WO2022262686A1 - Kras g12d inhibitors - Google Patents
Kras g12d inhibitors Download PDFInfo
- Publication number
- WO2022262686A1 WO2022262686A1 PCT/CN2022/098467 CN2022098467W WO2022262686A1 WO 2022262686 A1 WO2022262686 A1 WO 2022262686A1 CN 2022098467 W CN2022098467 W CN 2022098467W WO 2022262686 A1 WO2022262686 A1 WO 2022262686A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- halogen
- compound
- pharmaceutically acceptable
- stereoisomer
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 294
- 238000000034 method Methods 0.000 claims abstract description 54
- 102200006539 rs121913529 Human genes 0.000 claims abstract description 28
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 11
- 201000011510 cancer Diseases 0.000 claims abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 9
- 201000010099 disease Diseases 0.000 claims abstract description 7
- 230000000694 effects Effects 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 288
- 229910052799 carbon Inorganic materials 0.000 claims description 267
- 229910052739 hydrogen Inorganic materials 0.000 claims description 261
- 229910052736 halogen Inorganic materials 0.000 claims description 187
- 150000002367 halogens Chemical class 0.000 claims description 187
- 150000003839 salts Chemical class 0.000 claims description 88
- 125000003545 alkoxy group Chemical group 0.000 claims description 75
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 44
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 42
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 28
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 27
- 229910052731 fluorine Inorganic materials 0.000 claims description 26
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims description 22
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 21
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
- 239000003480 eluent Substances 0.000 claims description 20
- LGIBDQRYOFBMTC-UHFFFAOYSA-N dnc010031 Chemical compound C1=CC(O)=CC=C1C1C(=O)NC2=CC=CC=C2C2=C3C1=CNC3=NC=C2 LGIBDQRYOFBMTC-UHFFFAOYSA-N 0.000 claims description 18
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 230000014759 maintenance of location Effects 0.000 claims description 14
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 10
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 5
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 4
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 175
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- 239000000243 solution Substances 0.000 description 118
- -1 heterocycylalkyl Chemical group 0.000 description 108
- 239000011541 reaction mixture Substances 0.000 description 106
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 92
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 89
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 59
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
- 235000019439 ethyl acetate Nutrition 0.000 description 53
- 239000012044 organic layer Substances 0.000 description 53
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 52
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 41
- 239000012267 brine Substances 0.000 description 39
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- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 36
- 239000012074 organic phase Substances 0.000 description 34
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 32
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
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- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 20
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- 239000003208 petroleum Substances 0.000 description 17
- 125000001424 substituent group Chemical group 0.000 description 17
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 14
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
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- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
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- 238000001516 cell proliferation assay Methods 0.000 description 8
- 125000000753 cycloalkyl group Chemical group 0.000 description 8
- GGFLAUXTEQHVKF-UHFFFAOYSA-N 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound C(C)C=1C(=CC=C2C=C(C=C(C=12)B1OC(C(O1)(C)C)(C)C)OCOC)F GGFLAUXTEQHVKF-UHFFFAOYSA-N 0.000 description 7
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- ZHFNKPFAFPQIBL-UHFFFAOYSA-N 2-[3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OB(C2=C(C3CC3)C(Cl)=CC(OCOC)=C2)OC1(C)C ZHFNKPFAFPQIBL-UHFFFAOYSA-N 0.000 description 6
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- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 5
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- HNINFCBLGHCFOJ-DTORHVGOSA-N tert-butyl (1s,5r)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Chemical compound C1NC[C@H]2CC[C@@H]1N2C(=O)OC(C)(C)C HNINFCBLGHCFOJ-DTORHVGOSA-N 0.000 description 5
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- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JQRYUMGHOUYJFW-UHFFFAOYSA-N pyridine;trihydrobromide Chemical compound [Br-].[Br-].[Br-].C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1 JQRYUMGHOUYJFW-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 239000012363 selectfluor Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- YPNVIBVEFVRZPJ-UHFFFAOYSA-L silver sulfate Chemical compound [Ag+].[Ag+].[O-]S([O-])(=O)=O YPNVIBVEFVRZPJ-UHFFFAOYSA-L 0.000 description 1
- 229910000367 silver sulfate Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- LZCVVMQABORALM-UHFFFAOYSA-N spiro[2.5]octyl Chemical group [CH]1CC11CCCCC1 LZCVVMQABORALM-UHFFFAOYSA-N 0.000 description 1
- LMUMMJCCZMWLEN-UHFFFAOYSA-N spiro[3.3]heptyl Chemical group [CH]1CCC11CCC1 LMUMMJCCZMWLEN-UHFFFAOYSA-N 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical class [H]S* 0.000 description 1
- UKHQRARQNZOXRL-UHFFFAOYSA-N trimethyltin Chemical compound C[SnH](C)C UKHQRARQNZOXRL-UHFFFAOYSA-N 0.000 description 1
- CCRMAATUKBYMPA-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C.C[Sn](C)C CCRMAATUKBYMPA-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000003039 volatile agent Substances 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
- 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
-
- 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
- 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
- C07D487/08—Bridged systems
Definitions
- the present invention is directed to novel compounds which are KRAS G12D inhibitors, their synthesis and their use for treating diseases or conditions, such as cancer.
- the present invention relates to compounds that inhibit the activity of KRAS G12D, pharmaceutical compositions comprising the compounds and methods of use therefor.
- KRAS Kristen rat sarcoma viral oncogene homolog
- the KRAS G12D mutation is widespread in human cancers. Due to the structural characteristics of the KRAS G12D protein itself, there is a lack of suitable pockets on the surface as the target of drug action. Therefore, the research of drugs specific to G12D has been progressing slowly for a long time, and there is still an urgent need to develop effective inhibitors of KRAS G12D.
- the present invention provides novel compounds, their analogues including stereoisomers, or pharmaceutically acceptable salts, which are useful as KRAS G12D inhibitors.
- the present invention also provides processes and intermediates for making the compounds of the present invention.
- the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and at least one of the compounds of the present invention or stereoisomers thereof, or pharmaceutically acceptable salts thereof.
- the compounds of the invention may be used in the treatment of diseases or conditions associated with KRAS G12D activity.
- the compounds of the present invention may be used for the manufacture of a medicament for the treatment of diseases or conditions associated with KRAS G12D activity.
- the present invention is directed to a method of treating a cancer comprising administering to a patient in need of such treatment a compound of the present invention as described above.
- a cancer includes, but not limited to, a lung cancer, a colorectal cancer, pancreatic cancers, biliary cancers etc.
- the present invention is directed to a method for separating atropisomers of the compound of the present invention.
- Aspect 1 provided herein is a compound of the formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
- R 1 is selected from H, C 1-6 alkyl, halogen and C 1-6 alkoxy,
- R 2 is selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, and -CH 2 OCONR 5 R 5 ,
- R 5 is independently selected from H and C 1-6 alkyl, and R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocycle,
- R 3 and R 4 are independently selected from H, C 1-6 alkyl, halogen, -CN, C 1-6 alkoxy, optionally substituted amino and C 2-6 alkenyl,
- X is independently selected from C and N,
- R 6 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, C 1-6 haloalkyl, optionally substituted amino, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl, is selected from
- R 7 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl,
- R 8 is selected from H, halogen, -CO 2 R 9 , -CONR 9 R 9 , -CN, C 1-3 alkyl, C 1-3 hydroxyalkyl and 3-6 membered heteroaryl,
- R 9 is independently selected from H and C 1-6 alkyl
- connection site denotes a connection site.
- Aspect 2 In the compounds of Aspect 1, R 1 is selected from H, C 1-6 alkyl and halogen.
- R 1 is selected from H, C 1-6 alkyl and F, preferably, is H or F.
- Aspect 3 In the compounds of Aspect 1 or 2, R 2 is selected from H, C 1-6 alkyl, halogen, and -CH 2 OCONR 5 R 5 , and R 5 is independently selected from H and C 1-6 alkyl. In the compounds of Aspect 1 or 2, R 2 is selected from H, C 1-3 alkyl, and -CH 2 OCONR 5 R 5 , and R 5 is independently selected from H and C 1-3 alkyl, preferably R 2 is H or -CH 2 OCON (CH 3 ) 2 .
- Aspect 4 In the compounds of any of Aspects 1-3, R 1 is selected from H, C 1-6 alkyl and F, and R 2 is selected from H, C 1-3 alkyl, and -CH 2 OCONR 5 R 5 , and R 5 is independently selected from H and C 1-3 alkyl. In the compounds of any of Aspects 1-3, R 1 is selected from H and F, and R 2 is selected from H, and -CH 2 OCON (CH 3 ) 2 .
- Aspect 5 In the compounds of any of Aspects 1-4, when X attached to R 3 is N, R 3 is absent. In the compounds of any of Aspects 1-4, when X attached to R 3 is C, R 3 is selected from H, C 1-6 alkyl, halogen, -CN, C 1-6 alkoxy, optionally substituted amino and C 2-6 alkenyl. In the compounds of any of Aspects 1-4, when X attached to R 3 is C, R 3 is selected from H, C 1-6 alkyl, halogen, -N (CH 3 ) 2 and -O-C 3 cycloalkyl.
- Aspect 7 In the compounds of any of Aspects 1-6, when X attached to R 8 is N, R 8 is absent. In the compounds of any of Aspects 1-6, when X attached to R 8 is C, R 8 is selected from H, halogen, -CO 2 R 9 , -CONR 9 R 9 , -CN, C 1-3 alkyl, C 1-3 hydroxyalkyl and 3-6 membered heteroaryl, and R 9 is independently selected from H and C 1-6 alkyl.
- X attached to R 8 is C
- R 8 is selected from halogen, -CO 2 R 9 , -CONR 9 R 9 , -CN, C 1-3 alkyl, C 1-3 hydroxyalkyl and 3-6 membered heteroaryl
- R 9 is independently selected from H and C 1-6 alkyl.
- Aspect 8 In the compounds of any of Aspects 1-7, is selected from wherein R 6 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl. In the compounds of any of Aspects 1-7, is selected from R 6 is independently selected from H, C 1-6 alkyl, halogen, C 1-3 haloalkyl, and C 3-4 cycloalkyl.
- Aspect 9 In the compounds of any of Aspects 1-8, is selected from R 7 is selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, C 2- 6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl. In the compounds of any of Aspects 1-8, is selected from R 7 is selected from H, C 1-6 alkyl and halogen.
- Aspect 10 Provided herein is a compound of the formula I-1, a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
- R 1 is selected from H, C 1-6 alkyl, halogen and C 1-6 alkoxy
- R 2 is selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, and -CH 2 OCONR 5 R 5 ,
- R 5 is independently selected from H and C 1-6 alkyl, and R 5 and R 5 are optionally taken together with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocycle,
- R 6 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl, is selected from
- R 7 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl, and
- connection site denotes a connection site.
- R 1 is selected from H, C 1-6 alkyl and halogen. In the compounds of Aspect 10, R 1 is H or F. In the compounds of Aspect 10, R 1 is H. In the compounds of Aspect 10, R 1 is C 1-6 alkyl, preferably C 1-3 alkyl. In the compounds of Aspect 10, R 1 is halogen, preferably, F.
- Aspect 12 In the compounds of Aspect 10 or 11, R 2 is selected from H, C 1-6 alkyl, halogen, and -CH 2 OCONR 5 R 5 , and R 5 is independently selected from H and C 1-6 alkyl. In the compounds of Aspect 10 or 11, R 2 is selected from H, C 1-3 alkyl, and -CH 2 OCONR 5 R 5 , and R 5 is independently selected from H and C 1-3 alkyl, preferably, R 2 is H or -CH 2 OCON (CH 3 ) 2 . In the compounds of Aspect 10 or 11, R 2 is H. In the compounds of Aspect 10 or 11, R 2 is -CH 2 OCON (CH 3 ) 2 .
- Aspect 13 In the compounds of any of Aspects 10-12, is selected from wherein R 6 is selected from H, C 1-6 alkyl, halogen, C 1-6 haloalkyl, and C 3-6 cycloalkyl. In the compounds of any of Aspects 10-12, is selected from wherein R 6 is selected from H, C 1-6 alkyl, halogen, C 1-3 haloalkyl, and C 3 cycloalkyl.
- any of Aspects 10-12 is In the compounds of any of Aspects 10-12, is In the compounds of any of Aspects 10-12, is In the compounds of any of Aspects 10-12, is In the compounds of any of Aspects 10-12, is wherein R 6 is selected from H, C 1-6 alkyl, halogen, C 1-3 haloalkyl, and C 3 cycloalkyl. In the compounds of any of Aspects 10-12, is wherein R 6 is C 3 cycloalkyl.
- Aspect 14 In the compounds of any of Aspects 10-13, is selected from R 7 is selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl. In the compounds of any of Aspects 10-13, is selected from R 7 is selected from H, C 1-6 alkyl and halogen. In the compounds of any of Aspects 10-13, is selected from R 7 is H.
- Aspect 15 Provided herein is a compound of the formula I-2, a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
- R 1 is selected from H, C 1-6 alkyl, halogen and C 1-6 alkoxy
- R 2 is selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, and -CH 2 OCONR 5 R 5 ,
- R 5 is independently selected from H and C 1-6 alkyl, and R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocycle,
- R 3 and R 4 are independently selected from H, C 1-6 alkyl, halogen, -CN, C 1-6 alkoxy, optionally substituted amino and C 2-6 alkenyl,
- R 6 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, C 1-6 haloalkyl, optionally substituted amino, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl, is selected from
- R 7 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl, and
- connection site denotes a connection site.
- Aspect 16 In the compounds of Aspect 15, R 1 is selected from H, C 1-6 alkyl and halogen. In the compounds of Aspect 15, R 1 is selected from H, C 1-3 alkyl and F. In the compounds of Aspect 15, R 1 is H.
- Aspect 17 In the compounds of Aspect 15 or 16, R 2 is selected from H, C 1-6 alkyl, halogen, and -CH 2 OCONR 5 R 5 , and R 5 is independently selected from H and C 1-6 alkyl.
- R 2 is selected from H, C 1-3 alkyl, and -CH 2 OCONR 5 R 5 , and R 5 is independently selected from H and C 1-3 alkyl.
- R 2 is selected from H and C 1-3 alkyl.
- R 2 is H.
- R 2 is -CH 2 OCONR 5 R 5
- R 5 is independently selected from H and C 1-3 alkyl.
- R 2 is -CH 2 OCON (CH 3 ) 2 .
- Aspect 18 In the compounds of any of Aspects 15-17, R 3 and R 4 are independently selected from H, C 1-6 alkyl, halogen, -CN, C 1-6 alkoxy, and C 2-6 alkenyl. In the compounds of any of Aspects 15-17, R 3 and R 4 are independently selected from H, C 1- 6 alkyl and halogen. In the compounds of any of Aspects 15-17, R 3 is selected from H and C 1-6 alkyl, and R 4 is selected from H and C 1-6 alkyl. In the compounds of any of Aspects 15-17, R 3 is H, and R 4 is H.
- Aspect 19 In the compounds of any of Aspects 15-18, is selected from wherein R 6 is selected from H, C 1-6 alkyl, halogen, C 1-6 haloalkyl, and C 3-6 cycloalkyl. In the compounds of any of Aspects 15-18, is selected from wherein R 6 is C 3 cycloalkyl. In the compounds of any of Aspects 15-18, is In the compounds of any of Aspects 15-18, is wherein R 6 is C 3 cycloalkyl.
- Aspect 20 In the compounds of any of Aspects 15-19, is selected from R 7 is selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl. In the compounds of any of Aspects 15-19, is selected from R 7 is selected from H, C 1-6 alkyl and halogen. In the compounds of any of Aspects 15-19, is selected from R 7 is selected from H and C 1-6 alkyl. In the compounds of any of Aspects 15-19, is selected from R 7 is selected from H and C 1-3 alkyl. In the compounds of any of Aspects 15-19, is selected from R 7 is H.
- Aspect 21 Provided herein is a compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
- R 1 is selected from H, C 1-6 alkyl, halogen and C 1-6 alkoxy,
- R 2 is selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino and - (CH 2 ) n OCONR 5 R 5 , n is an integer from 0 to 8,
- R 5 is independently selected from H and C 1-6 alkyl, wherein R 5 and R 5 are optionally taken together with the nitrogen atom to which they are attached to form a 3-to 10-membered heterocycle,
- R 3 and R 4 are independently selected from H, C 1-6 alkyl, halogen, -CN, C 1-6 alkoxy, optionally substituted amino and C 2-6 alkenyl,
- R 6 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl, is selected from
- R 7 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl, and
- connection site denotes a connection site.
- Aspect 22 In the compounds of Aspect 21, R 1 is selected from H, C 1-6 alkyl, and halogen. In the compounds of Aspect 21, R 1 is selected from H, and halogen. In the compounds of Aspect 21, R 1 is selected from H, C 1-6 alkyl, F, Cl and Br. In the compounds of Aspect 21, R 1 is selected from H, C 1-3 alkyl, F and Cl. In the compounds of Aspect 21, R 1 is H. In the compounds of Aspect 21, R 1 is F.
- Aspect 23 In the compounds of Aspect 21 or 22, R 2 is selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, and - (CH 2 ) n OCONR 5 R 5 , n is an integer from 0 to 6, R 5 is independently selected from H, C 1-6 alkyl, and halogen substituted C 1-6 alkyl. In the compounds of Aspect 21 or 22, R 2 is selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, and - (CH 2 ) n OCONR 5 R 5 , n is an integer from 0 to 4, R 5 is independently selected from H, C 1-6 alkyl, and halogen substituted C 1-6 alkyl.
- R 2 is selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, and - (CH 2 ) n OCONR 5 R 5 , n is an integer from 0 to 3, R 5 is independently selected from H, C 1-6 alkyl, and halogen substituted C 1-6 alkyl.
- R 2 is selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, and - (CH 2 ) n OCONR 5 R 5 , n is an integer from 0 to 2, R 5 is independently selected from H, C 1-6 alkyl, and halogen substituted C 1-6 alkyl.
- R 2 is selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, and - (CH 2 ) n OCONR 5 R 5 , n is 0 or 1, R 5 is independently selected from H, C 1-6 alkyl, and halogen substituted C 1-6 alkyl.
- R 2 is selected from H, C 1-6 alkyl, halogen, and -OCONR 5 R 5 , R 5 is independently selected from H, C 1- 6 alkyl, and halogen substituted C 1-6 alkyl.
- R 2 is selected from H, C 1-6 alkyl, halogen, and -CH 2 OCONR 5 R 5 , R 5 is independently selected from H, C 1-6 alkyl, and halogen substituted C 1-6 alkyl.
- R 2 is selected from H, C 1-6 alkyl, halogen, and -CH 2 OCONR 5 R 5 , R 5 is independently selected from H, C 1-6 alkyl, and halogen substituted C 1-6 alkyl.
- R 2 is selected from H, C 1-6 alkyl, halogen, and -CH 2 OCONR 5 R 5 , R 5 is independently selected from H, and C 1-6 alkyl.
- R 2 is selected from H, C 1-6 alkyl, halogen, and -CH 2 OCONR 5 R 5 , R 5 is independently selected from H, and C 1-3 alkyl.
- R 2 is selected from H, C 1-6 alkyl, halogen, and -CH 2 OCONR 5 R 5 , R 5 is independently selected from C 1-3 alkyl.
- R 2 is selected from H, C 1-6 alkyl, halogen, and -CH 2 OCONR 5 R 5 , R 5 is independently selected from C 1-3 alkyl.
- R 2 is selected from H, C 1-6 alkyl, halogen, and -CH 2 OCONR 5 R 5 , R 5 is methyl.
- R 2 is selected from H, C 1-6 alkyl, and -CH 2 OCONR 5 R 5 , R 5 is methyl.
- R 2 is selected from H, C 1-3 alkyl, and -CH 2 OCONR 5 R 5 , R 5 is methyl.
- R 2 is selected from H, C 1-6 alkyl and halogen.
- R 2 is selected from H and C 1-6 alkyl.
- R 2 is selected from H and C 1-3 alkyl. In the compounds of Aspect 21 or 22, R 2 is H. In the compounds of Aspect 21 or 22, R 2 is -CH 2 OCONR 5 R 5 , R 5 is methyl.
- Aspect 24 In the compounds of any of Aspects 21-23, R 3 and R 4 are independently selected from H, C 1-6 alkyl, halogen, and C 1-6 alkoxy. In the compounds of any of Aspects 21-23, R 3 and R 4 are independently selected from –CN. In the compounds of any of Aspects 21-23, R 3 and R 4 are independently selected from C 2-6 alkenyl. In the compounds of any of Aspects 21-23, R 3 and R 4 are independently selected from H, C 1- 6 alkyl, and halogen. In the compounds of any of Aspects 21-23, R 3 and R 4 are independently selected from H, C 1-6 alkyl, F, Cl and Br.
- R 3 and R 4 are independently selected from H, C 1-3 alkyl, F, Cl and Br. In the compounds of any of Aspects 21-23, R 3 and R 4 are independently selected from H, C 1-3 alkyl, F and Cl. In the compounds of any of Aspects 21-23, R 3 and R 4 are independently selected from H, F and Cl. In the compounds of any of Aspects 21-23, R 3 is F, and R 4 is F. In the compounds of any of Aspects 21-23, R 3 is Cl, and R 4 is F. In the compounds of any of Aspects 21-23, R 3 is H, and R 4 is F.
- Aspect 25 In the compounds of any of Aspects 21-24, is selected from R 6 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, and C 3-6 cycloalkyl. In the compounds of any of Aspects 21-24, is selected from In the compounds of any of Aspects 21-24, is selected from
- any of Aspects 21-24 is selected from In the compounds of any of Aspects 21-24, is In the compounds of any of Aspects 21-24, is In the compounds of any of Aspects 21-24, is In the compounds of any of Aspects 21-24, is In the compounds of any of Aspects 21-24, is selected from R 6 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, and C 3-6 cycloalkyl. In the compounds of any of Aspects 21-24, is selected from R 6 is selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, and C 3-6 cycloalkyl.
- R 6 is selected from H, C 1-6 alkyl, halogen, and C 3-6 cycloalkyl.
- R 6 is selected from H, C 1-6 alkyl and halogen.
- R 6 is selected from C 3-6 cycloalkyl.
- R 6 is C 3 cycloalkyl.
- is selected from R 6 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, and C 3-6 cycloalkyl.
- R 6 is independently selected from H, C 1-6 alkyl, halogen, and C 3-6 cycloalkyl. In the compounds of any of Aspects 21-24, is selected from R 6 is selected from H, C 1-6 alkyl, and halogen. In the compounds of any of Aspects 21-24, is selected from R 6 is selected from C 3-6 cycloalkyl. In the compounds of any of Aspects 21-24, is selected from R 6 is C 3 cycloalkyl.
- R 6 is independently selected from H, C 1-6 alkyl, halogen, halogen substituted C 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl.
- is selected from R 6 is independently selected from H, C 1-6 alkyl, halogen, halogen substituted C 1-6 alkyl, C 1-6 alkoxy, and C 3-6 cycloalkyl.
- is selected from R 6 is independently selected from H, C 1-6 alkyl, halogen, halogen substituted C 1-6 alkyl, and C 1-6 alkoxy.
- R 6 is independently selected from H, C 1-6 alkyl, halogen, and halogen substituted C 1-6 alkyl. In the compounds of any of Aspects 21-24, is selected from R 6 is independently selected from H, C 1-6 alkyl, and halogen substituted C 1-6 alkyl. In the compounds of any of Aspects 21-24, is selected from R 6 is independently selected from H, C 1-3 alkyl, and halogen substituted C 1-3 alkyl. In the compounds of any of Aspects 21-24, is selected from R 6 is independently selected from C 1-3 alkyl, and C 1-3 alkyl substituted with F.
- any of Aspects 21-24 is selected from one R 6 is selected from C 1-3 alkyl, and the other R 6 is selected from C 1-3 alkyl substituted with F. In the compounds of any of Aspects 21-24, is selected from one R 6 is selected from C 1-3 alkyl, and the other R 6 is –CF 3 . In the compounds of any of Aspects 21-24, is selected from one R 6 is –CH 3 , and the other R 6 is –CF 3 . In the compounds of any of Aspects 21-24, is selected from R 6 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, and C 3-6 cycloalkyl.
- R 6 is independently selected from H, C 1-6 alkyl, and halogen. In the compounds of any of Aspects 21-24, is selected from R 6 is independently selected from H, C 1-3 alkyl, and halogen. In the compounds of any of Aspects 21-24, is selected from R 6 is independently selected from H, C 1-3 alkyl, and halogen. In the compounds of any of Aspects 21-24, is selected from R 6 is independently selected from H, C 1-3 alkyl, F and Cl. In the compounds of any of Aspects 21-24, is selected from R 6 is independently selected from C 1-3 alkyl, F and Cl. In the compounds of any of Aspects 21-24, is selected from R 6 is independently selected from F and Cl. In the compounds of any of Aspects 21-24, is selected from R 6 is independently selected from R 6 is independently selected from F and Cl. In the compounds of any of Aspects 21-24, is selected from R 6 is independently selected from R 6 is independently selected from H, C 1-6 alkyl, and halogen. In
- R 7 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl.
- R 7 is independently selected from H, C 1-6 alkyl, halogen, and C 3-6 cycloalkyl.
- R 7 is independently selected from H, C 1-6 alkyl and halogen.
- is selected from R 7 is independently selected from H, C 1- 3 alkyl and halogen.
- R 7 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl.
- R 7 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, and C 3-6 cycloalkyl.
- R 7 is independently selected from H, C 1-6 alkyl, halogen, and C 3-6 cycloalkyl.
- R 7 is independently selected from H, C 1-6 alkyl, and halogen.
- R 7 is independently selected from H, C 1-3 alkyl, and halogen. In the compounds of any of Aspects 21-24, is R 7 is selected from H, C 1-3 alkyl, F, Cl and Br. In the compounds of any of Aspects 21-24, is R 7 is selected from H, C 1-3 alkyl, F and Cl. In the compounds of any of Aspects 21-24, is R 7 is selected from H, and C 1-3 alkyl. In the compounds of any of Aspects 21-24, is R 7 is selected from H, methyl, elthyl and propyl. In the compounds of any of Aspects 21-24, is R 7 is selected from H, and methyl. In the compounds of any of Aspects 21-24, is R 7 is H.
- Aspect 26 In the compounds of Aspect 21, wherein R 1 is selected from H, C 1-6 alkyl, and halogen, R 2 is selected from H, C 1-6 alkyl and halogen, R 3 and R 4 are independently selected from H, C 1-6 alkyl and halogen, is selected from is selected from R 7 is independently selected from H, C 1-3 alkyl and halogen, and denotes a connection site.
- Aspect 27 In the compounds of Aspect 26, wherein is
- Aspect 28 In the compounds of Aspect 26, wherein is
- Aspect 29 In the compounds of Aspect 26, wherein is
- Aspect 30 In the compounds of Aspect 26, wherein R 1 is F, R 2 is H, R 3 is F, R 4 is H or F, is R 7 is H, and denotes a connection site.
- Aspect 31 In the compounds of Aspect 26, wherein R 1 is F, R 2 is H, R 3 is F, R 4 is H or F, is is selected from R 7 is independently selected from H, and denotes a connection site.
- Aspect 32 In the compounds of Aspect 31, wherein R 3 is F, R 4 is F, is R 7 is H.
- Aspect 33 In the compounds of Aspect 21, wherein R 1 is selected from H, C 1-6 alkyl, and halogen, R 2 is selected from - (CH 2 ) n OCONR 5 R 5 , n is an integer from 0 to 4, R 5 is independently selected from H and C 1-6 alkyl, wherein R 5 and R 5 are optionally taken together with the nitrogen atom to which they are attached to form a 3-to 6-membered heterocycle, R 3 and R 4 are independently selected from H, C 1-6 alkyl and halogen, is is selected from R 7 is independently selected from H, C 1-3 alkyl and halogen, and denotes a connection site.
- Aspect 34 In the compounds of Aspect 33, wherein R 1 is selected from H, C 1-3 alkyl, and F, preferably R 1 is H, R 2 is selected from - (CH 2 ) n OCONR 5 R 5 , n is an integer from 1 to 2, R 5 is independently selected from H and C 1-3 alkyl, wherein R 5 and R 5 are optionally taken together with the nitrogen atom to which they are attached to form a 3-to 6-membered heterocycle, R 3 and R 4 are independently selected from H, C 1-3 alkyl and F, preferably R 3 and R 4 are independently F, is is selected from R 7 is independently selected from H, and denotes a connection site.
- Aspect 35 In the compounds of Aspect 32 or 33, wherein R 2 is selected from -CH 2 OCONR 5 R 5 , each of R 5 is independently selected from H and C 1-3 alkyl, preferably, each of R 5 is -CH 3 .
- Aspect 36 In the compounds of Aspect 32 or 33, wherein R 2 is selected from -CH 2 OCONR 5 R 5 , wherein R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form a 3-to 6-membered heterocycle.
- Aspect 37 In the compounds of Aspect 36, wherein R 2 is selected from -CH 2 OCONR 5 R 5 , wherein R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form
- Aspect 38 In the compounds of any of Aspects 32-36, wherein is R 7 is H.
- Aspect 39 Provided herein is a compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
- R 1 is selected from H, C 1-6 alkyl, and halogen
- R 2 is selected from H, C 1-6 alkyl, halogen, and -CH 2 OCONR 5 R 5 ,
- R 5 is independently selected from H and C 1-6 alkyl
- R 3 is selected from H, C 1-6 alkyl, halogen, -N (CH 3 ) 2 , and –O-C 3-6 cycloalkyl,
- R 4 is selected from H, C 1-6 alkyl, halogen, -CN, -N (CH 3 ) 2 , C 2-6 alkenyl and –O-C 3-6 cycloalkyl, is selected from
- R 6 is independently selected from H, C 1-6 alkyl, halogen, and C 3 cycloalkyl, is selected from
- R 7 is independently selected from H, C 1-6 alkyl, and halogen
- connection site denotes a connection site.
- Aspect 40 Provided herein is a compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
- R 1 is selected from H, C 1-6 alkyl, and halogen, preferably is H,
- R 2 is selected from H, C 1-6 alkyl, halogen, and -CH 2 OCONR 5 R 5 ,
- R 5 is independently selected from H and C 1-6 alkyl
- R 3 is selected from halogen, preferably is F,
- R 4 is selected from H, C 1-6 alkyl, halogen, -CN, -N (CH 3 ) 2 , C 2-6 alkenyl and –O-C 3-6 cycloalkyl, is selected from is selected from
- R 7 is independently selected from H, C 1-6 alkyl, and halogen
- connection site denotes a connection site.
- Aspect 41 Provided herein is a compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
- R 1 is selected from H
- R 2 is selected from H, and -CH 2 OCON (CH 3 ) 2 ,
- R 3 is selected from halogen, preferably is F,
- R 4 is selected from H, C 1-3 alkyl, and halogen
- R 7 is independently selected from H, C 1-3 alkyl, and halogen
- connection site denotes a connection site.
- Aspect 42 Provided herein is a compound of the formula I-4, a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
- R 1 is selected from H, C 1-6 alkyl, halogen and C 1-6 alkoxy
- R 2 is selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, and -CH 2 OCONR 5 R 5 ,
- R 5 is independently selected from H and C 1-6 alkyl, and R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocycle,
- R 3 is selected from H, C 1-6 alkyl, halogen, -CN, C 1-6 alkoxy, optionally substituted amino and C 2-6 alkenyl,
- R 6 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, C 1-6 haloalkyl, optionally substituted amino, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl, is selected from
- R 7 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl,
- R 8 is selected from halogen, -CO 2 R 9 , -CONR 9 R 9 , -CN, C 1-3 alkyl, C 1-3 hydroxyalkyl and 3-6 membered heteroaryl,
- R 9 is independently selected from H and C 1-6 alkyl
- connection site denotes a connection site.
- Aspect 43 In the compounds of Aspect 42, wherein R 1 is selected from H, C 1-3 alkyl, and halogen, R 2 is selected from H, C 1-3 alkyl, halogen and -CH 2 OCONR 5 R 5 , R 5 is independently selected from H and C 1-3 alkyl, wherein R 5 and R 5 are optionally taken together with the nitrogen atom to which they are attached to form a 4-to 6-membered heterocycle, R 3 is selected from H, C 1-6 alkyl and halogen, is selected from is selected from R 7 is independently selected from H, C 1-6 alkyl and halogen, R 8 is selected from hydrogen, halogen and C 1-3 alkyl, and denotes a connection site.
- R 1 is selected from H, C 1-3 alkyl, and halogen
- R 2 is selected from H, C 1-3 alkyl, halogen and -CH 2 OCONR 5 R 5
- R 5 is independently selected from H and C 1-3 alkyl, wherein R 5 and
- Aspect 44 In the compounds of Aspect 42 or 43, wherein is selected from
- R 1 is selected from H
- R 2 is selected from H
- R 3 and R 4 are independently selected from H
- F and Cl is selected from is R 7 is H.
- Nonlimiting examples of the compounds of formula I are selected from the group consisting of:
- Aspect 45 there is provided a pharmaceutical composition which comprises a compound of formula I (including formulas I-1 to I-4) , a pharmaceutically acceptable salt thereof or stereoisomer thereof and one or more pharmaceutically acceptable excipients.
- Aspect 46 there is provided a method of treating various disorders, comprising administering a subject in need thereof a compound of formula I (including formulas I-1 to I-4) , a pharmaceutically acceptable salt thereof or stereoisomer thereof.
- Aspect47 there is provided the use of a compound of formula I (including formulas I-1 to I-4) , a pharmaceutically acceptable salt thereof or a stereoisomer thereof, in the manufacture of a medicament for the treatment of diseases or conditions associated with KRAS G12D activity.
- Aspect 48 there is provided a method for making a compound of formula I (including formulas I-1 to I-4) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.
- Aspect 49 there is provided a method for separating atropisomers of the compound according to the present invention, wherein the method comprises the following steps: i) providing atropisomers of the compound according to the present invention;
- Aspect 50 in the method of Aspect 49, wherein the HPLC method is conducted under the following conditions: Column Pursuit XRs C18 (4.6*250mm, 5.0 ⁇ m) ; eluent A: 0.02%TFA in H2O; eluent B: 0.02%TFA in CAN; gradient: 10%B to 95%B in 10 min, 95%B from 10 to 12 min, then 10%B in 13 min, 10%B from 13-20 min at a flow rate of 1.2 mL/min, 220 &254 nM.
- Aspect 52 in the method of any of Aspect 49-51, wherein the compound is Example 39.
- references made in the singular may also include the plural.
- references made in the singular may also include the plural.
- “a” and “an” may refer to either one, or one or more.
- any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.
- Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.
- the indication of the number of members in groups that contain one or more heteroatom (s) relates to the total number of atoms of all the ring members or the total of all the ring and carbon chain members.
- the indication of the number of carbon atoms in groups that consist of a combination of carbon chain and carbon ring structure relates to the total number of carbon atoms of all the carbon ring and carbon chain members.
- a ring structure has at least three members.
- aryl-C 1-6 alkyl means an aryl group which is bound to a C 1-6 alkyl group, the latter of which is bound to the core or to the group to which the substituent is attached.
- Alkyl denotes monovalent, saturated hydrocarbon chains, which may be present in both straight-chain (unbranched) and branched form. If an alkyl is substituted, the substitution may take place independently of one another, by mono-or polysubstitution in each case, on all the hydrogen-carrying carbon atoms.
- alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
- C 1 -C 6 alkyl denotes alkyl having 1 to 6 carbon atoms.
- Example alkyl groups include, but are not limited to, methyl (Me) , ethyl (Et) , propyl (e.g., n-propyl and isopropyl) , butyl (e.g., n-butyl, isobutyl, t-butyl) , pentyl (e.g., n-pentyl, isopentyl, neopentyl) , and hexyl (e.g., n-hexyl, isohexyl, t-hexyl) .
- alkyl also applies if alkyl is a part of another (combined) group such as for example C x-y alkylamino or C x-y alkyloxy.
- Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.
- Cycloalkyl is made up of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. The systems are saturated. In bicyclic hydrocarbon rings two rings are joined together so that they have at least two carbon atoms in common. In spiro-hydrocarbon rings one carbon atom (spiroatom) belongs to two rings together.
- a cycloalkyl is to be substituted, the substitutions may take place independently of one another, in the form of mono-or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Cycloalkyl itself may be linked as a substituent to the molecule via every suitable position of the ring system.
- cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.0] hexyl, bicyclo [3.2.0] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octyl, bicyclo [4.3.0] nonyl (octahydroindenyl) , bicyclo [4.4.0] decyl (decahydronaphthyl) , bicyclo [2.2.1] heptyl (norbornyl) , bicyclo [4.1.0] heptyl (norcaranyl) , bicyclo [3.1.1] heptyl (pinanyl) , spiro [2.5] octyl, spiro [3.3] heptyl etc.
- cycloalkyl also applies if cycloalkyl is part of another (combined) group as for example in C x-y cycloalkylamino, C x-y cycloalkyloxy or C x-y cycloalkylalkyl.
- Alkenyl is intended to include hydrocarbon chains of either straight or branched configuration having the specified number of carbon atoms and one or more, preferably one to two, carbon-carbon double bonds that may occur in any stable point along the chain.
- C 2 to C 6 alkenyl or “C 2-6 alkenyl” (or alkenylene) , is intended to include C 2 , C 3 , C 4 , C 5 , and C 6 alkenyl groups.
- alkenyl examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl.
- Alkynyl is intended to include hydrocarbon chains of either straight or branched configuration having one or more, preferably one to three, carbon-carbon triple bonds that may occur in any stable point along the chain.
- C 2 to C 6 alkynyl or “C 2-6 alkynyl” (or alkynylene) , is intended to include C 2 , C 3 , C 4 , C 5 , and C 6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
- alkoxy refers to an –O-alkyl group.
- C 1-6 alkoxy (or alkyloxy) , is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 alkoxy groups.
- Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy) , and t-butoxy.
- substituted means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that normal valencies are maintained and that the substitution results in a stable compound.
- substituents are selected from, for example, substituents such as alkyl, cycloalkyl, aryl, heterocyclo, halo, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or arylalkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, arylalkylthio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfon
- a substituent has a dash (-) that is not between two letters or symbols; this is used to indicate a point of attachment for a substituent.
- -CONH 2 is attached through the carbon atom.
- Optically active forms may be prepared by resolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, for example, by chromatography or fractional crystallization. Depending on the process conditions the end products of the present invention are obtained either in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the invention. If so desired, one form of a compound may be converted into another form.
- a free base or acid may be converted into a salt; a salt may be converted into the free compound or another salt; a mixture of isomeric compounds of the present invention may be separated into the individual isomers.
- Compounds of the present invention, free form and salts thereof, may exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention.
- 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 configuration isomers.
- the configuration isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers.
- pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
- examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids.
- the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
- the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington: The Science and Practice of Pharmacy, 22 nd Edition, Allen, L.V. Jr., Ed. ; Pharmaceutical Press, London, UK (2012) , the disclosure of which is hereby incorporated by reference.
- salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable.
- salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
- Treating refers to administering at least one compound and /or at least one stereoisomer thereof, and /or at least one pharmaceutically acceptable salt thereof disclosed herein to a subject in recognized need thereof that has, for example, cancer.
- terapéuticaally effective amount refers to an amount of at least one compound and /or at least one stereoisomer thereof, and /or at least one pharmaceutically acceptable salt thereof disclosed herein effective to "treat” as defined above, a disease or disorder in a subject.
- cancer refers to or describes the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia.
- the term “inhibitor” refers to biological or chemical substance that interferes with or otherwise reduces the physiological and/or biochemical action of another biological or chemical molecule. In some embodiments, the inhibitor or antagonist specifically binds to the other molecule.
- a “subject, ” “patient” or “individual” includes a mammal, such as a human or other animal, and typically is human.
- the subject e.g., patient, to whom the therapeutic agents and compositions are administered, is a mammal, typically a primate, such as a human.
- the primate is a monkey or an ape.
- the subject can be male or female and can be any suitable age, including infant, juvenile, adolescent, adult, and geriatric subjects.
- the subject is a non-primate mammal, such as a rodent, a dog, a cat, a farm animal, such as a cow or a horse, etc.
- the compounds in the present invention can be synthesized in a number of ways well to one skilled in the art of organic synthesis described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods are not limited as those described below.
- the references cited here are incorporated by reference in their entirety.
- Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, 3 rd edition, John Wiley &Sons) . These groups are removed at certain stage of the compound synthesis using the methods that are apparent to those skilled in the art.
- Step 1 5- (2- (4-Fluorophenyl) acetyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione
- Step 3 4- (4-Fluorophenyl) -3-oxobutanoic acid
- Step 5 7-Fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalene-1, 3-diol
- Step 6 7-Fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-ol
- Step 7 7-Fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl trifluoromethanesulfonate
- Step 8 ( (2-Fluoro-6- (methoxymethoxy) -8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane
- Step 1 7-Fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl pivalate
- reaction mixture was diluted with DCM (150 mL) and water (150 mL) , and then the aqueous layer was extracted with DCM (100 mL) . The combined organic phase was dried over Na 2 SO 4 and concentrated. The residue was purified by column chromatography to give the title product (20.0 g, crude) as yellow oil.
- Step 2 8-Ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl pivalate
- Step 3 8-Ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl pivalate
- Step 4 8-Ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-ol
- Step 5 8-Ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yltrifluoromethane sulfonate
- Step 6 2- (8-Ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane
- Step 2 2- (3-Bromo-5-chloro-4-cyclopropylphenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane
- Step 4 1-Bromo-3-chloro-2-cyclopropyl-5- (methoxymethoxy) benzene
- Step 5 2- (3-Chloro-2-cyclopropyl-5- (methoxymethoxy) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane
- Step 4 2- (5-Chloro-6-fluoro-4- (methoxymethoxy) naphthalen-2-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane
- Step 6 5-Chloro-6-fluoro-4- (methoxymethoxy) naphthalen-2-yl acetate
- Step 7 5-Chloro-6-fluoro-4-hydroxynaphthalen-2-yl acetate
- Step 8 5-Chloro-6-fluoro-4- ( ( (trifluoromethyl) sulfonyl) oxy) naphthalen-2-yl acetate
- Step 10 8-Chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yltrifluoro methanesulfonate
- Step 11 (8-Chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) trimethyl stannane
- Step 3 6, 7-Dichloropyrido [2, 3-d] pyrimidine-2, 4-diol
- Step 4 2, 4, 6, 7-Tetrachloropyrido [2, 3-d] pyrimidine
- Step 5 Tert-butyl (1R, 5S) -3- (2, 6, 7-trichloropyrido [2, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 6 Tert-butyl (1R, 5S) -3- (6, 7-dichloro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [2, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 7 Tert-butyl (1R, 5S) -3- (6-chloro-7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [2, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 8 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6-chloro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [2, 3-d] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol
- Step 1 Tert-butyl (1R, 5S) -3- (6-chloro-7- (3-chloro-2-cyclopropyl-5- (methoxy methoxy) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [2, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 2 3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6-chloro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [2, 3-d] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol
- Step 1 7-Bromopyrido [3, 2-d] pyrimidine-2, 4 (1H, 3H) -dione
- Step 2 7-Bromo-2, 4-dichloropyrido [3, 2-d] pyrimidine
- Step 3 Tert-butyl (1R, 5S) -3- (2, 6, 7-trichloropyrido [2, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 4 Tert-butyl (1R, 5S) -3- (7-bromo-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 5 Tert-butyl (1R, 5S) -3- (7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 6 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol
- Step 1 Tert-butyl (1R, 5S) -3- (7- (3-chloro-2-cyclopropyl-5- (methoxymethoxy) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin -4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 2 3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol
- Step 1 Tert-butyl (1R, 5S) -3- (7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 2 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
- Step 3 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
- Step 2 Tert-butyl (1R, 5S) -3- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 3 Tert-butyl (1R, 5S) -3- (7-bromo-6-chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 4 Tert-butyl (1R, 5S) -3- (6-chloro-7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 5 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6-chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol
- Step 3 Tert-butyl (1R, 5S) -3- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 4 Tert-butyl (1R, 5S) -3- (7-bromo-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 5 Tert-butyl (1R, 5S) -3- (7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthal en-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 6 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (tetrahydro-1 H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol
- Step 1 Tert-butyl (1R, 5S) -3- (7-bromo-2, 8-difluoroquinazolin-4-yl) -3, 8-diaza bicyclo [3.2.1] octane-8-carboxylate
- Step 2 Tert-butyl (1R, 5S) -3- (7-bromo-2- ( (3- ( ( (tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 3 Tert-butyl (1R, 5S) -3- (7-bromo-8-fluoro-2- ( (3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 4 Tert-butyl (1R, 5S) -3- (7-bromo-2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 5 Tert-butyl (1R, 5S) -3- (7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 6 (7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoroquinazolin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate
- Step 1 Tert-butyl (1R, 5S) -3- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 2 Tert-butyl (1R, 5S) -3- (7-bromo-2- ( (3- ( ( (tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 3 Tert-butyl (1R, 5S) -3- (7-bromo-6, 8-difluoro-2- ( (3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 4 Tert-butyl (1R, 5S) -3- (7-bromo-2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 5 Tert-butyl (1R, 5S) -3- (7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 6 (7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoroquinazolin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate
- Step 1 Tert-butyl (1R, 5S) -3- (2- ( (1- ( ( (dimethylcarbamoyl) oxy) methyl) hexa hydropentalen-3a (1H) -yl) methoxy) -7- (8-ethyl-7-fluoro-3- (methoxyethoxy) aphthalen-1-yl) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 2 (7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl) -8-fluoroquinazolin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate
- Step 1 Tert-butyl (1R, 5S) -3- (7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo 3.2.1] octane-8-carboxylate
- Step 2 (7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate
- Step 3 Methyl 4-bromo-3, 5-difluoro-2- (3- (2, 2, 2-trichloroacetyl) ureido) benzoate
- Step 6 Tert-butyl (1R, 5S) -3- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 7 Tert-butyl (1R, 5S) -3- (7-bromo-6-chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 8 Tert-butyl (1R, 5S) -3- (7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 9 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6-chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol
- Step 1 Tert-butyl (1R, 5S) -3- (7-bromo-6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 2 Tert-butyl (1R, 5S) -3- (7-bromo-2- ( (3- ( ( (tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6-chloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 3 Tert-butyl (1R, 5S) -3- (7-bromo-6-chloro-8-fluoro-2- ( (3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 4 Tert-butyl (1R, 5S) -3- (7-bromo-6-chloro-2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 5 Tert-butyl (1R, 5S) -3- (6-chloro-2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 6 (7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6-chloro-7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoroquinazolin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate
- Step 1 Tert-butyl (1R, 5S) -3- (6-chloro-2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 2 (7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6-chloro-7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoroquinazolin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate
- Step 1 Tert-butyl (1R, 5S) -3- (7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 2 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol
- Step 1 Tert-butyl (1R, 5S) -3- (7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 2 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2- fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol
- Step 1 Tert-butyl (1R, 5S) -3- (7-bromo-8-fluoro-2- ( ( (2R) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 2 Tert-butyl (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- the reaction mixture was stirred at 95 °C for 16 h.
- the reaction mixture was cooled, water (10 mL) was added.
- the mixture was extracted with ethyl acetate (10 mL x 3) .
- the organic layer was washed with water (10 mL) , brine (10 mL) and dried over sodium sulfate.
- the organic layer was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title product (140 mg, 46.5%yield) as a white solid.
- Step 3 Tert-butyl (1R, 5S) -3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- the mixture was stirred at 25 °C for 16 h. After completion, the mixture was cooled to r.t., then water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3) . The organic layer was washed with water (10 mL) , brine (10 mL) and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford the crude product, which was used in the next step without further purification.
- Step 4 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
- Step 1 Tert-butyl (1R, 5S) -3- (7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 2 3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-4-cyclopropylphenol
- Step 1 Tert-butyl (1R, 5S) -3- (7-bromo-6, 8-difluoro-2- ( ( (2R) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 2 Tert-butyl (1R, 5S) -3- (7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 3 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol
- CHIRAL_SFC Analysis method column: Cellulose-SZ 100x4.6mm 3.0um; co solvent: MeOH (60%DCM+20mMNH3) . Retention time of atropisomer 1 is 1.896 min. and atropisomer 2 is 2.145 min.
- Step 1 Tert-butyl (1R, 5S) -3- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 2 Tert-butyl (1R, 5S) -3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 3 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
- Step 1 Tert-butyl (1R, 5S) -3- (7- (3-chloro-2-cyclopropyl-5- (methoxymethoxy) phenyl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 2 3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-4-cyclopropylphenol
- Step 4 8-Chloro-2-fluoro-6-methoxy-3, 4-dihydronaphthalen-1 (2H) -one
- Step 7 8-Chloro-2-fluoro-6-methoxynaphthalen-1-yl trifluoromethanesulfonate
- Step 8 8-Chloro-1-cyclopropyl-2-fluoro-6-methoxynaphthalene
- Step 10 8-Chloro-1-cyclopropyl-2-fluoro-6- (methoxymethoxy) naphthalene
- Step 11 2- (8-Cyclopropyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane
- Step 12 Tert-butyl (1R, 5S) -3- (7- (8-cyclopropyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 13 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-cyclopropyl-6-fluoronaphthalen-2-ol
- the KRAS G12D pERK assay biochemical assay was carried out by Pharmaron.
- the KRAS G12D pERK assay was performed in AGS Cell lines.
- Example # IC 50 Example # IC 50 Example 1 C Example 7 C Example 4 C Example 11 A Example 6 B
- A means ⁇ 0.2 uM
- B means ⁇ 0.2 uM and ⁇ 2 uM
- C means > 2 uM
- the Cell proliferation assay was carried out by Pharmaron.
- the cell proliferation assay was performed in AGS Cell lines (expressing KRAS G12D) in 3D model.
- Trpsinize cells with 2 mL TrypLE TM Express Enzyme at room temperature (RT) or 37°C until the cells detach.
- Example # GI 50 Example # GI 50 Example 1 B Example 29 A Example 4 C Example 31 A Example 6 B Example 32 B Example 7 C Example 33 A Example 11 A Example 34 A Example 16 A Example 35 A Example 26 A Example 36 A Example 27 A Example 37 A Example 28 A Example 39 A
- A means ⁇ 0.5 uM
- B means ⁇ 0.5 uM and ⁇ 5 uM
- C means > 5 uM
- the protein binding assay was carried out by Pharmaron Inc.
- KRAS [G12D] cRaf binding assay was performed with a KRAS-G12D-cRAF binding assay kit commercially available from Cisbio (Catalog number: 63ADK000CB21PEG) . Binding reactions were carried out with test compounds, at concentrations 300 nM, 100 nM, 33 nM, 11 nM, 3.7 nM, 1.2 nM, 0.4 nM, 0.13 nM, 45.7 pM, 15.3 pM and 5.1 pM were applied to a well within a 384-well plate.
- Example # IC 50 (nM) Example # IC 50 (nM) Example 11 27.3 Example 31 15.5 Example 16 18.3 Example 34 22.1 Example 26 17.0 Example 35 17.8 Example 27 19.4 Example 36 16.4 Example 28 16.7 Example 37 15.4 Example 29 17.0 Example 39 20.5
- the KRAS G12D pERK assay biochemical assay was carried out by Pharmaron.
- the KRAS G12D pERK assay was performed in GP2D Cell lines.
- Trpsinize cells with 2 mL TrypLE TM Express Enzyme at room temperature (RT) or 37°C until the cells detach.
- Example 39 GI 50 (nM) Mixture 0.65 atropisomer 1 0.26 atropisomer 2 13.95
Abstract
Disclosed are novel compounds which are KRAS G12D inhibitors, their synthesis and their use for treating diseases or conditions, such as cancer, and in particular for inhibiting the activity of KRAS G12D, pharmaceutical compositions comprising the compounds and methods of use therefor.
Description
The present invention is directed to novel compounds which are KRAS G12D inhibitors, their synthesis and their use for treating diseases or conditions, such as cancer. In particular, the present invention relates to compounds that inhibit the activity of KRAS G12D, pharmaceutical compositions comprising the compounds and methods of use therefor.
Kristen rat sarcoma viral oncogene homolog (KRAS) is a membrane-bound protein located on the inner side of the cell membrane. When a mutation in KRAS causes an abnormality in the encoded protein, the mutated protein will activate downstream signaling pathways, causing excessive activation of cell proliferation, differentiation, and survival, which in turn leads to the occurrence and spread of tumors.
Among the KRAS mutations, the KRAS G12D mutation is widespread in human cancers. Due to the structural characteristics of the KRAS G12D protein itself, there is a lack of suitable pockets on the surface as the target of drug action. Therefore, the research of drugs specific to G12D has been progressing slowly for a long time, and there is still an urgent need to develop effective inhibitors of KRAS G12D.
Therefore, there remains a need to provide novel compounds which are used as inhibitors of KRAS G12D. The compounds of the invention help meet this need.
SUMMARY OF THE INVENTION
The present invention provides novel compounds, their analogues including stereoisomers, or pharmaceutically acceptable salts, which are useful as KRAS G12D inhibitors.
The present invention also provides processes and intermediates for making the compounds of the present invention.
The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and at least one of the compounds of the present invention or stereoisomers thereof, or pharmaceutically acceptable salts thereof.
The compounds of the invention may be used in the treatment of diseases or conditions associated with KRAS G12D activity.
The compounds of the present invention may be used for the manufacture of a medicament for the treatment of diseases or conditions associated with KRAS G12D activity.
There is a need to develop new KRAS G12D inhibitors that demonstrate sufficient efficacy for treating KRAS G12D-mediated cancer.
In another aspect, the present invention is directed to a method of treating a cancer comprising administering to a patient in need of such treatment a compound of the present invention as described above. Examples of such cancer includes, but not limited to, a lung cancer, a colorectal cancer, pancreatic cancers, biliary cancers etc.
In one aspect, the present invention is directed to a method for separating atropisomers of the compound of the present invention.
These and other features of the invention will be set forth in expanded form as the disclosure continues.
Aspect 1: provided herein is a compound of the formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein:
R
1 is selected from H, C
1-6 alkyl, halogen and C
1-6 alkoxy,
R
2 is selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, optionally substituted amino, and -CH
2OCONR
5R
5,
R
5 is independently selected from H and C
1-6 alkyl, and R
5 and R
5 are taken together with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocycle,
R
3 and R
4 are independently selected from H, C
1-6 alkyl, halogen, -CN, C
1-6 alkoxy, optionally substituted amino and C
2-6 alkenyl,
X is independently selected from C and N,
R
6 is independently selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, C
1-6 haloalkyl, optionally substituted amino, C
2-6 alkenyl, C
2-6 alkynyl and C
3-6 cycloalkyl,
is selected from
R
7 is independently selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, optionally substituted amino, C
2-6 alkenyl, C
2-6 alkynyl and C
3-6 cycloalkyl,
R
8 is selected from H, halogen, -CO
2R
9, -CONR
9R
9, -CN, C
1-3 alkyl, C
1-3 hydroxyalkyl and 3-6 membered heteroaryl,
R
9 is independently selected from H and C
1-6 alkyl, and
Aspect 2: In the compounds of Aspect 1, R
1 is selected from H, C
1-6 alkyl and halogen.
In the compounds of Aspect 1, R
1 is selected from H, C
1-6 alkyl and F, preferably, is H or F.
Aspect 3: In the compounds of Aspect 1 or 2, R
2 is selected from H, C
1-6 alkyl, halogen, and -CH
2OCONR
5R
5, and R
5 is independently selected from H and C
1-6 alkyl. In the compounds of Aspect 1 or 2, R
2 is selected from H, C
1-3 alkyl, and -CH
2OCONR
5R
5, and R
5 is independently selected from H and C
1-3 alkyl, preferably R
2 is H or -CH
2OCON (CH
3)
2.
Aspect 4: In the compounds of any of Aspects 1-3, R
1 is selected from H, C
1-6 alkyl and F, and R
2 is selected from H, C
1-3 alkyl, and -CH
2OCONR
5R
5, and R
5 is independently selected from H and C
1-3 alkyl. In the compounds of any of Aspects 1-3, R
1 is selected from H and F, and R
2 is selected from H, and -CH
2OCON (CH
3)
2.
Aspect 5: In the compounds of any of Aspects 1-4, when X attached to R
3 is N, R
3 is absent. In the compounds of any of Aspects 1-4, when X attached to R
3 is C, R
3 is selected from H, C
1-6 alkyl, halogen, -CN, C
1-6 alkoxy, optionally substituted amino and C
2-6 alkenyl. In the compounds of any of Aspects 1-4, when X attached to R
3 is C, R
3 is selected from H, C
1-6 alkyl, halogen, -N (CH
3)
2 and -O-C
3 cycloalkyl.
Aspect 6: In the compounds of any of Aspects 1-5, when X attached to R
4 is N, R
3 is absent. In the compounds of any of Aspects 1-5, when X attached to R
3 is C, R
3 is selected from H, C
1-6 alkyl, halogen, -CN, C
1-6 alkoxy, optionally substituted amino and C
2-6 alkenyl. In the compounds of any of Aspects 1-5, when X attached to R
3 is C, R
3 is selected from H, C
1-3 alkyl, halogen, -CN, -N (CH
3)
2, -O-C
3 cycloalkyl and –CH=CH
2. Aspect 7: In the compounds of any of Aspects 1-6, when X attached to R
8 is N, R
8 is absent. In the compounds of any of Aspects 1-6, when X attached to R
8 is C, R
8 is selected from H, halogen, -CO
2R
9, -CONR
9R
9, -CN, C
1-3 alkyl, C
1-3 hydroxyalkyl and 3-6 membered heteroaryl, and R
9 is independently selected from H and C
1-6 alkyl. In the compounds of any of Aspects 1-6, X attached to R
8 is C, R
8 is selected from halogen, -CO
2R
9, -CONR
9R
9, -CN, C
1-3 alkyl, C
1-3 hydroxyalkyl and 3-6 membered heteroaryl, and R
9 is independently selected from H and C
1-6 alkyl.
Aspect 8: In the compounds of any of Aspects 1-7,
is selected from
wherein R
6 is independently selected from H, C
1-6 alkyl, halogen, C
1-6 haloalkyl, C
2-6 alkenyl, C
2-6 alkynyl and C
3-6 cycloalkyl. In the compounds of any of Aspects 1-7,
is selected from
R
6 is independently selected from H, C
1-6 alkyl, halogen, C
1-3 haloalkyl, and C
3-4 cycloalkyl.
Aspect 9: In the compounds of any of Aspects 1-8,
is selected from
R
7 is selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, optionally substituted amino, C
2-
6 alkenyl, C
2-6 alkynyl and C
3-6 cycloalkyl. In the compounds of any of Aspects 1-8,
is selected from
R
7 is selected from H, C
1-6 alkyl and halogen.
Aspect 10: Provided herein is a compound of the formula I-1, a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein R
1 is selected from H, C
1-6 alkyl, halogen and C
1-6 alkoxy,
R
2 is selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, optionally substituted amino, and -CH
2OCONR
5R
5,
R
5 is independently selected from H and C
1-6 alkyl, and R
5 and R
5 are optionally taken together with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocycle,
R
6 is independently selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, optionally substituted amino, C
2-6 alkenyl, C
2-6 alkynyl and C
3-6 cycloalkyl,
is selected from
R
7 is independently selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, optionally substituted amino, C
2-6 alkenyl, C
2-6 alkynyl and C
3-6 cycloalkyl, and
Aspect 11: In the compounds of Aspect 10, R
1 is selected from H, C
1-6 alkyl and halogen. In the compounds of Aspect 10, R
1 is H or F. In the compounds of Aspect 10, R
1 is H. In the compounds of Aspect 10, R
1 is C
1-6 alkyl, preferably C
1-3 alkyl. In the compounds of Aspect 10, R
1 is halogen, preferably, F.
Aspect 12: In the compounds of Aspect 10 or 11, R
2 is selected from H, C
1-6 alkyl, halogen, and -CH
2OCONR
5R
5, and R
5 is independently selected from H and C
1-6 alkyl. In the compounds of Aspect 10 or 11, R
2 is selected from H, C
1-3 alkyl, and -CH
2OCONR
5R
5, and R
5 is independently selected from H and C
1-3 alkyl, preferably, R
2 is H or -CH
2OCON (CH
3)
2. In the compounds of Aspect 10 or 11, R
2 is H. In the compounds of Aspect 10 or 11, R
2 is -CH
2OCON (CH
3)
2.
Aspect 13: In the compounds of any of Aspects 10-12,
is selected from
wherein R
6 is selected from H, C
1-6 alkyl, halogen, C
1-6 haloalkyl, and C
3-6 cycloalkyl. In the compounds of any of Aspects 10-12,
is selected from
wherein R
6 is selected from H, C
1-6 alkyl, halogen, C
1-3 haloalkyl, and C
3 cycloalkyl. In the compounds of any of Aspects 10-12,
is
In the compounds of any of Aspects 10-12,
is
In the compounds of any of Aspects 10-12,
is
In the compounds of any of Aspects 10-12,
is
wherein R
6 is selected from H, C
1-6 alkyl, halogen, C
1-3 haloalkyl, and C
3 cycloalkyl. In the compounds of any of Aspects 10-12,
is
wherein R
6 is C
3 cycloalkyl.
Aspect 14: In the compounds of any of Aspects 10-13,
is selected from
R
7 is selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, optionally substituted amino, C
2-6 alkenyl, C
2-6 alkynyl and C
3-6 cycloalkyl. In the compounds of any of Aspects 10-13,
is selected from
R
7 is selected from H, C
1-6 alkyl and halogen. In the compounds of any of Aspects 10-13,
is selected from
R
7 is H.
Aspect 15: Provided herein is a compound of the formula I-2, a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein R
1 is selected from H, C
1-6 alkyl, halogen and C
1-6 alkoxy,
R
2 is selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, optionally substituted amino, and -CH
2OCONR
5R
5,
R
5 is independently selected from H and C
1-6 alkyl, and R
5 and R
5 are taken together with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocycle,
R
3 and R
4 are independently selected from H, C
1-6 alkyl, halogen, -CN, C
1-6 alkoxy, optionally substituted amino and C
2-6 alkenyl,
R
6 is independently selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, C
1-6 haloalkyl, optionally substituted amino, C
2-6 alkenyl, C
2-6 alkynyl and C
3-6 cycloalkyl,
is selected from
R
7 is independently selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, optionally substituted amino, C
2-6 alkenyl, C
2-6 alkynyl and C
3-6 cycloalkyl, and
Aspect 16: In the compounds of Aspect 15, R
1 is selected from H, C
1-6 alkyl and halogen. In the compounds of Aspect 15, R
1 is selected from H, C
1-3 alkyl and F. In the compounds of Aspect 15, R
1 is H.
Aspect 17: In the compounds of Aspect 15 or 16, R
2 is selected from H, C
1-6 alkyl, halogen, and -CH
2OCONR
5R
5, and R
5 is independently selected from H and C
1-6 alkyl.
In the compounds of Aspect 15 or 16, R
2 is selected from H, C
1-3 alkyl, and -CH
2OCONR
5R
5, and R
5 is independently selected from H and C
1-3 alkyl. In the compounds of Aspect 15 or 16, R
2 is selected from H and C
1-3 alkyl. In the compounds of Aspect 15 or 16, R
2 is H. In the compounds of Aspect 15 or 16, R
2 is -CH
2OCONR
5R
5, and R
5 is independently selected from H and C
1-3 alkyl. In the compounds of Aspect 15 or 16, R
2 is -CH
2OCON (CH
3)
2.
Aspect 18: In the compounds of any of Aspects 15-17, R
3 and R
4 are independently selected from H, C
1-6 alkyl, halogen, -CN, C
1-6 alkoxy, and C
2-6 alkenyl. In the compounds of any of Aspects 15-17, R
3 and R
4 are independently selected from H, C
1-
6 alkyl and halogen. In the compounds of any of Aspects 15-17, R
3 is selected from H and C
1-6 alkyl, and R
4 is selected from H and C
1-6 alkyl. In the compounds of any of Aspects 15-17, R
3 is H, and R
4 is H.
Aspect 19: In the compounds of any of Aspects 15-18,
is selected from
wherein R
6 is selected from H, C
1-6 alkyl, halogen, C
1-6 haloalkyl, and C
3-6 cycloalkyl. In the compounds of any of Aspects 15-18,
is selected from
wherein R
6 is C
3 cycloalkyl. In the compounds of any of Aspects 15-18,
is
In the compounds of any of Aspects 15-18,
is
In the compounds of any of Aspects 15-18,
is
wherein R
6 is C
3 cycloalkyl.
Aspect 20: In the compounds of any of Aspects 15-19,
is selected from
R
7 is selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, optionally substituted amino, C
2-6 alkenyl, C
2-6 alkynyl and C
3-6 cycloalkyl. In the compounds of any of Aspects 15-19,
is selected from
R
7 is selected from H, C
1-6 alkyl and halogen. In the compounds of any of Aspects 15-19,
is selected from
R
7 is selected from H and C
1-6 alkyl. In the compounds of any of Aspects 15-19,
is selected from
R
7 is selected from H and C
1-3 alkyl. In the compounds of any of Aspects 15-19,
is selected from
R
7 is H.
Aspect 21: Provided herein is a compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein:
R
1 is selected from H, C
1-6 alkyl, halogen and C
1-6 alkoxy,
R
2 is selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, optionally substituted amino and - (CH
2)
nOCONR
5R
5, n is an integer from 0 to 8,
R
5 is independently selected from H and C
1-6 alkyl, wherein R
5 and R
5 are optionally taken together with the nitrogen atom to which they are attached to form a 3-to 10-membered heterocycle,
R
3 and R
4 are independently selected from H, C
1-6 alkyl, halogen, -CN, C
1-6 alkoxy, optionally substituted amino and C
2-6 alkenyl,
R
6 is independently selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, optionally substituted amino, C
2-6 alkenyl, C
2-6 alkynyl and C
3-6 cycloalkyl,
is selected from
R
7 is independently selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, optionally substituted amino, C
2-6 alkenyl, C
2-6 alkynyl and C
3-6 cycloalkyl, and
Aspect 22: In the compounds of Aspect 21, R
1 is selected from H, C
1-6 alkyl, and halogen. In the compounds of Aspect 21, R
1 is selected from H, and halogen. In the compounds of Aspect 21, R
1 is selected from H, C
1-6 alkyl, F, Cl and Br. In the compounds of Aspect 21, R
1 is selected from H, C
1-3 alkyl, F and Cl. In the compounds of Aspect 21, R
1 is H. In the compounds of Aspect 21, R
1 is F.
Aspect 23: In the compounds of Aspect 21 or 22, R
2 is selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, and - (CH
2)
nOCONR
5R
5, n is an integer from 0 to 6, R
5 is independently selected from H, C
1-6 alkyl, and halogen substituted C
1-6 alkyl. In the compounds of Aspect 21 or 22, R
2 is selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, and - (CH
2)
nOCONR
5R
5, n is an integer from 0 to 4, R
5 is independently selected from H, C
1-6 alkyl, and halogen substituted C
1-6 alkyl. In the compounds of Aspect 21 or 22, R
2 is selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, and - (CH
2)
nOCONR
5R
5, n is an integer from 0 to 3, R
5 is independently selected from H, C
1-6 alkyl, and halogen substituted C
1-6 alkyl. In the compounds of Aspect 21 or 22, R
2 is selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, and - (CH
2)
nOCONR
5R
5, n is an integer from 0 to 2, R
5 is independently selected from H, C
1-6 alkyl, and halogen substituted C
1-6 alkyl. In the compounds of Aspect 21 or 22, R
2 is selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, and - (CH
2)
nOCONR
5R
5, n is 0 or 1, R
5 is independently selected from H, C
1-6 alkyl, and halogen substituted C
1-6 alkyl. In the compounds of Aspect 21 or 22, R
2 is selected from H, C
1-6 alkyl, halogen, and -OCONR
5R
5, R
5 is independently selected from H, C
1-
6 alkyl, and halogen substituted C
1-6 alkyl. In the compounds of Aspect 21 or 22, R
2 is selected from H, C
1-6 alkyl, halogen, and -CH
2OCONR
5R
5, R
5 is independently selected from H, C
1-6 alkyl, and halogen substituted C
1-6 alkyl. In the compounds of Aspect 21 or 22, R
2 is selected from H, C
1-6 alkyl, halogen, and -CH
2OCONR
5R
5, R
5 is independently selected from H, C
1-6 alkyl, and halogen substituted C
1-6 alkyl. In the compounds of Aspect 21 or 22, R
2 is selected from H, C
1-6 alkyl, halogen, and -CH
2OCONR
5R
5, R
5 is independently selected from H, and C
1-6 alkyl. In the compounds of Aspect 21 or 22, R
2 is selected from H, C
1-6 alkyl, halogen, and -CH
2OCONR
5R
5, R
5 is independently selected from H, and C
1-3 alkyl. In the compounds of Aspect 21 or 22, R
2 is selected from H, C
1-6 alkyl, halogen, and -CH
2OCONR
5R
5, R
5 is independently selected from C
1-3 alkyl. In the compounds of Aspect 21 or 22, R
2 is selected from H, C
1-6 alkyl, halogen, and -CH
2OCONR
5R
5, R
5 is independently selected from C
1-3 alkyl. In the compounds of Aspect 21 or 22, R
2 is selected from H, C
1-6 alkyl, halogen, and -CH
2OCONR
5R
5, R
5 is methyl. In the compounds of Aspect 21 or 22, R
2 is selected from H, C
1-6 alkyl, and -CH
2OCONR
5R
5, R
5 is methyl. In the compounds of Aspect 21 or 22, R
2 is selected from H, C
1-3 alkyl, and -CH
2OCONR
5R
5, R
5 is methyl. In the compounds of Aspect 21 or 22, R
2 is selected from H, C
1-6 alkyl and halogen. In the compounds of Aspect 21 or 22, R
2 is selected from H and C
1-6 alkyl. In the compounds of Aspect 21 or 22, R
2 is selected from H and C
1-3 alkyl. In the compounds of Aspect 21 or 22, R
2 is H. In the compounds of Aspect 21 or 22, R
2 is -CH
2OCONR
5R
5, R
5 is methyl.
Aspect 24: In the compounds of any of Aspects 21-23, R
3 and R
4 are independently selected from H, C
1-6 alkyl, halogen, and C
1-6 alkoxy. In the compounds of any of Aspects 21-23, R
3 and R
4 are independently selected from –CN. In the compounds of any of Aspects 21-23, R
3 and R
4 are independently selected from C
2-6 alkenyl. In the compounds of any of Aspects 21-23, R
3 and R
4 are independently selected from H, C
1-
6 alkyl, and halogen. In the compounds of any of Aspects 21-23, R
3 and R
4 are independently selected from H, C
1-6 alkyl, F, Cl and Br. In the compounds of any of Aspects 21-23, R
3 and R
4 are independently selected from H, C
1-3 alkyl, F, Cl and Br. In the compounds of any of Aspects 21-23, R
3 and R
4 are independently selected from H, C
1-3 alkyl, F and Cl. In the compounds of any of Aspects 21-23, R
3 and R
4 are independently selected from H, F and Cl. In the compounds of any of Aspects 21-23, R
3 is F, and R
4 is F. In the compounds of any of Aspects 21-23, R
3 is Cl, and R
4 is F. In the compounds of any of Aspects 21-23, R
3 is H, and R
4 is F.
Aspect 25: In the compounds of any of Aspects 21-24,
is selected from
R
6 is independently selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, and C
3-6 cycloalkyl. In the compounds of any of Aspects 21-24,
is selected from
In the compounds of any of Aspects 21-24,
is selected from
In the compounds of any of Aspects 21-24,
is selected from
In the compounds of any of Aspects 21-24,
is
In the compounds of any of Aspects 21-24,
is
In the compounds of any of Aspects 21-24,
is
In the compounds of any of Aspects 21-24,
is selected from
R
6 is independently selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, and C
3-6 cycloalkyl. In the compounds of any of Aspects 21-24,
is selected from
R
6 is selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, and C
3-6 cycloalkyl. In the compounds of any of Aspects 21-24,
is selected from
R
6 is selected from H, C
1-6 alkyl, halogen, and C
3-6 cycloalkyl. In the compounds of any of Aspects 21-24,
is selected from
R
6 is selected from H, C
1-6 alkyl and halogen. In the compounds of any of Aspects 21-24,
is selected from
R
6 is selected from C
3-6 cycloalkyl. In the compounds of any of Aspects 21-24,
is selected from
R
6 is C
3 cycloalkyl. In the compounds of any of Aspects 21-24,
is selected from
R
6 is independently selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, and C
3-6 cycloalkyl. In the compounds of any of Aspects 21-24,
is selected from
R
6 is independently selected from H, C
1-6 alkyl, halogen, and C
3-6 cycloalkyl. In the compounds of any of Aspects 21-24,
is selected from
R
6 is selected from H, C
1-6 alkyl, and halogen. In the compounds of any of Aspects 21-24,
is selected from
R
6 is selected from C
3-6 cycloalkyl. In the compounds of any of Aspects 21-24,
is selected from
R
6 is C
3 cycloalkyl. In the compounds of any of Aspects 21-24,
is selected from
R
6 is independently selected from H, C
1-6 alkyl, halogen, halogen substituted C
1-6 alkyl, C
1-6 alkoxy, and C
3-6 cycloalkyl. In the compounds of any of Aspects 21-24,
is selected from
R
6 is independently selected from H, C
1-6 alkyl, halogen, halogen substituted C
1-6 alkyl, C
1-6 alkoxy, and C
3-6 cycloalkyl. In the compounds of any of Aspects 21-24,
is selected from
R
6 is independently selected from H, C
1-6 alkyl, halogen, halogen substituted C
1-6 alkyl, and C
1-6 alkoxy. In the compounds of any of Aspects 21-24,
is selected from
R
6 is independently selected from H, C
1-6 alkyl, halogen, and halogen substituted C
1-6 alkyl. In the compounds of any of Aspects 21-24,
is selected from
R
6 is independently selected from H, C
1-6 alkyl, and halogen substituted C
1-6 alkyl. In the compounds of any of Aspects 21-24,
is selected from
R
6 is independently selected from H, C
1-3 alkyl, and halogen substituted C
1-3 alkyl. In the compounds of any of Aspects 21-24,
is selected from
R
6 is independently selected from C
1-3 alkyl, and C
1-3 alkyl substituted with F. In the compounds of any of Aspects 21-24,
is selected from
one R
6 is selected from C
1-3 alkyl, and the other R
6 is selected from C
1-3 alkyl substituted with F. In the compounds of any of Aspects 21-24,
is selected from
one R
6 is selected from C
1-3 alkyl, and the other R
6 is –CF
3. In the compounds of any of Aspects 21-24,
is selected from
one R
6 is –CH
3, and the other R
6 is –CF
3. In the compounds of any of Aspects 21-24,
is selected from
R
6 is independently selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, and C
3-6 cycloalkyl. In the compounds of any of Aspects 21-24,
is selected from
R
6 is independently selected from H, C
1-6 alkyl, and halogen. In the compounds of any of Aspects 21-24,
is selected from
R
6 is independently selected from H, C
1-3 alkyl, and halogen. In the compounds of any of Aspects 21-24,
is selected from
R
6 is independently selected from H, C
1-3 alkyl, and halogen. In the compounds of any of Aspects 21-24,
is selected from
R
6 is independently selected from H, C
1-3 alkyl, F and Cl. In the compounds of any of Aspects 21-24,
is selected from
R
6 is independently selected from C
1-3 alkyl, F and Cl. In the compounds of any of Aspects 21-24,
is selected from
R
6 is independently selected from F and Cl. In the compounds of any of Aspects 21-24,
is
In the compounds of any of Aspects 21-24,
is selected from
R
7 is independently selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, C
2-6 alkenyl, C
2-6 alkynyl and C
3-6 cycloalkyl. In the compounds of any of Aspects 21-24,
is selected from
R
7 is independently selected from H, C
1-6 alkyl, halogen, and C
3-6 cycloalkyl. In the compounds of any of Aspects 21-24,
is selected from
R
7 is independently selected from H, C
1-6 alkyl and halogen. In the compounds of any of Aspects 21-24,
is selected from
R
7 is independently selected from H, C
1-
3 alkyl and halogen. In the compounds of any of Aspects 21-24,
is
R
7 is independently selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, C
2-6 alkenyl, C
2-6 alkynyl and C
3-6 cycloalkyl. In the compounds of any of Aspects 21-24,
is
R
7 is independently selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, and C
3-6 cycloalkyl. In the compounds of any of Aspects 21-24,
is
R
7 is independently selected from H, C
1-6 alkyl, halogen, and C
3-6 cycloalkyl. In the compounds of any of Aspects 21-24,
is
R
7 is independently selected from H, C
1-6 alkyl, and halogen. In the compounds of any of Aspects 21-24,
is
R
7 is independently selected from H, C
1-3 alkyl, and halogen. In the compounds of any of Aspects 21-24,
is
R
7 is selected from H, C
1-3 alkyl, F, Cl and Br. In the compounds of any of Aspects 21-24,
is
R
7 is selected from H, C
1-3 alkyl, F and Cl. In the compounds of any of Aspects 21-24,
is
R
7 is selected from H, and C
1-3 alkyl. In the compounds of any of Aspects 21-24,
is
R
7 is selected from H, methyl, elthyl and propyl. In the compounds of any of Aspects 21-24,
is
R
7 is selected from H, and methyl. In the compounds of any of Aspects 21-24,
is
R
7 is H.
Aspect 26: In the compounds of Aspect 21, wherein R
1 is selected from H, C
1-6 alkyl, and halogen, R
2 is selected from H, C
1-6 alkyl and halogen, R
3 and R
4 are independently selected from H, C
1-6 alkyl and halogen,
is selected from
is selected from
R
7 is independently selected from H, C
1-3 alkyl and halogen, and
denotes a connection site.
Aspect 30: In the compounds of Aspect 26, wherein R
1 is F, R
2 is H, R
3 is F, R
4 is H or F,
is
R
7 is H, and
denotes a connection site.
Aspect 31: In the compounds of Aspect 26, wherein R
1 is F, R
2 is H, R
3 is F, R
4 is H or F,
is
is selected from
R
7 is independently selected from H, and
denotes a connection site.
Aspect 33: In the compounds of Aspect 21, wherein R
1 is selected from H, C
1-6 alkyl, and halogen, R
2 is selected from - (CH
2)
nOCONR
5R
5, n is an integer from 0 to 4, R
5 is independently selected from H and C
1-6 alkyl, wherein R
5 and R
5 are optionally taken together with the nitrogen atom to which they are attached to form a 3-to 6-membered heterocycle, R
3 and R
4 are independently selected from H, C
1-6 alkyl and halogen,
is
is selected from
R
7 is independently selected from H, C
1-3 alkyl and halogen, and
denotes a connection site.
Aspect 34: In the compounds of Aspect 33, wherein R
1 is selected from H, C
1-3 alkyl, and F, preferably R
1 is H, R
2 is selected from - (CH
2)
nOCONR
5R
5, n is an integer from 1 to 2, R
5 is independently selected from H and C
1-3 alkyl, wherein R
5 and R
5 are optionally taken together with the nitrogen atom to which they are attached to form a 3-to 6-membered heterocycle, R
3 and R
4 are independently selected from H, C
1-3 alkyl and F, preferably R
3 and R
4 are independently F,
is
is selected from
R
7 is independently selected from H, and
denotes a connection site.
Aspect 35: In the compounds of Aspect 32 or 33, wherein R
2 is selected from -CH
2OCONR
5R
5, each of R
5 is independently selected from H and C
1-3 alkyl, preferably, each of R
5 is -CH
3.
Aspect 36: In the compounds of Aspect 32 or 33, wherein R
2 is selected from -CH
2OCONR
5R
5, wherein R
5 and R
5 are taken together with the nitrogen atom to which they are attached to form a 3-to 6-membered heterocycle.
Aspect 37: In the compounds of Aspect 36, wherein R
2 is selected from -CH
2OCONR
5R
5, wherein R
5 and R
5 are taken together with the nitrogen atom to which they are attached to form
Aspect 38: In the compounds of any of Aspects 32-36, wherein
is
R
7 is H. Aspect 39: Provided herein is a compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein:
R
1 is selected from H, C
1-6 alkyl, and halogen,
R
2 is selected from H, C
1-6 alkyl, halogen, and -CH
2OCONR
5R
5,
R
5 is independently selected from H and C
1-6 alkyl,
R
3 is selected from H, C
1-6 alkyl, halogen, -N (CH
3)
2, and –O-C
3-6 cycloalkyl,
R
4 is selected from H, C
1-6 alkyl, halogen, -CN, -N (CH
3)
2, C
2-6 alkenyl and –O-C
3-6 cycloalkyl,
is selected from
R
7 is independently selected from H, C
1-6 alkyl, and halogen, and
Aspect 40: Provided herein is a compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein:
R
1 is selected from H, C
1-6 alkyl, and halogen, preferably is H,
R
2 is selected from H, C
1-6 alkyl, halogen, and -CH
2OCONR
5R
5,
R
5 is independently selected from H and C
1-6 alkyl,
R
3 is selected from halogen, preferably is F,
R
4 is selected from H, C
1-6 alkyl, halogen, -CN, -N (CH
3)
2, C
2-6 alkenyl and –O-C
3-6 cycloalkyl,
is selected from
is selected from
R
7 is independently selected from H, C
1-6 alkyl, and halogen, and
Aspect 41: Provided herein is a compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein:
R
1 is selected from H,
R
2 is selected from H, and -CH
2OCON (CH
3)
2,
R
3 is selected from halogen, preferably is F,
R
4 is selected from H, C
1-3 alkyl, and halogen,
R
7 is independently selected from H, C
1-3 alkyl, and halogen, and
Aspect 42: Provided herein is a compound of the formula I-4, a pharmaceutically acceptable salt thereof or a stereoisomer thereof,
wherein R
1 is selected from H, C
1-6 alkyl, halogen and C
1-6 alkoxy,
R
2 is selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, optionally substituted amino, and -CH
2OCONR
5R
5,
R
5 is independently selected from H and C
1-6 alkyl, and R
5 and R
5 are taken together with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocycle,
R
3 is selected from H, C
1-6 alkyl, halogen, -CN, C
1-6 alkoxy, optionally substituted amino and C
2-6 alkenyl,
R
6 is independently selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, C
1-6 haloalkyl, optionally substituted amino, C
2-6 alkenyl, C
2-6 alkynyl and C
3-6 cycloalkyl,
is selected from
R
7 is independently selected from H, C
1-6 alkyl, halogen, C
1-6 alkoxy, optionally substituted amino, C
2-6 alkenyl, C
2-6 alkynyl and C
3-6 cycloalkyl,
R
8 is selected from halogen, -CO
2R
9, -CONR
9R
9, -CN, C
1-3 alkyl, C
1-3 hydroxyalkyl and 3-6 membered heteroaryl,
R
9 is independently selected from H and C
1-6 alkyl, and
Aspect 43: In the compounds of Aspect 42, wherein R
1 is selected from H, C
1-3 alkyl, and halogen, R
2 is selected from H, C
1-3 alkyl, halogen and -CH
2OCONR
5R
5, R
5 is independently selected from H and C
1-3 alkyl, wherein R
5 and R
5 are optionally taken together with the nitrogen atom to which they are attached to form a 4-to 6-membered heterocycle, R
3 is selected from H, C
1-6 alkyl and halogen,
is selected from
is selected from
R
7 is independently selected from H, C
1-6 alkyl and halogen, R
8 is selected from hydrogen, halogen and C
1-3 alkyl, and
denotes a connection site.
The invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention also encompasses all combinations of alternative aspects of the invention noted herein. It is understood that any and all Aspects of the present invention may be taken in conjunction with any other Aspect to describe additional embodiments of the present invention. Furthermore, any elements (including individual variable definitions) of an Aspect are meant to be combined with any and all other elements from any of the Aspects to describe additional aspects. For example, in preferred embodiments of Aspect 21, R
1 is selected from H, and C
1-3 alkyl, R
2 is selected from H, C
1-3 alkyl and -CH
2OCON (CH
3)
2, R
3 and R
4 are independently selected from H, F and Cl,
is selected from
is
R
7 is H.
Nonlimiting examples of the compounds of formula I are selected from the group consisting of:
, a pharmaceutically acceptable salt thereof or stereoisomer thereof.
Aspect 45: there is provided a pharmaceutical composition which comprises a compound of formula I (including formulas I-1 to I-4) , a pharmaceutically acceptable salt thereof or stereoisomer thereof and one or more pharmaceutically acceptable excipients.
Aspect 46: there is provided a method of treating various disorders, comprising administering a subject in need thereof a compound of formula I (including formulas I-1 to I-4) , a pharmaceutically acceptable salt thereof or stereoisomer thereof.
Aspect47: there is provided the use of a compound of formula I (including formulas I-1 to I-4) , a pharmaceutically acceptable salt thereof or a stereoisomer thereof, in the manufacture of a medicament for the treatment of diseases or conditions associated with KRAS G12D activity.
Aspect 48: there is provided a method for making a compound of formula I (including formulas I-1 to I-4) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.
Aspect 49: there is provided a method for separating atropisomers of the compound according to the present invention, wherein the method comprises the following steps: i) providing atropisomers of the compound according to the present invention;
ii) using HPLC method and SFC method sequentially to separate the atropisomers to obtain atropisomer 1 and atropisomer 2.
Aspect 50: in the method of Aspect 49, wherein the HPLC method is conducted under the following conditions: Column Pursuit XRs C18 (4.6*250mm, 5.0 μm) ; eluent A: 0.02%TFA in H2O; eluent B: 0.02%TFA in CAN; gradient: 10%B to 95%B in 10 min, 95%B from 10 to 12 min, then 10%B in 13 min, 10%B from 13-20 min at a flow rate of 1.2 mL/min, 220 &254 nM.
Aspect 51: in the method of Aspect 49 or 50, wherein the SFC method is conducted under the following conditions: column: CHIRAL ART Cellulose-SZ 3cm × 25cm, 5um; mobile phase: CO2: [MeOH: DCM = 1: 1 (0.2%2mM NH3 MeOH) ] = 55: 45; flow rate: 80 mL/min.
Aspect 52: in the method of any of Aspect 49-51, wherein the compound is Example 39.
DEFINITIONS
Unless specifically stated otherwise herein, references made in the singular may also include the plural. For example, “a” and “an” may refer to either one, or one or more.
Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences. Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.
The indication of the number of members in groups that contain one or more heteroatom (s) (e.g. heteroaryl, heteroarylalkyl, heterocyclyl, heterocycylalkyl) relates to the total number of atoms of all the ring members or the total of all the ring and carbon chain members.
The indication of the number of carbon atoms in groups that consist of a combination of carbon chain and carbon ring structure (e.g. cycloalkylalkyl, arylalkyl) relates to the total number of carbon atoms of all the carbon ring and carbon chain members. Obviously, a ring structure has at least three members.
In general, for groups comprising two or more subgroups (e.g. heteroarylalkyl, heterocycylalkyl, cycloalkylalkyl, arylalkyl) the last named subgroup is the radical attachment point, for example, the substituent aryl-C
1-6alkyl means an aryl group which is bound to a C
1-6alkyl group, the latter of which is bound to the core or to the group to which the substituent is attached.
Alkyl denotes monovalent, saturated hydrocarbon chains, which may be present in both straight-chain (unbranched) and branched form. If an alkyl is substituted, the substitution may take place independently of one another, by mono-or polysubstitution in each case, on all the hydrogen-carrying carbon atoms.
As used herein, the term “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, “C
1-C
6 alkyl” denotes alkyl having 1 to 6 carbon atoms. Example alkyl groups include, but are not limited to, methyl (Me) , ethyl (Et) , propyl (e.g., n-propyl and isopropyl) , butyl (e.g., n-butyl, isobutyl, t-butyl) , pentyl (e.g., n-pentyl, isopentyl, neopentyl) , and hexyl (e.g., n-hexyl, isohexyl, t-hexyl) .
By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl etc. without any further definition are meant saturated hydrocarbon groups with the corresponding number of carbon atoms, wherein all isomeric forms are included.
The above definition for alkyl also applies if alkyl is a part of another (combined) group such as for example C
x-yalkylamino or C
x-yalkyloxy.
Halogen relates to fluorine, chlorine, bromine and/or iodine atoms.
Cycloalkyl is made up of the subgroups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spiro-hydrocarbon rings. The systems are saturated. In bicyclic hydrocarbon rings two rings are joined together so that they have at least two carbon atoms in common. In spiro-hydrocarbon rings one carbon atom (spiroatom) belongs to two rings together.
If a cycloalkyl is to be substituted, the substitutions may take place independently of one another, in the form of mono-or polysubstitutions in each case, on all the hydrogen-carrying carbon atoms. Cycloalkyl itself may be linked as a substituent to the molecule via every suitable position of the ring system.
Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.0] hexyl, bicyclo [3.2.0] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octyl, bicyclo [4.3.0] nonyl (octahydroindenyl) , bicyclo [4.4.0] decyl (decahydronaphthyl) , bicyclo [2.2.1] heptyl (norbornyl) , bicyclo [4.1.0] heptyl (norcaranyl) , bicyclo [3.1.1] heptyl (pinanyl) , spiro [2.5] octyl, spiro [3.3] heptyl etc.
The above definition for cycloalkyl also applies if cycloalkyl is part of another (combined) group as for example in C
x-ycycloalkylamino, C
x-ycycloalkyloxy or C
x-ycycloalkylalkyl.
If the free valency of a cycloalkyl is saturated, then an alicyclic group is obtained.
"Alkenyl" is intended to include hydrocarbon chains of either straight or branched configuration having the specified number of carbon atoms and one or more, preferably one to two, carbon-carbon double bonds that may occur in any stable point along the chain. For example, "C
2 to C
6 alkenyl" or "C
2-6 alkenyl" (or alkenylene) , is intended to include C
2, C
3, C
4, C
5, and C
6 alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl.
"Alkynyl" is intended to include hydrocarbon chains of either straight or branched configuration having one or more, preferably one to three, carbon-carbon triple bonds that may occur in any stable point along the chain. For example, "C
2 to C
6 alkynyl" or "C
2-6 alkynyl" (or alkynylene) , is intended to include C
2, C
3, C
4, C
5, and C
6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.
The term “alkoxy” or “alkyloxy” refers to an –O-alkyl group. “C
1-6 alkoxy” (or alkyloxy) , is intended to include C
1, C
2, C
3, C
4, C
5, and C
6 alkoxy groups. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy) , and t-butoxy.
As referred to herein, the term “substituted” means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that normal valencies are maintained and that the substitution results in a stable compound. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N) .
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom in which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a substituent is noted as “optionally substituted” , the substituents are selected from, for example, substituents such as alkyl, cycloalkyl, aryl, heterocyclo, halo, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or arylalkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, arylalkylthio, alkylthiono, arylthiono, arylalkylthiono, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, sulfonamido, e.g. -SO
2NH
2, substituted sulfonamido, nitro, cyano, carboxy, carbamyl, e.g. -CONH
2, substituted carbamyl e.g. -CONHalkyl, -CONHaryl, -CONHarylalkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or arylalkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclyl, e.g., indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl and the like, and substituted heterocyclyl, unless otherwise defined.
For purposes of clarity, where a substituent has a dash (-) that is not between two letters or symbols; this is used to indicate a point of attachment for a substituent. For example, -CONH
2 is attached through the carbon atom.
Additionally, for purposes of clarity, when there is no substituent shown at the end of a solid line, this indicates that there is a methyl (CH
3) group connected to the bond.
Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof where such isomers exist. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Many geometric isomers of C=C double bonds, C=N double bonds, ring systems, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Cis-and trans- (or E-and Z-) geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. The present compounds can be isolated in optically active or racemic forms. Optically active forms may be prepared by resolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, for example, by chromatography or fractional crystallization. Depending on the process conditions the end products of the present invention are obtained either in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the invention. If so desired, one form of a compound may be converted into another form. A free base or acid may be converted into a salt; a salt may be converted into the free compound or another salt; a mixture of isomeric compounds of the present invention may be separated into the individual isomers. Compounds of the present invention, free form and salts thereof, may exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention.
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 configuration isomers. The configuration isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers.
As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington: The Science and Practice of Pharmacy,
22nd Edition, Allen, L.V. Jr., Ed. ; Pharmaceutical Press, London, UK (2012) , the disclosure of which is hereby incorporated by reference.
For therapeutic use, salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
"Treating" , "treat" or "treatment" or "alleviation" refers to administering at least one compound and /or at least one stereoisomer thereof, and /or at least one pharmaceutically acceptable salt thereof disclosed herein to a subject in recognized need thereof that has, for example, cancer.
The term "therapeutically effective amount" refers to an amount of at least one compound and /or at least one stereoisomer thereof, and /or at least one pharmaceutically acceptable salt thereof disclosed herein effective to "treat" as defined above, a disease or disorder in a subject.
As used herein, “cancer” refers to or describes the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia.
As used herein, the term “inhibitor” refers to biological or chemical substance that interferes with or otherwise reduces the physiological and/or biochemical action of another biological or chemical molecule. In some embodiments, the inhibitor or antagonist specifically binds to the other molecule.
A “subject, ” “patient” or “individual” includes a mammal, such as a human or other animal, and typically is human. In some embodiments, the subject, e.g., patient, to whom the therapeutic agents and compositions are administered, is a mammal, typically a primate, such as a human. In some embodiments, the primate is a monkey or an ape. The subject can be male or female and can be any suitable age, including infant, juvenile, adolescent, adult, and geriatric subjects. In some embodiments, the subject is a non-primate mammal, such as a rodent, a dog, a cat, a farm animal, such as a cow or a horse, etc.
METHODS OF PREPARATION
The compounds in the present invention can be synthesized in a number of ways well to one skilled in the art of organic synthesis described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods are not limited as those described below. The references cited here are incorporated by reference in their entirety.
The methods of synthesis described hereinafter are intended as an illustration of the invention, without restricting its subject matter and the scope of the compounds claimed to these examples. Where the preparation of starting compounds is not described, they are commercially obtainable or may be prepared analogously to known compounds or methods described herein. Substances described in the literature are prepared according to the published methods of synthesis. Compounds of formula I may be synthesized by reference to methods illustrated in the following schemes. As shown herein, the end compound is a product having the same structural formula depicted as formula I. It will be understood that any compound of formula I may be prepared by the selection of reagents with appropriate substitution. Solvents, temperature, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M. Wuts (1999) Protective Groups in Organic Synthesis, 3
rd edition, John Wiley &Sons) . These groups are removed at certain stage of the compound synthesis using the methods that are apparent to those skilled in the art.
Compounds of Formula I may be prepared by reference to the methods illustrated in the following Schemes. As shown therein the end product is a compound having the same structural formula as Formula I. It will be understood that any compound of Formula I may be produced by the schemes by the suitable selection of reagents with appropriate substitution. Solvents, temperatures, pressures, and other reaction conditions may readily be selected by one of ordinary skill in the art. Starting materials are commercially available or readily prepared by one of ordinary skill in the art. Constituents of compounds are as defined herein or elsewhere in the specification.
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
EXAMPLES
The invention is further defined in the following Examples. It should be understood that the Examples are given by way of illustration only. From the above discussion and the Examples, one skilled in the art can ascertain the essential characteristics of the invention, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt the invention to various uses and conditions. As a result, the invention is not limited by the illustrative examples set forth herein below, but rather is defined by the claims appended hereto. Although only some of the Example compounds are specifically synthesized as below, the other Example compounds can be synthesized similarly, which is obvious to one skilled in the art.
The following table shows the part abbreviation of the present invention:
Intermediate preparation
Unless otherwise stated, starting materials for the preparation of intermediates and Examples are commercially available.
Intermediate-1
( (2-Fluoro-6- (methoxymethoxy) -8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane
Step 1: 5- (2- (4-Fluorophenyl) acetyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione
To a solution of 2- (4-fluorophenyl) acetic acid (30.0 g, 0.19 mol) , Meldrum's acid (30.8 g, 0.21 mol) , DMAP (2.0 g, 16.5 mmol) in CH
3CN (90 mL) was added DIPEA (54.1 g, 0.42 mol) while maintaining the temperature below 45 ℃, then pivaloyl chloride (25.8 g, 0.21 mol) was slowly added over 0.3 h while maintaining the temperature below 45 ℃. The resulting solution was stirred at 45 ℃ for 3 h. The mixture was cooled to 0 ℃, then aq. HCl (1 M, 300 mL) was slowly added, and the resulting solution was stirred at 0 ℃ for 2 h. The mixture was filtered. And the cake was dried to give the title product (45.0 g, 82.5%yield) as a white solid.
1H NMR (400 MHz, DMSO-d
6) δ 15.50 (s, 1H) , 7.44 -7.31 (m, 2H) , 7.16 (t, J = 8.8 Hz, 2H) , 4.37 (s, 2H) , 1.70 (s, 6H) .
Step 2: Tert-butyl 4- (4-fluorophenyl) -3-oxobutanoate
A solution of 5- (2- (4-fluorophenyl) acetyl) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (45.0 g) in t-BuOH (140 mL) was stirred at 90 ℃ for 2 h. The mixture was concentrated to give the crude product. The solid was slurred in petroleum ether (35 mL) , the mixture was filtered. The cake was dried to give the title product (37.5 g, 92.5%yield) as a light-yellow solid.
1H NMR (400 MHz, DMSO-d
6) δ 7.25 -7.18 (m, 2H) , 7.14 (t, J = 8.9 Hz, 2H) , 3.86 (s, 2H) , 3.55 (s, 2H) , 1.40 (s, 9H) .
Step 3: 4- (4-Fluorophenyl) -3-oxobutanoic acid
To a solution of tert-butyl 4- (4-fluorophenyl) -3-oxobutanoate (37.5 g, 0.15 mol) in DCM (80 mL) was added TFA (80 mL) , the mixture was stirred at 20 ℃ for 1 h. The mixture was concentrated to dryness. The residue was slurred in petroleum ether (50 mL) , then the mixture was filtered. The cake was dried to give the title product (26.0 g, 89.1%yield) as a white solid.
1H NMR (400 MHz, DMSO-d
6) δ 7.22 (dd, J = 8.3, 5.9 Hz, 2H) , 7.14 (t, J = 8.8 Hz, 2H) , 3.89 (s, 2H) , 3.55 (s, 2H) .
Step 4: 7-Fluoronaphthalene-1, 3-diol
A solution of 4- (4-fluorophenyl) -3-oxobutanoic acid (26.0 g, 0.13 mol) in CF
3SO
3H (250 mL) was stirred at 25 ℃ for 24 h. The reaction mixture was cooled to 0 ℃, and slowly added into ice-water (200 mL) . The mixture was filtered to give the crude product. The solid was slurred in petroleum ether (100 mL) , and then filtered. The cake was dried to give the title product (20.0 g, 84%yield) as a light-yellow solid.
1H NMR (400 MHz, DMSO-d
6) δ 10.24 (s, 1H) , 9.52 (s, 1H) , 7.64 (dd, J = 8.6, 5.2 Hz, 1H) , 7.57 (dd, J = 10.8, 2.6 Hz, 1H) , 7.24 (t, J = 9.08 Hz, 1H) , 6.64 (d, J = 1.48 Hz, 1H) , 6.56 (d, J = 1.6 Hz, 1H) .
Step 5: 7-Fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalene-1, 3-diol
To the mixture of 7-fluoronaphthalene-1, 3-diol (20.0 g, 0.11 mol) , 2-bromoethynyl (triisopropyl) silane (32 g, 0.12 mol) and AcOK (23.0 g, 0.22 mol) in dioxane (130 mL) was added dichlororuthenium; l-isopropyl-4-methyl-benzene dimer (7.0 g, 11 mmol) under N
2. The mixture was stirred at 110 ℃ for 5 h. The mixture was filtered and concentrated. The residue was purified by column chromatography to give the title product (22.0 g, 54.6%yield) as black oil.
1H NMR (400 MHz, CDCl
3) δ 9.16 (s, 1H) , 7.59 (dd, J = 9.1, 5.6 Hz, 1H) , 7.16 (t, J = 8.8 Hz, 1H) , 6.75 (d, J = 2.4 Hz, 1H) , 6.68 (d, J = 2.2 Hz, 1H) , 1.21 -1.14 (m, 21H) .
Step 6: 7-Fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-ol
To the mixture of 7-fluoro-8- ( (triisopropylsilyl) ethynyl) naphthalene-l, 3-diol (3.0 g, 8.3 mmol) and DIEA (3.2 g, 25.1 mmol) in DCM (30 mL) was added MOMCl (0.87 g, 10.8 mmol) at 0 ℃. The mixture was warmed to 15 ℃ and stirred for 0.5 h. The mixture was diluted with ice-water (20 mL) , extracted with ethyl acetate (30 mL x 2) . The combined organic phase was washed with brine (20 mL) , dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give the title product (2.0 g, 59.4%yield) as a yellow solid.
1H NMR (400 MHz, CDCl
3) δ 9.12 (s, 1H) , 7.65 (dd, J = 9.1, 5.6 Hz, 1H) , 7.18 (t, J = 8.8 Hz, 1H) , 6.96 (d, J = 2.4 Hz, 1H) , 6.80 (d, J = 2.2 Hz, 1H) , 5.24 (s, 2H) , 3.50 (s, 3H) , 1.21 -1.14 (m, 21H) .
Step 7: 7-Fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl trifluoromethanesulfonate
To a solution of 7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-ol (2.0 g, 4.9 mmol) , DIEA (1.9 g, 14.9 mmol) in DCM (30 mL) was added Tf
2O (2.1 g, 7.4 mmol) at -40 ℃, the mixture was stirred at -40 ℃ for 0.5 h. The reaction mixture was diluted with ice-water (50 mL) , then extracted with DCM (80 mL) . The combined organic phase was dried over Na
2SO
4 and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title product (2.0 g, 75.3%yield) as yellow oil.
1H NMR (400 MHz, CDCl
3) δ 7.70 (dd, J = 9.1, 5.4 Hz, 1H) , 7.42 (d, J = 2.3 Hz, 1H) , 7.37 -7.28 (m, 2H) , 5.27 (s, 2H) , 3.51 (s, 3H) , 1.42 -1.21 (m, 21H) .
Step 8: ( (2-Fluoro-6- (methoxymethoxy) -8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane
To a mixture of 7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yltrifluoromethanesulfonate (2.0 g, 3.7 mmol) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (1.9 g, 7.4 mmol) and AcOK (1.1 g, 11.2 mmol) in toluene (20 mL) was added Pd (dppf) Cl
2 (0.27 g, 0.37 mmol) . The mixture was degassed and stirred at 130 ℃ for 3 h. The reaction mixture was filtered and concentrated. To the residue was added EtOAc (20 mL) and water (15 mL) . The organic phase was washed with brine (10 mL) , dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography, then triturated with MeCN (3 mL) to give the title product (1.4 g, 73.1%yield) as a yellow solid. LCMS: (ES+) : m/z 513.4 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 7.66 (dd, J = 9.0, 5.7 Hz, 1H) , 7.51 (d, J = 2.5 Hz, 1H) , 7.38 (d, J = 2.6 Hz, 1H) , 7.22 (t, J = 8.8 Hz, 1H) , 5.27 (s, 2H) , 3.50 (s, 3H) , 1.44 (s, 12H) , 1.27 (s, 21H) .
Intermediate-2
2- (8-Ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane
Step 1: 7-Fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl pivalate
To the solution of 7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-ol (12.1 g, 0.030 mol) , DMAP (729 mg, 59.7 mmol) , TEA (9.0 g, 0.090 mol) in DCM (120 mL) was added 2, 2-dimethylpropanoyl chloride (10.8 g, 0.089 mol) dropwise at 0 ℃, and the mixture was stirred at 20 ℃ for 1 h. The reaction mixture was diluted with DCM (150 mL) and water (150 mL) , and then the aqueous layer was extracted with DCM (100 mL) . The combined organic phase was dried over Na
2SO
4 and concentrated. The residue was purified by column chromatography to give the title product (20.0 g, crude) as yellow oil.
Step 2: 8-Ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl pivalate
To the solution of 7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl pivalate (20.0 g, 0.041 mol) in DMF (340 mL) was added CsF (62.0 g, 0.41 mol) , and the mixture was stirred at 20 ℃ for 0.25 h. To the reaction mixture was added water (2.0 L) , and then the mixture was extracted with ethyl acetate (500 mL x 2) . The combined organic phase was washed with brine (300 mL) and dried over Na
2SO
4. The organic layer was concentrated to give the title product (16.3 g, crude) as yellow oil. LCMS: (ES+) : m/z 331.1 [M+1]
+.
Step 3: 8-Ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl pivalate
To the solution of 8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-ylpivalate (16.3 g, 0.049 mol) in MeOH (160 mL) was added Pd/C (1.6 g, 10 w%) under N
2. The suspension was degassed and purged with H
2 several times. The mixture was stirred under H
2 (15 psi) at 20 ℃ for 20 mins. After completion, the mixture was filtered. The filtrates were concentrated to give the title product (15.0 g, crude) . LCMS: (ES+) : m/z 335.2 [M+1]
+.
Step 4: 8-Ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-ol
To the solution of 8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-ylpivalate (15.0 g, 0.045 mol) in MeOH (225 mL) was added KOH (7.5 g, 0.13 mol) , and the mixture was stirred at 20 ℃ for 0.5 h. After completion, the solution was adjusted to pH = 4 with 0.5 M aq. HCl at 0 ℃. The mixture was extracted with ethyl acetate (300 mL x 2) . The combined organic phase was washed with brine (200 mL) , dried over Na
2SO
4, filtered and concentrated. The residue was purified by column chromatography to give the title product (2.8 g, 37%yield overall 4 steps) as a yellow solid.
1H NMR (400 MHz, CDCl
3) δ 7.55 -7.43 (m, 1H) , 7.18 (t, J = 9.2 Hz, 1H) , 6.98 (d, J = 2.4 Hz, 1H) , 6.57 (d, J = 2.0 Hz, 1H) , 5.32 (s, 1H) , 5.25 (s, 2H) , 3.52 (s, 3H) , 3.40 -3.25 (m, 2H) , 1.30 (t, J = 7.6 Hz, 3H) . LCMS: (ES+) : m/z 251.1 [M+1]
+.
Step 5: 8-Ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yltrifluoromethane sulfonate
To the solution of 8-Ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-ol (2.8 g, 0.011 mol) and DIEA (4.3 g, 0.034 mol) in DCM (60 mL) was added Tf
2O (4.7 g, 0.017 mol) dropwise at -40 ℃, and then the mixture was stirred at -40 ℃ for 0.5 h. The reaction mixture was quenched with ice-water (50 mL) , then extracted with DCM (50 mL x 2) . The combined organic phase was dried over Na
2SO
4 and concentrated. The residue was purified by column chromatography to give the title product (3.8 g, 90%yield) as yellow oil.
1H NMR (400 MHz, CDCl
3) δ 7.64 -7.60 (m, 1H) , 7.42 (s, 1H) , 7.36 (s, 1H) , 7.35 -7.26 (m, 1H) , 5.27 (s, 2H) , 3.52 (s, 3H) , 3.26 -3.21 (m, 2H) , 1.21 (t, J = 7.2 Hz, 3H) .
Step 6: 2- (8-Ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane
To a solution of 8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yltrifluoro methanesulfonate (3.8 g, 10.0 mmol) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (5.0 g, 20.0 mmol) and AcOK (2.9 g, 30.0 mmol) in 1, 4-dioxane (38 mL) was added Pd (dppf) Cl
2 (728.0 mg, 0.99 mmol) under N
2. The mixture was degassed and stirred at 100 ℃ for 1 h. After completion, the mixture was diluted with ethyl acetate (100 mL) and water (100 mL) . The aqueous layer was extracted with ethyl acetate (100 mL) . The combined organic phases were washed with saturated brine (100 mL) , dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give the title product (2.0 g, 55 %yield) as yellow oil.
1H NMR (400 MHz, CDCl
3) δ 7.48 (dd, J = 9.0, 5.8 Hz, 1H) , 7.32 -7.28 (m, 2H) , 7.12 (t, J = 9.2 Hz, 1H) , 5.19 (s, 2H) , 3.42 (s, 3H) , 3.05 (qd, J = 17.6, 7.5, 2.5 Hz, 2H) , 1.36 (s, 12H) , 1.19 (t, J = 1.6 Hz, 3H) .
Intermediate-3
2- (3-Chloro-2-cyclopropyl-5- (methoxymethoxy) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane
Step 1: 1-Bromo-3-chloro-2-cyclopropylbenzene
To a solution of 1-bromo-3-chloro-2-iodobenzene (9.8 g, 0.031 mol) and K
3PO
4 (23.6 g, 0.11 mol) in dioxane (75 mL) and H
2O (25 mL) was added Pd (dppf) Cl
2 (1.1 g, 1.5 mmol) , then cyclopropylboronic acid (3.4 g, 0.040 mol) was added. The mixture was stirred at 100 ℃ for 18 h. Upon completion, the reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (200 mL x 3) . The combined organic layers were dried over Na
2SO
4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title product (6.0 g, 87%yield) as a white solid.
1H NMR (400 MHz, CDCl
3) δ 7.45 (d, J =8.0 Hz, 1H) , 7.29 (d, J =8.0 Hz, 1H) , 6.97 (t, J = 7.8 Hz, 1 H) , 1.79 -1.74 (m, 1H) , 1.17 (dd, J =14.3, 6.4 Hz, 2H) , 0.77 (dd, J = 12.6, 6.4 Hz, 2H) .
Step 2: 2- (3-Bromo-5-chloro-4-cyclopropylphenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane
A mixture of 1-bromo-3-chloro-2-cyclopropylbenzene (6.0 g, 0.026 mol) , 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolane (19.8 g, 0.078 mol) , (Ir (OMe) (cod) )
2 (0.86g, 1.3 mmol) and 4-tert-butyl-2- (4-tert-butyl-2-pyridyl) pyridine (420 mg, 1.5 mmol) in hexane (120 mL) was degassed and purged with N
2 for 3 times. The mixture was stirred at 60 ℃℃ for 2 h. After completion, the reaction mixture was concentrated to afford the title product (27.0 g, crude) as brown oil, which was used in next step directly.
Step 3: 3-Bromo-5-chloro-4-cyclopropylphenol
To a solution of 2- (3-bromo-5-chloro-4-cyclopropylphenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (27.0 g, 0.076 mol) in THF (150 mL) and H
2O (75 mL) was added AcOH (292 g, 4.8 mol) and H
2O
2 (49.0 g, 1.4 mol) , the mixture was stirred at 0 ℃ for 1 h. Upon completion, the reaction mixture was diluted with H
2O (200 mL) and extracted with ethyl acetate (200 mL x 3) . The combined organic layers were dried over Na
2SO
4 and filtered. The filtrates were concentrated under reduced pressure. The residue was purified by column chromatography to give the title product (8.0 g) as a yellow solid. LCMS: (ES
-) : m/z 246.9 [M+1]
+.
Step 4: 1-Bromo-3-chloro-2-cyclopropyl-5- (methoxymethoxy) benzene
To a solution of 3-bromo-5-chloro-4-cyclopropylphenol (8.0 g, 0.033 mol) and DIEA (25.1 g, 0.19 mmol) in dichloromethane (80 mL) was added chloro (methoxy) methane (5.2 g, 0.065 mol) at 0 ℃. The mixture was stirred at 20 ℃ for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography to afford the title product (2.1 g, 22%yield) as colorless oil.
Step 5: 2- (3-Chloro-2-cyclopropyl-5- (methoxymethoxy) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane
To a solution of 1-bromo-3-chloro-2-cyclopropyl-5- (methoxymethoxy) benzene (2.2 g, 7.5 mmol) , KOAc (2.2 g, 22.8 mmol) and 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (3.9 g, 15.2 mmol) in 1, 4-dioxane (30 mL) was added Pd (dppf) Cl
2 (0.58 g, 0.8 mmol) . The mixture was stirred at 100 ℃ for 4 h. Upon completion, the reaction mixture was added into water (50 mL) and extracted with ethyl acetate (50 mL x 3) . The organic layer was dried over Na
2SO
4, filtered and concentrated. The residue was purified by column chromatography to afford the title product (2.2 g, 86%yield) as colorless oil.
1H NMR (400 MHz, CDCl
3) δ 7.19 (d, J = 2.4 Hz, 1H) , 7.03 (d, J = 2.4 Hz, 1H) , 5.11 (s, 2H) , 3.45 (s, 3H) , 1.63 -1.70 (m, 1H) , 1.26 (s, 12H) , 1.10 -1.15 (m, 2H) , 0.70 -0.72 (m, 2H)
Intermediate-4
(8-Chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) trimethylstannane
Step 1: 5-Chloro-6-fluoro-1, 4-dihydro-1, 4-epoxynaphthalene
To a mixture of l-bromo-3-chloro-2, 4-difluorobenzene (19.5 g, 0.087 mol) and furan (11.7 g, 0.174 mol, 13.5 mL) in toluene (190 mL) was added n-BuLi (2.5 M, 41.2 mL) dropwise over 0.5 h at -15 ℃. The mixture was allowed to warm to room temperature and stirred for 12 h. The mixture was quenched with water (200 mL) and was filtered. The aqueous layer was extracted with ethyl acetate (200 mL x 2) . The combined organic layer was dried over Na
2SO
4 and filtered. The filtrates were concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title product (13.5 g, 84%purity) as yellow oil.
1H NMR (400 MHz, CDCl
3) δ 7.09 -7.06 (m, 2H) , 7.06 -7.01 (m, 1H) , 6.73 (dd, J = 7.6, 9.6 Hz, 1H) , 5.87 (s, 1H) , 5.74 (s, 1H) .
Step 2: 8-Chloro-7-fluoronaphthalen-1-ol
A mixture of 5-chloro-6-fluoro-1, 4-dihydro-1, 4-epoxynaphthalene (11 g, 56.1 mmol) in con. hydrochloric acid (67.9 mL, 0.68 mol) and EtOH (82 mL) was stirred at 80 ℃for 6 h. The reaction mixture was concentrated under vacuum. The residue was adjusted to pH ~ 7 with aq. sat. NaHCO
3, and then extracted with ethyl acetate (100 mL x 2) . The combined organic layer was dried over Na
2SO
4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title product (7.1 g) as a white solid. LCMS: (ES
+) : m/z 195.1 [M-1]
-.
1H NMR (400 MHz, CDCl
3) δ 7.91 (s, 1H) , 7.75 (dd, J = 5.2, 8.8 Hz, 1H) , 7.42 -7.36 (m, 2H) , 7.31 -7.26 (m, 1H) , 7.08 -7.07 (m, 1H) .
Step 3: 1-Chloro-2-fluoro-8- (methoxymethoxy) naphthalene
To a solution of 8-chloro-7-fluoronaphthalen-1-ol (14.3 g, 72.9 mmol) in DCM (300 mL) were added DIEA (28.2 g, 218.8 mmol) and chloro (methoxy) methane (11.7 g, 145.9 mmol) in one portion at 0 ℃ under N
2. The mixture was stirred at 25 ℃ for 3 h. The mixture was quenched with water (350 mL) . The organic phase was separated and concentrated. To the residue was added sat. aq. NH
4Cl (200 mL) . The mixture was extracted with ethyl acetate (150 mL x 2) . The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give the title product (16.7 g, 95%yield) as yellow oil.
1H NMR (400 MHz, CDCl
3) δ 7.69 (dd, J = 9.0, 5.5 Hz, 1H) , 7.48 (d, J = 8.0 Hz, 1H) , 7.37 (t, J = 8.0 Hz, 1H) , 7.30 (t, J = 8.8 Hz, 1H) , 7.22 (d, J = 7.7 Hz, 1H) , 5.33 (s, 2H) , 3.60 (s, 3H) .
Step 4: 2- (5-Chloro-6-fluoro-4- (methoxymethoxy) naphthalen-2-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane
A mixture of l-chloro-2-fluoro-8- (methoxymethoxy) naphthalene (16.7 g, 69.8 mmol) , 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (17.6 g, 69.5 mmol) , Ir (OMe) (cod) )
2 (2.2 g, 3.4 mmol) and dtbbpy (2.2 g, 8.3 mmol) in THF (340 mL) was degassed, and then the mixture was stirred at 60 ℃ for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography to give the title product (27 g, crude) as yellow oil.
Step 5: 5-Chloro-6-fluoro-4- (methoxymethoxy) naphthalen-2-ol
To a solution of 2- [5-chloro-6-fluoro-4- (methoxymethoxy) -2-naphthyl] -4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolane (27 g, crude) in THF (280 mL) and H
2O (140 mL) were added H
2O
2 (70 g, 0.62 mol, 30 w%) and AcOH (225 g, 3.7 mol) at 10 ℃. The mixture was stirred at 25 ℃ for 1 h. After completion, the mixture was quenched with sat. Na
2SO
3 solution (600 mL x 2) , extracted with ethyl acetate (400 mL x 2) . The combined organic phases were washed with sat. brine (600 mL) , dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give the title product (3.3 g) as an off-white solid. LCMS: (ES
+) : m/z 255.1 [M-1]
-.
1H NMR (400 MHz, CDCl
3) δ 7.49 (dd, J = 5.2, 8.8 Hz, 1H) , 7.25 (t, J = 8.8 Hz, 1H) , 6.89 (d, J = 2.0 Hz, 1H) , 6.81 (d, J = 2.4 Hz, 1H) , 5.45 (br s, 1H) , 5.31 (s, 2H) , 3.58 (s, 3H) .
Step 6: 5-Chloro-6-fluoro-4- (methoxymethoxy) naphthalen-2-yl acetate
To the solution of 5-chloro-6-fluoro-4- (methoxymethoxy) naphthalen-2-ol (3.3 g, 12.8 mmol) , TEA (2.6 g, 25.7 mmol) and DMAP (159 mg, 1.2 mmol) in DCM (66 mL) was added acetyl chloride (1.5 g, 19.3 mmol) dropwise at 0 ℃. The reaction mixture was warmed to 25 ℃ and stirred for 0.5 h. After completion, the mixture was diluted with water (50 mL) . The organic layer was separated, and the aqueous phase was extracted with DCM (60 mL x 2) . The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give the title product (3.2 g) as a white solid.
1H NMR (400 MHz, CDCl
3) δ 7.64 (dd, J = 5.2, 8.8 Hz, 1H) , 7.31 (t, J = 8.8 Hz, 1H) , 7.24 (d, J = 1.8 Hz, 1H) , 7.00 (d, J = 2.0 Hz, 1H) , 5.33 (s, 2H) , 3.58 (s, 3H) , 2.34 (s, 3H) .
Step 7: 5-Chloro-6-fluoro-4-hydroxynaphthalen-2-yl acetate
To the solution of [5-chloro-6-fluoro-4- (methoxymethoxy) -2-naphthyl] acetate (3.2 g, 10.7 mmol) in MeCN (32 mL) was added HCl/dioxane (4 M, 32 mL) at 0 ℃, and then the mixture was stirred at 0 ℃ for 1 h. After completion, the mixture was concentrated. The residue was quenched with sat. aq. NaHCO
3 (50 mL) and extracted with ethyl acetate (80 mL x 2) . The combined organic phase was washed with brine (50 mL) , dried over anhydrous Na
2SO
4 and filtered. The filtrates were concentrated to give the title product (2.4 g, 88%yield) as a white solid, which was used in the next step without further purification. LCMS: (ES
+) : m/z 253.1 [M-1]
-.
1H NMR (400 MHz, CDCl
3) δ8.05 (s, 1H) , 7.70 (dd, J = 5.2, 9.2 Hz, 1H) , 7.30 (t, J = 8.8 Hz, 1H) , 7.18 (d, J = 2.4 Hz, 1H) , 6.86 (d, J = 2.0 Hz, 1H) , 2.34 (s, 3H) .
Step 8: 5-Chloro-6-fluoro-4- ( ( (trifluoromethyl) sulfonyl) oxy) naphthalen-2-yl acetate
To the solution of (5-chloro-6-fluoro-4-hydroxy-2-naphthyl) acetate (2.4 g, 9.4 mmol) and DIPEA (3.6 g, 28.3 mmol) in DCM (48 mL) was added Tf
2O (4.0 g, 14.1 mmol) dropwise at -40 ℃, then the reaction was warmed to 25 ℃ and stirred for 0.5 h. After completion, the mixture was quenched with water (50 mL) , extracted with DCM (80 mL x 2) . The combined organic phase was washed with brine (50 mL) , dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give the title product (2.1 g, 59.8 %yield) as a yellow solid.
1H NMR (400 MHz, CDCl
3) δ 7.80 (dd, J = 5.2, 9.0 Hz, 1H) , 7.71 (d, J = 2.0 Hz, 1H) , 7.47 -7.43 (m, 2H) , 2.38 (s, 3H) .
Step 9: 8-Chloro-7-fluoro-3-hydroxynaphthalen-1-yltrifluoromethanesulfonate
To the mixture of [5-chloro-6-fluoro-4- (trifluoromethylsulfonyloxy) -2-naphthyl] acetate (2.1 g, 5.6 mmol) in H
2O (5 mL) and THF (20 mL) was added LiOH (270 mg, 11.2 mmol) at 0 ℃. The mixture was stirred at 0 ℃ for 1 h. After completion, the mixture was concentrated, and the pH was adjusted to 6 with AcOH. The resulting mixture was extracted with ethyl acetate (60 mL x 2) . The combined organic phase was washed with brine (50 mL) , dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give the title product (2.2 g, crude) as a yellow solid.
1H NMR (400 MHz, CDCl
3) δ 7.64 (dd, J =5.2, 8.8 Hz, 1H) , 7.38 (t, J = 8.8 Hz, 1H) , 7.27 (d, J = 2.4 Hz, 1H) , 7.22 (d, J = 2.4 Hz, 1H) .
Step 10: 8-Chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yltrifluoro methanesulfonate
To the solution of (8-chloro-7-fluoro-3-hydroxy-l-naphthyl) trifluoromethanesulfonate (2.2 g, crude) and DIEA (2.5 g, 19.3 mmol) in DCM (40 mL) was added MOMCl (1.0 g, 12.9 mmol) at 0 ℃, the mixture was stirred at 0 ℃ for 1 hr. After completion, the reaction was quenched by water (40 mL) at 0 ℃, extracted with DCM (100 mL) . The organic layer was washed with brine (60 mL) , dried over Na
2SO
4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the title product (1.9 g, 87 %yield overall 2 steps) as yellow oil.
1H NMR (400 MHz, CDCl
3) δ 7.71 (dd, J = 5.2, 8.8 Hz, 1H) , 7.46 (d, J = 2.4 Hz, 1H) , 7.39 -7.35 (m, 2H) , 5.29 (s, 2H) , 3.52 (s, 3H)
Step 11: (8-Chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) trimethyl stannane
To the mixture of 8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl trifluoromethanesulfonate (1.9 g, 4.9 mmol) , trimethyl (trimethylstannyl) stannane (4.8 g, 14.7 mmol) and LiCl (621 mg, 14.7 mmol) in toluene (46 mL) was added Pd (PPh
3)
4 (567 mg, 0.49 mmol) under N
2. The mixture was stirred at 110 ℃ for 16 h. After completion, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (120 mL x 2) . The combined organic phase was washed with saturated brine (100 mL) , dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give the title product (1.1 g, 80%purity) as colorless oil.
1H NMR (400 MHz, CDCl
3) δ 7.67 -7.64 (m, 1H) , 7.59 (d, J = 2.4 Hz, 1H) , 7.37 (d, J = 2.4 Hz, 1H) , 7.32 (t, J = 8.8 Hz, 1H) , 5.29 (s, 2H) , 3.53 (s, 3H) , 0.44 (s, 9H)
Example 1
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6-chloro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [2, 3-d] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol
Step 1: 2-Amino-5, 6-dichloronicotinic acid
To a solution of 2-amino-6-chloronicotinic acid (5.0 g, 27 mmol) in DMF (25 mL) was added NCS (4.1 g, 30 mmol) , the mixture was stirred at 70 ℃ for 12 h. The mixture was cooled to 25 ℃ and poured into water (100 mL) . Filtered and the cake was washed with water (10 mL x 2) , then dried to afford the title product (5.0 g, 90%yield) as a white solid. LCMS: (ES
+) : m/z = 206.9 [M+1]
+.
Step 2: 2-Amino-5, 6-dichloronicotinamide
To a solution of 2-amino-5, 6-dichloronicotinic acid (5.0 g, 25 mmol) in THF (50 mL) was added SOCl
2 (6 mL) . The mixture was stirred at room temperature overnight. The reaction mixture was concentrated. To the residue was added THF (50 mL) and ammonia (20 mL) . The mixture was stirred at room temperature for 1 h. The mixture was concentrated to afford the title product (5.0 g, 100%yield) as a white solid. LCMS: (ES
+) : m/z = 205.9 [M+1]
+.
Step 3: 6, 7-Dichloropyrido [2, 3-d] pyrimidine-2, 4-diol
To a solution of 2-amino-5, 6-dichloronicotinamide (2.0 g, 9.8 mmol) in toluene (20 mL) was added oxalyl chloride (1 mL) , the mixture was stirred at 110 ℃ for 1 h. The mixture was cooled and filtered. The cake was washed with toluene (10 mL x 2) . The cake was dried to afford the title product (1.3 g, 57.2%yield) as a yellow solid.
1H NMR (400 MHz, DMSO-d
6) δ 12.06 (s, 1H) , 11.70 (s, 1H) , 8.40 (s, 1H) .
Step 4: 2, 4, 6, 7-Tetrachloropyrido [2, 3-d] pyrimidine
To a solution of 6, 7-dichloropyrido [2, 3-d] pyrimidine-2, 4-diol (1.3 g, 5.6 mmol) in toluene (20 mL) was added DIPEA (2.2 g, 16.8 mmol) and POCl
3 (2.6 g, 16.8 mmol) , the mixture was stirred at 110 ℃ for 1 h. The mixture was cooled and concentrated under reduced pressure to give the title product (1.2 g, crude) as a black oil, which was used in the next step directly.
Step 5: Tert-butyl (1R, 5S) -3- (2, 6, 7-trichloropyrido [2, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of 2, 4, 6, 7-tetrachloropyrido [2, 3-d] pyrimidine (1.2 g, 4.5 mmol) in DCM (20 mL) was added DIPEA (1.7 g, 13.4 mmol) and tert-butyl (1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1.1 g, 5.3 mmol) at -60 ℃, the mixture was stirred at -60 ℃ for 1 h. The mixture was poured into water (10 mL) , extracted with DCM (20 mL x 2) . The organic layer was dried over Na
2SO
4 and filtered. The filtrates were concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the title product (0.8 g, 40.3%yield) as a yellow solid. LCMS: (ES
+) : m/z = 444.1 [M+1]
+.
Step 6: Tert-butyl (1R, 5S) -3- (6, 7-dichloro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [2, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (140 mg, 1.3 mmol) in THF (10 mL) was added NaH (60 mg, 1.35 mmol, 60 w%) at 0 ℃, the mixture was stirred at 0 ℃ for 0.5 h. Then tert-butyl (1R, 5S) -3- (2, 6, 7-trichloropyrido [2, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (600 mg, 1.3 mmol) was added, the mixture was stirred at 0 ℃ for 3 h. The mixture was poured into water (10 mL) , and extracted with DCM (10 mL x 2) . The organic layer was dried over Na
2SO
4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the title product as a yellow solid (0.4 g, 53.9%yield) . LCMS: (ES
+) : m/z = 549.3 [M+1]
+.
Step 7: Tert-butyl (1R, 5S) -3- (6-chloro-7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [2, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (2, 6, 7-trichloropyrido [2, 3-d] pyrimidin-4-yl) -3, 8- diazabicyclo [3.2.1] octane-8-carboxylate (100 mg, 0.18 mmol) in toluene (0.5 mL) was added (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) trimethylstannane (220 mg, 0.54 mmol) , BINAP (23 mg, 0.03 mmol) , CuI (10 mg, 0.05 mmol) and Pd (dppf) Cl
2 (13 mg, 0.02 mmol) under N
2. The mixture was stirred at 100 ℃ for 8 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC to give the title product (40 mg, 36.4%yield) as a yellow oil. LCMS: (ES
+) : m/z = 753.2 [M+1]
+.
Step 8: 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6-chloro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [2, 3-d] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol
To a solution of tert-butyl (1R, 5S) -3- (6-chloro-7- (8-chloro-7-fluoro-3- (methoxy methoxy) naphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [2, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (50 mg, 0.07 mmol) in dioxane (0.5 mL) was added HCl/dioxane (4 M, 1 mL) . The mixture was stirred at 25 ℃ for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (18.3 mg, 99%purity) as a yellow solid. LCMS: (ES
+) : m/z = 609.2 [M+1]
+.
1H NMR (400 MHz, MeOD) δ 8.31 (s, 1H) , 7.84 (dd, J = 8.9, 5.2 Hz, 1H) , 7.44 (t, J = 13.0 Hz, 1H) , 7.38 -7.32 (m, 2H) , 4.84 -4.76 (m, 2H) , 4.53 (dd, J = 29.7, 13.2 Hz, 2H) , 4.12 -3.74 (m, 4H) , 3.40 -3.38 (m, 1H) , 3.29 -3.21 (m, 1H) , 3.06 -2.95 (m, 2H) , 2.26 -1.76 (m, 12H) .
Example 4
3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6-chloro-2- ( (tetrahydro-1H- pyrrolizin-7a (5H) -yl) methoxy) pyrido [2, 3-d] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol
Step 1: Tert-butyl (1R, 5S) -3- (6-chloro-7- (3-chloro-2-cyclopropyl-5- (methoxy methoxy) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [2, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (6, 7-dichloro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [2, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.2 g, 0.36 mmol) in toluene (2 mL) and H
2O (0.4 mL) was added 2- (3-chloro-2-cyclopropyl-5- (methoxymethoxy) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (0.25 g, 0.72 mmol) , Pd (PPh
3)
2Cl
2 (25 mg, 0.03 mmol) , Cs
2CO
3 (0.23 g, 0.72 mmol) under N
2, the mixture was stirred at 100 ℃ for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC to give the title product (20 mg, 7.5%yield) as a yellow oil. LCMS: (ES
+) : m/z = 725.3 [M+1]
+.
Step 2: 3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6-chloro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [2, 3-d] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol
To a solution of tert-butyl (1R, 5S) -3- (6-chloro-7- (3-chloro-2-cyclopropyl-5- (methoxy methoxy) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [2, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (20 mg, 0.02 mmol) in dioxane (0.5 mL) was added HCl/dioxane (4 M, 0.1 mL) , the mixture was stirred at 25 ℃ for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (2.1 mg, 95%purity) as a yellow solid. LCMS: (ES
+) : m/z = 581.2 [M+1]
+.
1H NMR (400 MHz, MeOD) δ 8.29 (s, 1H) , 7.01 -6.98 (m, 2H) , 4.57 (d, J = 13.7 Hz, 2H) , 4.18 (s, 2H) , 3.88 (d, J = 13.3 Hz, 2H) , 3.52 -3.45 (m, 2H) , 3.19 -3.12 (m, 2H) , 2.21 -1.88 (m, 15H) , 0.83 -0.76 (m, 2H) , 0.14 -0.08 (m, 2H) .
Example 6
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol
Step 1: 7-Bromopyrido [3, 2-d] pyrimidine-2, 4 (1H, 3H) -dione
A solution of 3-amino-5-bromo-pyridine-2-carboxylic acid (2.0 g, 9.3 mmol) and urea (5.6 g, 93 mmol) was stirred at 200 ℃ for 2 h. The mixture was cooled, then water (20 mL) was added. The precipitate was filtered and dried to provide the title product (2.1 g, 94 %yield) , which was used in the next step without further purification. LCMS: (ES
-) : m/z = 241.9 [M+1]
+.
Step 2: 7-Bromo-2, 4-dichloropyrido [3, 2-d] pyrimidine
A solution of 7-bromo-pyrido [2, 3-d] pyrimidine-2, 4-diol (2.1 g, 8.7 mmol) , POCl
3 (20 mL) and DIPEA (2 mL) was stirred at 130 ℃ for 10 h. The volatiles were concentrated under reduced pressure, and the residue was azeotroped with toluene (10 mL x 2) . The residue was treated with EtOAc (20 mL) and filtered through a pad of Celite. The filtrates were concentrated under reduced pressure to provide the title product (0.9 g, crude) , which was used in the next step without further purification.
Step 3: Tert-butyl (1R, 5S) -3- (2, 6, 7-trichloropyrido [2, 3-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of 7-bromo-2, 4-dichloropyrido [3, 2-d] pyrimidine (0.9 g, 3.2 mmol) in DCM (10 mL) was added DIPEA (0.7 g, 5.4 mmol) and tert-butyl (1R, 5S) -3, 8- diazabicyclo [3.2.1] octane-8-carboxylate (0.8 g, 3.7 mmol) at -60 ℃. The mixture was stirred at -60 ℃ for 1 h. The mixture was poured into water (10 mL) and extracted with DCM (10 mL x 2) . The organic layer was dried over Na
2SO
4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the title product (1.2 g, 40.3%yield) as a white solid. LCMS: (ES
+) : m/z =454.1 [M+1]
+.
Step 4: Tert-butyl (1R, 5S) -3- (7-bromo-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (310 mg, 2.2 mmol) in THF (10 mL) was added NaH (100 mg, 2.5 mmol, 60 w%) at 0 ℃ under N
2, the mixture was stirred at 0 ℃ for 0.5 h. Then tert-butyl (1R, 5S) -3- (7-bromo-2-chloropyrido [3, 2-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (600 mg, 1.5 mmol) was added, the mixture was stirred at 0 ℃ for 3 h. The mixture was poured into water (10 mL) , then extracted with DCM (10 mL x 2) . The organic layer was dried over Na
2SO
4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the title product (0.5 g, 60.9%yield) as a white solid. LCMS: (ES
+) : m/z = 559.3 [M+1]
+.
Step 5: Tert-butyl (1R, 5S) -3- (7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (40 mg, 0.072 mmol) and (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) trimethylstannane (100 mg, crude) in toluene (1 mL) was added Pd (dppf) Cl
2 (5.2 mg, 0.0072 mmol) , BINAP (10 mg, 0.016 mmol) and CuI (4.0 mg, 0.021 mmol) under N
2, the mixture was stirred at 100 ℃ for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC to afford the title product (18.9 mg, 99%purity) as a yellow oil. LCMS: (ES
+) : m/z = 360.1 [M+1]
+.
Step 6: 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol
To a solution of tert-butyl (1R, 5S) -3- (7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (18.9 mg, 0.026 mmol) in MeCN (1 mL) was added HCl/dioxane (4 M, 2 mL) at 0 ℃, the mixture was stirred at 0 ℃ for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (4.7 mg, 99%purity) as a white solid. LCMS: (ES
+) : m/z = 576.3 [M+1]
+.
1H NMR (400 MHz, MeOD) δ 8.57 (d, J = 2.2 Hz, 1H) , 7.83 -7.79 (m, 2H) , 7.40 (t, J = 8.8 Hz 1H) , 7.33 (d, J = 2.2 Hz, 1H) , 7.11 (d, J =2.56 Hz, 1H) , 4.48 (s, 2H) , 3.74 (s, 2H) , 3.54 -3.45 (m, 4H) , 3.17 -3.08 (m, 2H) , 2.30 -1.90 (m, 14H)
Example 7
3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol
Step 1: Tert-butyl (1R, 5S) -3- (7- (3-chloro-2-cyclopropyl-5- (methoxymethoxy) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin -4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (110 mg, 0.19 mmol) and 2- (3-chloro-2-cyclopropyl-5- (methoxymethoxy) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (66 mg, 0.19 mmol) in DMF (2 mL) and water (0.4 mL) was added Na
2CO
3 (33 mg, 0.31 mmol) and Pd (PPh
3)
2Cl
2 (14 mg, 0.019 mmol) under N
2, then the mixture was stirred at 95 ℃ for 2 h. The mixture was cooled, and water (10 mL) was added, then extracted with EtOAc (10 mL x 2) . The organic layer was washed with water (5 mL) , brine (5 mL) and dried over Na
2SO
4. The organic layer was concentrated under reduced pressure. The residue was purified by prep-TLC to give the title product (20 mg, 14.7%yield) as a yellow oil. LCMS: (ES
+) : m/z = 346.3 [1/2M+1]
+.
Step 2: 3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-7-yl) -5-chloro-4-cyclopropylphenol
To a solution of tert-butyl (1R, 5S) -3- (7- (3-chloro-2-cyclopropyl-5- (methoxymethoxy) phenyl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (20 mg, 0.02 mmol) in MeCN (0.5 mL) was added 4 M HCl/dioxane (1 mL) . The mixture was stirred at 25 ℃ for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (2.3 mg, 95%purity) as a white solid. LCMS: (ES
+) : m/z = 547.3 [M+1]
+.
1H NMR (400 MHz, MeOD) δ 8.71 (d, J = 2.0 Hz, 1H) , 7.89 (d, J = 2.0 Hz, 1H) , 6.95 (d, J = 2.4 Hz, 1H) , 6.73 (d, J = 2.0 Hz, 1H) , 4.55 (s, 2H) , 3.73 (s, 2H) , 3.67 -3.58 (m, 2H) , 3.53 -3.45 (m, 2H) , 3.28 -3.20 (m, 2H) , 2.36 -1.95 (m, 14H) , 1.94 -1.86 (m, 1H) , 0.77 -0.70 (m, 2H) , 0.09 -0.03 (m, 2H) .
Example 8
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: Tert-butyl (1R, 5S) -3- (7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.2 g, 0.35 mmol) and ( (2-fluoro-6- (methoxymethoxy) -8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (0.2 g, 0.39 mmol) in DMF (5 mL) and water (1 mL) was added Na
2CO
3 (0.06 g, 0.56 mmol) and Pd (PPh
3)
2Cl
2 (25.0 mg, 0.035 mmol) under N
2. The mixture was stirred at 95 ℃ for 2 h. The mixture was cooled and water (10 mL) was added, extracted with EtOAc (10 mL x 2) . The organic layer was washed with water (5 mL) , brine (5 mL) and dried over Na
2SO
4. The organic layer was concentrated under reduced pressure. The residue was purified by prep-TLC to give the title product (80 mg, 25.8%yield) as a yellow oil. LCMS: (ES
+) : m/z = 433.5 [1/2M+1]
+.
Step 2: 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
To a mixture of tert-butyl (1R, 5S) -3- (7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (80 mg, 0.093 mmol) in DMF (2 mL) was added CsF (70 mg, 0.46 mmol) . The mixture was stirred at 25 ℃ for 1 h. The mixture was cooled, and water (5 mL) was added, extracted with EtOAc (10 mL x 2) . The organic layer was washed with water (5 mL) , brine (5 mL) and dried over Na
2SO
4. The organic layer was concentrated under the reduced pressure. The residue was purified by prep-TLC to give the title product (40 mg, 60.3%yield) as a yellow oil. LCMS: (ES
+) : m/z = 355.3 [1/2M+1]
+.
Step 3: 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
To a solution of tert-butyl (1R, 5S) -3- (7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 2-d] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (20 mg, 0.028 mmol) in MeCN (0.5 mL) was added HCl/dioxane (4 M, 1 mL) , the mixture was stirred at 25 ℃ for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by prep- HPLC to afford the title product (5.0 mg, 95%purity) as a white solid. LCMS: (ES
+) : m/z = 566.3 [M+1]
+.
1H NMR (400 MHz, MeOD) δ 8.60 (d, J = 1.6Hz, 1H) , 7.85-7.82 (m, 2H) , 7.35 -7.31 (m, 2H) , 7.11 (d, J = 2.0 Hz, 1H) , 4.53 (s, 2H) , 3.84 (m, 2H) , 3.60 -3.55 (m, 2H) , 3.52 -3.45 (m, 2H) , 3.42 (s, 1H) , 3.22 -3.16 (m, 2H) , 2.32 -2.24 (m, 3H) , 2.22 -2.10 (m, 5H) , 2.08 -2.01 (m, 2H) , 1.99 -1.93 (m, 4H) .
Example 11
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6-chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol
Step 1: 7-Bromo-2, 4, 6-trichloro-8-fluoroquinazoline
To a solution of 7-bromo-6-chloro-8-fluoroquinazoline-2, 4-diol (0.5 g, 1.7 mmol) in toluene (5 mL) was added DIPEA (0.67 g, 5.1 mmol) and POCl
3 (0.77 g, 5.1 mmol) , the mixture was stirred at 100 ℃ for 2 h. The mixture was concentrated under reduced pressure to give the title product (550 mg, crude) as a brown oil.
Step 2: Tert-butyl (1R, 5S) -3- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of 7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline (0.55 g, 1.7 mmol) in DCM (5 mL) was added DIPEA (0.33 g, 2.5 mmol) and tert-butyl (1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.37 g, 1.7 mmol) , the mixture was stirred at -60 ℃ for 0.5 h. The mixture was poured into water (20 mL) , extracted with DCM (20 mL x 3) . The combined organic layer was washed with brine (30 mL) and dried over Na
2SO
4. Filtered and the filtrates were concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title product (530 mg, 99%purity) as a yellow solid. LCMS: (ES
+) : m/z = 505.0, 507.0 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 7.75 (d, J = 1.9 Hz, 1H) , 4.39 (s, 4H) , 3.71 (s, 2H) , 1.96 (s, 2H) , 1.72 (s, 2H) , 1.52 (s, 9H) .
Step 3: Tert-butyl (1R, 5S) -3- (7-bromo-6-chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.5 g, 0.99 mmol) in DMSO (3 mL) was added (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (0.42 , 2.9 mmol) and KF (0.46 g, 7.9 mmol) under N
2, the mixture was stirred at 90 ℃ for 6 h. The mixture was poured into water (20 mL) , extracted with DCM (30 mL x 3) . The combined organic layer was washed with brine (30 mL) and dried over Na
2SO
4. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title product (450 mg, 99%purity) as a yellow solid. LCMS: (ES
+) : m/z = 610.2, 612.2 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 7.67 (s, 1H) , 4.60 -4.09 (m, 6H) , 3.62 (m, 4H) , 2.74 (s, 2H) , 2.19 (s, 2H) , 1.99 (d, J = 43.9 Hz, 6H) , 1.76 (s, 4H) , 1.52 (s, 9H) .
Step 4: Tert-butyl (1R, 5S) -3- (6-chloro-7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-6-chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (40 mg, 0.065 mmol) and (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) trimethylstannane (100 mg) in toluene (1 mL) was added Pd (dppf) Cl
2 (4.6 mg, 0.0065 mmol) , BINAP (8.1 mg, 0.013 mmol) and CuI (3.7 mg, 0.019 mmol) under N
2, the mixture was stirred at 100 ℃ for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC to afford the title product (20 mg, 99%purity) as a yellow oil. LCMS: (ES
+) : m/z = 770.3 [M+1]
+.
Step 5: 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6-chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol
To a solution of tert-butyl (1R, 5S) -3- (6-chloro-7- (8-chloro-7-fluoro-3- (methoxy methoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (20 mg, 0.026 mmol) in ACN (1 mL) was added HCl/dioxane (4 M, 2 mL) at 0 ℃, the mixture was stirred at 0 ℃ for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (3.7 mg, 99%purity) as a white solid. LCMS: (ES
+) : m/z = 625.2 [M+1]
+.
1H NMR (400 MHz, MeOD) δ 7.94 (s, 1H) , 7.81 (dd, J = 9.2, 5.6 Hz, 1H) , 7.41 -7.36 (m, 2H) , 7.03 (d, J = 2.0 Hz, 1H) , 4.74 -4.49 (m, 4H) , 3.85 -3.80 (m, 3H) , 3.70 -3.60 (m, 4H) , 2.32 -1.88 (m, 13H) .
Example 16
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol
Step 1: 7-Bromo-8-fluoroquinazoline-2, 4-diol
A mixture of 2-amino-4-bromo-3-fluorobenzoic acid (2.0 g, 8.5 mmol) and urea (5.1 g, 85.5 mmol) was heated at 200 ℃ for 5 h. The reaction mixture was cooled and poured into water (100 mL) . Then the resulting mixture was filtered to afford the title product (2.1 g, 94.8%yield) as yellow solid. LCMS: (ESI) : m/z = 259.0 [M+1]
+.
Step 2: 7-Bromo-2, 4-dichloro-8-fluoroquinazoline
To a solution of 7-bromo-8-fluoroquinazoline-2, 4-diol (0.5 g, 1.9 mmol) in toluene (20 mL) was added DIPEA (0.75 g, 5.8 mmol) and POCl
3 (0.9 g, 5.8 mmol) , and the reaction mixture was stirred at 110 ℃ for 1 h. The mixture was cooled and concentrated under reduced pressure to give the title product (0.6 g, crude) as black oil and used next step directly.
Step 3: Tert-butyl (1R, 5S) -3- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of 7-bromo-2, 4-dichloro-8-fluoroquinazoline (0.6 g, 2.0 mmol) in DCM (5 mL) was added DIPEA (0.8 g, 6.1 mmol) and tert-butyl (1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.5 g, 2.4 mmol) at -60 ℃. The reaction mixture was stirred at -60 ℃ for 1 h. The mixture was poured into water (10 mL) and extracted with DCM (10 mL x 3) . The combined organic phase was dried over Na
2SO
4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the title product (0.4 g, 41.8%yield) as yellow solid. LCMS: (ESI) : m/z = 471.0/473.1 [M+1]
+.
Step 4: Tert-butyl (1R, 5S) -3- (7-bromo-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.4 g, 0.8 mmol) in DMSO (4 mL) was added (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (0.36 g, 2.5 mmol) and KF (0.39 g, 6.7 mmol) . The reaction mixture was stirred at 100 ℃ for 2 h. The mixture was added water (10 mL) and extracted with DCM (10 mL x 3) . The combined organic phase was dried over Na
2SO
4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the title product (280 mg, 57.3%yield) as yellow oil. LCMS: (ESI) : m/z = 576.2 [M+1]
+.
Step 5: Tert-butyl (1R, 5S) -3- (7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthal en-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.10 g, 0.17 mmol) in toluene (1 mL) was added (8-chloro-7-fluoro-3- (methoxy methoxy) naphthalen-1-yl) trimethylstannane (0.21 g, 0.52 mmol) , BINAP (20 mg, 0.03 mmol) , CuI (10 mg, 0.05 mmol) and Pd (dppf) Cl
2 (13 mg, 0.02 mmol) under N
2. The reaction mixture was stirred at 100 ℃ for 8 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC to give the title product (60 mg, 47.0%yield) as yellow oil. LCMS: (ESI) : m/z = 368.5 [1/2M+1]
+.
Step 6: 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (tetrahydro-1 H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol
To a solution of tert-butyl (1R, 5S) -3- (7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (60 mg, 0.08 mmol) in dioxane (0.5 mL) was added HCl/dioxane (4 M, 0.1 mL) . The reaction mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (9.2 mg, 99%purity) as yellow solid. LCMS: (ESI) : m/z = 592.0 [M+1]
+.
1H NMR (400 MHz, MeOD) δ 7.90 (d, J = 8.9 Hz, 1H) , 7.80 (dd, J = 9.0, 5.2 Hz, 1H) , 7.42 -7.35 (m, 2H) , 7.33 (d, J = 2.3 Hz, 1H) , 7.10 (s, 1H) , 4.74 -4.62 (m, 4H) , 4.13 -4.04 (m, 2H) , 3.86 -3.74 (m, 2H) , 3.71-3.63 (m, 2H) , 3.28 -3.24 (m, 2H) , 2.37 -2.04 (m, 12H)
Example 26
(7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoroquinazolin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate
Step 1: Tert-butyl (1R, 5S) -3- (7-bromo-2, 8-difluoroquinazolin-4-yl) -3, 8-diaza bicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1.4 g, 2.3 mmol) in anhydrous DMSO (14 mL) was added KF (1.4 g, 24.1 mmol) , the reaction mixture was stirred at 100 ℃ for 8 h. The reaction mixture was cooled, water (100 mL) was added. The mixture was extracted with EtOAc (50 mL x 3) . The organic phase was dried over Na
2SO
4 and evaporated under reduced pressure. The residue was purified by column chromatography to afford the title product (1.1 g) as a yellow solid. LCMS: (ES
+) : m/z 455.0 [M+1]
+.
Step 2: Tert-butyl (1R, 5S) -3- (7-bromo-2- ( (3- ( ( (tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of (3- ( ( (tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizin- 7a (5H) -yl) methanol (1.1 g, 3.9 mmol) in THF (20 mL) was added NaH (158 mg, 3.9 mmol, 60 wlp-%) at 0 ℃ under N
2. The reaction mixture was stirred at 0 ℃ for 0.5 h. Then tert-butyl (1R, 5S) -3- (7-bromo-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.9 g, 1.9 mmol) was added. The reaction mixture was stirred at 0 ℃ for 3 h. To the mixture was added water (30 mL) , and extracted with DCM (30 mL x 3) . The organic phase was dried over Na
2SO
4 and evaporated under reduced pressure. The residue was purified by column chromatography to afford the title product (0.8 g) as a yellow solid. LCMS: (ES
+) : m/z 720.2 [M+1]
+.
Step 3: Tert-butyl (1R, 5S) -3- (7-bromo-8-fluoro-2- ( (3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-2- ( (3- ( ( (tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.8 g, 1.1 mmol) in THF (10 mL) was added TBAF (6 mL, 1 mol/L, 6.0 mmol) . The reaction mixture was stirred at r.t. for 4 h. The mixture was poured into water (50 mL) , extracted with EtOAc (30 mL x 3) . The organic phase was dried over Na
2SO
4 and evaporated under reduced pressure. The residue was purified by column chromatography to afford the title product (0.5 g) as a yellow solid. LCMS: (ES
+) : m/z 606.2 [M+1]
+.
Step 4: Tert-butyl (1R, 5S) -3- (7-bromo-2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-8-fluoro-2- ( (3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.5 g, 0.8 mmol) in tetrahydrofuran (5 mL) was added 4-nitrophenyl chloroformate (0.3 g, 1.7 mmol) , followed by Et
3N (0.3 g, 2.5 mmol) . The mixture was stirred at r.t. for 1 h, then methylamine (2.0 M, 3.4 mL, 6.8 mmol) was added. The mixture was stirred at r.t. for 2 h. The mixture was poured into water (20 mL) , extracted with EtOAc (20 mL x 3) . The organic phase was dried over Na
2SO
4 and evaporated under reduced pressure. The residue was purified by column chromatography to afford the title product (0.3 g) as yellow solid. LCMS: (ES
+) : m/z 677.2 [M+1]
+.
Step 5: Tert-butyl (1R, 5S) -3- (7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.1 g, 0.1 mmol) and (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-b1-yl) trimethylstannane (60 mg, crude) in toluene (1 mL) was added Pd (dppf) Cl
2 (10 mg, 0.015 mmol) , BINAP (20.0 mg, 0.032 mmol) and CuI (10 mg, 0.053 mmol) under N
2. The reaction mixture was stirred at 100 ℃ for 16 h. The reaction mixture was evaporated under reduced pressure. The residue was purified by prep-TLC to afford the title product (50 mg) as yellow oil. LCMS: (ES
+) : m/z 419.3 [1/2M+1]
+.
Step 6: (7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoroquinazolin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate
To a solution of tert-butyl (1R, 5S) -3- (7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (50 mg, 0.060 mmol) in MeCN (0.5 mL) was added HCl/dioxane (4 M, 1 mL) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to afford the title product (4.7 mg, 99.1%purity) as a white solid. LCMS: (ES
+) : m/z 693.2 [M+1
+.
1H NMR (400 MHz, CDCl
3) δ 7.87 (dd, J = 8.4, 2.6 Hz, 1H) , 7.80 (dd, J = 8.8, 5.4 Hz, 1H) , 7.41 –7.30 (m, 3H) , 7.10 (t, J = 2.4 Hz, 1H) , 4.70 –4.52 (m, 4H) , 4.50 –4.40 (m, 1H) , 4.40 –4.30 (m, 1H) , 4.21-4.10 (m, 1H) , 3.91 (s, 2H) , 3.83 –3.64 (m, 2H) , 3.53 -3.45 (m, 1H) , 3.38 -3.33 (m, 1H) , 2.87 (t, J = 12.2 Hz, 6H) , 2.43 -2.26 (m, 2H) , 2.24 –1.92 (m, 10H) .
Example 27
(7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate
Step 1: Tert-butyl (1R, 5S) -3- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (3.5 g, 7.1 mmol) in anhydrous DMSO (30 mL) was added KF (3.3 g, 57.4 mmol) under N
2. The reaction mixture was stirred at 100 ℃ for 8 h. The reaction mixture was cooled to r.t., then poured into water (50 mL) . The aqueous phase was extracted with EtOAc (60 mL x 3) . The combined organic phase was washed with brine (30 mL) and dried over Na
2SO
4. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title product (4.5 g) as a yellow solid. LCMS: (ES+) : m/z 473.0 [M+1]
+.
Step 2: Tert-butyl (1R, 5S) -3- (7-bromo-2- ( (3- ( ( (tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of (3- ( ( (tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (3.0 g, 10.6 mmol) in THF (30 mL) was added NaH (421 mg, 10.6 mmol, 60 w%) at 0 ℃ under N
2. The reaction mixture was stirred at 0 ℃ for 0.5 h. Then tert-butyl (1R, 5S) -3- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (2.5 g, 5.2 mmol) in THF (30 mL) was added. The reaction mixture was stirred at 0 -20 ℃ for 3 h. The reaction mixture was poured into water (50 mL) . The aqueous phase was extracted with DCM (60 mL x 3) . The combined organic phase was washed with brine (30 mL) and dried over Na
2SO
4. The organic layer was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title product (1.5 g) as a yellow solid. LCMS: (ES+) : m/z 369.7 [1/2M+1]
+.
Step 3: Tert-butyl (1R, 5S) -3- (7-bromo-6, 8-difluoro-2- ( (3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-2- ( (3- ( ( (tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1.5 g, 2.0 mmol) in THF (15 mL) was added TBAF (12 mL, 1 mol/L, 12.0 mmol) . The reaction mixture was stirred at 25 ℃for 4 h. The reaction mixture was poured into water (50 mL) . The aqueous phase was extracted with EtOAc (50 mL x 3) . The combined organic phase was washed with brine (50 mL x 2) and dried over Na
2SO
4. The organic layer was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title product (1.2 g) as a yellow solid. LCMS: (ES
+) : m/z 624.2 [M+1]
+.
Step 4: Tert-butyl (1R, 5S) -3- (7-bromo-2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-6, 8-difluoro-2- ( (3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1.2 g, 1.9 mmol) in THF (10 mL) was added 4-nitrophenyl chloroformate (774 mg, 3.8 mmol) , followed by Et
3N (584 mg, 5.7 mmol) . The mixture was stirred at 25 ℃ for 1 h. Then methylamine (2.0 M, 5.8 mL, 11.5 mmol) was added. The mixture was stirred at 25 ℃ for 2 h. The reaction mixture was poured into water (40 mL) . The aqueous phase was extracted with EtOAc (50 mL x 3) . The combined organic phase was washed with brine (30 mL) and dried over Na
2SO
4. The organic layer was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title product (680 mg, 52.3%yield) as a yellow oil. LCMS: (ES
+) : m/z 695.2 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 7.31 (d, J = 9.5 Hz, 1H) , 4.48 –4.20 (m, 6H) , 4.19 –4.11 (m, 1H) , 3.47 (d, J = 44.1 Hz, 3H) , 2.92 (s, 6H) , 2.77 (d, J = 7.0 Hz, 1H) , 2.22 (s, 1H) , 1.94 (s, 13H) , 1.51 (s, 9H)
Step 5: Tert-butyl (1R, 5S) -3- (7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.1 g, 0.15 mmol) and (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) trimethylstannane (60 mg, crude) in toluene (1 mL) was added Pd (dppf) Cl
2 (10 mg, 0.015 mmol) , BINAP (20.0 mg, 0.032 mmol) and CuI (10 mg, 0.053 mmol) under N
2. The reaction mixture was stirred at 100 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC to afford the title product (50 mg) as a yellow oil. LCMS: (ES
+) : m/z 428.3 [1/2M+1]
+.
Step 6: (7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-chloro-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoroquinazolin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate
To a solution of tert-butyl (1R, 5S) -3- (7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (50 mg, 0.06 mmol) in MeCN (0.5 mL) was added HCl/dioxane (4 M, 1.0 mL) . The reaction mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to afford the product (18.8 mg, 98.1%purity) as a white solid. LCMS: (ES+) : m/z 711.3 [M+1]
+.
1H NMR (400 MHz, MeOD) δ 7.82 (dd, J = 9.2, 5.6 Hz, 1H) , 7.63 (d, J = 9.4 Hz, 1H) , 7.43-7.37 (m, 2H) , 7.14 (d, J = 2.2 Hz, 1H) , 4.71 -4.47 (m, 5H) , 4.39 -4.31 (m, 1H) , 4.27 -4.18 (m, 1H) , 4.17 -4.09 (m, 2H) , 3.91-3.74 (m, 2H) , 3.60 -3.53 (m, 1H) , 3.43 -3.34 (m, 1H) , 2.95 -2.85 (m, 6H) , 2.48 -2.32 (m, 2H) , 2.25 -2.01 (m, 10H) .
Example 28
(7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoroquinazolin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate
Step 1: Tert-butyl (1R, 5S) -3- (2- ( (1- ( ( (dimethylcarbamoyl) oxy) methyl) hexa hydropentalen-3a (1H) -yl) methoxy) -7- (8-ethyl-7-fluoro-3- (methoxyethoxy) aphthalen-1-yl) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (60 mg, 0.089 mmol) , 2- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (64 mg, 0.18 mmol) and sodium carbonate (33 mg, 0.31 mmol) in dioxane (1.0 mL) and water (0.25 mL) was added Pd (PPh
3)
4 (10 mg, 0.01 mmol) , the mixture was degassed with N
2 for 5-10 mins. The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure at 40 ℃. The residue was purified by prep-TLC to afford the title product (20 mg) as yellow oil. LCMS: (ES
+) : m/z 416.3 [1/2M+1]
+.
Step 2: (7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3- hydroxynaphthalen-1-yl) -8-fluoroquinazolin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate
To a solution of tert-butyl (1R, 5S) -3- (2- ( (1- ( ( (dimethylcarbamoyl) oxy) methyl) hexahydropentalen-3a (1H) -yl) methoxy) -7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (20 mg, 0.027 mmol) in MeCN (0.5 mL) was added HCl/dioxane (4 M, 1 mL) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to afford the title product (2.7 mg, 97.8%purity) as a yellow solid. LCMS: (ES
+) : m/z 687.3 [M+1]
+.
1H NMR (400 MHz, MeOD) δ 7.90 (d, J = 8.0 Hz, 1H) , 7.70 -7.63 (m, 1H) , 7.42 -7.35 (m, 1H) , 7.29 -7.21 (m, 2H) , 6.96 -6.92 (m, 1H) , 4.70 -4.54 (m, 5H) , 4.51 -4.43 (m, 1H) , 4.40 -4.30 (m, 1H) , 4.25 -4.14 (m, 1H) , 4.02 -3.93 (m, 2H) , 3.84 -3.70 (m, 2H) , 3.40 -3.34 (m, 1H) , 2.88 (t, J = 13.2 Hz, 6H) , 2.51 -2.28 (m, 4H) , 2.25 -2.15 (m, 2H) , 2.11 -1.97 (m, 8H) , 0.76 (t, J = 6.5 Hz, 3H) .
Example 29
(7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate
Step 1: Tert-butyl (1R, 5S) -3- (7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo 3.2.1] octane-8-carboxylate
A solution of tert-butyl (1R, 5S) -3- (7-bromo-2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (180 mg, 0.26 mmol) , 2- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (187 mg, 0.52 mmol) , Pd (PPh
3)
4 (30 mg, 0.026 mmol) and Na
2CO
3 (41 mg, 0.39 mmol) in dioxane/H
2O (2 mL/0.5 mL) was stirred at 110 ℃ for 16 h under N
2. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC to give crude product (110 mg) as yellow oil. Then it was purified by prep-HPLC (TFA) to afford to afford the title product (68 mg) as a white solid. LCMS: (ES
+) : m/z 425.3 [1/2M+1]
+.
Step 2: (7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -6, 8-difluoroquinazolin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate
To a solution of tert-butyl (1R, 5S) -3- (7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin- 7a (5H) -yl) methoxy) -6, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (68 mg, 0.08 mmol) in MeCN (0.5 mL) was added HCl/dioxane (4 M, 1.0 mL) . The reaction mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (32.2 mg, 99%HPLC purity, retention time: 7.930 min) as a white solid. HPLC method: Column: Pursuit XRs C18 (4.6*250mm, 5.0 μm) ; eluent A: 0.02%TFA in H
2O; eluent B: 0.02%TFA in CAN; gradient: 10%B to 100%B in 10 min, 100%B from 10 to12 min, then to 10%B in 13 min, 10%B to 20 min at a flow rate of 1.2 mL/min, 220 &254 nM. LCMS: (ES+) : m/z 705.3 [M+1]
+.
1H NMR (400 MHz, MeOD) δ 7.81 (d, J = 9.2 Hz, 1H) , 7.75 -7.67 (m, 1H) , 7.35 -7.32 (m, 1H) , 7.28 (t, J =9.4 Hz, 1H) , 7.02 -6.98 (m, 1H) , 4.82 -4.72 (m, 4H) , 4.56 -4.48 (m, 1H) , 4.40 -4.24 (m, 4H) , 4.10 -3.92 (m, 2H) , 3.68 -3.56 (m, 1H) , 3.50 -3.38 (m, 1H) , 2.92 (d, J = 28.2 Hz, 6H) , 2.63 -2.50 (m, 1H) , 2.49 -2.37 (m, 3H) , 2.30 -2.04 (m, 10H) , 0.82 (t, J = 6.4 Hz, 3H) .
Example 31
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6, 8-difluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol
Step 1: 3-Bromo-2, 4-difluoro-6-iodoaniline
A solution of 3-bromo-2, 4-difluoroaniline (5.0 g, 24.1 mmol) and silver sulfate (7.4 g, 24.1 mmol) and iodine (6.7 g, 26.5 mmol) in ethanol (100 mL) was stirred at 20 ℃ for 4 h. The mixture was filtered and the filtrates were concentrated under reduced pressure. The residue was purified by flash chromatography to afford the title product (5.4 g, 67.5%yield) as yellow solid.
1H NMR (400 MHz, CDCl
3) δ 7.28 (dd, J = 7.5, 2.2 Hz, 1H) , 4.05 (s, 2H) .
Step 2: Methyl 2-amino-4-bromo-3, 5-difluorobenzoate
Under carbon monoxide, a solution of 3-bromo-2, 4-difluoro-6-iodoaniline (5.4 g, 16.2 mmol) and Pd (dppf) Cl
2 (1.1 g, 1.6 mmol) in methanol (180 mL) was stirred at 25 ℃for 5 min. Then triethylamine (7.5 mL, 113.2 mmol) was added, and the mixture was stirred at 25 ℃ for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to afford the title product (3.0 g, 67.5%yield) as yellow solid. LCMS: (ESI) : m/z = 265.9 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 7.46 (dd, J = 9.2, 2.2 Hz, 1H) , 5.71 (s, 2H) , 3.89 (s, 3H) .
Step 3: Methyl 4-bromo-3, 5-difluoro-2- (3- (2, 2, 2-trichloroacetyl) ureido) benzoate
To a solution of methyl 2-amino-4-bromo-3, 5-difluorobenzoate (2.0 g, 7.5 mmol) in THF (30 mL) was added 2, 2, 2-trichloroacetyl isocyanate (1.6 g, 8.3 mmol) at 0 ℃. The reaction mixture was stirred at 25 ℃ for 0.5 h. The mixture was concentrated under reduced pressure. The residue was triturated with MTBE (30 mL) to afford the title product (3.2 g, crude) as a white solid.
Step 4: 7-Bromo-6, 8-difluoroquinazoline-2, 4-diol
A solution of methyl 4-bromo-3, 5-difluoro-2- (3- (2, 2, 2-trichloroacetyl) ureido) benzoate (3.2 g, 7.0 mmol) in NH
3. H
2O (30 mL) was stirred at 25 ℃ for 1 h. The reaction mixture was filtered and the filter cake was dried under reduced pressure. The residue was triturated with MTBE (30 mL) to afford the title product (1.8 g, crude) as white solid. LCMS: (ESI) : m/z = 275.0, 276.8 [M-1]
-.
1H NMR (400 MHz, DMSO-d
6) δ 7.55 (dd, J = 8.3, 1.5 Hz, 1H) .
Step 5: 7-Bromo-2, 4, 6-trichloro-8-fluoroquinazoline
A solution of 7-bromo-6, 8-difluoroquinazoline-2, 4-diol (1.0 g, 3.6 mmol) in POCI
3 (30 mL) was stirred at 120 ℃ for 5 min. Then DIEA (9.3 g, 72.2 mmol) was added and stirred at 120 ℃ for 3 h. The mixture was concentrated under reduced pressure to afford the title product (1.1 g, crude) as yellow oil, which was used for next step without purification.
Step 6: Tert-butyl (1R, 5S) -3- (7-bromo-2-chloro-6, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of 7-bromo-2, 4, 6-trichloro-8-fluoroquinazoline (1.1 g, crude) in DCM (10 mL) was added DIEA (0.9 g, 7.0 mmol) . Then tert-butyl (1R, 5S) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.89 g, 4.2 mmol) was added at -60 ℃. The reaction mixture was stirred at -60 ℃ for 0.5 h. The mixture was poured into water (20 mL) , then extracted with DCM (20 mL x 3) . The combined organic phases were washed with brine (30 mL) and dried over Na
2SO
4. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title product (0.42 g, crude) as a yellow solid. LCMS: (ESI) : m/z = 488.6, 490.6 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 7.39 (td, J = 9.2, 2.0 Hz, 1H) , 4.37 (d, J = 11.4 Hz, 4H) , 3.62 (s, 2H) , 2.01 -1.91 (m, 2H) , 1.74 (d, J = 7.5 Hz, 2H) , 1.52 (s, 9H) .
Step 7: Tert-butyl (1R, 5S) -3- (7-bromo-6-chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-2-chloro-6, 8-difluoro-quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.42 g, 0.86 mmol) in DMSO (3 mL) was added (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (0.36 g, 2.5 mmol) and KF (0.4 g, 6.8 mmol) under N
2. The mixture was stirred at 95 ℃ for 5 h. The mixture was poured into water (20 mL) , then extracted with DCM (30 mL x 3) . The combined organic phases were washed with brine (30 mL) and dried over Na
2SO
4. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to afford the product (0.23 g, crude) as yellow solid. LCMS: (ESI) : m/z = 594.2, 596.2 [M+1]
+.
Step 8: Tert-butyl (1R, 5S) -3- (7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-6-chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.23 g, 0.38 mmol) and (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) trimethylstannane (0.23 g, 0.58 mmol) in Toluene (1 mL) was added Pd (dppf) Cl
2 (28 mg, 0.038 mmol) , BINAP (48 mg, 0.077 mmol) and CuI (22 mg, 0.116 mmol) under N
2 atmosphere. The mixture was stirred at 100 ℃ for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC to afford the title product (80 mg, 20%purity) as yellow oil. LCMS: (ESI) : m/z = 377.7 [1/2M+1]
+.
Step 9: 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6-chloro-8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol
To a solution of tert-butyl (1R, 5S) -3- (7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (80.0 mg, 0.11 mmol) in MeCN (2 mL) was added HCl/dioxane (4 M, 4 mL) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (4.4 mg, 96%purity) as white solid. LCMS: (ESI) : m/z = 610.2 [M+1]
+.
1H NMR (400 MHz, CDCl
3) δ 7.58 (dd, J = 9.1, 5.5 Hz, 1H) , 7.28 -7.27 (m, 1H) , 7.25 -7.19 (m, 3H) , 4.41-4.28 (m, 4H) , 3.66 -3.59 (m, 2H) , 3.55 -3.36 (m, 4H) , 2.84 -2.74 (m, 2H) , 2.22 -2.15 (m, 2H) , 2.02 -1.89 (m, 5H) , 1.83 -1.72 (m, 7H) .
Example 32
(7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6-chloro-7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoroquinazolin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate
Step 1: Tert-butyl (1R, 5S) -3- (7-bromo-6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-2, 6-dichloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (4.8 g, 9.5 mmol) in DMSO (40 mL) was added KF (4.4 g, 75.9 mmol) . The mixture was stirred at 100 ℃ for 8 h. The mixture was cooled, poured into water (100 mL) and extracted with EtOAc (20 mL x 4) . The organic phase was dried over Na
2SO
4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title product (4.0 g, 86.1%yield) as yellow solid. LCMS: (ESI) : m/z = 489.0 [M+1]
+.
Step 2: Tert-butyl (1R, 5S) -3- (7-bromo-2- ( (3- ( ( (tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6-chloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of (3- ( ( (tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (3.5 g, 16.2 mmol) in THF (40 mL) was added NaH (0.66 g, 16.5 mmol, 60 w%) at 0 ℃ under N
2 atmosphere. The reaction mixture was stirred at 0 ℃for 0.5 h. Then tert-butyl (1R, 5S) -3- (7-bromo-6-chloro-2, 8-difluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (4.0 g, 8.1 mmol) was added. The mixture was stirred at 0 ℃ for 3 h. The mixture was added into water (10 mL) and extracted with DCM (10 mL x 3) . The organic phase was dried over Na
2SO
4 and concentrated. The residue was purified by column chromatography to give the title product (3.0 g, 48.6%yield) as yellow oil. LCMS: (ESI) : m/z = 754.1 [M+1]
+.
Step 3: Tert-butyl (1R, 5S) -3- (7-bromo-6-chloro-8-fluoro-2- ( (3- (hydroxymethyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-2- ( (3- ( ( (tert-butyldimethylsilyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -6-chloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (1.5 g, 2.0 mmol) in THF (10 mL) was added TBAF (1.0 mol/L, 12 mL, 12.0 mmol) , the mixture was stirred at 20 ℃ for 4 h. The mixture was poured into water (50 mL) and extracted with EtOAc (10 mL x 3) . The organic phase was dried over Na
2SO
4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title product (0.74 g, 57.9%yield) as yellow oil. LCMS: (ESI) : m/z = 640.2 [M+1]
+.
Step 4: Tert-butyl (1R, 5S) -3- (7-bromo-6-chloro-2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-6-chloro-8-fluoro-2- ( (3- (hydroxy methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.74 g) in THF (5 mL) was added 4-nitrophenyl chloroformate (0.35 g, 1.7 mmol) and by Et
3N (0.35 g, 3.5 mmol) . The mixture was stirred at 20 ℃ for 1 h, then methylamine (2.0 M, 4.6 mL, 9.2 mmol) was added. The mixture was stirred at 20 ℃ for 2 h. The mixture was poured into water (20 mL) and extracted with EtOAc (10 mL x 3) . The organic phase was dried over Na
2SO
4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title product (0.35 g, 42.5%yield) as yellow oil. LCMS: (ESI) : m/z = 711.1 [M+1]
+.
Step 5: Tert-butyl (1R, 5S) -3- (6-chloro-2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
A solution of tert-butyl (1R, 5S) -3- (7-bromo-6-chloro-2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.13 g, 0.16 mmol) , ( (2-fluoro-6- (methoxymethoxy) -8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (0.17 g, 0.33 mmol) , Na
2CO
3 (0.072 g, 0.67 mmol) and Pd (PPh
3)
4 (0.024 g, 0.021 mmol) in dioxane/water (1 mL/0.25 mL) was stirred at 95 ℃ for 3 h under N
2. The mixture was cooled and poured into water (10 mL) , extracted with ethyl acetate (10 mL x 3) . The organic layer was washed with water (10 mL) , brine (10 mL) and dried over sodium sulfate. The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC to give the title product (0.13 g, crude) as yellow oil. LCMS: (ESI) : m/z = 431.0 [1/2M+1]
+.
Step 6: (7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6-chloro-7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoroquinazolin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate
To a solution of tert-butyl (1R, 5S) -3- (6-chloro-2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.13 g, 0.15 mmol) in MeCN (0.5 mL) was added HCl/dioxane (4 M, 1 mL) . The mixture was stirred at 25 ℃ for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (9.5 mg, 95%purity) as a yellow solid. LCMS: (ESI) : m/z = 717.2 [M+1]
+.
1H NMR (400 MHz, CDCl
3) : δ 7.70 -7.62 (m, 2H) , 7.38 -7.32 (m, 2H) , 7.21 -1.13 (m, 2H) , 4.51 -4.20 (m, 6H) , 3.93 -3.82 (m, 1H) , 3.77 -3.67 (m, 2H) , 3.64 -3.52 (m, 2H) , 3.34 -3.26 (m, 1H) , 2.87 -2.79 (m, 8H) , 2.38 -2.28 (m, 1H) , 2.16 -1.59 (m, 12H) .
Example 33
(7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6-chloro-7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoroquinazolin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate
Step 1: Tert-butyl (1R, 5S) -3- (6-chloro-2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
A solution of tert-butyl (1R, 5S) -3- (7-bromo-6-chloro-2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.13 g, 0.16 mmol) , 2- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (0.12 g, 0.33 mmol) , Na
2CO
3 (0.072 g, 0.67 mmol) and Pd (PPh
3)
4 (0.024 g, 0.021 mmol) in dioxane/water (1 mL/0.25 mL) was stirred at 95 ℃ for 3 h under N
2. The mixture was cooled, poured into water (10 mL) and extracted with EtOAc (10 mL x 3) . The organic layer was washed with water (10 mL) , brine (10 mL) and dried over Na
2SO
4. The organic layer was concentrated under reduced pressure. The residue was purified by prep-TLC to give the title product (50.0 mg, crude) as yellow oil. LCMS: (ESI) : m/z =434.0 [1/2M+1]
+.
Step 2: (7a- ( ( (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6-chloro-7- (8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl) -8-fluoroquinazolin-2-yl) oxy) methyl) hexahydro-1H-pyrrolizin-3-yl) methyl dimethylcarbamate
To a solution of tert-butyl (1R, 5S) -3- (6-chloro-2- ( (3- ( ( (dimethylcarbamoyl) oxy) methyl) tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -7- (8-ethyl-7-fluoro-3- (methoxy methoxy) naphthalen-1-yl) -8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.13 g, 0.15 mmol) in MeCN (0.5 mL) was added HCl/dioxane (4 M, 1 mL) . The reaction mixture was stirred at 25 ℃ for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (0.8 mg, 92%purity) as yellow solid. LCMS: (ESI) : m/z = 721.2 [M+1]
+.
Example 34
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol
Step 1: Tert-butyl (1R, 5S) -3- (7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
A solution of tert-butyl (1R, 5S) -3- (7-bromo-8-fluoro-2- ( ( (2R, 7aS) -2-fluoro tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (200 mg, 0.33 mmol) , (8-chloro-7-fluoro-3- (methoxy methoxy) naphthalen-1-yl) trimethylstannane (272 mg, 0.67 mmol) , Pd (dppf) Cl
2 (25 mg, 0.033 mmol) , BINAP (42 mg, 0.067 mmol) and CuI (19.2 mg, 0.10 mmol) in toluene (2 mL) was stirred at 110 ℃ for 16 h under N
2. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-TLC to afford crude product (100 mg, 70%purity) as yellow oil. The residue was purified by prep-HPLC to offer the title product (45 mg) as a white solid. LCMS: (ES
+) : m/z 377.7 [1/2M+1]
+.
Step 2: 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-6-fluoronaphthalen-2-ol
To a solution of tert-butyl (1R, 5S) -3- (7- (8-chloro-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (45 mg, 0.06 mmol) in DCM (2 mL) was added HCl/dioxane (4 M, 4 mL) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (23.1 mg, 99.2%purity) as a white solid. LCMS: (ES
+) : m/z 610.3 [M+1]
+.
1H NMR (400 MHz, MeOD) δ 8.03 (d, J = 8.68 Hz, 1H) , 7.82 (dd, J = 9.28, 5.6 Hz, 1H) , 7.56 (t, J = 7.6 Hz, 1H) , 7.41 (t, J = 8.88 Hz, 1H) , 7.37 (d, J = 2.42 Hz, 1H) , 7.12 (t, J = 2.0 Hz, 1H) , 5.59 (d, J = 51.8 Hz, 1H) , 5.04 -4.92 (m, 2H) , 4.86 -4.79 (m, 1H) , 4.31 (s, 2H) , 4.15 -3.82 (m, 5H) , 3.51 -3.42 (m, 1H) , 2.83 -2.57 (m, 2H) , 2.53 -2.44 (m, 1H) , 2.42 -2.30 (m, 2H) , 2.28 -2.11 (m, 5H) .
19F NMR (376 MHz, Methanol-d
4) δ: 113.46, 130.13, 174.07.
Example 35
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2- fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol
Step 1: Tert-butyl (1R, 5S) -3- (7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-8-fluoro-2- ( ( (2R) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-Carboxylate (120 mg, 0.20 mmol) , 2- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (120 mg, 0.29 mmol) , sodium carbonate (78 mg, 0.73 mmol) in dioxane (2.0 mL) and water (0.4 mL) was added Pd (PPh
3)
4 (24 mg, 0.021 mmol) , the reaction mixture was stirred at 95 ℃ for 16 h under N
2. The reaction mixture was cooled and water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3) . The organic layer was washed with water (10 mL) , brine (10 mL) and dried over Na
2SO
4. The organic layer was concentrated under the reduced pressure. The residue was purified by prep-TLC to give the title product (26 mg, crude) as yellow oil. LCMS: (ES
+) : m/z 374.8 [1/2M+1]
+.
Step 2: 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2- fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol
To a solution of tert-butyl (1R, 5S) -3- (7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (26 mg, 0.035 mmol) in MeCN (0.5 mL) was added HCl/dioxane (4 M, 1.0 mL) . The reaction mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (11.7 mg, 94.6%HPLC purity, retention time: 7.669 min) as a white solid. HPLC method: Column Pursuit XRs C18 (4.6*250mm, 5.0 μm) ; eluent A: 0.02%TFA in H
2O; eluent B: 0.02%TFA in CAN; gradient: 10%B to 95%B in 10 min, 95%B from 10 to 12 min, then 10%B in 13 min, 10%B from 13-20 min at a flow rate of 1.2 mL/min, 220 &254 nM. Chemical Formula: C
34H
36F
3N
5O
2; Molecular Weight: 603.28. LCMS: (ES+) : m/z 604.3 [M+1]
+.
1H NMR (400 MHz, MeOD) : δ 8.14 (s, 1H) , 7.74 -7.62 (m, 2H) , 7.31 (m, 1H) , 7.27 (t, J = 9.2 Hz, 1H) , 6.98 (s, 1H) , 5.62 (d, J = 50.9 Hz, 1H) , 5.21 -4.95 (m, 4H) , 4.47 -4.16 (m, 4H) , 4.11 -3.79 (m, 3H) , 3.53 -3.41 (m, 1H) , 2.94 -1.97 (m, 12H) , 0.90 -0.75 (m, 3H) .
Example 36
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: Tert-butyl (1R, 5S) -3- (7-bromo-8-fluoro-2- ( ( (2R) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-2-chloro-8-fluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (500 mg, 1.0 mmol) in DMSO (5 mL) was added ( (2R) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (500 mg, 3.1 mmol) and KF (500 mg, 8.6 mmol) . The reaction mixture was stirred at 95 ℃ for 16 h. To the mixture was added water (10 ml) , and extracted with DCM (10 mL x 3) . The organic phase was dried over Na
2SO
4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel to give the title product (350 mg, 54.4%yield) as a yellow solid. LCMS: (ES
+) : m/z 594.2 [M+1]
+.
Step 2: Tert-butyl (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-8-fluoro-2- ( ( (2R) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.2 g, 0.33 mmol) , ( (2-fluoro-6- (methoxymethoxy) -8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (0.26 g, 0.50 mmol) and sodium carbonate (0.13 g, 1.2 mmol) in dioxane (5.0 mL) and water (1.0 mL) was added Pd (PPh
3)
4 (40.0 mg, 0.035 mmol) , the reaction vessel was degassed with N
2 for 5-10 mins. The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was cooled, water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3) . The organic layer was washed with water (10 mL) , brine (10 mL) and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title product (140 mg, 46.5%yield) as a white solid.
1H NMR (400 MHz, CDCl
3) : δ 7.74 (dd, J = 9.0, 5.7 Hz, 1H) , 7.62 (d, J = 9.0 Hz, 1H) , 7.45 (d, J = 2.3 Hz, 1H) , 7.36 (t, J = 6.5 Hz, 1H) , 7.25 (t, J = 8.7 Hz, 1H) , 7.10 (d, J = 2.1 Hz, 1H) , 5.77 (s, 5H) , 5.45 (dd, J = 51.6, 11.3 Hz, 1H) , 5.26 –5.19 (m, 2H) , 4.96 (s, 1H) , 4.72 (dd, J = 73.5, 11.6 Hz, 2H) , 4.52 –4.32 (m, 3H) , 4.14 –3.94 (m, 2H) , 3.57 –3.48 (m, 1H) , 3.45 (s, 3H) , 3.27 (s, 1H) , 2.68 (dd, J = 37.2, 13.4 Hz, 1H) , 2.45 (dd, J = 33.4, 19.8 Hz, 2H) , 2.23 (s, 3H) , 1.97 (s, 2H) , 1.68 (d, J =52.2 Hz, 2H) , 1.46 (s, 9H) , 0.90 –0.67 (m, 18H) , 0.61 –0.48 (m, 3H) .
Step 3: Tert-butyl (1R, 5S) -3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.14 g, 0.15 mmol) in DMF (5 mL) was added CsF (237 mg, 1.56 mmol) . The mixture was stirred at 25 ℃ for 16 h. After completion, the mixture was cooled to r.t., then water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3) . The organic layer was washed with water (10 mL) , brine (10 mL) and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford the crude product, which was used in the next step without further purification.
Step 4: 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
To a solution of tert-butyl (1R, 5S) -3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (100 mg, 0.13 mmol) in MeCN (1 mL) was added HCl/dioxane (4 M, 2 mL) . The reaction mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated. The residue was purified by prep-HPLC to afford the title product (20.2 mg, 99.6%HPLC purity, retention time: 7.410 min) as a white solid. HPLC method: Column Pursuit XRs C18 (4.6*250mm, 5.0 μm) ; eluent A: 0.02%TFA in H
2O; eluent B: 0.02%TFA in CAN; gradient: 10%B to 95%B in 10 min, 95%B from 10 to 12 min, then 10%B in 13 min, 10%B from 13-20 min at a flow rate of 1.2 mL/min, 220 &254 nM. LCMS: (ES+) : m/z 600.2 [M+1]
+.
1H NMR (400 MHz, MeOD) : δ 7.89 -7.79 (m, 2H) , 7.38 -7.26 (m, 3H) , 7.09 (d, J = 2.4 Hz, 1H) , 5.43 (d, J = 51.4 Hz, 1H) , 4.68 -4.40 (m, 5H) , 3.94 (s, 2H) , 3.78 -3.51 (m, 5H) , 3.28 -3.24 (m, 1H) , 2.58 -2.25 (m, 3H) , 2.23 -2.13 (m, 2H) , 2.08 -1.95 (m, 5H) .
Example 37
3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-4-cyclopropylphenol
Step 1: Tert-butyl (1R, 5S) -3- (7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (200 mg, 0.33 mmol) , 2- (3-chloro-2-cyclopropyl-5-(methoxymethoxy) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (171 mg, 0.50 mmol) , sodium carbonate (125 mg, 1.1 mmol) in dioxane (3.5 mL) and water (0.7 mL) was added Pd (PPh
3)
4 (39 mg, 0.034 mmol) , the reaction vessel was degassed with N
2 for 5-10 mins. The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was cooled to r.t., then water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3) . The organic layer was washed with water (10 mL) , brine (10 mL) and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title product (20 mg) as a white solid. LCMS: (ES
+) : m/z 363.8 [1/2M+1]
+.
Step 2: 3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-4-cyclopropylphenol
To a solution of tert-butyl (1R, 5S) -3- (7- (3-chloro-2-cyclopropyl-5- (methoxymethoxy) phenyl) -8-fluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (20 mg, 0.027 mmol) in MeCN (0.5 mL) was added HCl/dioxane (4 M, 1.0 mL) . The reaction mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC to afford the title product (10 mg, 97%HPLC purity, retention time: 7.569 min) as a white solid. HPLC method: Column Pursuit XRs C18 (4.6*250mm, 5.0 μm) ; eluent A: 0.02%TFA in H
2O; eluent B: 0.02%TFA in CAN; gradient: 10%B to 95%B in 10 min, 95%B from 10 to 12 min, then 10%B in 13 min, 10%B from 13-20 min at a flow rate of 1.2 mL/min, 220 &254 nM. LCMS: (ES+) : m/z 582.2 [M+1]
+.
1H NMR (400 MHz, MeOD) : δ 8.09 (s, 1H) , 7.57 (s, 1H) , 6.98 (s, 1H) , 6.70 (s, 1H) , 5.62 (m, J = 51.7 Hz, 1H) , 5.18 -4.97 (m, 3H) , 4.42 -3.83 (m, 7H) , 3.52 -3.42 (m, 1H) , 2.92 -2.08 (m, 1H) , 1.90 -1.78 (m, 11H) , 0.82 -0.58 (m, 2H) , 0.23 -0.01 (m, 2H) .
Example 39
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol
Step 1: Tert-butyl (1R, 5S) -3- (7-bromo-6, 8-difluoro-2- ( ( (2R) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-2, 6, 8-trifluoroquinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (0.5 g, 1.3 mmol) in DMSO (5 mL) was added ( (2R) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methanol (500 mg, 3.1 mmol) and KF (500 mg, 8.6 mmol) . The reaction mixture was stirred at 95 ℃ for 16 h. The mixture was cooled to r.t., then water (10 mL) was added. The mixture was extracted with DCM (10 mL x 3) . The combined organic phase was dried over Na
2SO
4 and evaporated. The residue was purified by column chromatography on silica gel to give title product (350 mg, 54.4%yield) as a yellow solid. LCMS: (ES
+) : m/z 613.2 [M+1]
+.
Step 2: Tert-butyl (1R, 5S) -3- (7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a solution of tert-butyl (1R, 5S) -3- (7-bromo-6, 8-difluoro-2- ( ( (2R) -2-fluoro tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (220 mg, 0.36 mmol) , 2- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (220 mg, 0.54 mmol) and sodium carbonate (143 mg, 1.3 mmol) in dioxane (2.0 mL) and water (0.4 mL) was added Pd (PPh
3)
4 (44 mg, 0.038 mmol) , the reaction vessel was degassed with N
2 for 5-10 mins. The reaction mixture was stirred at 95 ℃ for 16 h. The reaction mixture was cooled to r.t., then water (10 mL) was added. The mixture was extracted with ethyl acetate (10 mL x 3) . The organic layer was washed with water (10 mL) , brine (10 mL) and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title product (50 mg) as a white solid. LCMS: (ES
+) : m/z 383.9 [1/2M+1]
+.
Step 3: 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-ethyl-6-fluoronaphthalen-2-ol
To a solution of tert-butyl (1R, 5S) -3- (7- (8-ethyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (50 mg, 0.065 mmol) in MeCN (0.5 mL) was added HCl/dioxane (4 M, 1.0 mL) . The reaction mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC to afford the title product (13 mg, 93.9%HPLC purity, retention time: 7.808 min) as a white solid. HPLC method: Column Pursuit XRs C18 (4.6*250mm, 5.0 μm) ; eluent A: 0.02%TFA in H
2O; eluent B: 0.02%TFA in CAN; gradient: 10%B to 95%B in 10 min, 95%B from 10 to 12 min, then 10%B in 13 min, 10%B from 13-20 min at a flow rate of 1.2 mL/min, 220 &254 nM.
Another batch of 101.6 mg racemic title product was obtained following the same procedure. After separation by SFC, 37.2 mg of atropisomer 1 with 97.4%ee &99.5%HPLC purity and 37.6 mg of atropisomer 2 with 95.2%ee &96.8%HPLC purity were obtained respectively. Chemical Formula: C
34H
35F
4N
5O
2; M. W. : 621.68.
SFC condition: column: CHIRAL ART Cellulose-SZ 3cm × 25cm, 5um; mobile phase: CO2: [MeOH: DCM = 1: 1 (0.2%2mM NH3 MeOH) ] = 55: 45; flow rate: 80 mL/min.
CHIRAL_SFC Analysis method: column: Cellulose-SZ 100x4.6mm 3.0um; co solvent: MeOH (60%DCM+20mMNH3) . Retention time of atropisomer 1 is 1.896 min. and atropisomer 2 is 2.145 min.
Atropisomer 1: LCMS: (ES
+) : m/z 622.3 [M+1]
+.
1H NMR (400 MHz, Methanol-d
4) δ7.67 (dd, J = 8.9, 6.0 Hz, 1H) , 7.61 (d, J = 10.2 Hz, 1H) , 7.28 (d, J = 2.2 Hz, 1H) , 7.24 (t, J = 9.3 Hz, 1H) , 6.97 (d, J = 2.1 Hz, 1H) , 5.30 (d, J = 53.4 Hz, 2H) , 4.47 (t, J = 14.3 Hz, 2H) , 4.24 (dd, J = 29.4, 10.4 Hz, 2H) , 3.73 –3.53 (m, 4H) , 3.27 –3.16 (m, 2H) , 3.01 (d, J = 5.3 Hz, 1H) , 2.64 –2.52 (m, 1H) , 2.37 (dd, J = 24.1, 9.3 Hz, 2H) , 2.29 –2.10 (m, 3H) , 2.05 –1.93 (m, 2H) , 1.86 (s, 5H) , 0.80 (t, J = 7.4 Hz, 3H) .
19F NMR (376 MHz, Methanol-d
4) δ -118.74 (d, J = 34.8 Hz) , -121.19, -124.40 (d, J = 4.4 Hz) , -173.61.
Atropisomer 2: LCMS: (ES
+) : m/z 622.3 [M+1]
+.
1H NMR (400 MHz, Methanol-d
4) δ7.67 (dd, J = 8.8, 6.0 Hz, 1H) , 7.60 (d, J = 9.9 Hz, 1H) , 7.28 (d, J = 2.4 Hz, 1H) , 7.24 (t, J = 9.4 Hz, 1H) , 6.97 (d, J = 2.3 Hz, 1H) , 5.30 (d, J = 54.2 Hz, 1H) , 4.46 (dd, J =35.3, 12.6 Hz, 2H) , 4.23 (dd, J = 33.4, 10.4 Hz, 2H) , 3.70 –3.49 (m, 4H) , 3.27 -3.15 (m, 2H) , 3.07 –2.94 (m, 1H) , 2.64 –2.48 (m, 1H) , 2.46 –2.30 (m, 2H) , 2.29 –2.08 (m, 3H) , 2.06 –1.72 (m, 7H) , 0.79 (t, J = 7.4 Hz, 3H) .
19F NMR (376 MHz, Methanol-d
4) δ -118.86 (d, J = 4.2 Hz) , -121.20, -124.39 (d, J = 4.5 Hz) , -173.63.
Example 40
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
Step 1: Tert-butyl (1R, 5S) -3- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a 50 mL round bottom flask, tert-butyl (1R, 5S) -3- (7-bromo-6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (200 mg, 0.327 mmol) , ( (2-fluoro-6- (methoxy methoxy) -8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (251 mg, 0.49 mmol) , Potassium phosphate tribasic (174 mg, 0.82 mmol) , dioxane (6.0 mL) and water (2.0 mL) were added. The reaction vessel was degassed with N
2 for 5-10 mins. To the same reaction mixture, Methanesulfonato (diadamantyl-n-butylphosphino) -2'-amino-1, 1'-biphenyl-2-yl) palladium (II) dichloromethane adduct, min. 95% [cataCXium (R) A Palladacycle Gen. 3] (36 mg, 0.050 mmol) was added, and the mixture again degassed with N
2 for 5-10 mins. The reaction mixture was stirred at 60 ℃ for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product: isomer 1 (20 mg) and isomer 2 (30 mg) as white solid. LCMS: (ES
+) : m/z 459.8 [1/2M+1]
+.
Step 2: Tert-butyl (1R, 5S) -3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To the solution of tert-butyl (1R, 5S) -3- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8 diazabicyclo [3.2.1] octane-8-carboxylate isomer 1 (20 mg, 0.022 mmol) in DMF (2 mL) was added CsF (16 mg, 0.105 mmol) . The mixture was stirred at 25 ℃ for 2 h. After completion, the reaction mixture was cooled and water (5 mL) was added. The aqueous layer was extracted with EtOAc (10 mL x 3) . The organic layer was washed with water, brine and dried over sodium sulfate. The organic layer was evaporated under reduced pressure to give the crude title product (30 mg) , which was used int the next step without further purification.
Following the same procedure, the de-TIPS reaction of tert-butyl (1R, 5S) -3- (6, 8-difluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8 diazabicyclo [3.2.1] octane-8-carboxylate isomer 2 give the title crude product (40 mg) .
Step 3: 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
To a solution of tert-butyl (1R, 5S) -3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) - yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate isomer 1 (30 mg, 0.039 mmol) in MeCN (0.5 mL) was added HCl/dioxane (4 M, 1 mL) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product isomer 1 (1.7 mg, 98.7%HPLC purity, retention time: 7.454 min) as a white solid.
To a solution of tert-butyl (1R, 5S) -3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate isomer 2 (40 mg, 0.053 mmol) in MeCN (0.5 mL) was added HCl/dioxane (4 M, 1 mL) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product isomer 2 (4.2 mg, 97.4%HPLC purity, retention time: 7.490 min) as a white solid. HPLC method: Column Pursuit XRs C18 (4.6*250mm, 5.0 μm) ; eluent A: 0.02%TFA in H
2O; eluent B: 0.02%TFA in CAN; gradient: 10%B to 95%B in 10 min, 95%B from 10 to 12 min, then 10%B in 13 min, 10%B from 13-20 min at a flow rate of 1.2 mL/min, 220 &254 nM. Chemical Formula: C
34H
31F
4N
5O
2, Molecular Weight: 617.65. LCMS: (ES
+) : m/z 618.3 [M+H]
+. Isomer 1:
1H NMR (400 MHz, MeOD) δ7.86 (dd, J = 9.2, 5.8 Hz, 1H) , 7.54 (d, J = 9.6 Hz, 1H) , 7.36 -7.28 (m, 2H) , 7.11 (d, J = 2.0 Hz, 1H) , 5.41 (d, J = 52.6 Hz, 1H) , 4.57 (d, J = 13.2 Hz, 1H) , 4.53 -4.36 (m, 3H) , 3.92 (s, 2H) , 3.77 -3.42 (m, 5H) , 3.26 -3.15 (m, 1H) , 2.55 -2.33 (m, 2H) , 2.32 -2.21 (m, 1H) , 2.19 -2.08 (m, 2H) , 2.06 -1.92 (m, 6H) . Isomer 2:
1H NMR (400 MHz, MeOD) δ 7.86 (dd, J = 9.2, 5.8 Hz, 1H) , 7.57 (d, J = 9.6 Hz, 1H) , 7.37 -7.29 (m, 2H) , 7.11 (d, J = 1.8 Hz, 1H) , 5.46 (d, J = 52.8 Hz, 1H) , 4.64 (d, J = 21.6 Hz, 1H) , 4.59 -4.45 (m, 3H) , 4.06 (s, 2H) , 3.87 -3.58 (m, 5H) , 3.29 -3.25 (m, 1H) , 2.62 -2.42 (m, 2H) , 2.38 -2.28 (m, 1H) , 2.27 -2.17 (m, 2H) , 2.14 -1.97 (m, 6H) .
Example 41
3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2- fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-4-cyclopropylphenol
Step 1: Tert-butyl (1R, 5S) -3- (7- (3-chloro-2-cyclopropyl-5- (methoxymethoxy) phenyl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
A solution of tert-butyl (1R, 5S) -3- (7-bromo-6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (500 mg, 0.81 mmol) , 2- (3-chloro-2-cyclopropyl-5- (methoxymethoxy) phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (553 mg, 1.0 mmol) , Pd (PPh
3)
4 (95 mg, 0.08 mmol) and Na
2CO
3 (303 mg, 2.8 mmol) in dioxane/H
2O (8 mL/2 mL) was stirred at 110 ℃ for 16 h under N
2. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the crude product (600 mg, 60%purity) as yellow oil. The residue was purified by prep-HPLC (TFA) to afford the title product (220 mg) as a white gum. LCMS: (ES
+) : m/z 372.8 [1/2M+1]
+.
Step 2: 3- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-chloro-4-cyclopropylphenol
To a solution of tert-butyl (1R, 5S) -3- (7- (3-chloro-2-cyclopropyl-5- (methoxymethoxy) phenyl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (220 mg, 0.29 mmol) in MeCN (2 mL) was added HCl/dioxane (4 M, 4 mL) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to afford the title product (120 mg, 99.2%HPLC purity, retention time: 7.693 min) . HPLC method: Column Pursuit XRs C18 (4.6*250mm, 5.0 μm) ; eluent A: 0.02%TFA in H
2O; eluent B: 0.02%TFA in CAN; gradient: 10%B to 95%B in 10 min, 95%B from 10 to 12 min, then 10%B in 13 min, 10%B from 13-20 min at a flow rate of 1.2 mL/min, 220 &254 nM. LCMS: (ES
+) : m/z 600.3 [M+1]
+.
1H NMR (400 MHz, MeOD) δ 7.65 (d, J = 10.8 Hz, 1H) , 6.96 (d, J = 1.8 Hz, 1H) , 6.65 (d, J = 1.6 Hz, 1H) , 5.52 (d, J = 52.0 Hz, 1H) , 4.71-4.51 (m, 4H) , 4.13 (s, 2H) , 3.91 -3.68 (m, 5H) , 3.42 -3.33 (m, 1H) , 2.70 -2.44 (m, 2H) , 2.42 -2.33 (m, 1H) , 2.32 -2.21 (m, 2H) , 2.19 -2.02 (m, 5H) , 1.78 -1.69 (m, 1H) , 0.66 -0.55 (m, 2H) , 0.19 -0.13 (m, 2H) .
Example 56
4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-cyclopropyl-6-fluoronaphthalen-2-ol
Step 1: (E) -6-Methoxy-3, 4-dihydronaphthalen-1 (2H) -one O-methyl oxime
To a solution of 6-methoxy-3, 4-dihydronaphthalen-1 (2H) -one (30 g, 1.0 eq) and O-methylhydroxylamine hydrochloride (16.1 g, 1.2 eq) in ethanol (300 mL) and pyridine (19.1 g, 1.5 eq) was stirred at 25 ℃ for 2 h. The reaction mixture was concentrated to give an oil. The oil was dissolved in dichloromethane, washed with aq. HCl (2 M) , aq. sat. Na
2CO
3 and brine in sequence. The organic layer was dried over Na
2SO
4 and filtered. The filtrates were concentrated to afford the title product (36.4 g) as a yellow oil, which was used directly in the next step without purification. LCMS: (ES
+) : m/z 206.1 [M+1]
+.
Step 2: (E) -8-Chloro-6-methoxy-3, 4-dihydronaphthalen-1 (2H) -one O-methyl oxime
A solution of (E) -6-methoxy-3, 4-dihydronaphthalen-1 (2H) -one O-methyl oxime (36.4 g, 1.0 eq) , NCS (23.7 g, 1.0 eq) and Pd (OAc)
2 (1.98 g, 0.05 eq) in AcOH (360 mL) was stirred at 80 ℃ for 2 h. The reaction mixture was poured into water and filtered. The cake was dried to afford the title product (48 g) as a black oil, which was used directly in the next step without purification. LCMS: (ES
+) : m/z 240.1 [M+1]
+.
Step 3: 8-Chloro-6-methoxy-3, 4-dihydronaphthalen-1 (2H) -one
A solution of (E) -8-chloro-6-methoxy-3, 4-dihydronaphthalen-1 (2H) -one O-methyl oxime (48 g, 1.0 eq) in concentrated hydrochloric acid (240 mL) and 1, 4-dioxane (360 mL) was stirred at 100 ℃ for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with aq. NaOH (1N) , water and brine in sequence. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate = 4/1) to afford the title product (24.8 g) as a yellow solid. LCMS: (ES
+) : m/z 233.1 [M+23]
+.
Step 4: 8-Chloro-2-fluoro-6-methoxy-3, 4-dihydronaphthalen-1 (2H) -one
To a solution of 8-chloro-6-methoxy-3, 4-dihydronaphthalen-1 (2H) -one (24.8 g, 1.0 eq) and selectfluor (62.8 g, 1.5 eq) in MeOH (250 ml) was added concentrated sulfuric acid (2 mL) . The reaction mixture was stirred at 50 ℃ for 5 h. The reaction mixture was concentrated, diluted with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate and filtered. The filtrates were concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate = 10/1) to afford the title product (26 g) as a yellow solid. LCMS: (ES+) : m/z 251.1 [M+23]
+.
Step 5: 2-Bromo-8-chloro-2-fluoro-6-methoxy-3, 4-dihydronaphthalen-1 (2H) -one
A solution of 8-chloro-2-fluoro-6-methoxy-3, 4-dihydronaphthalen-1 (2H) -one (26 g, 1.0 eq) and pyridinium tribromide (39.9 g, 1.1 eq) in acetonitrile (260 mL) was stirred at 60 ℃ for 30 min. The reaction mixture was concentrated. The residue was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate and filtered. The filtrates were concentrated. The residue was purified by column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate = 10/1) to afford the title product (33.4 g) as a yellow solid. LCMS: (ES
+) : m/z 329.0 [M+23]
+.
Step 6: 8-Chloro-2-fluoro-6-methoxynaphthalen-1-ol
A solution of 2-bromo-8-chloro-2-fluoro-6-methoxy-3, 4-dihydronaphthalen-1 (2H) -one (33.4 g, 1.0 eq) and lithium bromide (20.6 g, 2.2 eq) in DMF (300 mL) was stirred at 100 ℃ for 30 min. The reaction mixture was concentrated. The residue was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate and filtered. The filtrates were concentrated. The residue was purified by column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate = 10/1) to afford the title product (20.3 g) as a yellow solid. LCMS: (ES
-) : m/z 225.0 [M-1]
-.
Step 7: 8-Chloro-2-fluoro-6-methoxynaphthalen-1-yl trifluoromethanesulfonate
To a solution of 8-chloro-2-fluoro-6-methoxynaphthalen-1-ol (20 g, 1.0 eq) and TEA (49.9 g, 2.0 eq) in DCM (200 mL) was added Tf
2O at 0 ℃. The mixture was stirred at 0 ℃ for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate and filtered. The filtrates were concentrated. The residue was purified by column chromatography on silica gel (PE to PE/EA=10/1) to afford the title product (31 g) as a yellow solid.
1H NMR (400 MHz, MeOD) δ 7.96 (dd, J = 9.2, 5.2 Hz, 1H) , 7.53 (t, J = 9.6 Hz, 1H) , 7.43 (d, J = 2.4 Hz, 1H) , 7.37 (d, J = 2.4 Hz, 1H) , 3.93 (s, 3H) .
Step 8: 8-Chloro-1-cyclopropyl-2-fluoro-6-methoxynaphthalene
A solution of 8-chloro-2-fluoro-6-methoxynaphthalen-1-yltrifluoromethanesulfonate (5.0 g, 1.0 eq) , cyclopropylboronic acid (1.55 g, 1.3 eq) , K
3PO
4 (10.6 g, 3.6 eq) and Pd(dppf) Cl
2 (1.0 g, 0.1 eq) in dioxane (50 mL) and H
2O (10 mL) was stirred at 100 ℃for 4 h under N
2. The reaction mixture was filtered, diluted with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate and filtered. The filtrates were concentrated. The residue was purified by column chromatography on silica gel (petroleum ether) to afford the title product (2.5 g) as a yellow oil.
1H NMR (400 MHz, MeOD) δ 7.66 (dd, J = 8.9, 5.5 Hz, 1H) , 7.29 (d, J = 2.3 Hz, 1H) , 7.22 -7.14 (m, 2H) , 3.88 (s, 3H) , 2.33 -2.22 (m, 1H) , 1.15-1.11 (m, 2H) , 0.67 -0.57 (m, 2H) .
Step 9: 4-Chloro-5-cyclopropyl-6-fluoronaphthalen-2-ol
To a solution of 8-chloro-1-cyclopropyl-2-fluoro-6-methoxynaphthalene (2.3 g, 1.0 eq) in DCM (25 mL) was added BBr
3 (4.6 g, 2.0 eq) at -78 ℃. The mixture was stirred at -40 ℃ for 2 h. The reaction mixture was poured into ice water and diluted with ethyl acetate. The organic layer was washed with aq. sat. sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and filtered. The filtrates were concentrated. The residue was purified by column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate = 4/1) to afford the title product (1.1 g) as a colorless oil.
Step 10: 8-Chloro-1-cyclopropyl-2-fluoro-6- (methoxymethoxy) naphthalene
To a solution of 4-chloro-5-cyclopropyl-6-fluoronaphthalen-2-ol (1.0 g, 1.0 eq) and DIPEA (1.63 g, 3.0 eq) in DCM (10 mL) . The mixture was cooled to 0 ℃ and added MOMBr (1.05 g, 2.0 eq) . The mixture was stirred at 0 ℃ for 0.5 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate and filtered. The filtrates were concentrated. The residue was purified by column chromatography on silica gel (petroleum ether) to afford the title product (1.0 g) as a yellow oil.
1H NMR (400 MHz, MeOD) δ 7.66 (dd, J = 9.0, 5.4 Hz, 1H) , 7.38 (dd, J = 10.7, 2.4 Hz, 2H) , 7.20 (t, J = 9.6 Hz, 1H) , 5.28 (d, J = 3.8 Hz, 2H) , 3.49 (s, 3H) , 2.34 –2.23 (m, 1H) , 1.15 (q, J = 5.5 Hz, 2H) , 0.63 (d, J = 5.5 Hz, 2H) .
Step 11: 2- (8-Cyclopropyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane
A solution of 8-chloro-1-cyclopropyl-2-fluoro-6- (methoxymethoxy) naphthalene (1.0 g, 1.0 eq) B
2pin
2 (1.36 g, 1.5 eq) , KOAc (1.05 g, 3.0 eq) , Pd
2 (dba)
3 (327 mg, 0.1 eq) and PCy
3 (112 mg, 0.1 eq) in dioxane (10 ml) and H
2O (1 ml) was stirred at 90 ℃ overnight under N
2. The reaction mixture was filtered, diluted with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate and filtered. The filtrates were concentrated. The residue was purified by column chromatography on silica gel (petroleum ether to petroleum ether/ethyl acetate=10/1) to afford the title product (120 mg) as a yellow oil.
1H NMR (400 MHz, CDCl
3) δ 7.50 (dd, J = 8.9, 5.5 Hz, 1H) , 7.44 (d, J = 2.5 Hz, 1H) , 7.32 –7.27 (m, 1H) , 7.07 (dd, J = 16.4, 6.9 Hz, 1H) , 5.20 (d, J = 6.4 Hz, 2H) , 3.43 (s, 3H) , 2.31 –2.20 (m, 1H) , 1.32 (s, 12H) , 1.03 -1.01 (m, 2H) , 0.52 -0.44 (m, 2H) .
Step 12: Tert-butyl (1R, 5S) -3- (7- (8-cyclopropyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
To a 50 mL round bottom flask, tert-butyl (1R, 5S) -3- (7-bromo-6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (56 mg, 0.092 mmol) , 2- (8-cyclopropyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (40 mg, 0.10 mmol) , Cs
2CO
3 (60 mg, 0.18 mmol) and 1, 4-dioxane (2.0 mL) were added. The reaction vessel was degassed with N
2 for 5-10 mins. To the same reaction mixture, Pd(xantphos) Cl
2 (18 mg, 0.024 mmol) was added, and the mixture was degassed with N
2 for 5-10 mins. The reaction mixture was stirred at 90 ℃ for 16 h. The reaction mixture was evaporated under reduced pressure. The residue was purified by prep-TLC to afford the title product (20 mg) as a red oil. LCMS: (ES
+) : m/z 389.8 [1/2M+1]
+.
Step 13: 4- (4- ( (1R, 5S) -3, 8-Diazabicyclo [3.2.1] octan-3-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-7-yl) -5-cyclopropyl-6-fluoronaphthalen-2-ol
To a solution of tert-butyl (1R, 5S) -3- (7- (8-cyclopropyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -6, 8-difluoro-2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) quinazolin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate (20 mg, 0.026 mmol) in MeCN (0.5 mL) was added HCl/1, 4-dioxane (4 M, 1 mL) at 25 ℃. The reaction mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title product (2.8 mg, 98.4%HPLC purity, retention time: 8.024 min) as a white solid. HPLC method: Column Pursuit XRs C18 (4.6*250mm, 5.0 μm) ; eluent A: 0.02%TFA in H
2O; eluent B: 0.02%TFA in CAN; gradient: 10%B to 95%B in 10 min, 95%B from 10 to 12 min, then 10%B in 13 min, 10%B from 13-20 min at a flow rate of 1.2 mL/min, 220 &254 nM. Chemical Formula: C
35H
35F
4N
5O
2, Molecular Weight: 633.69. LCMS: (ES
+) : m/z 634.3 [M+1]
+.
1H NMR (400 MHz, DMSO-d
6) δ 7.66 (dd, J = 9.2, 5.8 Hz, 1H) , 7.49 (d, J = 10.6 Hz, 1H) , 7.22 -7.15 (m, 2H) , 6.98 (d, J = 10.6 Hz, 1H) , 5.15 (d, J = 54.0 Hz, 1H) , 4.22 (d, J = 12.8 Hz, 1H) , 4.10 (d, J = 12.2 Hz, 1H) , 3.91 (dd, J =39.0, 10.8 Hz, 2H) , 3.60 -3.56 (m, 2H) , 2.99 -2.94 (m, 2H) , 2.88 (s, 1H) , 2.88 (s, 1H) , 2.73 -2.66 (m, 1H) , 2.03 -1.53 (m, 12H) , 1.18 -1.13 (m, 2H) , 0.26 -0.05 (m, 4H) .
Pharmacological testing
1. KRAS G12D pERK assay:
The KRAS G12D pERK assay biochemical assay was carried out by Pharmaron.
The KRAS G12D pERK assay was performed in AGS Cell lines.
General assay procedure:
a) seed cells in 384 well plate and, incubate at 37℃, 5%CO2 overnight.
b) Add 200 nL serial diluted compound (final 0.5%DMSO) by Echo 550, incubate cells at 37℃&5%CO2.
c) Fixed cells
d) Wash with PBS once and permeate cells
e) Wash with PBS once.
f) Blocking at RT for 1 hr.
g) Remove blocking buffer and add primary antibody, incubate at 4℃ overnight.
h) Wash with PBST, soak 2 min each round, total 3 times.
i) Add secondary antibody, incubate at RT away from light.
j) Wash with PBST, soak 2 min each round, total 3 times.
k) Centrifuge plate up-side-down at 1000 rpm, 1 min and scan the plate withOdyssey CLx.
The results of KRAS G12D pERK assay are in the following Table 1.
Table 1: The result of KRAS G12D pERK assay
Example # | IC 50 | Example # | IC 50 |
Example 1 | C | Example 7 | C |
Example 4 | C | Example 11 | A |
Example 6 | B |
A means < 0.2 uM, B means ≥ 0.2 uM and ≤ 2 uM, C means > 2 uM
2. Cell proliferation Assay
Materials and instruments
The Cell proliferation assay was carried out by Pharmaron.
The cell proliferation assay was performed in AGS Cell lines (expressing KRAS G12D) in 3D model.
Cell culture
a) Day 1, seed cells in T75 flask,
b) Day 3, remove medium, and rinse with DPBS once,
c) Trpsinize cells with 2 mL TrypLE
TM Express Enzyme at room temperature (RT) or 37℃ until the cells detach.
d) Add 5 mL fresh culture medium, suspend cells then centrifuge at 1000 rpm for 5 min at RT.
e) Discard the supernatant and re-suspend cells with 5 mL fresh medium, count cells by Countess
TM II.
f) Seed cells back to T75 flask for further culture or into assay plates for 3D Cell Proliferation Assay.
3D Cell Proliferation Assay Experiment Procedure
a) Day 1. Add 200 nl diluted compound into each well with Echo. Seed cells into 384-well plate, 40 μl medium per well.
b) Day 8. Add 3D CTG reagent to each well.
c) Record signal using Envision
The results of proliferation in AGS cell lines are in the following Table 2.
Table 2: The result of proliferation in AGS cell lines
Example # | GI 50 | Example # | GI 50 |
Example 1 | B | Example 29 | A |
Example 4 | C | Example 31 | A |
Example 6 | B | Example 32 | B |
Example 7 | C | Example 33 | A |
Example 11 | A | Example 34 | A |
Example 16 | A | Example 35 | A |
Example 26 | A | Example 36 | A |
Example 27 | A | Example 37 | A |
Example 28 | A | Example 39 | A |
A means < 0.5 uM, B means ≥ 0.5 uM and ≤ 5 uM, C means > 5 uM
3. KRAS G12D protein binding assay
The protein binding assay was carried out by Pharmaron Inc.
KRAS [G12D] : : cRaf binding assay was performed with a KRAS-G12D-cRAF binding assay kit commercially available from Cisbio (Catalog number: 63ADK000CB21PEG) . Binding reactions were carried out with test compounds, at concentrations 300 nM, 100 nM, 33 nM, 11 nM, 3.7 nM, 1.2 nM, 0.4 nM, 0.13 nM, 45.7 pM, 15.3 pM and 5.1 pM were applied to a well within a 384-well plate. 5 uL of Tag2-KRASG12D, GTP and Tag1-cRAF were added to each well and the binding reactions were allowed to take place at 25 ℃ for 15 minutes. At the end of the reaction, 10 uL anti-Tag1-Tb
3+ and anti-Tag2-XL665 mixture were added to the assay plates and further incubate for 3 hours at 4 ℃. The reaction mixtures were measured on fluorescence plate reader (Perkin Elmer Envision 2104) at wavelength 665 nm and 615 nm. Data was analyzed Graphpad Prism 8, from which IC
50 of each test compounds was determined by non-linear regression equation based on the readout ratio of 665nm/615nm of each test sample. The results of representative examples were showed in Table 3.
Table 3: The result of KRAS G12D Protein binding assay
Example # | IC 50 (nM) | Example # | IC 50 (nM) |
Example 11 | 27.3 | Example 31 | 15.5 |
Example 16 | 18.3 | Example 34 | 22.1 |
Example 26 | 17.0 | Example 35 | 17.8 |
Example 27 | 19.4 | Example 36 | 16.4 |
Example 28 | 16.7 | Example 37 | 15.4 |
Example 29 | 17.0 | Example 39 | 20.5 |
4. Cell proliferation Assay
Materials and instruments:
The KRAS G12D pERK assay biochemical assay was carried out by Pharmaron.
The KRAS G12D pERK assay was performed in GP2D Cell lines.
Cell culture
a) Day 1, seed cells in T75 flask,
b) Day 3, remove medium, and rinse with DPBS once,
c) Trpsinize cells with 2 mL TrypLE
TM Express Enzyme at room temperature (RT) or 37℃ until the cells detach.
d) Add 5 mL fresh culture medium, suspend cells then centrifuge at 1000 rpm for 5 min at RT.
e) Discard the supernatant and re-suspend cells with 5 mL fresh medium, count cells by Countess
TM II.
f) Seed cells back to T75 flask for further culture or into assay plates for 3D Cell Proliferation Assay.
3D Cell Proliferation Assay Experiment Procedure
a) Day 1. Add 200 nl diluted compound into each well with Echo. Seed cells into 384-well plate, 40 μl medium per well.
b) Day 8. Add 3D CTG reagent to each well.
c) Record signal using Envision
The results of proliferation in GP2D cell lines are in the following Table 4.
Table 4: The result of proliferation in GP2D cell lines
Example 39 | GI 50 (nM) |
Mixture | 0.65 |
atropisomer 1 | 0.26 |
atropisomer 2 | 13.95 |
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.
The disclosures of all publications, patents, patent applications and published patent applications referred to herein are hereby incorporated herein by reference in their entirety.
Claims (58)
- A compound of the formula I-1, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, where the compound is of the formula I-1:wherein R 1 is selected from H, C 1-6 alkyl, halogen and C 1-6 alkoxy,R 2 is selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, and -CH 2OCONR 5R 5,R 5 is independently selected from H and C 1-6 alkyl, and R 5 and R 5 are optionally taken together with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocycle,R 6 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl,R 7 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl, and
- The compound of the formula I-1, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1, wherein R 1 is selected from H, C 1-6 alkyl and halogen.
- The compound of the formula I-1, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 1 or 2, wherein R 1 is selected from H and F.
- The compound of the formula I-1, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any of claims 1-3, wherein R 2 is selected from H, C 1- 6 alkyl, halogen, and -CH 2OCONR 5R 5, and R 5 is independently selected from H and C 1-6 alkyl.
- The compound of the formula I-1, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any of claims 1-4, wherein R 2 is selected from H, C 1- 3 alkyl, and -CH 2OCONR 5R 5, and R 5 is independently selected from H and C 1-3 alkyl.
- A compound of the formula I-2, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the compound is of the formula I-2:wherein R 1 is selected from H, C 1-6 alkyl, halogen and C 1-6 alkoxy,R 2 is selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, and -CH 2OCONR 5R 5,R 5 is independently selected from H and C 1-6 alkyl, and R 5 and R 5 are optionally taken together with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocycle,R 3 and R 4 are independently selected from H, C 1-6 alkyl, halogen, -CN, C 1-6 alkoxy, optionally substituted amino and C 2-6 alkenyl,R 6 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, C 1-6 haloalkyl, optionally substituted amino, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl,R 7 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl, and
- The compound of the formula I-2, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 10, wherein R 1 is selected from H, C 1-6 alkyl and halogen.
- The compound of the formula I-2, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 10 or 11, wherein R 1 is selected from H, C 1-3 alkyl and F.
- The compound of the formula I-2, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any of claims 10-12, wherein R 2 is selected from H, C 1-6 alkyl, halogen, and -CH 2OCONR 5R 5, and R 5 is independently selected from H and C 1-6 alkyl.
- The compound of the formula I-2, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any of claims 10-13, wherein R 2 is selected from H, C 1-3 alkyl, and -CH 2OCONR 5R 5, and R 5 is independently selected from H and C 1-3 alkyl.
- The compound of the formula I-2, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any of claims 10-14, wherein R 3 and R 4 are independently selected from H, C 1-6 alkyl, halogen, -CN, C 1-6 alkoxy, and C 2-6 alkenyl.
- The compound of the formula I-2, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any of claims 10-15, wherein R 3 and R 4 are independently selected from H, C 1-6 alkyl and halogen.
- The compound of the formula I-2, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any of claims 10-18, wherein is selected from R 7 is selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl.
- A compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, where the compound is of the formula I-3:wherein:R 1 is selected from H, C 1-6 alkyl, halogen and C 1-6 alkoxy,R 2 is selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino and - (CH 2) nOCONR 5R 5, n is an integer from 0 to 8,R 5 is independently selected from H and C 1-6 alkyl, wherein R 5 and R 5 are optionally taken together with the nitrogen atom to which they are attached to form a 3-to 10-membered heterocycle,R 3 and R 4 are independently selected from H, C 1-6 alkyl, halogen, -CN, C 1-6 alkoxy, optionally substituted amino and C 2-6 alkenyl,R 6 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl,R 7 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl, and
- The compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 21, wherein R 1 is selected from H, C 1-6 alkyl, and halogen.
- The compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 21 or 22, wherein R 1 is selected from H, and halogen.
- The compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any of claims 21-23, wherein R 1 is H or F.
- The compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any of claims 21-24, wherein R 2 is selected from H, C 1-6 alkyl, halogen and - (CH 2) nOCONR 5R 5, n is 0 or 1, and R 5 is independently selected from H, and C 1-6 alkyl, wherein R 5 and R 5 are optionally taken together with the nitrogen atom to which they are attached to form a 4-to 6-membered heterocycle.
- The compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any of claims 21-25, wherein R 2 is selected from H, C 1-6 alkyl, and -CH 2OCONR 5R 5, and R 5 is independently selected from C 1-3 alkyl, wherein R 5 and R 5 are optionally taken together with the nitrogen atom to which they are attached to form a 4-to 6-membered heterocycle.
- The compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any of claims 21-26, wherein R 3 and R 4 are independently selected from H, C 1-6 alkyl, and halogen.
- The compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any of claims 21-27, wherein R 3 and R 4 are independently selected from H, C 1-3 alkyl, F, Cl and Br.
- The compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any of claims 21-28, wherein R 3 and R 4 are independently selected from H, F and Cl.
- The compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any of claims 21-29, wherein R 3 is F, and R 4 is F or Cl.
- The compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 21,wherein R 1 is selected from H, C 1-6 alkyl, and halogen,R 2 is selected from H, C 1-6 alkyl and halogen,R 3 and R 4 are independently selected from H, C 1-6 alkyl and halogen,R 7 is independently selected from H, C 1-3 alkyl and halogen, and
- The compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 21,wherein R 1 is selected from H, C 1-6 alkyl, and halogen,R 2 is selected from - (CH 2) nOCONR 5R 5, n is an integer from 0 to 4, R 5 is independently selected from H and C 1-6 alkyl, wherein R 5 and R 5 are optionally taken together with the nitrogen atom to which they are attached to form a 3-to 6-membered heterocycle, R 3 and R 4 are independently selected from H, C 1-6 alkyl and halogen,R 7 is independently selected from H, C 1-3 alkyl and halogen, and
- The compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 41,wherein R 1 is selected from H, C 1-3 alkyl, and F, preferably R 1 is H,R 2 is selected from - (CH 2) nOCONR 5R 5, n is an integer from 1 to 2, R 5 is independently selected from H and C 1-3 alkyl, wherein R 5 and R 5 are optionally taken together with the nitrogen atom to which they are attached to form a 3-to 6-membered heterocycle, R 3 and R 4 are independently selected from H, C 1-3 alkyl and F, preferably R 3 and R 4 are independently F,R 7 is independently selected from H, and
- The compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 41 or 42, wherein R 2 is selected from -CH 2OCONR 5R 5, each of R 5 is independently selected from H and C 1-3 alkyl, preferably, each of R 5 is -CH 3.
- The compound of the formula I-3, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 41 or 42, wherein R 2 is selected from -CH 2OCONR 5R 5, wherein R 5 and R 5 are taken together with the nitrogen atom to which they are attached to form a 3-to 6-membered heterocycle.
- A compound of the formula I, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, where the compound is of the formula I-4:wherein R 1 is selected from H, C 1-6 alkyl, halogen and C 1-6 alkoxy,R 2 is selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, and -CH 2OCONR 5R 5,R 5 is independently selected from H and C 1-6 alkyl, wherein R 5 and R 5 are optionally taken together with the nitrogen atom to which they are attached to form a 4-to 10-membered heterocycle,R 3 is selected from H, C 1-6 alkyl, halogen, -CN, C 1-6 alkoxy, optionally substituted amino and C 2-6 alkenyl,R 6 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, C 1-6 haloalkyl, optionally substituted amino, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl,R 7 is independently selected from H, C 1-6 alkyl, halogen, C 1-6 alkoxy, optionally substituted amino, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl,R 8 is selected from hydrogen, halogen, -CO 2R 9, -CONR 9R 9, -CN, C 1-3 alkyl, C 1-3 hydroxyalkyl and 3-6 membered heteroaryl,R 9 is independently selected from H and C 1-6 alkyl, and
- The compound of the formula I-4, a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to claim 47,wherein R 1 is selected from H, C 1-3 alkyl, and halogen,R 2 is selected from H, C 1-3 alkyl, halogen and -CH 2OCONR 5R 5, R 5 is independently selected from H and C 1-3 alkyl, wherein R 5 and R 5 are optionally taken together with the nitrogen atom to which they are attached to form a 4-to 6-membered heterocycle, R 3 is selected from H, C 1-6 alkyl and halogen,R 7 is independently selected from H, C 1-6 alkyl and halogen,R 8 is selected from hydrogen, halogen and C 1-3 alkyl, and
- A pharmaceutical composition which comprises a compound, a pharmaceutically acceptable salt thereof or stereoisomer thereof according to any one of claims 1-50 and one or more pharmaceutically acceptable excipients.
- A method of treating a cancer, comprising administering a subject in need thereof a therapeutically effective amount of the compound, a pharmaceutically acceptable salt thereof or stereoisomer thereof according to any one of claims 1-50.
- Use of the compound, a pharmaceutically acceptable salt thereof or stereoisomer thereof according to any one of claims 1-50 in the manufacture of a medicament for the treatment of diseases or conditions associated with KRAS G12D activity.
- A method for resolving atropisomers of the compound having the following structure:i) providing atropisomers of the compound; andii) using HPLC method and SFC method sequentially to resolve the atropisomers to obtain atropisomer 1 and atropisomer 2, wherein a retention time of the atropisomer 1 is 1.896 min and a retention time of the atropisomer 2 is 2.145 min.
- The method according to claim 54, wherein the HPLC method is conducted under the following conditions: Column Pursuit XRs C18 (4.6*250mm, 5.0 μm) ; eluent A: 0.02%TFA in H2O; eluent B: 0.02%TFA in CAN; gradient: 10%B to 95%B in 10 min, 95%B from 10 to 12 min, then 10%B in 13 min, 10%B from 13-20 min at a flow rate of 1.2 mL/min, 220 &254 nM.
- The method according to claim 54 or 55, wherein the SFC method is conducted under the following conditions: column: CHIRAL ART Cellulose-SZ 3cm × 25cm, 5um; mobile phase: CO2: [MeOH: DCM = 1: 1 (0.2%2mM NH3 MeOH) ] = 55: 45; flow rate: 80 mL/min.
- Atropisomer 1 which is obtained by the method of any one of claims 54-56, wherein a retention time of the atropisomer 1 is 1.896 min.
- Atropisomer 2 which is obtained by the method of any one of claims 54-56, wherein a retention time of the atropisomer 2 is 2.145 min.
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WO2021041671A1 (en) * | 2019-08-29 | 2021-03-04 | Mirati Therapeutics, Inc. | Kras g12d inhibitors |
WO2022002102A1 (en) * | 2020-06-30 | 2022-01-06 | InventisBio Co., Ltd. | Quinazoline compounds, preparation methods and uses thereof |
WO2022042630A1 (en) * | 2020-08-26 | 2022-03-03 | InventisBio Co., Ltd. | Heteroaryl compounds, preparation methods and uses thereof |
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WO2022068921A1 (en) * | 2020-09-30 | 2022-04-07 | 上海医药集团股份有限公司 | Quinazoline compound and application thereof |
WO2022098625A1 (en) * | 2020-11-03 | 2022-05-12 | Mirati Therapeutics, Inc. | Kras g12d inhibitors |
WO2022105859A1 (en) * | 2020-11-20 | 2022-05-27 | Jacobio Pharmaceuticals Co., Ltd. | Kras g12d inhibitors |
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WO2021041671A1 (en) * | 2019-08-29 | 2021-03-04 | Mirati Therapeutics, Inc. | Kras g12d inhibitors |
WO2022002102A1 (en) * | 2020-06-30 | 2022-01-06 | InventisBio Co., Ltd. | Quinazoline compounds, preparation methods and uses thereof |
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