氨基。
在一些实施方案中，R 4选自卤素、羟基、氰基、氨基、C 1-6烷基、C 3-6环烷基或3-8元杂环基，所述C 1-6烷基、C 3-6环烷基或3-8元杂环基任选地被R 4a取代。
在一些实施方案中，R 4选自卤素、羟基、氰基、氨基或C 1-4烷基，所述C 1-4烷基任选地被R 4a取代。
在一些实施方案中，R 4选自卤素、氨基或C 1-4烷基，所述C 1-4烷基任选地被R 4a取代。
在一些实施方案中，R 3选自H、卤素、羟基、氰基、氨基、C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、C 3-6环烷基、3-8元杂环基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、5-10元杂芳基、-C(O)R 3a、-C(O)N(R 3a) 2、-C(O)OR 3a、-S(O) 2R 3a、-S(O) 2N(R 3a) 2、-NHC(O)R 3a或-N(C 1-4烷基)C(O)R 3a，所述C 1-6烷基、C 3-6环烷基、3-8元杂环基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)或5-10元杂芳基任选地被R 3b取代。
在一些实施方案中，R 3选自H、卤素、羟基、氰基、氨基、-NH-C 3-6环烷基、C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-C(O)R 3a、-C(O)OR 3a、-S(O) 2-C 1-4烷基或5-10元杂芳基，所述-NH-C 3-6环烷基、C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、 -O-C 3-6环烷基或5-10元杂芳基任选地被R 3b取代。
在一些实施方案中，R 3选自H、卤素、羟基、氰基、氨基、C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-S(O) 2-C 1-4烷基或5-10元杂芳基，所述C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基或5-10元杂芳基任选地被R 3b取代。
在一些实施方案中，R 3选自H、卤素、羟基、氰基、氨基、C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基或-S(O) 2-C 1-4烷基，所述C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基或-O-C 3-6环烷基任选地被R 3b取代。
在一些实施方案中，R 3选自H、卤素、羟基、氰基、氨基、-NH-C 3-6环烷基、C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、-O-C 1-6烷基、-C(O)R 3a、-C(O)OR 3a、-S(O) 2-C 1-4烷基或5-10元杂芳基，所述-NH-C 3-6环烷基、C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基任选地被R 3b取代。
在一些实施方案中，R 3选自H、卤素、羟基、氰基、氨基、C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、-O-C 1-6烷基、-S(O) 2-C 1-4烷基或5-10元杂芳基，所述C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基任选地被R 3b取代。
在一些实施方案中，R 3选自H、卤素、羟基、氰基、氨基、C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、-O-C 1-6烷基或-S(O) 2-C 1-4烷基，所述C 1-6烷基或-O-C 1-6烷基任选地被R 3b取代。
在一些实施方案中，R 3选自H、C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、-O-C 1-6烷基、-S(O) 2-C 1-4烷基或5-10元杂芳基，所述C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基任选地被R 3b取代。
在一些实施方案中，R 3选自H、C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、-O-C 1-6烷基或-S(O) 2-C 1-4烷基，所述C 1-6烷基或-O-C 1-6烷基任选地被R 3b取代。
在一些实施方案中，R 3选自H、C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基或-O-C 1-6烷基，所述C 1-6烷基或-O-C 1-6烷基任选地被R 3b取代。
在一些实施方案中，R 3选自H、氨基、-NH-C 3-6环烷基、-C(O)R 3a、-C(O)OR 3a、C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基，所述-NH-C 3-6环烷基、C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基任选地被R 3b取代。
在一些实施方案中，R 3选自H、氨基、-NH-环丁基、-C(O)R 3a、-C(O)OR 3a、C 1-3烷基、-O-C 1-3烷基或吡唑基，所述-NH-环丁基、C 1-3烷基、-O-C 1-3烷基或吡唑基任选地被R 3b取代。
在一些实施方案中，R 3选自H、氨基、-O-CH 3、CF 3、-O-CH 2CHF 2、-O-CF 2H、-C(O)CH 3、C(O)OH、
Figure PCTCN2022074591-appb-000018
在一些实施方案中，R 3选自H、C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基，所述C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基任选地被R 3b取代。
在一些实施方案中，R 3选自H、C 1-6烷基或-O-C 1-6烷基，所述C 1-6烷基或-O-C 1-6烷基任选地被R 3b取代。
在一些实施方案中，R 3选自-C(O)R 3a、-C(O)OR 3a、C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基，所述C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基任选地被R 3b取代。
在一些实施方案中，R 3选自-O-CH 3、-O-CH 2CHF 2、-O-CF 2H、-C(O)CH 3、C(O)OH或
Figure PCTCN2022074591-appb-000019
在一些实施方案中，R 3a选自H或CH 3。
在一些实施方案中，R 3b独立地选自卤素、羟基、氰基、氨基或3-8元杂环基。
在一些实施方案中，R 3b独立地选自卤素或C 1-6烷基。
在一些实施方案中，R 3b独立地选自F或CH 3。
在一些实施方案中，R 3b独立地选自卤素或C 1-6烷基。
在一些实施方案中，R 3b独立地选自卤素。
在一些实施方案中，R 2选自以下基团：
Figure PCTCN2022074591-appb-000020
Figure PCTCN2022074591-appb-000021
在一些实施方案中，R 5选自C 1-3氘代烷基、C 1-3烷基或C 1-3卤代烷基。
在一些实施方案中，R 5选自CH 3、CD 3、CF 3、CHF 2或CH 2F。
在一些实施方案中，R 6选自H、氘、C 1-3氘代烷基、C 1-3烷基或C 1-3卤代烷基。
在一些实施方案中，R 6选自H、氘、CH 3或CD 3。
在一些实施方案中，n选自0、1或2。
在一些实施方案中，n为2。
在一些实施方案中，式(I)所示化合物或其药学上可接受的盐选自式(II)所示化合物或其药学上可接受的盐，
Figure PCTCN2022074591-appb-000022
其中，A、L、R 1、R 2、R 4、R 5、R 6、n如上文的定义，R 3选自羟基、氰基、氨基、C 1-3氘 代烷基、-O-C 1-3氘代烷基、C 1-6烷基、C 3-6环烷基、3-8元杂环基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、5-10元杂芳基、-C(O)R 3a、-C(O)N(R 3a) 2、-C(O)OR 3a、-S(O) 2R 3a、-S(O) 2N(R 3a) 2、-NHC(O)R 3a或-N(C 1-4烷基)C(O)R 3a，所述C 1-6烷基、C 3-6环烷基、3-8元杂环基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)或5-10元杂芳基任选地被R 3b取代；所述R 3a独立地选自H或C 1-6烷基；所述R 3b选自卤素、羟基、氰基、氨基或3-8元杂环基。
在一些实施方案中，R 3选自羟基、氰基、氨基、C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、-O-C 1-6烷基、-C(O)R 3a、-C(O)OR 3a、-S(O) 2-C 1-4烷基或5-10元杂芳基，所述C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基任选地被R 3b取代。
在一些实施方案中，R 3选自羟基、氰基、氨基、C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、-O-C 1-6烷基、-S(O) 2-C 1-4烷基或5-10元杂芳基，所述C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基任选地被R 3b取代。
在一些实施方案中，R 3选自羟基、氰基、氨基、C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、-O-C 1-6烷基或-S(O) 2-C 1-4烷基，所述C 1-6烷基或-O-C 1-6烷基任选地被R 3b取代。
在一些实施方案中，R 3选自C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、-O-C 1-6烷基、-C(O)R 3a、-C(O)OR 3a、-S(O) 2-C 1-4烷基或5-10元杂芳基，所述C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基任选地被R 3b取代。
在一些实施方案中，R 3选自C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、-O-C 1-6烷基、-S(O) 2-C 1-4烷基或5-10元杂芳基，所述C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基任选地被R 3b取代。
在一些实施方案中，R 3选自C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、-O-C 1-6烷基或-S(O) 2-C 1-4烷基，所述C 1-6烷基或-O-C 1-6烷基任选地被R 3b取代。
在一些实施方案中，R 3选自H、-C(O)R 3a、-C(O)OR 3a、C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基，所述C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基任选地被R 3b取代。
在一些实施方案中，R 3选自-C(O)R 3a、-C(O)OR 3a、C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基，所述C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基任选地被R 3b取代。
在一些实施方案中，R 3选自H、C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基，所述C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基任选地被R 3b取代。
在一些实施方案中，式(I)所示化合物或其药学上可接受的盐选自式(III)所示化合物或其药学上可接受的盐，
Figure PCTCN2022074591-appb-000023
其中，环A、L、YR 3、R 4、R 5、R 6、n如上文的定义，R 1选自氰基、C 1-6烷基或C 3-6环烷基；R 2选自任选地被R 2b和/或R 2c取代的以下基团：
Figure PCTCN2022074591-appb-000024
Figure PCTCN2022074591-appb-000025
在一些实施方案中，式(I)所示化合物或其药学上可接受的盐选自式(IV)所示化合物或其药学上可接受的盐，
Figure PCTCN2022074591-appb-000026
其中，环A、L、R 3、R 4、R 5、R 6、n如上文的定义，R 1选自氰基、C 1-6烷基或C 3-6环烷基，R 2选自任选地被R 2b和/或R 2c取代的以下基团：
Figure PCTCN2022074591-appb-000027
Figure PCTCN2022074591-appb-000028
在一些实施方案中，式(I)所示化合物或其药学上可接受的盐选自式(V)所示化合物或其药学上可接受的盐，
Figure PCTCN2022074591-appb-000029
其中，环A、L、R 3、R 4、R 5、R 6、n如上文的定义，R 1选自氰基、C 1-6烷基或C 3-6环烷基，R 2选自任选地被R 2b和/或R 2c取代的以下基团：
Figure PCTCN2022074591-appb-000030
Figure PCTCN2022074591-appb-000031
在一些实施方案中，式(I)所示化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐，
Figure PCTCN2022074591-appb-000032
Figure PCTCN2022074591-appb-000033
Figure PCTCN2022074591-appb-000034
Figure PCTCN2022074591-appb-000035
Figure PCTCN2022074591-appb-000036
Figure PCTCN2022074591-appb-000037
进一步，本发明还提供了一种药物组合物，所述药物组合物包含式(I)所示化合物或其药学上可接受的盐，以及药学上可接受的辅料。
进一步，本发明涉及的式(I)化合物所示或其药学上可接受的盐，或其药物组合物在制备预防或者治疗与SOS1相关疾病的药物中的用途。
进一步，本发明涉及的式(I)化合物所示或其药学上可接受的盐，或其药物组合物在预防或者治疗与SOS1相关疾病中的用途。
进一步，本发明涉及预防或者治疗SOS1相关疾病的式(I)化合物或其药学上可接受的盐，或其药物组合物。
本发明还涉及预防或治疗SOS1相关疾病的方法，该方法包括给以患者治疗上有效剂量的包含本发明所述的式(I)化合物或其药学上可接受的盐的药物制剂。进一步，所述SOS1相关疾病选自癌症。
另一方面，本发明提供式(Ⅰ)化合物或其药学上可接受的盐、或其药物组合物在制备预防或者治疗癌症药物中的用途。
另一方面，本发明提供式(Ⅰ)化合物或其药学上可接受的盐、或其药物组合物在预防或者治疗癌症中的用途。
另一方面，本发明提供预防或者治疗癌症的式(Ⅰ)化合物或其药学上可接受的盐、或其药物组合物。
另一方面，本发明提供预防或治疗癌症的方法，包括对给以患者治疗上给予治疗有效量的式(I)化合物或其药学上可接受的盐、或其药物组合物。
术语定义和说明
除非另有说明，本发明说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本发明说明书记载的范围内。
术语“药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐，包括无机酸和碱、有机酸和碱的盐。
本发明的化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、对映异构体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
本文中消旋体或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985，62:114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮，如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。
术语“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐或前体药物与其它化学组分的混合物，其它组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进化合物对生物体的给药。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取 代，氧代不会发生在芳香基上。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH 2CH 3)、单取代的(如CH 2CH 2F)、多取代的(如CHFCH 2F、CH 2CHF 2等)或完全被取代的(CF 2CF 3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
术语“C 1-6烷基”应理解为表示具有1、2、3、4、5或6个碳原子的直链或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1，2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3，3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等。术语“C 1-3烷基”应理解为表示具有1、2、3个碳原子的直链或支链饱和一价烃基。
术语“卤素”指氟、氯、溴或碘，优选为氟、氯或溴。
术语“C 3-10环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～10个碳原子。环烷基的例子如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基，或者是双环烃基如十氢化萘环。根据本发明，所述双环烃环包括桥环、螺环或并环结构。术语“C 3- 8环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～8个原子。术语“C 3-6环烷基”应理解为表示饱和的一价单环或双环烃环，其具有3～6个原子。
术语“C 6-10芳基”应理解为具有6、7、8、9、10个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环，特别是具有6个碳原子的环(“C 6芳基”)，例如苯基；或者具有9个碳原子的环(“C 9芳基”)，例如茚满基或茚基，或者具有10个碳原子的环(“C 10芳基”)，例如四氢化萘基、二氢萘基或萘基。
术语“3-10元杂环基”应理解为具有3-10个环原子的饱和的或部分不饱和的一价单环或双环。所述双环包括桥环、螺环、稠环。所述杂环基中的“杂”包括但不限于独立地选自N、O、S、C(＝O)、C(＝S)、S(＝O)、S(O) 2的原子和/或原子团。特别地，所述杂环基可以是单环的，包括但不限于：4元环，如氮杂环丁烷基、氧杂环丁烷基；5元环，如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基；或6元环，如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、1,1-二氧硫代吗啉基、哌嗪基、三噻烷基、
Figure PCTCN2022074591-appb-000038
或7元环，如二氮杂环庚烷基或
Figure PCTCN2022074591-appb-000039
任选地，所述杂环基可以是双环的，例如但不限于5,5元环，如六氢环戊并[c]吡咯-2(1H)-基环，或者5,6元双环，如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。所述的环可以是部分不饱和的，即它可以包含一个或多个双键，例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基或
Figure PCTCN2022074591-appb-000040
或者，它可以是苯并稠合的，例如但不限于二氢异喹啉基。术语“3-8元杂环基”应理解为具有3-8个环原子的饱和的或部分不饱和的一价单环或双环。术语“3-6元杂环基”应理解为具有3-6个环原子的饱和的或部分不饱和的一价单环或双环。
术语“苯并5-7元杂环基”应理解为包括苯并5-7个环原子的饱和的或部分不饱和杂环形成的双环，所述双环为稠环，所述苯并5-7元杂环基中的“杂”包括但不限于独立地选自N、O、S、C(＝O)、C(＝S)、S(＝O)、S(O) 2的原子和/或原子团。特别的，苯并5-7元杂环基可以包括但 不限于：苯并四氢呋喃基、苯并四氢吡咯基、苯并四氢吡啶基等。
术语“5-10元杂芳基”应理解为包括这样的一价单环、双环或三环芳香族环系，特别是5或6或9或10个环原子，另外在每一种情况下可为苯并稠合的。所述杂芳基中的“杂”表示芳香环中包括但不限于独立地选自N、O、S、C(＝O)、C(＝S)、S(＝O)、S(O) 2的原子和/或原子团。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基等以及它们的苯并衍生物，例如苯并呋喃基、苯并噻吩基、苯并噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物，例如喹啉基、喹唑啉基、异喹啉基等；或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物；或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。
术语“苯并5-7元杂芳基”应理解为包括苯并5-7个环原子不饱和杂环形成的双环，所述双环为稠环，所述苯并5-7元杂芳基中的“杂”表示芳香环中包括但不限于独立地选自N、O、S、C(＝O)、C(＝S)、S(＝O)、S(O) 2的原子和/或原子团。特别的，苯并5-7元杂芳基可以包括但不限于：苯并噻吩基、苯并噻唑基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、喹啉基、喹唑啉基、异喹啉基等。
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“治疗有效量”意指(i)治疗特定疾病、病况或疾病，(ii)减轻、改善或消除特定疾病、病况或疾病的一种或多种症状，或(iii)延迟本文中所述的特定疾病、病况或疾病的一种或多种症状发作的本发明化合物的用量。构成“治疗有效量”的本发明化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本发明公开内容而确定。
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。适用于上述制剂的典型的“药学上可接受的载体”的实例为：糖类，淀粉类，纤维素及其衍生物等在药物制剂中常用到的辅料。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。词语“包括(comprise)”、“含有(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。
本文所述的化合物的所有施用方法中，每天给药的剂量为0.01mg/kg体重到200mg/kg体重。
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。
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
具体实施方式
以下实施例详细说明发明的技术方案，但本发明的保护范围包括但不限于此。
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。NMR位移的单位为10 - 6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)；“IC 50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。
缩略词：
Et 3N和TEA：三乙胺；ACN：乙腈；DIPEA和DIEA：N,N-二异丙基乙胺；dioxane：1,4-二氧六环；DMF：N,N-二甲基甲酰胺；AcOH：乙酸；Ac 2O：乙酸酐；Cs 2CO 3：碳酸铯；THF：四氢呋喃；DMSO：二甲基亚砜；DCM：二氯甲烷；DMAP:4-二甲氨基吡啶；TFA：三氟乙酸；Pd(dppf)Cl 2：1,1'-二(二苯膦基)二茂铁二氯化钯；Pd 2(dba) 3：三(亚苄基丙酮)二钯；X-Phos：2-双环己基磷-2',4',6'-三异丙基联苯；POCl 3：三氯氧磷；t-Bu-xphos：2-二-叔丁膦基-2',4',6'-三异丙基联苯；BrettePhos Pd G3：甲磺酸(2-二环己基膦-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯基-2-基)钯；BrettPhos：2-(二环己基膦)3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯；t-BuONa：叔丁醇钠；：对甲苯磺酸一水合物；SeO 2：二氧化硒；(CF 3CO) 2O：三氟甲磺酸酐；xantphos：4,5-双二苯基膦-9,9-二甲基氧杂蒽；HATU：2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；MeNH 3Cl：甲胺盐酸盐；BINAP：1,1'-联萘-2,2'-双二苯膦；DCE：1,2-二氯乙烷；Tf 2O：三氟甲磺酸酐；NBS:N-溴代丁二酰亚胺；PyAOP：(3H-1,2,3-三唑并[4,5-b]吡啶-3-氧基)三-1-吡咯烷基六氟磷酸盐；DBU：1,8-二氮杂双环[5.4.0]十一碳-7-烯；Ru-phos：2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯；DAST：二乙胺基三氟化硫；NMP：N-甲基吡咯烷酮；HCF 2OTf：二氟甲基三氟甲磺酸盐；NH 2PMB：4-甲氧基苄胺；Tributyl(1-ethoxyvinyl)stannane：三丁基(1-乙氧基乙烯)锡；Pd(PPh 3) 2Cl 2：双三苯基磷二氯化钯；Me 3S(O)I：三甲基碘化亚砜；t-BuOH：叔丁醇；t-BuOK：叔丁醇钾；PMBCl：对甲氧基苯甲基氯；PhNTF 2：苯基双(三氟甲烷磺酰)亚胺；DPPP：1,3-双(二苯膦)丙烷。
实施例1：(R)-N-(1-(3-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-6-吗啉代喹啉-4-胺
Figure PCTCN2022074591-appb-000041
步骤1：(R)-6-溴-7-甲氧基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹啉-4-胺的合成
Figure PCTCN2022074591-appb-000042
将6-溴-4-氯-7-甲氧基喹啉(150mg，0.55mmol)、(R)-1-(3-硝基-5-(三氟甲基)苯基)乙烷-1-胺(155mg，0.66mmol)，N,N-二异丙基乙胺(129mg，1.00mmol)加入到3mL二甲基亚砜中，氩气保护下130℃搅拌反应，8小时后反应完毕。将反应液加入到30mL饱和氯化钠水溶液中，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，过滤，有机层浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤2：(R)-7-甲氧基-6-吗啉代-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹啉-4-胺的合成
Figure PCTCN2022074591-appb-000043
将(R)-6-溴-7-甲氧基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹啉-4-胺(100mg，0.21mmol)，吗啡啉(18.5mg，0.21mmol)，三二亚苄基丙酮二钯(12.2mg，0.01mmol)，2-二环己基磷-2,4,6-三异丙基联苯(20.3mg，0.04mmol)，碳酸铯(138mg，0.45mmol)加入到2mL二氧六环中，氩气保护下100℃搅拌，3小时后反应完毕。加入40mL水，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，过滤，有机层浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤3：(R)-N-(1-(3-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-6-吗啉代喹啉-4-胺的合成
Figure PCTCN2022074591-appb-000044
将铁粉(25.8mg，0.46mmol)和氯化铵(1.23mg，0.02mmol)溶于2mL水，加热至100℃回流半小时；将(R)-7-甲氧基-6-吗啉代-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹啉-4-胺(55.0mg，0.11mmol)的乙醇溶液(2mL)加入反应体系中，100℃搅拌4小时后反应完毕。加入20mL水，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，过滤，有机层浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
1H NMR(400MHz,CDCl 3)δ8.27(d,J＝5.4Hz,1H),7.35(s,1H),7.06(s,1H),7.00(s,1H),6.81(d,J＝6.81Hz,2H),6.11(d,J＝5.4Hz,1H),5.01-4.97(m,1H),4.68-4.60(m,1H),3.99-3.96(m,7H),3.85(s,2H),3.25-3.18(m,4H),1.69(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):447.2.
实施例2：(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-吗啉代喹啉-4-胺
Figure PCTCN2022074591-appb-000045
步骤1：(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基喹啉-4-胺的合成
Figure PCTCN2022074591-appb-000046
将6-溴-4-氯-7-甲氧基喹啉(200mg，0.73mmol)，(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺(166mg，0.88mmol)，N,N-二异丙基乙胺(189mg，1.47mmol)溶于3mL二甲基亚砜中，氩气保护下于135℃下搅拌14小时后反应完毕。将反应液加入到40mL饱和氯化钠水溶液中，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，过滤，有机层浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤2：(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-吗啉代喹啉-4-胺的合成
Figure PCTCN2022074591-appb-000047
将(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基喹啉-4-胺(90.0mg，0.21mmol)，吗啡啉(27.7mg，0.31mmol)，三(二亚苄基丙酮)二钯(19.4mg，0.02mmol)，2-双环己基羰基-2'，4'，6'-三取代基联苯(20.2mg，0.04mmol)，碳酸铯(138mg，0.42mmol)溶于2mL二氧六环中，氩气保护下100℃反应3小时反应完毕。将反应液加入到30mL水中，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，过滤，有机层浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.10(d,J＝5.3Hz,1H),7.65(s,1H),7.58(t,J＝7.5Hz,1H),7.51(t,J＝7.1Hz,1H),7.40-7.13(m,4H),6.01(d,J＝5.4Hz,1H),5.07-5.03(m,1H),3.89(s,3H),3.81(t,J＝4.6Hz,4H),3.17-3.07(m,4H),1.66(d,J＝6.8Hz,3H).
LC/MS(m/z,MH +):432.2.
实施例3：(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)喹啉-4-胺
Figure PCTCN2022074591-appb-000048
将(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基喹啉-4-胺(60.0mg，0.14mmol)，1-(四氢-2H-吡喃-4-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑(58.9mg，0.21mmol)，1,1'-二(二苯膦基)二茂铁二氯化钯(10.3mg，0.01mmol)，碳酸钾(39.0mg，0.28mmol)溶于2mL二氧六环/水混合溶液中(V:V＝10/1)，氩气保护下90℃搅拌2小时后反应完毕。加入20mL水稀释，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，过滤，有机层浓缩后，残余物经柱层析(二氯甲烷/甲醇梯度洗脱)分离，得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.27(s,1H),8.18-8.16(m,2H),7.62-7.58(m,1H),7.54-7.50(m,1H),7.40-7.13(m,4H),6.04(d,J＝5.5Hz,1H),5.10-5.07(m,1H),4.52-4.48(m,1H),4.02-3.94(m,5H),3.56-3.44(m,2H),2.06-2.01(m,4H),1.68(d,J＝6.8Hz,3H).
LC/MS(m/z,MH +):497.2.
实施例4：(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-(1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)喹啉-4-胺
Figure PCTCN2022074591-appb-000049
参照实施例3制备方法，不同的是将1-(四氢-2H-吡喃-4-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑替换为1-(氧杂环丁烷-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.60(s,1H),8.36(s,1H),8.31(s,1H),8.17(d,J＝5.3Hz,1H),7.62-7.58(m,1H),7.54-7.50(m,1H),7.40-7.13(m,4H),6.04(d,J＝5.5Hz,1H),5.72-5.68(m,1H),5.11-5.07(m,1H),4.98-4.95(m,4H),3.97(s,3H),1.68(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):469.2.
实施例5：(R)-1-(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-1H-吡唑-1-基)-2-甲基丙-2-醇
Figure PCTCN2022074591-appb-000050
参照实施例3制备方法，不同的是将1-(四氢-2H-吡喃-4-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑替换为2-甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑-1-基)丙-2-醇，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.59(s,1H),8.23(s,1H),8.17-8.16(m,2H),7.62-7.58(m,1H),7.54-7.50(m,1H),7.40-7.13(m,4H),6.03(d,J＝5.4Hz,1H),5.10-5.07(m,1H),4.78(s,1H),4.09(s,2H),3.97(s,3H),1.68(d,J＝6.7Hz,3H),1.12(s,6H).
LC/MS(m/z,MH +):485.2.
实施例6：(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-(2-氧杂-6-氮杂-螺[3.3]庚-6-基)喹啉-4-胺
Figure PCTCN2022074591-appb-000051
参照实施例2制备方法，不同的是将步骤2中的吗啡啉替换为2-氧杂-6-氮杂-螺[3,3]庚烷，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.00(d,J＝5.2Hz,1H),7.58-7.49(m,2H),7.39-7.00(m,5H),5.98(d,J＝5.3Hz,1H),5.06-5.02(m,1H),4.76(s,4H),4.18-4.12(m,4H),3.85(s,3H),1.67(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):444.2.
实施例7：(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-(1-甲基-1H-吡唑-4-基)喹啉-4-胺
Figure PCTCN2022074591-appb-000052
参照实施例3制备方法，不同的是将1-(四氢-2H-吡喃-4-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑替换为1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.57(s,1H),8.22(s,1H),8.18-8.14(m,2H),7.60(t,J＝7.5Hz,1H),7.51(t,J＝7.1Hz,1H),7.40-7.13(m,4H),6.03(d,J＝5.4Hz,1H),5.16-5.00(m,1H),3.97(s,3H),3.95(s,3H),1.68(d,J＝6.8Hz,3H).
LC/MS(m/z,MH +):426.17.
实施例8：(R)-4-(4-(((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)硫代吗啉-1,1-二氧化物
Figure PCTCN2022074591-appb-000053
参照实施例2制备方法，不同的是将步骤2中的吗啡啉替换为硫代吗啉-1,1-二氧化物，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.12(d,J＝5.2Hz,1H),7.82(s,1H),7.57(t,J＝7.4Hz,1H),7.51(t,J＝6.9Hz,1H),7.40-7.13(m,4H),6.01(d,J＝5.4Hz,1H),5.09-5.02(m,1H),3,91(s,3H),3.62-3.52(m,4H),3.33-3.28(m,4H),1.65(t,J＝6.7Hz,3H).
LC/MS(m/z,MH +):480.2.
实施例9：(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)吡啶并[2,3-d]嘧啶-4胺
Figure PCTCN2022074591-appb-000054
步骤1：6-溴-4-氯-2-甲基吡啶并[2,3-d]嘧啶的合成
Figure PCTCN2022074591-appb-000055
将6-溴-2-甲基-3H-吡啶并[2,3-d]嘧啶-4-酮(500mg,2.08mmol)加入到反应瓶中，加入三氯氧磷(5mL)和N,N-二异丙基乙胺(404mg,3.12mmol)，反应液100℃加热搅拌，1小时后反应完毕。将反应液减压浓缩，除去大部分三氯氧磷，然后加入少量二氯甲烷，将混合物倒入冰中，待冰完全融化，用饱和碳酸氢钠调节体系pH至7-8，然后用乙酸乙酯萃取(60mL×3)，合并有机层，饱和食盐水洗涤，无水硫酸钠充分干燥，然后过滤，滤液减压浓缩后得标题化合物。
步骤2：(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[2,3-d]嘧啶-4-胺的合成
Figure PCTCN2022074591-appb-000056
将6-溴-4-氯-2-甲基吡啶并[2,3-d]嘧啶(450mg,1.74mmol)，(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺(362mg,1.91mmol)，加到反应瓶中，加入二甲基亚砜(7mL)和N,N-二异丙基乙胺(675mg,5.22mmol)，反应液加热至90℃，8小时后反应完毕。将反应液冷却后倒入水中，然后用乙酸乙酯萃取(50mL×3)，合并有机层，水洗，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离纯化，得标题化合物。
步骤3：(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-(1-(四氢-2H-吡喃-4-基)-1H-吡唑-4-基)吡啶并[2,3-d]嘧啶-4胺的合成
Figure PCTCN2022074591-appb-000057
将(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[2,3-d]嘧啶-4-胺(50mg,122μmol)，1-(四氢吡喃-4-基)-1H-吡唑-4-硼酸频哪醇酯(40.6mg,0.15mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(8.90mg,0.01mmol)，碳酸钾(33.6mg,0.24mmol)加入到反应瓶中，加入二氧六环和水的混合溶剂(v:v＝10：1，1.6mL)，氩气保护下加热至100℃，5小时后反应完毕。将反应液冷却后减压浓缩经柱层析(二氯甲烷/甲醇梯度洗脱)分离，制得标题化合物。
DMSO-d6 δ H9.24-9.23(m,1H),8.97-8.95(m,1H),8.61(d,J＝7.1Hz,1H),8.44(s,1H),8.08(s,1H),7.71(t,J＝7.2Hz,1H),7.52(t,J＝6.8Hz,1H),7.38-7.11(m,2H),5.84-5.77(m,1H),4.52-4.44(m,1H),4.01-3.98(m,2H),3.53-3.47(m,2H),2.38(s,3H),2.07-1.94(m,4H),1.64(d,J＝7.0Hz,3H).
LC/MS(m/z,MH +):483.2.
实施例10：(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-(1-(氧杂环丁烷-3-基)-1H-吡唑-4-基)吡啶并[2,3-d]嘧啶-4-胺
Figure PCTCN2022074591-appb-000058
参照实施例9的制备方法，将1-(四氢吡喃-4-基)-1H-吡唑-4-硼酸频哪醇酯换成1-(氧杂环丁烷-3-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑，制得标题化合物。
DMSO-d6 δ H9.26-9.25(m,1H),9.01-9.00(m,1H),8.62(d,J＝7.1Hz,1H),8.55(s,1H),8.21(s,1H),7.70(t,J＝7.3Hz,1H),7.52(t,J＝6.9Hz,1H),7.38-7.11(m,2H),5.84-5.77(m,1H),5.71-5.60(m,1H),5.01-4.93(m,4H),2.39(s,3H),1.65(d,J＝7.0Hz,3H).
LC/MS(m/z,MH +):455.1.
实施例11：(R)-1-(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)-2-甲基丙烷-2-醇
Figure PCTCN2022074591-appb-000059
参照实施例9的制备方法，将1-(四氢吡喃-4-基)-1H-吡唑-4-硼酸频哪醇酯换成2-甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二噁硼烷-2-基)-1H-吡唑-1-基)丙烷-2-醇，制得标题化合物。
DMSO-d6 δ H9.25-9.24(m,1H),8.99-8.98(m,1H),8.64(d,J＝7.2Hz,1H),8.29(s,1H),8.08(s,1H),7.70(t,J＝7.4Hz,1H),7.52(t,J＝6.9Hz,1H),7.38-7.11(m,2H),5.84-5.77(m,1H),4.84(s,1H),4.09(s,2H),2.38(s,3H),1.64(d,J＝7.0Hz,3H),1.12(s,6H).
LC/MS(m/z,MH +):471.1.
实施例12：(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-吗啉基吡啶并[2,3-d]嘧啶-4-胺
Figure PCTCN2022074591-appb-000060
将(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[2,3-d]嘧啶-4-胺(150mg,0.37mmol)，吗啉(127mg,1.46mmol)，碳酸铯(238mg,730μmol)，2-二环己基磷-2,4,6-三异丙基联苯(34.8mg,72.9μmol)和三(二亚苄基丙酮)二钯(33.4mg,0.04mmol)加入到反应瓶中，加入无水1,4-二氧六环(6mL)，氩气保护下加热至100℃，8小时后反应完毕。将反应液冷却后过滤，滤液减压浓缩后经柱层析(二氯甲烷/甲醇梯度洗脱)分离纯化，得标题化合物。
DMSO-d6 δ H8.88(d,J＝2.9Hz,1H)，8.46(d,J＝7.2Hz,1H),8.05(d,J＝3.0Hz,1H),7.66(t,J＝7.2Hz,1H),7.50(t,J＝6.9Hz,1H),7.38-7.11(m,2H),5.83-5.76(m,1H),3.83-3.81(m,4H),3.31-3.29(m,4H),2.33(s,3H),1.61(d,J＝7.1Hz,3H).
LC/MS(m/z,MH +):418.1.
实施例13：N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-6-(((2S，6R)-2,6-二甲基吗啉基)-2-甲基吡啶并[2,3-d]嘧啶-4-胺
Figure PCTCN2022074591-appb-000061
参照实施例12的制备方法，将吗啉换成顺式-2,6-二甲基吗啉，制得标题化合物。
DMSO-d6 δ H8.89(d,J＝2.8Hz,1H),8.44(d,J＝7.2Hz,1H),7.99(d,J＝2.8Hz,1H),7.67(t,J＝7.3Hz,1H),7.50(t,J＝6.9Hz,1H),7.38-7.11(m,2H),5.83-5.76(m,1H),3.79-3.75(m,4H),2.45-2.39(m,2H),2.33(s,3H),1.62(d,J＝7.1Hz,3H),1.21(d,J＝6.1Hz,6H).
LC/MS(m/z,MH +):446.1.
实施例14：(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-(2-氧杂-6-氮杂-螺[3.3]庚-6-基)吡啶并[2,3-d]嘧啶-4-胺
Figure PCTCN2022074591-appb-000062
参照实施例12的制备方法，将吗啉替换为2-氧杂-6-氮杂-螺[3.3]庚烷，制得标题化合物。
DMSO-d6 δ H8.39-8.35(m,2H),7.69-7.64(m,2H),7.50(t,J＝6.4Hz,1H),7.38-7.10(m,2H),5.81-5.74(m,1H),4.77(s,4H),4.20-4.16(m,4H),2.32(s,3H),1.61(d,J＝7.1Hz,3H).
LC/MS(m/z,MH +):430.1.
实施例15：(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-(1-甲基-1H-吡唑-4-基)吡啶并[2,3-d]嘧啶-4-胺
Figure PCTCN2022074591-appb-000063
参照实施例9的制备方法，将1-(四氢吡喃-4-基)-1H-吡唑-4-硼酸频哪醇酯替换为1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑，制得标题化合物。
DMSO-d6 δ H9.21(d,J＝2.1Hz,1H),8.97(d,J＝2.1Hz,1H),8.60(d,J＝7.1Hz,1H),8.31(s,1H),8.05(s,1H),7.71(t,J＝7.3Hz,1H),7.52(t,J＝6.9Hz,1H),7.39-7.11(m,2H),5.84-5.77(m,1H),3.93(s,3H),2.39(s,3H),1.65(d,J＝7.0Hz,3H).
LC/MS(m/z,MH +):413.2.
实施例16：N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)蝶啶-4-胺
Figure PCTCN2022074591-appb-000064
步骤1：3-氨基-6-氯-5-甲氧基吡嗪-2-羧酸甲酯
Figure PCTCN2022074591-appb-000065
将3-氨基-5,6-二氯吡嗪-2-羧酸甲酯(8.90g,40.2mmol)，甲醇钠(2.20g,40.2mmol)加入到90mL甲醇中，80℃应14小时结束，冷却后抽滤，滤饼烘干得标题化合物。
步骤2：3-氨基-6-氯-5-甲氧基吡嗪-2-羧酸
Figure PCTCN2022074591-appb-000066
将3-氨基-6-氯-5-甲氧基吡嗪-2-羧酸甲酯(5.50g,25.2mmol)加入到50mL甲醇中，加入氢氧化钠(4.00g,0.10mmol)的15mL水溶液，90℃下加热搅拌30min反应完毕。反应液浓缩，加水，调pH至3～5，析出固体。抽滤，滤饼烘干得标题化合物。
步骤3：6-氯-7-甲氧基-2-甲基-4H-吡嗪并[2,3-d][1,3]恶嗪-4-酮
Figure PCTCN2022074591-appb-000067
将3-氨基-6-氯-5-甲氧基吡嗪-2-羧酸(4.50g,22.1mmol)加入到30mL乙酸酐中，加热至100℃搅拌，2个小时后反应完毕，浓缩制得标题化合物。
步骤4：6-氯-7-甲氧基-2-甲基蝶啶-4(3H)-酮
Figure PCTCN2022074591-appb-000068
将6-氯-7-甲氧基-2-甲基-4H-吡嗪并[2,3-d][1,3]恶嗪-4-酮(2.00g,8.80mmol)加入到10mL氨甲醇溶液中，40℃反应5小时，反应液浓缩后制得标题化合物。
步骤5：(S)-7-甲氧基-2-甲基-6-((四氢呋喃-3-基)氧基)蝶啶-4(3H)-酮
Figure PCTCN2022074591-appb-000069
将(S)-四氢呋喃-3-醇(290mg,3.30mmol)加入到5mL四氢呋喃中，加入NaH(132mg,3.30mmol)，20℃反应10min，加入6-氯-7-甲氧基-2-甲基蝶啶-4(3H)-酮(500mg,2.20mmol)，升至90℃搅拌2个小时后反应完毕，浓缩后制得标题化合物。
步骤6：(S)-7-甲氧基-2-甲基-6-((四氢呋喃-3-基)氧基)蝶啶-4-基-2,4,6-三异丙基苯磺酸酯
Figure PCTCN2022074591-appb-000070
将((S)-7-甲氧基-2-甲基-6-((四氢呋喃-3-基)氧基)蝶啶-4(3H)-酮(600mg,2.10mmol)，2,4,6-三异丙基苯磺酰氯(760mg,2.50mmol)，N,N-二异丙基乙胺(541mg,4.20mmol)，4-二甲氨基吡啶(25.0mg,0.20mmol)加入到10mL DCM(二氯甲烷)中，20℃搅拌1个小时后反应结束，反应液直接用于下一步。
步骤7：7-甲氧基-2-甲基-N-((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)-6-(((S)-四氢呋喃-3-基)氧基)蝶啶-4-胺
Figure PCTCN2022074591-appb-000071
将(S)-7-甲氧基-2-甲基-6-((四氢呋喃-3-基)氧基)蝶啶-4-基-2,4,6-三异丙基苯磺酸酯(544mg,2.10mmol)，三乙胺(424mg,4.20mmol)，(R)-1-(3-硝基-5-(三氟甲基)苯基)乙烷-1-胺(491mg,2.10mmol)置于10mL二甲基亚砜中，80℃搅拌20min后反应结束。加入50mL水，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，过滤，滤液浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，制得标题化合物。
步骤8：N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-甲氧基-2-甲基-6-(((S)-四氢呋喃-3-基)氧基)蝶啶-4-胺
Figure PCTCN2022074591-appb-000072
将7-甲氧基-2-甲基-N-((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)-6-(((S)-四氢呋喃-3-基)氧基)蝶啶-4-胺(100mg,0.20mmol)，铁粉(61.0mg,1.10mmol)，氯化铵(5.40mg,0.10mmol)溶于5mL乙醇中，加入2mL水，90℃下搅拌1小时后反应结束。趁热过滤，滤液浓缩后，所得残余物经柱层析(二氯甲烷/甲醇梯度洗脱)分离，制得标题化合物。
DMSO-d6 δ H7.86-7.80(m,1H),6.91(s,1H),6.84(s,1H),6.70(s,1H),5.98-5.92(m,1H),5.65-5.40(m,2H),4.12-4.02(m,4H),3.93-3.74(m,4H),2.40-2.31(m,4H),2.11-2.06(m,1H),1.57(d,J＝7.0Hz,3H).
LC/MS(m/z,MH +):465.2.
实施例17 (R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-(1-(甲基磺酰基)-1H-吡唑-4-基)喹啉-4-胺
Figure PCTCN2022074591-appb-000073
参照实施例3制备方法，不同的是将1-(四氢-2H-吡喃-4-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑替换为1-(甲基磺酰基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.72(s,2H),8.66(s,1H),8.22(d,J＝5.4Hz,1H),7.61(t,J＝7.3Hz,1H),7.53(t,J＝6.9Hz,1H),7.45-7.13(m,4H),6.08(d,J＝5.5Hz,1H),5.16-5.06(m,1H),4.01(s,3H),3.64(s,3H),1.70(d,J＝6.8Hz,3H).
LC/MS(m/z,MH +):491.2.
实施例18 (R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-(1-(甲基磺酰基)-3,6-二氢吡啶-1(2H)-4-基)喹啉-4-胺
Figure PCTCN2022074591-appb-000074
步骤1 (R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯的合成
Figure PCTCN2022074591-appb-000075
将(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基喹啉-4-胺(424mg,1.00mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(463mg,1.50mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(73.1mg，0.10mmol)，碳酸钾(276mg,2.00mmol)加入到10mL1,4-二氧六环中，加入1mL水，氩气保护下加热至100℃搅拌4小时后反应完 毕。将反应液浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，制得标题化合物。
步骤2 (R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-(1,2,3,6-四氢吡啶-4-基)喹啉-4-胺的合成
Figure PCTCN2022074591-appb-000076
将(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(260mg，0.50mmol)加入到5mL二氯甲烷中，加入到5mL三氟乙酸，室温搅拌1小时后反应完毕。将反应液浓缩，加入20mL乙酸乙酯，用饱和碳酸氢钠水溶液调节pH至7-9，有机层用无水硫酸钠干燥，过滤，浓缩后制得标题化合物。
步骤3 (R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-(1-(甲基磺酰基)-3,6-二氢吡啶-1(2H)-4-基)喹啉-4-胺的合成
Figure PCTCN2022074591-appb-000077
将(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-(1,2,3,6-四氢吡啶-4-基)喹啉-4-胺(120mg，0.28mmol)，N,N-二异丙基乙胺(108mg，0.84mmol)加入到10mL无水二氯甲烷中，加入甲磺酸酐(58.7mg，0.34mmol)，室温搅拌2小时后反应完毕。加入30mL水，二氯甲烷萃取，合并有机层，无水硫酸钠干燥，过滤，有机层浓缩后，所得残余物经柱层析(二氯甲烷/甲醇梯度洗脱)分离，制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ H 13.72(s,1H),9.13(d,J＝7.0Hz,1H),8.52(s,1H),8.43(d,J＝7.0Hz,1H),7.68(t,J＝7.3Hz,1H),7.60(t,J＝7.0Hz,1H),7.38-6.97(m,4H),6.59(d,J＝7.2Hz,1H),6.07-5.96(m,1H),5.47-5.37(m,1H),3.95(s,3H),3.92-3.88(m,2H),2.98(s,3H),2.65-2.59(m,2H),1.72(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):506.1.
实施例19 (R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-(1-(甲基磺酰基)哌啶-4-基)喹啉-4-胺
Figure PCTCN2022074591-appb-000078
将(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-(1-(甲基磺酰基)-3,6-二氢吡啶-1(2H)-4-基)喹啉-4-胺(60.0mg，0.12mmol)，钯碳(10mg)，加入到5mL甲醇中，加入0.5mL乙酸，通入氢气后室温搅拌8小时后反应完毕。抽滤，滤液浓缩后，经柱层析(二氯甲烷/甲醇梯度洗脱)分离，制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ H8.22(s,1H),8.16(d,J＝5.3Hz,1H),7.57(t,J＝7.1Hz,1H),7.51(t,J＝7.0Hz,1H),7.39-7.38(m,1H),7.30-7.12(m,3H),6.02(d,J＝5.5Hz,1H),5.08-5.04(m,1H),3.90(s,3H),3.76-3.73(m,2H),3.19-3.13(m,1H),2.91-2.84(m,5H),2.06-1.88(m,4H),1.66(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):508.1.
实施例20 (R)-环丙基(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)哌啶-1-基)甲酮
Figure PCTCN2022074591-appb-000079
参照实施例18制备方法，不同的是将甲磺酸酐替换为环丙基甲酰氯，同法制得(R)-环丙基(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-1,2,3,6-四氢吡啶-1-基)甲酮，进一步参照实施例19，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.30-8.22(m,2H),7.85(s,1H),7.59(t,J＝7.1Hz,1H),7.54(t,J＝6.9Hz,1H),7.39-7.12(m,3H),6.15(d,J＝5.6Hz,1H),5.16-5.10(m,1H),4.70-4.0(m,1H),4.50-4.45(m,1H),3.93(s,3H),3.30-3.10(m,2H),2.75-2.55(m,2H),2.12-1.74(m,4H),1.68(d,J＝6.7Hz,3H),0.85-0.65(m,4H).
LC/MS(m/z,MH +):498.2.
实施例21 (R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-(1-(三氟乙酰基)哌啶-4-基)喹啉-4-胺
Figure PCTCN2022074591-appb-000080
参照实施例18制备方法，不同的是将甲磺酸酐替换为三氟乙酸酐，同法制得(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-(1-(三氟乙酰基)-1,2,3,6-四氢吡啶--4-基)喹啉-4-胺，进一步参照实施例19，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ.8.22-8.11(m,2H),7.59-7.50(m,2H),7.41-7.12(m,4H),6.03(d,J＝5.0Hz,1H),5.13-4.99(m,1H),4.54(d,J＝12.5Hz,1H),4.04(d,J＝12.4Hz,1H),3.91(s,3H),3.49-3.36(m,2H),3.10-3.07(m,1H),2.08-1.70(m,4H),1.66(d,J＝6.6Hz,3H).
LC/MS(m/z,MH +):526.2.
实施例22 (R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-(4,4-二氟哌啶-1-基)-7-甲氧基喹啉-4-胺
Figure PCTCN2022074591-appb-000081
参照实施例2制备方法，不同的是将步骤2中的吗啡啉替换为4,4-二氟哌啶，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.11(d,J＝5.3Hz,1H),7.75(s,1H),7.58(t,J＝7.4Hz,1H),7.51(t,J＝7.1Hz,1H),7.43-7.09(m,4H),6.01(d,J＝5.5Hz,1H),5.11-5.01(m,1H),3.91(s,3H),3.28-3.15(m,4H),2.25-2.09(m,4H),1.65(d,J＝6.8Hz,3H).
LC/MS(m/z,MH +):466.2.
实施例23 (R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-(3,6-二氢-2H-吡喃-4-基)-7-甲氧基喹啉-4-胺
Figure PCTCN2022074591-appb-000082
参照实施例3制备方法，不同的是将1-(四氢-2H-吡喃-4-基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1H-吡唑替换为3,6-二氢-2H-吡喃-4-硼酸频哪醇酯，同法制得标题化合物。
1H NMR(400MHz,CDCl 3)δ8.34(d,J＝5.4Hz,1H),7.55(s,1H),7.51(t,J＝7.3Hz,1H),7.45(t,J＝7.3Hz,1H),7.33(s,1H),7.19-6.81(m,3H),6.08(d,J＝5.4Hz,1H),5.96-5.93(m,1H),5.10-5.01(m,1H),4.41-4.35(m,2H),3.97(t,J＝5.4Hz,2H),3.94(s,3H),2.63-2.57(m,2H),1.74(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):429.2.
实施例24 (R)-1-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)氮杂环丁烷-3-腈
Figure PCTCN2022074591-appb-000083
参照实施例2制备方法，不同的是将步骤2中的吗啡啉替换为3-乙腈环丁胺盐酸盐，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.04(d,J＝5.3Hz,1H),7.56(t,J＝7.3Hz,1H),7.51(t,J＝6.8Hz,1H),7.42-7.00(m,5H),6.00(d,J＝5.4Hz,1H),5.10-4.99(m,1H),4.32-4.24(m,2H),4.17-4.06(m,2H),3.86(s,3H),3.85–3.78(m,1H),1.65(d,J＝6.8Hz,3H).
LC/MS(m/z,MH +):427.2.
实施例25 (R)-N-(1-(3-(3-(1,1-二氟乙基)-2-氟苯基)乙基)-7-甲氧基-6-吗啉代喹啉-4-胺
Figure PCTCN2022074591-appb-000084
参照实施例2制备方法，不同的是将步骤1中的(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺替换为(R)-1-(3-(1,1-二氟乙基)-2-氟苯基)乙烷-1-胺，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.10(d,J＝5.0Hz,1H),7.65(s,1H),7.54(t,J＝7.1Hz,1H),7.45(t,J＝7.2Hz,1H),7.23(t,J＝7.6Hz,2H),7.16(s,1H),6.01(d,J＝5.4Hz,1H),5.10-5.00(m,1H),3.89(s,3H),3.81(t,J＝4.3Hz,4H),3.20-3.04(m,4H),2.05(t,J＝19.2Hz,4H),1.66(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):446.2.
实施例26 (R)-N-(1-(3-(1-(1-，1-二氟乙基)-2-氟苯基)乙基)-7-甲氧基-6-(2-氧杂-6-氮杂螺[3.3]庚-6-基)喹啉-4-胺
Figure PCTCN2022074591-appb-000085
参照实施例2制备方法，不同的是将步骤1中的(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺替换为(R)-1-(3-(1,1-二氟乙基)-2-氟苯基)乙烷-1-胺，同时将步骤2中的吗啡啉替换为2-氧杂-6-氮杂-螺[3,3]庚烷，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.01(d,J＝5.1Hz,1H),7.52(t,J＝7.3Hz,1H),7.44(t,J＝7.1Hz,1H),7.21(t,J＝7.7Hz,1H),7.10-7.00(m,3H),5.97(d,J＝5.3Hz,1H),5.08-4.99(m,1H),4.76(s,4H),4.15(q,J＝8.5Hz,4H),3.85(s,3H),2.05(t,J＝19.2Hz,3H),1.65(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):458.2.
实施例27 (R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-3,6-二氢-2H-噻喃1,1-二氧化物
Figure PCTCN2022074591-appb-000086
参照实施例3制备方法，不同的是将1-(四氢-2H-吡喃-4-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1H-吡唑替换为4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-3,6-二氢-2H-噻喃1,1-二氧化物，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.35(d,J＝5.4Hz,1H),7.59(s,1H),7.52(t,J＝7.0Hz,1H),7.45(t,J＝7.3Hz,1H),7.34(s,1H),7.18(t,J＝7.7Hz,1H),7.09-6.81(m,2H),6.10(d,J＝5.5Hz,1H),5.76-5.74(m,1H),5.12-5.01(m,1H),3.95(s,3H),3.90-3.84(m,2H),3.31-3.28(m,2H),3.22-3.15(m,2H),1.76(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):477.2
实施例28 N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-((R-3-甲基吗啉代)喹啉-4-胺
Figure PCTCN2022074591-appb-000087
参照实施例2制备方法，不同的是将步骤2中的吗啡啉替换为3-(R)-3-甲基吗啉，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.24(d,J＝6.2Hz,1H),7.95(s,1H),7.64(t,J＝7.2Hz,1H),7.56(t,J＝7.0Hz,1H),7.40-7.13(m,4H),6.27(d,J＝6.4Hz,1H),5.28-5.18(m,1H),3.92(s,3H),3.90-3.70(m,4H),3.49-3.30(m,2H),2.87-2.90(m,1H),1.70(d,J＝6.7Hz,3H),0.90(d,J＝6.3Hz,3H).
LC/MS(m/z,MH +):446.2
实施例29 (R)-4-(4-(((1-(3-(1,1-二氟乙基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)硫代吗啉1,1-二氧化物
Figure PCTCN2022074591-appb-000088
参照实施例2制备方法，不同的是将步骤1中的(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺替换为(R)-1-(3-(1,1-二氟乙基)-2-氟苯基)乙烷-1-胺，同时将步骤2中的吗啡啉替换为硫代吗啉-1,1-二氧化物，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.13(d,J＝4.8Hz,1H),7.85(s,1H),7.52(t,J＝7.2Hz,1H),7.45(t,J＝7.1Hz,1H),7.24-7.18(m,4H),6.01(d,J＝5.3Hz,1H),5.09-5.00(m,1H),3.91(s,3H),3.68-3.49(m,4H),3.34-3.30(m,4H),2.10-2.00(m,3H),1.65(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):494.2
实施例30 (R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)硫代吗啉1,1-二氧化物
Figure PCTCN2022074591-appb-000089
参照实施例2制备方法，不同的是将步骤1中的6-溴-4-氯-7-甲氧基喹啉替换为6-溴-4-氯-7-甲氧基-2-甲基喹啉，同时将步骤2中的吗啡啉替换为硫代吗啉-1,1-二氧化物，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ7.80(s,1H),7.59(t,J＝7.2Hz,1H),7.51(t,J＝6.9Hz,1H),7.40(s,1H),7.33-7.10(m,3H),5.96(s,1H),5.12-5.00(m,1H),3.89(s,3H),3.60-3.50(m,4H),3.30-3.25(m,4H),2.26(s,3H),1.64(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):494.2
实施例31 (R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基-6-(2-氧杂-6-氮杂-螺[3.3]庚烷-6-基)喹啉-4-胺
Figure PCTCN2022074591-appb-000090
参照实施例2制备方法，不同的是将步骤1中的6-溴-4-氯-7-甲氧基喹啉替换为6-溴-4-氯-7-甲氧基-2-甲基喹啉，同时将步骤2中的吗啡啉替换为2-氧杂-6-氮杂-螺[3,3]庚烷，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ7.58(t,J＝7.2Hz,1H),7.50(t,J＝6.8Hz,1H),7.39-6.90(m,5H),5.92(s,1H),5.13-4.96(m,1H),4.75(s,4H),4.12(q,J＝8.5Hz,4H),3.83(s,3H),2.23(s,3H),1.64(d,J＝6.8Hz,3H).
LC/MS(m/z,MH +):458.2
实施例32 (R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基-6-吗啉代喹啉-4-胺
Figure PCTCN2022074591-appb-000091
参照实施例2制备方法，不同的是将步骤1中的6-溴-4-氯-7-甲氧基喹啉替换为6-溴-4-氯-7-甲氧基-2-甲基喹啉，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ7.65-7.58(m,2H),7.51(t,J＝6.8Hz,1H),7.40-7.25(m,2H),7.18-7.01(m,1H),5.95(s,1H),5.10-5.00(m,1H),3.87(s,3H),3.80(t,J＝4.3Hz,4H),3.20-3.04(m,4H),2.26(s,3H),1.65(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):446.2
实施例33 (R)-4-(4-(((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)四氢-2H-噻喃1,1-二氧化物
Figure PCTCN2022074591-appb-000092
将(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-3,6-二氢-2H-噻喃1,1-二氧化物(100mg)加入到10mL甲醇中，加入钯碳(10mg)，通入氢气室温搅拌4小时后反应完毕，抽滤，滤液浓缩后经柱层析(二氯甲烷/甲醇梯度洗脱)分离，制得标题化合物。
1H NMR(400MHz,CDCl 3)δ8.34(d,J＝5.4Hz,1H),7.58(s,1H),7.52(t,J＝7.1Hz,1H),7.46(t,J＝7.2Hz,1H),7.37(s,1H),7.18(t,J＝7.7Hz,1H),7.09-6.81(m,1H),6.11(d,J＝5.5Hz,1H),5.29-5.26(m,1H),5.18-4.97(m,1H),3.97(s,3H),3.45-3.42(m,1H),3.31-3.17(m,4H),2.60-2.41(m,2H),2.33(d,J＝11.4Hz,2H),1.78(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):479.2
实施例34 6-(3-氧杂-8-氮杂双环[3.2.1]辛基-8-基)-N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基喹啉-4-胺
Figure PCTCN2022074591-appb-000093
参照实施例2制备方法，不同的是将步骤2中的吗啡啉替换为3-氧杂-8-氮杂双环[3.2.1]辛烷盐酸盐，同法制得标题化合物。
1H NMR(400MHz,CDCl 3)δ8.24(d,J＝4.8Hz,1H),7.50(t,J＝6.6Hz,1H),7.45(t,J＝7.4Hz,1H),7.33(s,1H),7.17(t,J＝7.7Hz,1H),7.08-6.81(m,2H),7.17(t,J＝7.7Hz,1H),6.08(d,J＝5.3Hz,1H),5.05-5.00(m,1H),4.95-4.90(m,1H),4.19-4.17(m,2H),4.05(d,J＝10.6Hz,2H),3.98(s,2H),3.69(d,J＝9.9Hz,2H),2.19–2.02(m,4H),1.73(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):458.2
实施例35 (R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)硫代吗啉1-氧化物
Figure PCTCN2022074591-appb-000094
参照实施例2制备方法，不同的是将步骤2中的吗啡啉替换为1-氧化硫代吗啉，同法制得标题化合物。
1H NMR(400MHz,CDCl 3)δ8.27(d,J＝5.5Hz,1H),7.54-7.45(m,2H),7.41(s,1H),7.34(s,1H),7.18(t,J＝7.7Hz,1H),7.09-6.82(m,1H),6.12(d,J＝5.6Hz,1H),5.54-5.53(m,1H),5.11-5.06(m,1H),4.00(s,3H),3.87-3.77(m,2H),3.60-3.28(m,2H),3.09-3.07(m,4H),1.76(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):464.2
实施例36 N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-(((S--四氢呋喃-3-基)氧基)喹啉-4-胺
Figure PCTCN2022074591-appb-000095
步骤1：(R)-4-(((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-醇的合成
Figure PCTCN2022074591-appb-000096
将(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基喹啉-4-胺(100mg)，2-二-叔丁膦基-2',4',6'-三异丙基联苯(39.9mg),三(二亚苄基丙酮)二钯(21.5mg),氢氧化钾(19.8mg)溶于1.5ml二氧六环和0.5ml水，氩气保护，100℃搅拌4小时。反应完毕，加入乙酸乙酯稀释，水洗，饱和食盐水洗涤，有机相无水硫酸钠干燥，过滤，浓缩，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤2：N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-(((S--四氢呋喃-3-基)氧基)喹啉-4-胺的合成
Figure PCTCN2022074591-appb-000097
将(R)-4-(((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-醇(61.0mg)，(R)-四氢呋喃-3-基4-甲基苯磺酸酯(48.9mg)，碳酸铯(54.8mg)溶于2ml N,N-二甲基甲酰胺，氩气保护，100℃搅拌16小时。反应完毕，加入乙酸乙酯稀释，水洗，饱和食盐水水洗，有机相无水硫酸钠干燥，过滤，浓缩，经制备HPLC(Triart C18 ExRS，乙腈/水梯度洗脱)纯化，制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.12(d,J＝5.3Hz,1H),7.74(s,1H),7.57(t,J＝7.5Hz,1H),7.51(t,J＝7.1Hz,1H),7.41-7.08(m,4H),6.04(d,J＝5.4Hz,1H),5.31-5.29(m,1H),5.11-5.01(m,1H),4.04-3.78(m,7H),2.37-2.08(m,1H),2.12–2.03(m,1H),1.66(d,J＝6.8Hz,3H).
LC/MS(m/z,MH +):433.2
实施例37 (R)-6-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-2-硫杂-6-氮杂螺 [3.3]庚烷2,2-二氧化物
Figure PCTCN2022074591-appb-000098
参照实施例2制备方法，不同的是将步骤2中的吗啡啉替换为2-硫杂-6-氮杂螺[3.3]庚烷,2,2-二氧化物，同法制得标题化合物。
1H NMR(400MHz,CDCl 3)δ8.19(d,J＝5.3Hz,1H),7.51(t,J＝6.9Hz,1H),7.45(t,J＝7.4Hz,1H),7.32(s,1H),7.16(t,J＝7.7Hz,1H),7.00-6.80(m,1H),6.53(s,1H),6.11(d,J＝5.5Hz,1H),5.27-5.15(m,1H),5.12-5.01(m,1H),4.38(s,4H),4.34-4.25(m,4H),3.93(s,3H),1.75(d,J＝6.6Hz,3H).
LC/MS(m/z,MH +):492.2
实施例38 (R)-1-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-4-甲基哌啶-4-醇
Figure PCTCN2022074591-appb-000099
步骤1：(R)-1-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)哌啶-4-酮的合成
Figure PCTCN2022074591-appb-000100
将(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基喹啉-4-胺(90.0mg)，哌啶酮(35.0mg)，三(二亚苄基丙酮)二钯(19.4mg)，2-双环己基羰基-2'，4'，6'-三取代基联苯(20.2mg)，碳酸铯(138mg)溶于2mL二氧六环中，氩气保护下100℃反应3小时反应完毕。将反应液加入到30mL水中，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，过滤，有机层浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤2：(R)-1-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-4-甲基哌啶-4-醇的合成
Figure PCTCN2022074591-appb-000101
将(R)-1-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)哌啶-4-酮(44.0mg)加入到5mL无水四氢呋喃中，冷却至-20℃，滴加甲基溴化镁的1M/L溶液(0.1mL)，滴加完毕后移至室温搅拌2小时后反应完毕，加入到冰水中淬灭，乙酸乙酯萃取，饱和食盐水洗涤，有机相无水硫酸钠干燥，过滤，浓缩，所得残余物经制备HPLC(Triart C18 ExRS，乙腈/水梯度洗脱)纯化制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.51-8.49(m,1H),8.26(d,J＝6.6Hz,1H),7.88(s,1H),7.65(t,J＝7.5Hz,1H),7.57(t,J＝7.2Hz,1H),7.39-7.12(m,3H),6.39(d,J＝6.7Hz,1H),5.37–5.27(m,1H),4.34(s,1H),3.94(s,3H),3.23-3.04(m,4H),1.72(d,J＝6.7Hz,3H),1.70-1.60(m,4H),1.22(s,3H).
LC/MS(m/z,MH +):460.2
实施例39 (R)-1-(3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-3-羟基氮杂环丁烷-1-基)乙烷-1-酮
Figure PCTCN2022074591-appb-000102
步骤1：3-(4-氯-7-甲氧基喹啉-6-基)-3-羟基氮杂环丁烷-1-羧酸叔丁酯的合成
Figure PCTCN2022074591-appb-000103
将6-溴-4-氯-7-甲氧基喹啉(200mg)溶解于5mL四氢呋喃中,随后于惰性气体保护下降温至-78℃，向其中滴加正丁基锂的己烷溶液(1.6M,0.64mL)，滴完于该温度下继续反应1小时后，向其中加入3-氧杂氮杂环丁烷-1-羧酸叔丁酯(138mg)，并于该温度下继续反应30分钟后，用饱和氯化铵溶液淬灭，经乙酸乙酯萃取，用无水硫酸铵干燥有机相，过滤，浓缩，所得残余物柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤2：(R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-3-羟基氮杂环丁烷-1-羧酸叔丁酯的合成
Figure PCTCN2022074591-appb-000104
将3-(4-氯-7-甲氧基喹啉-6-基)-3-羟基氮杂环丁烷-1-羧酸叔丁酯(156mg)和(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺(89mg)溶解于1mL1，4-二氧六环中，随后加入BrettePhos Pd G3(39mg),2-(二环己基膦)-3,6-二甲氧基-2'-4'-6'-三-I-丙基-11'-联苯(46mg)和叔丁醇钠(82mg)。于惰性气体保护下升温至100℃反应8小时后，反应液冷却至室温，用乙酸乙酯稀释后过滤，滤液浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤3：(R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)氮杂环丁烷-3-醇的合成
Figure PCTCN2022074591-appb-000105
将(R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-3-羟基氮杂环丁烷-1-羧酸叔丁酯(100mg)溶解于4mL的二氯甲烷中，于冰浴下，向其中滴加1mL三氟乙酸，滴完撤去冰浴继续反应1小时后，将反应液浓缩，得标题化合物粗品，直接进行下一步。
步骤4：(R)-1-(3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-3-羟基氮杂环丁烷-1-基)乙烷-1-酮的合成
Figure PCTCN2022074591-appb-000106
将(R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)氮杂环丁烷-3-醇(80mg)溶解于2mL甲醇中，于冰浴下加入N,N-二异丙基乙胺(74mg),向其中滴加乙酸酐(22mg)，加完撤去冰浴，继续反应1小时后反应完毕。反应液用乙酸乙酯稀释，并用饱和食盐水洗涤，用无水硫酸钠干燥有机相，浓缩后，所得残余物经柱层析(二氯甲烷/甲醇梯度洗脱)分离，得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.32(d,J＝6.6Hz,1H),8.20(d,J＝5.2Hz,1H),7.65-7.55(m,1H),7.53-7.48(m,2H),7.40-7.12(m,3H),6.09(d,J＝5.6Hz,1H),6.05(t,J＝5.1Hz,1H),5.10-5.04(m,1H),4.71-4.59(m,2H),4.29(d,J＝9.3Hz,1H),3.99(d,J＝10.4Hz,1H),3.89(s,3H),1.84- 1.82(m,3H),1.66(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):460.2
实施例40：(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)四氢-2H-吡喃-4-醇
Figure PCTCN2022074591-appb-000107
步骤1：4-(4-氯-7-甲氧基喹啉-6-基)四氢-2H-吡喃-4-醇的合成
Figure PCTCN2022074591-appb-000108
将6-溴-4-氯-7-甲氧基喹啉(200mg)溶解于4mL的THF中，随后于惰性气体保护下降温至-78℃,向其中滴加正丁基锂的己烷溶液(1.6M,0.64mL)，滴完于该温度下继续反应1小时后，向其中加入四氢吡喃-4-酮(80.82mg)，继续反应30分钟后，用饱和氯化铵溶液淬灭，经乙酸乙酯萃取，无水硫酸钠干燥有机相后，浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤2：(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)四氢-2H-吡喃-4-醇的合成
Figure PCTCN2022074591-appb-000109
将4-(4-氯-7-甲氧基喹啉-6-基)四氢-2H-吡喃-4-醇(70.00mg,0.24mmol)与(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺(49.59mg)溶解于1mL的1，4-二氧六环中，随后加入BrettePhos Pd G3(21.60mg),2-(二环己基膦)-3,6-二甲氧基-2'-4'-6'-三-I-丙基-11'-联苯(25.58mg)和叔丁醇钠(45.80mg)，体系于惰性气体保护下升温至100℃反应8小时后，反应液降温至室温，用乙酸乙酯稀释后过滤，滤液浓缩，所得残余物经柱层析(二氯甲烷/甲醇梯度洗脱)分离纯化，得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.48(s,1H),8.18(d,J＝5.3Hz,1H),7.63(t,J＝7.5Hz,1H),7.52(dd,J＝11.1,4.2Hz,1H),7.46–7.38(m,1H),7.29-7.13(m,3H),6.03(d,J＝5.4Hz,1H),5.08-5.04(m,2H),3.92-3.83(m,5H),3.76-3.72(m,2H),2.67–2.52(m,2H),1.65(d,J＝6.8Hz,3H),1.51(t,J＝10.8Hz,3H).
LC/MS(m/z,MH +):447.2
实施例41：(R)-2-环丙基-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-吗啉代喹啉-4-胺
Figure PCTCN2022074591-appb-000110
步骤1：3-((4-溴-3-甲氧基苯基)亚氨基)-3-环丙基丙酸乙酯的合成
Figure PCTCN2022074591-appb-000111
将4-溴-3-甲氧基苯胺(10.0g)，对甲苯磺酸一水合物(85.2mg)，环丙基羰基丙酸乙酯(8.5g)加入到200mL环己烷中，100℃反应6小时反应完毕。将反应液浓缩，残渣经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤2：6-溴-2-环丙基-7-甲氧基喹啉-4-醇的合成
Figure PCTCN2022074591-appb-000112
将3-(((4-溴-3-甲氧基苯基)亚氨基)-3-环丙基丙酸乙酯(1.60g)溶于8mL二苯醚中，氩气保护下230℃反应20分钟反应完毕。将反应液冷却至室温，加入石油醚，过滤，滤饼用石油醚洗涤，收集滤饼，烘干得标题化合物。
步骤3：6-溴-4-氯-2-环丙基-7-甲氧基喹啉的合成
Figure PCTCN2022074591-appb-000113
将6-溴-2-环丙基-7-甲氧基喹啉-4-醇(0.60g)加入到5mL三氯氧磷中，90℃反应2小时反应完毕。将反应液浓缩至干，加入冰水淬灭，并用饱和碳酸氢钠溶液调节pH至9，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，过滤，有机层浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤4：(R)-6-溴-2-环丙基-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基喹啉-4-胺的合成
Figure PCTCN2022074591-appb-000114
将6-溴-4-氯-2-环丙基-7-甲氧基喹啉(0.20g)，(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺(0.145g)，樟脑磺酸(59.4mg)加入到3mL二甲亚砜中，氩气氛围下130℃反应16小时反应完毕。将反应液加入到30mL饱和氯化钠水溶液中，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，过滤，有机层浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤5：(R)-2-环丙基-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-吗啉代喹啉-4-胺的合成
Figure PCTCN2022074591-appb-000115
将(R)-6-溴-2-环丙基-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基喹啉-4-胺(130mg)，吗啡啉(43.8mg)，三(二亚苄基丙酮)二钯(25.6mg)，2-双环己基羰基-2'，4'，6'-三取代基联苯(26.6mg)，碳酸铯(182mg)溶于2mL二氧六环中，氩气保护下100℃反应3小时反应完毕。将反应液倒入水中，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，过滤，有机层浓缩后，所得残余物经柱层析(二氯甲烷/甲醇梯度洗脱)分离，得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ7.61(t,J＝7.4Hz,1H),7.57(s,1H),7.52(t,J＝6.9Hz,1H),7.40-7.08(m,3H),7.00(s,1H),5.92(s,1H),5.13-5.02(m,1H),3.86(s,3H),3.79(t,J＝4.4Hz,4H),3.19-3.02(m,4H),1.82-1.76(m,1H),1.65(d,J＝6.7Hz,3H),0.85-0.71(m,4H).
LC/MS(m/z,MH +):472.2
实施例42：(R)-4-(((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-6-吗啉代喹啉-2-甲腈
Figure PCTCN2022074591-appb-000116
步骤1：6-溴-4-氯-7-甲氧基喹啉-2-甲醛的合成
Figure PCTCN2022074591-appb-000117
将6-溴-4-氯-7-甲氧基-2-甲基喹啉(0.80g)，二氧化硒(0.62g)加入到8mL二氧六环溶液中，100℃反应3小时反应完毕。将反应液倒入水中，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，过滤，有机层浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤2：6-溴-4-氯-7-甲氧基喹啉-2-甲醛肟的合成
Figure PCTCN2022074591-appb-000118
将6-溴-4-氯-7-甲氧基喹啉-2-甲醛(0.25g)，盐酸羟胺(0.12g)，碳酸钾(0.29g)加入到3mL乙醇/水混合溶液中(V:V＝2/1)，80℃反应2小时反应完毕。浓缩掉部分溶剂，再加水稀释，过滤，滤饼用水洗涤，收集滤饼，烘干得标题化合物。
步骤3：6-溴-4-氯-7-甲氧基喹啉-2-甲腈的合成
Figure PCTCN2022074591-appb-000119
将6-溴-4-氯-7-甲氧基喹啉-2-甲醛肟(0.17g)，三氟甲磺酸酐(0.30g)，加入到3mL二氯甲烷中，再缓慢加入三乙胺(0.27g)，0℃反应2小时反应完毕。将反应液倒入水中，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，过滤，有机层浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤4：(R)-6-溴-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-2-甲腈的合成
Figure PCTCN2022074591-appb-000120
将6-溴-4-氯-7-甲氧基喹啉-2-甲腈(0.20g)，(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺(0.145g)，樟脑磺酸(59.4mg)加入到3mL二甲亚砜中，氩气氛围下130℃反应16小时反应完毕。将反应液加入到30mL饱和氯化钠水溶液中，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，过滤，有机层浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤5：(R)-4-(((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-6-吗啉代喹啉-2-甲腈
Figure PCTCN2022074591-appb-000121
将(R)-6-溴-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-2-甲腈(130mg)，吗啡啉(43.8mg)，三(二亚苄基丙酮)二钯(25.6mg)，2-双环己基羰基-2'，4'，6'-三取代基联苯(26.6mg)，碳酸铯(182mg)溶于2mL二氧六环中，氩气保护下100℃反应3小时反应完毕。将反应液倒入水中，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，过滤，有机层浓缩后，所得残余物经柱层析(二氯甲烷/甲醇梯度洗脱)分离，得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ7.68-7.67(m,2H),7.60(t,J＝7.3Hz,1H),7.55(t,J＝7.0Hz,1H),7.40-7.13(m,3H),6.52(s,1H),5.20-5.15(m,1H),3.92(s,3H),3.81(t,J＝4.4Hz,4H),3.21-3.14(m,4H),1.68(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):457.2
实施例43 (R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基-6-(氧杂环丁烷-3-基氧基)喹啉-4-胺
Figure PCTCN2022074591-appb-000122
参照实施例36的合成方法，不同的是将步骤2中的(R)-4-(((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-醇替换为(R)-4-(((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-2-甲基-6-醇，同时(R)-四氢呋喃-3-基4-甲基苯磺酸酯替换为3-碘氧杂环丁烷，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.04(s,1H),7.66(t,J＝7.5Hz,1H),7.62(s,1H),7.56(t,J＝7.1Hz,1H),7.39-7.12(m,3H),6.30(s,1H),5.57-5.52(m,1H),5.28-5.21(m,1H),5.06-5.01(m,2H),4.66-4.59(m,2H),3.93(s,3H),2.41(s,3H),1.71(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):433.2
实施例44 (R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)氧杂环丁烷-3-醇
Figure PCTCN2022074591-appb-000123
参照实施例40的合成方法，不同的是将步骤1中的四氢吡喃-4-酮替换为3-氧杂环丁酮，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.26(s,1H),8.20(d,J＝5.4Hz,1H),7.59(t,J＝7.4Hz,1H),7.52(t,J＝7.1Hz,1H),7.45(d,J＝7.0Hz,1H),7.40-7.13(m,3H),6.06(d,J＝5.5Hz,1H),5.95(s,1H),5.18(d,J＝6.9Hz,1H),5.13(d,J＝7.0Hz,1H),5.09-5.06(m,1H),4.77(d,J＝6.9Hz,2H),3.86(s,3H),1.66(d,J＝6.8Hz,3H).
LC/MS(m/z,MH +):419.2
实施例45 (R)-6-环丙基-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基喹啉-4-胺
Figure PCTCN2022074591-appb-000124
步骤1：(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基喹啉-4-胺的合成
Figure PCTCN2022074591-appb-000125
将6-溴-4-氯-7-甲氧基-2-甲基喹啉(210mg)，(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺(166mg)，N,N-二异丙基乙胺(189mg)溶于3mL二甲基亚砜中，氩气保护下130℃搅拌14小时后反应完毕。将反应液加入到40mL饱和氯化钠水溶液中，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，过滤，有机层浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤2：(R)-6-环丙基-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基喹啉-4-胺的合成
Figure PCTCN2022074591-appb-000126
将(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基喹啉-4-胺(60.0mg)，环丙基硼酸(20.9mg)，1,1'-二(二苯膦基)二茂铁二氯化钯(10.3mg，0.01mmol)，碳酸钾(39.0mg，0.28mmol)溶于2mL二氧六环/水混合溶液中(V:V＝10/1)，氩气保护下90℃搅拌2小时后反应完毕。加入20mL水稀释，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，过滤，有机层浓缩后，所得残余物经柱层析(二氯甲烷/甲醇梯度洗脱)分离，得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.06(s,1H),7.92(s,1H),7.64(t,J＝7.6Hz,1H),7.56(t,J＝6.9Hz,1H),7.39-7.12(m,3H),6.25(s,1H),5.26-5.21(m,1H),3.94(s,3H),2.40(s,3H),2.23-2.16(m,1H),1.68(d,J＝6.8Hz,3H),1.05-0.84(m,4H).
LC/MS(m/z,MH +):401.2
实施例46 (R)-1-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-N，3-二甲基氮杂环丁烷-3-羧酰胺
Figure PCTCN2022074591-appb-000127
步骤1：(R)-1-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-3-甲基氮杂环丁烷-3-羧酸甲酯的合成
Figure PCTCN2022074591-appb-000128
将(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基喹啉-4-胺(425.24mg)，3-甲基氮杂环丁烷-3-羧酸甲酯(180mg)溶于1，4-二氧六环(3mL)，加入三(二亚苄基丙酮)二钯(99.5mg)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(125.7mg)，碳酸铯(706.5mg)，氩气保护下加热至100℃搅拌，6小时后反应完毕。反应液浓缩后经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得到目标化合物。
步骤2：(R)-1-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-3-甲基氮杂环丁烷 -3-羧酸的合成
Figure PCTCN2022074591-appb-000129
将(R)-1-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-3-甲基氮杂环丁烷-3-羧酸甲酯(100mg)溶于甲醇/四氢呋喃/水＝4/1/1(v:v，2mL)，加入氢氧化锂(24mg)，60℃下搅拌两小时后反应完毕。饱和氯化铵水溶液调节pH至7-8，乙酸乙酯萃取，有机相浓缩后得到标题化合物。
步骤3：(R)-1-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-N，3-二甲基氮杂环丁烷-3-羧酰胺的合成
Figure PCTCN2022074591-appb-000130
将1-(4-((((R))-1-(3-(二氟甲基)-2-氟-苯基)乙基)氨基)-7-甲氧基-6-喹啉基)-3-甲基-氮杂环丁烷-3-羧酸(14.4mg)，甲胺盐酸盐(3.17mg)溶于N,N-二甲基甲酰胺(1mL)，加入N,N-二异丙基乙胺(12.15mg)，2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(17.74mg)，室温下搅拌两小时后反应完毕。有机层加入20mL水，乙酸乙酯萃取，合并有机层，浓缩后经柱层析(二氯甲烷/甲醇梯度洗脱)分离，制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.07(d,J＝5.6Hz,1H),785-7.83(m,1H),7.58(t,J＝7.3Hz,1H),7.52(t,J＝6.9Hz,1H),7.47(s,1H),7.39-7.09(m,4H),6.10(d,J＝5.7Hz,1H),5.17-5.06(m,1H),4.20(dd,J＝15.9,8.0Hz,2H),3.86(s,3H),3.79(dd,J＝18.4,7.9Hz,2H),2.63(d,J＝4.4Hz,3H),1.66(d,J＝6.7Hz,3H),1.56(s,3H).
LC/MS(m/z,MH +):474.2
实施例47：(R)-7-(2,2-二氟乙氧基)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-吗啉基吡啶并[2,3-d]嘧啶-4-胺
Figure PCTCN2022074591-appb-000131
步骤1：6,7-二氯-2-甲基吡啶并[2,3-d]嘧啶-4(3H)-酮
Figure PCTCN2022074591-appb-000132
将盐酸乙脒(250mg,2.65mmol)，2,5,6-三氯烟酸(500mg)，碘化亚铜(42.0mg),碳酸铯(719mg)溶于10ml N,N-二甲基甲酰胺，氩气保护，40℃搅拌16小时，80℃搅拌8小时。反应完毕，加入乙酸乙酯稀释，水洗，饱和食盐水洗涤，有机相无水硫酸钠干燥，过滤，浓缩，所得残余物柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤2：6-氯-7-(2,2-二氟乙氧基)-2-甲基吡啶并[2,3-d]嘧啶-4(3H)-酮
Figure PCTCN2022074591-appb-000133
将6,7-二氯-2-甲基吡啶并[2,3-d]嘧啶-4(3H)-酮(55.0mg)溶于2ml 2,2-二氟乙醇，加入氢化钠(47.8mg)，氩气保护，70℃搅拌3小时。反应完毕，加入乙酸乙酯稀释，水洗，饱和食盐水洗涤，有机相无水硫酸钠干燥，过滤，浓缩，所得残余物柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤3：4,6-二氯-7-(2,2-二氟乙氧基)-2-甲基吡啶并[2,3-d]嘧啶
Figure PCTCN2022074591-appb-000134
将6-氯-7-(2,2-二氟乙氧基)-2-甲基吡啶并[2,3-d]嘧啶-4(3H)-酮(65.0mg)溶于2ml乙腈，加入三氯氧膦(72.3mg)和N,N-二异丙基乙胺(76.2mg)，氩气保护，80℃搅拌1小时。反应完毕，反应液旋干得标题化合物粗品直接用于下一步反应。
步骤4：(R)-6-氯-7-(2,2-二氟乙氧基)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[2,3-d]嘧啶-4-胺
Figure PCTCN2022074591-appb-000135
将(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺(80.5mg)，4,6-二氯-7-(2,2-二氟乙氧基)-2-甲基吡啶并[2,3-d]嘧啶(70.0mg)溶于2ml二甲基亚砜，加入N,N-二异丙基乙胺(123mg)，氩气保护，80℃搅拌1小时。反应完毕，加入乙酸乙酯稀释，水洗，饱和食盐水洗涤，有机相无水硫酸钠干燥，过滤，浓缩，所得残余物柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤5：(R)-7-(2,2-二氟乙氧基)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-吗啉基吡啶并[2,3-d]嘧啶-4-胺
Figure PCTCN2022074591-appb-000136
将(R)-6-氯-7-(2,2-二氟乙氧基)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[2,3-d]嘧啶-4-胺(34mg)，吗啡啉(13.2mg)，2-二环己基磷-2,4,6-三异丙基联苯(7.26mg),三(二亚苄-BASE丙酮)二钯(6.97mg),碳酸铯(49.6mg)溶于2ml二氧六环，氩气保护，100℃搅拌16小时。反应完毕，加入乙酸乙酯稀释，水洗，饱和食盐水洗涤，有机相无水硫酸钠干燥，过滤，浓缩，所得残余物经制备HPLC(Triart C18 ExRS，乙腈/水梯度洗脱)分离，得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.37(d,J＝7.2Hz,1H),8.07(s,1H),7.67(t,J＝7.5Hz,1H),7.50(t,J＝7.1Hz,1H),7.38-7.10(m,2H),6.48(tt,J＝54.6,3.3Hz,1H),5.83-5.73(m,1H),4.71(td,J＝15.3,3.3Hz,2H),3.80(t,J＝4.6Hz,4H),3.13-3.12(m,4H),2.32(s,3H),1.60(d,J＝7.1Hz,3H).
LC/MS(m/z,MH +):498.2
实施例48 (R)-1-(3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)-3-羟基氮杂环丁烷-1-基)乙-1-酮
Figure PCTCN2022074591-appb-000137
步骤1：3-(4-氯-7-甲氧基-2-甲基喹啉-6-基)-3-羟基氮杂环丁烷-1-羧酸叔丁酯的合成
Figure PCTCN2022074591-appb-000138
将6-溴-4-氯-7-甲氧基-2-甲基喹啉(200mg)溶解于5mL四氢呋喃中,随后于惰性气体保护下降温至-78℃，向其中滴加正丁基锂的己烷溶液(0.64mL)，滴完于该温度下继续反应1小时后，向其中加入3-氧代氮杂环丁烷-1-羧酸叔丁酯(138mg)，并于该温度下继续反应30分钟后，用饱和氯化铵溶液淬灭，经乙酸乙酯萃取，用无水硫酸钠干燥有机相，浓缩，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤2：(R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)-3-羟基氮杂环丁烷-1-羧酸叔丁酯的合成
Figure PCTCN2022074591-appb-000139
将3-(4-氯-7-甲氧基-2-甲基喹啉-6-基)-3-羟基氮杂环丁烷-1-羧酸叔丁酯(170mg)和(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺(89mg)溶解于1mL1，4-二氧六环中，随后加入BrettePhos Pd G3(39mg)，2-(二环己基膦)-3,6-二甲氧基-2'-4'-6'-三-I-丙基-11'-联苯(46mg)和叔丁醇钠(82mg)。于惰性气体保护下升温至100℃反应8小时后，反应液冷却至室温，用乙酸乙酯稀释后过滤，滤液浓缩，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤3：(R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)氮杂环丁醇的合成
Figure PCTCN2022074591-appb-000140
将(R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)-3-羟基氮杂环丁烷-1-羧酸叔丁酯(100mg)溶解于4mL的二氯甲烷中，于冰浴下，向其中滴加1mL三氟乙酸，滴完撤去冰浴继续反应1小时后，将反应液浓缩，得标题化合物粗品，直接进行下一步。
步骤4：(R)-1-(3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)-3-羟基氮杂环丁烷-1-基)乙-1-酮的合成
Figure PCTCN2022074591-appb-000141
将(R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)氮杂环丁醇(80mg)溶解于2mL甲醇中，于冰浴下加入N,N-二异丙基乙胺(74mg)，向其中滴加乙酸酐(22mg)，加完撤去冰浴，继续反应1小时后反应完毕。反应液用乙酸乙酯稀释，并用饱和食 盐水洗涤，用无水硫酸钠干燥有机相，过滤，浓缩后所得残余物经柱层析(二氯甲烷/甲醇梯度洗脱)分离，得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.24(d,J＝5.7Hz,1H),7.64-7.59(m,1H),7.52(t,J＝7.1Hz,1H),7.43-7.11(m,4H),6.05(s,1H),6.00(d,J＝5.9Hz,1H),5.11-5.06(m,1H),4.69-4.57(m,2H),4.28(d,J＝9.3Hz,1H),3.97(d,J＝10.3Hz,1H),3.87(s,3H),2.29(d,J＝1.8Hz,3H),1.82(d,J＝1.6Hz,3H),1.65(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):474.2.
实施例49 (R)-1-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)-N，3-二甲基氮杂环丁烷-3-羧酰胺
Figure PCTCN2022074591-appb-000142
参考实施例46的制备方法，不同的是将步骤1中的(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基喹啉-4-胺替换为(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基喹啉-4-胺，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ7.84-7.79(m,1H),7.59(t,J＝7.3Hz,1H),7.51(t,J＝6.8Hz,1H),7.40-7.12(m,2H),7.04(s,1H),7.00(s,1H),6.94(d,J＝7.0Hz,1H),5.92(s,1H),5.12-4.97(m,1H),4.18-4.12(m,2H),3.82(s,3H),3.77-3.71(m,2H),2.63(d,J＝4.5Hz,3H),2.24(s,3H),1.63(d,J＝6.7Hz,3H),1.55(s,3H).
LC/MS(m/z,MH +):487.2.
实施例50 (R)-1-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)-4-甲基哌啶-4-醇
Figure PCTCN2022074591-appb-000143
Figure PCTCN2022074591-appb-000144
将(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基喹啉-4-胺(120mg)，4-甲基-4-羟基哌啶(115mg)，三(二亚苄基丙酮)二钯(4.50mg)，1,1'-联萘-2,2'-双二苯膦(6.20mg)，叔丁醇钠(144mg)加入到5mL 1,4-二氧六环中，氩气保护下80℃搅拌3小时后反应完毕。加入20mL水稀释，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，有机层浓缩后，经柱层析(石油醚/乙酸乙酯梯度洗脱)得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ7.65-7.57(m,2H),7.51(t,J＝6.9Hz,1H),7.41-7.08(m,3H),7.05(s,1H),5.93(s,1H),5.09-4.99(m,1H),4.27(s,1H),3.85(s,3H),3.14-3.05(m,4H),2.25(s,3H),1.70-1.63(m,7H),1.21(s,3H).
LC/MS(m/z,MH +):474.2.
实施例51：(R)-1-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)-3-甲基氮杂环丁烷-3-醇
Figure PCTCN2022074591-appb-000145
将(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基喹啉-4-胺(120mg)，三(二亚苄基丙酮)二钯(4.50mg)，3-甲基-3-吖啶醇(87.0mg)，1,1'-联萘-2,2'-双二苯膦(6.20mg)，叔丁醇钠(144mg)加入到5mL 1,4-二氧六环中，氩气保护下80℃搅拌3小时后反应完毕。加入20mL水稀释，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，过滤，有机层浓缩后，所得残余物经柱层析(二氯甲烷/甲醇梯度洗脱)分离，得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ7.62-7.56(m,1H),7.51(t,J＝7.1Hz,1H),7.40-7.12(m,2H),7.05(s,1H),7.00(s,1H),6.92(d,J＝7.2Hz,1H),5.93(s,1H),5.41(s,1H),5.09-5.01(m,1H),3.92- 3.87(m,2H),3.82(s,3H),3.80-3.74(m,2H),2.24(s,3H),1.64(d,J＝6.8Hz,3H),1.50(s,3H).
LC/MS(m/z,MH +):446.2.
实施例52 (R)-1-(7-(2,2-二氟乙氧基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-基)-4-甲基哌啶-4-醇
Figure PCTCN2022074591-appb-000146
参考实施例47的制备方法，不同的是将步骤5中的吗啡啉替换为4-甲基哌啶-4-醇，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.34(d,J＝7.3Hz,1H),8.09(s,1H),7.66(t,J＝7.3Hz,1H),7.50(t,J＝6.9Hz,1H),7.38-7.11(m,2H),6.47(tt,J＝54.6,3.4Hz,1H),5.81-5.74(m,1H),4.69(td,J＝15.2,3.1Hz,2H),4.34(s,1H),3.20-3.02(m,4H),2.31(s,3H),1.68-1.65(m,4H),1.59(d,J＝7.1Hz,3H),1.21(s,3H).
LC/MS(m/z,MH +):526.2.
实施例53 (R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-(3,6-二氢-2H-吡喃-4-基)-2-甲基-7-(1-甲基-1H-吡唑-3-基)喹啉-4-胺
Figure PCTCN2022074591-appb-000147
步骤1：6-溴-4-氯-2-甲基喹啉-7-醇的合成
Figure PCTCN2022074591-appb-000148
将6-溴-4-氯-7-甲氧基-2-甲基喹啉(5.00g)加入到反应瓶中，装上氩气球，置换气体三次，气体保护下加入无水1,2-二氯乙烷(100mL)，然后放入冰浴中冷却至0℃，然后加入三溴化硼的二氯甲烷溶液(2M,26.2mL)。反应液在冰浴下搅拌30分钟，然后放入50℃油浴中反应过夜。冷却至室温，加入水将反应淬灭，加入饱和碳酸氢钠溶液调节pH至7-8，有大量固体析出，抽滤，滤饼用少量乙酸乙酯打浆，过滤，收集滤饼，干燥，滤液浓缩后有固体析出，过滤，滤饼再干燥，合并两批滤饼得标题化合物。
步骤2：6-溴-4-氯-2-甲基喹啉-7-基三氟甲磺酸酯的合成
Figure PCTCN2022074591-appb-000149
将6-溴-4-氯-2-甲基喹啉-7-醇(1.50g)加入到反应瓶中，加入二氯甲烷(20mL)和四氢呋喃(20mL)，然后装上氩气球，置换气体三次，气体保护下冷却至-20℃，加入无水吡啶(522mg)，搅拌下缓慢滴加三氟甲磺酸酐(3.11g)。滴加完毕，升至室温反应3小时。将反应液倒入冰水中，用乙酸乙酯萃取(50mL×3)，合并有机层，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离纯化，得标题化合物。
步骤3：6-溴-4-氯-2-甲基-7-(1-甲基-1H-吡唑-3-基)喹啉的合成
Figure PCTCN2022074591-appb-000150
将6-溴-4-氯-2-甲基喹啉-7-基三氟甲磺酸酯(200mg)，1-甲基-1H-吡唑-3-硼酸频哪醇酯(108mg)，碳酸铯(322mg)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(36.2mg)和无水1,4-二氧六环(3.2mL)加入到反应瓶中，装上氩气球，置换气体三次，气体保护下放入80℃油浴中反应3小时。将反应液减压浓缩后经柱层析(石油醚/乙酸乙酯梯度洗脱)分离纯化，得标题化合物。
步骤4：4-氯-6-(3,6-二氢-2H-吡喃-4-基)-2-甲基-7-(1-甲基-1H-吡唑-3-基)喹啉的合成
Figure PCTCN2022074591-appb-000151
将6-溴-4-氯-2-甲基-7-(1-甲基-1H-吡唑-3-基)喹啉(150mg)，3,6-二氢-2H-吡喃-4-硼酸频哪醇酯(103mg)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(32.6mg)，磷酸钾(189mg)和1,4-二氧六环(3.75mL)/水(0.75mL)加入到反应瓶中，装上氩气球，置换气体三次，气体保护下放入100℃油浴中反应2小时。将反应液减压浓缩后经柱层析(石油醚/乙酸乙酯梯度洗脱)分离纯化，得标题化合物。
步骤5：(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-(3,6-二氢-2H-吡喃-4-基)-2-甲基-7-(1-甲基-1H-吡唑-3-基)喹啉-4-胺的合成
Figure PCTCN2022074591-appb-000152
将4-氯-6-(3,6-二氢-2H-吡喃-4-基)-2-甲基-7-(1-甲基-1H-吡唑-3-基)喹啉(52mg)，(1R)-1-[3-(二氟甲基)-2-氟苯基]乙胺(31.84mg)，叔丁醇钠(29.41mg)，Brettphos Pd G3(13.87mg)，Brettphos(8.21mg)，1,4-二氧六环(1.7mL)加入到反应瓶中，装上氩气球，置换气体三次，气体保护下放入100℃由于中反应过夜。将反应液过滤，滤液减压浓缩后，所得残余物经制备HPLC(Triart C18 ExRS，乙腈/水梯度洗脱)纯化得标题化合物。
DMSO-d6 δ H8.25(s,1H),7.93(s,1H),7.75(d,J＝2.2Hz,1H),7.68-7.57(m,2H),7.57-7.49(m,1H),7.34-7.27(m,1H),7.27(t,J＝67.5Hz,1H),6.54(d,J＝2.2Hz,1H),6.13(s,1H),5.85-5.80(m,1H),5.19-5.06(m,1H),4.30-4.22(m,2H),3.91(s,3H),3.79-3.70(m,2H),2.35(s,3H),2.15-2.07(m,2H),1.67(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):493.2.
实施例54：(R)-3-(7-(2,2-二氟乙氧基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹啉-6-基)氧杂环丁烷-3-醇
Figure PCTCN2022074591-appb-000153
步骤1：6-溴-4-氯-7-(2,2-二氟乙氧基)-2-甲基喹啉的合成
Figure PCTCN2022074591-appb-000154
将6-溴-4-氯-2-甲基喹啉-7-醇(700mg)溶解于5mL的DMF中，随后加入1,1-二氟-2-碘乙烷(493mg)和碳酸钾(708mg)，反应体系于50℃下反应过夜后，加入乙酸乙酯稀释，随后用饱和食盐水洗涤后分液，用无水硫酸钠干燥有机相后，浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤2：3-(4-氯-7-(2,2-二氟乙氧基)-2-甲基-6-喹啉基)氧杂环丁烷-3-醇的合成
Figure PCTCN2022074591-appb-000155
将6-溴-4-氯-7-(2,2-二氟乙氧基)-2-甲基喹啉(200mg)溶解于10mL超干的四氢呋喃中，随后于氩气保护下降温至-10℃后，向其中滴加异丙基氯化镁氯化锂络合物的四氢呋喃溶液(1.3M,1.83mL)滴完，于该温度下继续反应1h后，向其中加入3-氧杂环丁酮(171mg)，加完移至室温下继续反应半小时后，用饱和氯化铵溶液淬灭，用乙酸乙酯萃取，合并有机相经无水硫酸钠干燥后过滤，浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离纯化，得标题化合物。
步骤3：(R)-3-(7-(2,2-二氟乙氧基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹啉-6-基)氧杂环丁烷-3-醇的合成
Figure PCTCN2022074591-appb-000156
将3-(4-氯-7-(2,2-二氟乙氧基)-2-甲基-6-喹啉基)氧杂环丁烷-3-醇(100mg)，(1R)-1-(3-(二氟甲基)-2-氟-苯基)乙胺(63.1mmg)，BrettPhos Pd G3(27.4mg)，BrettPhos(32.5mg)以及叔丁醇钠(58.2mg)溶解于1mL的1,4-二氧六环中，随后于氩气保护下，升温至100℃反应3h后，反应液冷却至室温，并用乙酸乙酯稀释后，过滤，将滤液浓缩后，所得残余物经柱层析(二氯甲烷/甲醇梯度洗脱)分离，得标题化合物。
DMSO-d6 δ H8.31(s,1H),7.79(s,1H),7.66-7.61(m,1H),7.54(t,J＝6.6Hz,1H),7.44-7.02(m,3H),6.57-6.28(m,1H),6.18(s,1H),6.02(s,1H),5.18-5.12(m,3H),4.74(d,J＝7.0Hz,2H),4.48-4.36(m,2H),2.36(s,3H),1.67(d,J＝6.8Hz,3H).
LC/MS(m/z,MH +):483.2.
实施例55 (R)-1-(4-((1-(3-(1,1-二氟乙基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)-4-甲基哌啶-4-醇
Figure PCTCN2022074591-appb-000157
步骤1 (R)-6-溴-N-(1-(3-(1,1-二氟乙基)-2-氟苯基)乙基)-7-甲氧基-2-甲基喹啉-4-胺
Figure PCTCN2022074591-appb-000158
将6-溴-4-氯-7-甲氧基-2-甲基喹啉(200mg)，((R)-1-(3-(1,1-二氟乙基)-2-氟苯基)乙烷-1-胺(166mg)，N,N-二异丙基乙胺(189mg)溶于3mL二甲基亚砜中，氩气保护下135℃搅拌14小时后反应完毕。将反应液加入到40mL饱和氯化钠水溶液中，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，过滤，有机层浓缩后，所得残余物柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤2 (R)-1-(4-((1-(3-(1,1-二氟乙基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)-4-甲基哌啶-4-醇的合成
Figure PCTCN2022074591-appb-000159
将(R)-6-溴-N-(1-(3-(1,1-二氟乙基)-2-氟苯基)乙基)-7-甲氧基-2-甲基喹啉-4-胺(120mg)，4-甲基-4-羟基哌啶(115mg)，三(二亚苄基丙酮)二钯(4.50mg)，1,1'-联萘-2,2'-双二苯膦(6.20mg)，叔丁醇钠(144mg)加入到5mL 1,4-二氧六环中，氩气保护下80℃搅拌3小时后反应完毕。加入20mL水稀释，乙酸乙酯萃取，合并有机层，无水硫酸钠干燥，过滤，有机层浓缩后，所得残余物柱层析(二氯甲烷/甲醇梯度洗脱)分离，得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ7.63(s,1H),7.57(t,J＝7.4Hz,1H),7.44(t,J＝7.4Hz,1H),7.24(t,J＝7.7Hz,1H),7.12(d,J＝7.1Hz,1H),7.05(s,1H),5.93(s,1H),5.08-5.01(m,1H),4.28(s,1H),3.85(s,3H),3.14-3.06(m,4H),2.25(s,3H),2.06(t,J＝19.1Hz,3H),1.71-1.63(m,7H),1.22(s,3H).
LC/MS(m/z,MH +):488.2.
实施例56：((R)-1-(4-(7-(2,2-二氟乙氧基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶 并[2,3-d]嘧啶-6-基)哌啶-1-基)乙烷-1-酮
Figure PCTCN2022074591-appb-000160
步骤1：2-氨基-5-溴-6-氯吡啶-3-羧酸的合成
Figure PCTCN2022074591-appb-000161
将2-氨基-6-氯吡啶-3-羧酸(25.0g)溶于150mL N,N-二甲基甲酰胺中，分批加入N-溴代丁二酰亚胺(28.4g)，加热至70℃搅拌2小时后反应完毕。将反应液冷却至室温，倒入500ml冰水混合物中，抽滤，滤饼用水洗涤三次，滤饼干燥后制得标题化合物。
步骤2：6-溴-7-氯-2-甲基-吡啶并[2,3-d][1,3]恶嗪-4-酮的合成
Figure PCTCN2022074591-appb-000162
将2-氨基-5-溴-6-氯吡啶-3-羧酸(36.0g)溶于500mL乙酸酐中，加热至130℃搅拌36小时后反应完毕，将反应液冷却至室温，浓缩干燥后直接投入下一步中。
步骤3：6-溴-7-氯-2-甲基-3H-吡啶并[2,3-d]嘧啶-4-酮的合成
Figure PCTCN2022074591-appb-000163
将上述步骤2所得粗品溶于1L四氢呋喃中，-30℃条件下滴加氨甲醇(7.0mol/L，415mL)至反应液中，滴加完毕后，反应体系升至室温反应12小时后反应完毕。将反应液倒入1L冰水中，加入4N稀盐酸调节pH至8-9，有淡黄色固体析出，过滤，滤饼用水洗涤三次后干燥，随后用石油醚：乙酸乙酯＝3：1(V:V)打浆纯化得标题化合物。
步骤4：6-溴-7-(2,2-二氟乙氧基)-2-甲基吡啶并[2,3-d]嘧啶-4(3H)-酮
Figure PCTCN2022074591-appb-000164
将6-溴-7-氯-2-甲基-3H-吡啶并[2,3-d]嘧啶-4-酮(550mg)溶于2ml 2,2-二氟乙醇，加入氢化钠(90.0mg)，氩气保护，70℃搅拌3小时。反应完毕，加入乙酸乙酯稀释，水洗，饱和食盐水 洗涤，有机相无水硫酸钠干燥，过滤，浓缩，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤5：(R)-6-溴-7-(2,2-二氟乙氧基)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[2,3-d]嘧啶-4-胺的合成
Figure PCTCN2022074591-appb-000165
将6-溴-7-(2,2-二氟乙氧基)-2-甲基吡啶并[2,3-d]嘧啶-4(3H)-酮(320mg)，(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺(190mg)，(3H-1,2,3-三唑并[4,5-b]吡啶-3-氧基)三-1-吡咯烷基六氟磷酸盐(780mg)，1,8-二氮杂双环[5.4.0]十一碳-7-烯(300mg)加入到5mL N,N-二甲基甲酰胺中，室温搅拌1小时后反应完毕，将反应液加入到20mL水中，乙酸乙酯萃取，合并有机层，浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，制得标题化合物。
步骤6：(R)-1-(4-(7-(2,2-二氟乙氧基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶基[2,3-d]嘧啶-6-基)-3,6-二氢吡啶-1(2H)-基)乙-1-酮的合成
Figure PCTCN2022074591-appb-000166
将(R)-6-溴-7-(2,2-二氟乙氧基)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[2,3-d]嘧啶-4-胺(240mg)，1-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-基)乙烷-1-酮(130mg)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(73.1mg)，碳酸钾(276mg)加入到10mL1,4-二氧六环中，加入1mL水，氩气保护下加热至100℃搅拌4小时后反应完毕。将反应液浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤7：((R)-1-(4-(7-(2,2-二氟乙氧基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶基[2,3-d]嘧啶-6-基)哌啶-1-基)乙烷-1-酮的合成
Figure PCTCN2022074591-appb-000167
将(R)-1-(4-(7-(2,2-二氟乙氧基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-基)-3,6-二氢吡啶-1(2H)-基)乙烷-1-酮(200mg)，钯碳(10mg)，加入到5mL甲醇中，加入0.5mL乙酸，通入氢气后室温搅拌8小时后反应完毕。抽滤，滤液浓缩后，所得残余物经柱层析(二氯甲烷/甲醇梯度洗脱)分离，制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ H8.57(s,1H),8.47(d,J＝7.2Hz,1H),7.65(t,J＝7.4Hz,1H),7.50(t,J＝6.9Hz,1H),7.37-7.10(m,2H),6.45(tt,J＝54.6,3.4Hz,1H),5.80-5.73(m,1H),4.91-4.53(m,3H),4.00-3.97(m,1H),3.23-3.04(m,2H),2.66-2.60(m,1H),2.33(s,3H),2.05(s,3H).1.95-1.84(m,2H),1.68-1.54(m,5H).
LC/MS(m/z,MH +):538.2.
实施例57：(R)-1-(7-(2,2-二氟乙氧基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-基)-N，3-二甲基氮杂环丁烷-3-甲酰胺
Figure PCTCN2022074591-appb-000168
步骤1：(R)-1-(7-(2,2-二氟乙氧基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-基)-3-甲基氮杂环丁烷-3-羧酸甲酯的合成
Figure PCTCN2022074591-appb-000169
将(R)-6-溴-7-(2,2-二氟乙氧基)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[2,3-d]嘧啶-4-胺(200mg)，3-甲基氮杂环丁烷-3-羧酸甲酯(100mg)溶于1，4-二氧六环(3mL)，加入三(二亚苄基丙酮)二钯(37.3mg)，2-二环己基膦-2',4',6'-三异丙基联苯(38.8mg)，碳酸铯(530.5mg)，氩气保护下加热至100℃搅拌，6小时后反应完毕。反应液浓缩经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤2：(R)-1-(7-(2,2-二氟乙氧基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-基)-N，3-二甲基氮杂环丁烷-3-甲酰胺的合成
Figure PCTCN2022074591-appb-000170
将1-(7-(2,2-二氟乙氧基)-4((((R)-1-(3-(二氟甲基)-2-氟-苯基)乙基)氨基)-2-甲基-吡啶并[2,3-d]嘧啶-6-基)-3-甲基-氮杂环丁烷-3-羧酸甲酯(60mg)溶于DMSO/ACN＝2/1(2mL)，加入氢氧化钠水溶液(88.97mg，444.86μmol,，含量20％)，室温下搅拌一小时后监测反应。反应完毕。向其中加入HATU(211.3mg)，甲胺盐酸盐(7.5mg)，N,N-二异丙基乙胺(43mg)，继续室温下搅拌一小时后监测反应，反应完毕，经制备HPLC(Triart C18 ExRS，乙腈/水梯度洗脱)分离，制得目标化合物。
1H NMR(400MHz,DMSO-d 6)δ H 8.16(d,J＝7.2Hz,1H),7.85(d,J＝4.5Hz,1H),7.64(t,J＝7.2Hz,1H),7.54(s,1H),7.49(t,J＝7.0Hz,1H),7.37-7.10(m,2H),6.61-6.29(m,1H),5.79-5.72(m,1H),4.66(td,J＝15.2,3.1Hz,2H),4.17(t,J＝7.8Hz,2H),3.76(t,J＝8.6Hz,2H),2.63(d,J＝4.4Hz,3H),2.29(s,3H),1.59(d,J＝7.0Hz,3H),1.56(s,3H).
LC/MS(m/z,MH +):539.2.
实施例58：(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-吗啉代-7-(三氟甲基)吡啶并[2,3-d]嘧啶-4-胺
Figure PCTCN2022074591-appb-000171
步骤1：2-氨基-5-溴-6-(三氟甲基)烟酸的合成
Figure PCTCN2022074591-appb-000172
将2-氨基-6-(三氟甲基)烟酸(500mg)溶解在N,N-二甲基甲酰胺(10mL)中，搅拌，淡黄色清液，将N-溴代丁二酰亚胺(604mg)加入反应体系，升温70℃反应半小时。将反应液缓慢滴加入40毫升水中，搅拌分散半小时，抽滤，滤饼干燥得标题化合物。
步骤2：6-溴-2-甲基-7-(三氟甲基)-吡啶并[2,3-d][1,3]恶嗪-4-酮的合成
Figure PCTCN2022074591-appb-000173
将2-氨基-5-溴-6-(三氟甲基)烟酸(640mg)置于反应管中；加入乙酸酐(10mL)，搅拌升温 130℃反应6小时。降温体系，减压脱除溶剂，得标题化合物，未纯化直接用于下一步反应。
步骤3：6-溴-2-甲基-7-(三氟甲基)吡啶并[2,3-d]嘧啶-4(3H)-酮的合成
Figure PCTCN2022074591-appb-000174
将6-溴-2-甲基-7-(三氟甲基)-吡啶并[2,3-d][1,3]恶嗪-4-酮(700mg)溶解在四氢呋喃(20mL)中，氩气置换三次，滴加氨甲醇(10mL)，有白色固体析出，室温反应过夜，减压脱除溶剂，除去部分溶剂，向体系中加入4N盐酸调节pH≈3，再加入饱和碳酸氢钠溶液，调节pH≈7，大量固体析出，抽滤，滤饼用水冲洗，干燥，得标题化合物。
步骤4：(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-7-(三氟甲基)吡啶并[2,3-d]嘧啶-4-胺的合成
Figure PCTCN2022074591-appb-000175
将6-溴-2-甲基-7-(三氟甲基)吡啶并[2,3-d]嘧啶-4(3H)-酮(311mg)，(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐(146mg)置于反应管中，真空除水除氧，将1,8-二偶氮杂双螺环[5.4.0]十一-7-烯(461mg)溶于N,N-二甲基甲酰胺(2mL)中，加入体系中，氩气置换三次，搅拌反应20分钟后冰浴，加入(3H-1,2,3-三唑并[4,5-B]吡啶-3-氧基)三-1-吡咯烷基六氟磷酸盐(789.57mg)的N,N-二甲基甲酰胺(1mL)溶液，搅拌10分钟，撤去冰浴，升温至室温反应1.5小时。水浴10摄氏度左右，将体系缓慢泼入15mL水中，有大量黄色固体析出，搅拌分散半小时，抽滤，滤饼经柱层析纯化(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤5：(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-吗啉代-7-(三氟甲基)吡啶并[2,3-d]嘧啶-4-胺的合成
Figure PCTCN2022074591-appb-000176
将6-溴-N-[((1R)-1-[3-(二氟甲基)-2-氟-苯基]乙基]-2-甲基-7-(三氟甲基)吡啶并[2,3-d]嘧啶-4-胺(100mg)，吗啉(72.7mg)，2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(19.5mg)，三(二亚苄基丙酮)二钯(19.1mg)和碳酸铯(272mg)加入到反应瓶中，加入无水1,4-二氧六环(4mL)，然后装上氩气球，置换气体三次，气体保护下放入100℃油浴中反应2小时。将反应液加压浓缩后经柱层析分离纯化(石油醚/乙酸乙酯梯度洗脱)，得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ H9.09(s,1H),8.91(d,J＝6.9Hz,1H),7.70(t,J＝7.2Hz,1H),7.53(t,J＝7.0Hz,1H),7.39-7.11(m,2H),5.83-5.76(m,1H),3.81-3.72(m,4H),3.02-2.96(m,4H),2.40(s,3H),1.65(d,J＝7.0Hz,3H).
LC/MS(m/z,MH +):486.2.
实施例59：(R)-6-(4-氨基-4-甲基哌啶-1-基)-7-(2,2-二氟乙氧基)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[2,3-d]嘧啶-4-胺
Figure PCTCN2022074591-appb-000177
步骤1：(R)-(1-(7-(2,2-二氟乙氧基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯的合成
Figure PCTCN2022074591-appb-000178
将6-溴-7-(2,2-二氟乙氧基)-N-((1R)-1-(3-(二氟甲基)-2-氟-苯基)乙基)-2-甲基吡啶并[2,3-d]嘧啶-4-胺(80mg)，N-(4-甲基-4-哌啶基)氨基甲酸叔丁酯(41.9mg)，2-二环己基膦-2',4',6'-三异丙基联苯(15.5mg)，三(二亚苄基丙酮)二钯(14.9mg)和碳酸铯(159mg)加入到反应瓶中，加入无水1,4-二氧六环(3mL)，装上氩气球，置换气体三次，气体保护下放入100℃油浴中反应过夜。将反应液减压浓缩后经柱层析分离纯化(二氯甲烷/甲醇梯度洗脱)，得标题化合物。
步骤2：(R)-6-(4-氨基-4-甲基哌啶-1-基)-7-(2,2-二氟乙氧基)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[2,3-d]嘧啶-4-胺的合成
Figure PCTCN2022074591-appb-000179
将(R)-(1-(7-(2,2-二氟乙氧基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-基)-4-甲基哌啶-4-基)氨基甲酸叔丁酯(79mg)用二氯甲烷(2mL)溶解，室温搅拌下加入 三氟乙酸(0.5mL)，然后反应2小时。将反应液减压浓缩，然后加入少量二氯甲烷和水溶解稀释，用饱和碳酸氢钠溶液调节pH至8，用乙酸乙酯萃取，有机相合并，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩后经prep-HPLC(Triart C18 ExRS，乙腈/水梯度洗脱)纯化，冻干得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ H8.33(d,J＝7.2Hz,1H),8.07(s,1H),7.66(t,J＝7.4Hz,1H),7.50(t,J＝6.9Hz,1H),7.37-7.10(m,2H),6.62-6.31(m,1H),5.80-5.77(m,1H),4.69(td,J＝15.2,3.2Hz,2H),3.18-3.11(m,4H),2.31(s,3H),1.66-1.52(m,7H),1.13(s,3H).
LC/MS(m/z,MH +):525.2.
实施例60：(R)-1-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)吡啶-2(1H)-酮
Figure PCTCN2022074591-appb-000180
将(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-2-甲基喹啉-4-胺(100mg)，碘化亚铜(95.0mg)和反式-(1R,2R)-N,N'-二甲基1,2-环己烷二胺加入10mL甲苯中，加入碳酸钾(200mg)，2-吡啶酮(100mg)后氩气保护加热至110℃，16小时后反应完毕，反应液浓缩后经柱层析(二氯甲烷/甲醇梯度洗脱)分离，制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ H8.49(s,1H),7.64-7.52(m,5H),7.39-7.12(m,3H),6.51(dd,J＝9.2,2.7Hz,1H),6.34(t,J＝6.6Hz,1H),6.19(s,1H),5.20-5.08(m,1H),3.84(s,3H),2.39(s,3H),1.61(dd,J＝6.6,2.2Hz,3H).
LC/MS(m/z,MH +):454.2.
实施例61：(R)-1-(3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)-3-氟氮杂环丁烷-1基)乙烷-1-酮-2,2,2-D3
Figure PCTCN2022074591-appb-000181
步骤1：(R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)-3-羟基氮杂环丁烷-1-甲酸叔丁酯的合成
Figure PCTCN2022074591-appb-000182
将3-(4-氯-7-甲氧基-2-甲基喹啉-6-基)-3-羟基氮杂环丁烷-1-羧酸叔丁酯(400.00mg)溶解于1mL的超干1,4-二氧六环中，随后向其中加入(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺(299 mg)，BrettPhos Pd G3(113mg),BrettPhos(113mg)以及叔丁醇钠(202mmol)，体系于氩气保护下升温至100℃反应4h后，反应液冷却至室温，用乙酸乙酯稀释后过滤，滤液浓缩后经柱层析(石油醚/乙酸乙酯梯度洗脱)分离纯化，制得标题化合物。
步骤2：(R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)-3-氟氮杂环丁烷-1-甲酸叔丁酯的合成
Figure PCTCN2022074591-appb-000183
将(R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)-3-羟基氮杂环丁烷-1-甲酸叔丁酯(100mg)溶解于5mL超干二氯甲烷中，随后降温至0℃后，向其中滴加二乙胺基三氟化硫(36.4mg)滴完，反应液移至室温继续反应2小时后，用饱和碳酸氢钠溶液淬灭，用乙酸乙酯萃取后，合并有机相经饱和食盐水洗涤后干燥，浓缩后经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，制得标题化合物。
步骤3：(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-(3-氟氮杂环丁烷-3-基)-7-甲氧基-2-甲基喹啉-4-胺的合成
Figure PCTCN2022074591-appb-000184
将(R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)-3-氟氮杂环丁烷-1-甲酸叔丁酯(100mg)溶解于5mL超干二氯甲烷中，随后向其中滴加1mL三氟乙酸，体系于室温下反应1小时后，浓缩，剩余物直接进行下一步反应，无需纯化。
步骤4：(R)-1-(3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)-3-氟氮杂环丁烷-1-基)乙-1-酮-2,2,2-D3的合成
Figure PCTCN2022074591-appb-000185
将(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-(3-氟氮杂环丁烷-3-基)-7-甲氧基-2-甲基喹啉-4-胺(80.0mg)溶解于5mL甲醇中，随后向其中加入DIEA(119mg)，加完向其中滴加乙酸酐-D6(29.9mg)滴完于室温下继续反应30分钟后，反应液浓缩经制备经HPLC(Triart C18 ExRS，流动相：乙腈/水)分离纯化制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ H8.40-8.38(m,1H),7.64-7.60(m,1H),7.56-7.53(m,1H),7.47-7.42(m,1H),7.33-7.15(m,3H),6.06(d,J＝4.6Hz,1H),5.15-5.10(m,1H),3.93-4.64(m,3H),4.35-4.26(m,1H),3.93(s,3H),2.33(s,3H),1.68(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):479.2.
实施例62：(R)-1-(3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-3-甲氧基氮 杂环丁烷-1-基)乙烷-1-酮
Figure PCTCN2022074591-appb-000186
步骤1：3-(4-氯-7-甲氧基喹啉-6-基)-3-甲氧基氮杂环丁烷-1-羧酸叔丁酯的合成
Figure PCTCN2022074591-appb-000187
将3-(4-氯-7-甲氧基喹啉-6-基)-3-羟基氮杂环丁烷-1-羧酸叔丁酯(100mg)溶解于5mL超干DMF中，随后降温至0℃后，向其中分批次加入NaH(12.1mg,60％)加完于该温度下继续反应30分钟后，向其中滴加碘甲烷(38.9mg)加完于室温下继续反应1小时后，反应液倒入5mL冰水中，随后用乙酸乙酯萃取，合并有机相经无水硫酸钠干燥后，过滤，浓缩，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，制得标题化合物。
步骤2：(R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-3-甲氧基氮杂环丁烷-1-羧酸叔丁酯的合成
Figure PCTCN2022074591-appb-000188
将3-(4-氯-7-甲氧基喹啉-6-基)-3-甲氧基氮杂环丁烷-1-羧酸叔丁酯(100mg)溶解于1mL超干1,4-二氧六环中，随后向其中加入(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺(74.9mg)，BrettPhos Pd G3(23.9mg)，BrettPhos(28.3mg)以及叔丁醇钠(50.7mg)，加完于氩气保护下升温至100℃反应4小时后，反应液冷却至室温，用乙酸乙酯稀释后过滤，滤液浓缩后经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，制得标题化合物。
步骤3：(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-(3-甲氧基氮杂环丁烷-3-基)喹啉-4-胺的合成
Figure PCTCN2022074591-appb-000189
将(R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-3-甲氧基氮杂环丁烷-1-羧酸叔丁酯(120mg)溶解于5mL超干二氯甲烷中，随后向其中滴加1mL三氟乙酸，体系于室温下反应1小时后浓缩，剩余物直接进行下一步反应，无需纯化。
步骤4：(R)-1-(3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-3-甲氧基氮杂环丁烷-1-基)乙烷-1-酮的合成
Figure PCTCN2022074591-appb-000190
将(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-甲氧基-6-(3-甲氧基氮杂环丁烷-3-基)喹啉-4-胺(90.0mg)溶解于5mL二氯甲烷中，随后向其中加入DIEA(107mg)，加完向其中滴加乙酸酐(31.9mg)滴完于室温下继续反应30分钟后，反应液浓缩后制备经HPLC(Triart C18 ExRS，流动相：乙腈/水)分离纯化，制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.30(d,J＝7.0Hz,1H),8.22(dd,J＝5.4,1.5Hz,1H),7.61-7.41(m,3H),7.40-7.13(m,3H),6.07-6.06(m,1H),5.10-5.06(m,1H),4.65-4.41(m,3H),4.13-4.09(m,1H),3.88(s,3H),2.98(d,J＝6.7Hz,3H),1.84(d,J＝4.0Hz,3H),1.68(d,J＝6.8Hz,3H).
LC/MS(m/z,MH +):474.2.
实施例63：(R)-1-(3-氨基-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)氮杂环丁烷-1-基)乙烷-1-酮
Figure PCTCN2022074591-appb-000191
步骤1：(R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-3-羟基氮杂环丁烷-1-羧酸叔丁酯的合成
Figure PCTCN2022074591-appb-000192
将3-(4-氯-7-甲氧基喹啉-6-基)-3-羟基氮杂环丁烷-1-羧酸叔丁酯(150mg)溶解于1mL的超干1,4-二氧六环中，随后向其中加入(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺(116mg)，BrettPhos Pd G3(37.3mg)，BrettPhos Pd(44.1mg)以及叔丁醇钠(79.0mg)，于氩气保护下，升温至100℃反应4小时后，反应液冷却至室温，用乙酸乙酯稀释后过滤，滤液浓缩后经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，制得标题化合物。
步骤2：(R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-3-氟氮杂环丁烷-1-羧酸叔丁酯的合成
Figure PCTCN2022074591-appb-000193
将(R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-3-羟基氮杂环丁烷- 1-羧酸叔丁酯(60.0mg)溶解于5mL超干二氯甲烷中，随后降温至0℃后，向其中滴加DAST(22.4mg)，滴完后于室温下继续反应2小时后，用饱和碳酸氢钠溶液淬灭，经乙酸乙酯萃取后，合并有机相后，经无水硫酸钠干燥后，过滤，滤液浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，制得标题化合物。
步骤3：(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-(3-氟氮杂环丁烷-3-基)-7-甲氧基喹啉-4-胺的合成
Figure PCTCN2022074591-appb-000194
将(R)-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-3-氟氮杂环丁烷-1-羧酸叔丁酯(60.0mg)溶解于5mL超干二氯甲烷中，随后向其中滴加1mL三氟乙酸，体系于室温下反应1小时后，浓缩，剩余物直接进行下一步反应，无需纯化。
步骤4：(R)-1-(3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-3-氟氮杂环丁烷-1-基)乙烷-1-酮的合成
Figure PCTCN2022074591-appb-000195
将(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-(3-氟氮杂环丁烷-3-基)-7-甲氧基喹啉-4-胺(48.0mg)溶解于5mL二氯甲烷中，随后向其中加入DIEA(44.7mg)，加完向其中滴加乙酸酐(17.5mg)滴完于室温下继续反应30分钟后，反应液浓缩后经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，制得标题化合物。
步骤5：(R)-1-(3-氨基-3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)氮杂环丁烷-1-基)乙烷-1-酮的合成
Figure PCTCN2022074591-appb-000196
将(R)-1-(3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基喹啉-6-基)-3-氟氮杂环丁烷-1-基)乙烷-1-酮(50.0mg)分散于3mL氨-甲醇溶液中，随后于微波，100℃下反应2小时后，反应液冷却至室温，浓缩后经制备HPLC(Triart C18 ExRS，流动相：乙腈/水)分离纯化，制得标题化合物。。
1H NMR(400MHz,DMSO-d 6)δ8.21-8.19(m,2H),7.61-7.44(m,3H),7.40-7.13(m,3H),6.06(t,J＝5.7Hz,1H),5.12-5.07(m,1H),4.71-4.46(m,2H),4.18(d,J＝8.7Hz,1H),3.92-3.88(m,4H),1.81(d,J＝1.8Hz,3H),1.67(dd,J＝6.9,1.7Hz,3H).
LC/MS(m/z,MH +):459.2.
实施例64：(R)-1-(7-(二氟甲氧基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹啉-6-基)- 4-甲基哌啶-4-醇
Figure PCTCN2022074591-appb-000197
步骤1：(R)-6-溴-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹啉-7-醇的合成
Figure PCTCN2022074591-appb-000198
将6-溴-4-氯-2-甲基喹啉-7-醇(500mg)溶解于5mL的超干N-甲基吡咯烷酮中，随后向其中加入(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐(478mg)和碳酸钾(976mg)在氩气保护下，于微波下，在150℃下反应4小时后，反应液冷却至室温，用乙酸乙酯稀释后过滤，有机相用饱和食盐水洗涤后，干燥有机相，浓缩后剩余物经(乙酸乙酯和石油醚混合溶剂,v:v＝10:1)打浆后过滤，烘干滤饼制得标题化合物。
步骤2：(R)-6-溴-7-(二氟甲氧基)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基喹啉-4-胺的合成
Figure PCTCN2022074591-appb-000199
将(R)-6-溴-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹啉-7-醇(100mg)溶解于1mL乙腈中，随后向其中加入1mL 6M的氢氧化钾水溶液，最后向其中加入二氟甲基三氟甲磺酸盐(51.6mg)，加完于室温下继续反应10分钟后，反应液用1M的柠檬酸水溶液调节pH＝7左右后，用乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，浓缩，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，制得标题化合物。
步骤3：(R)-1-(7-(二氟甲氧基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹啉-6-基)-4-甲基哌啶-4-醇的合成
Figure PCTCN2022074591-appb-000200
将(R)-6-溴-7-(二氟甲氧基)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基喹啉-4-胺(60.0mg)溶解于1mL超干的1,4-二氧六环中，随后向其中加入4-甲基哌啶-4-醇(21.8mg)，Pd 2(dba) 3(11.6mg),BINAP(15.7mg)和叔丁醇钠(24.3mg)，体系于氩气保护下升温至100℃反应6小时后，反应液冷却至室温，用乙酸乙酯稀释后过滤，滤液浓缩后经制备HPLC(Triart C18 ExRS,流动相：乙腈/水)分离纯化制得标题化合物。
实施例65：(R)-1-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-6-基)-4-甲基哌啶-4-醇
Figure PCTCN2022074591-appb-000201
参考实施例56的合成路线，采用上述路线制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.31(s,1H),8.03(s,1H),7.66(t,J＝7.5Hz,1H),7.50(t,J＝7.1Hz,1H),7.29(t,J＝7.7Hz,1H),7.24(t,J＝54.4Hz,1H),5.78(p,J＝7.0Hz,1H),4.33(s,1H),3.97(s,3H),3.20–2.97(m,4H),2.31(s,3H),1.70-1.58(m,7H),1.21(s,3H).
LC/MS(m/z,MH +):476.2.
实施例66：(R)-1-(7-(2,2-二氟乙氧基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-yl)-N,4-二甲基哌啶-4-甲酰胺
Figure PCTCN2022074591-appb-000202
参考实施例57的合成方法，不同的是将步骤1中的3-甲基氮杂环丁烷-3-羧酸甲酯替换为4-甲基-4-哌啶甲酸甲酯，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.41(s,1H),8.04(s,1H),7.67-7.63(m,2H),7.50(t,J＝7.0Hz,1H),7.29(t,J＝7.7Hz,1H),7.24(t,J＝54.4Hz,1H),6.63-6.32(m,1H),5.85-5.69(m,1H),4.69 (td,J＝15.2,2.7Hz,2H),3.33-3.32(m,2H),2.88-2.76(m,2H),2.62(d,J＝4.4Hz,3H),2.31(s,3H),2.21-2.18(m,2H),1.60-1.52(m,5H),1.15(s,3H).
LC/MS(m/z,MH +):567.2.
实施例67：(R)-N4-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-吗啉代吡啶并[2,3-d]嘧啶-4,7-二胺
Figure PCTCN2022074591-appb-000203
参考实施例47的合成方法，采用上述技术路线，制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.01(s,1H),7.94(d,J＝7.4Hz,1H),7.65(t,J＝7.3Hz,1H),7.48(t,J＝6.8Hz,1H),7.29(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.58(bs,2H),5.75(p,J＝7.0Hz,1H),3.86-3.77(m,4H),2.91-2.89(m,4H),2.24(s,3H),1.56(d,J＝7.1Hz,3H).
LC/MS(m/z,MH +):433.2.
实施例68：(R)-1-(3-(7-(2,2-二氟乙氧基)-4-(1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-基)-3-羟基氮杂环丁烷-1-基)乙烷-1-酮
Figure PCTCN2022074591-appb-000204
将(R)-6-溴-7-(2,2-二氟乙氧基)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[2,3-d]嘧 啶-4-胺(200mg)溶解于10mL超干的四氢呋喃中，随后于氩气保护下降温至-80℃后，向其中滴加正丁基锂的正己烷溶液(2.00mL)，1-乙酰氮杂丁-3-酮(171mg)，加完移至室温下继续反应半小时后，用饱和氯化铵溶液淬灭，用乙酸乙酯萃取，合并有机相经无水硫酸钠干燥后过滤，浓缩后经柱层析(石油醚/乙酸乙酯梯度洗脱)分离纯化，得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.82(s,1H),8.67(d,J＝7.3Hz,1H),7.73-7.63(m,1H),7.51(t,J＝7.1Hz,1H),7.30(t,J＝7.7Hz,1H),7.24(t,J＝54.4Hz,1H),6.45(s,1H),6.39(tt,J＝54.3,3.2Hz,1H),5.82-5.77(m,1H),4.80-4.59(m,3H),4.48(dd,J＝10.3,4.4Hz,1H),4.22-4.20(m,1H),3.94-3.91(m,1H),2.35(d,J＝1.5Hz,3H),1.81(s,3H),1.60(d,J＝7.1Hz,3H).
LC/MS(m/z,MH +):526.2.
实施例69：(R)-N-(1-(7-(2,2-二氟乙氧基)-4-(1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-基)-4-甲基哌啶-4-基)乙酰胺
Figure PCTCN2022074591-appb-000205
将(R)-6-(4-氨基-4-甲基哌啶-1-基)-7-(2,2-二氟乙氧基)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[2,3-d]嘧啶-4-胺(200mg)溶解于10mL超干的二氯甲烷中，加入DIEPA(200mg)，滴加乙酸酐(50.0mg)，滴加完毕后室温搅拌1小时，随后将反应液浓缩，经柱层析(二氯甲烷/甲醇梯度洗脱)分离，制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.34(d,J＝7.3Hz,1H),8.04(s,1H),7.66(t,J＝7.5Hz,1H),7.50(t,J＝7.1Hz,1H),7.39(s,1H),7.30(t,J＝7.7Hz,1H),7.24(t,J＝54.4Hz,1H),6.48(tt,J＝54.3,3.1Hz,1H),5.77(p,J＝7.2Hz,1H),4.70(td,J＝15.3,3.4Hz,2H),3.24-3.21(m,2H),3.00-2.85(m,2H),2.33-2.25(m,5H),1.85(s,3H),1.67-1.62(m,2H),1.59(d,J＝7.1Hz,3H),1.34(s,3H).
LC/MS(m/z,MH +):567.2.
实施例70：(R)-1-(3-(7-(2,2-二氟乙氧基)-4-(1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-基)-3-甲氧基氮杂环丁烷-1-基)乙烷-1-酮
Figure PCTCN2022074591-appb-000206
将(R)-1-(3-(7-(2,2-二氟乙氧基)-4-(1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-基)-3-羟基氮杂环丁烷-1-基)乙烷-1-酮(50.0mg)溶解于2mL无水N,N-二甲基甲酰胺中，加入NaH(4.0mg)，室温搅拌30分钟后加入碘甲烷，室温搅拌2小时后反应完毕，反应液浓缩后经制备HPLC(流动相：乙腈/水)分离纯化，制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.78(s,1H),8.58(t,J＝6.3Hz,1H),7.67(q,J＝8.1Hz,1H),7.51(t,J＝6.1Hz,1H),7.31(t,J＝7.7Hz,1H),7.24(t,J＝54.4Hz,1H),6.42(tt,J＝54.5,3.3Hz,1H),5.82-5.72(m,1H),4.79–4.64(m,2H),4.62-4.51(m,1H),4.49–4.35(m,2H),4.14-4.01(m,1H),3.02(d,J＝2.1Hz,3H),2.35(d,J＝1.8Hz,3H),1.83(d,J＝4.3Hz,3H),1.62(d,J＝7.1Hz,3H).
LC/MS(m/z,MH +):540.2.
实施例71：(R)-1-(4-(7-(2,2-二氟乙氧基)-4-(1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[2,3-d]嘧啶-6-基)哌嗪-1-基)乙烷-1-酮
Figure PCTCN2022074591-appb-000207
参考实施例59的制备方法，不同的是将N-(4-甲基-4-哌啶基)氨基甲酸叔丁酯替换为1-乙酰基哌嗪，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.34(d,J＝7.2Hz,1H),8.09(s,1H),7.66(t,J＝7.1Hz,1H),7.50(t,J＝7.0Hz,1H),7.29(t,J＝7.7Hz,1H),7.24(t,J＝54.4Hz,1H),6.49(tt,J＝54.5,3.3Hz,1H),5.78(p,J＝7.1Hz,1H),4.72(td,J＝15.2,3.2Hz,2H),3.72-3.55(m,4H),3.18-3.03(m,4H),2.32(s,3H),2.07(s,3H),1.60(d,J＝7.1Hz,3H).
LC/MS(m/z,MH +):539.2.
实施例72：N-7-(3,3-二氟环丁基)-N-4-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-(2-甲基氧杂环丁烷-2-基)吡啶并[2,3-d]嘧啶-4,7-二胺
Figure PCTCN2022074591-appb-000208
步骤1：6-溴-7-((3,3-二氟环丁基)氨基)-2-甲基-吡啶并[2,3-d]嘧啶-4-醇的合成
Figure PCTCN2022074591-appb-000209
将6-溴-7-氯-2-甲基吡啶并[2,3-d]嘧啶-4-醇(500mg)溶解于5mL的DMF中，随后向其中加入3,3-二氟环丁胺(234mg)和N,N-二异丙基乙胺(470mg)随后升温至80℃反应2小时后，将反应液浓缩，经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤2：6-溴-N-7-(3,3-二氟环丁基)-N-4-((1R)-1-(3-(二氟甲基)-2-氟-苯基)乙基)-2-甲基-吡啶并[2,3-d]嘧啶-4,7-二胺的合成
Figure PCTCN2022074591-appb-000210
将6-溴-7-((3,3-二氟环丁基)氨基)-2-甲基-吡啶并[2,3-d]嘧啶-4-醇(500mg)溶解于10mL的DMF中，向其中加入(1R)-1-(3-(二氟甲基)-2-氟-苯基)乙胺(392mg)和(3H-1,2,3-三唑并(4,5-B)吡啶-3-氧基)三-1-吡咯烷基六氟磷酸盐(1.13g)，最后向其中加入DBU(661mg)加完升温至60℃ 反应4小时后反应完毕，反应液冷却至室温，加入乙酸乙酯稀释后，用饱和食盐水洗涤，用无水硫酸钠干燥有机相后，浓缩经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤3：1-(7-((3,3-二氟环丁基)氨基)-4-(((1R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-吡啶并[2,3-d]嘧啶-6-基)乙酮的合成
Figure PCTCN2022074591-appb-000211
将6-溴-N-7-(3,3-二氟环丁基)-N-4-((1R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-吡啶并[2,3-d]嘧啶-4,7-二胺(430mg)和三丁基(1-乙氧基乙烯)锡(360mg)加入到2mL的超干1，4-二氧六环中，随后向其中加入双三苯基磷二氯化钯(5.85mg)和三乙胺(168mg)，反应液于氩气保护下，升温至100℃反应4小时后，冷却至室温，并向其中加入1mL 2M的稀盐酸，继续反应1小时后，反应液加入5mL饱和碳酸氢钠溶液，并加入乙酸乙酯稀释，随后分液，水相经乙酸乙酯萃取后，合并有机相，经无水硫酸钠干燥后，过滤，浓缩，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，得标题化合物。
步骤4：N-7-(3,3-二氟环丁基)-N-4-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基-6-(2-甲基氧杂环丁烷-2-基)吡啶并[2,3-d]嘧啶-4,7-二胺的合成
Figure PCTCN2022074591-appb-000212
将三甲基碘化亚砜(22.9mg)溶解于1mL的叔丁醇中，随后向其中加入叔丁醇钾(11.7mg)反应液在50℃下反应30分钟后，向其中加入1-(7-((3,3-二氟环丁基)氨基)-4-(((1R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基-吡啶并[2,3-d)嘧啶-6-基)乙酮(10.0mg)，加完于该温度下继续反应6小时后，反应液加入乙酸乙酯稀释，随后过滤，滤液浓缩后经制备HPLC(Triart C18 ExRS,流动相：乙腈/水)分离，得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ7.71-7.58(m,1H),7.51-7.39(m,1H),7.37-7.19(m,2H),7.12-6.98(m,1H),5.70-5.53(m,2H),4.78-4.61(m,1H),3.74-3.61(m,1H),3.60-3.48(m,1H),3.04-2.74(m,4H),3.04-2.74(m,3H),1.74-1.66(m,1H),1.58-1.43(m,3H),1.19(s,3H).
LC/MS(m/z,MH +):508.2.
实施例73：(R)-1-(3-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)-3-甲 氧基氮杂丁烷-1-基)乙烷-1-酮
Figure PCTCN2022074591-appb-000213
参考实施例62的制备方法，不同的是将步骤1中的3-(4-氯-7-甲氧基喹啉-6-基)-3-羟基氮杂环丁烷-1-羧酸叔丁酯替换为3-(4-氯-7-甲氧基-2-甲基喹啉-6-基)-3-羟基氮杂环丁烷-1-羧酸叔丁酯，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.22(d,J＝5.8Hz,1H),7.65-7.56(m,1H),7.52(t,J＝6.9Hz,1H),7.52(t,J＝6.9Hz,1H),6.01(d,J＝3.4Hz,1H),5.13-5.01(m,1H),4.65-4.38(m,3H),4.13-4.06(m,1H),3.86(s,3H),2.96(d,J＝5.7Hz,3H),2.29(d,J＝1.2Hz,3H),1.84(d,J＝3.8Hz,3H),1.67(d,J＝6.8Hz,3H).
LC/MS(m/z,MH +):488.2.
实施例74：(R)-1-(4-(4-(1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-甲氧基-2-甲基喹啉-6-基)-4-甲氧基哌啶-1-基)乙烷-1-酮
Figure PCTCN2022074591-appb-000214
参考实施例48步骤1，将3-氧代氮杂环丁烷-1-羧酸叔丁酯替换为N-叔丁氧羰基-4-哌啶酮，制得4-(4-氯-7-甲氧基-2-甲基喹啉-6-基)-4-羟基哌啶-1-羧酸叔丁酯。
参考实施例62的制备方法，不同的是将步骤1中的3-(4-氯-7-甲氧基喹啉-6-基)-3-羟基氮杂环丁烷-1-羧酸叔丁酯替换为4-(4-氯-7-甲氧基-2-甲基喹啉-6-基)-4-羟基哌啶-1-羧酸叔丁酯，同法制得标题化合物。
1H NMR(400MHz,DMSO-d 6)δ8.05(d,J＝2.6Hz,1H),7.66-7.59(m,1H),7.52(t,J＝7.1Hz,1H),7.33(t,J＝6.4Hz,1H),7.31-7.27(m,1H),7.26(t,J＝54.4Hz,1H),7.15(s,1H),5.98(d,J＝1.6Hz,1H),5.11-5.00(m,1H),4.41-4.30(m,1H),3.86(s,3H),3.77-3.66(m,1H),3.49-3.35(m,1H),2.98(d,J＝4.2Hz,3H),2.94-2.84(m,1H),2.46-2.31(m,2H),2.28(s,3H),2.12-1.94(m,5H),1.65(d,J＝6.7Hz,3H).
LC/MS(m/z,MH +):516.2.
实施例75：(R)-1-(4-(7-乙酰基-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹啉-6-基)-4-甲氧基哌啶-1-基)乙烷-1-酮
Figure PCTCN2022074591-appb-000215
步骤1：6-溴-4-氯喹啉-7-醇的合成
Figure PCTCN2022074591-appb-000216
将6-溴-4-氯-7-甲氧基喹啉(3.00g)溶解在二氯乙烷(25mL)中，氮气置换，冰水浴加入BBr 3(13.8g)，自然回温反应十分钟，黄色浊液，升温至50℃，搅拌反应过夜后，将反应液倒入冰水中淬灭，加入碳酸氢钠固体调pH至7，抽滤，滤饼干燥，得标题化合物2.80g。
步骤2：6-溴-4-氯-7-((4-甲氧基苄基)氧基)喹啉的合成
Figure PCTCN2022074591-appb-000217
将6-溴-4-氯喹啉-7-醇(2.80g)，对甲氧基苯甲基氯(PMBCl2.36g)置于反应瓶中，冰浴，加入DMF(150mL)，黄色浊液，置换氮气，加入NaH(557mg)，搅拌半小时，黄色清液，冰浴条件下，加入对甲氧基苯甲基氯(PMBCl 2.36g)，反应过夜后将反应液倒入450毫升冰水中淬灭，抽滤，得标题化合物3.00g。
步骤3：4-(4-氯-7-((4-甲氧基苄基)氧基)喹啉-6-基)-4-羟基哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2022074591-appb-000218
将6-溴-4-氯-7-((4-甲氧基苄基)氧基)喹啉(3.00g)置于三口瓶，除水除氧，加入THF(300mL)，-78℃下滴加n-BuLi(9.51mmol)，加完搅拌半小时，-78℃下滴加4-氧代哌啶-1-羧酸叔丁酯(3.16g)的THF溶液，反应完全后向反应液中加入饱和氯化铵水溶液，调pH至7，分液，有机相水洗，干燥，过滤，浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，制得标题化合物1.00g。
步骤4：4-(4-氯-7-((4-甲氧基苄基)氧基)喹啉-6-基)-4-甲氧基哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2022074591-appb-000219
将4-(4-氯-7-((4-甲氧基苄基)氧基)喹啉-6-基)-4-羟基哌啶-1-羧酸叔丁酯(1.00g)溶解在DMF(8mL)中，氮气置换，冰浴条件下加入NaH(144mg)，搅拌半小时，冰浴条件下加入MeI(568mg)，搅拌反应一小时后将反应液倒入冰水中淬灭，乙酸乙酯萃取，分液，有机相水洗，干燥，过滤，浓缩后，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，制得标题化合物0.50g。
步骤5：(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-((4-甲氧基苄基)氧基)喹啉-6-基)-4- 甲氧基哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2022074591-appb-000220
将4-(4-氯-7-((4-甲氧基苄基)氧基)喹啉-6-基)-4-甲氧基哌啶-1-羧酸叔丁酯(500mg),(R)-1-(3-(二氟甲基)-2-氟苯基)乙-1-胺(221mg),Brett Phos G3(176mg),Brett Phos(104mg),叔丁醇钠(280mg)全部置于反应管中，除水除氧，氩气置换，加入二氧六环(8mL)，升温至100℃搅拌反应4小时后，降温体系至室温，浓缩后经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，制得标题化合物0.30g。
步骤6：(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-羟基喹啉-6-基)-4-甲氧基哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2022074591-appb-000221
将(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-((4-甲氧基苄基)氧基)喹啉-6-基)-4-甲氧基哌啶-1-羧酸叔丁酯(300mg)溶于甲醇，加入钯碳(60mg)，置换氢气，反应一小时后过滤除去钯碳，浓缩后制得标题化合物。
步骤7：(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-((((三氟甲基)磺酰基)氧基)喹啉-6-基)-4-甲氧基哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2022074591-appb-000222
将(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-羟基喹啉-6-基)-4-甲氧基哌啶-1-羧酸叔丁酯(230mg)，苯基双(三氟甲烷磺酰)亚胺(PhNTF 2 237mg)，TEA(85.3mg)置于反应管中，除水除氧，氮气置换，加入DCM(7mL)，室温搅拌反应两小时后向反应液中加入水淬灭，DCM萃取，有机相用无水硫酸钠干燥，过滤，浓缩，所得残余物经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，制得标题化合物0.20g。
步骤8：(R)-4-(7-乙酰基-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹啉-6-基)-4-甲氧基哌啶-1-羧酸叔丁酯的合成
Figure PCTCN2022074591-appb-000223
将(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-((((三氟甲基)磺酰基)氧基)喹啉-6-基)-4-甲氧基哌啶-1-羧酸叔丁酯(50.0mg)，Pd(PPh 3) 2Cl 2(15.5mg)置于反应管中，除水除氧，置换氮气，加入三丁基(1-乙氧基乙烯基)锡(53.3mg)，1,4-二氧六环(5mL)，升温至100℃搅拌反应四小时后加水淬灭，乙酸乙酯萃取，有机相合并脱溶，经柱层析(石油醚/乙酸乙酯梯度洗脱)分离，制得标题化合物。
步骤9：(R)-1-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-(4-甲氧基哌啶-4-基)喹啉-7-基)乙烷-1-酮盐酸盐的合成
Figure PCTCN2022074591-appb-000224
将(R)-4-(7-乙酰基-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹啉-6-基)-4-甲氧基哌啶-1-羧酸叔丁酯(20.0mg)溶解在盐酸-二氧六环(5mL)中，室温搅拌半小时后反应完毕，浓缩后制得标题化合物。
步骤10：(R)-1-(4-(7-乙酰基-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹啉-6-基)-4-甲氧基哌啶-1-基)乙烷-1-酮的合成
Figure PCTCN2022074591-appb-000225
将(R)-1-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-(4-甲氧基哌啶-4-基)喹啉-7-基)乙烷-1-酮盐酸盐(16.5mg)，醋酸酐(4.64mg)，TEA(7.08mg)置于甲醇(1mL)中，室温搅拌过夜后反应完毕，将反应液浓缩后经制备HPLC(Triart C18 ExRS,流动相：乙腈：水)分离纯化制得标题化合物。
1H NMR(400MHz,MeOD)δ8.45-8.41(m,2H),8.07-8.00(m,1H),7.89-7.82(m,1H),7.72(t,J＝7.5Hz,1H),7.59(t,J＝7.3Hz,1H),7.37(t,J＝7.8Hz,1H),7.01(td,J＝54.6,8.8Hz,1H),5.59-5.47(m,1H),4.58-4.35(m,1H),3.95-3.72(m,1H),3.62-3.48(m,1H),3.19(d,J＝2.2Hz,3H),3.15-2.98(m,1H),2.70(s,3H),2.59-2.48(m,1H),2.27-2.17(m,1H),2.14(d,J＝8.7Hz,3H),2.11-1.89(m,2H),1.81-1.74(m,3H).
LC/MS(m/z,MH +):514.2
实施例76：(R)-6-(1-乙酰基-4-甲氧基哌啶-4-基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹啉-7-羧酸
Figure PCTCN2022074591-appb-000226
步骤1：(R)-6-(1-(叔丁氧基羰基)-4-甲氧基哌啶-4-基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹啉-7-羧酸甲酯的合成
Figure PCTCN2022074591-appb-000227
将(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-7-((((三氟甲基)磺酰基)氧基)喹啉-6-基)-4-甲氧基哌啶-1-羧酸叔丁酯(130mg)，醋酸钯(8.61mg,38.37μmol)，DPPP(1,3-双(二苯膦)丙烷15.8mg)，TEA(58.2mg)置于反应管中，加入5mL DMSO，0.5mL水，通入CO气体后升温至80℃搅拌反应4小时后反应完毕。将反应液倒入水中淬灭，乙酸乙酯萃取，有机相合并，用无水硫酸钠干燥后制得标题化合物。
步骤2：(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-(4-甲氧基哌啶-4-基)喹啉-7-羧酸甲酯盐酸盐的合成
Figure PCTCN2022074591-appb-000228
将(R)-6-(1-(叔丁氧基羰基)-4-甲氧基哌啶-4-基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹啉-7-羧酸甲酯(140mg)溶解在盐酸-二氧六环(3mL)，室温搅拌反应半小时后反应完毕，将反应液浓缩后制得标题化合物。
步骤3：(R)-6-(1-乙酰基-4-甲氧基哌啶-4-基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹啉-7-羧酸甲酯的合成
Figure PCTCN2022074591-appb-000229
将(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-(4-甲氧基哌啶-4-基)喹啉-7-羧酸甲酯盐酸盐(116mg)，乙酸酐(31.6mg)，TEA(48.2mg)溶解在MeOH(3mL)中，室温搅拌反应一小时后反应完毕。将反应液浓缩后制得标题化合物。
步骤4：(R)-6-(1-乙酰基-4-甲氧基哌啶-4-基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹啉-7- 羧酸的合成
Figure PCTCN2022074591-appb-000230
将(R)-6-(1-乙酰基-4-甲氧基哌啶-4-基)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹啉-7-羧酸甲酯(50.0mg)溶解在水(2mL)，MeOH(2mL)中，加入NaOH(11.3mg)，室温搅拌反应两小时后反应完毕，将反应液加入到20mL水中，用饱和氯化铵水溶液调节pH至3-4，乙酸乙酯萃取，合并有机层，浓缩后经制备HPLC(Triart C18 ExRS，流动相：乙腈/水)分离纯化，制得标题化合物。
1H NMR(400MHz,MeOD)δ8.36(s,1H),8.29(s,1H),8.14-8.06(m,1H),8.00-7.93(m,1H),7.79-7.70(m,1H),7.68-7.59(m,1H),7.45-7.35(m,1H),7.04(td,J＝54.6,6.9Hz,1H),5.84-5.72(m,1H),4.51-4.36(m,1H),3.98-3.76(m,1H),3.67-3.45(m,1H),3.22(d,J＝7.2Hz,3H),3.15-2.99(m,1H),2.56(t,J＝11.9Hz,1H),2.37(dd,J＝29.5,14.0Hz,1H),2.14(d,J＝5.7Hz,3H),2.11-1.90(m,2H),1.84(t,J＝6.0Hz,3H).
LC/MS(m/z,MH +):516.2.
生物学活性及相关性质测试
实验例1：本发明实施例对SOS1与KRAS G12D结合抑制活性的测定
使用KRAS-G12D/SOS1 BINDING ASSAY KITS(Cisbio，货号：63ADK000CB21PEH)评估本发明的化合物对KRASG12D::SOS1结合抑制的影响。
实验方法：
用100％DMSO将阳性对照BAY-293和待测化合物(10mM储液)稀释5倍至0.1mM，在384孔稀释板中以1:3进行等比稀释11个浓度。使用Echo转移0.1μL梯度稀释的化合物溶液到384孔板中，每个化合物做2个复孔，1000rpm/min，离心1min。转移5μL 4 X KRAS G12D(终浓度1X)及GTP溶液(终浓度10μΜ，sigma，货号：V900868)到384反应板中，1000rpm/min，离心1min，25℃孵育15min。转移5μL 4 X SOS1溶液(终浓度1X)到384反应板中，1000rpm/min，离心1min，25℃孵育45min。BAY-293化合物终浓度为10，3.33，1.11，0.37，0.12，0.04，0.014，0.0046，0.0015，0.0005，0.00017，0uM。待测化合物终浓度10，3.33，1.11，0.37，0.12，0.04，0.014，0.0046，0.0015，0.0005，0.00017，0uM。DMSO终浓度均为0.5％。转移10μL 2X检测试剂溶液到384反应板中，1000rpm/min，离心1min，4℃孵育180min。使用Envision多功能酶标仪读取激发波长665nm和发射波长615nm。665/615Ratio信号强度用于表征酶的活性程度。
数据处理方法：通过Graphpad Prism 8非线性回归方程拟合化合物IC 50：
阴性对照：DMSO
阳性对照：10μM BAY-293
利用以下非线性拟合公式来得到化合物的IC 50(半数抑制浓度)：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)*HillSlope))
X:化合物浓度log值
Y:665/615 Ratio
试验结果：在本实验条件下，测试化合物对KRASG12D::SOS1结合具有良好的抑制活性。测试化合物相应的活性测试结果具体见表1。
表1 本专利实施例对KRAS G12D::SOS1结合的抑制活性测试结果
实施例 IC 50(nM)
1 2.08
2 2.79
3 4.92
4 4.50
12 7.68
实验例2：本发明实施例对H358细胞增殖抑制活性的测定
通过CellTiter-Glo发光法细胞活力检测试剂盒方法评估本发明的化合物对H358细胞增殖的影响。
实验方法：
H358细胞(ATCC，CRL-5807)在含有10％FBS(Gibco，10100147)和100U/mL青链霉素混合液(Gibco，15140163)的RPMI1640(Hyclone，SH30256.01)完全培养基中培养，当细胞生长达80-90％时，将细胞消化吹散后种植于96孔板(Corning，4515)，每孔3000细胞(180μl RPMI1640完全培养基)，然后将96孔板置于37℃、5％CO 2的培养箱中培养过夜。
过夜后使用排枪每孔加入20μL稀释后的化合物，将96孔板置于37℃、5％CO 2的培养箱中继续培养。7天后吸取100μL上清液，弃去，每孔加50μL
Figure PCTCN2022074591-appb-000231
3D Cell Viability Assay液体，室温450rpm震荡30min，待细胞完全裂解之后，酶标仪选择“Luminescence”读板。该实验中，未加细胞组(用1640培养基替代)作为100％抑制组，加细胞未加化合物组作为0％抑制组。
化合物对H358细胞增殖抑制的百分比可以用以下公式计算：
抑制百分比＝100*(0％抑制组信号值-待测化合物特定浓度下信号值)/(0％抑制组信号值-100％抑制组信号值)。
化合物IC 50值由8个浓度点用XLfit(ID Business Solutions Ltd.，UK)软件通过以下公式计算：
Y＝Bottom+(Top-Bottom)/(1+10^((logIC 50-X)×slope factor))
其中Y为抑制百分比，X为待测化合物浓度的对数值，Bottom为最小抑制百分比，Top为最大抑制百分比，slope factor为曲线斜率系数。
试验结果：在本实验条件下，本发明实施例对H358细胞具有良好的增殖抑制活性。测试化合物相应的活性测试结果具体见表2。
表2 本专利实施例对H358细胞增殖抑制活性测试结果
实施例 IC 50(nM)
1 30.3
2 24.6
3 48.1
4 126.2
5 85.6
6 10.7
8 6.1
9 61.1
10 79.2
11 140.5
12 29.8
17 154.0
18 70.3
19 374
20 118
21 307
22 119
23 64.1
24 96.6
25 54.5
26 45.1
27 48.4
28 114.0
29 12.8
30 34.6
31 116.8
32 12.3
33 36.2
34 111.4
35 14.6
36 85.7
37 42.1
38 102.1
39 41.3
40 102.7
41 130.7
42 231.8
43 146.3
44 119.6
45 254.7
46 33.1
47 74.2
48 45.1
49 36.4
50 91.6
51 304.1
52 65.9
53 117.6
54 184.9
55 93.5
56 58.4
57 22.9
58 61.9
59 46.2
62 29.5
65 92.8
66 33.4
67 59.2
69 50.2
70 156.1
71 57.3
73 118.4
74 13.0
实验例3 本发明化合物的药代动力学性质检测
试验动物
健康成年BALB/c小鼠，雌性，平均分组，每组3只，3只灌胃，3只静脉，小鼠购自北京维通利华实验动物技术有限公司，动物生产许可证号：SCXK(浙)2019-0001。
药物配制
称取一定量本发明化合物，溶于DMSO 5％+PG 20％+无水乙醇5％+solutol 10％+水60％，配制成10mg/mL，用于灌胃。称取一定量本发明化合物，溶于DMSO 1％+PG 4％+无水乙醇1％+solutol 2％+水92％，配制成3mg/mL或配制成2mg/mL，用于静脉注射。
给药方式
灌胃组：BALB/c小鼠禁食过夜后灌胃给药，给药剂量均为10mg/kg，给药体积均为1mL/kg。
静脉组：BALB/c小鼠禁食过夜后静脉给药，给药剂量均为3mg/kg，给药体积均为1mL/kg。
操作方法
小鼠灌胃或静脉给药后，于给药后5min，15min，30min，1h，2h，4h，6h，由眼眶采血40μL，5μL EDTA-K2抗凝，12000rpm，4℃，5分钟离心分离血浆，于-20℃保存。
测定不同浓度的药物灌胃或静脉给药后小鼠血浆中待测化合物含量：取样品室温融解，涡旋1min；定量转移15μL至2mL 96孔板中，加入150μL内标沉淀剂，振荡(1200rpm*3min)；离心(4000rpm*15min)，转移上清100μL至1mL 96孔板中；氮气吹干，加入100μL复溶液(乙腈水1：9)，振荡摇匀(900rpm*3min),20μL进样分析。LC/MS/MS条件：流动相A:0.1％甲酸水溶液，流动相B：0.1％甲酸乙腈，色谱柱：ACE C18 5μm(3.0mm*50mm)，柱温：35℃，流速0.5mL/min。
试验结果
在本实验条件下，测试化合物表现出较好的药代动力学性质，结果具体见表3和表4。
表3 小鼠单次灌胃给予化合物后药代动力学参数
实施例 Cmax(ng/mL) T max(hr) AUClast(hr*ng/mL) T 1/2(hr)
1 116.9 0.4 344.0 1.5
2 420.3 0.5 1371.1 2.0
3 157.3 0.3 164.7 0.8
4 170.3 0.3 308.6 1.0
12 697.3 0.1 274.4 0.3
47 1293.3 0.3 3177.1 0.9
表4 小鼠单次静脉给予化合物后药代动力学参数
实施例 C 0(ng/mL) T 1/2(hr) AUClast(hr*ng/mL) Vss(L/Kg)
1* 463.4 1.1 228.2 8.1
2 900.0 1.1 473.3 6.1
3 1064.7 0.9 499.1 3.8
4 1001.1 1.1 449.5 4.4
12 2579.4 0.3 491.3 1.3
47 5251.7 0.5 1509.2 0.7
*单次静脉给药量为2mg/Kg
实验例4 本发明化合物对H358细胞p-ERK通路的影响
通过Advanced phospho-ERK(Thr202/Tyr204)cellular kit试剂盒方法评估本发明的化合物对H358细胞p-ERK通路的影响。
实验方法概述如下：
H358细胞(ATCC，CRL-5807)在含有10％FBS(Gibco，10100147)和100U/mL青链霉素混合液(Gibco，15140163)的RPMI1640(ThermoFisher，A1049101)完全培养基中培养，当细胞在培养容器中覆盖率达80-90％时，将细胞吹散后种植于96孔板(Corning，3599)，每孔50000细胞(90μl RPMI1640完全培养基)，静置5分钟之后放于37℃、5％CO 2的培养箱中培养6h，更换为无血清的RPMI1640饥饿过夜。
过夜后用排枪每孔加入10μL稀释后的化合物，将96孔板置于37℃、5％CO 2的培养箱中培养1h。倾倒上清，PBS洗一遍，每孔加50μL裂解液(Advanced phospho-ERK(Thr202/Tyr204)cellular kit，64AERPEH)，室温450rpm震荡1h，待细胞完全裂解之后，取16uL上清加入到384孔(PE,6007299)，加入混合好的抗体(d2/Eu＝1:1),室温孵育4h，酶标仪选择HTRF读板，Ratio＝Signal 665nm/Signal 620nm x 10  4。该实验中，未加细胞组(用1640培养基替代)作为100％抑制组，加细胞但是未加化合物组作为0％抑制组。
化合物对H358细胞p-ERK通路抑制的百分比可以用以下公式计算：
抑制百分比＝100*(0％抑制组信号值-待测化合物特定浓度下信号值)/(0％抑制组信号值-100％抑制组信号值)。
化合物IC 50值由8个浓度点用XLfit(IDBusiness Solutions Ltd.UK)软件通过以下公式计算：
Y＝Bottom+(Top-Bottom)/(1+10^((logIC 50-X)×slope factor))
其中Y为抑制百分比，X为待测化合物浓度的对数值，Bottom为最小抑制百分比，Top为最大抑制百分比，slope factor为曲线斜率系数。使用默认拟合曲线来拟合S形曲线斜率以确定IC 50值。
表5 本专利实施例对p-ERK抑制测试结果
实施例 IC 50(nM)
38 41.9
39 13.3
40 25.0
43 103.5
44 38.2
45 110.0
46 34.7
47 17.14
48 143.11
49 34.7
50 38.1
51 179.4
52 20.0
53 69.8
54 71.0
56 36.6
57 27.5
58 81.6
59 55.3
61 42.5
62 17.3
64 121.1
65 124.3
66 41.1
67 48.4
68 112.8
69 37.4
70 135.3
71 47.5
73 86.4
74 22.1

Claims (21)

  1. 一种式(I)所示化合物或其药学上可接受的盐，
    Figure PCTCN2022074591-appb-100001
    其中，
    X选自CH或N；
    Y选自CH或N；
    Z选自CH或N；
    R 1选自H、CN、C 1-6烷基或C 3-6环烷基；
    环A选自C 6-10芳基、苯并5-7元杂环基或苯并5-7元杂芳基；
    L选自化学键或O；
    R 2选自C 3-10环烷基、C 6-10芳基、3-10元杂环基或5-10元杂芳基，所述C 3-10环烷基、C 6- 10芳基、3-10元杂环基或5-10元杂芳基任选地被R 2b和/或R 2c取代；
    R 2b选自-OR 2c、-N(R 2c) 2、卤素、羟基、氰基、氨基、-C(O)R 2c、-C(O)NHR 2c、-C(O)NH 2、-NHR 2c、-C(O)H、-C(O)OH、-S(O) 2NHR 2c、-NHC(O)H、-N(C 1-4烷基)C(O)H、-C(O)N(R 2c) 2、-C(O)OR 2c、-S(O) 2R 2c、-S(O) 2N(R 2c) 2、-NHC(O)R 2c或-N(C 1-4烷基)C(O)R 2c；
    R 2c独立地选自C 1-6烷基、C 1-3氘代烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基或5-10元杂芳基，所述C 1-6烷基、C 3-10环烷基、C 6-10芳基、3-10元杂环基、5-10元杂芳基任选地被R 2d取代；
    R 2d选自卤素、羟基、氰基、氨基、-C(O)R 2f、-C(O)N(R 2f) 2、-C(O)OR 2f、-S(O) 2R 2f、-S(O) 2N(R 2f) 2、-N(C 1-4烷基)R 2f、-NHC(O)R 2f或-N(C 1-4烷基)C(O)R 2f；
    R 2f独立地选自H或C 1-6烷基；
    R 3选自H、卤素、羟基、氰基、氨基、-NH-C 3-6环烷基、C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、C 3-6环烷基、3-8元杂环基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、5-10元杂芳基、-C(O)R 3a、-C(O)N(R 3a) 2、-C(O)OR 3a、-S(O) 2R 3a、-S(O) 2N(R 3a) 2、-NHC(O)R 3a或-N(C 1-4烷基)C(O)R 3a，所述-NH-C 3-6环烷基、C 1-6烷基、C 3-6环烷基、3-8元杂环基、-O-C 1- 6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)或5-10元杂芳基任选地被R 3b取代；
    所述R 3a独立地选自H或C 1-6烷基；
    所述R 3b独立地选自卤素、羟基、氰基、氨基、3-8元杂环基或C 1-6烷基；
    R 4选自卤素、羟基、氰基、氨基、C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、3-8元杂环基、5-10元杂芳基或-S(O) 2-C 1-4烷基，所述C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、3-8元杂环基或5-10元杂芳基任选地被R 4a取代；所述R 4a选自卤素、羟基、氰基或氨基；
    R 5选自C 1-3氘代烷基、C 1-6烷基或C 1-6卤代烷基；
    R 6选自H、氘、C 1-3氘代烷基、C 1-6烷基或C 1-6卤代烷基；
    n选自0、1、2、3或4；
    其中，当X选自N，Z选自CH时，R 1选自CN或C 3-6环烷基；
    当X、Z选自N时，R 1选自CN、C 1-6烷基或C 3-6环烷基；
    当X、Z选自CH时，R 3选自羟基、氰基、氨基、C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、C 3-6环烷基、3-8元杂环基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、5-10元 杂芳基、-C(O)R 3a、-C(O)N(R 3a) 2、-C(O)OR 3a、-S(O) 2R 3a、-S(O) 2N(R 3a) 2、-NHC(O)R 3a或-N(C 1- 4烷基)C(O)R 3a，所述C 1-6烷基、C 3-6环烷基、3-8元杂环基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)或5-10元杂芳基任选地被R 3b取代。
  2. 根据权利要求1所述式((I))所示化合物或其药学上可接受的盐，其特征在于：环A选自苯基、茚满基、茚基、四氢化萘基、二氢萘基或萘基。
  3. 根据权利要求1或2所述式(I)所示化合物或其药学上可接受的盐，其特征在于：R 2选自C 3-10环烷基、3-10元杂环基或5-10元杂芳基，所述C 3-10环烷基、3-10元杂环基或5-10元杂芳基任选地被R 2b和/或R 2c取代；或者
    R 2选自3-10元杂环基或5-10元杂芳基，所述3-10元杂环基或5-10元杂芳基任选地被R 2b和/或R 2c取代。
  4. 根据权利要求1-3任一项所述式((I))所示化合物或其药学上可接受的盐，其特征在于：R 2选自任选地被R 2b和/或R 2c取代的以下基团：
    Figure PCTCN2022074591-appb-100002
  5. 根据权利要求1-4任一项所述式(I)所示化合物或其药学上可接受的盐，其特征在于：R 2b选自-OR 2c、卤素、羟基、氰基、氨基、-C(O)R 2c、-C(O)OR 2c、-S(O) 2R 2c、-C(O)NHR 2c或-NHC(O)R 2c；或者R 2b选自卤素、羟基、氰基、氨基、-C(O)R 2c、-S(O) 2R 2c或-C(O)NHR 2c。
  6. 根据权利要求1-5任一项所述式(I)所示化合物或其药学上可接受的盐，其特征在于：
    R 2c选自C 1-6烷基、C 1-3氘代烷基、C 3-10环烷基或3-10元杂环基，所述C 1-6烷基、C 3-10环烷基或3-10元杂环基任选地被R 2d取代。
  7. 根据权利要求1-6任一项所述式(I)所示化合物或其药学上可接受的盐，其特征在于：R 4选自卤素、羟基、氰基、氨基、C 1-6烷基、C 3-6环烷基或3-8元杂环基，所述C 1-6烷基、C 3-6环烷基或3-8元杂环基任选地被R 4a取代。
  8. 根据权利要求1-7任一项所述式(I)所示化合物或其药学上可接受的盐，其特征在于：R 3选自H、卤素、羟基、氰基、氨基、-NH-C 3-6环烷基、C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基、-C(O)R 3a、-C(O)OR 3a、-S(O) 2-C 1-4烷基或5-10元杂芳基，所述-NH-C 3-6环烷基、C 1-6烷基、C 3-6环烷基、-O-C 1-6烷基、-O-C 3-6环烷基或5-10元杂芳基任选地被R 3b取代；或者
    R 3选自H、卤素、羟基、氰基、氨基、-NH-C 3-6环烷基、C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、-O-C 1-6烷基、-C(O)R 3a、-C(O)OR 3a、-S(O) 2-C 1-4烷基或5-10元杂芳基，所述-NH-C 3-6环烷基、C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基任选地被R 3b取代；或者
    R 3选自H、氨基、-NH-C 3-6环烷基、-C(O)R 3a、-C(O)OR 3a、C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基，所述-NH-C 3-6环烷基、C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基任选地被R 3b取代。
  9. 根据权利要求1-8任一项所述式(I)所示化合物或其药学上可接受的盐，其特征在于：R 5选自C 1-3氘代烷基、C 1-3烷基或C 1-3卤代烷基。
  10. 根据权利要求1-9任一项所述式(I)所示化合物或其药学上可接受的盐，其特征在于：R 6选自H、氘、C 1-3氘代烷基、C 1-3烷基或C 1-3卤代烷基；或者R 6选自H、氘、CH 3或CD 3。
  11. 根据权利要求1-10任一项所述式((I))所示化合物或其药学上可接受的盐，其特征在于：n选自0、1或2；或者n选自2。
  12. 根据权利要求1-7或9-11任一项所述式(I)所示化合物或其药学上可接受的盐，其特征在于：式(I)所示化合物或其药学上可接受的盐选自式(II)所示化合物或其药学上可接受的盐，
    Figure PCTCN2022074591-appb-100003
    其中，环A、L、R 1、R 2、R 4、R 5、R 6、n如权利要求1-7或9-11任一项的定义，R 3选自羟基、氰基、氨基、C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、C 3-6环烷基、3-8元杂环基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)、5-10元杂芳基、-C(O)R 3a、-C(O)N(R 3a) 2、-C(O)OR 3a、-S(O) 2R 3a、-S(O) 2N(R 3a) 2、-NHC(O)R 3a或-N(C 1-4烷基)C(O)R 3a，所述C 1- 6烷基、C 3- 6环烷基、3-8元杂环基、-O-C 1-6烷基、-O-C 3-6环烷基、-O-(3-8元杂环基)或5-10元杂芳基任选地被R 3b取代；所述R 3a独立地选自H或C 1-6烷基；所述R 3b选自卤素、羟基、氰基、氨基或3-8元杂环基。
  13. 根据权利要求12所述式(I)所示化合物或其药学上可接受的盐，其特征在于：R 3选自C 1-3氘代烷基、-O-C 1-3氘代烷基、C 1-6烷基、-O-C 1-6烷基、-C(O)R 3a、-C(O)OR 3a、-S(O) 2-C 1-4烷基或5-10元杂芳基，所述C 1-6烷基、-O-C 1-6烷基或5-10元杂芳基任选地被R 3b取代。
  14. 根据权利要求1-11任一项所述式(I)所示化合物或其药学上可接受的盐，其特征在于：式(I)所示化合物或其药学上可接受的盐选自式(III)所示化合物或其药学上可接受的盐，
    Figure PCTCN2022074591-appb-100004
    其中，环A、L、Y、R 3、R 4、R 5、R 6、n如权利要求1-11任一项的定义，R 1选自氰基、C 1-6烷基或C 3-6环烷基，R 2选自任选地被R 2b和/或R 2c取代的以下基团：
    Figure PCTCN2022074591-appb-100005
    Figure PCTCN2022074591-appb-100006
  15. 根据权利要求14所述式(I)所示化合物或其药学上可接受的盐，其特征在于：式(I)所示化合物或其药学上可接受的盐选自式(IV)所示化合物或其药学上可接受的盐，
    Figure PCTCN2022074591-appb-100007
    其中，环A、L、R 3、R 4、R 5、R 6、n如权利要求14的定义，R 1选自氰基、C 1-6烷基或C 3-6环烷基，R 2选自任选地被R 2b和/或R 2c取代的以下基团：
    Figure PCTCN2022074591-appb-100008
  16. 根据权利要求14所述式(I)所示化合物或其药学上可接受的盐，其特征在于：式(I)所示化合物或其药学上可接受的盐选自式(V)所示化合物或其药学上可接受的盐，
    Figure PCTCN2022074591-appb-100009
    其中，环A、L、R 3、R 4、R 5、R 6、n如权利要求14的定义，R 1选自氰基、C 1-6烷基或C 3-6环烷基，R 2选自任选地被R 2b和/或R 2c取代的以下基团：
    Figure PCTCN2022074591-appb-100010
    Figure PCTCN2022074591-appb-100011
    Figure PCTCN2022074591-appb-100012
  17. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐，其特征在于：式(I)所示化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐，
    Figure PCTCN2022074591-appb-100013
    Figure PCTCN2022074591-appb-100014
    Figure PCTCN2022074591-appb-100015
    Figure PCTCN2022074591-appb-100016
    Figure PCTCN2022074591-appb-100017
    Figure PCTCN2022074591-appb-100018
  18. 一种药物组合物，所述药物组合物包含权利要求1-17任一项式(I)所示化合物或其药学上可接受的盐，以及药学上可接受的辅料。
  19. 权利要求1-17任一项式(I)所示化合物或其药学上可接受的盐，或权利要求18所述药物组合物在制备预防或者治疗与SOS1相关疾病的药物中的用途。
  20. 一种预防或治疗SOS1相关疾病的方法，所述方法包括给以患者治疗上有效剂量的包含权利要求1-17任一项式(I)所示化合物或其药学上可接受的盐，或权利要求18所述药物组合物。
  21. 根据权利要求19所述的用途或权利要求20所述的方法，其特征在于：所述SOS1相关疾病选自癌症。
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