WO2024085661A1 - Nouveaux composés tri-hétérocycliques - Google Patents
Nouveaux composés tri-hétérocycliques Download PDFInfo
- Publication number
- WO2024085661A1 WO2024085661A1 PCT/KR2023/016192 KR2023016192W WO2024085661A1 WO 2024085661 A1 WO2024085661 A1 WO 2024085661A1 KR 2023016192 W KR2023016192 W KR 2023016192W WO 2024085661 A1 WO2024085661 A1 WO 2024085661A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- fluoro
- naphthalen
- ethyl
- mmol
- dihydro
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 150
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
- 102100030708 GTPase KRas Human genes 0.000 claims abstract description 3
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 claims abstract description 3
- -1 halo C1-C3 alkoxy Chemical group 0.000 claims description 252
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims description 48
- 239000001257 hydrogen Substances 0.000 claims description 48
- 229910052736 halogen Inorganic materials 0.000 claims description 35
- 150000002367 halogens Chemical class 0.000 claims description 35
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 26
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 26
- 125000001188 haloalkyl group Chemical group 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 22
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 230000000155 isotopic effect Effects 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 239000012453 solvate Substances 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 15
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 14
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 0.000 claims description 11
- 201000011510 cancer Diseases 0.000 claims description 10
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 125000000565 sulfonamide group Chemical group 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 6
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 4
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 2
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- 239000004480 active ingredient Substances 0.000 claims 1
- 229940121649 protein inhibitor Drugs 0.000 abstract description 4
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- 239000000243 solution Substances 0.000 description 234
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 82
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 58
- 239000012071 phase Substances 0.000 description 51
- 239000012074 organic phase Substances 0.000 description 50
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 48
- 238000005160 1H NMR spectroscopy Methods 0.000 description 46
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- 238000002474 experimental method Methods 0.000 description 32
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
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- 238000012360 testing method Methods 0.000 description 18
- 125000004122 cyclic group Chemical group 0.000 description 17
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- 230000035772 mutation Effects 0.000 description 16
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 13
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 13
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- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- ADRDEXBBJTUCND-UHFFFAOYSA-N pyrrolizidine Chemical compound C1CCN2CCCC21 ADRDEXBBJTUCND-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 102000009929 raf Kinases Human genes 0.000 description 1
- 108010077182 raf Kinases Proteins 0.000 description 1
- 102000005912 ran GTP Binding Protein Human genes 0.000 description 1
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- 125000006413 ring segment Chemical group 0.000 description 1
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- 102000030938 small GTPase Human genes 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
- NXQKSXLFSAEQCZ-SFHVURJKSA-N sotorasib Chemical compound FC1=CC2=C(N(C(N=C2N2[C@H](CN(CC2)C(C=C)=O)C)=O)C=2C(=NC=CC=2C)C(C)C)N=C1C1=C(C=CC=C1O)F NXQKSXLFSAEQCZ-SFHVURJKSA-N 0.000 description 1
- 229940073531 sotorasib Drugs 0.000 description 1
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- 239000000725 suspension Substances 0.000 description 1
- XIRUXUKRGUFEKC-ZETCQYMHSA-N tert-butyl (2s)-2-(hydroxymethyl)azetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@H]1CO XIRUXUKRGUFEKC-ZETCQYMHSA-N 0.000 description 1
- BFFLLBPMZCIGRM-QMMMGPOBSA-N tert-butyl (2s)-2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1CO BFFLLBPMZCIGRM-QMMMGPOBSA-N 0.000 description 1
- GSAPPURHQAMLCE-UHFFFAOYSA-N tert-butyl n-(2-acetylphenyl)carbamate Chemical compound CC(=O)C1=CC=CC=C1NC(=O)OC(C)(C)C GSAPPURHQAMLCE-UHFFFAOYSA-N 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
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- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- WARKYKQCOXTIAO-UHFFFAOYSA-N tributyl(2-ethoxyethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)\C=C/OCC WARKYKQCOXTIAO-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/06—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/16—Peri-condensed systems
Definitions
- the present disclosure relates to novel triheterocyclic compounds, and more specifically to novel triheterocyclic compounds useful as KRAS protein inhibitors, and a pharmaceutical composition including the same for treating cancers.
- the RAS gene is responsible for signal transduction within the mitogen activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K) pathways, and is known as an oncogene due to frequent mutations.
- the RAS gene family is divided into KRAS, NRAS, and HRAS, in which these three genes encode four proteins, the splice variants K-Ras4A and K-Ras4B, N-Ras, and H-Ras.
- K-Ras is the most frequently mutated isoform in Ras-induced cancer (86%), followed by N-Ras (11%) and H-Ras (3%) (Non-patent Document 1).
- Non-patent Document 2 Oncogenic changes in KRAS are observed in 15.95% of cancers including pancreatic cancer, lung cancer, colon adenocarcinoma, colorectal cancer, and rectal adenocarcinoma.
- Gain-of-function missense mutations mostly located at codons 12, 13, and 61, constitutively activate RAS proteins and are detected in various types of human cancer. 98% of tumor Ras mutations are found in active site amino acid residues G12, G13 and Q61, and these mutations impair intrinsic and GAP-mediated GTP hydrolysis and abnormally activate downstream signaling (Non-Patent Document 3). K-Ras G12 mutations (89%) predominate in human cancers, followed by G13 mutations (9%) and Q61 mutations (1%).
- Codon 12 mutations include codon 12 Gly ⁇ Asp (G12D) (36%), codon 12 Gly ⁇ Val (G12V) (23%), and codon 12 Gly ⁇ Cys (G12C) (14%), and G12D is the most common mutation among the mutations of codon 12. Additionally, mutations at codon 13 Gly ⁇ Asp (G13D) (7%) and codon 61 Gln ⁇ His (Q61H) (0.6%) are also (Non-patent Document 1).
- KRAS may be an efficient target for cancer therapy.
- the present inventors developed a new KRAS inhibitor, thereby completing the present invention.
- Non-Patent Document 2 J Cancer Metastasis Treat 2021;7:26
- Non-Patent Document 3 Cancer Biol Ther. 2006 August; 5(8): 928-932
- novel triheterocyclic compounds having KRAS protein inhibitory activity.
- the present disclosure relates to: novel triheterocyclic compounds; stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof; and a pharmaceutical composition including the same for treating cancers.
- a pharmaceutical composition including the compound selected from compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof.
- the present disclosure relates to novel triheterocyclic compounds useful as KRAS protein inhibitors, and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof, and a pharmaceutical composition including the same for treating cancers.
- X is N or CR 11 ;
- R 1 is R 1A -substituted or unsubstituted phenyl, R 1A -substituted or unsubstituted naphthyl, R 1A -substituted or unsubstituted benzothiophenyl;
- each R 1A is independently selected from hydrogen, hydroxy, a halogen, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, NH 2 , NH(C 1 -C 3 alkyl), N(C 1 -C 3 alkyl) 2 , and CN;
- R 2 is hydrogen or a halogen
- R 3 is hydrogen, -O-L-W, or ;
- L is a bond or L A -substituted or unsubstituted C 1 -C 3 alkylene;
- L A is hydrogen, a halogen, or C 1 -C 3 alkyl
- W is R 6 -substituted or unsubstituted C 1 -C 3 alkyl, R 6 -substituted or unsubstituted 3- to 10-membered monocyclic heterocycle, or R 6 -substituted or unsubstituted 6- to 14-membered bicyclic heterocycle;
- R 4 is hydrogen, R 4A -substituted or unsubstituted C 1 -C 6 haloalkyl, R 4A -substituted or unsubstituted C 1 -C 6 alkyl, R 4A -substituted or unsubstituted C 3 -C 10 cycloalkyl, R 4A -substituted or unsubstituted C 5 -C 8 aryl, R 4A -substituted or unsubstituted 3- to 10-membered heterocycle, or R 4A -substituted or unsubstituted 5- to 10-membered heteroaryl;
- R 4A wherein two of R 4A together form R 4B -substituted or unsubstituted C 3 -C 10 cycloalkyl, R 4B -substituted or unsubstituted C 5 -C 8 aryl, R 4B -substituted or unsubstituted 3- to 10-membered heterocycle, or R 4B -substituted or unsubstituted 5- to 10-membered heteroaryl;
- each R 5 is independently selected from hydrogen, hydroxy, a halogen, C 1 -C 3 haloalkyl, and C 1 -C 3 alkyl,
- each R 7 is independently selected from hydrogen, amino, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, and a 3- or 4-membered heterocycle;
- each R 8 is independently selected from hydrogen, amino, and C 1 -C 3 alkyl
- R 9 and R 10 are each independently selected from hydrogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C(O)NH 2 , C(O)CH 3 , and a 3- to 6-membered heterocycle;
- each R 11 is independently selected from hydrogen, hydroxy, a halogen, C 1 -C 3 haloalkyl, and C 1 -C 3 alkyl,
- n is an integer selected from 0 to 2;
- heterocycles or heteroaryls each comprise 1 to 3 heteroatoms independently selected from N, O, and S.
- L is methylene
- W is R 6 -substituted or unsubstituted 3- to 10-membered monocyclic heterocycle or R 6 -substituted or unsubstituted 6- to 14-membered bicyclic heterocycle;
- W may be a substituted monocyclic or bicyclic non-aromatic ring, for example, it includes, but is not limited to,
- L is methylene
- each W is independently R 6 -substituted or unsubstituted
- W may be 1-methylpyrrolidinyl ( ), 1-(2,2-difluoroethyl)azetidine ( ), 2-fluorohexahydro-1 H -pyrrolizinyl ( ), 2,6-dimethylidenehexahydro-1 H -pyrrolizinyl ( ), 1-methyloctahydro-1 H -cyclopenta[ b ]pyridine ( ), or 2-oxabicyclo[2.1.1]hexane ( ), but is not limited thereto.
- W may be a substituted 4-membered to 10-membered heterocycle.
- W may be morpholine ( ), but is not limited thereto.
- R 4 is R 4A -substituted or unsubstituted C 1 -C 3 alkyl
- R 4A together form 5- to 10-membered heteroaryl selected from saturated or partially unsaturated isoquinoline or quinoline;
- each R 4C is independently selected from hydrogen, a halogen, C 1 -C 3 alkyl, NH 2 , NH(C 1 -C 3 alkyl), and N(C 1 -C 3 alkyl) 2 .
- R 4 may be substituted or unsubstituted C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, azetidinyl, pyrrolizinyl, or pyridinyl, but is not limited thereto.
- R 4 may be C 3 -C 10 cycloalkyl including spiro C 3 -C 10 cycloalkyl, each substituted or unsubstituted by R 4A .
- R 4 may be each substituted or unsubstituted spiro[3.3]alkanyl (e.g., ), but is not limited thereto.
- R 4 may be substituted with halogen, amino, (C 1 -C 6 alkyl)amino, di(C 1 -C 6 alkyl)amino, aminopyridine, aminopyrazine, aminopyrimidine, amino(C 3 -C 10 cycloalkyl), di( C 1 -C 6 alkyl)amino(C 3 -C 10 cycloalkyl), or 1-morpholino(C 3 -C 10 cycloalkyl) (e.g., 1-morpholin-4-ylcyclobutyl( )), but is not limited thereto.
- halogen amino, (C 1 -C 6 alkyl)amino, di(C 1 -C 6 alkyl)amino, aminopyridine, aminopyrazine, aminopyrimidine, amino(C 3 -C 10 cycloalkyl), di( C 1 -C 6 alkyl)amino(C 3 -C 10 cycloalkyl), or 1-morpholino(
- R 4 may be for example, C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl substituted with halogen, amino, (C 1 -C 6 alkyl)amino, di(C 1 -C 6 alkyl)amino, aminopyridine, aminopyrazine, aminopyrimidine, amino (C 3 -C 10 cycloalkyl), di(C 1 -C 6 alkyl)amino(C 3 -C 10 cycloalkyl), or 1-morpholin-4-ylcyclobutyl.
- R 4 may be, for example, unsubstituted azetidinyl or unsubstituted pyrrolizinyl.
- R 4 may be, for example, amino substituted spiro[3.3]heptanyl, amino substituted pyridine, or amino substituted C 3 -C 10 cycloalkyl.
- each R 11 is independently selected from hydrogen, a halogen, C 1 -C 3 haloalkyl, and C 1 -C 3 alkyl;
- R 1 is R 1A -substituted or unsubstituted benzothiophenyl
- each R 1A is independently selected from hydrogen, a halogen, NH 2 , NH(C 1 -C 3 alkyl), N(C 1 -C 3 alkyl) 2 , and CN.
- R 1 is , , or
- R 2 is F
- R 3 is hydrogen, -O-L-W, or ;
- L is methylene
- W is , , , , , , , , , , , , , , or ,
- R 4 is , , , , , , , , , , , , , , or ,
- n is selected from 1 and 2.
- the compound is selected from the group consisting of the following compounds and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof:
- a pharmaceutical composition including the compound selected from compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof.
- the pharmaceutical composition exhibits KRAS protein inhibitory activity.
- halogen used herein refers to fluorine, chlorine, bromine or iodine, unless stated otherwise.
- alkyl refers to a straight-chain or branched, saturated, monovalent hydrocarbon group, unless stated otherwise.
- alkylene used herein refers to a divalent straight-chain or branched hydrocarbon group having (-CH 2 -) n , and includes, but is not limited to, methylene, ethylene, propylene, butylene, isobutylene, etc., unless stated otherwise.
- alkenyl used herein refers to a monovalent hydrocarbon group including at least one carbon-carbon double bond, where each double bond has an E- or Z- type configuration, unless stated otherwise.
- alkynyl used herein refers to refers to a monovalent hydrocarbon radical including at least one carbon-carbon triple bond, unless stated otherwise.
- alkoxy refers to a straight-chain or branched hydrocarbon residue linked by oxygen, unless stated otherwise.
- aryl refers to an aromatic group that may be substituted or unsubstituted, and includes monocyclic, bicyclic, or more than bicyclic aromatic groups that may be substituted or unsubstituted, and may include unsaturated or partially saturated aryl, unless stated otherwise. For examples, it includes, but is not limited to, C 6-15 aryl, and may include, but is not limited to, phenyl, biphenyl, naphthyl, toluyl etc.
- heteroaryl refers to an aromatic group including one or more heteroatoms selected from N, O, and S, that may be substituted or unsubstituted, and includes monocyclic, bicyclic, or more than bicyclic aromatic groups that may be substituted or unsubstituted, and may include unsaturated or partially saturated heteroaryl, unless stated otherwise.
- heteroaryl includes, but is not limited to, C 4-15 heteroaryl, and may include, but is not limited to, morpholinyl, piperidinyl, pyrrolidinyl, or pyrrolizinyl etc.
- fused heteroaryl refers to an unsaturated or partially saturated, substituted or unsubstituted ring system in which the heteroaryl group is linked in a fused manner with another aryl, heteroaryl or heterocycloalkyl group, unless stated otherwise.
- it may include a C 8-20 heteroaryl, and may include, but is not limited to, a 9-membered, 10-membered, 11-membered, 12-membered, 13-membered, 14-membered or 15-membered benzo-fused heteroaryl group.
- it may include, but is not limited to, a 5+5 fused ring system, 5+6 fused ring system, 5+7 fused ring system, 6+6 fused ring system, or 6+7 fused ring system.
- it may include, but is not limited to, pyrrolizine, benzothiazole, benzothiazolinyl, benzothiophenyl, benzofuranyl, isobenzofuranyl, benzothionyl, indolyl, isoindolinyl, indazolyl, indazolinyl, benzimidazolinyl, benzoxazolinyl, benzisoxazolinyl, benzothiadiazolinyl, benzoxadiazolinyl, benztriazolinyl, quinolinyl, isoquinolinyl, quinazolinyl, etc.
- partially saturated used herein refers to including at least one saturated site, i.e., at least one single bond, within an aryl, heteroaryl, or fused heteroaryl ring as defined above.
- unsaturated used herein refers to an aryl, heteroaryl, or fused heteroaryl ring as defined above that does not include a saturated site, i.e., a single bond.
- cycloalkyl refers to a saturated or partially unsaturated, monocyclic, bicyclic, or polycyclic hydrocarbon ring that may be substituted or unsubstituted, and it may include bridged cycloalkyl, fused cycloalkyl, and spirocycloalkyl, unless stated otherwise.
- it includes, but is not limited to, C 3-10 cycloalkyl or C 3-6 cycloalkyl, and may include, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
- cycloalkylene used herein refers to a radical (divalent radical) derived from cycloalkene.
- heterocycloalkyl used herein refers to cycloalkyl including one or more heteroatoms selected from N, O, and S, that may be substituted or unsubstituted, and includes monocyclic, bicyclic, or more than bicyclic aromatic groups that may be substituted or unsubstituted, unless stated otherwise.
- heterocycle refers to a saturated, partially unsaturated, or aromatic ring, monocyclic, bicyclic, or polycyclic ring comprising one or more heteroatoms selected from N, O, and S, which may be substituted or unsubstituted, and it may include bridged heterocycles, fused heterocycles, and spiroheterocycles, unless otherwise specified.
- heterocycloalkyl includes, but is not limited to, C 4-15 heterocycloalkyl and may include, but is not limited to, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydro-2 H -pyranyl, imidazolidinyl, pyrrolidin-2-one, pyrrolizinyl, or pyrrolyl, etc.
- the heterocycles may be carbon linkages or heteroatom linkages, for example, it may be connected to the base molecule through a cyclic atom (may be C or N).
- the heterocycle connected to the base molecule through the nitrogen of the ring atoms of the heterocycle may include, but is not limited to, N-morpholinyl, N-piperidinyl, N-pyrrolidinyl, or N-pyrrolyl, etc.
- fused heterocycle or “fused cycloalkyl” used herein refers to a substituted or unsubstituted ring system, and it can be classified into bicyclic, tricyclic, tetracyclic, or more polycyclic fused cycloalkyl, depending on the number of rings, unless stated otherwise.
- Fused cycloalkyls are polycyclic rings in which each ring shares an adjacent pair of carbon atoms with the other ring, and one or more rings may share one or more double bonds, but none of these rings has a fully conjugated ⁇ -electron system.
- C 3-20 fused cycloalkyl includes, but is not limited to, C 3-20 fused cycloalkyl and may include, but is not limited to, a 5+5 fused ring system, 5+6 fused ring system, 5+7 fused ring system, 6+6 fused ring system, or 6+7 fused ring system depending on the number of atoms forming each of the two rings being fused.
- a bicyclic fused cycloalkyl also referred to as "bicycloalkyl” or "bicyclic heterocycle” includes any combination of saturated, unsaturated, and aromatic bicyclic rings, as valence permits.
- an aromatic ring e.g., pyridyl, may be fused to a saturated or unsaturated ring.
- fused heterocycloalkyl refers to a substituted or unsubstituted fused cycloalkyl including one or more heteroatoms selected from N, O, and S, for example, it includes, but is not limited to, C 8-20 fused heterocycloalkyl.
- bicyclic fused heterocycloalkyl is also referred to as "heterobicycloalkyl” and it includes, but is not limited to, a 5+5 fused ring system, 5+6 fused ring system, 5+7 fused ring system, 6+6 fused ring system, or 6+7 fused ring system depending on the number of atoms forming each of the two rings being fused.
- it may be hexahydro-1H-pyrrolizine, but is not limited thereto.
- stereoisomers refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. It is a compound that has the same chemical or molecular formula but is optically or sterically different.
- enantiomers used herein refers to various stereoisomers and geometric isomers that may exist for the compound according to the present disclosure.
- the present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are non-superimposeable mirror images of one another.
- Compounds of Formula 1 according to one aspect of the present disclosure may have an asymmetric carbon center (asymmetric carbon) and therefore may exist as enantiomers ( R or S isomers), racemates, diastereomers, or any mixtures thereof, and all these isomers and mixtures are included within the scope of the present disclosure.
- the compounds herein described may have asymmetric centers, geometric centers (e.g., double bond), or both. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
- the compounds described herein have one or more chiral centers. It is understood that if an absolute stereochemistry is not expressly indicated, then each chiral center may independently be of the R-configuration or the S-configuration or a mixture thereof.
- compounds described herein include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions.
- Racemic mixtures of R-enantiomer and S-enantiomer, and enantio-enriched stereomeric mixtures comprising of R- and S-enantiomers, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology.
- optically active or racemic forms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms, by synthesis from optically active starting materials, or through use of chiral auxiliaries.
- atropisomers refers to all stereoisomers that can be separated from each other. It is an isomer that occurs when the single bond formed between carbon and carbon among the bonds that make up the compound cannot rotate freely due to a bulky substituent. It refers to stereoisomers resulting from an asymmetric axis and includes complete isolation of stable non-interconverting diastereomeric or enantiomeric species. Additionally, it can result from limited rotation around a single bond, where rotational barriers are high enough to allow differentiation of isomeric species.
- Compounds according to one embodiment may generate atropisomers with a high probability.
- tautomers refers to one of two or more structural isomers that readily convert from one isomeric form to another and that exist in equilibrium. Compounds according to one embodiment may also include “tautomers”. The tautomers result from the exchange of a single bond with an adjacent double bond and the concomitant transfer of the proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. The tautomeric forms may be in equilibrium or sterically fixed in one form by appropriate substitution.
- solvates may include a molecular complex comprising a compound of Formula 1 and one or more pharmaceutically acceptable solvent molecules, such as ethanol or water. Complexes where the solvent molecule is water are also referred to as “hydrates.”
- pharmaceutically acceptable salts used herein includes any salt as long as it has low toxicity to the human body and does not adversely affect the biological activity and physicochemical properties of the parent compound.
- Compounds according to one embodiment may include "isotopic variants.”
- the present disclosure also encompasses isotopically-labeled compounds which are identical to those compounds as described herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature ("isotopologues").
- the compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more atoms that constituted such compounds.
- isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H ("D"), 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
- a compound described herein can have one or more H atoms replaced with deuterium.
- references to or depiction of a certain element such as hydrogen or H is meant to include all isotopes of that element.
- an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
- Compounds comprising radioisotopes such as tritium, 14 C, 32 P and 35 S are thus within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those skilled in the art based on the disclosure herein.
- compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
- compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C- enriched carbon are within the scope of the present disclosure.
- certain isotopically-labeled compounds can be useful in compound and/or substrate tissue distribution assays.
- Tritiated ( 3 H) and carbon-14 ( 14 C) isotopes can be particularly preferred for their ease of preparation and detectability.
- substitution with heavier isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and hence can be preferred in some circumstances.
- Isotopically-labeled compounds can generally be prepared by following procedures analogous to those disclosed herein, for example, in the Examples section, by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.
- Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds.
- Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
- treatment used herein includes treatment, improvement, amelioration, or management of disease.
- treating or “treatment” used herein refers to inhibiting disease, for example, inhibiting a disease, condition or disorder, preventing further development of pathology and/or symptoms, improving disease, or reversing pathology and/or symptoms, for example, reducing the severity of the disease, in a subject who experiences or shows a pathology or symptom of a disease, condition or disorder.
- preventing refers to prevention of a disease, for example, prevention of a disease, condition, or disorder in a subject that may be predisposed to have the disease, condition, or disorder but have not yet experienced or exhibited pathology or a symptom of the disease.
- subject or “patient” used herein refers to any animal, including mammals, for example, mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates and humans.
- the terms “having,” “may have,” “including,” or “may include” may refer to the presence of a feature (e.g., a component such as a number, component, etc.), and does not exclude the presence of additional features.
- Kirsten Rat Sarcoma Virus Oncogene Homolog is a GTPase that integrates signals from outside the cell into intracellular proliferation and survival signals and it is a member of the small GTPase family of Ras, Rho, Rab, Arf, and Ran. It receives signals from various receptor tyrosine kinases, especially EGFR at the upper level, and transmits signals mainly to Raf and PI3K at the lower level through the GTPase cycle of KRAS, thereby regulating various processes including cell proliferation.
- KRAS plays a significant role in cancer, but inhibiting its activity has been challenging due to the structure of the protein. Attempts to block signaling have shown some promise but have also presented issues with toxicity and treatment resistance. However, the discovery of the switch II pocket and compounds that bind to mutant cysteine have led to the development of adagrasib and sotorasib, which have been approved by the FDA for non-small cell lung cancer.
- KRAS inhibitor compounds that inhibit a mutation in any one of KRAS codons 12, 13, and 61, such as at least one of, but not limited to, KRAS G12D, KRAS G12V, KRAS G12C, KRAS G13D, and KRAS Q61H mutations.
- a pharmaceutical composition including the compound selected from compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts thereof for the treatment of cancer.
- the composition may comprise the compound selected from compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts as a therapeutically effective amount.
- the composition may comprise other therapeutic drugs in addition to the compound selected from compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts.
- the composition may further include a pharmaceutically acceptable carrier or excipient.
- the composition may comprise the compound selected from compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, and pharmaceutically acceptable salts or other therapeutic drugs in the range of 0.005% to 100%, and a pharmaceutically acceptable carrier or excipient may be included in the remaining range.
- the compound selected from compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, or the pharmaceutical composition including the same can be used for cancer treatment.
- the compound selected from compounds of Formula 1 and stereoisomers, diastereomers, enantiomers, atropisomers, isotopic variants, tautomers, solvates, or the pharmaceutical composition including the same can exhibit KRAS protein inhibitory activity.
- the compounds and pharmaceutical compositions of the present disclosure may be provided in any suitable administration route and dosage form acceptable in the pharmaceutical arts.
- the structure of the synthesized compound can be verified by methods known to those skilled in the art, such as nuclear magnetic resonance (NMR) spectroscopy and/or mass spectroscopy.
- NMR nuclear magnetic resonance
- the numerical range expressed using the term “to” includes a range including the numerical values written before and after the term “to” as the lower limit and upper limit, respectively.
- Example 1-Int-1 (5.00 g, 18.9 mmol) in MeOH (50 mL, 10 vol) was added 0.1M NaOH (25.0 mL, 5 vol) at room temperature and stirred for 30 min, followed by an addition of Ethyliodide (2.20 mL, 28.4 mmol) at room temperature and the reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and acidified with conc.
- Step 2 7-chloro-5-(2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethoxy)-2-(ethylthio)-8-fluoropyrido[4,3-d]pyrimidin-4(3H)-one (Example 1-Int-5)
- Example 1-Int-4 (1.17 g, 6.80 mmol) in THF (10 mL, 10 vol) was added NaH (0.67 g, 15.3 mmol) at 0°C and stirred for 1 h at 0°C. To this was added 5,7-Dichloro-2-(ethylthio)-8-fluoropyrido[4,3- d ]pyrimidin-4(3 H )-one
- Step 1a To a stirred solution of 1-(aminomethyl)- N , N -dimethylcyclobutan-1-amine Example 1-Int-3 (1.00 g, 7.80 mmol) in THF (10 mL, 10 vol) was added 2-bromoethan-1-ol (0.97 g, 7.80 mmol) and TEA (3.26 mL, 23.4 mmol) at 0°C and the reaction mixture was allowed to warm up to room temperature and stirred for 18 h. Progress of the reaction was monitored by LC-MS.
- Step 3 1-((5-chloro-2-(ethylthio)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Example 1-Int-6)
- reaction mixture was diluted with water ice cold water (20 mL) and extracted with 10% methanol in DCM (2 x 50 mL), combined organic layer was washed with brine solution (100 mL), dried over anhydrous Na 2 SO 4 , filtered and evaporated under reduced pressure to get crude compound.
- Step 4 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylthio)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Example 1-Int-8)
- Step 5 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylsulfonyl)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Example 1-Int-9)
- Step 6 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Example 1-Int-10)
- reaction mixture was allowed to warm up to room temperature and stirred for 4 h. Progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice cold water (30 mL) and extracted with ethyl acetate (2 x 15 mL), combined organic layer was washed with brine solution (10 mL), dried over anhydrous Na 2 SO 4 , filtered and evaporated under reduced pressure to get crude compound 1-((5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2 R ,7 aS )-2-fluorotetrahydro-1 H -pyrrolizin-7 a (5 H )-yl)methoxy)-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)methyl)- N , N -d
- Step 7 4-(10-((1-(dimethylamino)cyclobutyl)methyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 1)
- Example 1 (0.037 g, Y: 12%) as a white solid.
- Example 2-Int-1 (7.60 g, 28.69 mmol) in MeOH (477 mL, 63 vol) was added 0.1M NaOH (477 mL, 240.99 mmol) and MeI (3.30 mL, 40.17 mmol) at room temperature and the reaction mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (250 mL) and acidified with conc.
- Step 2 7-chloro-5-(2-(((1-(dimethylamino)cyclobutyl)methyl)amino)ethoxy)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4(3H)-one (Example 2-Int-3)
- Example 1-Int-4 (0.37 g, 2.16 mmol) in THF (10 mL, 20 vol) was added NaH (0.35 g, 8.09 mmol) at 0°C and stirred for 1 h at 0°C. To this was added 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3- d ]pyrimidin-4(3 H )-one
- Example 2-Int-2 (0.50 g, 1.80 mmol) at 0°C and the reaction mixture was allowed to warm up to room temperature and stirred for 18 h.
- Step 3 1-((5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Example 2-Int-4)
- reaction mixture was diluted with ice cold water (20 mL) and extracted with ethyl acetate (2 x 20 mL), combined organic layer was washed with brine solution (20 mL), dried over anhydrous Na 2 SO 4 , filtered and evaporated under reduced pressure to get crude compound.
- Step 4 1-((4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Example 2-Int-6)
- Step 5 1-((4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Example 2-Int-7)
- Step 6 1-((4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Example 2-Int-8)
- reaction mixture was allowed to warm up to room temperature and stirred for 1.5 h. Progress of the reaction was monitored by TLC and LC-MS. After completion of the reaction, the reaction mixture was diluted with ice cold water (20 mL) and extracted with 10% MeOH in DCM (2 x 20 mL), combined organic layer was washed with brine solution (20 mL), dried over anhydrous Na 2 SO 4 , filtered and evaporated under reduced pressure to get crude compound.
- Step 7 1-((5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Example 2-Int-9)
- reaction mixture was diluted with ice cold water (20 mL) and extracted with 10% MeOH in DCM (2 x 20 mL), combined organic layer was washed with brine solution (20 mL), dried over anhydrous Na 2 SO 4 , filtered and evaporated under reduced pressure to get crude compound.
- Step 8 4-(10-((1-(dimethylamino)cyclobutyl)methyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 2)
- Step 1 tert -butyl (3-acetylpyridin-2-yl)carbamate (Example 3-Int-2)
- Step 2 tert-butyl (S,Z)-(3-(1-((2-hydroxypropyl)imino)ethyl)pyridin-2-yl)carbamate (Example 3-Int-3)
- Step 3 tert-butyl (3-(1-(((S)-2-hydroxypropyl)amino)ethyl)pyridin-2-yl)carbamate (Example 3-Int-4)
- Step 4 tert-butyl (3-(1-(((S)-2-((7-chloro-8-fluoro-2-(methylthio)-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)propyl)amino)ethyl)pyridin-2-yl)carbamate (Example 3-Int-5)
- Step 5 tert-butyl (3-(1-((S)-5-chloro-4-fluoro-8-methyl-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 3-Int-6)
- Step 6 3-(1-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 3-Int-7)
- Step 7 3-(1-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 3-Int-8)
- Step 8 3-(1-((S)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 3-Int-9)
- Step 9 4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 3)
- Step 10 Example 3a and Example 3b
- Example 3a 4-((S)-10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol
- Example 3b 4-((S)-10-((S)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol
- Example 4-Int-1 (5 g, 27.024 mmol) in DCM (75 mL) was added ethyl glycinate hydrochloride (3.77 g, 27.024 mmol), Mg 2 SO 4 (3.74 g, 31.078mmol) and TEA (5.47 g, 54.048mmol). The mixture was stirred at 25°C for 14 h under Argon. The reaction was detected by LCMS. The resulting mixture was filtered, the filter cake was washed with DCM (25 mL). The filtrate was concentrated under reduced pressure to get residue. The residue was diluted with H 2 O (50 mL), extracted with MTBE (50 mL).
- Step 2 ethyl (E)-2-((4-bromobenzylidene)amino)-4-(chloromethyl)-2-(2-(chloromethyl)allyl)pent-4-enoate (Example 4-Int-3)
- Step 3 ethyl 2,6-dimethylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (Example 4-Int-4)
- Step 4 ethyl 2,6-dimethylenetetrahydro-1H-pyrrolizine-7a(5H)-carboxylate (Example 4-Int-5)
- Step 6 3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 4-Int-7)
- the mixture was stirred at 100°C for 4 h under Argon.
- the reaction was detected by LCMS.
- LCMS detected the desired product.
- the reaction mixture was diluted with H 2 O (140 mL).
- the resulting mixture was extracted with EA (100 mL).
- the combined organic layers were washed with brine (120 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to get residue.
- Step 7 3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 4-Int-8)
- the resulting mixture was stirred at 25°C for 2 h under Argon.
- the reaction was detected by LCMS.
- LCMS detected the desired product.
- the reaction was quenched with the solution of NaHSO 3 at 0°C.
- the resulting mixture was concentrated under reduced pressure to get residue.
- the residue was diluted with H 2 O (100 mL).
- the mixture was extracted with EA (3 ⁇ 40 mL).
- the combined organic layers were washed with brine (80 mL), dried over anhydrous Na 2 SO 4 .
- Step 8 3-(1-((S)-2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 4-Int-9)
- Step 9 3-(1-((S)-2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 4-Int-10)
- the mixture was stirred at 25°C for 1 h under Argon.
- the reaction was detected by LCMS.
- LCMS detected the desired product.
- the reaction mixture was purified by reversed-phase flash chromatography with the following conditions: C18 silica gel; mobile phase, ACN in H 2 O (0.1% FA), 10% to 50% gradient in 15 min; detector, UV 254 nm to give the desired product 3-(1-(( S )-2-((2,6-dimethylenetetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (80 mg, 53% yield
- Step 10 4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 4)
- Step 1 3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 5-Int-2)
- Step 2 3-(1-((S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 5-Int-3)
- Step 3 4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-8-methyl-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 5)
- Step 1 3-(1-((S)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 6-Int-2)
- Step 2 3-(1-((S)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 6-Int-3)
- Step 3 4-((8 S )-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2 R ,7a S )-2-fluorotetrahydro-1 H -pyrrolizin-7a(5 H )-yl)methoxy)-8-methyl-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 6)
- Example 6a 4-((S)-10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
- Example 6b 4-((S)-10-((S)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
- Step 1 3-(1-((S)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 7-Int-2)
- reaction mixture was quenched with NH 4 Cl (aq, 10 mL) and the solution was extracted with EA (2 x 20 mL). The organic phase was washed with brine (10 mL), dried over Na 2 SO 4 (s). The organic phase was concentrated under reduced pressure.
- Step 2 3-(1-((S)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 7-Int-3)
- Step 3 4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 7)
- Step 2 (S)-(1-(2,2-difluoroethyl)azetidin-2-yl)methanol (Example 8-Int-3)
- Step 3 3-(1-((S)-2-(((S)-1-(2,2-difluoroethyl)azetidin-2-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 8-Int-4)
- reaction mixture was quenched with conc. NH 4 Cl (aq, 5 mL) and the solution was extracted with EA (2 x 20 mL). The organic phase was washed with brine (10 mL), dried over Na 2 SO 4 (s). The organic phase was concentrated under reduced pressure.
- Step 4 3-(1-((S)-2-(((S)-1-(2,2-difluoroethyl)azetidin-2-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 8-Int-5)
- Step 5 4-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-2-(((S)-1-(2,2-difluoroethyl)azetidin-2-yl)methoxy)-4-fluoro-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol ( Example 8)
- the reaction mixture was stirred at 25°C for 1 h.
- the reaction mixture was diluted with DCM /MeOH(10/1 mL).
- the mixture was washed with con. NaHCO 3 (aq, 10 mL), then washed with brine (10 mL), dried over Na 2 SO 4 (s).
- the organic phase was concentrated under reduced pressure.
- Step 1 3-(1-((S)-2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 9-Int-2)
- Step 2 3-(1-((S)-2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 9-Int-3)
- Step 3 4-((8S)-2-((2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 9)
- Step 1 tert-butyl (3-(1-((S)-5-chloro-4-fluoro-8-methyl-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 10-Int-1)
- Step 2 tert-butyl (3-(1-((S)-5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 10-Int-3)
- Step 3 3-(1-((S)-5-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 10-Int-5)
- the mixture was stirred at 100°C for 2 h under Argon.
- the reaction was detected by LCMS.
- LCMS detected the desired product.
- the reaction mixture was diluted with H 2 O (40 mL).
- the resulting mixture was extracted with EA (20 mL).
- the combined organic layers were washed with brine (40 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to get residue.
- Prep-HPLC Prep-HPLC(Waters 2767 Column:Xbridge C18,19*250 mm, 10 ⁇ m;Mobile Phase A: 0.05% NH 3 H 2 O/H 2 O, B: ACN; flow rate: 20 mL/min; gradient: 39-39%; Retention Time:8.8-12.8 min of 16 min to give the desired products.
- Example 10a 4-((S)-10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5,6-difluoronaphthalen-2-ol (7.90 mg, 4% yield) as a white solid.
- Example 10b 4-((S)-10-((S)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5,6-difluoronaphthalen-2-ol (5.90 mg, 3%) as a white solid.
- Step 1 3-(1-((S)-5-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 11-Int-2)
- reaction mixture was stirred at 100°C for 4 h under N 2 . Upon completion, the reaction mixture was added water (5 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layer was filtered and concentrated, dried over Na 2 SO 4 .
- Step 2 3-((8S)-10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-chloro-4-cyclopropylphenol (Example 11)
- the reaction mixture was stirred at 25°C for 1 h.
- the reaction mixture was diluted with DCM /MeOH(10/1 mL ⁇ 2).
- the mixture was washed with con. NaHCO 3 (aq, 10 mL), then washed with brine (10 mL), dried over Na 2 SO 4 (s).
- the organic phase was concentrated under reduced pressure.
- Step 1 tert-butyl (Z)-(3-(1-((2-hydroxyethyl)imino)ethyl)pyridin-2-yl)carbamate (Example 12-Int-1)
- Example 3-Int-2 (20 g, 84.65 mmol) in EtOH (200 mL) were added 2-aminoethan-1-ol (15.5 g, 253.95 mmol) at 25°C under N 2 . The mixture was stirred at 90°C for 2h. The reaction was detected by LCMS. LCMS detected the desired product. The reaction mixture was concentrated under reduced pressure. The residue was diluted with H 2 O (200 mL), extracted with EA (120 mL). dried over Na 2 SO 4 . Filtered and concentrated under reduced pressure to get residue.
- Step 2 tert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate (Example 12-Int-2)
- Step 3 tert-butyl (3-(1-((2-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)amino)ethyl)pyridin-2-yl)carbamate (Example 12-Int-3)
- the reaction was detected by LCMS. LCMS detected the desired product.
- the reaction was quenched by the addition of H 2 O (30 mL) at 0°C. The reaction mixture was concentrated under reduced pressure to get residue. The residue was diluted with H 2 O (150 mL), extracted with EA (100 mL). dried over Na 2 SO 4 . Filtered and concentrated under reduced pressure to get the crude.
- Step 4 tert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 12-Int-4)
- the resulting mixture was stirred for additional 16 h at 25°C under Argon.
- the reaction was detected by LCMS.
- LCMS detected the desired product.
- the reaction mixture was diluted with H 2 O (150 mL), extracted with EA (100 mL). dried over Na 2 SO 4 . Filtered and concentrated under reduced pressure to get the crude.
- Step 5 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 12-Int-5)
- the mixture was stirred at 100°C for 2 h under Argon.
- the reaction was detected by LCMS.
- LCMS detected the desired product.
- the reaction mixture was diluted with H 2 O (100 mL).
- the resulting mixture was extracted with EA (60 mL).
- the combined organic layers were washed with brine (80 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to get residue.
- Step 6 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 12-Int-6)
- Step 7 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 12-Int-7)
- the reaction was quenched by the addition of H 2 O (4 mL) at 0°C.
- the reaction mixture was concentrated under reduced pressure to get residue.
- the residue was diluted with H 2 O (30 mL), extracted with EA (20 mL). dried over Na 2 SO 4 . Filtered and concentrated under reduced pressure to get the crude.
- Step 8 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraaza cyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 12-Int-8)
- the reaction was detected by LCMS.
- LCMS detected the desired product.
- the reaction mixture was purified by reversed-phase flash chromatography with the following conditions: C18 silica gel; mobile phase, ACN in H 2 O (0.1% FA), 10% to 50% gradient in 15 min; detector, UV 254 nm to give the desired product 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-8,9-dihydro-10 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalen-10-yl)ethyl)pyridin-2-amine (70 mg, 56% yield) as a yellow solid.
- MS: m/z 723.9 (M+H, ESI+).
- Step 9 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((1-(morpholinomethyl)cyclopropyl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 12)
- Step 1 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 13-Int-1)
- Step 2 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 13-Int-2)
- Step 3 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 13)
- Step 4 Example 13a and Example 13b
- Example 13a 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
- Example 13b 4-(10-((S)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol
- Step 1a tert-butyl (3-acetylpyridin-2-yl)carbamate (Example 14-Int-2b)
- Example 14-Int-2a (4.00 g, 29.4 mmol) in t -BuOH (20 mL, 5 vol.) was added (Boc) 2 O (10.0 mL, 44.1 mmol) at room temperature and the reaction mixture was heated to 80°C and stirred for 5 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get solid, the solid was filtered and dried under high vacuum to get crude compound tert- butyl (3-acetylpyridin-2-yl)carbamate Example 14-Int-2b (5.0 g, crude) as a pale yellow solid. The crude compound was used as such in next step without further purification. MS (LC-MS): 237.28 m/z [M+H].
- Step 2a tert-butyl (E)-(3-(1-((2-hydroxyethylidene)amino)ethyl)pyridin-2-yl)carbamate (Example 14-Int-2d)
- Example 14-Int-2b (5.00 g, 21.2 mmol) and 2-aminoethan-1-ol
- Example 14-Int-2c (2.50 g, 31.8 mmol) in THF (50 mL, 10 vol) was added titanium ethoxide (14.5 g, 63.6 mmol) at room temperature and the reaction mixture was stirred at room temperature for 12 h. Progress of the reaction was monitored by TLC.
- Step 3a tert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate (Example 14-Int-2)
- Step 1 tert-butyl (3-(1-((2-((7-chloro-2-(ethylthio)-8-fluoro-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)amino)ethyl)pyridin-2-yl)carbamate (Example 14-Int-3)
- Example 1-Int-2 (1.80 g, 6.14 mmol) in THF (31 mL, 17 vol) was added NaH (1.00 g, 27.6 mmol) at 0°C and stirred for 30 min, followed by an addition of tert -butyl (3-(1-((2-hydroxyethyl)amino)ethyl)pyridin-2-yl)carbamate
- Example 14-Int-2 (2.00 g, 7.37 mmol) at 0°C and the reaction mixture was stirred at 0°C for 1 h.
- reaction mixture was diluted with water and extracted with ethyl acetate (2 x 50 mL), combined organic layer was washed with brine solution, dried over anhydrous Na 2 SO 4 , filtered and evaporated under reduced pressure to get crude compound.
- Step 2 tert-butyl (3-(1-(5-chloro-2-(ethylthio)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 14-Int-4)
- Step 3 3-(1-(5-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylthio)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 14-Int-6)
- Step 4 3-(1-(5-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(ethylsulfonyl)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 14-Int-7)
- Step 5 3-(1-(5-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 14-Int-9)
- reaction mixture was stirred at 0°C for 15 min. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (twice), combined organic layer was washed with brine solution, dried over anhydrous Na 2 SO 4 , filtered and evaporated under reduced pressure to get crude compound.
- Step 6 4-(10-(1-(2-Aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 14)
- Example 14a 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol
- Example 14b 4-(10-((S)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol
- Step 1 3-(1-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 15-Int-1)
- Step 2 3-(1-(2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 15-Int-2)
- Step 3 4 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 15)
- the reaction mixture was diluted with DCM /MeOH(10/1 mL ⁇ 2). The mixture was washed with con. NaHCO 3 (aq, 10 mL), then washed with brine (10 mL), dried over Na 2 SO 4 (s). The organic phase was concentrated under reduced pressure.
- Step 1 tert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 16-Int-1)
- the reaction was quenched with the solution of NaHSO 3 at 0°C.
- the resulting mixture was concentrated under reduced pressure to get residue.
- the residue was diluted with H 2 O (50 mL).
- the mixture was extracted with EA (3 ⁇ 30 mL).
- the combined organic layers were washed with brine (60 mL), dried over anhydrous Na 2 SO 4 .
- Step 2 tert-butyl (3-(1-(5-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-yl)carbamate (Example 16-Int-2)
- Step 3 3-(1-(5-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 16-Int-3)
- the mixture was stirred at 100°C for 2 h under Argon.
- the reaction was detected by LCMS.
- LCMS detected the desired product.
- the reaction mixture was diluted with H 2 O (40 mL).
- the resulting mixture was extracted with EA (20 mL).
- the combined organic layers were washed with brine (40 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to get residue.
- Step 4 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5,6-difluoronaphthalen-2-ol (Example 16)
- Step 1 3-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 17-Int-1)
- reaction mixture was quenched with conc. NH 4 Cl (aq, 5 mL) and the solution was extracted with EA (10 mL). The organic phase was washed with brine (10 mL), dried over Na 2 SO 4 (s). The organic phase was concentrated under reduced pressure.
- Step 2 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 17-Int-2)
- reaction mixture was stirred at room temperature for 2 h under N 2 .
- the reaction mixture was quenched with water (10 mL) and the solution was extracted with EA (10 mL). The organic phase was washed with brine (10 mL), dried over Na 2 SO 4 (s).
- Step 3 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 17-Int-3)
- Step 4 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-methoxytetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 17)
- Step 1 3-(1-(4-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 18-Int-1)
- Step 2 3-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 18-Int-2)
- reaction mixture was stirred at room temperature for 2 h under N 2 .
- the reaction mixture was quenched with water (10 mL) and the solution was extracted with EA (10 mL).
- the organic phase was washed with brine (10 mL x 3), dried over Na 2 SO 4 (s).
- Step 3 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 18)
- Step 1 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 19-Int-1)
- the mixture was stirred at 100°C for 2 h under Argon.
- the reaction was detected by LCMS.
- LCMS detected the desired product.
- the reaction mixture was diluted with H 2 O (80 mL).
- the resulting mixture was extracted with EA (40 mL).
- the combined organic layers were washed with brine (60 mL), dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure to get residue.
- Step 2 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 19-Int-2)
- the reaction was detected by LCMS. LCMS detected the desired product.
- the reaction was quenched with the solution of NaHSO 3 at 0°C.
- the resulting mixture was concentrated under reduced pressure to get residue.
- the residue was diluted with H 2 O (50 mL).
- the mixture was extracted with EA (3 ⁇ 30 mL).
- the combined organic layers were washed with brine (80 mL), dried over anhydrous Na 2 SO 4 .
- Step 3 3-(1-(2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 19-Int-3)
- Step 4 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-((2,6-dimethylenetetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 19)
- Step 1 tert-butyl (Z)-(2-(1-((2-hydroxyethyl)imino)ethyl)phenyl)carbamate (Example 20-Int-2)
- Step 2 tert-butyl (2-(1-((2-hydroxyethyl)amino)ethyl)phenyl)carbamate (Example 20-Int-3)
- Step 3 tert-butyl (2-(1-((2-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)amino)ethyl)phenyl)carbamate (Example 20-Int-4)
- Step 4 tert-butyl (2-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (Example 20-Int-5)
- Step 5 tert-butyl (2-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (Example 20-Int-6)
- Step 6 tert-butyl (2-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (Example 20-Int-7)
- Step 7 tert-butyl (2-(1-(4-fluoro-5-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (Example 20-Int-8)
- Step 8 tert-butyl (2-(1-(5-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)phenyl)carbamate (Example 20-Int-9)
- the mixture was stirred at 25°C for 1 h under Argon.
- the reaction was detected by LCMS.
- LCMS detected the desired product.
- the resulting mixture was diluted with H 2 O (80 mL).
- the resulting mixture was extracted with EA (3 ⁇ 50 mL).
- the combined organic layers were washed with brine (120 mL), dried over anhydrous Na 2 SO 4 .
- Step 9 4-(10-(1-(2-aminophenyl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol (Example 20)
- Step 1 4-(10-(1-(2-aminophenyl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 21)
- Step 1 4-(10-((R)-1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 22)
- Step 1 3-(1-ethoxyvinyl)-5-methylpyridin-2-amine (Example 23-Int-2)
- Step 4 tert-butyl (Z)-(3-(1-((2-hydroxyethyl)imino)ethyl)-5-methylpyridin-2-yl)carbamate (Example 23-Int-5)
- Step 5 tert-butyl (3-(1-((2-hydroxyethyl)amino)ethyl)-5-methylpyridin-2-yl)carbamate (Example 23-Int-6)
- Step 6 tert-butyl (3-(1-((2-((7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)amino)ethyl)-5-methylpyridin-2-yl)carbamate (Example 23-Int-7)
- reaction mixture was quenched with conc. NH 4 Cl (aq, 20 mL) and the solution was extracted with EA (30 mL). The organic phase was washed with brine (20 mL), dried over Na 2 SO 4 (s). The organic phase was concentrated under reduced pressure.
- Step 7 tert-butyl (3-(1-(5-chloro-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-yl)carbamate (Example 23-Int-8)
- Step 8 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylthio)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (Example 23-Int-9)
- Step 9 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(methylsulfonyl)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (Example 23-Int-10)
- Step 10 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)-5-methylpyridin-2-amine (Example 23-Int-11)
- Step 11 4-(10-(1-(2-amino-5-methylpyridin-3-yl)ethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 23)
- Step 1 4-(((10-(1-(2-aminopyridin-3-yl)ethyl)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-2-yl)oxy)methyl)tetrahydro-2H-pyran-4-carbonitrile (Example 24-Int-1)
- Step 2 4-(((10-(1-(2-aminopyridin-3-yl)ethyl)-5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-2-yl)oxy)methyl)tetrahydro-2H-pyran-4-carbonitrile (Example 24)
- Step 1 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 25-Int-1)
- Step 2 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-(((6S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 25)
- Step 1 methyl (R)-1-(3-fluoropyrrolidine-1-carbonyl)cyclopropane-1-carboxylate (Example 26-Int-1)
- Step 3 3-(1-(5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 26-Int-3)
- Step 4 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-4-fluoro-2-((1-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 26)
- Step 3 3-(1-(2-(((S)-1-(2,2-difluoroethyl)pyrrolidin-2-yl)methoxy)-5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-8,9-dihydro-10H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-10-yl)ethyl)pyridin-2-amine (Example 27-Int-4)
- Step 4 4-(10-(1-(2-aminopyridin-3-yl)ethyl)-2-(((S)-1-(2,2-difluoroethyl)pyrrolidin-2-yl)methoxy)-4-fluoro-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol (Example 27)
- Step 1 7-chloro-8-fluoro-5-(2-(methylamino)ethoxy)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (Example 28-Int-2)
- Step 2 5-chloro-4-fluoro-10-methyl-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (Example 28-Int-3)
- Step 3 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-10-methyl-2-(methylthio)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (Example 28-Int-4)
- Step 4 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-10-methyl-2-(methylsulfonyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (Example 28-Int-5)
- Step 5 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalene (Example 28-Int-6)
- reaction mixture was stirred at 0°C for 30 min under N 2 and the solution of 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-10-methyl-2-(methylsulfonyl)-9,10-dihydro-8 H -7-oxa-1,3,6,10-tetraazacyclohepta[ de ]naphthalene (56 mg, 0.11 mmol) in THF (1 mL)was added dropwise to the above mixture. The reaction mixture was stirred at room temperature for 1 h under N 2 . The reaction mixture was quenched with conc.
- Step 6 5-ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol (Example 28)
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Abstract
L'invention concerne des composés tri-hétérocycliques, et plus spécifiquement des composés tri-hétérocycliques utiles en tant qu'inhibiteurs de la protéine KRAS, et une composition pharmaceutique les comprenant, pour le traitement de cancers.
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KR20220134463 | 2022-10-18 | ||
KR10-2022-0134463 | 2022-10-18 | ||
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KR20230056594 | 2023-04-28 |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2007034144A1 (fr) * | 2005-09-20 | 2007-03-29 | Astrazeneca Ab | Composes de 4- (ih-indazol-s-yl-amino)-quinazoline utilises comme inhibiteurs des tyrosines kinases erbb associees au recepteur pour traiter le cancer |
WO2018206539A1 (fr) * | 2017-05-11 | 2018-11-15 | Astrazeneca Ab | Composés hétéroaryle inhibant des protéines ras portant la mutation g12c |
WO2019215203A1 (fr) * | 2018-05-08 | 2019-11-14 | Astrazeneca Ab | Composés hétéroaryles tétracycliques |
CN112574224A (zh) * | 2019-09-30 | 2021-03-30 | 上海迪诺医药科技有限公司 | Kras g12c抑制剂及其应用 |
WO2022216762A1 (fr) * | 2021-04-08 | 2022-10-13 | Genentech, Inc. | Composés d'oxazépine et leurs utilisations dans le traitement du cancer |
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- 2023-10-18 WO PCT/KR2023/016192 patent/WO2024085661A1/fr unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007034144A1 (fr) * | 2005-09-20 | 2007-03-29 | Astrazeneca Ab | Composes de 4- (ih-indazol-s-yl-amino)-quinazoline utilises comme inhibiteurs des tyrosines kinases erbb associees au recepteur pour traiter le cancer |
WO2018206539A1 (fr) * | 2017-05-11 | 2018-11-15 | Astrazeneca Ab | Composés hétéroaryle inhibant des protéines ras portant la mutation g12c |
WO2019215203A1 (fr) * | 2018-05-08 | 2019-11-14 | Astrazeneca Ab | Composés hétéroaryles tétracycliques |
CN112574224A (zh) * | 2019-09-30 | 2021-03-30 | 上海迪诺医药科技有限公司 | Kras g12c抑制剂及其应用 |
WO2022216762A1 (fr) * | 2021-04-08 | 2022-10-13 | Genentech, Inc. | Composés d'oxazépine et leurs utilisations dans le traitement du cancer |
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