WO2022184178A1 - Kras g12d inhibitors - Google Patents
Kras g12d inhibitors Download PDFInfo
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- WO2022184178A1 WO2022184178A1 PCT/CN2022/079487 CN2022079487W WO2022184178A1 WO 2022184178 A1 WO2022184178 A1 WO 2022184178A1 CN 2022079487 W CN2022079487 W CN 2022079487W WO 2022184178 A1 WO2022184178 A1 WO 2022184178A1
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- WIPO (PCT)
- Prior art keywords
- alkyl
- membered
- haloc
- compound
- nhc
- Prior art date
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- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
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- 239000012876 carrier material Substances 0.000 description 1
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- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- WRJWRGBVPUUDLA-UHFFFAOYSA-N chlorosulfonyl isocyanate Chemical compound ClS(=O)(=O)N=C=O WRJWRGBVPUUDLA-UHFFFAOYSA-N 0.000 description 1
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- 238000011161 development Methods 0.000 description 1
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- 230000037213 diet Effects 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
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- BDTDECDAHYOJRO-UHFFFAOYSA-N ethyl n-(sulfanylidenemethylidene)carbamate Chemical compound CCOC(=O)N=C=S BDTDECDAHYOJRO-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
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- 238000002474 experimental method Methods 0.000 description 1
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- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
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- 125000002541 furyl group Chemical group 0.000 description 1
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- 235000011852 gelatine desserts Nutrition 0.000 description 1
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- 239000003979 granulating agent Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
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- 125000002346 iodo group Chemical group I* 0.000 description 1
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- 238000002955 isolation Methods 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
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- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- HQGPKMSGXAUKHT-BYPYZUCNSA-N methyl (2s)-5-oxopyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1CCC(=O)N1 HQGPKMSGXAUKHT-BYPYZUCNSA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
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- 239000002808 molecular sieve Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
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- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
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- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
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- 125000003226 pyrazolyl group Chemical group 0.000 description 1
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- 125000004076 pyridyl group Chemical group 0.000 description 1
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- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 102200006538 rs121913530 Human genes 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 1
- 241000894007 species Species 0.000 description 1
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- 229910052815 sulfur oxide Inorganic materials 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- HQMYWQCBINPHBB-MRVPVSSYSA-N tert-butyl (2r)-2-methyl-4-oxopiperidine-1-carboxylate Chemical compound C[C@@H]1CC(=O)CCN1C(=O)OC(C)(C)C HQMYWQCBINPHBB-MRVPVSSYSA-N 0.000 description 1
- FMLPQHJYUZTHQS-MRVPVSSYSA-N tert-butyl (3r)-3-methylpiperazine-1-carboxylate Chemical compound C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1 FMLPQHJYUZTHQS-MRVPVSSYSA-N 0.000 description 1
- HNINFCBLGHCFOJ-UHFFFAOYSA-N tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate Chemical compound C1NCC2CCC1N2C(=O)OC(C)(C)C HNINFCBLGHCFOJ-UHFFFAOYSA-N 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000006090 thiamorpholinyl sulfone group Chemical group 0.000 description 1
- 125000006089 thiamorpholinyl sulfoxide group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the invention relates to fused ring derivatives useful as KRAS G12D inhibitors, a composition containing the inhibitor and the use thereof.
- KRAS G12D glycine to aspartic acid
- X 1 is selected from CR 3 or N;
- n 1 , n 2 , n 3 , n 4 , and n 5 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
- R 3 and R 6 together with the atoms to which they are respectively attached form ring D, said ring D is selected from a 3-20 membered carbocyclic ring, a 3-20 membered heterocyclic ring, a 6-12 membered aryl ring or a 5-20 membered heteroaryl ring; each said ring D is independently optionally substituted with z 2 R S15 ;
- X 2 is selected from CR 21 R 22 , NR 23 , O, S, SO or SO 2 ;
- R 21 and R 22 are each independently selected from hydrogen, halogen, -C 1-6 alkyl, -OH, -OC 1-6 alkyl, -SH, -SC 1-6 alkyl, -NH 2 , -NH (C 1-6 alkyl) or -N (C 1-6 alkyl) 2 ;
- R 23 is selected from hydrogen or -C 1-6 alkyl
- R 2 is selected from -L- (3-12 membered heterocyclyl) , -L- (3-12 membered cycloalkyl) , -L- (6-12 member aryl) , -L- (5-12 membered heteroaryl) or -L-NR 24 R 25 ;
- Each L is independently selected from a bond or C 1-10 alkylene optionally substituted with one or more R S9 ;
- R 24 and R 25 are each independently selected from hydrogen or -C 1-10 alkyl optionally substituted with one or more R S10 ;
- Said 3-12 membered heterocyclyl in -L- (3-12 membered heterocyclyl) is optionally substituted with one or more R S11 ;
- Said 3-12 membered cycloalkyl in -L- (3-12 membered cycloalkyl) is optionally substituted with one or more R S12 ;
- Said 6-12 member aryl in -L- (6-12 member aryl) is optionally substituted with one or more R S13 ;
- Said 5-12 membered heteroaryl in -L- (5-12 membered heteroaryl) is optionally substituted with one or more R S14 ;
- n 1 , m 2 , m 3 , m 4 or m 5 is independently selected from 0, 1, 2, 3, 4, 5 or 6;
- n 6 or m 7 is independently selected from 0, 1, 2, 3, 4, 5 or 6;
- w 1 and w 2 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
- w 3 , w 4 , w 5 , w 6 and w 7 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; provided that w 6 and w 7 are not 0 at the same time;
- p 1 and p 2 are each independently selected from 0, 1, 2, 3, 4, 5, or 6, provided that p 1 and p 2 are not 0 at the same time;
- p 3 and p 4 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
- Y 6 is selected from O, S, NH or CH 2 , when Y 6 is selected from NH or CH 2 , the NH or CH 2 is optionally substituted with 1 or 2 R S6 ;
- s 1 and s 2 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
- s 3 and s 4 are each independently selected from 0, 1, 2, 3, 4, 5, or 6, provided that s 3 and s 4 are not 0 at the same time;
- r 1 and r 2 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
- r 3 and r 4 are each independently selected from 0, 1, 2, 3, 4, 5, or 6;
- v is selected from 0, 1, 2, 3, 4, 5 or 6;
- ring A is selected from a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, said heterocyclic or heteroaryl ring at each occurrence is independently contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
- Ring B and ring C are each independently selected from a 3-10 membered heterocyclic ring which is optionally further contains 1, 2, or 3 heteroatoms selected from N, O or S except the fused N atom;
- Each of R Sb is independently selected from halogen; -C 1-6 alkyl; haloC 1-6 alkyl; -CN; -OH; -NH 2 ; -NH (C 1-6 alkyl) ; -NH (C 1-6 alkyl) 2 ; -OC 1-6 alkyl; or -C 1-6 alkyl substituted with 1, 2 or 3 substituents selected form halogen, haloC 1-6 alkyl, -CN, -OH, -NH 2 , -NH (C 1-6 alkyl) , -NH (C 1-6 alkyl) 2 or -OC 1-6 alkyl;
- q 1 , q 2 , q 3 , q 4 , q 5 and q 6 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
- t 1 , t 2 , t 3 , t 4 and t 5 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
- R 61 , R 62 , R 71 , R 72 , R 73 , R 74 , R 81 , R 82 , R 83 , R 84 , R 91 , R 92 , R 93 , R 94 , R 101 , R 102 , R 103 , R 104 , R 111 , R 112 , R 113 and R 114 are each independently selected from are independently selected from hydrogen, halogen, -C 1-6 alkyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, -C 2-6 alkenyl, -C 2-6 alkynyl, -CN, -NH 2 , -NH (C 1-6 alkyl) , -N (C 1-6 alkyl) 2 , oxo, -OH, -O (C 1-6 alkyl) , -SH, -S (C 1-6 alkyl) , -S (haloC
- R 4 is selected from phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, wherein said R 4 is independently optionally substituted with 1, 2, 3, 4, 5, or 6 R 4a ;
- Each of R 4b is independently selected from halogen; -C 1-6 alkyl; haloC 1-6 alkyl; -CN; oxo; -OH; -NH 2 ; -NH (C 1-6 alkyl) ; -NH (C 1-6 alkyl) 2 ; -OC 1-6 alkyl; or -C 1-6 alkyl substituted with 1, 2 or 3 substituents selected form halogen, haloC 1-6 alkyl, -CN, -OH, -NH 2 , -NH (C 1-6 alkyl) , -NH (C 1-6 alkyl) 2 or -OC 1-6 alkyl;
- R 41 is selected from
- R 4c is selected from hydrogen, -C 1-30 alkyl, -C 2-30 alkenyl, -C 2-30 alkynyl, -C 0-6 alkylene- (3-20 membered carbocyclyl) , -C 0-6 alkylene- (3-20 membered heterocyclyl) , -C 0-6 alkylene- (6-10 membered aryl) or -C 0-6 alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R 4j ;
- R 5 is selected from hydrogen or
- z 1 or z 2 is independently selected from 0, 1, 2, 3, 4, 5 or 6;
- R 1 , R 4 , R 6 , X 2 , R 2 , R 5 , n 1 , n 2 , n 3 , n 4 , n 5 , R S1 , and z 1 have same definations as in [1] .
- R 1 , R 4 , R 6 , X 2 , R 2 , R 5 , n 1 , n 3 , n 4 , n 5 , R S1 , z 1 have same definations as in [1] .
- a compound of formula (III) a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:
- R 1 , R 4 , R S15 , X 2 , R 2 , R 5 , n 1 , n 2 , n 3 , n 4 , n 5 , R S1 , z 1 , and z 2 have same definations as in [1] .
- Ring D is selected from a 4-7 membered heterocyclic ring or a 5-6 membered heteroaryl ring; said heterocyclic ring at each occurrence is independently contain 1 or 2 ring heteroatoms selected from N, O or S; said heteroaryl ring at each occurrence is independently contain 1 or 2 ring heteroatoms selected from N, O or S.
- R 4 , R 6 , X 2 , R 2 , R 5 , n 1 , n 2 , n 3 , n 4 , n 5 , R S1 , and z 1 have same definations as in [1] .
- R 1 , R 2 , R 5 , R 6 , n 1 , n 2 , n 3 , n 4 , n 5 , R S1 , R 4a , z 1 , X 1 , and X 2 have same definations as in [1] .
- R 1 , R 2 , R 4 , R 5 , R 6 , n 3 , n 4 , n 5 , R S1 , z 1 , X 1 , X 2 have same definations as in [1] .
- n 6 is selected from 0, 1, 2, 3, 4, 5 or 6;
- z 3 selected from 0, 1, 2, 3, 4, 5 or 6.
- R 1 , R 2 , R 3 , R 4 , R 6 , n 1 , n 3 , n 4 , n 5 , R S1 , z 1 , and X 2 have same definations as in [1] ; and n 1 + n 3 + n 4 + n 5 ⁇ 6.
- R 1 , R 2 , R 3 , R 4 , R 6 , n 1 , n 3 , n 4 , n 5 , R S1 , z 1 , and X 2 have same definations as in [1] ; and n 1 + n 3 + n 4 + n 5 ⁇ 6.
- R 3 is selected from -H, -F, -Cl, -CH 3 , -CH (CH 3 ) 2 , -CF 3 , -S-CF 3 or
- n 1 , m 2 , m 3 , m 4 or m 5 is independently selected from 0, 1, 2, 3, 4, 5 or 6;
- w 3 , w 4 , w 5 , w 6 and w 7 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; provided that w 6 and w 7 are not 0 at the same time;
- p 1 and p 2 are each independently selected from 0, 1, 2, 3, 4, 5, or 6, provided that p 1 and p 2 are not 0 at the same time;
- Y 6 is selected from O, S, NH or CH 2 , when Y 6 is selected from NH or CH 2 , the NH or CH 2 is optionally substituted with 1 or 2 R S6 ;
- s 3 and s 4 are each independently selected from 0, 1, 2, 3, 4, 5, or 6, provided that s 3 and s 4 are not 0 at the same time;
- r 3 and r 4 are each independently selected from 0, 1, 2, 3, 4, 5, or 6;
- ring A at each occurrence is independently selected from a 4 membered carbocyclic ring, 5 membered carbocyclic ring, a, 6 membered carbocyclic ring, a 4 membered heterocyclic ring including 1 ring member selected from N, a 5 membered heterocyclic ring including 1 to 2 ring members selected from N, or O, a 6 membered heterocyclic ring including 1 to 2 ring members selected from N, O or S, a phenyl ring, a 5 membered heteroaryl ring including 1 to 2 ring members selected from N, O, or S, or a 6 membered heteroaryl ring including 1 ring member selected from N.
- Y 3 and Y 4 are each independently selected from O, S, SO 2 , NH or CH 2 , when Y 3 and Y 4 is selectd from NH or CH 2 , the NH or CH 2 is optionally substituted with 1 or 2 R S4 ;
- Y 6 is selected from O, S or NH, when Y 6 is selected from NH or CH 2 , the NH or CH 2 is optionally substituted with R S6 ;
- ring A at each occurrence is independently selected from a 4 membered carbocyclic ring, 5 membered carbocyclic ring, a, 6 membered carbocyclic ring, a 4 membered heterocyclic ring including 1 ring member selected from N, a 5 membered heterocyclic ring including 1 to 2 ring members selected from N, or O, a 6 membered heterocyclic ring including 1 to 2 ring members selected from N, O or S, a phenyl ring, a 5 membered heteroaryl ring including 1 to 2 ring members selected from N, O, or S, or a 6 membered heteroaryl ring including 1 ring member selected from N.
- Each of R S3 is independently selected from -F, -Cl, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) 2 , -CH 2 Cl, -CHCl 2 , -CCl 3 , -CH 2 F, -CHF 2 , -CF 3 , -CN, oxo, -NH 2 , -NH (CH 3 ) , -N (CH 3 ) 2 , -OH, -O-CH 3 , -O-CH 2 CH 3 , -SH, -S-CH 3 , -S-CH 2 CH 3 , -COOH, -COO (CH 3 ) , -COO (CH 2 CH 3 ) , -CH 2 OH, -CH 2 CH 2 OH, -CH (CH 3 ) OH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , or -CH (
- q 1 is selected from 0, 1, or 2;
- Each of R S4 is independently selected from -F, -Cl, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) 2 , -CH 2 Cl, -CHCl 2 , -CCl 3 , -CH 2 F, -CHF 2 , -CF 3 , -CN, oxo, -NH 2 , -NH (CH 3 ) , -N (CH 3 ) 2 , -OH, -O-CH 3 , -O-CH 2 CH 3 , -SH, -S-CH 3 , -S-CH 2 CH 3 , -COOH, -COO (CH 3 ) , -COO (CH 2 CH 3 ) , -CH 2 OH, -CH 2 CH 2 OH, -CH (CH 3 ) OH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , or -CH (
- q 2 is selected from 0, 1, or 2;
- Each of R S5 is independently selected from -F, -Cl, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) 2 , -CH 2 Cl, -CHCl 2 , -CCl 3 , -CH 2 F, -CHF 2 , -CF 3 , -CN, oxo, -NH 2 , -NH (CH 3 ) , -N (CH 3 ) 2 , -OH, -O-CH 3 , -O-CH 2 CH 3 , -SH, -S-CH 3 , -S-CH 2 CH 3 , -COOH, -COO (CH 3 ) , -COO (CH 2 CH 3 ) , -CH 2 OH, -CH 2 CH 2 OH, -CH (CH 3 ) OH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , or -CH (
- q 3 is selected from 0, 1, or 2;
- Each of R S6 is independently selected from -F, -Cl, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) 2 , -CH 2 Cl, -CHCl 2 , -CCl 3 , -CH 2 F, -CHF 2 , -CF 3 , -CN, oxo, -NH 2 , -NH (CH 3 ) , -N (CH 3 ) 2 , -OH, -O-CH 3 , -O-CH 2 CH 3 , -SH, -S-CH 3 , -S-CH 2 CH 3 , -COOH, -COO (CH 3 ) , -COO (CH 2 CH 3 ) , -CH 2 OH, -CH 2 CH 2 OH, -CH (CH 3 ) OH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , or -CH (
- q 4 is selected from 0, 1, or 2;
- Each of R S7 is independently selected from -F, -Cl, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH (CH 3 ) 2 , -CH 2 Cl, -CHCl 2 , -CCl 3 , -CH 2 F, -CHF 2 , -CF 3 , -CN, oxo, -NH 2 , -NH (CH 3 ) , -N (CH 3 ) 2 , -OH, -O-CH 3 , -O-CH 2 CH 3 , -SH, -S-CH 3 , -S-CH 2 CH 3 , -COOH, -COO (CH 3 ) , -COO (CH 2 CH 3 ) , -CH 2 OH, -CH 2 CH 2 OH, -CH (CH 3 ) OH, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , or -CH (
- q 5 is selected from 0, 1, or 2;
- R N1 or R N2 ) in R S8 is independently selected from hydrogen or -C 1-6 alkyl
- R N1 and R N2 in R S8 together with the nitrogen atom to which they are both attached form a 3-6 membered heterocyclic ring which is optionally substituted with one or more substituents selected from halogen, -C 1-6 alkyl, -OH, -OC 1-6 alkyl, -SH, -SC 1-6 alkyl, -NH 2 , -NH (C 1-6 alkyl) or -N (C 1-6 alkyl) 2 ;
- q 6 is selected from 0, 1, 2 or 3;
- Each of R S11 is selected from -C 1-3 alkyl.
- R N1 or R N2 ) in R S8 is independently selected from hydrogen or -C 1-6 alkyl
- R N1 and R N2 in R S8 together with the nitrogen atom to which they are both attached form a 3-6 membered heterocyclic ring which is optionally substituted with one or more substituents selected from halogen, -C 1-6 alkyl, -OH, -OC 1-6 alkyl, -SH, -SC 1-6 alkyl, -NH 2 , -NH (C 1-6 alkyl) or -N (C 1-6 alkyl) 2 ;
- q 6 is selected from 0, 1, 2 or 3.
- R 4 is selected from wherein said R 4 is independently optionally substituted with 1, 2, 3, 4, 5 or 6 R 4a ;
- Each of R 4a is independently selected from -F, -Cl, -C 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkoxy, -C 2-3 alkenyl, -C 2-3 alkynyl, -CN, -NH 2 , -NH (C 1-3 alkyl) , -N (C 1-3 alkyl) 2 , -OH, -O (C 1-3 alkyl) , -SH, -S (C 1-3 alkyl) , 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, wherein said -C 1-3 alkyl, haloC 1-3 alkyl, haloC 1-3 alkoxy, -C 2-3 alkenyl, -C 2-6 alkynyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl is independently optionally substituted with 1, 2 or 3 R 4b ;
- Each of R 4b is independently selected from -F; -C 1-3 alkyl; haloC 1-3 alkyl; -CN; -OH; -NH 2 ; -NH (C 1-3 alkyl) ; -NH (C 1-3 alkyl) 2 ; -OC 1-3 alkyl; or -C 1-3 alkyl substituted with 1, 2 or 3 substituents selected form -F, haloC 1-3 alkyl, -CN, -OH, -NH 2 , -NH (C 1-3 alkyl) , -NH (C 1-3 alkyl) 2 or -OC 1-3 alkyl.
- R 4 is selected from wherein said R 4 is independently optionally substituted with 1, 2 or 3 R 4a ;
- a pharmaceutical composition comprising a compound, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof of any one of [1] to [37] , and at least one pharmaceutically acceptable excipient.
- the cancer is selected from pancreatic cancer, colorectal cancer, endometrial cancer or lung cancer.
- the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
- a method of treating a subject having a cancer related to KRAS G12D mutant protein comprising administering to the subject a therapeutically effective amount of a compound, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof of any one of [1] to [37] ; or the pharmaceutical composition of [39] .
- the cancer is selected from pancreatic cancer, colorectal cancer, endometrial cancer or lung cancer.
- the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
- the cancer is selected from pancreatic cancer, colorectal cancer, endometrial cancer or lung cancer.
- the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
- KRAS G12D refers to a mutant form of a mammalian KRAS protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 12.
- the assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variantp. Gly12Asp.
- KRAS G12D inhibitor refers to compounds of the present invention that are represented by Formula (I) , as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRAS G12D.
- KRAS G12D-associated disease or disorder refers to diseases or disorders associated with or mediated by or having a KRAS G12D mutation.
- a non-limiting example of a KRAS G12D-associated disease or disorder is a KRAS G12D-associated cancer.
- the patient is a human.
- the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
- the subject has been identified or diagnosed as having a cancer having a KRAS G12D mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit) .
- the subject has a tumor that is positive for a KRAS G12D mutation (e.g., as determined using a regulatory agency-approved assay or kit) .
- the subject can be a subject with a tumor (s) that is positive for a KRas G12D mutation (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit) .
- the subject can be a subject whose tumors have a KRAS G12D mutation (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay) .
- the subject is suspected of having a KRAS G12D gene-associated cancer.
- the subject has a clinical record indicating that the subject has a tumor that has a KRAS G12D mutation (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein) .
- halogen or “halo” , as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo.
- the preferred halogen groups include -F, -Cl and -Br.
- alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched.
- -C 1-6 alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl.
- C 1-3 as in C 1-3 alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.
- haloalkyl such as -C 1-6 haloalkyl, -C 1-4 haloalkyl or -C 1-3 haloalkyl
- an alkyl chain such as -C 1-6 alkyl, -C 1-4 alkyl or -C 1-3 alkyl
- examples include trifluoromethyl, difluoromethyl and fluoromethyl.
- alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group defined above.
- methylene i.e., -CH 2 -
- ethylene i.e., -CH 2 -CH 2 -or -CH (CH 3 ) -
- propylene i.e., -CH 2 -CH 2 -CH 2 -, -CH (-CH 2 -CH 3 ) -or -CH 2 -CH (CH 3 ) -
- alkenyl means a straight or branch-chained hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms in length.
- C 2-6 alkenyl contains from 2 to 6 carbon atoms.
- Alkenyl group include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hepetenyl, octenyl and the like.
- alkynyl contains a straight or branch-chained hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms in length.
- C 2-6 alkynyl contains from 2 to 6 carbon atoms.
- Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
- alkoxy radicals are oxygen ethers formed from the previously described alkyl groups.
- aryl refers to an unsubstituted or substituted mono or polycyclic aromatic ring system containing carbon ring atoms.
- the preferred aryls are mono cyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.
- heterocyclic refers to unsubstituted and substituted mono or polycyclic non-aromatic ring system containing one or more heteroatoms, which comprising moncyclic heterocyclic ring, bicyclic heterocyclic ring, bridged heterocyclic ring, fused heterocyclic ring or sipro heterocyclic ring.
- Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides.
- the ring is three to ten membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two or three, are included within the present definition.
- heterocyclic groups include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone and oxadiazolyl.
- heteroaryl represents an aromatic ring system containing carbon (s) and at least one heteroatom.
- Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted.
- a monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms.
- a polycyclic heteroaryl ring may contain fused, spiro or bridged ring junction, for example, bycyclicheteroaryl is a polycyclic heteroaryl.
- Bicyclic heteroaryl rings may contain from 8 to 12 member atoms.
- Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (cabons and heteroatoms) .
- heteroaryl groups include, but are not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladeninyl, quinolinyl or isoquinolinyl.
- cycloalkyl refers to a substituted or unsubstituted monocyclic ring, bicyclic ring, bridged ring, fused ring, sipiro ring non-aromatic ring system only containing carbon atoms.
- Examplary “cycloalkyl” groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
- composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instan
- pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
- the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
- the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds in the present invention are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60%pure, more suitably at least 75%pure, especially at least 98%pure (%are on a weight for weight basis) .
- the present invention includes within its scope the prodrugs of the compounds of this invention.
- such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into the required compound.
- the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject.
- Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs” , ed. H. Bundgaard, Elsevier, 1985.
- the present invention includes compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
- the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
- the present invention includes all stereoisomers of the compound and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
- stereoisomer refers to an isomer in which atoms or groups of atoms in the molecule are connected to each other in the same order but differ in spatial arrangement, including conformational isomers and conformational isomers.
- the configuration isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers.
- the invention includes all possible stereoisomers of the compound.
- Certain of the compounds provided herein may exist as atropisomers, which are conformational stereoisomers that occur when rotation about a single bond in the molecule is prevented, or greatly slowed, as a result of steric interactions with other parts of the molecule.
- the compounds provided herein include all atropisomers, both as pure individual atropisomer preparations, enriched preparations of each, or a non-specific mixture of each. Where the rotational barrier about the single bond is high enough, and interconversion between conformations is slow enough, separation and isolation of the isomeric species may be permitted.
- the present invention is intended to include all isotopes of atoms occurring in the present compounds.
- Isotopes include those atoms having the same atomic number but different mass numbers.
- isotopes of hydrogen include deuterium and tritium.
- the isotopes of hydrogen can be denoted as 1 H (hydrogen) , 2 H (deuterium) and 3 H (tritium) . They are also commonly denoted as D for deuterium and T for tritium.
- CD 3 denotes a methyl group wherein all of the hydrogen atoms are deuterium.
- Isotopes of carbon include 13 C and 14 C.
- Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by prcesses analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.
- the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
- the present invention includes any possible solvates and polymorphic forms.
- a type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable.
- compositions of the present invention comprise a compound in present invention (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
- the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
- the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
- the compounds in present invention or a prodrug or a metabolite or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
- the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous) .
- the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
- compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion.
- the compound represented by Formula I or a pharmaceutically acceptable salt thereof may also be administered by controlled release means and/or delivery devices.
- the compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients.
- the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
- compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt.
- the compounds of Formula I or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
- the pharmaceutical carrier employed can be, for example, a solid, liquid or gas.
- solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
- liquid carriers are sugar syrup, peanut oil, olive oil, and water.
- gaseous carriers include carbon dioxide and nitrogen.
- oral liquid preparations such as suspensions, elixirs and solutions
- carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
- oral solid preparations such as powders, capsules and tablets.
- tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
- tablets may be coated by standard aqueous or nonaqueous techniques.
- a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
- Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
- Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
- a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 0.05 to about 95 percent of the total composition.
- Unit dosage forms will generally contain between from about 0.0lmg to about 2g of the active ingredient, typically 0.01mg, 0.02mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, l000mg, 1500mg or 2000mg.
- compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
- a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
- Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
- compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
- the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
- the final injectable form must be sterile and must be effectively fluid for easy syringability.
- the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , vegetable oils, and suitable mixtures thereof.
- compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 0.05wt%to about 10wt%of the compound, to produce a cream or ointment having a desired consistency.
- compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier (s) followed by chilling and shaping in molds.
- the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
- additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
- additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
- additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
- other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.
- dosage levels on the order of from about 0.001mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions or alternatively about 0.05mg to about 7g per patient per day.
- inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS) may be effectively treated by the administration of from about 0.001 to 50mg of the compound per kilogram of body weight per day or alternatively about 0.05mg to about 3.5g per patient per day.
- Oxalyl chloride (22.65 g, 178.45 mmol) was added to a mixed solution of 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid (20.06 g, 139.18 mmol) in DCM (100 mL) and DMF (100 mg, 1.37 mmol) at 0 °C under nitrogen atmosphere. The solution was stirred for 3 h at room temperature. The solution was concentrated to give a yellow semi-solid. The semi-solid was taken up in THF (50 mL) and the solution was cooled to 0 °C, and dimethylamine/THF (60 mL, 120 mmol, 2M) was added dropwise slowly and the resulting suspension was stirred for 2 hours.
- 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid 20.06 g, 139.18 mmol
- DCM 100 mL
- DMF 100 mg, 1.37 mmol
- Lithium aluminum hydride (3.21 g, 84.59 mmol) was added portion-wise to a solution of Intermediate 1-1 (INT 1-1, 7.37 g, 43.05 mmol) in THF at 0 °C, and the resulting solution was stirred for 2 h at room temperature. The solution was cooled to 0 °C. Water (3.5 mL) , NaOH solution (15%, 3.5 mL) , water (10 mL) were added portion-wise to give a white suspension. The resulting suspension was filtered through Celite, and the solids were washed with THF (150 mL) .
- Oxalyl chloride (53.55 g, 0.42 mmol) was added to a mixed solution of 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid (50.45 g, 350.04 mmol) in DCM (500 mL) and DMF (5.16 g, 70.59 mmol) at 0 °C under nitrogen atmosphere. The solution was stirred for about 3 hours at room temperature. The solution was concentrated under reduced pressure to give a yellow semi-solid.
- Lithium aluminum hydride (30 g, 790.51 mmol) was added portion-wise to a solution of INT 2-1 (70.05 g, 328.52 mmol) in THF (700 mL) at 0 °C, and the resulting solution was stirred for 3 h at room temperature. The solution was cooled to 0 °C and water (30 mL) , NaOH solution (15%, 30 mL) , water (90 mL) were added portion-wise to give a white suspension. The resulting suspension was filtered through Celite, and the solids were washed with THF (150 mL) .
- Trifluoromethanesulfonic anhydride (15.55 g, 55.12 mmol) and DIEA (7.37 g, 57.03 mmol) were added dropwise simultaneously to a solution of 1, 3-dihydroxynaphthalene (8.82 g, 55.07 mmol) in DCM (300 mL) at 10 °C. After stirring for 1 h, the solution was partitioned between water and DCM. The organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with hexane/EA) to give Intermediate 5-1 (INT 5-1, 6.92 g, 23.68 mmol) .
- INT 15 was synthesized with 2-amino-4-bromo-3-fluorobenzoic acid as starting material.
- the reaction mixture was stirred at room temperature for 3 h under hydrogen atmosphere. After filtration, the filter cake was rinsed with MeOH (100 ml x 2) . The filtrate was evaporated under reduced pressure.
- LCMS 247 [M+H] + .
- INT 18-1 (4.79 g, 23.32 mmol) and propionaldehyde (1.45 g, 24.95 mmol) were added in formic acid (50 ml) .
- the reaction mixture was stirred at room temperature for 1 h, and then concentrated under vacuum.
- the crude of INT 18-2 (6.11 g, 20.97 mmol) was obtained and used for the next step without further purification.
- the reaction mixture was stirred at 60°C for 1 h.
- the resulting mixture was extracted with EtOAc (100 mL x 2) and the organic layers were combined and dried over anhydrous Na 2 SO 4 . After filtration, the solvent was removed in vacuo and the crude of INT 18-3 (5.25 g, 19.23 mmol) was obtained and used for the next step without further purification.
- LCMS 264 [M+H] + .
- INT 18-7 (5.22 g, 13.31 mmol) was added in DCM (55 ml) .
- DAST (2.36 g, 14.64 mmol) was added dropwise to the mixture at 0°C.
- the mixture was stirred at room temperature for 1 h and quenched by adding Saturated sodium bicarbonate aqueous solution (100 ml) , and then the mixture was extracted with DCM (350 ml x 2) , washed with brine, dried over Na 2 SO 4 . The filtrate was evaporated under reduced pressure.
- LCMS 395 [M+H] + .
- tert-butyl 4-oxopiperidine-1-carboxylate (30.04 g, 150.76 mmol) was added in DCM (200 ml) and TFA (100 ml) , the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give INT 19-1 (15.09 g, 152.28 mmol) .
- LCMS 100 [M+H] + .
- INT 19-6 (11.49 g, 41.30 mmol) and TEA (12.55 g, 124.10 mmol) were added into a solution of DCM (150 ml) . After adding di-tert-butyl dicarbonate (9.10 g, 41.70 mmol) slowly, the mixture was stirred at room temperature for 1 h. The resulting mixture was extracted with EtOAc (500 mL x 2) and the organic layers were combined and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude of INT 19-7 (8.60 g, 22.73 mmol) was obtained and used for the next step without further purification. LCMS: 379 [M+H] +.
- INT 19-8 (5.30 g, 13.94 mmol) and 10%Pd (0.63 g, 2.83 mmol) were added in a solution of MeOH (80 ml) at room temperature.
- the reaction mixture was stirred at room temperature for 1 h under hydrogen atmosphere. After filtration, the filter cake was rinsed with MeOH (100 ml x 2) . The filtrate was evaporated under reduced pressure.
- reaction mixture was purified by Prep-HPLC (C18 column, A: 0.1%TFA in water, B: CH 3 CN, Gradient: 10%B to 35%B in 60 min at a flow rate of 40 mL/min, 232 nm) to afford the desired product Compound 12 (19.0 mg, 0.235 mmol, 2TFA salt) .
- reaction mixture was purified by Prep-HPLC (C18 column, A: 0.1%TFA in water, B: CH 3 CN, Gradient: 15%B to 45%B in 60 min at a flow rate of 40 mL/min, 239 nm) to afford Compound 14 (27.8 mg, 0.033 mmol, 2TFA salt) .
- Step 1 7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline (506 mg, 1.53 mmol) was added to a solution of INT 17 (374 mg, 1.52 mmol) and N, N-Diisopropylethylamine (304 mg, 2.35 mmol) dissolved in DCM (5 mL) at room temperature. The reaction mixture was stirred for 10 mins, and then concentrated under vacuum. The residue was dissolved in EtOAc (40 mL) and washed with water (30 mL) . The water phase was extracted with EtOAc (30 mL) and the combined organic layers were washed with brine (40 mL) , dried over Na 2 SO 4 and then filtered.
- INT 17 374 mg, 1.52 mmol
- N, N-Diisopropylethylamine 304 mg, 2.35 mmol
- Step 2 A mixture of compound 17-1 (656 mg, 1.21 mmol) , ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (378 mg, 2.37 mmol) , triethylenediamine (69 mg, 615.13 ⁇ mol) , Cesium carbonate (1.20 g, 3.68 mmol) and DMF (5 mL) were stirred at room temperature overnight. After quenched with water (50 mL) and extracted with EtOAc (40 mL x 2) , the organic layers were combined and washed with brine (40 mL) .
- Step 4 and Step 5 TFA (0.5 mL) was added to a solution of compound 17-3 (135.00 mg, 0.16 mmol) ) in DCM (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h, and then concentrated under vacuum. The residue was purified by Prep-HPLC to afford trifluoroacetate of compound 17 (90 mg, 0.02 mmol) .
- the Compound 17 was separated by Prep-HPLC-Gilson with the following conditions: Column, CHIRALPAK SB (2cm x 25cm, 5um) ; mobile phase, Hex (0.1%IPAM) /EtOH; Flowing rate: 20 mL/min. This results in compound 17A (the first eluting isomer, retention time 4.703 min, 0.3 mg ) . and compound 17B (the second eluting isomer, retention time 5.372 min, 0.6 mg ) . and compound 17C (the third eluting isomer, retention time 7.002 min, 9.3 mg) . LCMS: 650 [M+H] + .
- the INT 12 was applied for synthesis of compound 27 in the following Table 13 using the above procedure or modified procedure with corresponding materials.
- GDP-loaded HIS-KRAS (G12D, aa 1-169) was pre-incubated with a compound in the presence of 10nM GDPin a 384-well plate (Greiner) for 15 min, then purified SOS1 ExD (Flag tag, aa 564-1049) , BODIPY TM FL GTP (Invitrogen) and MAb (monoclonal antibody) Anti 6HIS-Tb cryptate Gold (Cisbio) were added to the assay wells (Final concentration: 1.5 nM GDP-loaded HIS-KRAS (G12D) , 5 nM GDP, 0.5 ⁇ M SOS1 ExD, 80 nM BODIPY TM FL GTP, 52.5 ng/mL MAb Anti 6HIS-Tb cryptate Gold) and incubated for 4 hours at 25 °C.
- TR-FRET signals were read on Tecan Spark multimode microplate reader.
- the parameters were F486: Excitation 340nm, Emission 486nm, Lag time 100 ⁇ s, Integration time 200 ⁇ s; F515: Excitation 340nm, Emission 515nm, Lag time 100 ⁇ s, Integration time 200 ⁇ s.
- the percent of activation of compounds treated wells were normalizedbetween vehicle control and low control. Then the data were analyzed using a 4-parameter logistic model to calculate IC 50 valuesThe results are shown in the following Table 1.
- GppNp-loaded HIS-KRAS (G12D, aa 1-169) was pre-incubated with a compound in the presence of 200 ⁇ M GTP in a 384-well plate (Greiner) for 15 min, then cRAF RBD (GST tag, aa 50-132, CreativeBioMart) , MAb Anti GST-d2 (Cisbio) and MAb Anti 6HIS-Tb cryptate Gold (Cisbio) were added to the assay wells (Final concentration: 2.0nM GppNp-loaded HIS-KRAS (G12D) , 100 ⁇ M GTP, 35nM cRAF RBD, 1 ⁇ g/mL MAb Anti GST-d2, 52.5 ng/mL MAb Anti 6HIS-Tb cryptate Gold) and incubated for 2 hours at 25 °C.
Abstract
Provided are KRAS G12D inhibitors of formula (I) or formula (IV), a composition containing the inhibitor and the use thereof.
Description
Cross-References to Related Applications
This application claims priority to PCT/CN2021/079415, filed March 5, 2021; PCT/CN2021/079448, filed March 6, 2021; PCT/CN2021/080222, filed March 11, 2021; PCT/CN2021/080572, filed March 12, 2021; PCT/CN2021/080599, filed March 12, 2021; PCT/CN2021/084322, filed March 31, 2021; PCT/CN2021/093764, filed May 14, 2021; PCT/CN2021/100187, filed June 15, 2021; PCT/CN2021/101089, filed June 18, 2021; PCT/CN2021/101188, filed June 21, 2021; PCT/CN2021/108808, filed July 28, 2021; PCT/CN2021/114094, filed August 23, 2021, each of which is incorporated herein in its entirety and for all purposes.
The invention relates to fused ring derivatives useful as KRAS G12D inhibitors, a composition containing the inhibitor and the use thereof.
Background Art
Cancer related KRAS mutation is hard to cure. Some progresses have been taken recently after many years of efforts, for example some promising clinical data have been reported when using Amg-510 and MRT-849 as the therapeutic agent. However, these compounds are directed to KRAS G12C mutation, the development of KRAS G12D (glycine to aspartic acid) inhibitors is extraordinarily hard. Thus, there remains a need in the art for improved compounds and methods for treating KRAS G12D mutated cancer. The present invention fulfills this need and provides other related advantages.
Summary of Invention
Provided herein is the following aspects:
[1] . A compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:
Wherein,
R
1 is selected from hydrogen, halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C
1-6alkyl, -C
2-6alkenyl, -C
2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, oxo, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
R
6 is selected from hydrogen, halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C
1-6alkyl, -C
2-6alkenyl, -C
2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, oxo, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
X
1 is selected from CR
3 or N;
n
1, n
2, n
3, n
4, and n
5 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
R
3 is selected from hydrogen, halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C
1-6alkyl, -C
2-6alkenyl, -C
2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
Optionally, R
3 and R
6 together with the atoms to which they are respectively attached form ring D, said ring D is selected from a 3-20 membered carbocyclic ring, a 3-20 membered heterocyclic ring, a 6-12 membered aryl ring or a 5-20 membered heteroaryl ring; each said ring D is independently optionally substituted with z
2 R
S15;
R
S15 is selected from hydrogen, halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NO
2, -N
3, oxo, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -OC (=O) O (C
1-6alkyl) , -NHC (=O) (OC
1-6alkyl) , -N (C
1-6alkyl) C (=O) (OC
1-6alkyl) , -OC (=O) NH (C
1-6alkyl) , -OC (=O) N (C
1-6alkyl)
2, -NHC (=O) NH
2, -NHC (=O) NH (C
1-6alkyl) , -NHC (=O) N (C
1-6alkyl)
2, -N (C
1-6alkyl) C (=O) NH
2, -N (C
1-6alkyl) C (=O) NH (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) N (C
1-6alkyl)
2, -S (=O) (OC
1-6alkyl) , -OS (=O) (C
1-6alkyl) , -S (=O) NH
2, -S (=O) NH (C
1-6alkyl) , -S (=O) N (C
1-6alkyl)
2, -NHS (=O) (C
1-6alkyl) , -N (C
1-6alkyl) S (=O) (C
1-6alkyl) , -S (=O)
2 (OC
1-6alkyl) , -OS (=O)
2 (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , -OS (=O)
2O (C
1-6alkyl) , -NHS (=O)
2O (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2O (C
1-6alkyl) , -OS (=O)
2NH
2, -OS (=O)
2NH (C
1-6alkyl) , -OS (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2NH
2, -NHS (=O)
2NH (C
1-6alkyl) , -NHS (=O)
2N (C
1-6alkyl)
2, -N (C
1-6alkyl) S (=O)
2NH
2, -N (C
1-6alkyl) S (=O)
2NH (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2N (C
1-6alkyl)
2, -PH (C
1-6alkyl) , -P (C
1-6alkyl)
2, -P (=O) H (C
1-6alkyl) , -P (=O) (C
1-6alkyl)
2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more R
Sa; each of (heterocyclyl and heteroaryl) at each occurrence is independently contain 1, 2, 3 or 4 heteroatoms selected from N, O, S, S (=O) or S (=O)
2;
X
2 is selected from CR
21R
22, NR
23, O, S, SO or SO
2;
R
21 and R
22 are each independently selected from hydrogen, halogen, -C
1-6alkyl, -OH, -OC
1-6alkyl, -SH, -SC
1-6alkyl, -NH
2, -NH (C
1-6alkyl) or -N (C
1-6alkyl)
2;
R
23 is selected from hydrogen or -C
1-6alkyl;
R
2 is selected from
-L- (3-12 membered heterocyclyl) , -L- (3-12 membered cycloalkyl) , -L- (6-12 member aryl) , -L- (5-12 membered heteroaryl) or -L-NR
24R
25;
Each L is independently selected from a bond or C
1-10 alkylene optionally substituted with one or more R
S9;
R
24 and R
25 are each independently selected from hydrogen or -C
1-10alkyl optionally substituted with one or more R
S10;
Said 3-12 membered heterocyclyl in -L- (3-12 membered heterocyclyl) is optionally substituted with one or more R
S11;
Said 3-12 membered cycloalkyl in -L- (3-12 membered cycloalkyl) is optionally substituted with one or more R
S12;
Said 6-12 member aryl in -L- (6-12 member aryl) is optionally substituted with one or more R
S13;
Said 5-12 membered heteroaryl in -L- (5-12 membered heteroaryl) is optionally substituted with one or more R
S14;
Y
2 is selected from O, S, SO, SO
2, C=O, NH or CH
2, when Y
2 is selected from NH or CH
2, the NH or CH
2 is optionally substituted with 1 or 2 R
S3;
m
1, m
2, m
3, m
4 or m
5 is independently selected from 0, 1, 2, 3, 4, 5 or 6;
m
6 or m
7 is independently selected from 0, 1, 2, 3, 4, 5 or 6;
Y
3 and Y
4 are each independently selected from O, S, SO, SO
2, C=O, NH or CH
2, when Y
3 and Y
4 is selectd from NH or CH
2, the NH or CH
2 is optionally substituted with 1 or 2 R
S4;
w
1 and w
2 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
w
3, w
4, w
5, w
6 and w
7 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; provided that w
6 and w
7 are not 0 at the same time;
Y
5 is selected from O, S, SO, SO
2, C=O, NH or CH
2, when Y
5 is selected from NH or CH
2, the NH or CH
2 is optionally substituted with 1 or 2 R
S5;
p
1 and p
2 are each independently selected from 0, 1, 2, 3, 4, 5, or 6, provided that p
1 and p
2 are not 0 at the same time;
p
3 and p
4 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
Y
6 is selected from O, S, NH or CH
2, when Y
6 is selected from NH or CH
2, the NH or CH
2 is optionally substituted with 1 or 2 R
S6;
s
1 and s
2 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
s
3 and s
4 are each independently selected from 0, 1, 2, 3, 4, 5, or 6, provided that s
3 and s
4 are not 0 at the same time;
r
1 and r
2 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
r
3 and r
4 are each independently selected from 0, 1, 2, 3, 4, 5, or 6;
v is selected from 0, 1, 2, 3, 4, 5 or 6;
ring A is selected from a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, said heterocyclic or heteroaryl ring at each occurrence is independently contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;
Ring B and ring C are each independently selected from a 3-10 membered heterocyclic ring which is optionally further contains 1, 2, or 3 heteroatoms selected from N, O or S except the fused N atom;
R
S1, R
S3, R
S4, R
S5, R
S6, R
S7, R
S8, R
S9, R
S10, R
S11, R
S12, R
S13 and R
S14 are each independently selected from halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NO
2, -N
3, oxo, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -OC (=O) O (C
1-6alkyl) , -NHC (=O) (OC
1-6alkyl) , -N (C
1-6alkyl) C (=O) (OC
1-6alkyl) , -OC (=O) NH (C
1-6alkyl) , -OC (=O) N (C
1-6alkyl)
2, -NHC (=O) NH
2, -NHC (=O) NH (C
1-6alkyl) , -NHC (=O) N (C
1-6alkyl)
2, -N (C
1-6alkyl) C (=O) NH
2, -N (C
1-6alkyl) C (=O) NH (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) N (C
1-6alkyl)
2, -S (=O) (OC
1-6alkyl) , -OS (=O) (C
1-6alkyl) , -S (=O) NH
2, -S (=O) NH (C
1-6alkyl) , -S (=O) N (C
1-6alkyl)
2, -NHS (=O) (C
1-6alkyl) , -N (C
1-6alkyl) S (=O) (C
1-6alkyl) , -S (=O)
2 (OC
1-6alkyl) , -OS (=O)
2 (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , -OS (=O)
2O (C
1-6alkyl) , -NHS (=O)
2O (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2O (C
1-6alkyl) , -OS (=O)
2NH
2, -OS (=O)
2NH (C
1-6alkyl) , -OS (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2NH
2, -NHS (=O)
2NH (C
1-6alkyl) , -NHS (=O)
2N (C
1-6alkyl)
2, -N (C
1-6alkyl) S (=O)
2NH
2, -N (C
1-6alkyl) S (=O)
2NH (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2N (C
1-6alkyl)
2, -PH (C
1-6alkyl) , -P (C
1-6alkyl)
2, -P (=O) H (C
1-6alkyl) , -P (=O) (C
1-6alkyl)
2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more R
Sa;
Each of R
Sa is independently selected from halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NO
2, -N
3, oxo, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -OC (=O) O (C
1-6alkyl) , -NHC (=O) (OC
1-6alkyl) , -N (C
1-6alkyl) C (=O) (OC
1-6alkyl) , -OC (=O) NH (C
1-6alkyl) , -OC (=O) N (C
1-6alkyl)
2, -NHC (=O) NH
2, -NHC (=O) NH (C
1-6alkyl) , -NHC (=O) N (C
1-6alkyl)
2, -N (C
1-6alkyl) C (=O) NH
2, -N (C
1-6alkyl) C (=O) NH (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) N (C
1-6alkyl)
2, -S (=O) (OC
1-6alkyl) , -OS (=O) (C
1-6alkyl) , -S (=O) NH
2, -S (=O) NH (C
1-6alkyl) , -S (=O) N (C
1-6alkyl)
2, -NHS (=O) (C
1-6alkyl) , -N (C
1-6alkyl) S (=O) (C
1-6alkyl) , -S (=O)
2 (OC
1-6alkyl) , -OS (=O)
2 (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , -OS (=O)
2O (C
1-6alkyl) , -NHS (=O)
2O (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2O (C
1-6alkyl) , -OS (=O)
2NH
2, -OS (=O)
2NH (C
1-6alkyl) , -OS (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2NH
2, -NHS (=O)
2NH (C
1-6alkyl) , -NHS (=O)
2N (C
1-6alkyl)
2, -N (C
1-6alkyl) S (=O)
2NH
2, -N (C
1-6alkyl) S (=O)
2NH (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2N (C
1-6alkyl)
2, -PH (C
1-6alkyl) , -P (C
1-6alkyl)
2, -P (=O) H (C
1-6alkyl) , -P (=O) (C
1-6alkyl)
2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; wherein said 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is independently optionally substituted with 1, 2, or 3 R
Sb;
Each of R
Sb is independently selected from halogen; -C
1-6alkyl; haloC
1-6alkyl; -CN; -OH; -NH
2; -NH (C
1-6alkyl) ; -NH (C
1-6alkyl)
2; -OC
1-6alkyl; or -C
1-6alkyl substituted with 1, 2 or 3 substituents selected form halogen, haloC
1-6alkyl, -CN, -OH, -NH
2, -NH (C
1-6alkyl) , -NH (C
1-6alkyl)
2 or -OC
1-6alkyl;
q
1, q
2, q
3, q
4, q
5 and q
6 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
R
2a, R
2b, R
2c, R
2d and R
2e are each independently selected from is selected from halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, oxo, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C
1-6alkyl, -C
2-6alkenyl, -C
2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, oxo, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
t
1, t
2, t
3, t
4 and t
5 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;
R
61, R
62, R
71, R
72, R
73, R
74, R
81, R
82, R
83, R
84, R
91, R
92, R
93, R
94, R
101, R
102, R
103, R
104, R
111, R
112, R
113 and R
114 are each independently selected from are independently selected from hydrogen, halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, oxo, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C
1-6alkyl, -C
2-6alkenyl, -C
2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, oxo, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
R
4 is selected from phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, wherein said R
4 is independently optionally substituted with 1, 2, 3, 4, 5, or 6 R
4a;
Each of R
4a is independently selected from halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, oxo, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl or R
41, wherein said -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is independently optionally substituted with 1, 2 or 3 R
4b;
Each of R
4b is independently selected from halogen; -C
1-6alkyl; haloC
1-6alkyl; -CN; oxo; -OH; -NH
2; -NH (C
1-6alkyl) ; -NH (C
1-6alkyl)
2; -OC
1-6alkyl; or -C
1-6alkyl substituted with 1, 2 or 3 substituents selected form halogen, haloC
1-6alkyl, -CN, -OH, -NH
2, -NH (C
1-6alkyl) , -NH (C
1-6alkyl)
2 or -OC
1-6alkyl;
R
4c is selected from hydrogen, -C
1-30alkyl, -C
2-30alkenyl, -C
2-30alkynyl, -C
0-6alkylene- (3-20 membered carbocyclyl) , -C
0-6alkylene- (3-20 membered heterocyclyl) , -C
0-6alkylene- (6-10 membered aryl) or -C
0-6alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R
4j;
R
4d and R
4e are each selected from hydrogen, -C
1-30alkyl, -C
2-30alkenyl, -C
2-30alkynyl, -C (=O) C
1-6alkyl, -C
0-6alkylene- (3-20 membered carbocyclyl) , -C
0-6alkylene- (3-20 membered heterocyclyl) , -C
0-6alkylene- (6-10 membered aryl) or -C
0-6alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R
4j;
R
4f and R
4g are each selected from hydrogen, -C
1-30alkyl, -C
2-30alkenyl, -C
2-30alkynyl, -C (=O) C
1-6alkyl, -C
0-6alkylene- (3-20 membered carbocyclyl) , -C
0-6alkylene- (3-20 membered heterocyclyl) , -C
0-6alkylene- (6-10 membered aryl) or -C
0-6alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R
4j;
R
4h, R
4i, R
4m, R
4n and R
4p are each selected from hydrogen, halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, oxo, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C
1-6alkyl, -C
2-6alkenyl, -C
2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, oxo, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
Optionally, R
4f and R
4g together with the atoms to which they are respectively attached form a 4-10 membered heterocyclyl ring, said 4-10 membered heterocyclyl ring optionally further contains 1 or 2 heteratoms selected from N, O, S, S (=O) or S (=O)
2 and optionally substituted with one or more R
4j;
Optionally, R
4f and R
4h together with the atoms to which they are respectively attached form a 4-10 membered heterocyclyl ring, said 4-10 membered heterocyclyl ring optionally further contains 1 or 2 heteratoms selected from N, O, S, S (=O) or S (=O)
2 and optionally substituted with one or more R
4j;
R
4j at each occurrence is independently selected from halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, oxo, -NO
2, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein said -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is independently optionally substituted with 1, 2 or 3 substituents selected from halogen; -C
1-6alkyl; haloC
1-6alkyl; -CN; oxo; -OH; -NH
2; -NH (C
1-6alkyl) ; -NH (C
1-6alkyl)
2; -OC
1-6alkyl; or -C
1-6alkyl substituted with 1, 2 or 3 substituents selected form halogen, haloC
1-6alkyl, -CN, -OH, -NH
2, -NH (C
1-6alkyl) , -NH (C
1-6alkyl)
2 or -OC
1-6alkyl;
R
51 and R
52 are each independently selected from are independently selected from hydrogen, halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, oxo, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C
1-6alkyl, -C
2-6alkenyl, -C
2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, oxo, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
R
53 is selected from hydrogen, -C
1-30alkyl, -C
2-30alkenyl, -C
2-30alkynyl, -C (=O) C
1-6alkyl, -C
0-6alkylene- (3-20 membered carbocyclyl) , -C
0-6alkylene- (3-20 membered heterocyclyl) , -C
0-6alkylene- (6-10 membered aryl) or -C
0-6alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R
5a;
R
5a at each occurrence is independently selected from halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, oxo, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;
z
1 or z
2 is independently selected from 0, 1, 2, 3, 4, 5 or 6;
Each of (heterocyclyl and heteroaryl) at each occurrence is independently contain 1, 2, 3 or 4 heteroatoms selected from N, O, S, S (=O) or S (=O)
2.
[2] . A compound of formula (IA) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:
Wherein, R
1, R
4, R
6, X
2, R
2, R
5, n
1, n
2, n
3, n
4, n
5, R
S1, and z
1 have same definations as in [1] .
[3] . A compound of formula (Ⅱ) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:
Wherein, R
1, R
4, R
6, X
2, R
2, R
5, n
1, n
3, n
4, n
5, R
S1, z
1 have same definations as in [1] .
[4] . A compound of formula (Ⅲ) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:
Wherein,
R
1, R
4, R
S15, X
2, R
2, R
5, n
1, n
2, n
3, n
4, n
5, R
S1, z
1, and z
2 have same definations as in [1] .
Ring D is selected from a 4-7 membered heterocyclic ring or a 5-6 membered heteroaryl ring; said heterocyclic ring at each occurrence is independently contain 1 or 2 ring heteroatoms selected from N, O or S; said heteroaryl ring at each occurrence is independently contain 1 or 2 ring heteroatoms selected from N, O or S.
[5] . A compound of formula (Ⅳ) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:
Wherein, R
4, R
6, X
2, R
2, R
5, n
1, n
2, n
3, n
4, n
5, R
S1, and z
1 have same definations as in [1] .
[6] . A compound of formula (V) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:
Wherein, R
1, R
2, R
5, R
6, n
1, n
2, n
3, n
4, n
5, R
S1, R
4a, z
1, X
1, and X
2 have same definations as in [1] .
[7] . A compound of formula (Ⅵ) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:
Wherein, R
1, R
2, R
4, R
5, R
6, n
3, n
4, n
5, R
S1, z
1, X
1, X
2 have same definations as in [1] .
Y
7 is selected from O, S, SO, SO
2, C=O, NH, CH
2, NH (C=O) , (C=O) NH, NH (S=O) , (S=O) NH, NHSO
2, SO
2NH;
n
6 is selected from 0, 1, 2, 3, 4, 5 or 6;
R
S16 is selected from hydrogen, halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, -CN, -NO
2, -N
3, oxo, -NH
2, -NH (C
1-6alkyl) , -N (C
1-6alkyl)
2, -OH, -O (C
1-6alkyl) , -SH, -S (C
1-6alkyl) , -S (haloC
1-6alkyl) , -S (=O) (C
1-6alkyl) , -S (=O)
2 (C
1-6alkyl) , -C (=O) (C
1-6alkyl) , -C (=O) OH, -C (=O) (OC
1-6alkyl) , -OC (=O) (C
1-6alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-6alkyl) , -C (=O) N (C
1-6alkyl)
2, -NHC (=O) (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) (C
1-6alkyl) , -OC (=O) O (C
1-6alkyl) , -NHC (=O) (OC
1-6alkyl) , -N (C
1-6alkyl) C (=O) (OC
1-6alkyl) , -OC (=O) NH (C
1-6alkyl) , -OC (=O) N (C
1-6alkyl)
2, -NHC (=O) NH
2, -NHC (=O) NH (C
1-6alkyl) , -NHC (=O) N (C
1-6alkyl)
2, -N (C
1-6alkyl) C (=O) NH
2, -N (C
1-6alkyl) C (=O) NH (C
1-6alkyl) , -N (C
1-6alkyl) C (=O) N (C
1-6alkyl)
2, -S (=O) (OC
1-6alkyl) , -OS (=O) (C
1-6alkyl) , -S (=O) NH
2, -S (=O) NH (C
1-6alkyl) , -S (=O) N (C
1-6alkyl)
2, -NHS (=O) (C
1-6alkyl) , -N (C
1-6alkyl) S (=O) (C
1-6alkyl) , -S (=O)
2 (OC
1-6alkyl) , -OS (=O)
2 (C
1-6alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-6alkyl) , -S (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2 (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2 (C
1-6alkyl) , -OS (=O)
2O (C
1-6alkyl) , -NHS (=O)
2O (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2O (C
1-6alkyl) , -OS (=O)
2NH
2, -OS (=O)
2NH (C
1-6alkyl) , -OS (=O)
2N (C
1-6alkyl)
2, -NHS (=O)
2NH
2, -NHS (=O)
2NH (C
1-6alkyl) , -NHS (=O)
2N (C
1-6alkyl)
2, -N (C
1-6alkyl) S (=O)
2NH
2, -N (C
1-6alkyl) S (=O)
2NH (C
1-6alkyl) , -N (C
1-6alkyl) S (=O)
2N (C
1-6alkyl)
2, -PH (C
1-6alkyl) , -P (C
1-6alkyl)
2, -P (=O) H (C
1-6alkyl) , -P (=O) (C
1-6alkyl)
2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -C
2-6alkenyl, -C
2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more R
Sa; each of (heterocyclyl and heteroaryl) at each occurrence is independently contain 1, 2, 3 or 4 heteroatoms selected from N, O, S, S (=O) or S (=O)
2;
z
3 selected from 0, 1, 2, 3, 4, 5 or 6.
[8] . A compound of formula (Ⅶ) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:
Wherein, R
1, R
2, R
3, R
4, R
6, n
1, n
3, n
4, n
5, R
S1, z
1, and X
2 have same definations as in [1] ; and n
1+ n
3+ n
4+ n
5≤6.
[9] . A compound of formula (Ⅷ) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:
Wherein, R
1, R
2, R
3, R
4, R
6, n
1, n
3, n
4, n
5, R
S1, z
1, and X
2 have same definations as in [1] ; and n
1+ n
3+ n
4+ n
5≤6.
[10] . The compound of [1] , wherein, the compound is any one of the formulas in the following Table 1:
Table 1
[11] . The compound of any one of [1] to [10] , wherein, R
1 is selected from hydrogen, -F, -Cl, -Br, -C
1-3alkyl, haloC
1-3alkyl, haloC
1-3alkoxy, -C
2-3alkenyl, -C
2-3alkynyl, -CN, oxo, -NH
2, -NH (C
1-3alkyl) , -N (C
1-3alkyl)
2, -OH, -O (C
1-3alkyl) , -SH, -S (C
1-3alkyl) , -S (=O) (C
1-3alkyl) , -S (=O)
2 (C
1-3alkyl) , -C (=O) (C
1-3alkyl) , -C (=O) OH, -C (=O) (OC
1-3alkyl) , -OC (=O) (C
1-3alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-3alkyl) , -C (=O) N (C
1-3alkyl)
2, -NHC (=O) (C
1-3alkyl) , -N (C
1-3alkyl) C (=O) (C
1-3alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-3alkyl) , -S (=O)
2N (C
1-3alkyl)
2, -NHS (=O)
2 (C
1-3alkyl) , -N (C
1-3alkyl) S (=O)
2 (C
1-3alkyl) , 6-10 membered cycloalkyl, 6-10 membered heterocyclyl, 6-8 membered aryl or 5-8 membered heteroaryl.
[12] . The compound of any one of [1] to [11] , wherein, R
1 is selected from -H, -F, -Cl, -CH
3, -CH
2CH
3, -CN, -COOH, -CH
2OH, -OH, -OCH
3, -OCH
2CH
3, -CF
3, -CHF
2, -NH
2, -NHCH
3, -N (CH
3)
2, -CH
2NH
2, -CH
2CH
2NH
2, -CH
2OH, -CH
2CH
2OH, -SH, -S-CH
3, -CH
2SH, -CH
2CH
2SH, -CH=CH
2, -C≡CH, -CHCH=CH
2, -OCF
3, -OCHF
2, -C (=O) NH
2, -C (=O) OCH
3,
[13] . The compound of any one of [1] to [12] , wherein, R
1 is -H or -F.
[14] . The compound of any one of [1] to [13] , wherein, R
3 is selected from hydrogen, -F, -Cl, -Br, -C
1-3alkyl, haloC
1-3alkyl, haloC
1-3alkoxy, -C
2-3alkenyl, -C
2-3alkynyl, -CN, oxo, -NH
2, -NH (C
1-3alkyl) , -N (C
1-3alkyl)
2, -OH, -O (C
1-3alkyl) , -SH, -S (C
1-3alkyl) , -S (haloC
1-3alkyl) , -S (=O) (C
1-3alkyl) , -S (=O)
2 (C
1-3alkyl) , -C (=O) (C
1-3alkyl) , -C (=O) OH, -C (=O) (OC
1-3alkyl) , -OC (=O) (C
1-3alkyl) , -C (=O) NH
2, -C (=O) NH (C
1-3alkyl) , -C (=O) N (C
1-3alkyl)
2, -NHC (=O) (C
1-3alkyl) , -N (C
1-3alkyl) C (=O) (C
1-3alkyl) , -S (=O)
2NH
2, -S (=O)
2NH (C
1-3alkyl) , -S (=O)
2N (C
1-3alkyl)
2, -NHS (=O)
2 (C
1-3alkyl) , -N (C
1-3alkyl) S (=O)
2 (C
1-3alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-8 membered heteroaryl.
[15] . The compound of any one of [1] to [14] , wherein, R
3 is selected from -H, -F, -Cl, -CH
3, -CH
2CH
3, -CH (CH
3)
2, -CN, -COOH, -CH
2OH, -OH, -OCH
3, -OCH
2CH
3, -CF
3, -CHF
2, -NH
2, -NHCH
3, -N (CH
3)
2, -CH
2NH
2, -CH
2CH
2NH
2, -CH
2OH, -CH
2CH
2OH, -SH, -S-CH
3, -S-CF
3, -CH
2SH, -CH
2CH
2SH, -CH=CH
2, -C≡CH, -CHCH=CH
2, -OCF
3, -OCHF
2, -C (=O) NH
2, -C (=O) OCH
3,
[16] . The compound of any one of [1] to [15] , wherein, R
3 is selected from -H, -F, -Cl, -CH
3, -CH (CH
3)
2, -CF
3, -S-CF
3 or
[17] . The compound of any one of [1] to [16] , wherein, R
3 is selected from -H.
[18] . The compound of any one of [1] to [17] , wherein, the moiety of -X
2-R
2 or -O-R
2 is selected from
Y
2 is selected from O, S, SO, SO
2, C=O, NH or CH
2, when Y
2 is selected from NH or CH
2, the NH or CH
2 is optionally substituted with 1 or 2 R
S3;
m
1, m
2, m
3, m
4 or m
5 is independently selected from 0, 1, 2, 3, 4, 5 or 6;
Y
3 and Y
4 are each independently selected from O, S, SO, SO
2, C=O, NH or CH
2, when Y
3 and Y
4 is selectd from NH or CH
2, the NH or CH
2 is optionally substituted with 1 or 2 R
S4;
w
3, w
4, w
5, w
6 and w
7 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; provided that w
6 and w
7 are not 0 at the same time;
Y
5 is selected from O, S, SO, SO
2, C=O, NH or CH
2, when Y
5 is selected from NH or CH
2, the NH or CH
2 is optionally substituted with 1 or 2 R
S5;
p
1 and p
2 are each independently selected from 0, 1, 2, 3, 4, 5, or 6, provided that p
1 and p
2 are not 0 at the same time;
Y
6 is selected from O, S, NH or CH
2, when Y
6 is selected from NH or CH
2, the NH or CH
2 is optionally substituted with 1 or 2 R
S6;
s
3 and s
4 are each independently selected from 0, 1, 2, 3, 4, 5, or 6, provided that s
3 and s
4 are not 0 at the same time;
r
3 and r
4 are each independently selected from 0, 1, 2, 3, 4, 5, or 6;
ring A at each occurrence is independently selected from a 4 membered carbocyclic ring, 5 membered carbocyclic ring, a, 6 membered carbocyclic ring, a 4 membered heterocyclic ring including 1 ring member selected from N, a 5 membered heterocyclic ring including 1 to 2 ring members selected from N, or O, a 6 membered heterocyclic ring including 1 to 2 ring members selected from N, O or S, a phenyl ring, a 5 membered heteroaryl ring including 1 to 2 ring members selected from N, O, or S, or a 6 membered heteroaryl ring including 1 ring member selected from N.
[19] . The compound of any one of [1] to [18] , wherein:
Y
2 is selected from O, C=O, NH or CH
2, when Y
2 is selected from NH or CH
2, the NH or CH
2 is optionally substituted with 1 or 2 R
S3;
m
1 is selected from 0, 1, 2 or 3; m
2 is selected from 0, 1, 2 or 3; m
3 is selected from 0, 1, 2 or 3; m
4 is selected from 0, 1, 2 or 3; m
5 is selected from 0, 1, 2 or 3;
Y
3 and Y
4 are each independently selected from O, S, SO
2, NH or CH
2, when Y
3 and Y
4 is selectd from NH or CH
2, the NH or CH
2 is optionally substituted with 1 or 2 R
S4;
w
3 is selected from 0, 1, 2 or 3; w
4 is selected from 0, 1, 2 or 3; w
5 is selected from 0, 1, 2 or 3; w
6 is selected from 0, 1, 2 or 3; w
7 is selected from 0, 1, 2 or 3; provided that w
6 and w
7 is not 0 at the same time;
Y
5 is selected from O, S, SO
2, NH, CH
2 or C=O, when Y
5 is selected from NH or CH
2, the NH or CH
2 is optionally substituted with 1 or 2 R
S5;
p
1 is selected from 1, 2, 3 or 4; p
2 is selected from 1, 2, 3 or 4;
Y
6 is selected from O, S or NH, when Y
6 is selected from NH or CH
2, the NH or CH
2 is optionally substituted with R
S6;
s
1 is selected from 1, 2, 3 or 4; s
2 is selected from 1, 2, 3 or 4;
r
3 is selected from 1, 2 or 3; r
4 is selected from 1, 2 or 3;
ring A at each occurrence is independently selected from a 4 membered carbocyclic ring, 5 membered carbocyclic ring, a, 6 membered carbocyclic ring, a 4 membered heterocyclic ring including 1 ring member selected from N, a 5 membered heterocyclic ring including 1 to 2 ring members selected from N, or O, a 6 membered heterocyclic ring including 1 to 2 ring members selected from N, O or S, a phenyl ring, a 5 membered heteroaryl ring including 1 to 2 ring members selected from N, O, or S, or a 6 membered heteroaryl ring including 1 ring member selected from N.
[20] . The compound of any one of [1] to [19] , wherein:
Each of R
S3 is independently selected from -F, -Cl, -CH
3, -CH
2CH
3, -CH
2CH
2CH
3, -CH (CH
3)
2, -CH
2Cl, -CHCl
2, -CCl
3, -CH
2F, -CHF
2, -CF
3, -CN, oxo, -NH
2, -NH (CH
3) , -N (CH
3)
2, -OH, -O-CH
3, -O-CH
2CH
3, -SH, -S-CH
3, -S-CH
2CH
3, -COOH, -COO (CH
3) , -COO (CH
2CH
3) , -CH
2OH, -CH
2CH
2OH, -CH (CH
3) OH, -CH
2NH
2, -CH
2CH
2NH
2, or -CH (CH
3) NH
2; preferably, each of R
S3 is independently selected from -F, -CH
3, -CH
2CH
3, -CF
3, -CN, oxo, -NH
2, -OH, -O-CH
3, -COOH, -COO (CH
3) , -CH
2OH, or -CH
2NH
2;
q
1 is selected from 0, 1, or 2;
Each of R
S4 is independently selected from -F, -Cl, -CH
3, -CH
2CH
3, -CH
2CH
2CH
3, -CH (CH
3)
2, -CH
2Cl, -CHCl
2, -CCl
3, -CH
2F, -CHF
2, -CF
3, -CN, oxo, -NH
2, -NH (CH
3) , -N (CH
3)
2, -OH, -O-CH
3, -O-CH
2CH
3, -SH, -S-CH
3, -S-CH
2CH
3, -COOH, -COO (CH
3) , -COO (CH
2CH
3) , -CH
2OH, -CH
2CH
2OH, -CH (CH
3) OH, -CH
2NH
2, -CH
2CH
2NH
2, or -CH (CH
3) NH
2; preferably, each of R
S4 is independently selected from -F, -CH
3, -CH
2CH
3, -CF
3, -CN, oxo, -NH
2, -OH, -O-CH
3, -COOH, -COO (CH
3) , -CH
2OH, or -CH
2NH
2;
q
2 is selected from 0, 1, or 2;
Each of R
S5 is independently selected from -F, -Cl, -CH
3, -CH
2CH
3, -CH
2CH
2CH
3, -CH (CH
3)
2, -CH
2Cl, -CHCl
2, -CCl
3, -CH
2F, -CHF
2, -CF
3, -CN, oxo, -NH
2, -NH (CH
3) , -N (CH
3)
2, -OH, -O-CH
3, -O-CH
2CH
3, -SH, -S-CH
3, -S-CH
2CH
3, -COOH, -COO (CH
3) , -COO (CH
2CH
3) , -CH
2OH, -CH
2CH
2OH, -CH (CH
3) OH, -CH
2NH
2, -CH
2CH
2NH
2, or -CH (CH
3) NH
2, preferably, each of R
S5 is independently selected from -F, -CH
3, -CH
2CH
3, -CF
3, -CN, oxo, -NH
2, -OH, -O-CH
3, -OCH
2-COO (CH
2CH
3) , -COOH, -COO (CH
3) , -CH
2OH, or -CH
2NH
2;
q
3 is selected from 0, 1, or 2;
Each of R
S6 is independently selected from -F, -Cl, -CH
3, -CH
2CH
3, -CH
2CH
2CH
3, -CH (CH
3)
2, -CH
2Cl, -CHCl
2, -CCl
3, -CH
2F, -CHF
2, -CF
3, -CN, oxo, -NH
2, -NH (CH
3) , -N (CH
3)
2, -OH, -O-CH
3, -O-CH
2CH
3, -SH, -S-CH
3, -S-CH
2CH
3, -COOH, -COO (CH
3) , -COO (CH
2CH
3) , -CH
2OH, -CH
2CH
2OH, -CH (CH
3) OH, -CH
2NH
2, -CH
2CH
2NH
2, or -CH (CH
3) NH
2, preferably, each of R
S6 is independently selected from -F, -CH
3, -CH
2CH
3, -CF
3, -CN, oxo, -NH
2, -OH, -O-CH
3, -OCH
2-COO (CH
2CH
3) , -COOH, -COO (CH
3) , -CH
2OH, or -CH
2NH
2;
q
4 is selected from 0, 1, or 2;
Each of R
S7 is independently selected from -F, -Cl, -CH
3, -CH
2CH
3, -CH
2CH
2CH
3, -CH (CH
3)
2, -CH
2Cl, -CHCl
2, -CCl
3, -CH
2F, -CHF
2, -CF
3, -CN, oxo, -NH
2, -NH (CH
3) , -N (CH
3)
2, -OH, -O-CH
3, -O-CH
2CH
3, -SH, -S-CH
3, -S-CH
2CH
3, -COOH, -COO (CH
3) , -COO (CH
2CH
3) , -CH
2OH, -CH
2CH
2OH, -CH (CH
3) OH, -CH
2NH
2, -CH
2CH
2NH
2, or -CH (CH
3) NH
2, preferably, each of R
S7 is independently selected from -F, -CH
3, -CH
2CH
3, -CF
3, -CN, oxo, -NH
2, -OH, -O-CH
3, -COOH, -COO (CH
3) , -CH
2OH, or -CH
2NH
2;
q
5 is selected from 0, 1, or 2;
Each of R
S8 at each occurrence is independently selected from halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -CN, oxo, -NR
N1R
N2, -OR
N1, -C (=O) R
N1, -C (=O) OR
N1, -OC (=O) R
N1, -C (=O) NR
N1R
N2, -NR
N1C (=O) R
N2, -OC (=O) OR
N1, -NR
N1C (=O) OR
N2, -OC (=O) NR
N1R
N2, -NR
N1C (=O) NR
N1R
N2, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein said -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally independently substituted with 1, 2 or 3 substituents selected from halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -CN, oxo, -NR
N1R
N2, -OR
N1, -C (=O) R
N1, -C (=O) OR
N1, -OC (=O) R
N1, -C (=O) NR
N1R
N2, -NR
N1C (=O) R
N2, -OC (=O) OR
N1, -NR
N1C (=O) OR
N2, -OC (=O) NR
N1R
N2, -NR
N1C (=O) NR
N1R
N2, 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
Each of (R
N1 or R
N2) in R
S8 is independently selected from hydrogen or -C
1-6alkyl;
Optionally, (R
N1 and R
N2) in R
S8 together with the nitrogen atom to which they are both attached form a 3-6 membered heterocyclic ring which is optionally substituted with one or more substituents selected from halogen, -C
1-6alkyl, -OH, -OC
1-6alkyl, -SH, -SC
1-6alkyl, -NH
2, -NH (C
1-6alkyl) or -N (C
1-6alkyl)
2;
q
6 is selected from 0, 1, 2 or 3;
Each of R
S11 is selected from -C
1-3alkyl.
[21] . The compound of any one of [1] to [20] , wherein, the moiety of -X
2-R
2 or -O-R
2 is selected from any one of the structures in the following Table 2:
Table 2
[22] . The compound of any one of [1] to [21] , wherein, the moiety of -X
2-R
2 or -O-R
2 is selected from
[23] . The compound of any one of [1] to [22] , wherein, each of R
S8 at each occurrence is independently selected from halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -CN, oxo, -NR
N1R
N2, -OR
N1, -C (=O) R
N1, -C (=O) OR
N1, -OC (=O) R
N1, -C (=O) NR
N1R
N2, -NR
N1C (=O) R
N2, -OC (=O) OR
N1, -NR
N1C (=O) OR
N2, -OC (=O) NR
N1R
N2, -NR
N1C (=O) NR
N1R
N2, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein said -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally independently substituted with 1, 2 or 3 substituents selected from halogen, -C
1-6alkyl, haloC
1-6alkyl, haloC
1-6alkoxy, -CN, oxo, -NR
N1R
N2, -OR
N1, -C (=O) R
N1, -C (=O) OR
N1, -OC (=O) R
N1, -C (=O) NR
N1R
N2, -NR
N1C (=O) R
N2, -OC (=O) OR
N1, -NR
N1C (=O) OR
N2, -OC (=O) NR
N1R
N2, -NR
N1C (=O) NR
N1R
N2, 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
Each of (R
N1 or R
N2) in R
S8 is independently selected from hydrogen or -C
1-6alkyl;
Optionally, (R
N1 and R
N2) in R
S8 together with the nitrogen atom to which they are both attached form a 3-6 membered heterocyclic ring which is optionally substituted with one or more substituents selected from halogen, -C
1-6alkyl, -OH, -OC
1-6alkyl, -SH, -SC
1-6alkyl, -NH
2, -NH (C
1-6alkyl) or -N (C
1-6alkyl)
2;
q
6 is selected from 0, 1, 2 or 3.
[24] . The compound of any one of [1] to [23] , wherein, each of R
S8 at each occurrence is independently selected from -F; methyl; -CF
3; -CN; oxo; -OH; -NH
2; -OCH
3; -NHC (=O) CH
3; -NHC (=O) OCH
3; -OC (=O) N (CH
3)
2; -NHC (=O) N (CH
3)
2;
or methyl substituted with -F, -Cl, methyl, -CF
3, -CN, oxo, -OH, -NH
2, -OCH
3, -NHC (=O) CH
3, -NHC (=O) OCH
3, -OC (=O) N (CH
3)
2, -NHC (=O) N (CH
3)
2,
[25] . The compound of any one of [1] to [24] , wherein, each of R
S8 at each occurrence is independently selected from -F, methyl, -CF
3, -CN, oxo, -OH, -NH
2, -OCH
3, -NHC (=O) CH
3, -NHC (=O) OCH
3, -OC (=O) N (CH
3)
2, -NHC (=O) N (CH
3)
2,
[26] . The compound of any one of [1] to [25] , wherein, the moiety of -X
2-R
2 or -O-R
2 is selected from any one of structures in the following Table 3:
Table 3
[27] . The compound of any one of [1] to [26] , wherein, the moiety of -X
2-R
2 or -O-R
2 is selected from
[28] . The compound of any one of [1] to [27] , wherein, the moiety of -X
2-R
2 or -O-R
2 is selected from
[29] . The compound of any one of [1] to [28] , wherein, R
4 is selected from
wherein said R
4 is independently optionally substituted with 1, 2, 3, 4, 5 or 6 R
4a;
Each of R
4a is independently selected from -F, -Cl, -C
1-3alkyl, haloC
1-3alkyl, haloC
1-3alkoxy, -C
2-3alkenyl, -C
2-3alkynyl, -CN, -NH
2, -NH (C
1-3alkyl) , -N (C
1-3alkyl)
2, -OH, -O (C
1-3alkyl) , -SH, -S (C
1-3alkyl) , 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, wherein said -C
1-3alkyl, haloC
1-3alkyl, haloC
1-3alkoxy, -C
2-3alkenyl, -C
2-6alkynyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl is independently optionally substituted with 1, 2 or 3 R
4b;
Each of R
4b is independently selected from -F; -C
1-3alkyl; haloC
1-3alkyl; -CN; -OH; -NH
2; -NH (C
1-3alkyl) ; -NH (C
1-3alkyl)
2; -OC
1-3alkyl; or -C
1-3alkyl substituted with 1, 2 or 3 substituents selected form -F, haloC
1-3alkyl, -CN, -OH, -NH
2, -NH (C
1-3alkyl) , -NH (C
1-3alkyl)
2 or -OC
1-3alkyl.
[30] . The compound of any one of [1] to [29] , wherein, R
4 is selected from
wherein said R
4 is independently optionally substituted with 1, 2 or 3 R
4a;
Each of R
4a is independently selected from -F, -Cl, methyl, ethyl, isopropyl, -CH=CH
2, -C≡CH, -C≡CCH
3, -C≡CD, -CH
2C≡CH, -CHF
2, -CF
3, -CH
2CF
3, -CH
2CHF
2, -CH
2CH
2F, -CH
2CH
2CH
2F, -OCF
3, -CN, -CH
2CH
2CN, -NH
2, -N (CH
3)
2, -NHCH
2CH
3, -CH
2-N (CH
3)
2, -OH, -CH
2OH, -CH
2CH
2OH, -OCH
3, -OC (CH
3)
2, -CH
2CH (CH
3)
2, -CH (CH
3) CH
2CH
3, -CH
2OCH
3, -SH, -SCH
3, -SCF
3, -OCHF
2, -CH (CF
3) OCH
3, -C (CH
3)
2OH, -CF (CH
3)
2, -OCH (CH
3)
2, cyclopropyl,
[31] . The compound of any one of [1] to [30] , wherein, R
4 is selected from any one of the structures in the following Table 4:
Table 4
[32] . The compound of any one of [1] to [31] , wherein, R
4 is selected from any one of structrues in the following Table 5:
Table 5
[33] . The compound of any one of [1] to [32] , wherein, R
4 is selected from any one of structures in the following Table 6:
Table 6
[34] . The compound of any one of [1] to [33] , wherein, R
41 is selected from any one of structures in the following Table 7:
Table 7
[35] . The compound of any one of [1] to [34] , wherein, R
4 is selected from any one of structures in the following Table 8:
Table 8
[36] . The compound of any one of [1] to [35] , wherein, R
5 is selected from hydrogen or any one of structures in the following Table 9:
Table 9
[37] . The compound of any one of [1] to [36] , wherein, the compound is selected from any one of compounds in the following Table 10:
Table 10
[38] . An intermediate selected from any one of intermediates in the following Table 11:
Table 11
[39] . A pharmaceutical composition comprising a compound, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof of any one of [1] to [37] , and at least one pharmaceutically acceptable excipient.
[40] . Use of a compound, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof of any one of [1] to [37] ; or the pharmaceutical composition of [39] for the manufacture of a medicament for the treatment of cancer related to KRAS G12D mutant protein. In some embodiments, the cancer is selected from pancreatic cancer, colorectal cancer, endometrial cancer or lung cancer. In some embodiments, the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
[41] . A method of treating a subject having a cancer related to KRAS G12D mutant protein, said method comprising administering to the subject a therapeutically effective amount of a compound, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof of any one of [1] to [37] ; or the pharmaceutical composition of [39] . In some embodiments, the cancer is selected from pancreatic cancer, colorectal cancer, endometrial cancer or lung cancer. In some embodiments, the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
[42] . A compound, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof of any one of [1] to [37] ; or the pharmaceutical composition of [39] for use in the treatment of cancer related to KRAS G12D mutant protein. In some embodiments, the cancer is selected from pancreatic cancer, colorectal cancer, endometrial cancer or lung cancer. In some embodiments, the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
Definition
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents, patent applications, and publications referred to herein are incorporated by reference.
As used herein, “KRAS G12D” refers to a mutant form of a mammalian KRAS protein that contains an amino acid substitution of an aspartic acid for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variantp. Gly12Asp.
As used herein, a “KRAS G12D inhibitor” refers to compounds of the present invention that are represented by Formula (I) , as described herein. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRAS G12D.
A “KRAS G12D-associated disease or disorder” as used herein refers to diseases or disorders associated with or mediated by or having a KRAS G12D mutation. A non-limiting example of a KRAS G12D-associated disease or disorder is a KRAS G12D-associated cancer.
As used herein, the term “subject, ” “individual” or “patient” used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer having a KRAS G12D mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit) . In some embodiments, the subject has a tumor that is positive for a KRAS G12D mutation (e.g., as determined using a regulatory agency-approved assay or kit) . The subject can be a subject with a tumor (s) that is positive for a KRas G12D mutation (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit) . The subject can be a subject whose tumors have a KRAS G12D mutation (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay) . In some embodiments, the subject is suspected of having a KRAS G12D gene-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a KRAS G12D mutation (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein) .
The term “halogen” or “halo” , as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. The preferred halogen groups include -F, -Cl and -Br.
The term “alkyl” , as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched. For example, -C
1-6alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. Similary, C
1-3, as in C
1-3alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.
The term “haloalkyl” (such as -C
1-6haloalkyl, -C
1-4haloalkyl or -C
1-3haloalkyl) as used herein, unless otherwise indicated, an alkyl chain (such as -C
1-6alkyl, -C
1-4alkyl or -C
1-3alkyl) as defined herein in which one or more (such as one, two or three) hydrogen has been replaced by a halogen. Examples include trifluoromethyl, difluoromethyl and fluoromethyl.
The term “alkylene” means a difunctional group obtained by removal of a hydrogen atom from an alkyl group defined above. For example, methylene (i.e., -CH
2-) , ethylene (i.e., -CH
2-CH
2-or -CH (CH
3) -) and propylene (i.e., -CH
2-CH
2-CH
2-, -CH (-CH
2-CH
3) -or -CH
2-CH (CH
3) -) .
The term “alkenyl” means a straight or branch-chained hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms in length. For example, “C
2-6alkenyl” contains from 2 to 6 carbon atoms. Alkenyl group include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hepetenyl, octenyl and the like.
The term “alkynyl” contains a straight or branch-chained hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms in length. For example, “C
2-6alkynyl” contains from 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
The term “alkoxy” radicals are oxygen ethers formed from the previously described alkyl groups.
The term “aryl” , as used herein, unless otherwise indicated, refers to an unsubstituted or substituted mono or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are mono cyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.
The term “heterocyclic” , as used herein, unless otherwise indicated, refers to unsubstituted and substituted mono or polycyclic non-aromatic ring system containing one or more heteroatoms, which comprising moncyclic heterocyclic ring, bicyclic heterocyclic ring, bridged heterocyclic ring, fused heterocyclic ring or sipro heterocyclic ring. Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides. Preferably, the ring is three to ten membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two or three, are included within the present definition. Examples of such heterocyclic groups include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone and oxadiazolyl.
The term “heteroaryl” , as used herein, unless otherwise indicated, represents an aromatic ring system containing carbon (s) and at least one heteroatom. Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted. A monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms. A polycyclic heteroaryl ring may contain fused, spiro or bridged ring junction, for example, bycyclicheteroaryl is a polycyclic heteroaryl. Bicyclic heteroaryl rings may contain from 8 to 12 member atoms. Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (cabons and heteroatoms) . Examples of heteroaryl groups include, but are not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladeninyl, quinolinyl or isoquinolinyl.
The term “carbocyclic” refers to a substituted or unsubstituted monocyclic ring, bicyclic ring, bridged ring, fused ring, sipiro ring non-aromatic ring system only containing carbon atoms. Examplary “cycloalkyl” groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
The term “composition” , as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instan
The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds in the present invention are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60%pure, more suitably at least 75%pure, especially at least 98%pure (%are on a weight for weight basis) .
The present invention includes within its scope the prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs" , ed. H. Bundgaard, Elsevier, 1985.
It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques know in the art as well as those methods set forth herein.
The present invention includes compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
The present invention includes all stereoisomers of the compound and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
The term “stereoisomer” as used in the present invention refers to an isomer in which atoms or groups of atoms in the molecule are connected to each other in the same order but differ in spatial arrangement, including conformational isomers and conformational isomers. The configuration isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers. The invention includes all possible stereoisomers of the compound.
Certain of the compounds provided herein may exist as atropisomers, which are conformational stereoisomers that occur when rotation about a single bond in the molecule is prevented, or greatly slowed, as a result of steric interactions with other parts of the molecule. The compounds provided herein include all atropisomers, both as pure individual atropisomer preparations, enriched preparations of each, or a non-specific mixture of each. Where the rotational barrier about the single bond is high enough, and interconversion between conformations is slow enough, separation and isolation of the isomeric species may be permitted.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. The isotopes of hydrogen can be denoted as
1H (hydrogen) ,
2H (deuterium) and
3H (tritium) . They are also commonly denoted as D for deuterium and T for tritium. In the application, CD
3 denotes a methyl group wherein all of the hydrogen atoms are deuterium. Isotopes of carbon include
13C and
14C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by prcesses analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.
When a tautomer of the compound in the present inventon exists, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
When the compound in present invention and pharmaceutically acceptable salts thereof exist in the form of solvates or polymorphic forms, the present invention includes any possible solvates and polymorphic forms. A type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable.
The pharmaceutical compositions of the present invention comprise a compound in present invention (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
In practice, the compounds in present invention or a prodrug or a metabolite or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous) . Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula I or a pharmaceutically acceptable salt thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt. The compounds of Formula I or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
The pharmaceutical carrier employed can be, for example, a solid, liquid or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.
A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient. For example, a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 0.05 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about 0.0lmg to about 2g of the active ingredient, typically 0.01mg, 0.02mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, l000mg, 1500mg or 2000mg.
Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , vegetable oils, and suitable mixtures thereof.
Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 0.05wt%to about 10wt%of the compound, to produce a cream or ointment having a desired consistency.
Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier (s) followed by chilling and shaping in molds.
In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula I or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.
Generally, dosage levels on the order of from about 0.001mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions or alternatively about 0.05mg to about 7g per patient per day. For example, inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS) , may be effectively treated by the administration of from about 0.001 to 50mg of the compound per kilogram of body weight per day or alternatively about 0.05mg to about 3.5g per patient per day.
It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
These and other aspects will become apparent from the following written description of the invention.
It is to be understood that, if any prior art publication is referred to herein; such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art in any country.
The disclosures of all publications, patents, patent applications and published patent applications referred to herein by an identifying citation are hereby incorporated herein by reference in their entirety.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is apparent to those skilled in the art that certain minor changes and modifications will be practiced. Therefore, the description and Examples should not be construed as limiting the scope of the invention.
METHODS OF PREPRATION
Compounds of the present invention can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. The examples which outline specific synthetic route, and the generic schemes below are meant to provide guidance to the ordinarily skilled synthetic chemist, who will readily appreciate that the solvent, concentration, reagent, protecting group, order of synthetic steps, time, temperature, and the like can be modified as necessary, well within the skill and judgment of the ordinarily skilled artisan.
Examples
The following examples are provided to better illustrate the present invention. All parts and percentages are by weight and all temperatures are degrees celsius, unless explicitly stated otherwise. The abbreviations in the following Table 12 have been used in the examples:
Table 12
Preparation of INT 1
Oxalyl chloride (22.65 g, 178.45 mmol) was added to a mixed solution of 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid (20.06 g, 139.18 mmol) in DCM (100 mL) and DMF (100 mg, 1.37 mmol) at 0 ℃ under nitrogen atmosphere. The solution was stirred for 3 h at room temperature. The solution was concentrated to give a yellow semi-solid. The semi-solid was taken up in THF (50 mL) and the solution was cooled to 0 ℃, and dimethylamine/THF (60 mL, 120 mmol, 2M) was added dropwise slowly and the resulting suspension was stirred for 2 hours. EtOAc (200 mL) was added and the mixture was washed with brine (2 x 200 mL) . The organic layer was dried over anhydrous Na
2SO
4 and concentrated to yield Intermediate 1-1 (INT 1-1, 7.37 g, 43.05 mmol) as a yellow/brown oil. MS m/z: 172 [M+H]
+.
Lithium aluminum hydride (3.21 g, 84.59 mmol) was added portion-wise to a solution of Intermediate 1-1 (INT 1-1, 7.37 g, 43.05 mmol) in THF at 0 ℃, and the resulting solution was stirred for 2 h at room temperature. The solution was cooled to 0 ℃. Water (3.5 mL) , NaOH solution (15%, 3.5 mL) , water (10 mL) were added portion-wise to give a white suspension. The resulting suspension was filtered through Celite, and the solids were washed with THF (150 mL) . The combined filtrates were concentrated and purified by silica gel chromatography (eluting with DCM: MeOH = 1: 10, v/v) to give Intermediate 1 (INT 1, 3.79 g, 29.33 mmol) as a pale yellow oil. MS m/z: 130 [M+H]
+.
Preparation of INT 2
Oxalyl chloride (53.55 g, 0.42 mmol) was added to a mixed solution of 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid (50.45 g, 350.04 mmol) in DCM (500 mL) and DMF (5.16 g, 70.59 mmol) at 0 ℃ under nitrogen atmosphere. The solution was stirred for about 3 hours at room temperature. The solution was concentrated under reduced pressure to give a yellow semi-solid. The semi-solid was dissolved in DCM (100 mL) and the resulting solution was added dropwise to a solution of morpholine (34.00 g, 390.27 mmol) and TEA (52.93 g, 523.08 mmol) in DCM (500 mL) at 0 ℃. The resulting suspension was stirred for 18 hours. Water (500 mL) was added and the mixture was extracted with EA. The organic layer was washed with aq. citric acid (5 %, 500 mL) followed by brine (500 mL) , then dried over anhydrous Na
2SO
4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc: Hex ) to yield INT 2-1 (70.05 g, 328.52 mmol, 93.85%yield) as a brown oil. MS m/z: 214 [M+H]
+.
Lithium aluminum hydride (30 g, 790.51 mmol) was added portion-wise to a solution of INT 2-1 (70.05 g, 328.52 mmol) in THF (700 mL) at 0 ℃, and the resulting solution was stirred for 3 h at room temperature. The solution was cooled to 0 ℃ and water (30 mL) , NaOH solution (15%, 30 mL) , water (90 mL) were added portion-wise to give a white suspension. The resulting suspension was filtered through Celite, and the solids were washed with THF (150 mL) . The combined filtrates were concentrated and purified by silica gel chromatography (eluting with DCM : MeOH = 1: 50, v/v) to give INT 2 (40.61 g, 237.16 mmol, 72.19 yield) as a colorless oil. MS m/z: 172 [M+H]
+.
Preparation of INT 3
2-Methoxy-N-methylethan-1-amine (1.0 g, 11.2 mmol) , 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid (1.8 g, 12.3 mmol) , EDCI (2.4 g, 12.3 mmol) and HOBt (1.7 g, 12.3 mmol) were placed in the reaction flask. DCM (130 mL) was added and the mixture was stirred at room temperature for overnight. Upon completion, the reaction mixture was concentrated under reduced pressure. Water (50 mL) was added to the reaction mixture, and then extracted with EtOAc (50 mL x 3) , and the combined organic layers were washed with saturated brine and saturated NaHCO
3 solution, then dried over anhydrous sodium sulfate. The solution was concentrated to give a residue (crude, INT 3-1) , which was used for next step without further purification. LCMS: 216.1 [M+H]
+.
To a solution of INT 3-1 (1.1 g, 5.1 mmol) in THF (51 mL) , LiAlH
4 (388 mg, 10.3 mmol) was added at 0 ℃. The mixture was stirred at room temperature for 3 hours. Upon completion, sodium sulfate decahydrate (2.5 g, 7.7 mmol, 1.5 eq) and ether (14 mL) was added to the reaction mixture at 0 ℃. The mixture was stirred at room temperature overnight. The reaction mixture was filtered. The filtrate was concentrated under vacuum to obtain a residue (750 mg, crude INT-3) , which was used for next step without further purification. LCMS: 174.2 [M+H]
+.
Preparation of INT 4
To a solution of 1- (methoxycarbonyl) cyclopropane-1-carboxylic acid (15.18 g, 105.32 mmol) in DCM (200 mL) was added DMF (0.15 mL, 1.93 mmol) and cooled to 0 ℃, then Oxalyl chloride (19.50 g, 153.63 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h and concentrated under vacuum. Then it was dissolved in DCM (50 mL) , added dropwise to a solution of (1S, 4S) -2-oxa-5-azabicyclo [2.2.1] heptane hydrochloride (19.90 g, 146.76 mmol) and TEA (50 mL, 359.72 mmol) in DCM (200 mL) . The resulting mixture was quenched by water (100 mL) and extracted, the organic layers was dried over Na
2SO
4 and concentrated under vacuum to afford INT 4-1 (24.93 g, 105.0%yield) . MS m/z: 226 [M+H]
+.
To a solution of INT 4-1 (24.93 g, 110.68 mmol) in THF (200 mL) was added dropwise LiAlH
4 (200 mL, 110.68 mmol, 1 M in THF) at 0 ℃. The mixture was stirred at room temperature for 2 h and quenched by water (8 mL) , followed with 15%NaOH (aq., 8 mL) , water (24 mL) and filtered, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with 0 –40%EtOAc in Hex to afford INT 4 (17.15 g, 93.58 mmol, 84.5%yield) . MS m/z: 184 [M+H]
+.
Preparation of INT 5
Trifluoromethanesulfonic anhydride (15.55 g, 55.12 mmol) and DIEA (7.37 g, 57.03 mmol) were added dropwise simultaneously to a solution of 1, 3-dihydroxynaphthalene (8.82 g, 55.07 mmol) in DCM (300 mL) at 10 ℃. After stirring for 1 h, the solution was partitioned between water and DCM. The organic phase was dried over anhydrous Na
2SO
4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with hexane/EA) to give Intermediate 5-1 (INT 5-1, 6.92 g, 23.68 mmol) .
To a solution of INT 5-1 (6.87 g, 23.51 mmol) and 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (11.66 g, 45.92 mmol) in 1.4-dioxane (100 mL) were added KOAc (8.39 g, 85.49 mmol) and Pd (dppf) Cl
2 (1.73 g, 2.36 mmol) . The reaction mixture was stirred at 85 ℃ for 4.5 hours under nitrogen atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (150 mL, 100 mL) . The combined organic layers were washed with brine (150 mL) , dried over anhydrous Na
2SO
4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluting with Hex: EA =30: 1~15: 1, v/v) to give Intermediate 5 (INT-5, 7.14 g, 26.43 mmol) . MS m/z: 271 [M+H]
+.
Preparation of INT 6
Following the procedure described in WO2021041671, INT 6 was synthesized with naphthalene-1, 3-diol as starting material.
Preparation of INT 7
Following the procedure of WO2021041671, INT 7 was synthesized with 2- (4-fluorophenyl) acetic acid as starting material.
Preparation of INT 8
To a solution of 2- (6-bromo-2, 3-difluorophenyl) acetonitrile (3.82 g, 16.46 mmol) in DMF (40 mL) was added t-BuOK (2.03 g, 18.09 mmol) at -10 ℃ and stirred for 15 min, then a solution of O-ethyl carbonisothiocyanatidate (2.34 g, 17.84 mol) was added. The mixture was stirred at 100 ℃ for 2 hours. The resulting mixture was added to water (100 mL) , filtered and the filter cake was collected.. The solid was dried at 40 ℃ for 20 hours to afford INT 8-1 (5.38 g, 15.68 mmol) . MS (ESI, m/z) : 343 [M+H]
+.
To a solution of INT 8-1 (5.38 g, 15.68 mmol) in MeOH (20 mL) was added NaOH solution (3.54 g, 88.51mmol, in 17 mL water) , then stirred at 110 ℃ for 8 hours. The resulting mixture was quenched with water (80 mL) , filtered and the filter cake was collected. The solid was dried at 40 ℃ for 20 hours to afford INT 8-2 (3.33 g, 12.28 mmol) . MS (ESI, m/z) : 271 [M+H]
+.
To a solution of INT 8-2 (3.33 g, 12.28 mmol) , DIEA (2194 mg, 16.98 mmol) and DMAP (86 mg, 0.70 mmol) in THF (50 mL) was added (Boc)
2O (2782 mg, 12.75 mmol) . The reaction mixture was stirred at 40 ℃ for 4 hours. The resulting mixture was concentrated in vacuum. The residue was purified by silica gel chromatography (eluting with Hex: EtOAc =100: 1~ 40: 1, v/v) to afford INT 8-3 (3.73 g, 10.05 mmol) . MS (ESI, m/z) : 371 [M+H]
+.
A solution of INT 8-3 (735 mg, 1.98 mmol) , 4, 4, 4', 4', 5, 5, 5', 5'-Octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (4147 mg, 16.33 mmol) , Pd (PPh
3)
4 (274 mg, 237.11 μmol) , KOAc (795 mg, 8.10 mmol) in dioxane (20 ml) was stirred at 95 ℃ for 6 hours under nitrogen atmosphere. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (20 mL) . The organic layer was dried over Na
2SO
4 and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with Hex: EtOAc =50: 1~10: 1, v/v) to afford INT 8 (0.53 g, 1.27 mmol) . MS (ESI, m/z) : 417 [M-1]
+.
Preparation of INT 9
Following the procedure of CN112574224, INT 9 was synthesized with 4-bromo-2, 6-difluorobenzonitrile as starting material.
Preparation of INT 10
A solution of 4-bromo-6-nitro-1H-indazole (5.00 g, 20.66 mmol) , iron powder (5.73 g, 102.61 mmol) , NH
4Cl (5.48 g, 102.45 mmol) in water/ethanol (17 mL/75 mL) was stirred at 80 ℃ for 2 hours under nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and filtered, the filtration was dried in vacuum The residue was purified by silica gel chromatography (Hex: EtOAc =2: 1, v/v) to afford the desired product INT 10-1 (3.73 g, 17.59 mmol) . MS m/z: 212 [M+1]
+, 214 [M+3]
+.
INT 10-1 (3.73 g, 17.59 mmol, in 37 mL DMF) was added to a solution of chloral hydrate (5.79 g, 35.01 mmol) , Na
2SO
4 (20.07 g, 141.30 mmol) , hydrochloric acid (7.5 mL) in water (75 mL) . The mixture was stirred at 90 ℃ for 1 hour, then hydroxylamine hydrochloride (7.29 g, 104.91 mmol) was added in portions. The mixture was stirred at 90 ℃ for overnight. The mixture was allowed to cool to room temperature and quenched with water (60 mL) , then filtered, the filter cake was dried in vacuum to afford the desired product INT 10-2 (4.22 g, 14.91 mmol) . MS m/z: 283 [M+1]
+, 285 [M+3]
+.
A solution of INT 10-2 (4.22 g, 14.91 mmol) in con. H
2SO
4 (28 mL) was stirred at 60 ℃ for 2 hours under nitrogen atmosphere. The mixture was allowed to cool to room temperature and quenched with ice-water (100 mL) , then stirred for 0.5 hour. The mixture was filtered and the filter cake was dried in vacuum at 42 ℃ to afford the desired product INT 10-3 (3.57 g, 13.42 mmol) . MS m/z: 266 [M+1]
+, 268 [M+3]
+.
To solution of INT 10-3 (3.57 g, 13.42 mmol) in 1, 4-dioxane (55 mL) was added NaOH (5.36 g, 134.01 mmol, in 7 mL water) at 0 ℃. Then H
2O
2 (7.65 g, 67.47 mmol, 30%wt) was added dropwise. The reaction solution was raised to room temperature and stirred for 2 hours. The mixture was quenched by sat. Na
2S
2O
3 (4 mL) , then concentrated in vacuum. The residue was purified by reverse column to afford the desired product INT 10-4 (2.51 g, 7.84 mmol) . MS m/z: 254 [M-H]
-.
To a solution of INT 10-4 (2.25 g, 8.79 mmol) , NH
4Cl (4.63 g, 86.56 mmol) , DIEA (3.47 g, 26.85 mmol) in DMF (65 mL) was added HATU (3.40 g, 8.94 mmol) in portions at 0 ℃. The mixture was stirred at room temperature for 48 hours under nitrogen atmosphere. The mixture was extracted with EtOAc (300 mL) , the organic layer was washed with brine (300 mL) , dried over Na
2SO
4 and concentrated under vacuum. The residue was purified by silica gel chromatography (eluted with DCM: MeOH=2: 1, v/v) to afford the desired product INT 10-5 (0.79 g, 3.10 mmol) . MS m/z: 255 [M+1]
+, 257 [M+3]
+.
To a solution of INT 10-5 (0.78 g, 3.06 mmol) in 1, 4-dioxane (12 mL) was added thiophosgene (0.7 mL) . The mixture was stirred at 105 ℃ for 3 hours under nitrogen atmosphere. The solution was concentrated under vacuum. The residue was slurried with Hex (10 mL) , filtered and filter cake was dried in vacuum to afford the desired product INT 10-6 (0.89 g, 2.97 mmol) as a brown solid. MS m/z: 299 [M+1]
+, 301 [M+3]
+.
To a solution of INT 10-6 (835 mg, 2.79 mmol) in POCl
3 (10 mL) was added DIEA (2 mL) . The mixture was stirred at 100 ℃ for 2 hours under nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum. The residue was purified by silica gel chromatography (eluted with Hex: EtOAc = 10: 1, v/v) to afford the desired product INT 10 (307 mg, 0.97 mmol) . MS m/z: 317 [M+1]
+, 319 [M+1]
+.
Preparation of INT 11
To a solution of 2-amino-4-bromo-3-fluorobenzoic acid (40.40 g, 172.63 mmol) in DCM (650 mL) was added dropwise sulfurisocyanatidic chloride (57.46 g, 405.98 mmol) at 0 ℃. The reaction mixture was stirred at RT for 5 hours under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was mixed with hydrochloric acid (6 N, 600 mL) and stirred at 45 ℃ overnight under nitrogen atmosphere. The reaction mixture was filtered and the filter cake was washed with water (200 mL) , Hex (200 mL) , and dried at 45 ℃ for overnight under vacuum to afford the desired product (INT 11-1, 37.63 g, 145.27 mmol) . MS m/z: 257 [M-1] .
To a solution of INT 11-1 (37.63 g, 145.27 mmol) in phosphorus oxychloride (115 mL) was added DIEA (46.24 g, 357.78 mmol) dropwise at 0 ℃. The reaction mixture was stirred at 110 ℃ for 2 hours under nitrogen atmosphere. The mixture was concentrated under vacuum. The residue was dissolved in DCM (600 mL) and washed with water (400 mL) . The organic phase was concentrated under vacuum and the residue was suspended in Hex: EA (400 mL, 20: 1, v/v) . The mixture was filtrated and the filter cake was washed with Hex (100 mL) , dried at 40 ℃ for overnight under vacuum to afford the desired product (Intermediate 4, INT 4, 31.29 g, 105.74 mmol) as a yellow solid.
Preparation of INT 12
A reaction mixture of 2-chloro-3-fluoroisonicotinic acid (25.0 g, 142.5 mmol) , 4A molecular sieve (30 g) and TEA (43.3 g, 427.5 mmol) and t-BuOH (140.8 g, 1.9 mol) in toluene (200 ml) was stirred at 110 ℃ for 0.5 h under N
2, then the mixture was cooled to 25 ℃ and DPPA (58.8 g, 213.8 mmol) was added. The mixture was stirred at 110 ℃ for 2-3 h. After completion, the mixture was cooled to rt, filtered and the filtrate was concentrated. The crude was diluted with water (200 mL) and extracted with EtOAc (200 mL x 3) . The combined organic layer was washed with brine (200 mL x 3) , dried over Na
2SO
4 and concentrated. The crude was purified by silica gel column chromatography (petroleum ether/EtOAc = 30: 1) to afford INT 12-1 (24.5 g, 69.8%) as a white solid.
1H NMR (300MHz, CD
3OD) : δ 8.15 (t, J = 6.0 Hz, 1H) , 8.03 (d, J = 4.8 Hz, 1H) , 1.55 (s, 9H) . LCMS: 247.1 [M+H] .
To a solution of INT 12-1 (24.5 g, 99.3 mmol) in DCM (200 mL) was added TFA (120 mL) and the mixture was stirred at room temperature for 2 h. After completion, the mixture was diluted with water (200 mL) and extracted with DCM (200 mL x 3) . The aqueous phase was adjusted to pH = 8 by gradually adding a saturated aq. solution of Na
2CO
3, Then the aqueous layer was extracted with ethyl acetate (200 mL × 3) . The organic layer was dried over Na
2SO
4, concentrated to afford INT 12-2 (14.5 g, 100%) as a white solid.
1H NMR (300MHz, CDCl
3) : δ 7.82 (d, J = 5.4 Hz, 1H) , 6.60 (t, J = 6.0 Hz, 1H) , 4.38 (s, 2H) . LCMS: 147.1 [M+H]
+.
To a solution of INT 12-2 (14.5 g, 99.0 mmol) and NIS (26.7 g, 118.8 mmol) in MeCN (150 mL) was added TsOH·H
2O (951 mg, 5.0 mmol) . The mixture was stirred at 70 ℃ for 2 h. After completion, the mixture was quenched with H
2O (100 mL) and extracted with EtOAc (400 mL x 3) and brine (200 mL x 3) , dried over Na
2SO
4 and concentrated. The crude was purified by silica gel column chromatography (petroleum ether /EtOAc = 8: 1) to afford INT 12-3 (15.0 g, 55.5%) as a yellow solid.
1H NMR (300MHz, CDCl
3) : δ 8.17 (s, 1H) , 4.83 (s, 2H) . LCMS: 272.8 [M+H]
+.
To a solution of INT 12-3 (8.8 g, 32.3 mmol) in EtOH (130 mL) and DMSO (20 mL) was added Pd (PPh
3)
2Cl
2 (2.2 g, 3.2 mmol) and TEA (11.8 g, 116.3 mmol) under N
2. The suspension was degassed under vacuum and purged with CO several times. The mixture was stirred under CO at 80 ℃ for 15 h. After completion, the mixture was cooled to rt and the mixture was filtered. The filtrate was concentrated. Then the crude was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3) . The combined organic layer was washed with brine (50 mL x 3) , dried over Na
2SO
4 and concentrated to afford INT 12-4 (6.0 g, 85.7%) are yellow solid.
1H NMR (300MHz, DMSO-d
6) : δ 8.38 (s, 1H) , 7.61 (s, 2H) , 4.31 (q, J =7.2 Hz, 2H) , 1.31 (t, J = 7.2 Hz, 3H) . LCMS: 219.0 [M+H]
+.
To a solution of INT 12-4 (4.7 g, 21.5 mmol) in THF (47 mL) was added 2, 2, 2-trichloroacetyl isocyanate (4.9 g, 25.8 mmol) at 25 ℃. The mixture was stirred at 25 ℃ for 0.5-1 h. After completion, the mixture was concentrated and the crude product was triturated with MTBE (20 mL) at 25 ℃ to afford INT 12-5 (6.8 g, 77.3%) as a yellow solid.
1H NMR (300MHz, DMSO-d
6) : δ 11.95 (s, 1H) , 10.47 (s, 1H) , 8.64 (s, 1H) , 4.31 (q, J = 7.2 Hz, 2H) , 1.30 (t, J = 7.2 Hz, 3H) . LCMS: 407.8 [M+H]
+.
To a solution of INT 12-5 (6.8 g, 16.7 mmol) in MeOH (68 mL) was added NH
3·MeOH (7M/L, 12 mL, 83.5 mmol) at 25 ℃. The mixture was stirred at 25 ℃ temperature for 1 h. After completion, the mixture was concentrated under vacuum and the crude was triturated with MTBE (20 mL) to afford INT 12-6 (3.2 g, 88.9%) as a yellow solid.
1H NMR (300MHz, DMSO-d
6) : δ 8.32 (s, 1H) . LCMS: 213.9 ( [M-H]
+) .
To a solution of POCl
3 (17.0 mL) and DIEA (5.1 g, 39.5 mmol) was added INT 12-6 (1.7 g, 7.9 mmol, 1.0 eq) at 0 ℃. The mixture was stirred at 110 ℃ for 3.0 h. After completion, the mixture was concentrated and the crude was purified by silica gel column chromatography (petroleum ether /EtOAc =10: 1) to afford INT 12-7 (1.3 g, 65.0%) as a yellow solid.
1H NMR (300MHz, CDCl
3) : δ 9.30 (s, 1H) . LCMS: 251.8, 253.9 [M+H]
+.
Preparation of INT 13 and INT 14
Following the procedure of CN 104003992, INT 13-8 was obtained with methyl (S) -5-oxopyrrolidine-2-carboxylate as starting material.
To a solution of INT 13-8 (495 mg, 0.32 mmol) and titanium tetraisopropanolate (883 mg, 3.11 mmol) in THF (15 mL) was slowly added ethylmagnesium bromide (3.2 ml, 6.4 mmol, 2 mol/l in THF) at -15 ℃. The reaction solution was stirred at RT for 18 h. The reaction solution was quenched by water (5 mL) , and filtered, the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with Hex: EA =15: 1) to afford INT 13-9 (236 mg, 0.72 mmol) . MS m/z: 329 [M+H]
+.
To a solution of INT 13-9 (236 mg, 0.72 mmol) in MeOH (15 ml) was added Pd (OH)
2/C (265 mg, 25 %Pd content) . The reaction solution was stirred at RT for 5 h under hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated under vacuum. to afford INT 13 (159 mg, 92.85%yield) . MS m/z: 239 [M+H]
+.
Following the procedure of CN 104003992, INT 14-8 was obtained with methyl methyl (R) -5-oxopyrrolidine-2-carboxylate as starting material.
To a solution of INT 14-8 (588 mg, 1.86 mmol) and titanium tetraisopropanolate (1056 mg, 3.72 mmol) in THF (15 mL) was slowly added ethylmagnesium bromide (3.8 ml, 7.6 mmol, 2 mol/l in THF) at -15 ℃. The reaction solution was stirred at RT for 18 h. The reaction solution was quenched by water (5 mL) , and filtered, the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with Hex: EA =15: 1) to afford INT 14-9 (338 mg, 1.03 mmol) . MS m/z: 329 [M+H]
+.
To a solution of INT 14-9 (338 mg, 1.03 mmol) in MeOH (15 ml) was added Pd (OH)
2/C (339 mg, 25 %Pd content) . The reaction solution was stirred at RT for 7 h under hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated under vacuum. to afford INT 14 (225 mg, 91.74%yield) . MS m/z: 239 [M+H]
+.
Preparation of INT 15
Following the procedure of WO2016164675, INT 15 was synthesized with 2-amino-4-bromo-3-fluorobenzoic acid as starting material.
Preparation of INT 16
Following the procedure of US20200115375, INT 16 was synthesized with 5-fluoro-2-methoxyaniline as starting material.
Preparation of INT 17
Tert-butyl (R) -2-methyl-4-oxopiperidine-1-carboxylate (10.01 g, 46.94 mmol) was dissolved in DCM (50 mL) and TFA (50 ml) was added into the solution slowly at room temperature. The reaction mixture was stirred at room temperature for 0.5 h, and then concentrated under vacuum. The crude of INT 17-1 (20.12 g, 178.05 mmol) was obtained and used for the next step without further purification. LCMS: 114 [M+H]
+.
INT 17-1 (20.12 g, 178.05 mmol) and Na
2CO
3 (33.28 g, 313.99 mmol) were added in a solution of THF/water (300 ml, v/v = 2/1) . After adding benzyl chloroformate (36.01 g, 211.08 mmol) slowly, the mixture was stirred at room temperature for 1 h. The resulting mixture was extracted with EtOAc (300 mL x 2) and the organic layers were combined and dried over anhydrous Na
2SO
4. After filtration, the filtrate was concentrated under vacuum. The resulting residue was purified by silica gel chromatography (Hex: EA = 30: 1→ 4: 1, v/v) to give INT 17-2 (10.92 g, 44.15 mmol) . LCMS: 248 [M+H]
+.
Sodium hydride (60%dispersion in mineral oil) (1.99 g, 82.97 mmol) was dissolved in DMSO (200 ml) and the suspention was stirred at 60 ℃ for 0.5 h. When it was cooled to room temperature, trimethyl sulfoxide iodide (10.77 g, 48.96 mmol) was added and the resulting mixture was stirred for 0.5 h. INT 17-2 (10.92 g, 44.15 mmol) dissolved in DMSO (20 ml) was added dropwise to the mixture. The mixture was stirred at room temperature for 1 h and quenched by adding water (300 ml) , and then the mixture was extracted with EtOAc (350 ml x 2) , washed with brine, dried over Na
2SO
4. After filtration, the solvent was removed in vacuo and the crude of INT 17-3 (12.00 g, 45.95 mmol) was obtained and used for the next step without further purification. LCMS: 262 [M+H]
+.
INT 17-3 (12.00 g, 45.95 mmol) was added in a solution of NH
3. H
2O /MeCN (80 ml, v/v = 1/1) . The reaction mixture was stirred at 60℃ for 2 h, and then concentrated under vacuum. The crude of INT 17-4 (12.87 g, 46.23 mmol) was obtained and used for the next step without further purification. LCMS: 279 [M+H]
+.
INT 17-4 (12.87 g, 46.23 mmol) and K
2CO
3 (12.81 g, 92.67 mmol) were added into a solution of THF/water (200 ml, v/v = 1/1) . After adding di-tert-butyl dicarbonate (15.14 g, 69.36 mmol) slowly, the mixture was stirred at room temperature for 1 h. The resulting mixture was extracted with EtOAc (500 mL x 2) and the organic layers were combined and dried over anhydrous Na
2SO
4. After filtration, the filtrate was concentrated under vacuum. The crude of INT 17-5 (22.90 g, 60.51 mmol) was obtained and used for the next step without further purification. LCMS: 379 [M+H]
+.
INT 17-5 (22.90 g, 60.51 mmol) was dissolved in DCM (200 ml) , and then Diethylaminosulfur trifluoride (10.89 g, 67.54 mmol) was added dropwise to the mixture at 0℃. The mixture was stirred at room temperature for 1 h and quenched by adding Saturated sodium bicarbonate aqueous solution (100 ml) , and then the mixture was extracted with DCM (350 ml x 2) , washed with brine, dried over Na
2SO
4. The filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (Hex: EA = 30: 1→ 7: 3, v/v) to give INT 17-6 (9.30 g, 24.46 mmol) . LCMS: 381 [M+H]
+.
INT 17-6 (6.03 g, 15.87 mmol) and 10%Pd (6.01 g, 5.65 mmol) were added in a solution of THF/MeOH (60 ml, v/v = 1/1) at room temperature. The reaction mixture was stirred at room temperature for 3 h under hydrogen atmosphere. After filtration, the filter cake was rinsed with MeOH (100 ml x 2) . The filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (DCM : MeOH = 10: 1→ 10: 1, v/v) to give INT 17 (1.06 g, 4.30 mmol) . LCMS: 247 [M+H]
+.
Preparation of INT 18
1-Amino-3-Butene Hydrochloride (20.06 g, 186.50 mmol) and TEA (55.25 g, 546.03 mmol) were added in DCM (200 ml) . After adding Benzyl chloroformate (34.91 g, 204.61 mmol) slowly, the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (Hex: EA = 30: 1→ 4: 1, v/v) to give INT 18-1 (18.06 g, 84.89 mmol) . LCMS: 206 [M+H]
+.
INT 18-1 (4.79 g, 23.32 mmol) and propionaldehyde (1.45 g, 24.95 mmol) were added in formic acid (50 ml) . The reaction mixture was stirred at room temperature for 1 h, and then concentrated under vacuum. The crude of INT 18-2 (6.11 g, 20.97 mmol) was obtained and used for the next step without further purification. LCMS: 292 [M+H]
+.
INT 18-2 (6.03 g, 20.71 mmol) and LiOH (1.50 g, 62.63 mmol) were added in a solution of 1, 4-Dioxane/water (120 ml, v/v = 1/1) . The reaction mixture was stirred at 60℃ for 1 h. The resulting mixture was extracted with EtOAc (100 mL x 2) and the organic layers were combined and dried over anhydrous Na
2SO
4. After filtration, the solvent was removed in vacuo and the crude of INT 18-3 (5.25 g, 19.23 mmol) was obtained and used for the next step without further purification. LCMS: 264 [M+H]
+.
INT 18-3 (5.08 g, 19.27 mmol) was added in DCM (100 ml) . After adding Dess-Martin periodinane (12.07 g, 28.46 mmol) slowly, the mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (Hex: EA = 30: 1→ 3: 1, v/v) to give INT 18-4 (4.87 g, 18.62 mmol) . LCMS: 262 [M+H]
+.
Sodium hydride (60%dispersion in mineral oil) (0.89 g, 37.13 mmol) was dissolved in DMSO (50 ml) and the suspention was stirred at 60 ℃ for 0.5 h. When it was cooled to room temperature, trimethyl sulfoxide iodide (4.32 g, 19.62 mmol) was added and the resulting mixture was stirred for 0.5 h at room temperature. INT 18-4 (4.62 g, 17.68 mmol) dissolved in DMSO (20 ml) was added dropwise to the mixture. The mixture was stirred at room temperature for 1 h and quenched by adding water (100 ml) , and then the mixture was extracted with EtOAc (350 ml x 2) , washed with brine, dried over Na
2SO
4. The filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (Hex: EA = 30: 1→ 7: 3, v/v) to give INT 18-5 (4.12 g, 14.96 mmol) . LCMS: 276 [M+H]
+.
INT 18-5 (4.02 g, 14.58 mmol) was added in a solution of NH
3. H
2O /MeCN (80 ml, v/v = 1/1) .. The reaction mixture was stirred at 60℃ for 2 h, and then concentrated under vacuum. The crude of INT 18-6 (4.35 g, 14.89 mmol) was obtained and used for the next step without further purification. LCMS: 293 [M+H]
+.
INT 18-6 (4.30 g, 14.71 mmol) and TEA (4.36 g, 43.11 mmol) were added in DCM (40 ml) . After adding Di-tert-butyl dicarbonate (3.52 g, 16.11 mmol) slowly, the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (Hex: EA = 30: 1→ 3: 2, v/v) to give INT 18-7 (5.35 g, 13.64 mmol) . LCMS: 393 [M+H]
+.
INT 18-7 (5.22 g, 13.31 mmol) was added in DCM (55 ml) . After DAST (2.36 g, 14.64 mmol) was added dropwise to the mixture at 0℃. The mixture was stirred at room temperature for 1 h and quenched by adding Saturated sodium bicarbonate aqueous solution (100 ml) , and then the mixture was extracted with DCM (350 ml x 2) , washed with brine, dried over Na
2SO
4. The filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (Hex: EA = 30: 1→ 7: 3, v/v) to give INT 18-8 (0.99 g, 2.22 mmol) . LCMS: 395 [M+H]
+.
INT 18-8 (0.91 g, 2.31 mmol) and 10%Pd (0.27 g, 251.83 μmol) were added in MeOH (10 ml) at room temperature. The reaction mixture was stirred at room temperature for 1h under hydrogen atmosphere. After filtration, the filter cake was rinsed with MeOH (100 ml x 2) . The filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (DCM: MeOH = 10: 1→ 10: 1, v/v) to give INT 18 (0.45 g, 1.74 mmol) . LCMS: 261 [M+H]
+.
Preparation of INT 19
tert-butyl 4-oxopiperidine-1-carboxylate (30.04 g, 150.76 mmol) was added in DCM (200 ml) and TFA (100 ml) , the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give INT 19-1 (15.09 g, 152.28 mmol) . LCMS: 100 [M+H]
+.
INT 19-1 (15.09 g, 152.28 mmol) and TEA (61.79 g, 610.68 mmol) were added in DCM (200 ml) . After adding benzyl chloroformate (28.84 g, 169.08 mmol) slowly at 0℃, the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (Hex: EA = 30: 1→ 4: 1, v/v) to give INT 19-2 (32.04 g, 137.35 mmol) . LCMS: 234 [M+H]
+.
Into diethyl ether (300 ml) was added INT 19-2 (32.04 g, 137.35 mmol) at room temperature. The resulting mixture was cooled to -78℃. To the above mixture was added ethyl diazoacetate (20.35 g, 178.35 mmol) , boron trifluoride diethyl etherate (19.71 g, 138.93 mmol) dropwise over 10 min at -78℃. The resulting mixture was stirred for 1h at -78℃. The reaction was quenched by the addition of Potassium carbonate aqueous solution (100 ml) at room temperature and extracted with EA (3 x 500 mL) . The combined organic layers were washed with Potassium carbonate aqueous solution (3 x 200 mL) , dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Afforded INT 19-3 (46.40 g, 145.31 mmol) as a yellow oil. LCMS: 320 [M+H]
+.
To a stirred solution of INT 19-3 (46.40 g, 145.31 mmol) and KOH (16.46 g, 293.48 mmol) in methanol (300 mL) and water (60 mL) at room temperature. The resulting mixture was stirred for 2h at 55℃. The reaction was quenched with water (100 mL) and extracted with EA (3 x 400 mL) . The combined organic layers were washed with brine (3 x 300 mL) , dried over anhydrous Na2SO4 and concentrated. Afforded INT 19-4 (29.25 g, 118.31 mmol) as a yellow oil. LCMS: 248 [M+H]
+.
Sodium hydride (60%dispersion in mineral oil) (1.79 g, 74.88 mmol) was dissolved in DMSO (300 ml) and the suspention was stirred at 60 ℃ for 0.5 h. When it was cooled to room temperature, trimethyl sulfoxide iodide (9.86 g, 44.81 mmol) was added and the resulting mixture was stirred for 0.5 h. INT 19-4 (10.11 g, 40.88 mmol) dissolved in DMSO (20 ml) was added dropwise to the mixture. The mixture was stirred at room temperature for 1 h and quenched by adding water (300 ml) , and then the mixture was extracted with EtOAc (350 ml x 2) , washed with brine, dried over Na2SO4. After filtration, the solvent was removed in vacuo and the crude of INT 19-5 (10.99 g, 42.08 mmol) was obtained and used for the next step without further purification. LCMS: 262 [M+H] +.
INT 19-5 (10.99 g, 42.08 mmol) was added in a solution of NH3. H2O /MeCN (140 ml, v/v = 1/1) . The reaction mixture was stirred at 60℃ for 2 h, and then concentrated under vacuum. The crude of INT 19-6 (11.49 g, 41.30 mmol) was obtained and used for the next step without further purification. LCMS: 279 [M+H] +.
INT 19-6 (11.49 g, 41.30 mmol) and TEA (12.55 g, 124.10 mmol) were added into a solution of DCM (150 ml) . After adding di-tert-butyl dicarbonate (9.10 g, 41.70 mmol) slowly, the mixture was stirred at room temperature for 1 h. The resulting mixture was extracted with EtOAc (500 mL x 2) and the organic layers were combined and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The crude of INT 19-7 (8.60 g, 22.73 mmol) was obtained and used for the next step without further purification. LCMS: 379 [M+H] +.
INT 19-7 (8.60 g, 22.73 mmol) was dissolved in DCM (100 ml) , and then DAST (3.67 g, 22.81 mmol) was added dropwise to the mixture at 0℃. The mixture was stirred at room temperature for 1 h and quenched by adding Saturated sodium bicarbonate aqueous solution (100 ml) , and then the mixture was extracted with DCM (350 ml x 2) , washed with brine, dried over Na2SO4. The filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (Hex: EA = 4: 1 v/v) to give INT 19-8 (5.30 g, 13.94 mmol) . LCMS: 381 [M+H] +.
INT 19-8 (5.30 g, 13.94 mmol) and 10%Pd (0.63 g, 2.83 mmol) were added in a solution of MeOH (80 ml) at room temperature. The reaction mixture was stirred at room temperature for 1 h under hydrogen atmosphere. After filtration, the filter cake was rinsed with MeOH (100 ml x 2) . The filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (DCM : MeOH = 10: 1, v/v) to give INT 19 (2.85 g, 11.57 mmol) . LCMS: 247 [M+H] +.
Example 1
To a solution of INT 12 (460.0 mg, 1.82 mmol) in 1, 4-dioxane (5.0 mL) was added TEA (552.6 mg, 5.46 mmol) , tert-butyl piperazine-1-carboxylate (237.3 mg, 1.27 mmol) . The mixture was stirred at 10 ℃for 1 h. After completion, the mixture was quenched with H
2O (5.0 mL) and extracted with EtOAc (10 mL x 3) and brine (5 mL x 3) , dried over Na
2SO
4 and concentrated. The crude was purified by silica gel column chromatography (petroleum ether /EtOAc = 20: 1) to afford Compound 1-1 (390 mg, 53.3%) as a yellow solid.
1H NMR (300MHz, CDCl
3) : δ 8.88 (s, 1H) , 4.04-4.08 (m, 4H) , 3.67-3.70 (m, 4H) , 1.50 (s, 9H) . LCMS: 403.7, 405.7 [M+H]
+.
To a solution of Compound 1-1 (390.0 mg, 0.97 mmol) in DMSO (3.0 mL) was added (1- ( (dimethylamino) methyl) cyclopropyl) methanol (INT 1, 314.0 mg, 2.43 mmol) and KF (112.7 mg, 1.94 mmol) . The mixture was stirred at 80 ℃ for 2h. After completion, the mixture was cooled down to room temperature and extracted with EtOAc (10 mL x 3) and brine (10 mL x 3) , dried over Na
2SO
4. The residue was purified by silica gel column chromatography (Petroleum ether/EtOAc = 1: 1) to afford Compound 1-2 (320 mg, 66.7%) as a yellow solid.
1H NMR (300MHz, CDCl
3) : δ 8.73 (s, 1H) , 4.38 (s, 2H) , 3.93 (t, J = 4.8 Hz, 4H) , 3.65 (t, J = 5.1 Hz, 4H) , 2.34 (s, 2H) , 2.25 (s, 6H) , 1.50 (s, 9H) , 0.68 (s, 2H) , 0.48 (s, 2H) . LCMS: 494.8, 496.8 [M+H]
+.
To a solution of Compound 1-2 (120.0 mg, 0.24 mmol) in 1, 4-dioxane (2.0 mL) and H
2O (0.5 mL) was added INT 5 (196.0 mg, 0.73 mmol) , Pd (PPh
3)
4 (27.7 mg, 0.02 mmol) and Na
2CO
3 (77.0 mg, 0.73 mmol) . The mixture was stirred at 75 ℃ for 2 h. After completion, the reaction mixture was evaporated and H
2O (3 mL) was added. The solution was extracted with EtOAc (5 mL x 3) and brine (3 mL x 3) , dried over Na
2SO
4 and concentrated. The crude was purified by silica gel column chromatography (EtOAc) to afford Compound 1-2 (90 mg, 61.6%) as a brown solid.
1H NMR (300MHz, CDCl
3) : δ 8.81 (s, 1H) , 7.61-7.69 (m, 2H) , 7.35 (t, J = 6.9 Hz, 1H) , 7.19 (t, J = 8.1 Hz, 2H) , 7.05 (s, 1H) , 6.97 (s, 1H) , 4.38 (s, 2H) , 3.71-3.73 (m, 4H) , 3.45 (s, 4H) , 2.57 (s, 2H) , 2.44 (s, 6H) , 1.50 (s, 9H) , 0.74 (s, 2H) , 0.56 (s, 2H) . LCMS: 602.8 [M+H]
+.
To a solution of Compound 1-2 (90 mg, 0.15 mmol) in DCM (2.0 mL) was added TFA (0.7 mL) and the mixture was stirred at room temperature for 1-2 h. After completion, the mixture was concentrated and dried to give Compound 1 (64 mg, 85.3%) as a light yellow solid.
1H NMR (400MHz, DMSO-d
6) : δ 9.66 (s, 1H) , 9.30 (s, 1H) , 9.24 (s, 2H) , 7.82 (d, J = 8.0 Hz, 1H) , 7.51 (d, J = 8.4 Hz, 1H) , 7.45 (t, J = 7.2 Hz, 1H) , 7.32 (t, J = 2.4 Hz, 1H) , 7.27-7.23 (m, 2H) , 4.35 (s, 2H) , 4.15-4.14 (m, 4H) , 3.38 (s, 4H) , 3.22 (d, J = 5.6 Hz, 2H) , 2.86 (d, J = 4.4 Hz, 6H) , 1.50 (s, 9H) , 0.88 (t, J = 4.0 Hz, 2H) , 0.82 (t, J = 4.4 Hz, 2H) . LCMS: 503.3 [M+H]
+.
Example 2
TEA (798.5 mg, 7.89 mmol) , tert-butyl (1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (390.6 mg, 1.84 mmol) was added to a solution of INT 12 (660 mg, 2.63 mmol) dissolved in 1, 4-dioxane (4.0 mL) . The mixture was stirred at 15 ℃ for 30 min, quenched with H
2O (3.0 mL) , and extracted with EtOAc (10 mL x 3) . The organic layers were combined and washed with brine (5 mL x 3) , dried over Na
2SO
4 and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (Petroleum ether /EtOAc = 5: 1, v/v) to afford compound 2-1 (673 mg, 60.1%) as a yellow solid.
1H NMR (300MHz, CDCl
3) : δ 8.84 (s, 1H) , 4.56-4.52 (m, 2H) , 4.40-4.38 (m, 2H) , 3.71-3.70 (m, 2H) , 2.04-1.97 (m, 2H) , 1.68-1.66 (m, 2H) 1.52 (s, 9H) . LCMS: 428 [M+H]
+.
INT 1 (203.5 mg, 1.58 mmol) and KF (73.2 mg, 1.26 mmol) was added to a solution of compound 2-1 (270 mg, 0.63 mmol) dissolved in DMSO (4.0 mL) . The mixture was stirred at 80℃ for 2 h. After completion, the mixture was cooled down to room temperature and extracted with EtOAc (10 mL x 3) and brine (10 mL x 3) , dried over Na
2SO
4. The residue was purified by silica gel column chromatography (EtOAc) to afford compound 2-2 (200 mg, 60.9%) as a yellow solid.
1H NMR (300MHz, CDCl
3) : δ 8.70 (s, 1H) , 4.48-4.44 (m, 2H) , 4.35 (s, 4H) , 3.65-3.62 (m, 2H) , 2.34 (s, 2H) , 2.25 (s, 4H) , 1.96-1.93 (m, 2H) , 1.73-1.72 (m, 1H) , 1.70-1.69 (m, 1H) , 1.67-1.64 (m, 2H) , 1.51 (s, 9H) , 0.69-0.66 (m, 2H) , 0.49-0.45 (m, 2H) . LCMS: 521 [M+H
+] .
To a solution of compound 2-2 (100.0 mg, 0.19 mmol) in 1, 4-dioxane (2.0 mL) and H
2O (0.5 mL) was added INT 5 (153.9 mg, 0.73 mmol) , Pd (PPh
3)
4 (23.1 mg, 0.02 mmol) and Na
2CO
3 (60.4 mg, 0.57 mmol) . The mixture was stirred at 100 ℃ in a microwave reactor for 1 h. After completion, the reaction mixture was evaporated and H
2O (3 mL) was added. The solution extracted with EtOAc (5 mL x 3) and brine (3 mL x 3) , dried over Na
2SO
4 and concentrated. The crude was purified by silica gel column chromatography (DCM: MeOH = 10: 1, v/v) to afford compound 2-3 (115 mg, 95.3%) as a brown solid. LCMS: 629.3 [M+H]
+.
To a solution of compound 2-3 (115 mg, 0.15 mmol) in DCM (2.0 mL) was added TFA (0.7 mL) and the mixture was stirred at room temperature for 1-2 h. After completion, the mixture was concentrated and dried to give compound 2 (131 mg, 94.7%) as a light yellow solid.
1H NMR (400MHz, DMSO-d
6) : δ 10.07 (s, 1H) , 9.25 (s, 1H) , 7.82 (d, J = 8.4 Hz, 1H) , 7.52 (d, J =8.8 Hz, 1H) , 7.45 (t, J = 7.6 Hz, 1H) , 7.31 (d, J = 2.0 Hz, 1H) , 7.26 (d, J = 7.6 Hz, 1H) , 7.23 (d, J = 2.0 Hz, 1H) , 4.69 (d, J = 11.2 Hz, 2H) , 4.33 (s, 2H) , 4.20 (s, 2H) , 3.87 (d, J = 11.2 Hz, 2H) , 3.16 (brs, 2H) , 2.82 (s, 6H) , 1.96-1.92 (m, 4H) , 0.87-0.85 (m, 2H) , 0.78-0.75 (m, 2H) . LCMS: 529 [M+H]
+.
Example 3
INT 12 (6.28 g, 24.88 mmol) , DIPEA (6.37 g, 49.29 mmol) and tert-butyl 3, 8-diazabicyclo [3.2.1] octane-3-carboxylate (4.98 g, 23.46 mmol) were dissolved in DCM (60 mL) . The reaction mixture was stirred for 1 h at room temperature, and then concentrated under vacuum. The residue was dispersed in Hex: EA (200 mL, v/v= 10: 1) , and then filtered. The filter cake was dried in vacuum to afford Compound 3-1 (10.00 g, 23.35 mmol) as a light yellow solid. MS m/z: 428 [M+H]
+.
Compound 3-1 (204 mg, 0.48 mmol) , INT 2 (179 mg, 1.05 mmol) , and KF (72 mg, 1.24 mmol) were dissolved in DMSO (4 mL) . The reaction mixture was stirred at 105 ℃ overnight under nitrogen atmosphere, cooled to room temperature, and then water and EA were added. The organic layer was dried over Na
2SO
4 and concentrated under vacuum. The residue was purified by Pre-TLC (EA: Hex = 1: 15, v/v) to afford Compound 3-2 (197 mg, 0.35 mmol) . MS m/z: 563 [M+H]
+.
Compound 3-2 (197 mg, 0.35 mmol) and INT 6 (247 mg, 0.50 mmol) were dissolved in 1, 4-dioxane (6 mL) and water (2 mL) , and then Cs
2CO
3 (347 mg, 1.07 mmol) and Pd (dppf) Cl
2 (51 mg, 0.070 mmol) was added. The reaction mixture was stirred at 100 ℃ for 3 hrs under nitrogen atmosphere, and then filtered. The filtrate was concentrated under vacuum, and the residue was purified by Pre-TLC (Hex: EA=1: 1, v/v) to obtain Compound 3-3 (114 mg, 0.127 mmol) . MS m/z: 895 [M+H]
+.
Compound 3-3 (114 mg, 0.127 mmol) and CsF (79 mg, 0.52 mmol) were dissolved in DMF (2 mL) . The reaction mixture was stirred for 2 hrs under nitrogen atmosphere at R. T, diluted with water (20 mL) and then extracted with EA (2 x 20 mL) . The organic layers were combined, dried over Na
2SO
4 and concentrated under vacuum to afford Compound 3-4 (110 mg, 0.15 mmol) as a yellow solid. MS m/z: 739 [M+H]
+.
Compound 3-4 (110 mg, 0.15 mmol) , and HCl (1 mL, 1 M in 1, 4-dioxane) were dissolved in MeCN (4 mL) . The reaction mixture was stirred at R. T for 1.5 h. The mixture was concentrated under vacuum. The residue was purified by Prep-HPLC (Agela Venusil PrepG C18 column, 50 mm*250 mm, 10 um; A: 0.1%TFA in water, B: CH
3CN, Gradient: 10%B to 35%B in 35 min at a flow rate of 60 mL/min, 220 nm) to afford Compound 3 (29.2 mg, TFA salt) . MS m/z: 595 [M+H]
+.
1H NMR (400 MHz, Methanol-d
4) δ 9.15 (s, 1H) , 7.85 (dd, J = 8.3, 1.4 Hz, 1H) , 7.53 (dd, J = 7.1, 1.3 Hz, 1H) , 7.42 (dd, J = 8.3, 7.2 Hz, 1H) , 7.36 (d, J = 2.6 Hz, 1H) , 7.18 (d, J = 2.5 Hz, 1H) , 5.36 –5.26 (m, 2H) , 4.51 (d, J = 2.3 Hz, 2H) , 4.13 –3.64 (m, 8H) , 3.54 –3.45 (m, 2H) , 3.44 –3.32 (m, 2H) , 3.27 –3.10 (m, 2H) , 3.04 (s, 1H) , 2.43 –2.32 (m, 2H) , 2.23 –2.13 (m, 2H) , 1.01 –0.95 (m, 2H) , 0.93 –0.90 (m, 2H) .
Example 4
Compound 2-1 (303 mg, 0.77 mmol) , INT 2 (306 mg, 1.78 mmol) , and KF (129 mg, 2.22 mmol) were dissolved in DMSO (8 mL) . The reaction mixture was stirred for at 130 ℃ for 3 hrs under nitrogen atmosphere, cooled to room temperature, diluted with water (20 mL) , and extracted with EA (20 mL) . The organic layer was washed with brine (20 mL) , dried over Na
2SO
4 and concentrated under vacuum. The residue was purified by Pre-TLC to afford Compound 4-2 (208 mg, 0.37 mmol) . MS m/z: 563 [M+H]
+.
Compound 4-2 (97 mg, 0.18 mmol) and INT 6 (165 mg, 0.28 mmol) were dissolved in 1, 4-dioxane (6 mL) and water (2mL) , and then Pd (dppf) Cl
2 (18 mg, 17.76 μmol) and Cs
2CO
3 (181 mg, 555.10 μmol) were added . The reaction mixture was stirred for 4 hrs under nitrogen atmosphere at 100 ℃, diluted with water (8 mL) and extracted with EA (10 mL) . The organic layers were dried over Na
2SO
4 and concentrated under vacuum. The residue was purified by Pre-TLC to obtain Compound 4-3 (74 mg, 0.082 mmol) as a light yellow oil. MS m/z: 895 [M+H]
+.
A mixture of Compound 4-3 (74 mg, 0.082 mmol) and CsF (60 mg, 0.39 mmol) dispersed in DMF (5 mL) was stirred for 3 hrs under nitrogen atmosphere at room temperature, diluted with brine (10 mL) and extracted with EA (10 mL) . The organic layer was dried over Na
2SO
4 and concentrated under vacuum to afford Compound 4-4 (83 mg, 0.11 mmol) as a light yellow oil. MS m/z: 739 [M+H]
+.
A mixture of the Compound 4-4 (83 mg, 0.11 mmol) and HCl (a EA solution, 1 mL, 4 M) dissolved in MeCN (5 mL) was stirred for 2 hours at RT, and then concentrated under vacuum. The residue was purified by Prep-HPLC (Daisogel-C18 column, 50 mm*250 mm, 10 um; A: 0.1%TFA in water, B: CH
3CN, Gradient: 10%B to 40%B in 40 min at a flow rate of 60 mL/min, 280 nm) to afford Compound 4 (11 mg) . MS m/z: 595 [M+H]
+.
1H NMR (400 MHz, Methanol-d
4) δ 9.08 (s, 1H) , 7.87 –7.82 (m, 1H) , 7.52 (dd, J = 7.2, 1.3 Hz, 1H) , 7.42 (dd, J = 8.3, 7.2 Hz, 1H) , 7.36 (d, J = 2.6 Hz, 1H) , 7.17 (d, J = 2.6 Hz, 1H) , 4.51 (d, J = 4.8 Hz, 2H) , 4.32 –4.25 (m, 2H) , 4.12 –3.70 (m, 12H) , 3.26 –3.14 (m, 2H) , 3.04 (s, 1H) , 2.19 –2.10 (m, 4H) , 1.01 –0.95 (m, 2H) , 0.92 –0.88 (m, 2H) .
Example 5
Pd (dppf) Cl
2 (13 mg, 17.76 μmol) and Cs
2CO
3 (175 mg, 537.10 μmol) were added to a mixture of Compound 2-2 (95 mg, 0.18 mmol) and INT 6 (144 mg, 0.23 mmol) dissolved in 1, 4-dioxane (6 mL) and water (2 mL) . The reaction mixture was stirred at 100 ℃ for 3 hours under nitrogen atmosphere, diluted with water (8 mL) and then extracted with EA (10 mL) . The organic layer was dried over Na
2SO
4 and concentrated under vacuum. The residue was purified by Pre-TLC to obtain Compound 5-1 (30 mg, 0.035 mmol) as a light yellow oil. MS m/z: 853 [M+H]
+.
A mixture of the Compound 5-1 (30 mg, 0.035 mmol) and HCl (a EA solution, 4 M, 1 mL) dissolved in MeCN (2 mL) was stirred for 2 hours at R. T, and then concentrated under vacuum to obtain a residue containing Compound 5-2 which was used in next step directly without further purification.
A mixture of the residue containing Compound 5-2 (0.024 g, 0.034 mmol) and CsF (127 mg, 0.84 mmol) dispersed in DMF (5 mL) was stirred at room temperature for 5 hours under nitrogen atmosphere, diluted with aq K
2CO
3 (5%, 30 mL) , and then extracted with EA (20 x 2 mL) . The organic layers were combined, dried over Na
2SO
4 and then concentrated under vacuum. The residue was purified by Prep-HPLC (Agela Venusil PrepG C18 column, 30 mm*250 mm, 10 um; A: 0.1%TFA in water, B: CH
3CN, Gradient: 10%B to 30%B in 30 min at a flow rate of 40 mL/min, 280 nm) to afford Compound 5 (11 mg) . MS m/z: 553 [M+H]
+.
Example 6
A solution of Compound 2-1 (100 mg, 0.23 mmol) , INT 3 (121 mg, 0.70 mmol) and DIEA (91 mg, 0.70 mmol) in dioxane (1.5 mL) was stirred at 80-100 ℃ for two days. Upon completion, water (5 mL) was added to the reaction mixture, extracted with EtOAc (5 mL x 3) , and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solution was concentrated to give a residue, purified by pre-TLC (Dichloromethane/Methanol = 10: 1) to give Compound 6-1 (30 mg, 0.05 mmol, 23%yield) as a yellow solid. LCMS: 565.3 [M+H]
+.
Compound 6-1 (30 mg, 0.05 mmol) , INT 6 (34 mg, 0.07 mmol) , Pd (dppf) Cl
2 (8 mg, 0.01 mmol) and Cs
2CO
3 (52 mg, 0.16 mmol) were placed in an oven-dried Schlenk-tube. The tube was evacuated and filled with argon for three times. A solution of dioxane/H
2O (3/1, 2 mL) was added at room temperature. The mixture was stirred at 100 ℃ for 3 h. Upon completion, water (10 mL) was added to the reaction mixture, extracted with DCM (10 mL x 3) , and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solution was concentrated to give a residue, purified by pre-TLC (Dichloromethane/Methanol = 10: 1) to give Compound 6-2 (~ 5 mg, 0.0055 mmol, 11%yield) as a yellow solid. LCMS: 897.0 [M+H]
+.
To a solution of Compound 6-2 (5 mg, 0.0055 mmol) in CH
3CN (0.3 mL) was added HCl/dioxane (4 M, 0.05 ml) . After stirring at 0 ℃ for 1.5 h. The solution was concentrated to give Compound 6-3 (crude) as a yellow solid. It was used for next step without any further purification. LCMS: 753.0 [M+H]
+.
To a solution of Compound 6-3 (crude) in DMF (1.0 ml) , CsF (22.8 mg, 0.15 mmol) was added. The reaction mixture was stirred at 50 ℃ for 6 h. Upon completion, the solution was filtered, purified by pre-HPLC to give Compound 6 (~ 1.2 mg, 0.002 mmol) as a white solid. LCMS: 597.3 [M+H]
+.
Example 7
To a solution of Compound 2-1 (0.98 g, 2.29 mmol) and INT 4 (0.60 g, 3.27 mmol) in DMSO (20 mL) was added KF (0.45 g, 7.75 mmol) at room temperature. The reaction mixture was subjected to vacuum and backfilled with nitrogen four times and stirred at 125 ℃ for 18 h. The reaction mixture was cooled to room temperature, diluted with EA (60 mL) and water (60 mL) . The collected organic phase was dried over Na
2SO
4 and concentrated under reduced pressure. The residue was stirred with EA (5 mL) and filtered to give Compound 7-1 (0.85 g, 64%) . LCMS: 575 [M+H]
+.
A solution of Compound 7-1 (0.85 g, 1.48 mmol) , INT 7 (1.02 g, 1.99 mmol) , Cs
2CO
3 (0.97 g, 2.98 mmol) and cataCxium A Pd G
3 (0.1 g, 0.14 mmol) in toluene (45 mL) and water (9 mL) was stirred at 100 ℃ for 19.5 hours under nitrogen atmosphere. The reaction was diluted with water (10 mL) . The organic layer was dried over Na
2SO
4 and concentrated under reduced pressure. The residue was purified with silica gel chromatography to afford Compound 7-2 (0.95 g, 69 %) . LCMS: 925 [M+H]
+.
A solution of Compound 7-2 (0.95 g, 1.03 mmol) and HCl/Dioxane (4M, 4 mL) in MeCN (10 mL) was stirred at R. T for 3 h, and then concentrated under reduced pressure. The pH of the mixture of the residue, EA (10 mL) and water (10 mL) was adjusted to 9-10 with solid NaHCO
3, and then the organic layer was concentrated under reduced pressure to afford Compound 7-3 which was used to next step without further purification. LCMS: 781 [M+H]
+.
A mixture of Compound 7-3 (801 mg, 1.03 mmol) , CsF (2.47 g, 16.26 mmol) and DMF (10 mL) was stirred overnight at R. T for 18 hours, and then filtered. The filtrate was purified with Prep-HPLC to afford Compound 7 (315.8 mg, 23%) . LCMS: 625 [M+H]
+.
Example 8
A solution of INT 11 (530 mg, 2.10 mmol) , DIPEA (779 mg, 6.03 mmol) and (R) -tert-butyl 3-methylpiperazine-1-carboxylate (394 mg, 1.97 mmol) in DCM (10 mL) was stirred at room temperature for 2 h. The solution was concentrated under vacuum, the residue was dissolved in DCM (20 mL) , washed with brine (2 x 20 mL) , dried over Na
2SO
4 and concentrated in vacuum. The residue was poured into hexane (10 mL) and EA (10 mL) , stirred for 1 h at room temperature and filtered to give the desired product Compound 8-1 (690 mg, 1.66 mmol) . MS m/z: 416 [M+H]
+.
A solution of Compound 8-1 (690 mg, 1.66 mmol) , INT 2 (589mg, 3.44mmol) , KF (375mg, 6.45 mmol) in DMSO (10 mL) was stirred at 130 ℃ for 20 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and partitioned between water and EA. The organic layer was washed with brine, dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by Prep-TLC (n-hexane: EtOAc = 1: 1, v/v) to afford the desired product Compound 8-2 (653 mg, 1.19 mmol) . MS m/z: 551 [M+H]
+.
To a solution of Compound 8-2 (252 mg, 0.46 mmol) , INT 6 (282mg, 0.57 mmol) in 1, 4-dioxane (8 mL) and water (2 mL) was added Cs
2CO
3 (310mg, 0.95 mmol) and Pd (dppf) Cl
2 (73 mg, 0.010 mmol) . The reaction mixture was stirred at 100℃ for 2 hours under nitrogen atmosphere. The reaction was diluted with DCM (30 mL) and washed with water. The organic layer was dried over Na
2SO
4 and concentrated under vacuum. The residue was purified by Pre-TLC (n-hexane: EtOAc = 1: 1, v/v) to give Compound 8-3 (60 mg, 0.068 mmol) . MS m/z: 883 [M+H]
+.
A solution of Compound 8-3 (59 mg, 0.067 mmol) , CsF (137 mg, 0.90 mmol) in DMF (3 mL) was stirred at RT for 2 h. The reaction was diluted with EA (20 mL) and washed with brine (3 x 20 mL) . The organic layer was dried over Na
2SO
4 and concentrated under vacuum. The residue was purified by Pre-TLC (n-hexane: EtOAc = 1: 1, v/v) to give Compound 8-4 (57 mg, 0.078 mmol) . MS m/z: 727 [M+H]
+.
A solution of Compound 8-4 (55 mg, 0.076 mmol) , HCl/EA (4M, 5 mL) in DCM (5 mL) was stirred at RT for 1 h. The mixture was concentrated in vacuum. The residue was purified by Prep-HPLC to afford the desired product Compound 8 (1.2 mg, 0.002 mmol) . MS m/z: 583 [M+H]
+.
Example 9
A solution of Compound 3-1 (204 mg, 476.31 μmol) , ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (139 mg, 873.11 μmol) , KF (86 mg, 1.48 mmol) in DMSO (3 mL) was stirred at 80 ℃ for 16 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and partitioned between water (30 mL) and EA (20 mL) . The organic layer was dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by Prep-TLC (MeOH: DCM = 1: 10, v/v) to afford Compound 9-1 (252 mg, 457.32 μmol, 96.0%yield, ) . MS m/z: 551 [M+H]
+.
To a solution of Compound 9-1 (120 mg, 217.77 μmol) , INT 6 (140 mg, 283.08 μmol) in 1, 4-dioxane (4 mL) and water (1 mL) were added cesium carbonate (228 mg, 699 μmol) , PdCl
2 (dppf) (61 mg, 83.36 μmol) . The reaction mixture was stirred at 100 ℃ for 16 hours under nitrogen atmosphere. The reaction was diluted with EA (30 mL) and washed with brine. The organic layer was dried over Na
2SO
4 and concentrated under vacuum. The residue was purified by Pre-TLC (MeOH: DCM = 1: 10, v/v) to afford Compound 9-2 (0.08 g, 90.58 μmol, 41.6%yield) . MS m/z: 883 [M+H]
+.
To a solution of Compound 9-2 (77 mg, 87.18 μmol) in CH
3CN (6 mL) was added HCl (4 M in 1, 4-dioxane, 2 mL) . The reaction mixture was stirred at room temperature for 1 hours. The resulting mixture was concentrated under reduced pressure to afford Compound 9-3 and the residue was used to next step directly. MS m/z: 739 [M+H]
+.
To a solution of Compound 9-3 in DMF (3 mL) was added TBAF (1 M, 1 mL) and the reaction mixture was stirred at room temperature for 1 hours. The resulting mixture was concentrated under reduced pressure and the residue was purified by Pre-HPLC (Daisogel-C18, 50*250 mm, 10 μm, A: 0.1%TFA in water, B: CH
3CN, Gradient: 10%B to 35%B in 36 min at a flow rate of 60 mL/min, 240 nm) to afford Compound 9 (2.9 mg, 4.16 μmol, 4.7%yield, TFA salt) as a yellow solid. MS m/z: 583 [M+H]
+.
Example 10
A solution of Compound 8-1 (0.52 g, 1.24 mmol) , ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (400 mg, 2.51 mmol) , KF (230 mg, 3.95 mmol) in DMSO (8 mL) was stirred at 80 ℃ for 16 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and added water (30 mL) . The resulting suspension was filtered through Celite and washed with water (20 mL) , the residue was lyophilized to afford Compound 10-1 (574 mg, 1.06 mmol, 85.0%yield) . MS m/z: 539 [M+H]
+.
To a solution of Compound 10-1 (148 mg, 274.57 μmol) , INT 6 (188 mg, 380.14 μmol) in 1, 4-dioxane (8 mL) and water (2 mL) were added cesium carbonate (276 mg, 847.09 μmol) , PdCl
2 (dppf) (24 mg, 32.80 μmol) . The reaction mixture was stirred at 100 ℃ for 5 hours under nitrogen atmosphere. The reaction was diluted with EA (30 mL) and washed with water (30 mL) . The organic layer was dried over Na
2SO
4 and concentrated under vacuum. The residue was purified by Pre-TLC (MeOH: DCM =1:15, v/v) to afford Compound 10-2 (65 mg, 74.61 μmol, 27.2%yield, ) MS m/z: 871 [M+H]
+.
To a solution of Compound 10-2 (65 mg, 74.61 μmol) in CH
3CN (8 mL) was added HCl (4 M in 1, 4-dioxane, 2 mL) . The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure to afford Compound 10-3 and the residue was used to next step directly. MS m/z: 726 [M+H]
+.
To a solution of Compound 10-3 in DMF (4 mL) was added CsF (152 mg, 1.0 mmol) and the reaction mixture was stirred at 40 ℃ for 5 hours. The resulting mixture was concentrated under reduced pressure and the residue was purified by Pre-HPLC (Agela Venusil PrepG C18, 30*250 mm, 10 μm, A: 0.1%TFA in water, B: CH
3CN, Gradient: 15%B to 35%B in 21 min at a flow rate of 40 mL/min, 230 nm) to afford Compound 10 (6.7 mg, 13.1%yield, TFA salt) . MS m/z: 571 [M+H]
+.
Example 11
A solution of INT 14 (225 mg, 0.94 mmol) , INT 12 (245 mg, 0.97 mmol) and DIEA (297mg, 2.30 mmol) in DCM (15 ml) was stirred at 50 ℃ for 4 h. The solution was diluted with water (30 mL) , extracted with DCM (20mL) , dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 11-1 (315 mg, 0.69 mmol) . MS m/z: 454 [M+H]
+.
A solution of Compound 11-1 (315 mg, 0.69 mmol) , ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (173 mg, 1.09 mmol) , KF (132 mg, 2.27 mmol) in DMSO (10 mL) was stirred at 95 ℃ for 17 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and diluted with water (40 mL) , extracted with EA (2 x 30mL) . The organic layer was washed with aq. NaCl (40ml) then dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC to give Compound 11-2 (219 mg, 0.38 mmol) . MS m/z: 577 [M+H]
+.
To a solution of Compound 11-2 (117 mg, 0.20 mmol) , INT 7 (159 mg, 0.31 mmol) in toluene (4 mL) and water (1 mL) was added Cs
2CO
3 (160 mg, 0.49 mmol) , cataCXium A Pd G3 (33 mg, 0.045 mmol) . The reaction mixture was stirred at 100℃ for 20 hours under nitrogen atmosphere. The reaction was diluted with EA (40 mL) and washed with brine (40 ml) . The organic layer was dried over Na
2SO
4 and concentrated under vacuum. The residue was purified by Pre-TLC to give Compound 11-3 (72 mg, 0.078 mmol) . MS m/z: 927 [M+H]
+.
To a solution of Compound 11-3 (72 mg, 0.078 mmol) in ACN (3 mL) was added HCl (1 mL, 4mol/L in dioxane) and stirred at RT for 1 h. The residue was diluted with sat. aq. NaHCO
3 (20 mL) and extracted with EA (2 x 20 mL) . The organic layers combined, dried over Na
2SO
4 and concentrated under vacuum to give the desired product Compound 11-4 (74 mg, 0.095 mmol) . MS m/z: 783 [M+H]
+
To a solution of Compound 11-4 (74 mg, 0.095 mmol) in DMF (4 ml) was added CsF (0.48 g, 3.16 mmol) . The reaction mixture was stirred at 40 ℃ for overnight. The mixture was diluted with sat. aq. NaHCO
3 (20 mL) and extracted with EA (2 x 20 mL) . The organic layers combined, dried over Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-HPLC (C18 column, A: 0.1 %TFA in water, B: CH
3CN, Gradient: 15%B to 35%B in 32 min at a flow rate of 60 mL/min, 230 nm) to afford the desired product Compound 11 (34.4 mg, 0.040 mmol, 2TFA salt) . MS m/z: 627 [M+H]
+.
Example 12
Following the procedure described in WO2021027943, Compound 12-5 (430.8 mg) was synthesized with INT 6-3 as starting material.
A solution of Compound 12-5 (430 mg, 0.56 mmol) , m-CPBA (128 mg, 0.74 mmol) in DCM (12 mL) was stirred at room temperature for 1 h. The solution was quenched with sat. Na
2S
2O
3 (3 mL) and washed with sat. NaHCO
3 (20 mL) , brine (20 mL) . The organic layers combined, dried over Na
2SO
4 and concentrated under vacuum. The residue was purified by Pre-TLC (MeOH: DCM = 1: 15, v/v) to afford the desired product Compound 12-6 (422 mg, 0.488 mmol) as a brown solid. MS m/z: 787 [M+H]
+.
To a solution of ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (63 mg, 0.396 mmol) in THF (2 mL) was added sodium tert-butoxide (64 mg, 0.666 mmol) and stirred at 0 ℃ for 0.5 h under nitrogen atmosphere. Then Compound 12-6 (199 mg, 0.253 mmol) in THF (2 mL) was added to the mixture. The solution was concentrated under vacuum. The residue was purified by Prep-TLC (MeOH: DCM = 1: 15, v/v) to afford the desired product Compound 12-7 (52 mg, 0.059 mmol) . MS m/z: 882 [M+H]
+.
A solution of Compound 12-7 (52 mg, 0.059 mmol) , HCl (0.7 mL, 1 M in dioxane) in MeCN (3 mL) was stirred at RT for 1h. The mixture was concentrated in vacuum. The residue was diluted with sat. NaHCO
3 (20 mL) and extracted with EA (2 x 20 mL) . The organic layers combined, dried over Na
2SO
4 and concentrated under vacuum. The residue in DMF (3 mL) was added CsF (240 mg, 1.58 mmol) . The reaction mixture was stirred at 45 ℃ for 2 hours under nitrogen atmosphere. The reaction mixture was purified by Prep-HPLC (C18 column, A: 0.1%TFA in water, B: CH
3CN, Gradient: 10%B to 35%B in 60 min at a flow rate of 40 mL/min, 232 nm) to afford the desired product Compound 12 (19.0 mg, 0.235 mmol, 2TFA salt) . MS m/z: 582 [M+H]
+.
Example 13
INT 9 (600 mg, 1.89 mmol) and tert-butyl (1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (401 mg, 1.89 mmol) and TEA (574 mg, 5.67 mmol) were dispersed into 1, 4-dioxane (15 mL) . After stirring at room temperature for 2 h, the reaction mixture was poured into water (20 mL) and then extracted with EtOAc (20 mL) . The organic layers were combined, washed successively with water (10 mL) and brine (5 mL) , dried with anhydrous Na
2SO
4, and then filtered. The filtrate was concentrated to obtain a residue. The residue was dispersed in petroleum ether and then filtered to afford Compound 13-1 (760 mg, yield 81.6%) as a yellow solid.
1HNMR (300 MHz, CDCl
3) : δ 7.87 (s, 1H) , 7.83 (d, J = 2.1 Hz, 1H) , 6.98 (d, J = 2.1 Hz, 1H) , 4.33-4.30 (m, 4H) , 3.69-3.67 (m, 2H) , 1.91-1.90 (m, 4H) , 1.51 (s, 9H) . LCMS: 492.9, 494.9 [M+H]
+.
A mixture of Compound 13-1 (400 mg, 0.8 mmol) , INT 2 (417 mg, 2.4 mmol) , DABCO (92 mg, 0.8 mmol) , Cs
2CO
3 (792 mg, 2.4 mmol) and THF/DMF = 1: 1 (10 mL) was stirred for 3 h at 50 ℃, cooled to room temperature, poured into water (5 mL) and then extracted with EtOAc (5 mL x 3) . The combined organic layer was washed successively with water (5 mL x 2) and brine (5 mL x 2) , dried with anhydrous Na
2SO
4, and then filtered. The filtrate was concentrated to obtain a residue which was purified by Pre-TLC (eluted with petroleum ether /EtOAc= 1: 1) to afford Compound 13-2 (180 mg, yield 35.3%) as a yellow solid. LCMS: 628.3, 630.3 [M+H]
+.
Compound 13-2 (29.7 mg, 0.047 mmol) , INT 6 (35 mg, 0.071 mmol) , CataCXium A Pd G
3 (10 mg, 0.014 mmol) , Cs
2CO
3 (54 mg, 0.17 mmol) , toluene (2 mL) and water (0.5 mL) were placed in a microwave vial. Purged and maintained with an atmosphere of nitrogen, the reaction mixture was stirred at 100 ℃ for 30 min. EA and water were added to the resulting mixture, and the organic layer was concentrated under reduced pressure to obtain a residue which was purified by Pre-TLC (eluted with EA : Hex =1: 2, v/v) to afford Compound 13-3 (43 mg, 0.047 mmol) . MS: m/z 916 [M+H]
+.
HCl (a solution of 1, 4-dioxnae, 4 M, 2 mL) was added to a solution of Compound 13-3 (43 mg, 0.047 mmol) dissolved in CH
3CN (5 mL) . After stirring at room temperature for 30 min, the reaction mixture was concentrated under reduced pressure to afford a residue which was used in next step without further purification. MS: m/z 772 [M+H]
+ . CsF (3.71g, 24.42 mmol) was added to a solution of the residue dissolved in DMF (3 mL) . After stirring at room temperature for 24 h, the reaction mixture was filtered through a Celite. The filtrate was concentrated under vacuum to obtain a residue which was purified by Pre-HPLC (Daisogel-C18 column, 50*250 mm, 10 um; A: 0.1%TFA in water, B: CH
3CN, Gradient: 30%B to 45%B in 15 min at a flow rate of 60 mL/min, 230 nm) to give Compound 13 (10.8 mg) as a TFA salt. MS: m/z 616 [M+H]
+ .
Example 14
A solution of INT 10 (307 mg, 0.97 mmol) , DIPEA (381 mg, 2.95 mmol) and tert-butyl 3, 8-diazabicyclo [3.2.1] octane-3-carboxylate (220 mg, 1.04 mmol) in THF (9 mL) was stirred at room temperature for 1 h. The solution was extracted with EA (30 mL) , and washed with brine (20 mL) twice. The organic layers were dried over Na
2SO
4 and concentrated under vacuum to afford the desired product Compound 14-1 (448 mg, 0.91 mmol) as a light yellow solid. MS m/z: 493/495 [M+H]
+.
A solution of Compound 14-1 (448 mg, 0.91 mmol) , 4-toluenesulfonic acid (17 mg, 0.099 mmol) in THF (10 mL) was added 3, 4-Dihydro-2H-pyran (105 mg, 1.25 mmol) . The mixture was stirred at room temperature for overnight. The solution was extracted with EA (30 mL) , and washed with brine (20 mL) twice. The organic layers was dried over Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-TLC (Hex: EA= 2: 1, v/v) to afford the desired product Compound 14-2 (375 mg, 0.65 mmol) as a light yellow solid. MS m/z: 577/579 [M+H]
+.
A solution of Compound 14-2 (334 mg, 0.58 mmol) , INT 2 (120 mg, 0.70 mmol) , DABCO (41 mg, 0.37 mmol) , Cs
2CO
3 (286 mg, 0.88 mmol) in DMF/THF (1.4 mL/1.4 mL) was stirred at room temperature for overnight under nitrogen atmosphere. The mixture was partitioned between water and EA. The organic layer was dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC (Hex: EA = 1: 1, v/v) to afford the desired product Compound 14-3 (301 mg, 0.42 mmol) . MS m/z: 712/714 [M+H]
+.
To a solution of Compound 14-3 (164 mg, 0.23 mmol) , INT 6 (138 mg, 0.28 mmol) in toluene (2 mL) and water (0.5 mL) was added Cs
2CO
3 (228 mg, 0.70 mmol) and cataCXium A Pd G3 (21 mg, 0.029 mmol) . The reaction mixture was stirred at 100 ℃ for 0.5 hour under nitrogen atmosphere in microwave. The mixture was partitioned between water (20 mL) and EA (30 mL) . The organic layer was dried over Na
2SO
4 and concentrated in vacuum. The residue was purified by Pre-TLC (Hex: EA = 1: 1, v/v) to give the desired product Compound 14-4 (128 mg, 0.128 mmol) . MS m/z: 1000 [M+H]
+.
A solution of Compound 14-4 (128 mg, 0.128 mmol) , HCl (0.7 mL, 4 M in dioxane) in MeCN (3 mL) was stirred at RT for 1h. The mixture was concentrated in vacuum. The residue was diluted with sat. NaHCO
3 (20 mL) and extracted with EA (2 x 20 mL) . The organic layers combined, dried over Na
2SO
4 and concentrated under vacuum. The residue in DMF (3 mL) was added CsF (440 mg, 2.90 mmol) . The reaction mixture was stirred at 45 ℃ for overnight under nitrogen atmosphere. The reaction mixture was purified by Prep-HPLC (C18 column, A: 0.1%TFA in water, B: CH
3CN, Gradient: 15%B to 45%B in 60 min at a flow rate of 40 mL/min, 239 nm) to afford Compound 14 (27.8 mg, 0.033 mmol, 2TFA salt) . MS m/z: 616 [M+H]
+.
Example 15
To a solution of INT 11 (12.14 g, 41.02 mmol) and tert-butyl 3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (8.27 g, 38.96 mmol) in DCM (100 mL) was added DIEA (9.92 g, 76.76 mmol) at room temperature. The reaction mixture was stirred for 1.5 h, then EA (100 mL) and water (200 mL) were added. The organic phase was collected, and concentrated under reduced pressure. The obtained residue was slurred with EA (20 mL) and Hex (200 mL) , and filtered to give Compound 15-1 as an off-white solid (18.18 g, 93.5%) . MS m/z: 471 [M+H]
+.
A solution of Compound 15-1 (518 mg, 1.10 mmol) , INT 2 (375 mg, 2.19 mmol) , KF (265 mg, 4.56 mmol) in DMSO (10 mL) was stirred at 130 ℃ for 20 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature and partitioned between water and EA. The organic layer was washed with brine, dried over Na
2SO
4 and concentrated under vacuum. The residue was purified by Prep-TLC (n-hexane: EA = 1: 1, v/v) to afford the desired product Compound 15-2 (260 mg, 0.43 mmol) . MS m/z: 606 [M+H]
+.
A solution of Compound 15-2 (91 mg, 0.15 mmol) , INT 8 (79 mg, 0.19 mmol) , Pd (PPh
3)
4 (35 mg, 30.29 μmol) , NaCO
3 (38 mg, 0.36 mmol) in dioxane (4 ml) and water (1ml) was stirred at 100 ℃ for 4 hours under nitrogen atmosphere. The reaction was diluted with EA (30 mL) and washed with water (30 mL) . The organic layer was dried over Na
2SO
4 and concentrated under vacuum. The residue was purified by Pre-TLC to afford Compound 15-3 (28 mg, 34.23 μmol) . MS (ESI, m/z) : 818 [M+H]
+
To a solution of Compound 15-3 (28 mg, 0.12 μmol) in DCM (5 mL) was added TFA (1.5 ml) and the reaction mixture was stirred at RT for 1.5 hours. The resulting mixture was concentrated under reduced pressure and the residue was purified by Pre-HPLC (C18 column, 10 μm, A: 0.1%TFA in water, B: CH
3CN, Gradient: 15%B to 35 %B in 32 min at a flow rate of 40 mL/min, 240 nm) to afford Compound 15 (7.4 mg, 8.5 μmol, TFA salt) . MS (ESI, m/z) : 618 [M+H]
+.
Example 16
Following the procedure of Example 2, Compound 16-1 was obtained with Compound 2-1 as starting material.
A solution of Compound 16-1 (305 mg, 0.55 mmol) , INT 8 (307 mg, 0.73 mmol) , DPEPhosPdCl
2 (125 mg, 174.61 μmol) , CS
2CO
3 (352 mg, 1.08 mmol) in toluene (25 ml) was stirred at 105 ℃ for 7 hours under nitrogen atmosphere. The reaction was diluted with EA (30 mL) and washed with water (20 mL) . The organic layer was dried over Na
2SO
4 and concentrated under vacuum. The residue was purified by Pre-HPLC to afford Compound 16-2 (98 mg, 0.12 mmol) . MS (ESI, m/z) : 807 [M+H]
+.
To a solution of Compound 16-2 (98 mg, 0.12 mmol) in DCM (5 mL) was added TFA (1.5 ml) and the reaction mixture was stirred at RT for 3.5 hours. The resulting mixture was concentrated under reduced pressure and the residue was purified by Pre-HPLC (C18 column, A: 0.1%TFA in water, B: CH
3CN, Gradient: 15%B to 35 %B in 31 min at a flow rate of 60 mL/min, 230 nm) to afford Compound 16 (8.6 mg, 10.30 μmol, TFA salt) . MS (ESI, m/z) : 607 [M+H]
+.
Example 17
Step 1: 7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline (506 mg, 1.53 mmol) was added to a solution of INT 17 (374 mg, 1.52 mmol) and N, N-Diisopropylethylamine (304 mg, 2.35 mmol) dissolved in DCM (5 mL) at room temperature. The reaction mixture was stirred for 10 mins, and then concentrated under vacuum. The residue was dissolved in EtOAc (40 mL) and washed with water (30 mL) . The water phase was extracted with EtOAc (30 mL) and the combined organic layers were washed with brine (40 mL) , dried over Na
2SO
4 and then filtered. The filtrate was concentrated under vacuum, and the residue was purified by silica gel chromatography (Hex: EA = 30: 1→ 4: 1, v/v) to give compound 17-1 (702 mg, 1.30 mmol) as a yellow solid. LCMS: 539 [M+H]
+.
Step 2: A mixture of compound 17-1 (656 mg, 1.21 mmol) , ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (378 mg, 2.37 mmol) , triethylenediamine (69 mg, 615.13 μmol) , Cesium carbonate (1.20 g, 3.68 mmol) and DMF (5 mL) were stirred at room temperature overnight. After quenched with water (50 mL) and extracted with EtOAc (40 mL x 2) , the organic layers were combined and washed with brine (40 mL) . After concentrated in vacuum, the resulting residue was purified by silica gel chromatography (Hex: EA = 30: 1→ 1: 1, v/v) to give compound 17-2 (584 mg, 880.89 μmol) as a yellow solid. LCMS: 662 [M+H]
+.
Step 3: A mixture of compound 17-2 (104 mg, 156.87 μmol) , (2- ( (tert-butoxycarbonyl) amino) -7-fluorobenzo [d] thiazol-4-yl) boronic acid (98 mg, 313.98 μmol) , K
3PO
4 (102 mg, 480.53 μmol) , Pd (dppf) Cl
2 (15 mg, 20.50 μmol) and 1, 4-dioxane /water =5: 1 (2.4 mL) was stirred at 75 ℃ for 5 h under nitrogen atmosphere. The mixture was cooled to room temperature, and then poured into water (50 mL) . After being extracted with EtOAc (40 mL x 2) , the organic layers were combined and washed with brine (40 mL) , dried over anhydrous Na
2SO
4. The filtrate was concentrated under vacuum, and the residue was purified by Pre-TLC (EA/PE = 2/1, v/v) to afford compound 17-3 (135.00 mg, 158.76 μmol) as a white solid. LCMS: 850 [M+H]
+.
Step 4 and Step 5: TFA (0.5 mL) was added to a solution of compound 17-3 (135.00 mg, 0.16 mmol) ) in DCM (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h, and then concentrated under vacuum. The residue was purified by Prep-HPLC to afford trifluoroacetate of compound 17 (90 mg, 0.02 mmol) . LCMS: 650 [M+H]
+.
1H NMR (400 MHz, Methanol-d
4) δ 8.01 (s, 1H) , 7.26 (t, 1H) , 7.04 (t, 1H) , 5.62 (s, 1H) , 5.49 (s, 1H) , 4.69 (d, 2H) , 4.10 –3.72 (m, 5H) , 3.52 –3.37 (m, 1H) , 3.35 (d, 2H) , 2.77 –2.55 (m, 2H) , 2.47 –1.96 (m, 8H) , 1.51 (t, 3H) .
The Compound 17 was separated by Prep-HPLC-Gilson with the following conditions: Column, CHIRALPAK SB (2cm x 25cm, 5um) ; mobile phase, Hex (0.1%IPAM) /EtOH; Flowing rate: 20 mL/min. This results in compound 17A (the first eluting isomer, retention time 4.703 min, 0.3 mg ) . and compound 17B (the second eluting isomer, retention time 5.372 min, 0.6 mg ) . and compound 17C (the third eluting isomer, retention time 7.002 min, 9.3 mg) . LCMS: 650 [M+H]
+.
1H NMR (400 MHz, Methanol-d
4) δ 7.94 (s, 1H) , 7.22 (t, 1H) , 6.99 (t, 1H) , 5.37 (s, 1H) , 5.24 (s, 1H) , 4.29 (m, 1H) , 3.70 (dd, 2H) , 3.23 (m, 2H) , 3.02 (t, 1H) , 2.90 (s, 1H) , 2.84 (s, 1H) , 2.00 (t, 3H) , 1.47 (d, 3H) , 1.40 –1.25 (m, 6H) , 0.89 (d, 1H) . And compound 17D (the forth eluting isomer, retention time 8.653min, 10.8 mg) respectively. LCMS: 650 [M+H]
+.
1H NMR (400 MHz, Methanol-d
4) δ 7.94 (s, 1H) , 7.22 (t, 1H) , 6.99 (t, 1H) , 5.37 (s, 1H) , 5.23 (s, 1H) , 4.41 –4.18 (m, 3H) , 3.92 –3.66 (m, 2H) , 3.27 –3.12 (m, 2H) , 3.01 (s, 1H) , 2.86 (d, 2H) , 2.44 –1.81 (m, 8H) , 1.46 (t, 3H) , 1.29 (s, 4H) , 0.89 (d, 1H) .
The compound 18, 19, 20, 21, 22, 23, 24, 25 and 26 in the following Table 13 were synthesized using the above procedure or modified procedure with the corresponding starting materials.
The INT 12 was applied for synthesis of compound 27 in the following Table 13 using the above procedure or modified procedure with corresponding materials.
Table 13
Pharmacological Experiments
1. SOS1 catalyzed nucleotide exchange assay
GDP-loaded HIS-KRAS (G12D, aa 1-169) was pre-incubated with a compound in the presence of 10nM GDPin a 384-well plate (Greiner) for 15 min, then purified SOS1 ExD (Flag tag, aa 564-1049) , BODIPY
TM FL GTP (Invitrogen) and MAb (monoclonal antibody) Anti 6HIS-Tb cryptate Gold (Cisbio) were added to the assay wells (Final concentration: 1.5 nM GDP-loaded HIS-KRAS (G12D) , 5 nM GDP, 0.5μM SOS1 ExD, 80 nM BODIPY
TM FL GTP, 52.5 ng/mL MAb Anti 6HIS-Tb cryptate Gold) and incubated for 4 hours at 25 ℃. Wells containing same percent of DMSO served as vehicle control, and wells without KRAS served as low control. TR-FRET signals were read on Tecan Spark multimode microplate reader. The parameters were F486: Excitation 340nm, Emission 486nm, Lag time 100 μs, Integration time 200 μs; F515: Excitation 340nm, Emission 515nm, Lag time 100 μs, Integration time 200 μs. TR-FRET ratios for each individual wells were calculated by equation: TR-FRET ratio = (Signal F515/Signal F486) *10000. The percent of activation of compounds treated wells were normalizedbetween vehicle control and low control. Then the data were analyzed using a 4-parameter logistic model to calculate IC
50 valuesThe results are shown in the following Table 1.
2. GTP-KRAS and cRAF interaction assay
GppNp-loaded HIS-KRAS (G12D, aa 1-169) was pre-incubated with a compound in the presence of 200μM GTP in a 384-well plate (Greiner) for 15 min, then cRAF RBD (GST tag, aa 50-132, CreativeBioMart) , MAb Anti GST-d2 (Cisbio) and MAb Anti 6HIS-Tb cryptate Gold (Cisbio) were added to the assay wells (Final concentration: 2.0nM GppNp-loaded HIS-KRAS (G12D) , 100μM GTP, 35nM cRAF RBD, 1 μg/mL MAb Anti GST-d2, 52.5 ng/mL MAb Anti 6HIS-Tb cryptate Gold) and incubated for 2 hours at 25 ℃. Wells containing same percent of DMSO served as vehicle control, and wells without KRAS served as low control. HTRF signals were read on Tecan Spark multimode microplate reader and HTRF ratios were calculated under manufacturer's instructions. The percent of activation of compounds treated wells were normalized between vehicle control and low control. Then the data were analyzed using a 4-parameter logistic model to calculate IC
50 values. The results are shown in the Table 14.
Table 14
Claims (42)
- A compound of formula (I) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:Wherein,R 1 is selected from hydrogen, halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C 1-6alkyl, -C 2-6alkenyl, -C 2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, oxo, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;R 6 is selected from hydrogen, halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C 1-6alkyl, -C 2-6alkenyl, -C 2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, oxo, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;X 1 is selected from CR 3 or N;n 1, n 2, n 3, n 4, and n 5 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;R 3 is selected from hydrogen, halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein said -C 1-6alkyl, -C 2-6alkenyl, -C 2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;Optionally, R 3 and R 6 together with the atoms to which they are respectively attached form ring D, said ring D is selected from a 3-20 membered carbocyclic ring, a 3-20 membered heterocyclic ring, a 6-12 membered aryl ring or a 5-20 membered heteroaryl ring; each said ring D is independently optionally substituted with z 2 R S15;R S15 is selected from hydrogen, halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NO 2, -N 3, oxo, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -OC (=O) O (C 1-6alkyl) , -NHC (=O) (OC 1-6alkyl) , -N (C 1-6alkyl) C (=O) (OC 1-6alkyl) , -OC (=O) NH (C 1-6alkyl) , -OC (=O) N (C 1-6alkyl) 2, -NHC (=O) NH 2, -NHC (=O) NH (C 1-6alkyl) , -NHC (=O) N (C 1-6alkyl) 2, -N (C 1-6alkyl) C (=O) NH 2, -N (C 1-6alkyl) C (=O) NH (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) N (C 1-6alkyl) 2, -S (=O) (OC 1-6alkyl) , -OS (=O) (C 1-6alkyl) , -S (=O) NH 2, -S (=O) NH (C 1-6alkyl) , -S (=O) N (C 1-6alkyl) 2, -NHS (=O) (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) (C 1-6alkyl) , -S (=O) 2 (OC 1-6alkyl) , -OS (=O) 2 (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , -OS (=O) 2O (C 1-6alkyl) , -NHS (=O) 2O (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2O (C 1-6alkyl) , -OS (=O) 2NH 2, -OS (=O) 2NH (C 1-6alkyl) , -OS (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2NH 2, -NHS (=O) 2NH (C 1-6alkyl) , -NHS (=O) 2N (C 1-6alkyl) 2, -N (C 1-6alkyl) S (=O) 2NH 2, -N (C 1-6alkyl) S (=O) 2NH (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2N (C 1-6alkyl) 2, -PH (C 1-6alkyl) , -P (C 1-6alkyl) 2, -P (=O) H (C 1-6alkyl) , -P (=O) (C 1-6alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more R Sa; each of (heterocyclyl and heteroaryl) at each occurrence is independently contain 1, 2, 3 or 4 heteroatoms selected from N, O, S, S (=O) or S (=O) 2;X 2 is selected from CR 21R 22, NR 23, O, S, SO or SO 2;R 21 and R 22 are each independently selected from hydrogen, halogen, -C 1-6alkyl, -OH, -OC 1-6alkyl, -SH, -SC 1-6alkyl, -NH 2, -NH (C 1-6alkyl) or -N (C 1-6alkyl) 2;R 23 is selected from hydrogen or -C 1-6alkyl;R 2 is selected from -L- (3-12 membered heterocyclyl) , -L- (3-12 membered cycloalkyl) , -L- (6-12 member aryl) , -L- (5-12 membered heteroaryl) or -L-NR 24R 25;Each L is independently selected from a bond or C 1-10 alkylene optionally substituted with one or more R S9;R 24 and R 25 are each independently selected from hydrogen or -C 1-10alkyl optionally substituted with one or more R S10;Said 3-12 membered heterocyclyl in -L- (3-12 membered heterocyclyl) is optionally substituted with one or more R S11;Said 3-12 membered cycloalkyl in -L- (3-12 membered cycloalkyl) is optionally substituted with one or more R S12;Said 6-12 member aryl in -L- (6-12 member aryl) is optionally substituted with one or more R S13;Said 5-12 membered heteroaryl in -L- (5-12 membered heteroaryl) is optionally substituted with one or more R S14;Y 2 is selected from O, S, SO, SO 2, C=O, NH or CH 2, when Y 2 is selected from NH or CH 2, the NH or CH 2 is optionally substituted with 1 or 2 R S3;m 1, m 2, m 3, m 4 or m 5 is independently selected from 0, 1, 2, 3, 4, 5 or 6;m 6 or m 7 is independently selected from 0, 1, 2, 3, 4, 5 or 6;Y 3 and Y 4 are each independently selected from O, S, SO, SO 2, C=O, NH or CH 2, when Y 3 and Y 4 is selectd from NH or CH 2, the NH or CH 2 is optionally substituted with 1 or 2 R S4;w 1 and w 2 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;w 3, w 4, w 5, w 6 and w 7 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; provided that w 6 and w 7 are not 0 at the same time;Y 5 is selected from O, S, SO, SO 2, C=O, NH or CH 2, when Y 5 is selected from NH or CH 2, the NH or CH 2 is optionally substituted with 1 or 2 R S5;p 1 and p 2 are each independently selected from 0, 1, 2, 3, 4, 5, or 6, provided that p 1 and p 2 are not 0 at the same time;p 3 and p 4 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;Y 6 is selected from O, S, NH or CH 2, when Y 6 is selected from NH or CH 2, the NH or CH 2 is optionally substituted with 1 or 2 R S6;s 1 and s 2 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;s 3 and s 4 are each independently selected from 0, 1, 2, 3, 4, 5, or 6, provided that s 3 and s 4 are not 0 at the same time;r 1 and r 2 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;r 3 and r 4 are each independently selected from 0, 1, 2, 3, 4, 5, or 6;v is selected from 0, 1, 2, 3, 4, 5 or 6;ring A is selected from a 3-10 membered carbocyclic ring, a 3-10 membered heterocyclic ring, a 6-10 membered aryl ring or a 5-10 membered heteroaryl ring, said heterocyclic or heteroaryl ring at each occurrence is independently contains 1, 2, 3 or 4 heteroatoms selected from N, O or S;Ring B and ring C are each independently selected from a 3-10 membered heterocyclic ring which is optionally further contains 1, 2, or 3 heteroatoms selected from N, O or S except the fused N atom;R S1, R S3, R S4, R S5, R S6, R S7, R S8, R S9, R S10, R S11, R S12, R S13 and R S14 are each independently selected from halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NO 2, -N 3, oxo, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -OC (=O) O (C 1-6alkyl) , -NHC (=O) (OC 1-6alkyl) , -N (C 1-6alkyl) C (=O) (OC 1-6alkyl) , -OC (=O) NH (C 1-6alkyl) , -OC (=O) N (C 1-6alkyl) 2, -NHC (=O) NH 2, -NHC (=O) NH (C 1-6alkyl) , -NHC (=O) N (C 1-6alkyl) 2, -N (C 1-6alkyl) C (=O) NH 2, -N (C 1-6alkyl) C (=O) NH (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) N (C 1-6alkyl) 2, -S (=O) (OC 1-6alkyl) , -OS (=O) (C 1-6alkyl) , -S (=O) NH 2, -S (=O) NH (C 1-6alkyl) , -S (=O) N (C 1-6alkyl) 2, -NHS (=O) (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) (C 1-6alkyl) , -S (=O) 2 (OC 1-6alkyl) , -OS (=O) 2 (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , -OS (=O) 2O (C 1-6alkyl) , -NHS (=O) 2O (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2O (C 1-6alkyl) , -OS (=O) 2NH 2, -OS (=O) 2NH (C 1-6alkyl) , -OS (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2NH 2, -NHS (=O) 2NH (C 1-6alkyl) , -NHS (=O) 2N (C 1-6alkyl) 2, -N (C 1-6alkyl) S (=O) 2NH 2, -N (C 1-6alkyl) S (=O) 2NH (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2N (C 1-6alkyl) 2, -PH (C 1-6alkyl) , -P (C 1-6alkyl) 2, -P (=O) H (C 1-6alkyl) , -P (=O) (C 1-6alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more R Sa;Each of R Sa is independently selected from halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NO 2, -N 3, oxo, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -OC (=O) O (C 1-6alkyl) , -NHC (=O) (OC 1-6alkyl) , -N (C 1-6alkyl) C (=O) (OC 1-6alkyl) , -OC (=O) NH (C 1-6alkyl) , -OC (=O) N (C 1-6alkyl) 2, -NHC (=O) NH 2, -NHC (=O) NH (C 1-6alkyl) , -NHC (=O) N (C 1-6alkyl) 2, -N (C 1-6alkyl) C (=O) NH 2, -N (C 1-6alkyl) C (=O) NH (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) N (C 1-6alkyl) 2, -S (=O) (OC 1-6alkyl) , -OS (=O) (C 1-6alkyl) , -S (=O) NH 2, -S (=O) NH (C 1-6alkyl) , -S (=O) N (C 1-6alkyl) 2, -NHS (=O) (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) (C 1-6alkyl) , -S (=O) 2 (OC 1-6alkyl) , -OS (=O) 2 (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , -OS (=O) 2O (C 1-6alkyl) , -NHS (=O) 2O (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2O (C 1-6alkyl) , -OS (=O) 2NH 2, -OS (=O) 2NH (C 1-6alkyl) , -OS (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2NH 2, -NHS (=O) 2NH (C 1-6alkyl) , -NHS (=O) 2N (C 1-6alkyl) 2, -N (C 1-6alkyl) S (=O) 2NH 2, -N (C 1-6alkyl) S (=O) 2NH (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2N (C 1-6alkyl) 2, -PH (C 1-6alkyl) , -P (C 1-6alkyl) 2, -P (=O) H (C 1-6alkyl) , -P (=O) (C 1-6alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; wherein said 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is independently optionally substituted with 1, 2, or 3 R Sb;Each of R Sb is independently selected from halogen; -C 1-6alkyl; haloC 1-6alkyl; -CN; -OH; -NH 2; -NH (C 1-6alkyl) ; -NH (C 1-6alkyl) 2; -OC 1-6alkyl; or -C 1-6alkyl substituted with 1, 2 or 3 substituents selected form halogen, haloC 1-6alkyl, -CN, -OH, -NH 2, -NH (C 1-6alkyl) , -NH (C 1-6alkyl) 2 or -OC 1-6alkyl;q 1, q 2, q 3, q 4, q 5 and q 6 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;R 2a, R 2b, R 2c, R 2d and R 2e are each independently selected from is selected from halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, oxo, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C 1-6alkyl, -C 2-6alkenyl, -C 2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, oxo, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;t 1, t 2, t 3, t 4 and t 5 are each independently selected from 0, 1, 2, 3, 4, 5 or 6;R 61, R 62, R 71, R 72, R 73, R 74, R 81, R 82, R 83, R 84, R 91, R 92, R 93, R 94, R 101, R 102, R 103, R 104, R 111, R 112, R 113 and R 114 are each independently selected from are independently selected from hydrogen, halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, oxo, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C 1-6alkyl, -C 2-6alkenyl, -C 2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, oxo, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;R 4 is selected from phenyl, naphthyl, 5 membered heteroaryl, 6 membered heteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, wherein said R 4 is independently optionally substituted with 1, 2, 3, 4, 5, or 6 R 4a;Each of R 4a is independently selected from halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, oxo, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl or R 41, wherein said -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is independently optionally substituted with 1, 2 or 3 R 4b;Each of R 4b is independently selected from halogen; -C 1-6alkyl; haloC 1-6alkyl; -CN; oxo; -OH; -NH 2; -NH (C 1-6alkyl) ; -NH (C 1-6alkyl) 2; -OC 1-6alkyl; or -C 1-6alkyl substituted with 1, 2 or 3 substituents selected form halogen, haloC 1-6alkyl, -CN, -OH, -NH 2, -NH (C 1-6alkyl) , -NH (C 1-6alkyl) 2 or -OC 1-6alkyl;R 4c is selected from hydrogen, -C 1-30alkyl, -C 2-30alkenyl, -C 2-30alkynyl, -C 0-6alkylene- (3-20 membered carbocyclyl) , -C 0-6alkylene- (3-20 membered heterocyclyl) , -C 0-6alkylene- (6-10 membered aryl) or -C 0-6alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R 4j;R 4d and R 4e are each selected from hydrogen, -C 1-30alkyl, -C 2-30alkenyl, -C 2-30alkynyl, -C (=O) C 1-6alkyl, -C 0-6alkylene- (3-20 membered carbocyclyl) , -C 0-6alkylene- (3-20 membered heterocyclyl) , -C 0-6alkylene- (6-10 membered aryl) or -C 0-6alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R 4j;R 4f and R 4g are each selected from hydrogen, -C 1-30alkyl, -C 2-30alkenyl, -C 2-30alkynyl, -C (=O) C 1-6alkyl, -C 0-6alkylene- (3-20 membered carbocyclyl) , -C 0-6alkylene- (3-20 membered heterocyclyl) , -C 0-6alkylene- (6-10 membered aryl) or -C 0-6alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R 4j;R 4h, R 4i, R 4m, R 4n and R 4p are each selected from hydrogen, halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, oxo, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C 1-6alkyl, -C 2-6alkenyl, -C 2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, oxo, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;Optionally, R 4f and R 4g together with the atoms to which they are respectively attached form a 4-10 membered heterocyclyl ring, said 4-10 membered heterocyclyl ring optionally further contains 1 or 2 heteratoms selected from N, O, S, S (=O) or S (=O) 2 and optionally substituted with one or more R 4j;Optionally, R 4f and R 4h together with the atoms to which they are respectively attached form a 4-10 membered heterocyclyl ring, said 4-10 membered heterocyclyl ring optionally further contains 1 or 2 heteratoms selected from N, O, S, S (=O) or S (=O) 2 and optionally substituted with one or more R 4j;R 4j at each occurrence is independently selected from halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, oxo, -NO 2, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, wherein said -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is independently optionally substituted with 1, 2 or 3 substituents selected from halogen; -C 1-6alkyl; haloC 1-6alkyl; -CN; oxo; -OH; -NH 2; -NH (C 1-6alkyl) ; -NH (C 1-6alkyl) 2; -OC 1-6alkyl; or -C 1-6alkyl substituted with 1, 2 or 3 substituents selected form halogen, haloC 1-6alkyl, -CN, -OH, -NH 2, -NH (C 1-6alkyl) , -NH (C 1-6alkyl) 2 or -OC 1-6alkyl;R 51 and R 52 are each independently selected from are independently selected from hydrogen, halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, oxo, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C 1-6alkyl, -C 2-6alkenyl, -C 2-6alkynyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more substituents selected from halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, oxo, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;R 53 is selected from hydrogen, -C 1-30alkyl, -C 2-30alkenyl, -C 2-30alkynyl, -C (=O) C 1-6alkyl, -C 0-6alkylene- (3-20 membered carbocyclyl) , -C 0-6alkylene- (3-20 membered heterocyclyl) , -C 0-6alkylene- (6-10 membered aryl) or -C 0-6alkylene- (5-10 membered heteroaryl) , each of which is independently substituted with one or more R 5a;R 5a at each occurrence is independently selected from halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, oxo, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;z 1 or z 2 is independently selected from 0, 1, 2, 3, 4, 5 or 6;Each of (heterocyclyl and heteroaryl) at each occurrence is independently contain 1, 2, 3 or 4 heteroatoms selected from N, O, S, S (=O) or S (=O) 2.
- A compound of formula (IA) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:Wherein, R 1, R 4, R 6, X 2, R 2, R 5, n 1, n 2, n 3, n 4, n 5, R S1, and z 1 have same definations as in claim 1.
- A compound of formula (Ⅱ) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:Wherein, R 1, R 4, R 6, X 2, R 2, R 5, n 1, n 3, n 4, n 5, R S1, z 1 have same definations as in claim 1.
- A compound of formula (Ⅲ) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:Wherein,R 1, R 4, R S15, X 2, R 2, R 5, n 1, n 2, n 3, n 4, n 5, R S1, z 1, and z 2 have same definations as in claim 1.Ring D is selected from a 4-7 membered heterocyclic ring or a 5-6 membered heteroaryl ring; said heterocyclic ring at each occurrence is independently contain 1 or 2 ring heteroatoms selected from N, O or S; said heteroaryl ring at each occurrence is independently contain 1 or 2 ring heteroatoms selected from N, O or S.
- A compound of formula (Ⅳ) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:Wherein, R 4, R 6, X 2, R 2, R 5, n 1, n 2, n 3, n 4, n 5, R S1, and z 1 have same definations as in claim 1.
- A compound of formula (V) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:Wherein, R 1, R 2, R 5, R 6, n 1, n 2, n 3, n 4, n 5, R S1, R 4a, z 1, X 1, and X 2 have same definations as in claim 1.
- A compound of formula (Ⅵ) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:Wherein, R 1, R 2, R 4, R 5, R 6, n 3, n 4, n 5, R S1, z 1, X 1, X 2 have same definations as in claim 1.Y 7 is selected from O, S, SO, SO 2, C=O, NH, CH 2, NH (C=O) , (C=O) NH, NH (S=O) , (S=O) NH, NHSO 2, SO 2NH;n 6 is selected from 0, 1, 2, 3, 4, 5 or 6;R S16 is selected from hydrogen, halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, -CN, -NO 2, -N 3, oxo, -NH 2, -NH (C 1-6alkyl) , -N (C 1-6alkyl) 2, -OH, -O (C 1-6alkyl) , -SH, -S (C 1-6alkyl) , -S (haloC 1-6alkyl) , -S (=O) (C 1-6alkyl) , -S (=O) 2 (C 1-6alkyl) , -C (=O) (C 1-6alkyl) , -C (=O) OH, -C (=O) (OC 1-6alkyl) , -OC (=O) (C 1-6alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-6alkyl) , -C (=O) N (C 1-6alkyl) 2, -NHC (=O) (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) (C 1-6alkyl) , -OC (=O) O (C 1-6alkyl) , -NHC (=O) (OC 1-6alkyl) , -N (C 1-6alkyl) C (=O) (OC 1-6alkyl) , -OC (=O) NH (C 1-6alkyl) , -OC (=O) N (C 1-6alkyl) 2, -NHC (=O) NH 2, -NHC (=O) NH (C 1-6alkyl) , -NHC (=O) N (C 1-6alkyl) 2, -N (C 1-6alkyl) C (=O) NH 2, -N (C 1-6alkyl) C (=O) NH (C 1-6alkyl) , -N (C 1-6alkyl) C (=O) N (C 1-6alkyl) 2, -S (=O) (OC 1-6alkyl) , -OS (=O) (C 1-6alkyl) , -S (=O) NH 2, -S (=O) NH (C 1-6alkyl) , -S (=O) N (C 1-6alkyl) 2, -NHS (=O) (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) (C 1-6alkyl) , -S (=O) 2 (OC 1-6alkyl) , -OS (=O) 2 (C 1-6alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-6alkyl) , -S (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2 (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2 (C 1-6alkyl) , -OS (=O) 2O (C 1-6alkyl) , -NHS (=O) 2O (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2O (C 1-6alkyl) , -OS (=O) 2NH 2, -OS (=O) 2NH (C 1-6alkyl) , -OS (=O) 2N (C 1-6alkyl) 2, -NHS (=O) 2NH 2, -NHS (=O) 2NH (C 1-6alkyl) , -NHS (=O) 2N (C 1-6alkyl) 2, -N (C 1-6alkyl) S (=O) 2NH 2, -N (C 1-6alkyl) S (=O) 2NH (C 1-6alkyl) , -N (C 1-6alkyl) S (=O) 2N (C 1-6alkyl) 2, -PH (C 1-6alkyl) , -P (C 1-6alkyl) 2, -P (=O) H (C 1-6alkyl) , -P (=O) (C 1-6alkyl) 2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; wherein, said -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -C 2-6alkenyl, -C 2-6alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with one or more R Sa; each of (heterocyclyl and heteroaryl) at each occurrence is independently contain 1, 2, 3 or 4 heteroatoms selected from N, O, S, S (=O) or S (=O) 2;z 3 selected from 0, 1, 2, 3, 4, 5 or 6.
- A compound of formula (Ⅶ) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:Wherein, R 1, R 2, R 3, R 4, R 6, n 1, n 3, n 4, n 5, R S1, z 1, and X 2 have same definations as in claim 1; andn 1+ n 3+ n 4+ n 5≤6.
- A compound of formula (Ⅷ) , a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof:Wherein, R 1, R 2, R 3, R 4, R 6, n 1, n 3, n 4, n 5, R S1, z 1, and X 2 have same definations as in claim 1; andn 1+ n 3+ n 4+ n 5≤6.
- The compound of any one of claims 1 to 9, wherein, the compound is any one of the formulas in the Table 1 in the description of the present invention.
- The compound of any one of claims 1 to 10, wherein, R 1 is selected from hydrogen, -F, -Cl, -Br, -C 1-3alkyl, haloC 1-3alkyl, haloC 1-3alkoxy, -C 2-3alkenyl, -C 2-3alkynyl, -CN, oxo, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl) 2, -OH, -O (C 1-3alkyl) , -SH, -S (C 1-3alkyl) , -S (=O) (C 1-3alkyl) , -S (=O) 2 (C 1-3alkyl) , -C (=O) (C 1-3alkyl) , -C (=O) OH, -C (=O) (OC 1-3alkyl) , -OC (=O) (C 1-3alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-3alkyl) , -C (=O) N (C 1-3alkyl) 2, -NHC (=O) (C 1-3alkyl) , -N (C 1-3alkyl) C (=O) (C 1-3alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-3alkyl) , -S (=O) 2N (C 1-3alkyl) 2, -NHS (=O) 2 (C 1-3alkyl) , -N (C 1-3alkyl) S (=O) 2 (C 1-3alkyl) , 6-10 membered cycloalkyl, 6-10 membered heterocyclyl, 6-8 membered aryl or 5-8 membered heteroaryl.
- The compound of any one of claims 1 to 11, wherein, R 1 is selected from -H, -F, -Cl, -CH 3, -CH 2CH 3, -CN, -COOH, -CH 2OH, -OH, -OCH 3, -OCH 2CH 3, -CF 3, -CHF 2, -NH 2, -NHCH 3, -N (CH 3) 2, -CH 2NH 2, -CH 2CH 2NH 2, -CH 2OH, -CH 2CH 2OH, -SH, -S-CH 3, -CH 2SH, -CH 2CH 2SH, -CH=CH 2, -C≡CH, -CHCH=CH 2, -OCF 3, -OCHF 2, -C (=O) NH 2, -C (=O) OCH 3,
- The compound of any one of claims 1 to 12, wherein, R 1 is -H or -F.
- The compound of any one of claims 1 to 13, wherein, R 3 is selected from hydrogen, -F, -Cl, -Br, -C 1-3alkyl, haloC 1-3alkyl, haloC 1-3alkoxy, -C 2-3alkenyl, -C 2-3alkynyl, -CN, oxo, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl) 2, -OH, -O (C 1-3alkyl) , -SH, -S (C 1-3alkyl) , -S (haloC 1-3alkyl) , -S (=O) (C 1-3alkyl) , -S (=O) 2 (C 1-3alkyl) , -C (=O) (C 1-3alkyl) , -C (=O) OH, -C (=O) (OC 1-3alkyl) , -OC (=O) (C 1-3alkyl) , -C (=O) NH 2, -C (=O) NH (C 1-3alkyl) , -C (=O) N (C 1-3alkyl) 2, -NHC (=O) (C 1-3alkyl) , -N (C 1-3alkyl) C (=O) (C 1-3alkyl) , -S (=O) 2NH 2, -S (=O) 2NH (C 1-3alkyl) , -S (=O) 2N (C 1-3alkyl) 2, -NHS (=O) 2 (C 1-3alkyl) , -N (C 1-3alkyl) S (=O) 2 (C 1-3alkyl) , 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-8 membered heteroaryl.
- The compound of any one of claims 1 to 14, wherein, R 3 is selected from -H, -F, -Cl, -CH 3, -CH 2CH 3, -CH (CH 3) 2, -CN, -COOH, -CH 2OH, -OH, -OCH 3, -OCH 2CH 3, -CF 3, -CHF 2, -NH 2, -NHCH 3, -N (CH 3) 2, -CH 2NH 2, -CH 2CH 2NH 2, -CH 2OH, -CH 2CH 2OH, -SH, -S-CH 3, -S-CF 3, -CH 2SH, -CH 2CH 2SH, -CH=CH 2, -C≡CH, -CHCH=CH 2, -OCF 3, -OCHF 2, -C (=O) NH 2, -C (=O) OCH 3,
- The compound of any one of claims 1 to 16, wherein, R 3 is selected from -H.
- The compound of any one of claims 1 to 17, wherein, the moiety of -X 2-R 2 or -O-R 2 is selected fromY 2 is selected from O, S, SO, SO 2, C=O, NH or CH 2, when Y 2 is selected from NH or CH 2, the NH or CH 2 is optionally substituted with 1 or 2 R S3;m 1, m 2, m 3, m 4 or m 5 is independently selected from 0, 1, 2, 3, 4, 5 or 6;Y 3 and Y 4 are each independently selected from O, S, SO, SO 2, C=O, NH or CH 2, when Y 3 and Y 4 is selectd from NH or CH 2, the NH or CH 2 is optionally substituted with 1 or 2 R S4;w 3, w 4, w 5, w 6 and w 7 are each independently selected from 0, 1, 2, 3, 4, 5 or 6; provided that w 6 and w 7 are not 0 at the same time;Y 5 is selected from O, S, SO, SO 2, C=O, NH or CH 2, when Y 5 is selected from NH or CH 2, the NH or CH 2 is optionally substituted with 1 or 2 R S5;p 1 and p 2 are each independently selected from 0, 1, 2, 3, 4, 5, or 6, provided that p 1 and p 2 are not 0 at the same time;Y 6 is selected from O, S, NH or CH 2, when Y 6 is selected from NH or CH 2, the NH or CH 2 is optionally substituted with 1 or 2 R S6;s 3 and s 4 are each independently selected from 0, 1, 2, 3, 4, 5, or 6, provided that s 3 and s 4 are not 0 at the same time;r 3 and r 4 are each independently selected from 0, 1, 2, 3, 4, 5, or 6;ring A at each occurrence is independently selected from a 4 membered carbocyclic ring, 5 membered carbocyclic ring, a, 6 membered carbocyclic ring, a 4 membered heterocyclic ring including 1 ring member selected from N, a 5 membered heterocyclic ring including 1 to 2 ring members selected from N, or O, a 6 membered heterocyclic ring including 1 to 2 ring members selected from N, O or S, a phenyl ring, a 5 membered heteroaryl ring including 1 to 2 ring members selected from N, O, or S, or a 6 membered heteroaryl ring including 1 ring member selected from N.
- The compound of any one of claims 1 to 18, wherein:Y 2 is selected from O, C=O, NH or CH 2, when Y 2 is selected from NH or CH 2, the NH or CH 2 is optionally substituted with 1 or 2 R S3;m 1 is selected from 0, 1, 2 or 3; m 2 is selected from 0, 1, 2 or 3; m 3 is selected from 0, 1, 2 or 3; m 4 is selected from 0, 1, 2 or 3; m 5 is selected from 0, 1, 2 or 3;Y 3 and Y 4 are each independently selected from O, S, SO 2, NH or CH 2, when Y 3 and Y 4 is selectd from NH or CH 2, the NH or CH 2 is optionally substituted with 1 or 2 R S4;w 3 is selected from 0, 1, 2 or 3; w 4 is selected from 0, 1, 2 or 3; w 5 is selected from 0, 1, 2 or 3; w 6 is selected from 0, 1, 2 or 3; w 7 is selected from 0, 1, 2 or 3; provided that w 6 and w 7 is not 0 at the same time;Y 5 is selected from O, S, SO 2, NH, CH 2 or C=O, when Y 5 is selected from NH or CH 2, the NH or CH 2 is optionally substituted with 1 or 2 R S5;p 1 is selected from 1, 2, 3 or 4; p 2 is selected from 1, 2, 3 or 4;Y 6 is selected from O, S or NH, when Y 6 is selected from NH or CH 2, the NH or CH 2 is optionally substituted with R S6;s 1 is selected from 1, 2, 3 or 4; s 2 is selected from 1, 2, 3 or 4;r 3 is selected from 1, 2 or 3; r 4 is selected from 1, 2 or 3;ring A at each occurrence is independently selected from a 4 membered carbocyclic ring, 5 membered carbocyclic ring, a, 6 membered carbocyclic ring, a 4 membered heterocyclic ring including 1 ring member selected from N, a 5 membered heterocyclic ring including 1 to 2 ring members selected from N, or O, a 6 membered heterocyclic ring including 1 to 2 ring members selected from N, O or S, a phenyl ring, a 5 membered heteroaryl ring including 1 to 2 ring members selected from N, O, or S, or a 6 membered heteroaryl ring including 1 ring member selected from N.
- The compound of any one of claims 1 to 19, wherein:Each of R S3 is independently selected from -F, -Cl, -CH 3, -CH 2CH 3, -CH 2CH 2CH 3, -CH (CH 3) 2, -CH 2Cl, -CHCl 2, -CCl 3, -CH 2F, -CHF 2, -CF 3, -CN, oxo, -NH 2, -NH (CH 3) , -N (CH 3) 2, -OH, -O-CH 3, -O-CH 2CH 3, -SH, -S-CH 3, -S-CH 2CH 3, -COOH, -COO (CH 3) , -COO (CH 2CH 3) , -CH 2OH, -CH 2CH 2OH, -CH (CH 3) OH, -CH 2NH 2, -CH 2CH 2NH 2, or -CH (CH 3) NH 2; preferably, each of R S3 is independently selected from -F, -CH 3, -CH 2CH 3, -CF 3, -CN, oxo, -NH 2, -OH, -O-CH 3, -COOH, -COO (CH 3) , -CH 2OH, or -CH 2NH 2;q 1 is selected from 0, 1, or 2;Each of R S4 is independently selected from -F, -Cl, -CH 3, -CH 2CH 3, -CH 2CH 2CH 3, -CH (CH 3) 2, -CH 2Cl, -CHCl 2, -CCl 3, -CH 2F, -CHF 2, -CF 3, -CN, oxo, -NH 2, -NH (CH 3) , -N (CH 3) 2, -OH, -O-CH 3, -O-CH 2CH 3, -SH, -S-CH 3, -S-CH 2CH 3, -COOH, -COO (CH 3) , -COO (CH 2CH 3) , -CH 2OH, -CH 2CH 2OH, -CH (CH 3) OH, -CH 2NH 2, -CH 2CH 2NH 2, or -CH (CH 3) NH 2; preferably, each of R S4 is independently selected from -F, -CH 3, -CH 2CH 3, -CF 3, -CN, oxo, -NH 2, -OH, -O-CH 3, -COOH, -COO (CH 3) , -CH 2OH, or -CH 2NH 2;q 2 is selected from 0, 1, or 2;Each of R S5 is independently selected from -F, -Cl, -CH 3, -CH 2CH 3, -CH 2CH 2CH 3, -CH (CH 3) 2, -CH 2Cl, -CHCl 2, -CCl 3, -CH 2F, -CHF 2, -CF 3, -CN, oxo, -NH 2, -NH (CH 3) , -N (CH 3) 2, -OH, -O-CH 3, -O-CH 2CH 3, -SH, -S-CH 3, -S-CH 2CH 3, -COOH, -COO (CH 3) , -COO (CH 2CH 3) , -CH 2OH, -CH 2CH 2OH, -CH (CH 3) OH, -CH 2NH 2, -CH 2CH 2NH 2, or -CH (CH 3) NH 2, preferably, each of R S5 is independently selected from -F, -CH 3, -CH 2CH 3, -CF 3, -CN, oxo, -NH 2, -OH, -O-CH 3, -OCH 2-COO (CH 2CH 3) , -COOH, -COO (CH 3) , -CH 2OH, or -CH 2NH 2;q 3 is selected from 0, 1, or 2;Each of R S6 is independently selected from -F, -Cl, -CH 3, -CH 2CH 3, -CH 2CH 2CH 3, -CH (CH 3) 2, -CH 2Cl, -CHCl 2, -CCl 3, -CH 2F, -CHF 2, -CF 3, -CN, oxo, -NH 2, -NH (CH 3) , -N (CH 3) 2, -OH, -O-CH 3, -O-CH 2CH 3, -SH, -S-CH 3, -S-CH 2CH 3, -COOH, -COO (CH 3) , -COO (CH 2CH 3) , -CH 2OH, -CH 2CH 2OH, -CH (CH 3) OH, -CH 2NH 2, -CH 2CH 2NH 2, or -CH (CH 3) NH 2, preferably, each of R S6 is independently selected from -F, -CH 3, -CH 2CH 3, -CF 3, -CN, oxo, -NH 2, -OH, -O-CH 3, -OCH 2-COO (CH 2CH 3) , -COOH, -COO (CH 3) , -CH 2OH, or -CH 2NH 2;q 4 is selected from 0, 1, or 2;Each of R S7 is independently selected from -F, -Cl, -CH 3, -CH 2CH 3, -CH 2CH 2CH 3, -CH (CH 3) 2, -CH 2Cl, -CHCl 2, -CCl 3, -CH 2F, -CHF 2, -CF 3, -CN, oxo, -NH 2, -NH (CH 3) , -N (CH 3) 2, -OH, -O-CH 3, -O-CH 2CH 3, -SH, -S-CH 3, -S-CH 2CH 3, -COOH, -COO (CH 3) , -COO (CH 2CH 3) , -CH 2OH, -CH 2CH 2OH, -CH (CH 3) OH, -CH 2NH 2, -CH 2CH 2NH 2, or -CH (CH 3) NH 2, preferably, each of R S7 is independently selected from -F, -CH 3, -CH 2CH 3, -CF 3, -CN, oxo, -NH 2, -OH, -O-CH 3, -COOH, -COO (CH 3) , -CH 2OH, or -CH 2NH 2;q 5 is selected from 0, 1, or 2;Each of R S8 at each occurrence is independently selected from halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -CN, oxo, -NR N1R N2, -OR N1, -C (=O) R N1, -C (=O) OR N1, -OC (=O) R N1, -C (=O) NR N1R N2, -NR N1C (=O) R N2, -OC (=O) OR N1, -NR N1C (=O) OR N2, -OC (=O) NR N1R N2, -NR N1C (=O) NR N1R N2, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein said -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally independently substituted with 1, 2 or 3 substituents selected from halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -CN, oxo, -NR N1R N2, -OR N1, -C (=O) R N1, -C (=O) OR N1, -OC (=O) R N1, -C (=O) NR N1R N2, -NR N1C (=O) R N2, -OC (=O) OR N1, -NR N1C (=O) OR N2, -OC (=O) NR N1R N2, -NR N1C (=O) NR N1R N2, 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;Each of (R N1 or R N2) in R S8 is independently selected from hydrogen or -C 1-6alkyl;Optionally, (R N1 and R N2) in R S8 together with the nitrogen atom to which they are both attached form a 3-6 membered heterocyclic ring which is optionally substituted with one or more substituents selected from halogen, -C 1-6alkyl, -OH, -OC 1-6alkyl, -SH, -SC 1-6alkyl, -NH 2, -NH (C 1-6alkyl) or -N (C 1-6alkyl) 2;q 6 is selected from 0, 1, 2 or 3;Each of R S11 is selected from -C 1-3alkyl.
- The compound of any one of claims 1 to 20, wherein, the moiety of -X 2-R 2 or -O-R 2 is selected from any one of the structures in the Table 2 in the description of the present invention.
- The compound of any one of claims 1 to 22, wherein, each of R S8 at each occurrence is independently selected from halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -CN, oxo, -NR N1R N2, -OR N1, -C (=O) R N1, -C (=O) OR N1, -OC (=O) R N1, -C (=O) NR N1R N2, -NR N1C (=O) R N2, -OC (=O) OR N1, -NR N1C (=O) OR N2, -OC (=O) NR N1R N2, -NR N1C (=O) NR N1R N2, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms selected from N, O or S, phenyl or 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O or S, wherein said -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, 3-8 membered cycloalkyl, 4-8 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally independently substituted with 1, 2 or 3 substituents selected from halogen, -C 1-6alkyl, haloC 1-6alkyl, haloC 1-6alkoxy, -CN, oxo, -NR N1R N2, -OR N1, -C (=O) R N1, -C (=O) OR N1, -OC (=O) R N1, -C (=O) NR N1R N2, -NR N1C (=O) R N2, -OC (=O) OR N1, -NR N1C (=O) OR N2, -OC (=O) NR N1R N2, -NR N1C (=O) NR N1R N2, 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;Each of (R N1 or R N2) in R S8 is independently selected from hydrogen or -C 1-6alkyl;Optionally, (R N1 and R N2) in R S8 together with the nitrogen atom to which they are both attached form a 3-6 membered heterocyclic ring which is optionally substituted with one or more substituents selected from halogen, -C 1-6alkyl, -OH, -OC 1-6alkyl, -SH, -SC 1-6alkyl, -NH 2, -NH (C 1-6alkyl) or -N (C 1-6alkyl) 2;q 6 is selected from 0, 1, 2 or 3.
- The compound of any one of claims 1 to 23, wherein, each of R S8 at each occurrence is independently selected from -F; methyl; -CF 3; -CN; oxo; -OH; -NH 2; -OCH 3; -NHC (=O) CH 3; -NHC (=O) OCH 3; -OC (=O) N (CH 3) 2; -NHC (=O) N (CH 3) 2; or methyl substituted with -F, -Cl, methyl, -CF 3, -CN, oxo, -OH, -NH 2, -OCH 3, -NHC (=O) CH 3, -NHC (=O) OCH 3, -OC (=O) N (CH 3) 2, -NHC (=O) N (CH 3) 2,
- The compound of any one of claims 1 to 25, wherein, the moiety of -X 2-R 2 or -O-R 2 is selected from any one of structures in the Table 3 in the description of the present invention.
- The compound of any one of claims 1 to 28, wherein, R 4 is selected from wherein said R 4 is independently optionally substituted with 1, 2, 3, 4, 5 or 6 R 4a;Each of R 4a is independently selected from -F, -Cl, -C 1-3alkyl, haloC 1-3alkyl, haloC 1-3alkoxy, -C 2-3alkenyl, -C 2-3alkynyl, -CN, -NH 2, -NH (C 1-3alkyl) , -N (C 1-3alkyl) 2, -OH, -O (C 1-3alkyl) , -SH, -S (C 1-3alkyl) , 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, wherein said -C 1-3alkyl, haloC 1-3alkyl, haloC 1-3alkoxy, -C 2-3alkenyl, -C 2-6alkynyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl is independently optionally substituted with 1, 2 or 3 R 4b;Each of R 4b is independently selected from -F; -C 1-3alkyl; haloC 1-3alkyl; -CN; -OH; -NH 2; -NH (C 1-3alkyl) ; -NH (C 1-3alkyl) 2; -OC 1-3alkyl; or -C 1-3alkyl substituted with 1, 2 or 3 substituents selected form -F, haloC 1-3alkyl, -CN, -OH, -NH 2, -NH (C 1-3alkyl) , -NH (C 1-3alkyl) 2 or -OC 1-3alkyl.
- The compound of any one of claims 1 to 29, wherein, R 4 is selected from wherein said R 4 is independently optionally substituted with 1, 2 or 3 R 4a;Each of R 4a is independently selected from -F, -Cl, methyl, ethyl, isopropyl, -CH=CH 2, -C≡CH, -C≡CCH 3, -C≡CD, -CH 2C≡CH, -CHF 2, -CF 3, -CH 2CF 3, -CH 2CHF 2, -CH 2CH 2F, -CH 2CH 2CH 2F, -OCF 3, -CN, -CH 2CH 2CN, -NH 2, -N (CH 3) 2, -NHCH 2CH 3, -CH 2-N (CH 3) 2, -OH, -CH 2OH, -CH 2CH 2OH, -OCH 3, -OC (CH 3) 2, -CH 2CH (CH 3) 2, -CH (CH 3) CH 2CH 3, -CH 2OCH 3, -SH, -SCH 3, -SCF 3, -OCHF 2, -CH (CF 3) OCH 3, -C (CH 3) 2OH, -CF (CH 3) 2, -OCH (CH 3) 2, cyclopropyl,
- The compound of any one of claims 1 to 30, wherein, R 4 is selected from any one of the structures in the Table 4 in the description of the present invention.
- The compound of any one of claims 1 to 31, wherein, R 4 is selected from any one of structures in the Table 5 in the description of the present invention.
- The compound of any one of claims 1 to 32, wherein, R 4 is selected from any one of structures in the Table 6 in the description of the present invention.
- The compound of any one of claims 1 to 33, wherein, R 41 is selected from any one of structures in the Table 7 in the description of the present invention.
- The compound of any one of claims 1 to 34, wherein, R 4 is selected from any one of structures in the Table 8 in the description of the present invention.
- The compound of any one of claims 1 to 35, wherein, R 5 is selected from any one of structures in the Table 9 in the description of the present invention.
- The compound of any one of claims 1 to 36, wherein, the compound is selected from hydrogen or any one of compounds in the Table 10 in the description of the present invention.
- An intermediate selected from any one of intermediates in Table 11 in the description of the present invention.
- A pharmaceutical composition comprising a compound, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof of any one of claims 1 to 37, and at least one pharmaceutically acceptable excipient.
- Use of a compound, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof of any one of claims 1 to 37; or the pharmaceutical composition of claim 39 for the manufacture of a medicament for the treatment of cancer related to KRAS G12D mutant protein. In some embodiments, the cancer is selected from pancreatic cancer, colorectal cancer, endometrial cancer or lung cancer. In some embodiments, the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
- A method of treating a subject having a cancer related to KRAS G12D mutant protein, said method comprising administering to the subject a therapeutically effective amount of a compound, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof of any one of claims 1 to 37; or the pharmaceutical composition of claim 39. In some embodiments, the cancer is selected from pancreatic cancer, colorectal cancer, endometrial cancer or lung cancer. In some embodiments, the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
- A compound, a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof or a pharmaceutically acceptable salt of the atropisomer thereof of any one of claims 1 to 37; or the pharmaceutical composition of claim 39 for use in the treatment of cancer related to KRAS G12D mutant protein. In some embodiments, the cancer is selected from pancreatic cancer, colorectal cancer, endometrial cancer or lung cancer. In some embodiments, the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
Applications Claiming Priority (24)
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CNPCT/CN2021/079448 | 2021-03-06 | ||
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CNPCT/CN2021/093764 | 2021-05-14 | ||
CNPCT/CN2021/100187 | 2021-06-15 | ||
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CN2021101089 | 2021-06-18 | ||
CN2021101188 | 2021-06-21 | ||
CNPCT/CN2021/101188 | 2021-06-21 | ||
CNPCT/CN2021/108808 | 2021-07-28 | ||
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