WO2022262691A1 - Heterocyclic compounds as sos1 inhibitors - Google Patents
Heterocyclic compounds as sos1 inhibitors Download PDFInfo
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- WO2022262691A1 WO2022262691A1 PCT/CN2022/098492 CN2022098492W WO2022262691A1 WO 2022262691 A1 WO2022262691 A1 WO 2022262691A1 CN 2022098492 W CN2022098492 W CN 2022098492W WO 2022262691 A1 WO2022262691 A1 WO 2022262691A1
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- 150000002391 heterocyclic compounds Chemical class 0.000 title abstract description 8
- 239000003112 inhibitor Substances 0.000 title description 2
- 101100421901 Caenorhabditis elegans sos-1 gene Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 222
- 238000000034 method Methods 0.000 claims abstract description 59
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 10
- 230000001404 mediated effect Effects 0.000 claims abstract description 6
- 102000057028 SOS1 Human genes 0.000 claims abstract description 4
- 108700022176 SOS1 Proteins 0.000 claims abstract description 4
- 101100404726 Arabidopsis thaliana NHX7 gene Proteins 0.000 claims abstract 3
- 101100197320 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) RPL35A gene Proteins 0.000 claims abstract 3
- 101150100839 Sos1 gene Proteins 0.000 claims abstract 3
- 125000000217 alkyl group Chemical group 0.000 claims description 63
- 125000000623 heterocyclic group Chemical group 0.000 claims description 46
- 229910052736 halogen Inorganic materials 0.000 claims description 34
- 150000002367 halogens Chemical class 0.000 claims description 34
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 29
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 29
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 25
- 125000001072 heteroaryl group Chemical group 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 5
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 4
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present invention relates to heterocyclic compounds or their pharmaceutically acceptable salts thereof, suitable for regulating or inhibiting the activity of SOS1.
- the present invention also relates to methods for preparing the heterocyclic compounds or their pharmaceutically acceptable salts thereof.
- the present invention further relates to methods for treating and/or preventing diseases mediated by SOS1, in particular cancers, by the heterocyclic compounds or their pharmaceutically acceptable salts thereof.
- RAS family oncoproteins are small monomeric GTPase proteins, comprising three family members, KRAS (Kirsten rat sarcoma viral oncogene homolog) , HRAS (Harvey rat sarcoma viral oncogene homolog) and NRAS (neuroblastoma rat sarcoma viral oncogene homology) .
- KRAS Kerrsten rat sarcoma viral oncogene homolog
- HRAS Hardvey rat sarcoma viral oncogene homolog
- NRAS nerveroblastoma rat sarcoma viral oncogene homology
- RAS After receiving cellular signals from upstream tyrosine kinases, RAS exchanges the bound GDP to GTP induced by guanine nucleotide exchange factors (GEFs) such as SOS1 (Son of Sevenless 1) and then undergoes structural changes to become active or be in the on state, thereby activating downstream effector proteins and eventually leading to cell growth and division.
- GEFs guanine nucleotide exchange factors
- SOS1 Syn of Sevenless 1
- GEFs guanine nucleotide exchange factors
- GAPs exogenous protein GTPase activating proteins
- C x-y refers to a range of the number of carbon atoms, where x and y are both integers, for example, C 3-8 cycloalkyl stands for cycloalkyl having 3 to 8 carbon atoms.
- Alkyl refers to a saturated straight-chain or branched-chain hydrocarbyl substituent containing 1 to 20 carbon atoms, for example, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
- alkyl examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 1, 2-trimethylpropyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl.
- Alkylene refers to a saturated straight-chain or branched-chain hydrocarbyl divalent substituent containing 1 to 20 carbon atoms, for example, 1 to 6 carbon atoms or 1 to 4 carbon atoms.
- alkylene include but are not limited to -CH 2 -, -CH (CH 3 ) -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, - (CH 3 ) C (CH 3 ) -, -CH 2 CH 2 CH 2 CH 2 -and -CH 2 CH (CH 3 ) CH 2 -.
- Cycloalkyl refers to a saturated cyclic hydrocarbyl substituent containing 3 to 14 annular carbon atoms. Cycloalkyl can be a mono carbon ring substituent, typically containing 3 to 8, 3 to 7, or 3 to 6 carbon atoms. Unrestricted examples of monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl can also be a substituent with two or three mono carbon rings that are fused together, such as decahydronaphthyl.
- Heterocyclyl or heterocycle refers to a saturated or partially unsaturated monocyclic or polycyclic group containing 3 to 20 annular atoms, for example, 3 to 14, 3 to 12, 3 to 10, 3 to 8, 3 to 6, or 5 to 6 annular atoms in which one or more of the annular atoms are selected from N, O and S (O) m (where m is an integer from 0 to 2) .
- it can have 3 to 12 annular atoms, 3 to 10 annular atoms, 4 to 7 annular atoms, and 4 to 6 annular atoms, wherein 1 to 4 are heteroatoms, 1 to 3 are heteroatoms, or 1 to 2 are heteroatoms.
- monocyclic heterocyclyl examples include but are not limited to pyrrolidinyl, oxetanyl, piperidyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, homopiperazinyl and azetidinyl.
- Polycyclic heterocyclyl includes fused, bridged or spiro polycyclic heterocycle, such as octahydrocyclopenta [c] pyrrole, octahydropyrrole [1, 2-a] pyrazine, 3, 8-diazabicyclo [3.2.1] octane, 5-azaspiro [2.4] heptane and 2-oxa-7-azaspiro [3.5] nonane.
- Aryl or aryl ring refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6-to 10-membered, such as phenyl and naphthyl, most preferably phenyl.
- the aryl ring can be fused with a heteroaryl, heterocyclyl or cycloalkyl ring, and unrestricted examples include but are not limited to:
- Heteroaryl or heteroaryl ring refers to a heteroaromatic system containing 5 to 14 annular atoms, of which 1 to 4 annular atoms are selected from heteroatoms including O, S and N.
- Heteroaryl preferably is 5-to 10-membered, and more preferably 5-or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl and isoindolyl.
- the heteroaryl ring can be fused with an aryl, heterocyclyl or cycloalkyl ring, and unrestricted examples include but are not limited to:
- Halogen refers to F, Cl, Br, or I.
- Cyano refers to -CN.
- Carbonyl refers to -C (O) -.
- “Sulfonyl” refers to a -S (O) 2 -.
- Optional substitution or optionally substituted refers to that one or more hydrogen atoms in a group, preferably 1-5, for example, 1 to 3 hydrogen atoms, are independently substituted by a corresponding number of substituents.
- the substituents are located only in the possible chemical positions understood by those skilled in the art. For example, amino or hydroxyl groups with free hydrogen may be unstable when bound with carbon atoms with unsaturated bonds (such as olefinic) .
- the substituents include but are not limited to halogen, hydroxyl, cyano, nitro, oxo, -SF 5 , C 1-4 alkyl, C 3-7 cycloalkyl, etc.
- “Isomers” refer to compounds that have the same molecular formula, but their atomic binding position or spatial arrangement is different. Isomers with different arrangement of their atoms in space are called “stereoisomers” . Stereoisomers include optical isomers, geometric isomers, and conformational isomers.
- optical isomers include enantiomers and diastereomers.
- An enantiomer is one of two stereoisomers that are mirror images of each other and are non-superimposable.
- a racemic mixture, or racemate is one that has equal amounts of left-and right-handed enantiomers of a chiral molecule.
- Diastereomers are stereoisomers that are not mirror images of one another and are non-superimposable on one another. Methods for preparing and separating optical isomers are known in the art.
- the compounds of the present invention may also have geometric isomers resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclyl groups.
- the substituents around the carbon-carbon double bond or carbon-nitrogen bond are designated to be in a Z or E configuration, and the substituents around the cycloalkyl or heterocycle are designated to be in a cis or trans configuration.
- the compounds of the present invention may also show tautomerism, such as keto-enol tautomerism.
- the present invention includes any tautomeric or stereoisomeric forms and mixtures thereof and is not limited to any tautomeric or stereoisomeric forms used in the compound nomenclature or chemical structural formulae.
- isotopes include all isotopes of the atoms appearing in the compounds of the present invention. Isotopes include those atoms with the same atomic number but in different masses. Examples of isotopes suitable for incorporation into the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example but not limited to 2 H (D) , 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
- the isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the embodiments using appropriate isotopically labeled reagents instead of non-isotopically labeled reagents. Such compounds have various potential uses, for example, as standards and reagents in the determination of biological activities. In the case of stable isotopes such as deuterium 2 H (D) , 13 C and 15 N, such compounds have the potential to beneficially alter biological, pharmacological, or pharmacokinetic properties. Deuterium 2 H (D) is a preferable isotope of the present invention. For example, the hydrogens of -CH 3 can be substituted by D to -CD 3 .
- prodrugs refer to derivatives that are converted into biologically active compounds under the physiological condition in vivo, for example, by oxidation, reduction, and hydrolysis (each of which occurs with or without the participation of enzymes) .
- Examples of a prodrug are a compound of the present invention in which an amino is acylated, alkylated or phosphorylated, for example eicosanoyl amino, alanyl amino and pivaloyloxymethyl amino; a hydroxyl is acylated, alkylated or phosphorylated or converted into borate, for example acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaroyloxy and alanyloxy; a carbonyl is esterified or amidated; and a thiol forms a disulfide bridge with a carrier molecule that selectively delivers the drug to the target and/or to the cytosol of cells, such as peptide.
- Prodrugs can be prepared from the compounds of the present invention according to well-known methods.
- “Pharmaceutically acceptable salts” refer to salts derived from the compounds of the present invention with pharmaceutically acceptable bases or acids, including inorganic alkalis or acids and organic bases or acids, under the condition that the compounds contain one or more acidic or basic groups.
- Compounds of the present invention that contain acidic groups can exist in form of salts, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts.
- such salts include sodium salts, potassium salts, calcium salts, magnesium salts or ammonia or organic amine salts such as salts of ethylamine, ethanolamine, triethanolamine or amino acids.
- Compounds of the present invention that contain basic groups can exist in form of salts as inorganic or organic acid salts.
- acids examples include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalene disulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propanoic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acids known to those skilled in the art.
- the present invention further includes internal salts in addition to the mentioned salt forms.
- Each salt can be obtained by conventional methods known to those skilled in the art, for example by mixing a compound of the present invention with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with another salt.
- “Pharmaceutical composition” refers to a composition containing one or more of the compounds described herein or pharmaceutically acceptable salts, prodrugs, stable isotope derivatives and isomers thereof, and other components such as pharmaceutically acceptable carriers and excipients.
- “Cancers/tumors” include but are not limited to pancreatic cancer, lung cancer, colorectal cancer, multiple myeloma, liver cancer, cholangiocarcinoma, gastric cancer, kidney cancer, head and neck squamous cell carcinoma, thyroid cancer, prostate cancer, bladder cancer, renal cancer, breast cancer, ovarian cancer, urothelial cancer, cervical cancer, uterine cancer, endometrial cancer, acute myeloid leukemia, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, glioblastoma, and sarcomas.
- “Therapeutically effective amount” refers to the amount of the compound of the present invention that can effectively inhibit the functions of SOS1, and/or treat or prevent the diseases mediated by SOS1.
- “Patients” refer to mammals, preferably humans.
- SOS1 is a multi-domain protein with two binding sites, a catalytic site that binds GDP-bound RAS to promote guanine nucleotide exchange and an allosteric site that binds GTP-bound RAS to provide a positive feedback that increases RAS signaling.
- the present invention provides compounds that inhibit SOS1 activity, block the RAS: SOS1 protein-protein interaction, and therefore target RAS-driven tumors.
- the present invention provides heterocyclic compounds useful in inhibiting SOS1 activity.
- the compounds are shown in Formula (I) , or prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, and stereoisomers thereof,
- A is CR 3 or N
- X 1 and X 2 are independently CH or N;
- X 3 is CR 6 or N
- R 1 is H or C 1-6 alkyl, where one or more hydrogens of the alkyl are optionally substituted by D, halogen, -OR 4b or -NR 4b R 4c ;
- R 2 is H, cyano, halogen, -OR 4b , -NR 4b R 4c , C 1-6 alkyl, C 3-8 cycloalkyl or 4-10 membered heterocyclyl, where one or more hydrogens of the alkyl, cycloalkyl and heterocyclyl are optionally substituted by D, halogen, -OR 4b or -NR 4b R 4c ;
- R 3 is H, halogen, cyano, -OR 4b , -NR 4b R 4c , C 1-6 alkyl, C 3-8 cycloalkyl or 4-10 membered heterocyclyl, where one or more hydrogens of the alkyl, cycloalkyl and heterocyclyl are optionally substituted by D, halogen, -OR 4b or -NR 4b R 4c ;
- R 4 is halogen, cyano, -OR 4a , -NR 4b R 4c , -COOR 4b , -C (O) R 4b , -C (O) NR 4b R 4c , -NR 4b C (O) R 4c , -NR 4b S (O) 2 R 4c , -S (O) 2 NR 4b R 4c , C 1-6 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, where one or more hydrogens of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by R 4’ ;
- R 5 is H or NH 2 ;
- R 6 is H, halogen or C 1-6 alkyl
- R 7 is C 1-6 alkyl, C 3-8 cycloalkyl or 4-10 membered heterocyclyl, where one or more hydrogens of the alkyl, cycloalkyl and heterocyclyl are optionally substituted by D or halogen;
- L is C 1-6 alkylene, where one or more hydrogens of the alkylene are optionally substituted by D or halogen; for example, L is ethylene substituted with difluoro;
- R 4a is C 1-6 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, where one or more hydrogens of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by C 1-6 alkyl, fluorinated C 1-6 alkyl, C 3-8 cycloalkyl, -C (O) C 1-6 alkyl, -C (O) C 3-8 cycloalkyl or 4-10 membered heterocyclyl;
- R 4’ is D, halogen, oxo, -OR 4b , -NR 4b R 4c , -COOR 4b , -C (O) R 4b , -C (O) NR 4b R 4c , -NR 4b C (O) R 4c , C 1-6 alkyl or C 3-8 cycloalkyl, where one or more hydrogens of the alkyl are optionally substituted by D, halogen, -OR 4b or -NR 4b R 4c ; and
- R 4b and R 4c are independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl or 4-10 membered heterocyclyl, where one or more hydrogens of the alkyl, cycloalkyl and heterocyclyl are optionally substituted by D, halogen, and C 1-6 alkyl.
- the compounds shown in Formula (I) have the following Formula (II) ,
- A, X 1 , X 2 , R 1 -R 5 , R 4a , R 4’ , R 4b , and R 4c are the same as those described above in Formula (I) ;
- X 3 is CH, CF or N.
- R 1 is -CH 3 , -CHF 2 , - (CH 2 ) 1-2 OH, or – (CH 2 ) 1-2 OCH 3 .
- R 1 is -CH 3 .
- R 2 is H, halogen, cyano, -CH 3 , -OCH 3 , -CH 2 OH, or -CH 2 OCH 3 .
- R 2 is H or -CH 3 .
- R 3 is H, halogen, cyano, -CH 3 , or -OCH 3 .
- R 4 is -OR 4a .
- R 4 6-membered heterocyclyl substituted with -OCH 3 .
- R 4a is C 1-6 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, where one or more hydrogens of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by C 1-6 alkyl, fluorinated C 1-6 alkyl, C 3-8 cycloalkyl, -C (O) C 1-6 alkyl, -C (O) C 3-8 cycloalkyl, or 4-10 membered heterocyclyl.
- R 4 is:
- R 4 is C 3-8 cycloalkyl or 4-10 membered heterocyclyl, where one or more hydrogens of the cycloalkyl and heterocyclyl are optionally substituted by R 4’ .
- R 4 is:
- R 4 is C 6-12 aryl or 5-12 membered heteroaryl, where one or more hydrogens of the aryl and heteroaryl are optionally substituted by R 4’ .
- R 4 is:
- R 4’ is D, halogen, oxo, -OR 4b , -NR 4b R 4c , -COOR 4b , -C (O) R 4b , -C (O) NR 4b R 4c -NR 4b C (O) R 4c , C 1-6 alkyl, or C 3-8 cycloalkyl, where one or more hydrogens of the alkyl are optionally substituted by D, halogen, -OR 4b or -NR 4b R 4c ; R 4b and R 4c are independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl, or 4-10 membered heterocyclyl, where one or more hydrogens of the alkyl, cycloalkyl and heterocyclyl are optionally substituted by D, halogen, and C 1-6 alkyl.
- the present invention further relates to the following Compounds 1-80, or their pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers, and mixtures thereof.
- the compounds of the present invention effectively block the binding interaction between RAS and SOS1, having an IC 50 less than 1000 nM, preferably having an IC 50 less than 100 nM.
- the compounds of the present invention have a significant inhibitory effect on K562 and MIA PaCa-2 cell proliferations, having an IC 50 less than 1000 nM, preferably having an IC 50 less than 100 nM.
- the present invention further relates to pharmaceutical compositions comprising compounds of Formula (I) or pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, or isomers thereof, and pharmaceutically acceptable carriers or excipients.
- the pharmaceutical compositions are useful for the treatment or prevention of SOS1 mediated cancers, in particular of lung cancer such as non-small cell lung cancer (NSCLC) , colorectal cancer, pancreatic cancer, cholangiocarcinoma, and ovarian cancer.
- lung cancer such as non-small cell lung cancer (NSCLC) , colorectal cancer, pancreatic cancer, cholangiocarcinoma, and ovarian cancer.
- the present invention further relates to pharmaceutical combinations comprising compounds of the Formula (I) or pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, or isomers thereof, and additional anti-cancer agents.
- Compounds of Formula (I) and another anti-cancer agent may be present in the same pharmaceutical composition or in different pharmaceutical compositions.
- Compounds of Formula (I) and another anti-cancer agent may be administered simultaneously or sequentially in the same or different forms.
- the present invention further provides a method for treating or preventing cancers mediated by SOS1.
- the method comprises administering to a patient in need thereof a therapeutically effective amount of the compounds shown in Formula (I) or pharmaceutically acceptable salts, prodrugs, stable isotope derivatives and isomers thereof.
- the pharmaceuticals can be in any dosage form, including but not limited to tablets, capsules, a solution, a freeze-drying preparation and injectable.
- the pharmaceutical formulation of the present invention can be administered in form of a dosage unit containing a predetermined amount of active ingredient.
- a dosage unit may contain 1 mg to 1 g, preferably 10 mg to 500 mg of a compound of the present invention, depending on the disease being treatment, the method of administration, as well as age, weight, and condition of the patients.
- the pharmaceutical formulation can be prepared using methods well-known in the pharmaceutical field, for example, by formulating the active ingredient with one or more excipients or one or more adjuvants.
- the pharmaceutical formulation of the present invention is suitable for administration by any appropriate method, for example by oral (including buccal or sublingual) or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) .
- the present invention further provides methods for preparing the compounds.
- the preparation of the compounds of the present invention can be accomplished by the following exemplary methods and embodiments, but these methods and embodiments should not be considered as limitations to the scope of the present invention.
- the compounds of the present invention can be synthesized by methods known to those skilled in the art, or by methods described in the present invention.
- the products obtained at each step of reaction are isolated by separation techniques known in the art.
- the starting materials and chemical reagents used for the synthesis can be conventionally made based on literature (for example, SciFinder) or purchased.
- heterocyclic compounds shown in Formula (I) of the present invention can be synthesized according to the route shown below: 1) substitution of the leaving group X (halide, trisyl, etc. ) from Int1 by an amino intermediate Int2 under a basic condition to give A1; 2) conventional transformations of R', R” and/or R”' of A1 by synthetic methods known to those skilled in the art, such as hydrogenation, fluorination, hydrolysis, deprotection, amidation, reduction, hydroxylation, alkylation, coupling, etc., to afford the desired product.
- Intermediate Int1 can be synthesized according to the route shown below: 1) bromination of B1 to give B2; 2) base-catalyzed hydrolysis of ester B2, followed by amidation to give amide B3; 3) amidation of B3 with an acyl chloride under a basic condition or a nitrile under an acidic condition and subsequent ring closure to give B4; 4) chlorination with POCl 3 or trisylation with trisyl chloride of B4 to give B5; 5) Br of B5 can be converted into a variety of functional groups by coupling reactions to provide the intermediate Int1.
- Intermediate Int1 can also be synthesized according to the route shown below: 1) amidation of C1 and subsequent ring closure to give C2; 2) acid-catalyzed hydrolysis of C2 to give hydroxy C3; 3) alkoxylation of C4 with R” -leaving group under a basic condition to give C4; 4) chlorination with POCl 3 or trisylation with trisyl chloride of C4 to provide the intermediate Int1.
- Intermediate Int2 can be synthesized according to the route shown below: 1) deprotonation of D1 with LiHMDS, followed by fluorination with NFSI to give D2; 2) reduction of D2 with NaBH 4 to give alcohol D3; 3) alkoxylation of ether D3 to give D4; 4) Suzuki coupling of D4, followed by acid-catalyzed hydrolysis to give ketone D5; 5) Formation of a Schiff base between D5 and a sulfinamide chiral auxiliary, followed by reduction with LiBH 4 to give D6; 6) acid-catalyzed hydrolysis of D6 to provide the intermediate Int2.
- D2 can also be synthesized according to the route below: 1) fluorination of E1 with DAST to give E2; 2) nitration of E2 to give E3; 3) bromination of E3 to provide D2.
- the structure of a compound was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS) .
- NMR determination used a Bruker ASCEND-400 NMR spectrometer.
- the solvent for the determination was deuterated dimethyl sulfoxide (DMSO-d 6 ) , deuterated chloroform (CDC1 3 ) , or deuterated methanol (CD 3 OD) .
- the internal standard was tetramethylsilane (TMS) , and the chemical shift was given in a unit of 10 -6 (ppm) .
- MS determination used an Agilent SQD (ESI) mass spectrometer (Agilent 6120) .
- HPLC determination used Agilent 1260 DAD high pressure liquid chromatograph (column: Poroshell120 EC-C18, 50 ⁇ 3.0 mm, 2.7 ⁇ m) or Waters Arc high pressure liquid chromatograph (column: Sunfire C18, 150 ⁇ 4.6 mm, 5 ⁇ m) .
- Thin layer chromatography used GF254 silica gel plates from Qingdao Haiyang Chemical Co., Ltd. with a thickness of 0.15 to 0.2 mm, and the separation/purification of products by thin layer chromatography used silica plates with a thickness 0.4 to 0.5 mm.
- the reactions were carried out under an atmosphere of argon or nitrogen using a balloon with a volume of about 1 L.
- Hydrogenation was carried out under an atmosphere of hydrogen using a balloon with a volume of about 1 L that was attached to the reaction vessel after being vacuumed and filled with hydrogen repeatedly for 3 times.
- the microwave reaction used a CEM Discover-SP microwave reactor.
- reaction was run at room temperature.
- the reaction was monitored using Agilent LCMS (1260/6120) or thin layer chromatography.
- the solvent eluting systems for column chromatography and TLC included a) dichloromethane/methanol, b) petroleum ether/ethyl acetate, or other systems as indicated.
- the ratio of the solvents was adjusted according to the polarity of the compound, and further adjusted by addition of a small amount of TEA, or an acidic or alkaline reagent as needed.
- the compound purification was alternatively done using Waters’ MS-guided automated preparation system (abbreviated as prep-HPLC) with a MS detector (SQD2) , eluting at a flow rate of 20 mL/min in an appropriate acetonitrile/water (containing 0.1%TFA or formic acid) or acetonitrile/water (containing 0.05%of 25-28%ammonium hydroxide) gradient (XBridge-C18, 19 ⁇ 150 mm, 5 ⁇ m) .
- Some compounds were prepared as HCl salts after prep-HPLC purification by addition of 1 N HCl to the collected fractions, followed by drying under reduced pressure.
- PE refers to petroleum ether
- DMF refers to N, N-dimethylformamide.
- DMA refers to N, N-dimethylacetamide.
- THF tetrahydrofuran
- TFA trifluoroacidic acid
- DIPEA N, N-diisopropylethylamine
- TEA triethylamine
- DMAP refers to 4-dimethylaminopyridine.
- LiHMDS refers to lithium bis (trimethylsilyl) amide.
- the abbreviation LDA refers to lithium diisopropylamide.
- NFSI N-fluorobenzenesulfonimide
- TsCl refers to tosyl chloride.
- DAST refers to diethylaminosulphur trifluoride.
- NBS N-bromosuccinimide
- NIS refers to N-iodosuccinimide.
- NCS refers to N-chlorosuccinimide
- HOBT 1-hydroxybenzotriazole
- EDCI 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride.
- HATU refers to 2- (7-azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate.
- Pd (dppf) Cl 2 refers to [1, 1'-bis (diphenylphosphino) ferrocene] dichloropalladium.
- Xantphos refers to 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene.
- BINAP refers to 2, 2'-bis (diphenylphosphino) -1, 1'-binaphthyl.
- Pd 2 (dba) 3 refers to tris (dibenzylideneacetone) dipalladium.
- Mn (dpm) 3 refers to tris (2, 2, 6, 6-tetramethyl-3, 5-heptanedionato) manganese (III) .
- Step 4 1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethan-1-one (1e)
- Step 1 (R) -4- ( (1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-6- (N-methylmethylsulfonamido) quinazoline-2-carboxylic acid (9a)
- Compound 24 was prepared according to the procedures for Compound 22, except that a different amine was used instead of morpholine in Step 1.
- Compound 63 was synthesized according to the procedures for Compound 27, except that different compounds were used instead of 20 and methanol.
- Step 1 (R) -N- (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- (1, 2, 3, 6-tetrahydropyridin-4-yl) quinazolin-4-amine (28a)
- Compound 42 was prepared according to the procedures for Compound 28, except that a different acid chloride was used instead of acetyl chloride in Step 2.
- Compound 47 was prepared according to the procedures for Compound 41, except that a different acid chloride was used instead of acetyl chloride in Step 2.
- Example 30 1- ( (S) -3- ( (4- ( ( (R) -1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) pyrrolidin-1-yl) propan-1-one (Compound 44)
- Step 2. 1- ( (S) -3- ( (4- ( ( (R) -1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) pyrrolidin-1-yl) propan-1-one (44)
- Step 6 4- (2- ( (Benzyloxy) methyl) -7-methoxy-4- (2, 2, 2-trifluoroethoxy) quinazolin-6-yl) tetrahydro-2H-pyran-4-ol (65f)
- Step 8 2- ( (Benzyloxy) methyl) -7-methoxy-6- (4-methoxytetrahydro-2H-pyran-4-yl) quinazolin-4-ol (65h)
- Compound 78 was prepared according to the procedures of Step 10 to 11 for Compound 65, except that a different compound was used instead of 15j in Step 10.
- Compound 67 was prepared according to the procedures for Compound 68, except that a different compound was used instead of 8i in Step 2.
- Step 8 (R) -N- (1- (4-amino-6- (1, 1-difluoro-2-methoxyethyl) pyridin-2-yl) ethyl) -7-methoxy-6- (4-methoxytetrahydro-2H-pyran-4-yl) -2-methylquinazolin-4-amine (69)
- 70f was prepared according to the procedures of Step 4 to 6 for the preparation of 77 by replacing 77d with 70c.
- Compound 72 was prepared according to the procedures for Compound 70, except that a different compound was used instead of 70a in Step 1.
- Step 6 1- (6- (Bis (4-methoxybenzyl) amino) -4- (1, 1-difluoro-2-methoxyethyl) pyridin-2-yl) ethan-1-one (71g)
- Step 7 (R, Z) -N- (1- (6- (bis (4-methoxybenzyl) amino) -4- (1, 1-difluoro-2-methoxyethyl) pyridin-2-yl) ethylidene) -2-methylpropane-2-sulfinamide (71h)
- Step 8 (R) -N- ( (R) -1- (6- (bis (4-methoxybenzyl) amino) -4- (1, 1-difluoro-2-methoxyethyl) pyridin-2-yl) ethyl) -2-methylpropane-2-sulfinamide (71i)
- Step 7 (R) -N- (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -8-chloro-6- (4-fluorotetrahydro-2H-pyran-4-yl) -2-methylquinazolin-4-amine (75h)
- Step 8 (R) -N- (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -8-chloro-6- (4-methoxytetrahydro-2H-pyran-4-yl) -2-methylquinazolin-4-amine (75i)
- Compound 73 was synthesized according to the procedures of Steps for Compound 75, except that a different compound was used instead of 75i.
- Compound 74 was synthesized according to the procedures of Steps 1 to 8 for Compound 75, except that a different compound was used instead of 75a.
- Step 7 (R) -N- (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -2- (difluoromethyl) -7-methoxy-6- (4-methoxytetrahydro-2H-pyran-4-yl) quinazolin-4-amine (77)
- Step 6 was synthesized according to the procedures of Step 6 to Step 9 for Intermediate 15k, except that in Step 6, 79a was used instead of 15f.
- Step 6 to Step 7. N- ( (R) -1- (5-amino-3- (1, 1-difluoro-2-methoxyethyl) -2-methylphenyl) ethyl) -7-methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine (79)
- Step 10 was synthesized according to the procedures of Step 10 to Step 11 for Compound 65, except that in Step 10, 79e was used instead of 15j and 3g was used instead of 65i, respectively.
- Interference of the compound of the present invention on the interaction between SOS1 and KRAS G12C was assessed via detecting the binding affinity between two proteins using a biochemical method in the HTRF assay format (Table 1) .
- An assay buffer contained the following components: 25 mM HEPES, 10 mM MgCl 2 , 5 mM EDTA, 1 mM DTT, 0.01%BSA, 0.01%Triton X-100 and 0.04%Brij35.
- a KRAS G12C protein solution contained 20 nM human recombinant GDP-bound KRAS G12C protein with a His-tag (produced by Tsinghua University’s protein purification facility) in the assay buffer.
- a detection solution contained 20 nM human recombinant SOS1 protein with a GST-tag (produced by Tsinghua University’s protein purification facility) , 90 ng/mL Eu 3+ -labeled anti-His antibody (Cisbio, Cat. No. 61HI2KLA) and 1.2 ⁇ g/mL d2-labeled anti-GST antibody (Cisbio, Cat. No. 61GSTDLF) in the assay buffer.
- test compound was dissolved to 400 or 1000 ⁇ M in DMSO, followed by a serial 4-fold dilution with DMSO to a minimum concentration of 24 or 61 nM. Each concentration was further diluted 50 folds with the assay buffer.
- test compound was dissolved to 2.5, 5 mM or 10 mM in DMSO, followed by a serial 4-fold dilution with DMSO to a minimum concentration of 155, 310 or 620 nM. Each concentration was further diluted 50 folds with the respective cell culture medium for each cell line.
- K562 (Cobioer, Cat. No. CBP60529, a human myelogenous leukemia cell line with a wild type of KRAS) and MIA-PaCa-2 (Cobioer, Cat. No. CBP60544, a human pancreatic cancer cell line with a KRAS G12C mutation) were grown in RPMI 1640 medium (Gibco, Cat. No. 72400047) and DMEM medium (Gibco, Cat. No. 11995065) , respectively. All cell culture media were supplemented with 10%FBS (GBICO, Cat. No 10099-141) and 1%penicillin-streptomycin (Gibco, Cat. No. 15070063) .
- K562 and MIA-PaCa-2 cells were seeded in a 384-well and a 96-well cell culture plate at a density of 400 cells/well, respectively, and the plates were incubated overnight at 37°C/5%CO 2 in a humidity-controlled incubator. 3 ⁇ L (for well with K562 cells) or 10 ⁇ L (for well with MIA-PaCa-2 cells) of the test compound solution was added to each well and mixed gently, and the plates were continuously incubated at 37°C/5%CO 2 for 4-5 days. Cell proliferation was then assessed using a Cell Titer-Glo kit (Promega, Cat.
Abstract
Provided herein are heterocyclic compounds shown in Formula (I) and their pharmaceutically acceptable salts thereof suitable for inhibiting or regulating the activity of SOS1. These compounds are useful for preventing and/or treating SOS1-mediated diseases, in particular cancers. Aslo provided are methods for preparing the mentioned compounds.
Description
The present invention relates to heterocyclic compounds or their pharmaceutically acceptable salts thereof, suitable for regulating or inhibiting the activity of SOS1. The present invention also relates to methods for preparing the heterocyclic compounds or their pharmaceutically acceptable salts thereof. The present invention further relates to methods for treating and/or preventing diseases mediated by SOS1, in particular cancers, by the heterocyclic compounds or their pharmaceutically acceptable salts thereof.
BACKGROUND ART
RAS family oncoproteins are small monomeric GTPase proteins, comprising three family members, KRAS (Kirsten rat sarcoma viral oncogene homolog) , HRAS (Harvey rat sarcoma viral oncogene homolog) and NRAS (neuroblastoma rat sarcoma viral oncogene homology) . As a molecular switch cycling between binding to GDP and GTP, RAS regulates signal pathways that control cell survival, proliferation, and division. When RAS binds GDP, it is inactive or in the off state. After receiving cellular signals from upstream tyrosine kinases, RAS exchanges the bound GDP to GTP induced by guanine nucleotide exchange factors (GEFs) such as SOS1 (Son of Sevenless 1) and then undergoes structural changes to become active or be in the on state, thereby activating downstream effector proteins and eventually leading to cell growth and division. As RAS has a strong binding affinity to GTP and weak intrinsic GTPase activity, it is necessary for GTP-bound RAS to interact with exogenous protein GTPase activating proteins (GAPs) to increase catalytic activity on the hydrolysis of GTP to GDP, so as to be back to the off state. However, if RAS mutates, resulting in weakening interaction between RAS and GAPs, it would become continuously activated (in the on state) , which in turn would lead to excessively cell proliferating, preventing apoptosis and inducing tumor growth. In fact, KRAS mutations are very common in cancers with an incidence of about 20%, especially in tubular adenocarcinoma (98%) , rectal cancer (45%) , lung cancer (31%) and multiple myeloma (23%) . Mutations in HRAS and NRAS are also found in cancers, albeit with less incidence than in KRAS. RAS is considered as an attractive target for oncology; however, limited success has been achieved clinically.
Definitions
Unless otherwise stated, the following terms used in this application have the following meanings.
“C
x-y” refers to a range of the number of carbon atoms, where x and y are both integers, for example, C
3-8 cycloalkyl stands for cycloalkyl having 3 to 8 carbon atoms.
“Alkyl” refers to a saturated straight-chain or branched-chain hydrocarbyl substituent containing 1 to 20 carbon atoms, for example, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Unrestricted examples of alkyl include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 1, 2-trimethylpropyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl.
“Alkylene” refers to a saturated straight-chain or branched-chain hydrocarbyl divalent substituent containing 1 to 20 carbon atoms, for example, 1 to 6 carbon atoms or 1 to 4 carbon atoms. Unrestricted examples of alkylene include but are not limited to -CH
2-, -CH (CH
3) -, -CH
2CH
2-, -CH
2CH
2CH
2-, - (CH
3) C (CH
3) -, -CH
2CH
2CH
2CH
2-and -CH
2CH (CH
3) CH
2-.
“Cycloalkyl” refers to a saturated cyclic hydrocarbyl substituent containing 3 to 14 annular carbon atoms. Cycloalkyl can be a mono carbon ring substituent, typically containing 3 to 8, 3 to 7, or 3 to 6 carbon atoms. Unrestricted examples of monocyclic cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl can also be a substituent with two or three mono carbon rings that are fused together, such as decahydronaphthyl.
“Heterocyclyl or heterocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic group containing 3 to 20 annular atoms, for example, 3 to 14, 3 to 12, 3 to 10, 3 to 8, 3 to 6, or 5 to 6 annular atoms in which one or more of the annular atoms are selected from N, O and S (O)
m (where m is an integer from 0 to 2) . Preferably, it can have 3 to 12 annular atoms, 3 to 10 annular atoms, 4 to 7 annular atoms, and 4 to 6 annular atoms, wherein 1 to 4 are heteroatoms, 1 to 3 are heteroatoms, or 1 to 2 are heteroatoms. Unrestricted examples of monocyclic heterocyclyl include but are not limited to pyrrolidinyl, oxetanyl, piperidyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, homopiperazinyl and azetidinyl. Polycyclic heterocyclyl includes fused, bridged or spiro polycyclic heterocycle, such as octahydrocyclopenta [c] pyrrole, octahydropyrrole [1, 2-a] pyrazine, 3, 8-diazabicyclo [3.2.1] octane, 5-azaspiro [2.4] heptane and 2-oxa-7-azaspiro [3.5] nonane.
“Aryl or aryl ring” refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6-to 10-membered, such as phenyl and naphthyl, most preferably phenyl. The aryl ring can be fused with a heteroaryl, heterocyclyl or cycloalkyl ring, and unrestricted examples include but are not limited to:
“Heteroaryl or heteroaryl ring” refers to a heteroaromatic system containing 5 to 14 annular atoms, of which 1 to 4 annular atoms are selected from heteroatoms including O, S and N. Heteroaryl preferably is 5-to 10-membered, and more preferably 5-or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl and isoindolyl. The heteroaryl ring can be fused with an aryl, heterocyclyl or cycloalkyl ring, and unrestricted examples include but are not limited to:
“Halogen” refers to F, Cl, Br, or I.
“Cyano” refers to -CN.
“Oxo” refers to =O.
“Carbonyl” refers to -C (O) -.
“Sulfonyl” refers to a -S (O)
2-.
“Sulfinyl” refers to a -S (O) -.
“Optional substitution or optionally substituted” refers to that one or more hydrogen atoms in a group, preferably 1-5, for example, 1 to 3 hydrogen atoms, are independently substituted by a corresponding number of substituents. The substituents are located only in the possible chemical positions understood by those skilled in the art. For example, amino or hydroxyl groups with free hydrogen may be unstable when bound with carbon atoms with unsaturated bonds (such as olefinic) . The substituents include but are not limited to halogen, hydroxyl, cyano, nitro, oxo, -SF
5, C
1-4 alkyl, C
3-7 cycloalkyl, etc.
“Isomers” refer to compounds that have the same molecular formula, but their atomic binding position or spatial arrangement is different. Isomers with different arrangement of their atoms in space are called “stereoisomers” . Stereoisomers include optical isomers, geometric isomers, and conformational isomers.
The compounds of the present invention can exist as optical isomers. Optical isomers include enantiomers and diastereomers. An enantiomer is one of two stereoisomers that are mirror images of each other and are non-superimposable. A racemic mixture, or racemate is one that has equal amounts of left-and right-handed enantiomers of a chiral molecule. Diastereomers are stereoisomers that are not mirror images of one another and are non-superimposable on one another. Methods for preparing and separating optical isomers are known in the art. When a compound is a single isomer and its absolute configuration is determined, it is referred as a “R” or “S” isomer according to the configuration of the substituents around the chiral carbon atom; when its absolute configuration is not determined, it is referred as a (+) or (-) isomer according to its measured optical rotation value.
The compounds of the present invention may also have geometric isomers resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclyl groups. The substituents around the carbon-carbon double bond or carbon-nitrogen bond are designated to be in a Z or E configuration, and the substituents around the cycloalkyl or heterocycle are designated to be in a cis or trans configuration.
The compounds of the present invention may also show tautomerism, such as keto-enol tautomerism.
The present invention includes any tautomeric or stereoisomeric forms and mixtures thereof and is not limited to any tautomeric or stereoisomeric forms used in the compound nomenclature or chemical structural formulae.
“Isotopes” include all isotopes of the atoms appearing in the compounds of the present invention. Isotopes include those atoms with the same atomic number but in different masses. Examples of isotopes suitable for incorporation into the compounds of the present invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example but not limited to
2H (D) ,
3H,
13C,
14C,
15N,
17O,
18O,
31P,
32P,
35S,
18F and
36Cl. The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the embodiments using appropriate isotopically labeled reagents instead of non-isotopically labeled reagents. Such compounds have various potential uses, for example, as standards and reagents in the determination of biological activities. In the case of stable isotopes such as deuterium
2H (D) ,
13C and
15N, such compounds have the potential to beneficially alter biological, pharmacological, or pharmacokinetic properties. Deuterium
2H (D) is a preferable isotope of the present invention. For example, the hydrogens of -CH
3 can be substituted by D to -CD
3.
The compounds of the present invention can be administered in form of prodrugs. “Prodrugs” refer to derivatives that are converted into biologically active compounds under the physiological condition in vivo, for example, by oxidation, reduction, and hydrolysis (each of which occurs with or without the participation of enzymes) . Examples of a prodrug are a compound of the present invention in which an amino is acylated, alkylated or phosphorylated, for example eicosanoyl amino, alanyl amino and pivaloyloxymethyl amino; a hydroxyl is acylated, alkylated or phosphorylated or converted into borate, for example acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaroyloxy and alanyloxy; a carbonyl is esterified or amidated; and a thiol forms a disulfide bridge with a carrier molecule that selectively delivers the drug to the target and/or to the cytosol of cells, such as peptide. Prodrugs can be prepared from the compounds of the present invention according to well-known methods.
“Pharmaceutically acceptable salts” refer to salts derived from the compounds of the present invention with pharmaceutically acceptable bases or acids, including inorganic alkalis or acids and organic bases or acids, under the condition that the compounds contain one or more acidic or basic groups. Compounds of the present invention that contain acidic groups can exist in form of salts, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. For example, such salts include sodium salts, potassium salts, calcium salts, magnesium salts or ammonia or organic amine salts such as salts of ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of the present invention that contain basic groups can exist in form of salts as inorganic or organic acid salts. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalene disulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propanoic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acids known to those skilled in the art. If compounds of the present invention contain both acidic and basic groups in the molecule, the present invention further includes internal salts in addition to the mentioned salt forms. Each salt can be obtained by conventional methods known to those skilled in the art, for example by mixing a compound of the present invention with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with another salt.
“Pharmaceutical composition” refers to a composition containing one or more of the compounds described herein or pharmaceutically acceptable salts, prodrugs, stable isotope derivatives and isomers thereof, and other components such as pharmaceutically acceptable carriers and excipients.
“Cancers/tumors” include but are not limited to pancreatic cancer, lung cancer, colorectal cancer, multiple myeloma, liver cancer, cholangiocarcinoma, gastric cancer, kidney cancer, head and neck squamous cell carcinoma, thyroid cancer, prostate cancer, bladder cancer, renal cancer, breast cancer, ovarian cancer, urothelial cancer, cervical cancer, uterine cancer, endometrial cancer, acute myeloid leukemia, diffuse large B cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, glioblastoma, and sarcomas.
“Therapeutically effective amount” refers to the amount of the compound of the present invention that can effectively inhibit the functions of SOS1, and/or treat or prevent the diseases mediated by SOS1.
“Patients” refer to mammals, preferably humans.
SOS1 is a multi-domain protein with two binding sites, a catalytic site that binds GDP-bound RAS to promote guanine nucleotide exchange and an allosteric site that binds GTP-bound RAS to provide a positive feedback that increases RAS signaling. The present invention provides compounds that inhibit SOS1 activity, block the RAS: SOS1 protein-protein interaction, and therefore target RAS-driven tumors.
The present invention provides heterocyclic compounds useful in inhibiting SOS1 activity. The compounds are shown in Formula (I) , or prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, and stereoisomers thereof,
where:
A is CR
3 or N;
X
1 and X
2 are independently CH or N;
X
3 is CR
6 or N;
R
1 is H or C
1-6 alkyl, where one or more hydrogens of the alkyl are optionally substituted by D, halogen, -OR
4b or -NR
4bR
4c;
R
2 is H, cyano, halogen, -OR
4b, -NR
4bR
4c, C
1-6 alkyl, C
3-8 cycloalkyl or 4-10 membered heterocyclyl, where one or more hydrogens of the alkyl, cycloalkyl and heterocyclyl are optionally substituted by D, halogen, -OR
4b or -NR
4bR
4c;
R
3 is H, halogen, cyano, -OR
4b, -NR
4bR
4c, C
1-6 alkyl, C
3-8 cycloalkyl or 4-10 membered heterocyclyl, where one or more hydrogens of the alkyl, cycloalkyl and heterocyclyl are optionally substituted by D, halogen, -OR
4b or -NR
4bR
4c;
R
4 is halogen, cyano, -OR
4a, -NR
4bR
4c, -COOR
4b, -C (O) R
4b, -C (O) NR
4bR
4c, -NR
4bC (O) R
4c, -NR
4bS (O)
2R
4c, -S (O)
2NR
4bR
4c, C
1-6 alkyl, C
3-8 cycloalkyl, 4-10 membered heterocyclyl, C
6-12 aryl or 5-12 membered heteroaryl, where one or more hydrogens of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by R
4’;
R
5 is H or NH
2;
R
6 is H, halogen or C
1-6 alkyl;
R
7 is C
1-6 alkyl, C
3-8 cycloalkyl or 4-10 membered heterocyclyl, where one or more hydrogens of the alkyl, cycloalkyl and heterocyclyl are optionally substituted by D or halogen;
L is C
1-6 alkylene, where one or more hydrogens of the alkylene are optionally substituted by D or halogen; for example, L is ethylene substituted with difluoro;
R
4a is C
1-6 alkyl, C
3-8 cycloalkyl, 4-10 membered heterocyclyl, C
6-12 aryl or 5-12 membered heteroaryl, where one or more hydrogens of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by C
1-6 alkyl, fluorinated C
1-6 alkyl, C
3-8 cycloalkyl, -C (O) C
1-6 alkyl, -C (O) C
3-8 cycloalkyl or 4-10 membered heterocyclyl;
R
4’ is D, halogen, oxo, -OR
4b, -NR
4bR
4c, -COOR
4b, -C (O) R
4b, -C (O) NR
4bR
4c, -NR
4bC (O) R
4c, C
1-6 alkyl or C
3-8 cycloalkyl, where one or more hydrogens of the alkyl are optionally substituted by D, halogen, -OR
4b or -NR
4bR
4c; and
R
4b and R
4c are independently selected from H, C
1-6 alkyl, C
3-8 cycloalkyl or 4-10 membered heterocyclyl, where one or more hydrogens of the alkyl, cycloalkyl and heterocyclyl are optionally substituted by D, halogen, and C
1-6 alkyl.
In some embodiments, the compounds shown in Formula (I) have the following Formula (II) ,
where:
A, X
1, X
2, R
1-R
5, R
4a , R
4’, R
4b, and R
4c are the same as those described above in Formula (I) ;
X
3 is CH, CF or N.
In one embodiment, R
1 is -CH
3, -CHF
2, - (CH
2)
1-2OH, or – (CH
2)
1-2OCH
3.
In one preferred embodiment, R
1 is -CH
3.
In one embodiment, R
2 is H, halogen, cyano, -CH
3, -OCH
3, -CH
2OH, or -CH
2OCH
3.
In one preferred embodiment, R
2 is H or -CH
3.
In one embodiment, R
3 is H, halogen, cyano, -CH
3, or -OCH
3.
In one embodiment, R
4 is -OR
4a.
In one embodiment, R
4 = 6-membered heterocyclyl substituted with -OCH
3.
R
4a is C
1-6 alkyl, C
3-8 cycloalkyl, 4-10 membered heterocyclyl, C
6-12 aryl or 5-12 membered heteroaryl, where one or more hydrogens of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by C
1-6 alkyl, fluorinated C
1-6 alkyl, C
3-8 cycloalkyl, -C (O) C
1-6 alkyl, -C (O) C
3-8 cycloalkyl, or 4-10 membered heterocyclyl.
For example, R
4 is:
In another embodiment, R
4 is C
3-8 cycloalkyl or 4-10 membered heterocyclyl, where one or more hydrogens of the cycloalkyl and heterocyclyl are optionally substituted by R
4’. For example, R
4 is:
In another embodiment, R
4 is C
6-12 aryl or 5-12 membered heteroaryl, where one or more hydrogens of the aryl and heteroaryl are optionally substituted by R
4’. For example, R
4 is:
In one embodiment, R
4’ is D, halogen, oxo, -OR
4b, -NR
4bR
4c, -COOR
4b, -C (O) R
4b, -C (O) NR
4bR
4c -NR
4bC (O) R
4c, C
1-6 alkyl, or C
3-8 cycloalkyl, where one or more hydrogens of the alkyl are optionally substituted by D, halogen, -OR
4b or -NR
4bR
4c; R
4b and R
4c are independently selected from H, C
1-6 alkyl, C
3-8 cycloalkyl, or 4-10 membered heterocyclyl, where one or more hydrogens of the alkyl, cycloalkyl and heterocyclyl are optionally substituted by D, halogen, and C
1-6 alkyl.
The present invention further relates to the following Compounds 1-80, or their pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, isomers, and mixtures thereof.
The compounds of the present invention effectively block the binding interaction between RAS and SOS1, having an IC
50 less than 1000 nM, preferably having an IC
50 less than 100 nM. The compounds of the present invention have a significant inhibitory effect on K562 and MIA PaCa-2 cell proliferations, having an IC
50 less than 1000 nM, preferably having an IC
50 less than 100 nM.
The present invention further relates to pharmaceutical compositions comprising compounds of Formula (I) or pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, or isomers thereof, and pharmaceutically acceptable carriers or excipients. The pharmaceutical compositions are useful for the treatment or prevention of SOS1 mediated cancers, in particular of lung cancer such as non-small cell lung cancer (NSCLC) , colorectal cancer, pancreatic cancer, cholangiocarcinoma, and ovarian cancer.
The present invention further relates to pharmaceutical combinations comprising compounds of the Formula (I) or pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, or isomers thereof, and additional anti-cancer agents. Compounds of Formula (I) and another anti-cancer agent may be present in the same pharmaceutical composition or in different pharmaceutical compositions. Compounds of Formula (I) and another anti-cancer agent may be administered simultaneously or sequentially in the same or different forms.
The present invention further provides a method for treating or preventing cancers mediated by SOS1. The method comprises administering to a patient in need thereof a therapeutically effective amount of the compounds shown in Formula (I) or pharmaceutically acceptable salts, prodrugs, stable isotope derivatives and isomers thereof.
According to the present invention, the pharmaceuticals can be in any dosage form, including but not limited to tablets, capsules, a solution, a freeze-drying preparation and injectable.
The pharmaceutical formulation of the present invention can be administered in form of a dosage unit containing a predetermined amount of active ingredient. Such a unit may contain 1 mg to 1 g, preferably 10 mg to 500 mg of a compound of the present invention, depending on the disease being treatment, the method of administration, as well as age, weight, and condition of the patients. The pharmaceutical formulation can be prepared using methods well-known in the pharmaceutical field, for example, by formulating the active ingredient with one or more excipients or one or more adjuvants.
The pharmaceutical formulation of the present invention is suitable for administration by any appropriate method, for example by oral (including buccal or sublingual) or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) .
The present invention further provides methods for preparing the compounds. The preparation of the compounds of the present invention can be accomplished by the following exemplary methods and embodiments, but these methods and embodiments should not be considered as limitations to the scope of the present invention. Alternatively, the compounds of the present invention can be synthesized by methods known to those skilled in the art, or by methods described in the present invention. The products obtained at each step of reaction are isolated by separation techniques known in the art. The starting materials and chemical reagents used for the synthesis can be conventionally made based on literature (for example, SciFinder) or purchased.
The heterocyclic compounds shown in Formula (I) of the present invention can be synthesized according to the route shown below: 1) substitution of the leaving group X (halide, trisyl, etc. ) from Int1 by an amino intermediate Int2 under a basic condition to give A1; 2) conventional transformations of R', R” and/or R”' of A1 by synthetic methods known to those skilled in the art, such as hydrogenation, fluorination, hydrolysis, deprotection, amidation, reduction, hydroxylation, alkylation, coupling, etc., to afford the desired product.
Intermediate Int1 can be synthesized according to the route shown below: 1) bromination of B1 to give B2; 2) base-catalyzed hydrolysis of ester B2, followed by amidation to give amide B3; 3) amidation of B3 with an acyl chloride under a basic condition or a nitrile under an acidic condition and subsequent ring closure to give B4; 4) chlorination with POCl
3 or trisylation with trisyl chloride of B4 to give B5; 5) Br of B5 can be converted into a variety of functional groups by coupling reactions to provide the intermediate Int1.
Intermediate Int1 can also be synthesized according to the route shown below: 1) amidation of C1 and subsequent ring closure to give C2; 2) acid-catalyzed hydrolysis of C2 to give hydroxy C3; 3) alkoxylation of C4 with R” -leaving group under a basic condition to give C4; 4) chlorination with POCl
3 or trisylation with trisyl chloride of C4 to provide the intermediate Int1.
Intermediate Int2 can be synthesized according to the route shown below: 1) deprotonation of D1 with LiHMDS, followed by fluorination with NFSI to give D2; 2) reduction of D2 with NaBH
4 to give alcohol D3; 3) alkoxylation of ether D3 to give D4; 4) Suzuki coupling of D4, followed by acid-catalyzed hydrolysis to give ketone D5; 5) Formation of a Schiff base between D5 and a sulfinamide chiral auxiliary, followed by reduction with LiBH
4 to give D6; 6) acid-catalyzed hydrolysis of D6 to provide the intermediate Int2.
D2 can also be synthesized according to the route below: 1) fluorination of E1 with DAST to give E2; 2) nitration of E2 to give E3; 3) bromination of E3 to provide D2.
EXAMPLES
The structure of a compound was determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS) . NMR determination used a Bruker ASCEND-400 NMR spectrometer. The solvent for the determination was deuterated dimethyl sulfoxide (DMSO-d
6) , deuterated chloroform (CDC1
3) , or deuterated methanol (CD
3OD) . The internal standard was tetramethylsilane (TMS) , and the chemical shift was given in a unit of 10
-6 (ppm) . MS determination used an Agilent SQD (ESI) mass spectrometer (Agilent 6120) .
HPLC determination used Agilent 1260 DAD high pressure liquid chromatograph (column: Poroshell120 EC-C18, 50×3.0 mm, 2.7 μm) or Waters Arc high pressure liquid chromatograph (column: Sunfire C18, 150×4.6 mm, 5 μm) .
Thin layer chromatography (TLC) used GF254 silica gel plates from Qingdao Haiyang Chemical Co., Ltd. with a thickness of 0.15 to 0.2 mm, and the separation/purification of products by thin layer chromatography used silica plates with a thickness 0.4 to 0.5 mm.
Column chromatography generally used 200 to 300 mesh silica gel from Qingdao Haiyang Chemical Co., Ltd.
Known starting materials in the present invention were synthesized according to the methods known in the art, or purchased from ABCR GmbH&Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Beijing Ouhe Technology Co., Ltd., etc.
Unless otherwise stated in the embodiments, the reactions were carried out under an atmosphere of argon or nitrogen using a balloon with a volume of about 1 L.
Hydrogenation was carried out under an atmosphere of hydrogen using a balloon with a volume of about 1 L that was attached to the reaction vessel after being vacuumed and filled with hydrogen repeatedly for 3 times.
The microwave reaction used a CEM Discover-SP microwave reactor.
Unless otherwise stated in the embodiments, the reaction was run at room temperature.
The reaction was monitored using Agilent LCMS (1260/6120) or thin layer chromatography. The solvent eluting systems for column chromatography and TLC included a) dichloromethane/methanol, b) petroleum ether/ethyl acetate, or other systems as indicated. The ratio of the solvents was adjusted according to the polarity of the compound, and further adjusted by addition of a small amount of TEA, or an acidic or alkaline reagent as needed. The compound purification was alternatively done using Waters’ MS-guided automated preparation system (abbreviated as prep-HPLC) with a MS detector (SQD2) , eluting at a flow rate of 20 mL/min in an appropriate acetonitrile/water (containing 0.1%TFA or formic acid) or acetonitrile/water (containing 0.05%of 25-28%ammonium hydroxide) gradient (XBridge-C18, 19×150 mm, 5 μm) . Some compounds were prepared as HCl salts after prep-HPLC purification by addition of 1 N HCl to the collected fractions, followed by drying under reduced pressure.
The abbreviation PE refers to petroleum ether.
The abbreviation DMF refers to N, N-dimethylformamide.
The abbreviation DMA refers to N, N-dimethylacetamide.
The abbreviation THF refers to tetrahydrofuran.
The abbreviation TFA refers to trifluoroacidic acid.
The abbreviation DIPEA refers to N, N-diisopropylethylamine.
The abbreviation TEA refers to triethylamine.
The abbreviation DMAP refers to 4-dimethylaminopyridine.
The abbreviation LiHMDS refers to lithium bis (trimethylsilyl) amide.
The abbreviation LDA refers to lithium diisopropylamide.
The abbreviation NFSI refers to N-fluorobenzenesulfonimide.
The abbreviation TsCl refers to tosyl chloride.
The abbreviation DAST refers to diethylaminosulphur trifluoride.
The abbreviation NBS refers to N-bromosuccinimide.
The abbreviation NIS refers to N-iodosuccinimide.
The abbreviation NCS refers to N-chlorosuccinimide.
The abbreviation HOBT refers to 1-hydroxybenzotriazole.
The abbreviation EDCI refers to 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride.
The abbreviation HATU refers to 2- (7-azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate.
Pd (dppf) Cl
2 refers to [1, 1'-bis (diphenylphosphino) ferrocene] dichloropalladium.
Xantphos refers to 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene.
BINAP refers to 2, 2'-bis (diphenylphosphino) -1, 1'-binaphthyl.
Pd
2 (dba)
3 refers to tris (dibenzylideneacetone) dipalladium.
Mn (dpm)
3 refers to tris (2, 2, 6, 6-tetramethyl-3, 5-heptanedionato) manganese (III) .
Example 1. (R) -1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethan-1-amine (Intermediate 1g)
Step 1. Ethyl 2- (3-bromophenyl) -2, 2-difluoroacetate (1b)
To a solution of ethyl 2- (3-bromophenyl) acetate 1a (10 g, 41 mmol) in THF (50 mL) at -78℃ was added LiHMDS (2 M, 80 mL) slowly. The resulting mixture was stirred at -78℃ for 30 min, followed by slow addition of a solution of NFSI (26.0 g, 82 mmol) in THF (50 mL) . The mixture was then warmed to 0℃ and stirred for 1 h. The mixture was added with a solution of HCl (1 N) until pH = 7 and extracted with EtOAc (2×100 mL) . The combined organic phase was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (100%PE) to give the title compound 1b (5.2 g, 45%) .
Step 2. 2- (3-Bromophenyl) -2, 2-difluoroethan-1-ol (1c)
To a solution of 1b (5.2 g, 19 mmol) in ethanol (100 mL) was added NaBH
4 (1.41 g, 37.3 mmol) slowly. The mixture was stirred for 12 h and then added with Na
2SO
4·10H
2O (10 g) . The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc = 4/1) to give the title compound 1c (4.1 g, 93%) .
Step 3. 1-Bromo-3- (1, 1-difluoro-2-methoxyethyl) benzene (1d)
To a mixture of 1c (10.0 g, 42.2 mmol) and Cs
2CO
3 (41.0 g, 126 mmol) in DMF (150 mL) was added MeI (18.1 g, 128 mmol) slowly. The resulting mixture was stirred for 16 h, added with H
2O (200 mL) , and extracted with EtOAc (2×200 mL) . The combined organic phase was washed with saturated brine (200 mL) and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (100%PE) to give the title compound 1d (8.8 g, 83%) .
Step 4. 1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethan-1-one (1e)
A mixture of 1d (8.8 g, 35 mmol) , tributyl (1-ethoxyvinyl) stannane (17.0 g, 47.1 mml) , Pd (PPh
3)
2Cl
2 (2.4 g, 3.42 mmol) and TEA (10.62 g, 105 mmol) in dioxane (100 mL) was stirred at 80℃ for 16 h. After cooling to room temperature, the mixture was added with a solution of HCl (2 N, 100 mL) and stirred for 2 h. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc = 93/7) to give the title compound 1e (5.7 g, 76%) .
MS m/z (ESI) : 215 [M+1]
Step 5. (R) -N- ( (R) -1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethyl) -2-methylpropane-2-sulfinamide (1f)
A mixture of 1e (5.7 g, 27 mmol) , (R) -2-methylpropane-2-sulfinamide (6.45 g, 53.2 mmol) and Ti (OEt)
4 (24.3 g, 107 mmol) in THF (60 mL) was stirred at 80℃ for 16 h. After cooling to 0℃, the mixture was added with methanol (15 mL) and a solution of LiBH
4 in THF (2 N, 26 mL) sequentially. After further stirring for 2 h, the mixture was added with Na
2SO
4·10H
2O (10 g) and filtered. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 99/1) to give the title compound 1f (5.23 g, 61%) .
MS m/z (ESI) : 320 [M+1]
Step 6. (R) -1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethan-1-amine hydrochloride (1g)
A mixture of 1f (400 mg, 1.25 mmol) and a solution of HCl in dioxane (4 N, 5 mL) was stirred for 2 h. The mixture was concentrated to dryness under reduced pressure to give the title compound 1g (200 mg, 64%) .
MS m/z (ESI) : 216 [M+1]
Example 2. Methyl 6-bromo-4-chloro-7-methoxyquinazoline-2-carboxylate (Intermediate 1n)
Step 1. Methyl 2-amino-5-bromo-4-methoxybenzoate (1i)
To a solution of methyl 2-amino-4-methoxybenzoate 1h (5.0 g, 28 mmol) in chloroform (250 mL) at 0℃ was slowly added Br
2 (4.41 g, 27.6 mmol) . The resulting mixture was stirred at 25℃ for 1 h and then added with a saturated Na
2S
2O
3 aqueous solution (100 mL) . The organic phase was separated, washed with a saturated sodium bicarbonate aqueous solution (100 mL) and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc = 9/1) to give the title compound 1i (5.7 g, 79%) .
MS m/z (ESI) : 260, 262 [M+1]
Step 2. 2-Amino-5-bromo-4-methoxybenzoic acid (1j)
To a mixture of 1i (2.1 g, 8.1 mmol) in THF (20 mL) and MeOH (20 mL) was added a solution of LiOH in water (2 N, 20 mL) . The mixture was stirred at 25℃ for 16 h, adjusted to pH = 6 with HCl (1 N) and filtered. The residue was dried to give the title compound 1j (2.05 g) .
MS m/z (ESI) : 246, 248 [M+1]
Step 3. 2-Amino-5-bromo-4-methoxybenzamide (1k)
A mixture of 1j (1.90 g, 7.72 mmol) , HOBT (1.65 g, 12.2 mmol) , EDCI (2.30 g, 12.0 mmol) and a solution of NH
3 in dioxane (0.4 N, 150 mL) was stirred for 16 h. The mixture was concentrated to dryness and the residue was added with a saturated sodium bicarbonate solution (20 mL) and EtOAc (20 mL) . The organic phase was separated and concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the title compound 1k (1.70 g, 90%) .
MS m/z (ESI) : 245, 247 [M+1]
Step 4. Methyl 2- ( (4-bromo-2-carbamoyl-5-methoxyphenyl) amino) -2-oxoacetate (1l)
A mixture of 1k (2.0 g, 8.2 mmol) , TEA (1.65 g, 16.3 mmol) and methyl 2-chloro-2-oxoacetate (1.10 g, 8.89 mmol) in dichloromethane (30 mL) was stirred for 2 h and then filtered. The residue was dried to give the title compound (1l) (1.50 g, 56%) .
MS m/z (ESI) : 331, 333 [M+1]
Step 5. Methyl 6-bromo-4-hydroxy-7-methoxyquinazoline-2-carboxylate (1m)
To a mixture of 1l (800 mg, 2.42 mmol) and TEA (16 mL) in 1, 2-dichloroethane (20 mL) was added chlorotrimethylsilane (5 mL) . The resulting mixture was heated to 80℃ and stirred for 16 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was diluted with dichloromethane (20 mL) and washed with a saturated sodium bicarbonate aqueous solution (10 mL) . The organic phase was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 9/1) to give the title compound 1m (600 mg, 79%) .
MS m/z (ESI) : 313, 315 [M+1]
Step 6. Methyl 6-bromo-4-chloro-7-methoxyquinazoline-2-carboxylate (1n)
A mixture of 1m (600 mg, 1.92 mmol) , DMF (100 mg) and POCl
3 (15 mL) was heated to 80℃ and stirred for 1 h. After cooling to room temperature, the mixture was concentrated to dryness and the residue was diluted with EtOAc (20 mL) . The resulting mixture was washed with water (20 mL) , a saturated sodium bicarbonate aqueous solution (20 mL) and saturated brine (20 mL) sequentially. The organic phase was concentrated to dryness under reduced pressure and the residue was dried to give the title compound 1n (660 mg) .
MS m/z (ESI) : 331, 333 [M+1]
Example 3. (S) -7-Methoxy-2-methyl-6- ( (tetrahydrofuran-3-yl) oxy) quinazolin-4-yl-2, 4, 6-triisopropylbenzenesulfonate (Intermediate 3g)
Step 1. 6, 7-Dimethoxy-2-methylquinazolin-4 (3H) -one (3b)
To a solution of methyl 2-amino-4, 5-dimethoxybenzoate 3a (20.0 g, 94.7 mmol) in acetonitrile (50 mL) was added methanesulfonic acid (20 mL) , and the resulting mixture was heated to 100℃ and stirred for 2 days. After cooling to room temperature, the mixture was added with NaOH (40.0 g, 100 mmol) and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc = 4/1 to 7/3) to give the title compound 3b (14.0 g, 67%) .
MS m/z (ESI) : 221 [M+1]
Step 2. 6-Hydroxy-7-methoxy-2-methylquinazolin-4 (3H) -one (3c)
To a solution of 3b (11.0 g, 50.0 mmol) in methanesulfonic acid (20 mL) was added DL-methionine (11.2 g, 75.0 mmol) . The resulting mixture was stirred at 80℃ for 4 days. After cooling to room temperature, the mixture was added with water (100 mL) and filtered. The solid was dried under reduced pressure to give the title compound 3c (8.0 g, 78%) .
MS m/z (ESI) : 207 [M+1]
Step 3. (R) -Tetrahydrofuran-3-yl 4-methylbenzenesulfonate (3e)
To a solution of (R) -tetrahydrofuran-3-ol 3d (5.28 g, 60 mmol) , TEA (12.14 g, 120 mmol) and DMAP (732 mg, 6 mmol) in dichloromethane (80 mL) was added TsCl (12.6 g, 66 mmol) , and the resulting mixture was heated to 30℃ for 15 h. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc = 100/1 to 10/1) to give the title compound 3e (11.4 g, 78%) .
1H NMR (400 MHz, CDCl
3) δ 7.79 (d, J = 8.3 Hz, 2H) , 7.36 (d, J = 8.0 Hz, 2H) , 5.11 (dt, J = 4.6, 2.1 Hz, 1H) , 3.94 –3.76 (m, 2H) , 2.46 (s, 2H) , 2.09 (td, J = 7.8, 5.0 Hz, 1H) .
Step 4. (S) -7-Methoxy-2-methyl-6- ( (tetrahydrofuran-3-yl) oxy) quinazolin-4 (3H) -one (3f)
A mixture of 3e (1.18 g, 4.9 mmol) , 3c (1.44 g, 7 mmol) and Cs
2CO
3 (2.74 g, 8.4 mmol) in DMF (20 mL) was heated to 80℃ and stirred for 2 h. After cooling to room temperature, the mixture was concentrated to dryness, and the residue was purified by silica gel column chromatography (CH
2Cl
2/MeOH = 100/1 to 30/1) to give the title compound 3f (330 mg, 24%) .
MS m/z (ESI) : 277 [M+1]
Step 5. (S) -7-Methoxy-2-methyl-6- ( (tetrahydrofuran-3-yl) oxy) quinazolin-4-yl 2, 4, 6-triisopropylbenzenesulfonate (3g)
To a solution of 3f (330 mg, 1.19 mmol) , TEA (361 mg, 3.57 mmol) and DMAP (15 mg, 0.12 mmol) in dichloromethane (30 mL) was added 2, 4, 6-triisopropylbenzenesulfonyl chloride (542 mg, 1.79 mmol) . The resulting mixture was heated to 30℃ and stirred for 15 h. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc = 50/1 to 2/1) to give the title compound 3g (570 mg, 88%) .
MS m/z (ESI) : 543 [M+1]
Intermediates 17d, 21d, 23d, 25d, 26d, 38d, 40d and 50d were synthesized according to the procedures for Intermediate 3g, except that in the third step, different alcohols were used instead of 3d.
Example 4. (R) -1- (3- (1, 1-Difluoro-2-methoxyethyl) -2-fluorophenyl) ethan-1-amine hydrochloride (Intermediate 8i)
Step 1. Ethyl 2, 2-difluoro-2- (2-fluorophenyl) acetate (8b)
To a solution of ethyl 2-bromo-2, 2-difluoroacetate 8a (15.0 g, 73.9 mmol) in DMSO (250 mL) were added 1-fluoro-2-iodobenzene (24.61 g, 111mmol) and copper powder (7.04 g, 111 mmol) . The resulting mixture was stirred at 80℃ for 16 h under N
2. After cooling to room temperature, the mixture was added with water (100 mL) and extracted with EtOAc (3×100 mL) . The combined organic phase was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (PE/EtOAc =20/1) to give the title compound 8b (7.33 g, 45%) .
Step 2. 2, 2-Difluoro-2- (2-fluorophenyl) ethan-1-ol (8c)
To a solution of 8b (7.33 g, 33.6 mmol) in EtOH (100 mL) at 0℃ was added NaBH
4 (1.91 g, 50.4 mmol) . The resulting mixture was stirred at room temperature for 12 h, added with 1N HCl (80 mL) and extracted with dichloromethane (3×60 mL) . The combined organic phase was washed with saturated brine (80 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated to dryness to give the title compound 8c (5.48 g, 93%) .
Step 3. 1- (1, 1-Difluoro-2-methoxyethyl) -2-fluorobenzene (8d)
To a solution of 8c (5.48 g, 31.1 mmol) in DMF (50 mL) at 0℃ was added NaH (60%, 0.97 g, 40.4 mmol) . After stirring at room temperature for 1 h, to the mixture was added iodomethane (8.83 g, 62.2 mmol) . The mixture was stirred for another 12 h, added with a saturated NH
4Cl aqueous solution (50 mL) and extracted with EtOAc (3×50 mL) . The combined organic phase was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (PE/EtOAc = 50/1) to give the title compound 8d (4.58 g, 77%) .
Step 4. 3- (1, 1-Difluoro-2-methoxyethyl) -2-fluorobenzaldehyde (8e)
To a solution of 8d (1.58 g, 8.31 mmol) in THF (40 mL) at -78℃ was added LDA (2 N, 8.3 mL, 16.6 mmol) slowly over 0.5 h. After addition, the mixture was stirred at -78℃ for 1 h, added with DMF (1.22 g, 16.6 mmol) and stirred for another 4 h at -78℃. The mixture was added with a saturated NH
4Cl aqueous solution (40 mL) , filtered, and extracted with EtOAc (3×50 mL) . The combined organic phase was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (PE/EtOAc =10/1) to give the title compound 8e (0.95 g, 52%) .
MS m/z (ESI) : 219 [M+1]
Step 5. 1- (3- (1, 1-Difluoro-2-methoxyethyl) -2-fluorophenyl) ethan-1-ol (8f)
To a solution of 8e (0.95 g, 4.35 mmol) in THF (10 mL) at 0℃ was added methyl magnesium bromide (1 N in THF, 5.3 mL, 5.3 mmol) . After addition, the mixture was stirred at room temperature for 12 h, added with a saturated NH
4Cl aqueous solution (10 mL) and extracted with EtOAc (3×30 mL) . The combined organic phase was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (PE/EtOAc = 10/1) to give the title compound 8f (0.72 g, 71%) .
MS m/z (ESI) : 217 [M-H
2O+1]
Step 6. 1- (3- (1, 1-Difluoro-2-methoxyethyl) -2-fluorophenyl) ethan-1-one (8g)
To a solution of 8f (0.72 g, 3.1 mmol) in dichloromethane (10 mL) at 0℃ was added Dess-martin periodinane (1.58 g, 3.72 mmol) . The mixture was stirred at 0℃ for 2 h, added with a saturated NaHCO
3 aqueous solution (10 mL) and extracted with dichloromethane (3×20 mL) . The organic phase was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (PE/EtOAc = 10/1) to give the title compound 8g (0.66 g, 92%) .
MS m/z (ESI) : 233 [M+1]
Step 7. (R) -N- ( (R) -1- (3- (1, 1-Difluoro-2-methoxyethyl) -2-fluorophenyl) ethyl) -2-methylpropane-2-sulfinamide (8h)
To a solution of 8g (660 mg, 2.84 mmol) in THF (10 mL) were added (R) -2-methylpropane-2-sulfinamide (413 mg, 3.41 mmol) and titanium ethoxide (1.30 g, 5.68 mmol) . The resulting mixture was stirred at 80℃ for 12 h. The mixture was cooled to 0℃ and to which were added methanol (5 mL) and lithium borohydride (2 N, 2.84 mL) . The mixture was stirred at 0℃ for 1 h, added with a saturated NH
4Cl aqueous solution (5 mL) and extracted with EtOAc (3×10 mL) . The combined organic phase was dried over anhydrous Na
2SO
4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (CH
2Cl
2/EtOAc = 50/1) to give the title compound 8h (666 mg, 69%) .
MS m/z (ESI) : 338 [M+1]
Step 8. (R) -1- (3- (1, 1-Difluoro-2-methoxyethyl) -2-fluorophenyl) ethan-1-amine hydrochloride (8i)
To a solution of 8h (666 mg, 1.97 mmol) in EtOAc (2 mL) was added a solution of HCl in EtOAc (2 N, 10 mL) . The mixture was stirred for 1 h and then concentrated to dryness under reduced pressure to give the title compound 8i (532 mg, 100%) .
MS m/z (ESI) : 234 [M+1]
Intermediate 78c was synthesized according to the procedures of Step 1 to 3 for Intermediate 8i, except that in the first step, a different compound was used instead of 1-fluoro-2-iodobenzene.
Example 5. (S) -7-Methoxy-2- (methoxymethyl) -6- ( (tetrahydrofuran-3-yl) oxy) quinazolin-4-yl-2, 4, 6-triisopropylbenzenesulfonate (Intermediate 13d)
Step 1. 6, 7-Dimethoxy-2- (methoxymethyl) quinazolin-4 (3H) -one (13a)
A mixture of 3a (4.2 g, 20 mmol) , 2-methoxyacetonitrile (1.42 g, 20 mmol) and a solution of HCl in dioxane (4 N, 150 mL) was heated to 100℃ and stirred for 15 h. After cooling to room temperature, the reaction mixture was concentrated to dryness and the residue was dissolved in methanol (200 mL) . The resulting mixture was adjusted to pH =7~8 with a saturated sodium bicarbonate aqueous solution and then concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/1 to 20/1) to give the title compound 13a (2.7 g, 54%) .
MS m/z (ESI) : 251 [M+1]
Step 2 to Step 4. (S) -7-Methoxy-2- (methoxymethyl) -6- ( (tetrahydrofuran-3-yl) oxy) quinazolin-4-yl 2, 4, 6-triisopropylbenzenesulfonate (13d)
13d was prepared following the procedures of Step 2 to 5 for Intermediate 3g, except that 13a was used instead of 3b in Step 2.
MS m/z (ESI) : 573 [M+1]
Intermediates 51d and 58d were synthesized according to the procedures for Intermediate 13d, except that in the first step, different anilines were used instead of 3a.
Intermediate 66a was synthesized according to the procedure of Step 1 for Intermediate 13d, except that a different aniline was used instead of 3a.
Example 6. (R) -3- (1-Aminoethyl) -5- (1, 1-difluoro-2-methoxyethyl) aniline hydrochloride (Intermediate 15k)
Step 1. Methyl 2, 2-difluoro-2-phenylacetate (15b)
To a solution of methyl 2-oxo-2-phenylacetate 15a (73.9 g, 450 mmol) in dichloromethane (800 mL) was added DAST (108.9 g, 675 mmol) . The resulting mixture was heated to reflux for 8 h. After cooling to room temperature, the reaction mixture was added to a saturated sodium bicarbonate solution (2 L) and extracted with dichloromethane (2 × 800 mL) . The combined organic phase was washed with saturated brine (500 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE/ethyl acetate = 100/1 to 10/1) to give the title compound 15b (75 g, 90%) .
1H NMR (400 MHz, CDCl
3) δ 7.60 (dd, J = 7.8, 1.0 Hz, 2H) , 7.46 (dt, J = 16.7, 6.9 Hz, 3H) , 3.83 (s, 3H) .
Step 2. Methyl 2, 2-difluoro-2- (3-nitrophenyl) acetate (15c)
To a solution of 15b (51 g, 274 mmol) in concentrated sulfuric acid (200 mL) at 0℃ was added nitric acid (34.5 g, 548 mmol) . After stirring for 0.5 h, the mixture was cooled to -10℃ and to which ice (400 g) was added slowly. After the ice melted completely, the mixture was extracted with dichloromethane (2×500 mL) . The combined organic phase was washed with saturated brine (300 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (500 mL) and cooled to 0℃, followed by addition of thionyl chloride (20 mL) dropwise. After stirring for 0.5 h at 0℃, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (PE/ethyl acetate = 100/1 to 20/1) to give the title compound 15c (29 g, 46%) .
1H NMR (400 MHz, CDCl
3) δ 8.49 (s, 1H) , 8.39 (dd, J = 8.2, 1.3 Hz, 1H) , 7.97 (dd, J =7.8, 0.5 Hz, 1H) , 7.71 (t, J = 8.0 Hz, 1H) , 3.90 (s, 3H) .
Step 3. Methyl 2- (3-bromo-5-nitrophenyl) -2, 2-difluoroacetate (15d)
To a solution of 15c (36 g, 155 mmol) in concentrated sulfuric acid (110 mL) at 0℃ was added NBS (83 g, 467 mmol) . After stirring at 30℃ for 4 h, the reaction mixture was cooled to -10℃, and ice (300 g) was added slowly. After the ice melted completely, the mixture was extracted with dichloromethane (2 × 500 mL) . The combined organic phase was washed with saturated brine (300 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (800 mL) and cooled to 0℃, followed by addition of thionyl chloride (20 mL) dropwise. After stirring for 0.5 h at 0℃, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE/ethyl acetate =100/1 to 20/1) to give the title compound 15d (37 g, 77%) .
1H NMR (400 MHz, CDCl
3) δ 8.52 (t, J = 1.8 Hz, 1H) , 8.42 (d, J = 1.5 Hz, 1H) , 8.08 (s, 1H) , 3.92 (s, 3H) .
Step 4. 2- (3-Bromo-5-nitrophenyl) -2, 2-difluoroethan-1-ol (15e)
To a solution of 15d (43 g, 138 mmol) in ethanol (300 mL) was added sodium borohydride (7.8 g, 207 mmol) . After stirring for 1 h, the mixture was concentrated to dryness and the residue was purified by silica gel column chromatography (PE to dichloromethane/methanol = 10/1) to give the title compound 15e (31 g, 79%) .
1H NMR (400 MHz, CDCl
3) δ 8.47 (t, J = 1.8 Hz, 1H) , 8.34 (s, 1H) , 8.01 (s, 1H) , 4.03 (t, J = 12.5 Hz, 2H) , 2.56 (s, 1H) .
Step 5. 1-Bromo-3- (1, 1-difluoro-2-methoxyethyl) -5-nitrobenzene (15f)
A mixture of 15e (31 g, 110 mmol) , Cs
2CO
3 (54 g, 165 mmol) and iodomethane (78 g, 550 mmol) in acetonitrile (500 mL) was heated to reflux for 4 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE/ethyl acetate = 20/1) to give the title compound 15f (18 g, 55%) .
1H NMR (400 MHz, CDCl
3) δ 8.46 (t, J = 1.9 Hz, 1H) , 8.32 (s, 1H) , 7.99 (s, 1H) , 3.85 (t, J = 12.1 Hz, 2H) , 3.44 (s, 3H) .
Step 6. 1- (3- (1, 1-Difluoro-2-methoxyethyl) -5-nitrophenyl) ethan-1-one (15g)
A mixture of 15f (18 g, 61 mmol) , 1-ethoxyvinyl tri-n-butyltin (26 g, 73 mmol) , triethylamine (18.5 g, 182 mmol) and Pd (PPh
3)
2Cl
2 (4.2 g, 6.1 mmol) in 1, 4-dioxane (400 mL) was degassed and refilled with nitrogen, and heated to 100℃ for 15 h. The reaction mixture was cooled to 0℃ and added with hydrochloric acid (5 N, 400 mL) . After stirring for 1 h at 0℃, the mixture was extracted with ethyl acetate (2 × 500 mL) . The combined organic phase was washed with saturated brine (500 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE/ethyl acetate = 50/1 to 3/1) to give the title compound 15g (13 g, 82%) .
1H NMR (400 MHz, CDCl
3) δ 8.84 (t, J = 1.7 Hz, 1H) , 8.57 (d, J = 1.8 Hz, 1H) , 8.42 (s, 1H) , 3.89 (t, J = 12.0 Hz, 2H) , 3.44 (s, 3H) , 2.73 (s, 3H) .
Step 7. (E) -N- (1- (3- (1, 1-Difluoro-2-methoxyethyl) -5-nitrophenyl) ethylidene) -2-methylpropane-2-sulfinamide (15h)
A mixture of 15g (13 g, 50 mmol) , Ti (OiPr)
4 (34 g, 150 mmol) and (R) -2-methylpropane-2-sulfinamide (9.07g, 75 mmol) in THF (150 mL) was heated to 90℃ for 6 h. The reaction mixture was then cooled to 0℃, added with a saturated sodium bicarbonate solution (500 mL) and extracted with EtOAc (2×500 mL) . The combined organic phase was washed with saturated brine (500 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the title compound 15h (19 g, crude) .
MS m/z (ESI) : 363 [M+1]
Step 8. (R) -N- ( (R) -1- (3- (1, 1-Difluoro-2-methoxyethyl) -5-nitrophenyl) ethyl) -2-methylpropane-2-sulfinamide (15i)
To a mixture of 15h (19 g, crude) and Ti (OiPr)
4 (16.4 g, 50 mmol) in THF (200 mL) and methanol (40 mL) was added a solution of LiBH
4 in THF (2 M, 50 mL, 100 mmol) . The resulting mixture was stirred at 0℃ for 0.5 h and concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (1.5 L) , washed successively with saturated sodium bicarbonate solution (2×500 mL) and saturated brine (500 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE/ethyl acetate = 50/1 to 1/1) to give the title compound 15i (7.4 g, 41%) .
MS m/z (ESI) : 365 [M+1]
1H NMR (400 MHz, CDCl
3) δ 8.33 (d, J = 1.4 Hz, 1H) , 8.31 (s, 1H) , 7.86 (s, 1H) , 4.70 (dd, J = 6.6, 4.1 Hz, 1H) , 3.86 (t, J = 12.3 Hz, 2H) , 3.64 (d, J = 3.9 Hz, 1H) , 3.44 (s, 3H) , 1.60 (d, J = 6.6 Hz, 3H) , 1.26 (s, 9H) .
Step 9. (R) -1- (3- (1, 1-Difluoro-2-methoxyethyl) -5-nitrophenyl) ethan-1-amine hydrochloride (15j)
To a solution of 15i (7.4 g, 20 mmol) in dichloromethane (50 mL) was added a solution of HCl in ethyl acetate (1 M, 40 mL, 40 mmol) . After stirring for 1 h, the mixture was concentrated to dryness to give the title compound 15j (7.4 g, crude) .
MS m/z (ESI) : 261 [M+1]
Step 10. (R) -3- (1-Aminoethyl) -5- (1, 1-difluoro-2-methoxyethyl) aniline hydrochloride (15k)
A mixture of 15j (7.4 g, crude, about 20 mmol) and palladium on carbon (10%, 2.8 g) in methanol (150 mL) was stirred under hydrogen for 2 h and then filtered. The filtrate was concentrated to dryness under reduced pressure to give the title compound 15k (5.8 g) .
1H NMR (400 MHz, CD
3OD) δ 6.98 (s, 1H) , 6.95 (s, 2H) , 4.39 (d, J = 6.9 Hz, 1H) , 3.85 –3.79 (m, 2H) , 3.39 (s, 3H) , 1.62 (d, J = 6.9 Hz, 3H) .
Intermediates 49k and 52k were synthesized according to the procedures for Intermediate 15k, except that in Step 5, different reagents were used instead of iodomethane.
Intermediate 61k was synthesized according to the procedures of Step 2 to Step 10 for Intermediate 15k, except that in Step 2, a different reagent was used instead of 15b.
Intermediate 78g was synthesized according to the procedures of Step 6 to Step 9 for Intermediate 15k, except that in Step 2, a different compound was used instead of 15f.
Example 7. 6-Bromo-7-methoxy-2-methylquinazolin-4-yl 2, 4, 6-triisopropylbenzenesulfonate (Intermediate 18b)
Step 1. 6-Bromo-7-methoxy-2-methylquinazolin-4-ol (18a)
To a solution of 1i (17.0 g, 64.9 mmol) in acetonitrile (50 mL) was added methanesulfonic acid (20 mL) . The resulting mixture was heated to 100℃ and stirred for 2 days. After cooling to room temperature, the mixture was treated with a sodium hydroxide aqueous solution (2 N, 200 mL) and extracted with EtOAc (3×100 mL) . The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/0 to 19/1) to give the title compound 18a (12.5 g, 72%) .
MS m/z (ESI) : 269, 271 [M+1]
Step 2. 6-Bromo-7-methoxy-2-methylquinazolin-4-yl 2, 4, 6-triisopropylbenzenesulfonate (18b)
To a solution of 18a (1.62 g, 6.0 mmol) , 2, 4, 6-triisopropylbenzenesulfonyl chloride (2.72 g, 9.0 mmol) and DIPEA (1.55 g, 12.0 mmol) in dichloromethane (20 mL) was added DMAP (73 mg, 0.6 mmol) . The resulting mixture was stirred overnight and then concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc = 3/2 to 2/3) to give the title compound (2.4 g, 75%) .
MS m/z (ESI) : 535, 537 [M+1]
Intermediates 56b and 57b were synthesized according to the procedures for Intermediate 18b, except that different compounds were used instead of 1i.
Example 8. (R) -1- (4- (4- ( (1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethyl) amino) -2- (hydroxymethyl) -7-methoxyquinazolin-6-yl) piperidin-1-yl) ethan-1-one (Compound 1)
Step 1. Ethyl (R) -6-bromo-4- ( (1- (3- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxyquinazoline-2-carboxylate (1o)
A mixture of 1g (200 mg, 0.8 mmol) , 1n (250 mg, 0.75 mmol) and DIPEA (300 mg, 2.32 mmol) in DMSO (2 mL) was heated to 90℃ for 16 h. After cooling to room temperature, the mixture was purified by prep-HPLC to give the title compound 1o (308 mg, 72%) .
MS m/z (ESI) : 524, 526 [M+1]
Step 2. Ethyl (R) -6- (1- (tert-butoxycarbonyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -4- ( (1- (3- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxyquinazoline-2-carboxylate (1p)
A mixture of 1o (150 mg, 0.29 mmol) , Pd (dppf) Cl
2 (42 mg, 0.057 mmol) , tert-butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (150 mg, 0.485 mmol) and K
2CO
3 (120 mg, 0.87 mmol) in 1, 4-dioxane (2 mL) and water (0.5 mL) was heated at 60℃ for 16 h. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (PE/EtOAc = 2/3) to give the title compound 1p (200 mg) .
MS m/z (ESI) : 627 [M+1]
Step 3. Ethyl (R) -4- ( (1- (3- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-6- (1, 2, 3, 6-tetrahydropyridin-4-yl) quinazoline-2-carboxylate (1q)
A mixture of 1p (200 mg, 0.32 mmol) and a solution of HCl in EtOAc (2 M, 5 mL) was stirred for 2 h. The mixture was concentrated to dryness to give the title compound 1q (160 mg, 95%) .
MS m/z (ESI) : 527 [M+1]
Step 4. Ethyl (R) -6- (1-acetyl-1, 2, 3, 6-tetrahydropyridin-4-yl) -4- ( (1- (3- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxyquinazoline-2-carboxylate (1r)
To a mixture of 1q (160 mg, 0.30 mmol) , TEA (310 mg, 3.1 mmol) and acetic acid (91 mg, 1.5 mmol) in dichloromethane (2 mL) was added EDCI (175 mg, 0.91 mmol) . The resulting mixture was stirred for 1 h and then concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc = 3/7) to give the title compound 1r (140 mg, 81%) .
MS m/z (ESI) : 569 [M+1]
Step 5. Ethyl (R) -6- (1-acetylpiperidin-4-yl) -4- ( (1- (3- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxyquinazoline-2-carboxylate (1s)
A mixture of 1r (140 mg, 0.246 mmol) and 10%Pd/C (70 mg) in methanol (12 mL) was stirred under H
2 for 16 h and then filtered. The filtrate was concentrated to dryness to give the title compound 1s (100 mg, 71%) .
MS m/z (ESI) : 571 [M+1]
Step 6. (R) -1- (4- (4- ( (1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethyl) amino) -2- (hydroxymethyl) -7-methoxyquinazolin-6-yl) piperidin-1-yl) ethan-1-one (1)
To a solution of 1s (100 mg, 0.175 mmol) in methanol (10 mL) was added a solution of LiBH
4 in THF (2 M, 3 mL) . The reaction was stirred for 2 h and then quenched with water (1 mL) . The resulting mixture was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane/methanol =19/1) , followed by prep-HPLC purification to give the title compound 1 (36.8 mg, 40%) .
MS m/z (ESI) : 529 [M+1]
1H NMR (400 MHz, DMSO-d
6) δ 8.36 (d, J = 7.7 Hz, 1H) , 8.12 (s, 1H) , 7.65 (s, 1H) , 7.60 (d, J = 7.6 Hz, 1H) , 7.44 (d, J = 7.6 Hz, 1H) , 7.38 (d, J = 7.8 Hz, 1H) , 7.08 (s, 1H) , 5.71 (s, 1H) , 4.66 –4.58 (m, 2H) , 4.40 –4.30 (m, 2H) , 4.03 –3.81 (m, 6H) , 3.28 (s, 3H) , 3.25 –3.12 (m, 2H) , 2.68 –2.57 (m, 1H) , 2.05 (d, J = 1.7 Hz, 3H) , 1.92 –1.63 (m, 4H) , 1.61 (d, J =7.1 Hz, 3H) .
Example 9. (R) - (4- ( (1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-6-morpholinoquinazolin-2-yl) methanol (Compound 2)
Step 1. Ethyl (R) -4- ( (1- (3- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-6-morpholinoquinazoline-2-carboxylate (2a)
A mixture of 1o (100 mg, 0.20 mmol) , morpholine (51 mg, 0.59 mmol) , Pd
2 (dba)
3 (36 mg, 0.039 mmol) , Xantphos (23 mg, 0.04 mmol) and Cs
2CO
3 (192 mg, 0.59 mmol) in 1, 4-dioxane (5 mL) was heated to 80℃ for 16 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc = 3/2) to give the title compound 2a (80 mg, 77%) .
MS m/z (ESI) : 531 [M+1]
Step 2. (R) - (4- ( (1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-6-morpholinoquinazolin-2-yl) methanol (2)
To a solution of 2a (80 mg, 0.15 mmol) in methanol (2 mL) was added a solution of LiBH
4 in THF (2 M, 2 mL) . The reaction was stirred for 2 h and then quenched with water (1 mL) . The mixture was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 88/12) , followed by prep-HPLC purification to give the title compound 2 (14 mg, 19%) .
MS m/z (ESI) : 489 [M+1]
1H NMR (400 MHz, DMSO-d
6) δ 8.26 (d, J = 7.9 Hz, 1H) , 7.66 (s, 2H) , 7.61 (d, J = 7.7 Hz, 1H) , 7.44 (t, J = 7.6 Hz, 1H) , 7.38 (d, J = 7.8 Hz, 1H) , 7.08 (s, 1H) , 5.76 –5.66 (m, 1H) , 4.58 (t, J = 5.5 Hz, 1H) , 4.34 (t, J = 5.6 Hz, 2H) , 3.95 –3.83 (m, 5H) , 3.82 –3.71 (m, 4H) , 3.28 (s, 3H) , 3.12 –3.03 (m, 4H) , 1.62 (d, J = 7.1 Hz, 3H) .
Example 10. (R) -4- (4- ( (1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethyl) amino) -2- (hydroxymethyl) -7-methoxyquinazolin-6-yl) thiomorpholine-1, 1-dioxide formate (Compound 4)
Step 1. (R) - (6-Bromo-4- ( (1- (3- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxyquinazolin-2-yl) methanol (4a)
To a solution of 1o (2 g, 3.9 mmol) in ethanol (25 mL) was added a solution of LiBH
4 in THF (2 M, 5 mL) . The reaction was stirred for 2 h and then quenched with water (1 mL) . The mixture was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (PE/EtOAc = 1/1) to give the title compound 4a (920 mg, 49%) .
MS m/z (ESI) : 482, 484 [M+1]
Step 2. (R) -4- (4- ( (1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethyl) amino) -2- (hydroxymethyl) -7-methoxyquinazolin-6-yl) thiomorpholine-1, 1-dioxide formate (4)
A mixture of 4a (150 mg, 0.31 mmol) , thiomorpholine-1, 1-dioxide (168 mg, 1.24 mmol) , Pd
2 (dba)
3 (76 mg, 0.083 mmol) , Xantphos (48 mg, 0.083 mmol) and Cs
2CO
3 (405 mg, 1.24 mmol) in 1, 4-dioxane (5 mL) was heated to 80℃ and stirred for 16 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the title compound 4 (47 mg, 28%) .
MS m/z (ESI) : 537 [M+1]
1H NMR (400 MHz, DMSO-d
6) δ 8.26 (d, J = 7.8 Hz, 1H) , 8.14 (s, 1H) , 7.85 (s, 1H) , 7.65 (s, 1H) , 7.60 (d, J = 7.5 Hz, 1H) , 7.45 (t, J = 7.6 Hz, 1H) , 7.39 (d, J = 7.7 Hz, 1H) , 7.11 (s, 1H) , 5.74 –5.65 (m, 1H) , 4.61 (s, 1H) , 4.40 –4.29 (m, 2H) , 3.96 –3.83 (m, 5H) , 3.57 –3.47 (m, 4H) , 3.37 –3.24 (m, 4H) , 3.28 (s, 3H) , 1.61 (d, J = 7.1 Hz, 3H) .
Example 11. (R) - (4- ( (1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethyl) amino) -6- (isoxazol-4-yl) -7-methoxyquinazolin-2-yl) methanol formate (Compound 5)
A mixture of 4a (150 mg, 0.31 mmol) , isoxazol-4-ylboronic acid (100 mg, 0.89 mmol) , Pd (dppf) Cl
2 (35 mg, 0.048 mmol) and Cs
2CO
3 (405 mg, 1.24 mmol) in 1, 4-dioxane (4 mL) and H
2O (0.5 mL) was heated to 60℃ and stirred for 4 h. After cooling to room temperature, the mixture was concentrated to dryness and the residue was purified by prep-HPLC to give the title compound 5 (6.5 mg, 4.4%) .
MS m/z (ESI) : 471 [M+1]
1H NMR (400 MHz, DMSO-d
6) δ 9.38 (s, 1H) , 9.20 (s, 1H) , 8.66 (s, 1H) , 8.34 (d, J = 7.7 Hz, 1H) , 8.20 (s, 1H) , 7.66 (s, 1H) , 7.63 (d, J = 7.6 Hz, 1H) , 7.46 (t, J = 7.6 Hz, 1H) , 7.40 (d, J = 7.7 Hz, 1H) , 7.22 (s, 1H) , 5.78 –5.70 (m, 1H) , 4.69 (s, 1H) , 4.37 (t, J = 10.6 Hz, 2H) , 4.03 (s, 3H) , 3.88 (t, J = 13.9 Hz, 2H) , 3.28 (s, 3H) , 1.64 (d, J = 7.0 Hz, 3H) .
Example 12. (R) -1- (4- ( (1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethyl) amino) -2- (hydroxymethyl) -7-methoxyquinazolin-6-yl) piperidine-4-carboxylic acid (Compound 6)
Step 1. Methyl (R) -1- (4- ( (1- (3- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -2- (hydroxymethyl) -7-methoxyquinazolin-6-yl) piperidine-4-carboxylate (6a)
A mixture of 4a (150 mg, 0.31 mmol) , methyl piperidine-4-carboxylate (130 mg, 0.91 mmol) , Pd
2 (dba)
3 (76 mg, 0.083 mmol) , Xantphos (48 mg, 0.083 mmol) and Cs
2CO
3 (405 mg, 1.24 mmol) in 1, 4-dioxane (5 mL) was heated to 80℃ and stirred for 16 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc = 2/3) to give the title compound 6a (195 mg) .
MS m/z (ESI) : 545 [M+1]
Step 2. (R) -1- (4- ( (1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethyl) amino) -2- (hydroxymethyl) -7-methoxyquinazolin-6-yl) piperidine-4-carboxylic acid (6)
To a solution of 6a (195 mg, about 0.31 mmol) in THF (2 mL) and MeOH (2 mL) was added a solution of NaOH in H
2O (2 N, 2 mL) . After stirring for 2 h, the mixture was concentrated, and the residue was purified by prep-HPLC to give the title compound 6 (145 mg, 88%over two steps) .
MS m/z (ESI) : 531 [M+1]
1H NMR (400 MHz, DMSO-d
6) δ 8.25 (d, J = 7.8 Hz, 1H) , 7.65 (s, 2H) , 7.61 (d, J = 7.7 Hz, 1H) , 7.44 (t, J = 7.7 Hz, 1H) , 7.38 (d, J = 7.8 Hz, 1H) , 7.05 (s, 1H) , 5.74 –5.65 (m, 1H) , 4.57 (s, 1H) , 4.38 –4.29 (m, 2H) , 3.95 –3.77 (m, 5H) , 3.43 –3.25 (m, 2H) , 3.28 (s, 3H) , 2.74 (t, J = 11.3 Hz, 2H) , 2.43 (t, J = 10.5 Hz, 1H) , 1.95 (d, J = 10.9 Hz, 2H) , 1.84 –1.71 (m, 2H) , 1.61 (d, J = 7.1 Hz, 3H) .
Example 13. (R) -4- ( (1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethyl) amino) -2- (hydroxymethyl) -7-methoxyquinazoline-6-carboxylic acid (Compound 7)
Step 1. Methyl (R) -4- ( (1- (3- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -2- (hydroxymethyl) -7-methoxyquinazoline-6-carboxylate (7a)
To a 15-mL sealed tube were added 4a (200 mg, 0.415 mmol) , Pd (dppf) Cl
2 (85 mg, 0.12 mmol) , TEA (252 mg, 2.49 mmol) and MeOH (5 mL) . The resulting mixture was bubbled with carbon monoxide and the reaction vessel was sealed. The mixture was heated to 100℃ and stirred for 16 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc = 2/3) to give the title compound 7a (140 mg, 73%) .
MS m/z (ESI) : 462 [M+1]
Step 2. (R) -4- ( (1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethyl) amino) -2- (hydroxymethyl) -7-methoxyquinazoline-6-carboxylic acid (7)
A mixture of 7a (140 mg, 0.303 mmol) , NaOH aqueous solution (2 N, 2 mL) , THF (2 mL) and methanol (2 mL) was stirred for 2 h. The mixture was concentrated to dryness under reduced pressure and the residue was purified by prep-HPLC to give the title compound 7 (120 mg, 88%) .
MS m/z (ESI) : 448 [M+1]
1H NMR (400 MHz, DMSO-d
6) δ 12.93 (s, 1H) , 8.79 –8.70 (m, 2H) , 7.67 (s, 1H) , 7.61 (d, J = 7.6 Hz, 1H) , 7.44 (t, J = 7.6 Hz, 1H) , 7.38 (d, J = 7.8 Hz, 1H) , 7.14 (s, 1H) , 5.73 –5.64 (m, 1H) , 4.70 (s, 1H) , 4.37 (s, 2H) , 3.93 –3.83 (m, 5H) , 3.28 (s, 3H) , 1.59 (d, J = 7.1 Hz, 3H) .
Example 14. (R) -N- (4- ( (1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethyl) amino) -2- (hydroxymethyl) -7-methoxyquinazolin-6-yl) -N-methylmethanesulfonamide formate (Compound 9)
Step 1. (R) -4- ( (1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-6- (N-methylmethylsulfonamido) quinazoline-2-carboxylic acid (9a)
A mixture of 1o (150 mg, 0.294 mmol) , N-methylmethanesulfonamide (132 mg, 1.21 mmol) , Pd
2 (dba)
3 (76 mg, 0.083 mmol) , Xantphos (48 mg, 0.083 mmol) and Cs
2CO
3 (405 mg, 1.24 mmol) in 1, 4-dioxane (5 mL) was heated to 90℃ and stirred for 16 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 9/1) to give the title compound 9a (92 mg, 60%) .
MS m/z (ESI) : 525 [M+1]
Step 2. Methyl (R) -4- ( (1- (3- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-6- (N-methylmethylsulfonamido) quinazoline-2-carboxylate (9b)
A mixture of 9a (92 mg, 0.18 mmol) , concentrated sulfuric acid (20 mg) and methanol (2 mL) was heated to 70℃ and stirred for 16 h. The mixture was concentrated to dryness and the residue was purified by prep-HPLC to give the title compound 9b (52 mg, 55%) .
MS m/z (ESI) : 539 [M+1]
Step 3. (R) -N- (4- ( (1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethyl) amino) -2- (hydroxymethyl) -7-methoxyquinazolin-6-yl) -N-methylmethanesulfonamide formate (9)
To a solution of 9b (52 mg, 0.094mmol) in ethanol (5 mL) was added a solution of LiBH
4 in THF (2 M, 1 mL) . The reaction was stirred for 2 h and then quenched with water (1 mL) . The resulting mixture was concentrated to dryness under reduced pressure and the residue was purified by silica gel chromatography (dichloromethane/methanol = 19/1) , followed by prep-HPLC purification to give the title compound 9 (2.2 mg, 4.6%) .
MS m/z (ESI) : 511 [M+1]
1H NMR (400 MHz, CD
3OD) δ 8.48 (s, 1H) , 8.17 (s, 6H) , 7.64 (s, 1H) , 7.58 (d, J = 6.8 Hz, 1H) , 7.44 (dd, J = 8.7, 6.1 Hz, 3H) , 5.78 (q, J = 6.8 Hz, 1H) , 5.34 (t, J = 4.6 Hz, 1H) , 4.71 –4.61 (m, 3H) , 4.07 (s, 3H) , 3.83 (t, J = 13.0 Hz, 2H) , 3.74 –3.70 (m, 2H) , 3.34 (s, 3H) , 3.08 (s, 3H) , 1.71 (d, J = 7.1 Hz, 3H) .
Example 15. (R) -4- ( (1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethyl) amino) -2- (hydroxymethyl) -7-methoxy-N-methylquinazoline-6-carboxamide (Compound 10)
A mixture of 7 (95 mg, 0.21 mmol) , methanamine hydrochloride (45 mg, 0.67 mmol) , DIPEA (144 mg, 1.11 mmol) and HATU (170 mg, 0.447 mmol) in DMF (5 mL) was stirred for 2 h, and then added with water (3 mL) and EtOAc (5 mL) sequentially. The organic phase was separated and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc = 93/7) , followed by prep-HPLC purification to give the title compound 10 (32 mg, 33%) .
MS m/z (ESI) : 461 [M+1]
1H NMR (400 MHz, DMSO-d
6) δ 8.73 (d, J = 8.5 Hz, 2H) , 8.25 (d, J = 4.7 Hz, 1H) , 7.67 (s, 1H) , 7.62 (d, J = 7.6 Hz, 1H) , 7.44 (t, J = 7.6 Hz, 1H) , 7.38 (d, J = 7.7 Hz, 1H) , 7.15 (s, 1H) , 5.73 –5.64 (m, 1H) , 4.68 (t, J = 5.4 Hz, 1H) , 4.37 (t, J = 5.5 Hz, 2H) , 3.94 (s, 3H) , 3.87 (t, J = 13.9 Hz, 2H) , 3.29 (s, 3H) , 2.82 (d, J = 4.7 Hz, 3H) , 1.59 (d, J = 7.1 Hz, 3H) .
Compounds 11 and 12 were prepared according to the procedures for Compound 10, except that different amines were used instead of methanamine hydrochloride in Step 1.
1H NMR data of Compounds 11 and 12 are shown below:
Example 16. (R) -N- (1- (3- (1, 1-Difluoro-2-methoxyethyl) phenyl) ethyl) -2- (methoxymethyl) -6-morpholinopyrido [3, 4-d] pyrimidin-4-amine (Compound 14)
Step 1. Methyl 2-morpholino-5-nitroisonicotinate (14b)
A mixture of methyl 2-chloro-5-nitroisonicotinate 14a (2.0 g, 9.2 mmol) , morpholine (1.04 g, 11.9 mmol) and TEA (1.87 g, 18.5 mmol) in dichloromethane (40 mL) was stirred for 1 h. The mixture was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (PE/EtOAc = 4/1) to give the title compound 14b (2.3 g, 93%) .
MS m/z (ESI) : 268 [M+1]
Step 2. Methyl 5-amino-2-morpholinoisonicotinate (14c)
A mixture of 14b (2.3 g, 8.6 mmol) and 10%Pd/C (400 mg) in methanol (40 mL) was stirred under H
2 for 16 h and filtered. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (PE/EtOAc = 1/1) to give the title compound 14c (2.0 g, 98%) .
MS m/z (ESI) : 238 [M+1]
Step 3. 2- (Methoxymethyl) -6-morpholinopyrido [3, 4-d] pyrimidin-4-ol (14d)
A mixture of 14c (2.0 g, 8.4 mmol) , 2-methoxyacetonitrile (1.0 g, 14 mmol) and a solution of HCl in dioxane (4 N, 100 mL) was heated to 90℃ and stirred for 48 h. After cooling to room temperature, the mixture was concentrated to dryness, and the residue was diluted with EtOAc (100 mL) and washed with a saturated sodium bicarbonate aqueous solution. The organic phase was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 9/1) to give the title compound 14d (500 mg, 22%) .
MS m/z (ESI) : 277 [M+1]
Step 4. 2- (Methoxymethyl) -6-morpholinopyrido [3, 4-d] pyrimidin-4-yl 2, 4, 6-triisopropylbenzenesulfonate (14e)
A mixture of 14d (500 mg, 2.22 mmol) , 2, 4, 6-triisopropylbenzenesulfonyl chloride (950 mg, 3.14 mmol) , TEA (900 mg, 8.89 mmol) and DMAP (26 mg, 0.21 mmol) in dichloromethane (10 mL) was stirred for 16 h. The mixture was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (PE/EtOAc = 4/1) to give the title compound 14e (2.3 g, 93%) .
MS m/z (ESI) : 543 [M+1]
Step 5. (R) -N- (1- (3- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -2- (methoxymethyl) -6-morpholinopyrido [3, 4-d] pyrimidin-4-amine
A mixture of 14e (100 mg, 0.18 mmol) , 1g (60 mg, 0.24 mmol) and DIPEA (120 mg, 0.93 mmol) in DMF (2 mL) was heated to 90℃ and stirred for 16 h. After cooling to room temperature, the mixture was purified by prep-HPLC to give the title compound 14 (73 mg, 84%) .
MS m/z (ESI) : 474 [M+1]
1H NMR (400 MHz, DMSO-d
6) δ 9.00 (s, 1H) , 7.68 –7.58 (m, 3H) , 7.54 –7.43 (m, 2H) , 5.83 –5.74 (m, 1H) , 4.61 –4.57 (m, 2H) , 3.91 (t, J = 13.8 Hz, 2H) , 3.76 (m, 4H) , 3.63 –3.53 (m, 4H) , 3.46 (s, 3H) , 3.31 (s, 3H) , 1.69 (d, J = 7.0 Hz, 3H) .
Example 17. N- ( (R) -1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-methoxy-2- (methoxymethyl) -6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine (Compound 15)
Step 1. N- ( (R) -1- (3- (1, 1-Difluoro-2-methoxyethyl) -5-nitrophenyl) ethyl) -7-methoxy-2- (methoxymethyl) -6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine (15l)
A mixture of 13d (171 mg, 0.3 mmol) , 15j (90 mg, 0.3 mmol) and DIPEA (116 mg, 0.9 mmol) in DMSO (2 mL) was heated to 110℃ and stirred for 15 h. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×50 mL) . The combined organic phase was washed with saturated brine (30 mL) and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/1 to 40/1) to give the title compound 15l (165 mg) .
MS m/z (ESI) : 549 [M+1]
Step 2. N- ( (R) -1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-methoxy-2- (methoxymethyl) -6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine
A mixture of 15l (165 mg, 0.3 mmol) and 10%Pd/C (90 mg) in methanol (10 mL) was stirred for 15 h under H
2 and filtered. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/1 to 20/1) to give the title compound 15 (19 mg, 12%) .
MS m/z (ESI) : 519 [M+1]
1H NMR (400 MHz, CD
3OD) δ 7.66 (s, 1H) , 7.15 (s, 1H) , 6.89 (d, J = 13.2 Hz, 2H) , 6.71 (s, 1H) , 5.63 (d, J = 7.0 Hz, 1H) , 5.20 (d, J = 2.1 Hz, 1H) , 4.42 (s, 2H) , 4.05 –3.99 (m, 3H) , 3.98 –3.89 (m, 4H) , 3.74 (t, J = 13.3 Hz, 2H) , 3.39 (s, 3H) , 3.32 (s, 3H) , 2.32 –2.19 (m, 2H) , 1.64 (d, J = 7.0 Hz, 3H) .
Compounds 54 and 58 were synthesized according to the procedures for Compound 15, except that different replacement compounds (54b and 58d) were used during the synthesis instead of 13d and 15j, respectively.
1H NMR data of Compounds 54 and 58 are shown below:
Example 18. N- ( (R) -1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine (Compound 16)
A mixture of 3g (1.08 g, 2 mmol) , 15k (480 mg, 1.8 mmol) and DIPEA (775 mg, 6 mmol) in DMSO (10 mL) was heated to 100℃ and stirred for 10 h. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by prep-HPLC to give the title compound 16 (353 mg, 40%) .
MS m/z (ESI) : 489 [M+1]
1H NMR (400 MHz, CD
3OD) δ 7.62 (s, 1H) , 7.04 (s, 1H) , 6.90 (d, J = 14.4 Hz, 2H) , 6.72 (s, 1H) , 5.62 (q, J = 7.0 Hz, 1H) , 5.20 –5.15 (m, 1H) , 4.05 –3.97 (m, 3H) , 3.97 –3.87 (m, 4H) , 3.75 (t, J = 13.3 Hz, 2H) , 3.32 (s, 3H) , 2.45 (s, 3H) , 2.31 –2.17 (m, 2H) , 1.63 (d, J = 7.1 Hz, 3H) .
Compounds 3, 8, 13, 21, 23, 25, 26, 38, 39, 40, 49, 51, 52, 59, 60, 61, 66 and 80 were synthesized according to the procedures for Compound 16, except that different compounds were used instead of 3g and 15k.
1H NMR data of Compounds 3, 8, 13, 21, 23, 25, 26, 38, 39, 40, 49, 51, 52, 59, 60, 61, 66 and 80 are shown below:
Intermediates 17e, 18c, 50e, 56c and 57c were synthesized according to the procedures for Compound 16, except that different compounds were used instead of 3g and 15k.
Example 19. (R) -5- (4- ( (1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) -1-methylpyridin-2 (1H) -one (Compound 18)
To a mixture of 18c (96 mg, 0.2 mmol) , 1-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2 (1H) -one (94 mg, 0.4 mmol) and K
2CO
3 (78 mg, 0.6 mmol) in 1, 4-dioxane (5 mL) and water (1 mL) was added Pd (dppf) Cl
2 (14 mg, 0.02 mmol) . The reaction mixture was heated to 80℃ and stirred overnight. After cooling to room temperature, the mixture was added with water (20 mL) and extracted with EtOAc (3×20 mL) . The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the title compound 18 (18 mg, 18%) .
MS m/z (ESI) : 510 [M+1]
1H NMR (400 MHz, DMSO-d
6) δ 8.27 (s, 1H) , 8.15 (d, J = 8.1 Hz, 1H) , 7.93 (d, J = 2.5 Hz, 1H) , 7.66 (dd, J = 9.4, 2.6 Hz, 1H) , 7.10 (s, 1H) , 6.73 (d, J = 11.0 Hz, 2H) , 6.55 (s, 1H) , 6.47 (d, J = 9.4 Hz, 1H) , 5.61 –5.50 (m, 1H) , 5.29 (s, 2H) , 3.89 (s, 3H) , 3.77 (t, J = 14.0 Hz, 2H) , 3.52 (s, 3H) , 3.30 (s, 3H) , 2.39 (s, 3H) , 1.52 (d, J = 7.0 Hz, 3H) .
Example 20. (R) -N- (1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- (tetrahydro-2H-pyran-4-yl) quinazolin-4-amine (Compound 19)
Step 1. (R) -N- (1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -6- (3, 6-dihydro-2H-pyran-4-yl) -7-methoxy-2-methylquinazolin-4-amine (19a)
To a mixture of 18c (240 mg, 0.5 mmol) , 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (210 mg, 1.0 mmol) and K
2CO
3 (192 mg, 1.5 mmol) in 1, 4-dioxane (10 mL) and water (1 mL) was added Pd (dppf) Cl
2 (34 mg, 0.05 mmol) . The resulting mixture was heated to 80℃ and stirred for 4 h. After cooling to room temperature, the reaction mixture was added with water (20 mL) and extracted with EtOAc (3×20 mL) . The combined organic phase was dried over hydrous sodium sulphate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc = 2/3 to 0/100) to give the title compound 19a (180 mg, 87%) .
MS m/z (ESI) : 485 [M+1]
Step 2. (R) -N- (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- (tetrahydro-2H-pyran-4-yl) quinazolin-4-amine (19)
To a solution of 19a (48 mg, 0.1 mmol) in methanol (5 mL) under hydrogen atmosphere was added 10%Pd/C (20 mg) . The reaction mixture was stirred for 4 h, filtered and concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the title compound (17 mg, 35%) .
MS m/z (ESI) : 487 [M+1]
1H NMR (400 MHz, DMSO-d
6) δ 8.14 (s, 2H) , 7.00 (s, 1H) , 6.76 (s, 1H) , 6.72 (s, 1H) , 6.56 (s, 1H) , 5.63 –5.51 (m, 1H) , 5.30 (s, 2H) , 3.99 (d, J = 7.5 Hz, 2H) , 3.89 (s, 3H) , 3.77 (t, J = 14.0 Hz, 2H) , 3.48 (t, J = 10.9 Hz, 2H) , 3.29 (s, 3H) , 3.25 –3.14 (m, 1H) , 2.36 (s, 3H) , 1.94 –1.78 (m, 2H) , 1.68 (d, J = 11.2 Hz, 2H) , 1.54 (d, J = 7.0 Hz, 3H) .
Intermediate 55a was synthesized according to the procedure of Step 1 for Compound 19, except that a different compound was used instead of 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane.
Intermediates 56d, 57d and 62b were synthesized according to the procedure of Step 1 for Compound 19, except that different compounds were used instead of 18c.
Example 21. (R) -4- (4- ( (1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) tetrahydro-2H- pyran-4-ol (Compound 20)
To a solution of 19a (48 mg, 0.1 mmol) and PhSiH
3 (22 mg, 0.2 mmol) in propanol (4.5 mL) and dichloromethane (0.5 mL) was added Mn (dpm)
3 (6 mg, 0.01 mmol) . The resulting mixture was stirred at 40℃ overnight. After cooling to room temperature, the mixture was concentrated to dryness and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 19/1 to 9/1) , followed by prep-HPLC purification to give the title compound 20 (12 mg, 28%) .
MS m/z (ESI) : 503 [M+1]
1H NMR (400 MHz, DMSO-d
6) δ 8.39 (s, 1H) , 8.28 (d, J = 7.9 Hz, 1H) , 7.03 (s, 1H) , 6.77 (s, 1H) , 6.73 (s, 1H) , 6.55 (s, 1H) , 5.61 –5.49 (m, 1H) , 5.27 (s, 2H) , 5.00 (s, 1H) , 3.97 –3.64 (m, 11H) , 3.30 (s, 3H) , 2.37 (s, 3H) , 1.52 (dd, J = 15.0, 9.0 Hz, 5H) .
Compounds 29 and 30 were prepared according to the procedures for Compound 20, except that different compounds were used instead of 19a in Step 1.
1H NMR data of Compounds 29 and 30 are shown below:
Intermediates 55b, 56e, 57e and 62c were synthesized according to the procedure of Step 1 for Compound 20, except that different compounds were used instead of 19a.
Example 22. (R) -N- (1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-methoxy-2-methyl-6-morpholinoquinazolin-4-amine (Compound 22)
Step 1. 7-Methoxy-2-methyl-6-morpholinoquinazolin-4-ol (22a)
A mixture of 6-bromo-7-methoxy-2-methylquinazolin-4-ol 18a (538 mg, 2 mmol) , morpholine (522 mg, 6 mmol) , sodium tert-butyloxide (384 mg, 4 mmol) , BINAP (249 mg, 0.4 mmol) and Pd
2 (dba)
3 (183 mg, 0.2 mmol) in toluene (10 mL) was heated to 110℃ and stirred for 15 h. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/1 to 201) to give the title compound 22a (230 mg, 42%) .
MS m/z (ESI) : 276 [M+1]
Step 2. 7-Methoxy-2-methyl-6-morpholinoquinazolin-4-yl-2, 4, 6-triisopropylbenzenesulfonate (22b)
To a solution of 22a (230 mg, 0.84 mmol) , TEA (254 mg, 2.52 mmol) and DMAP (10 mg, 0.084 mmol) in dichloromethane (40 mL) was added 2, 4, 6-triisopropylbenzenesulfonyl chloride (380 mg, 1.25 mmol) . The resulting mixture was heated to 45℃ and stirred for 15 h. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (PE/EtOAc = 50/1 to 31) to give the title compound 22b (180 mg, 39%) .
MS m/z (ESI) : 542 [M+1]
Step 3. (R) -N- (1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-methoxy-2-methyl-6-morpholinoquinazolin-4-amine (22)
A mixture of 22b (180 mg, 0.33 mmol) , 15k (62 mg, 0.23 mmol) and DIPEA (128 mg, 0.99 mmol) in DMSO (4 mL) was heated to 110℃ and stirred for 15 h. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure and the residue was purified by prep-HPLC to give the title compound 22 (7.1 mg, 4.4%) .
MS m/z (ESI) : 488 [M+1]
1H NMR (400 MHz, CD
3OD) δ 7.63 (s, 1H) , 7.03 (s, 1H) , 6.92 (s, 1H) , 6.88 (s, 1H) , 6.72 (s, 1H) , 5.62 (d, J = 7.1 Hz, 1H) , 3.97 (s, 3H) , 3.92 –3.83 (m, 4H) , 3.75 (t, J = 13.3 Hz, 2H) , 3.33 (s, 3H) , 3.13 (dd, J = 5.3, 3.1 Hz, 4H) , 2.44 (s, 3H) , 1.63 (d, J = 7.1 Hz, 3H) .
Compound 24 was prepared according to the procedures for Compound 22, except that a different amine was used instead of morpholine in Step 1.
1H NMR data of Compound 24 are shown below:
Example 23. (R) -N- (1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-methoxy-6- (4-methoxytetrahydro-2H-pyran-4-yl) -2-methylquinazolin-4-amine (Compound 27)
To a solution of 20 (25 mg, 0.05 mmol) in dichloromethane (3 mL) was added DAST (12 mg, 0.075 mmol) . The resulting mixture was stirred for 1.5 h and then concentrated to dryness under reduced pressure. The residue was dissolved in methanol (3 mL) and to which was added sodium methoxide (5.4 mg, 0.10 mmol) . The resulting mixture was stirred at 80℃ for 4 h. After cooling to room temperature, the mixture was concentrated to dryness and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 19/1 to 9/1) , followed by prep-HPLC purification to give the title compound 27 (6.0 mg, 23%) .
MS m/z (ESI) : 517 [M+1]
1H NMR (400 MHz, DMSO-d
6) δ 8.30 (d, J = 8.1 Hz, 1H) , 8.08 (s, 1H) , 7.05 (s, 1H) , 6.77 (s, 1H) , 6.72 (s, 1H) , 6.56 (s, 1H) , 5.64 –5.54 (m, 1H) , 5.29 (s, 2H) , 3.87 (s, 3H) , 3.76 (dd, J = 24.5, 10.3 Hz, 6H) , 3.29 (s, 3H) , 2.93 (s, 3H) , 2.37 (s, 3H) , 2.24 –2.11 (m, 4H) , 1.54 (d, J = 7.0 Hz, 3H) .
Compounds 56, 57 and 62 were synthesized according to the procedures for Compound 27, except that different compounds were used instead of 20.
Compound 63 was synthesized according to the procedures for Compound 27, except that different compounds were used instead of 20 and methanol.
1H NMR data of Compound 56, 57, 62 and 63 are shown below:
Intermediate 55c was synthesized according to the procedure of Step 1 for Compound 27, except that a different compound was used instead of 20.
Example 24. (R) -1- (4- (4- ( (1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) piperidin-1-yl) ethan-1-one (Compound 28)
Step 1. (R) -N- (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- (1, 2, 3, 6-tetrahydropyridin-4-yl) quinazolin-4-amine (28a)
To a mixture of 18c (145 mg, 0.3 mmol) , tert-butyl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (113 mg, 0.6 mmol) and K
2CO
3 (77 mg, 0.6 mmol) in 1, 4-dioxane (5 mL) and water (0.5 mL) was added Pd (dppf) Cl
2 (22 mg, 0.03 mmol) . The resulting mixture was heated to 80℃ and stirred for 4 h. After cooling to room temperature, the mixture was added with a solution of HCl in 1, 4-dioxane (4 N, 5 mL) and stirred for 1 h. The mixture was concentrated to dryness under reduced pressure and the residue was purified by prep-HPLC to give the title compound 28a (120 mg, 83%) .
MS m/z (ESI) : 484 [M+1]
Step 2. (R) -1- (4- (4- ( (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) -3, 6-dihydropyridin-1 (2H) -yl) ethan-1-one (28b)
To a mixture of 28a (60 mg, 0.13 mmol) and NaHCO
3 (84 mg, 0.25 mmol) in THF (2.0 mL) and water (0.5 mL) at 0℃ was added acetyl chloride (15 mg, 0.19 mmol) . The resulting mixture was stirred for 0.5 h and then concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc = 1/4 to 0/100) to give the title compound 28b (50 mg, 77%) .
MS m/z (ESI) : 526 [M+1]
Step 3. (R) -1- (4- (4- ( (1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) piperidin-1-yl) ethan-1-one (28c)
To a solution of 28b (25 mg, 0.047 mmol) in methanol (5 mL) was added 10%Pd/C (25 mg) . The reaction mixture was stirred for 4 h under H
2 and filtered. The filtrate was concentrated to dryness and the residue was purified by prep-HPLC to give the title compound (4.1 mg, 17%) .
MS m/z (ESI) : 528 [M+1]
1H NMR (400 MHz, DMSO-d
6) δ 8.16 –8.04 (m, 2H) , 7.01 (s, 1H) , 6.74 (s, 1H) , 6.71 (s, 1H) , 6.56 (s, 1H) , 5.63 –5.49 (m, 1H) , 5.30 (s, 2H) , 4.60 (d, J = 12.7 Hz, 1H) , 3.96 (d, J =12.4 Hz, 1H) , 3.90 (s, 3H) , 3.77 (t, J = 14.0 Hz, 2H) , 3.29 (s, 3H) , 3.25 –3.11 (m, 2H) , 2.61 (t, J = 11.5 Hz, 1H) , 2.36 (s, 3H) , 2.04 (d, J = 1.7 Hz, 3H) , 1.87 –1.57 (m, 4H) , 1.53 (d, J =6.9 Hz, 3H) .
Compound 42 was prepared according to the procedures for Compound 28, except that a different acid chloride was used instead of acetyl chloride in Step 2.
1H NMR data of Compound 42 are shown below:
Intermediate 30a was synthesized according to the procedures of Steps 1 and 2 for Compound 28, except that a different acid chloride was used instead of acetyl chloride.
Example 25. N- ( (R) -1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- ( ( (S) -1-methylpyrrolidin-3-yl) oxy) quinazolin-4-amine (Compound 31)
To a solution of 17e (100 mg, 0.17 mmol) in THF (10 mL) was added lithium aluminum hydride (19 mg, 0.51 mmol) . The resulting mixture was heated to 80℃ and stirred for 1 h. After cooling to room temperature, the mixture was added with water (1 mL) and stirred for 10 min. The mixture was then filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the title compound 31 (3.5 mg, 4%) .
MS m/z (ESI) : 502 [M+1]
1H NMR (400 MHz, CD
3OD) δ 7.96 (s, 1H) , 7.13 (s, 1H) , 6.90 (s, 2H) , 6.75 (s, 1H) , 5.75 (q, J = 6.9 Hz, 1H) , 5.33 (s, 1H) , 4.01 (s, 3H) , 3.84 –3.56 (m, 5H) , 3.53 –3.42 (m, 1H) , 3.34 (d, J = 10.4 Hz, 3H) , 3.02 (s, 3H) , 2.62 (s, 4H) , 2.46 –2.31 (m, 1H) , 1.70 (d, J = 7.0 Hz, 3H) .
Example 26. (R) -N- (1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- (3-methyl-5, 6-dihydro- [1, 2, 4] triazolo [4, 3-a] pyrazin-7 (8H) -yl) quinazolin-4-amine (Compound 32)
Step 1. 6-Bromo-4-chloro-7-methoxy-2-methylquinazoline (32a)
To a solution of 18a (1.07 g, 4 mmol) in acetonitrile (10 mL) was added phosphorus oxychloride (20 mL) and the resulting mixture was heated to reflux for 4 h. After cooling to room temperature, the mixture was concentrated to dryness under reduce pressure and the residue was dissolved in EtOAc (200 mL) . The mixture was washed with a saturated sodium bicarbonate aqueous solution (50 mL) and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduce pressure. The residue was purified by silica gel column chromatography (PE/EtOAc = 10: 1 to 1: 2) to give the title compound 32a (1.07 g, 93%) .
MS m/z (ESI) : 287 [M+1]
Step 2. (R) -6-Bromo-N- (1- (3- (1, 1-difluoro-2-methoxyethyl) -5-nitrophenyl) ethyl) -7-methoxy-2-methylquinazolin-4-amine (32b)
A mixture of 32a (1.05 g, 3.65 mmol) , DIPEA (1.28 g, 9.9 mmol) and 15j (984 mg, 3.3 mmol) in DMSO (10 mL) was heated to 100℃ and stirred for 6 h. After cooling to room temperature, the reaction mixture was purified by prep-HPLC to give the title compound 32b (1.45 g, 86%) .
MS m/z (ESI) : 511 [M+1]
Step 3. (R) -N- (1- (3- (1, 1-difluoro-2-methoxyethyl) -5-nitrophenyl) ethyl) -7-methoxy-2-methyl-6- (3-methyl-5, 6-dihydro- [1, 2, 4] triazolo [4, 3-a] pyrazin-7 (8H) -yl) quinazolin-4-amine (32c)
A mixture of 32b (51 mg, 0.1 mmol) , 3-methyl-5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyrazine (28 mg, 0.2 mmol) , Cs
2CO
3 (65 mg, 0.2 mmol) , BINAP (12 mg, 0.02 mmol) and Pd
2 (dba)
3 (9 mg, 0.01 mmol) in 1, 4-dioxane (3 mL) was heated to 105℃ and stirred for 15 h. After cooling to room temperature, the reaction mixture was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/1 to 20/1) to give the title compound 32c (30 mg, 53%) .
MS m/z (ESI) : 569 [M+1]
Step 4. (R) -N- (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- (3-methyl-5, 6-dihydro- [1, 2, 4] triazolo [4, 3-a] pyrazin-7 (8H) -yl) quinazolin-4-amine (32)
A mixture of 32c (30 mg, 0.053 mmol) and 10%Pd/C (30 mg) in methanol (10 mL) was stirred for 6 h under H
2 and filtered. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by prep-HPLC to give the title compound 32 (13 mg, 46%) .
MS m/z (ESI) : 539 [M+1]
1H NMR (400 MHz, CD
3OD) δ 7.77 (s, 1H) , 7.07 (s, 1H) , 6.91 (d, J = 11.1 Hz, 2H) , 6.72 (s, 1H) , 5.63 (q, J = 7.0 Hz, 1H) , 4.48 (s, 2H) , 4.13 (t, J = 5.4 Hz, 2H) , 4.00 (s, 3H) , 3.76 (t, J = 13.3 Hz, 2H) , 3.66 –3.56 (m, 2H) , 3.33 (s, 3H) , 2.46 (d, J = 2.2 Hz, 6H) , 1.64 (d, J = 7.0 Hz, 3H) .
Compounds 33, 34, 35, 36 and 46 were prepared according to the procedures for Compound 32, except that different amines were used instead of 3-methyl-5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyrazine in Step 3.
1H NMR data of Compounds 33, 34, 35, 36 and 46 are shown below:
Intermediates 37a and 41a were synthesized according to the procedures of Steps 1 to 3 for Compound 32, except that different compounds were used instead of 5, 6, 7, 8-tetrahydro- [1, 2, 4] triazolo [4, 3-a] pyrazine.
Example 27. (R) - (1- (4- ( (1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) piperidin-4-yl) (morpholino) methanone (Compound 37)
Step 1. (R) -1- (4- ( (1- (3- (1, 1-Difluoro-2-methoxyethyl) -5-nitrophenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) piperidine-4-carboxylic acid (37b)
To a solution of 37b (20 mg, 0.035 mmol) in THF (3 mL) was added a lithium hydroxide aqueous solution (1 N, 1 mL) . The resulting mixture was stirred for 15 h and then added with acetic acid (200 mg) . The resulting mixture was concentrated to dry to give the title compound 37b (65 mg, crude) .
MS m/z (ESI) : 560 [M+1]
Step 2. (R) - (1- (4- ( (1- (3- (1, 1-Difluoro-2-methoxyethyl) -5-nitrophenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) piperidin-4-yl) (morpholino) methanone (37c)
To a mixture of 37b (65 mg, crude) , morpholine (15 mg) and DIPEA (45 mg, 0.35 mmol) in DMF (3 mL) was added HATU (40 mg, 0.11 mmol) . The resulting mixture was stirred for 0.5 h and then purified by prep-HPLC to give the title compound 37c (15 mg, 68%over two steps) .
MS m/z (ESI) : 629 [M+1]
Step 3. (R) - (1- (4- ( (1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) piperidin-4-yl) (morpholino) methanone (37)
A mixture of 37c (15 mg, 0.024 mmol) and 10%Pd/C (15 mg) in methanol (10 mL) was stirred for 4 h under H
2 and filtered. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by prep-HPLC to give the title compound 37 (4.9 mg, 34%) .
MS m/z (ESI) : 599 [M+1]
1H NMR (400 MHz, CD
3OD) δ 7.62 (s, 1H) , 7.01 (s, 1H) , 6.91 (s, 1H) , 6.88 (s, 1H) , 6.72 (s, 1H) , 5.62 (d, J = 7.0 Hz, 1H) , 3.97 (s, 3H) , 3.75 (t, J = 13.3 Hz, 2H) , 3.71 –3.52 (m, 10H) , 3.33 (s, 3H) , 2.78 (ddd, J = 20.3, 13.6, 6.6 Hz, 3H) , 2.45 (s, 3H) , 1.98 (dt, J = 12.1, 7.7 Hz, 2H) , 1.83 (d, J = 12.6 Hz, 2H) , 1.63 (d, J = 7.1 Hz, 3H) .
Example 28. (R) -1- (4- (4- ( (1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) piperazin-1-yl) ethan-1-one (Compound 41)
Step 1. (R) -N- (1- (3- (1, 1-Difluoro-2-methoxyethyl) -5-nitrophenyl) ethyl) -7-methoxy-2-methyl-6- (piperazin-1-yl) quinazolin-4-amine hydrochloride (41b)
To a solution of 41b (30 mg, 0.049 mmol) in dichloromethane (5 mL) was added hydrochloric acid (2 N, 2 mL) . The mixture was stirred for 6 h and then concentrated to dryness under reduced pressure to give the title compound 41b (28 mg) .
MS m/z (ESI) : 517 [M+1]
Step 2. (R) -1- (4- (4- ( (1- (3- (1, 1-difluoro-2-methoxyethyl) -5-nitrophenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) piperazin-1-yl) ethan-1-one (41c)
To a mixture of 41b (14 mg, 0.025 mmol) , saturated sodium bicarbonate aqueous solution (3 mL) and THF (3 mL) was added acetyl chloride (3 mg, 0.04 mmol) . The resulting mixture was stirred for 0.5 h, diluted with saturated brine (10 mL) and extracted with EtOAc (2 × 20 mL) . The combined organic phase was washed with saturated brine (15 mL) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness under reduced pressure to give the title compound 41c (16 mg) .
MS m/z (ESI) : 559 [M+1]
Step 3. (R) -1- (4- (4- ( (1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) piperazin-1-yl) ethan-1-one (41)
A mixture of 41c (16 mg, 0.025 mmol) and 10%Pd/C (15 mg) in methanol (10 mL) was stirred for 6 h under H
2 and filtered. The filtrate was concentrated to dryness under reduced pressure and the residue was purified by prep-HPLC to give the title compound 41 (0.9 mg, 7%) .
MS m/z (ESI) : 529 [M+1]
1H NMR (400 MHz, CD
3OD) δ 7.65 (s, 1H) , 7.03 (s, 1H) , 6.91 (s, 1H) , 6.88 (s, 1H) , 6.72 (s, 1H) , 5.62 (dd, J = 14.0, 6.9 Hz, 1H) , 3.99 (s, 3H) , 3.87 –3.63 (m, 6H) , 3.33 (s, 3H) , 3.12 (dd, J = 13.1, 8.0 Hz, 4H) , 2.45 (s, 3H) , 2.19 –2.11 (m, 3H) , 1.63 (d, J = 7.1 Hz, 3H) .
Compound 47 was prepared according to the procedures for Compound 41, except that a different acid chloride was used instead of acetyl chloride in Step 2.
1H NMR data of Compound 47 are shown below:
Example 29. (R) -N- (1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -6- (4-fluorotetrahydro-2H-pyran-4-yl) -7-methoxy-2-methylquinazolin-4-amine (Compound 43)
To a solution of 20 (20 mg, 0.04 mmol) in dichloromethane (5 mL) was added DAST (13 mg, 0.08 mmol) . The resulting mixture was stirred for 1 h and then concentrated to dryness. The residue was purified by prep-HPLC to give the title compound 43 (8.0 mg, 40%) .
MS m/z (ESI) : 505 [M+1]
1H NMR (400 MHz, CD
3OD) δ 8.51 (s, 1H) , 7.09 (s, 1H) , 6.91 (s, 1H) , 6.87 (s, 1H) , 6.74 (s, 1H) , 5.71 (dd, J = 13.7, 6.8 Hz, 1H) , 4.03 (s, 3H) , 3.95 –3.82 (m, 4H) , 3.76 (t, J = 13.2 Hz, 2H) , 3.35 (s, 3H) , 2.92 –2.66 (m, 2H) , 2.57 (s, 3H) , 1.80 –1.69 (m, 2H) , 1.66 (d, J = 7.0 Hz, 3H) .
Example 30. 1- ( (S) -3- ( (4- ( ( (R) -1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) pyrrolidin-1-yl) propan-1-one (Compound 44)
Step 1. N- ( (R) -1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- ( ( (S) -pyrrolidin-3-yl) oxy) quinazolin-4-amine (44a)
A mixture of 17e (300 mg, 0.51 mmol) and a solution of HCl in 1, 4-dioxane (4 N, 20 mL) was stirred for 1 h and then concentrated to dryness under reduced pressure to give the title compound 44a (300 mg, crude) .
MS m/z (ESI) : 488 [M+1]
Step 2. 1- ( (S) -3- ( (4- ( ( (R) -1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-2-methylquinazolin-6-yl) oxy) pyrrolidin-1-yl) propan-1-one (44)
To a mixture of 44a (80 mg, crude) and sodium bicarbonate (35 mg, 0.41 mmol) in THF (5 mL) and water (2 mL) at 0℃ was added a solution of propionyl chloride (19 mg, 0.21 mmol) in THF (5 mL) . The reaction mixture was stirred for 1 h and then concentrated to dryness under reduced pressure. The residue was purified by prep-HPLC to give the title compound 44 (5.1 mg, 7%) .
MS m/z (ESI) : 544 [M+1]
1H NMR (400 MHz, CD
3OD) δ 7.71 (d, J = 10.4 Hz, 1H) , 7.04 (t, J = 5.6 Hz, 1H) , 6.91 (s, 1H) , 6.88 (s, 1H) , 6.72 (s, 1H) , 5.63 (dd, J = 14.0, 6.9 Hz, 1H) , 3.94 (d, J = 1.6 Hz, 3H) , 3.76 (dd, J = 22.3, 9.1 Hz, 7H) , 3.33 (s, 3H) , 2.45 (d, J = 5.1 Hz, 3H) , 2.43 –2.24 (m, 4H) , 1.63 (d, J = 7.0 Hz, 3H) , 1.25 –1.03 (m, 3H) .
Compounds 17, 45, 50 and 55 were prepared according to the procedures for Compound 44, except that different compounds were used instead of 17e and propionyl chloride, respectively.
1H NMR data of Compounds 17, 45, 50 and 55 are shown below:
Example 31. N- ( (R) -1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- ( ( (S) -1- (2, 2, 2-trifluoroethyl) pyrrolidin-3-yl) oxy) quinazolin-4-amine (Compound 48)
Step 1. (R) -Pyrrolidin-3-yl benzenesulfonate (48b)
A mixture of tert-butyl (R) -3- ( (phenylsulfonyl) oxy) pyrrolidine-1-carboxylate 48a (981 mg, 3.0 mmol) and a solution of HCl in 1, 4-dioxane (4 N, 20 mL) was stirred for 1 h and then concentrated to dryness under reduced pressure to give the title compound 48b (1.0 g) .
MS m/z (ESI) : 228 [M+1]
Step 2. (R) -Pyrrolidin-3-yl benzenesulfonate (48c)
To a solution of 48b (1.0 g, crude) and 2, 2, 2-trifluoroethyl methanesulfonate (696 mg, 3.0 mmol) in dichloromethane (20 mL) was added DIPEA (775 mg, 6.0 mmol) . The resulting mixture was stirred for 2 h and then concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc = 9/1 to 7/3) to give the title compound 48c (300 mg, 32%over two steps) .
MS m/z (ESI) : 310 [M+1]
Step 3. (S) -7-Methoxy-2-methyl-6- ( (1- (2, 2, 2-trifluoroethyl) pyrrolidin-3-yl) oxy) quinazolin-4-ol (48d)
To a solution of 48c (300 mg, 0.97 mmol) and 7-methoxy-2-methylquinazoline-4, 6-diol (201 mg, 0.97 mmol) in DMF (5 mL) was added K
2CO
3 (267 mg, 1.94 mmol) . The resulting mixture was heated to 100℃ and stirred overnight. After cooling to room temperature, the mixture was purified by prep-HPLC to give the title compound 48d (160 mg, 45%) .
MS m/z (ESI) : 358 [M+1]
Step 4. (S) -7-Methoxy-2-methyl-6- ( (1- (2, 2, 2-trifluoroethyl) pyrrolidin-3-yl) oxy) quinazolin-4-yl 2, 4, 6-triisopropylbenzenesulfonate (48e)
To a solution of 48d (160 mg, 0.45 mmol) , 2, 4, 6-triisopropylbenzenesulfonyl chloride (163 mg, 0.54 mmol) and DIPEA (116 mg, 0.90 mmol) in dichloromethane (20 mL) was added DMAP (6 mg, 0.045 mmol) . The reaction mixture was stirred overnight and then concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc = 3/2 to 1/4) to give the title compound 48e (180 mg, 64%) .
MS m/z (ESI) : 624 [M+1]
Step 5. N- ( (R) -1- (3-Amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-methoxy-2-methyl-6- ( ( (S) -1- (2, 2, 2-trifluoroethyl) pyrrolidin-3-yl) oxy) quinazolin-4-amine (48)
To a solution of 48e (40 mg, 0.064 mmol) and 15k (22 mg, 0.096 mmol) in dimethylacetamide (2 mL) was added K
2CO
3 (18 mg, 0.13 mmol) . The resulting mixture was heated to 110℃ and stirred for 16 h. After cooling to room temperature, the mixture was purified by prep-HPLC to give the title compound 48 (3.5 mg, 10%) .
MS m/z (ESI) : 570 [M+1]
1H NMR (400 MHz, CD
3OD) δ 8.27 (s, 1H) , 7.98 (s, 1H) , 7.71 (s, 1H) , 7.42 (s, 1H) , 7.14 (s, 1H) , 5.14 (s, 1H) , 4.56 (d, J = 6.6 Hz, 1H) , 3.99 (s, 3H) , 3.92 (t, J = 12.8 Hz, 2H) , 3.43 (s, 3H) , 3.34 (d, J = 5.4 Hz, 1H) , 3.29 –3.22 (m, 2H) , 3.01 (t, J = 8.8 Hz, 2H) , 2.94 –2.82 (m, 1H) , 2.58 (s, 3H) , 2.38 (dt, J = 14.3, 7.1 Hz, 1H) , 2.16 –2.01 (m, 1H) , 1.71 (d, J = 6.6 Hz, 3H) .
Example 32. (R) -N- (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-methoxy-6- (1-methoxycyclobutyl) -2-methylquinazolin-4-amine (Compound 53)
Step 1. 1- (4-Chloro-7-methoxy-2-methylquinazolin-6-yl) cyclobutan-1-ol (53a)
To a solution of 32a (287 mg, 1 mmol) in THF (5 mL) at -78℃ was added n-BuLi (2.5 M, 0.44 mL, 1.1 mmol) . The resulting mixture was stirred at -78℃ for 1 h and then added with a solution of cyclobutanone (105 mg, 1.5 mmol) in THF (1 mL) . The resulting mixture was warmed to -20℃ and stirred for 0.5 h. The mixture was added with acetic acid (0.3 mL) and concentrated to dryness. The residue was purified by silica gel column chromatography (PE/EtOAc = 50/1 to 1/2) to give the title compound 53b (60 mg, 21%) .
MS m/z (ESI) : 279 [M+1]
Step 2. 4-Chloro-7-methoxy-6- (1-methoxycyclobutyl) -2-methylquinazoline (53b)
To a solution of 53b (60 mg, 0.21 mmol) in THF (5 mL) at 0℃ was added NaH (60%in mineral oil, 26 mg, 0.63 mmol) . The resulting mixture was stirred at 0℃ for 1 h and then added with iodomethane (149 mg, 1.05 mmol) . The resulting mixture was stirred at room temperature for 6 h and then added with acetic acid solution (0.5 mL in 5 mL water) and extracted with ethyl acetate (2×20 mL) . The combined organic phase was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc =100/1 to 1/1) to give the title compound 53b (29 mg, 47%) .
MS m/z (ESI) : 293 [M+1]
Step 3. (R) -N- (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-methoxy-6- (1-methoxycyclobutyl) -2-methylquinazolin-4-amine (53)
A mixture of 53b, 15k (40 mg, 0.15 mmol) , DIPEA (52 mg, 0.4 mmol) and DMSO (2 mL) was heated to 110℃ and stirred for 6 h. After cooling to room temperature, the mixture was purified by pre-HPLC to give the title compound 53 (0.9 mg, 1.8%) .
MS m/z (ESI) : 487 [M+1]
1H NMR (400 MHz, CD
3OD) δ 8.13 (s, 1H) , 7.02 (s, 1H) , 6.92 (s, 1H) , 6.89 (s, 1H) , 6.72 (s, 1H) , 5.65 (dd, J = 14.0, 6.9 Hz, 1H) , 3.93 (d, J = 19.2 Hz, 3H) , 3.75 (t, J = 13.3 Hz, 2H) , 3.32 (s, 3H) , 3.05 –2.88 (m, 3H) , 2.72 –2.62 (m, 2H) , 2.60 –2.32 (m, 5H) , 2.05 (dd, J =17.3, 6.6 Hz, 1H) , 1.76 –1.69 (m, 1H) , 1.63 (d, J = 7.1 Hz, 3H) .
Intermediates 54b and 69a were synthesized according to the procedures of Steps 1 to 3 for Compound 53, except that different compounds were used instead of cyclobutanone.
Example 33. (R) -N- (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-cyclopropyl-6- (4-methoxytetrahydro-2H-pyran-4-yl) -2-methylquinazolin-4-amine (Compound 64)
Step 1. Methyl 2-nitro-4-vinylbenzoate (64b)
To a mixture of methyl 4-bromo-2-nitrobenzoate 64a (2.60 g, 10.0 mmol) , 4, 4, 5, 5-tetramethyl-2-vinyl-1, 3, 2-dioxaborolane (2.31g, 15.0 mmol) , K
2CO
3 (2.76 g, 20.0 mmol) , 1, 4-dioxane (50 mL) and water (5 mL) was added Pd (dppf) Cl
2 (731 mg, 1.0 mmol) . The reaction mixture was heated to 80℃ and stirred for 4 hours under nitrogen atmosphere. After cooling to room temperature, the mixture was added with water (20 mL) and extracted with EtOAc (3×20 mL) . The combined organic phase was dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc = 4/1 to 7/3) to give the title compound 64b (1.8 g, 87%) .
MS m/z (ESI) : 208 [M+1]
Step 2. Methyl 4-cyclopropyl-2-nitrobenzoate (64c)
To a solution of trimethyl sulfoxonium iodide (1.59 g, 7.24 mmol) in DMSO was added t-BuOK (2.44 g, 21.72 mmol) . The mixture was stirred for 1 hour and then added with 64b (1.50 g, 7.24 mmol) . The resulting mixture was stirred for 1 h and purified by prep-HPLC to give the title compound 64c (340 mg, 21%) .
MS m/z (ESI) : 222 [M+1]
Step 3. Methyl 2-amino-4-cyclopropylbenzoate (64d)
To a solution of 64c (300 mg, 1.36 mmol) in acetic acid (1 mL) and ethanol (30 mL) was added zinc dust (881 mg, 13.56 mmol) . The reaction was stirred for 0.5 h and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc =7/3 to 1/1) to give the title compound 64d (250 mg, 96%) .
MS m/z (ESI) : 192 [M+1]
Step 4. Methyl 2-amino-5-bromo-4-cyclopropylbenzoate (64e)
To a solution of 64d (250 mg, 1.30 mmol) in DMF (5 mL) at 0℃ was added NBS (221 mg, 1.24 mmol) . The reaction mixture was stirred for 1 h at 0℃ and then added with Na
2S
2O
3 aqueous solution (10 mL) . The resulting mixture was extracted with ethyl acetate (3×10 mL) , dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc =7/3 to 3/2) to give the title compound 64e (180 mg, 51%) .
MS m/z (ESI) : 270, 272 [M+1]
Step 5. 6-Bromo-7-cyclopropyl-2-methylquinazolin-4-ol (64f)
To a solution of 64e (180 mg, 0.67 mmol) in acetonitrile (5 mL) was added methanesulfonic acid (1 mL) . The mixture was heated to 100℃ and stirred overnight. After cooling to room temperature, the mixture was treated with sodium hydroxide aqueous solution (2 M, 10 mL) , extracted with EtOAc (3×10 mL) , dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc =1/4 to 0/100) to give the title compound 64f (150 mg, 81%) .
MS m/z (ESI) : 279 [M+1]
Step 6. 7-Cyclopropyl-6- (3, 6-dihydro-2H-pyran-4-yl) -2-methylquinazolin-4-ol (64g)
To a mixture of 64f (280 mg, 1.0 mmol) , 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (315 mg, 1.5 mmol) , K
2CO
3 (414 mg, 3.0 mmol) , 1, 4-dioxane (10 mL) and water (1 mL) was added Pd (dppf) Cl
2 (74 mg, 0.1 mmol) . The resulting mixture was heated to 80℃ and stirred for 4 h under nitrogen atmosphere. After cooling to room temperature, the mixture was added with water (20 mL) and extracted with ethyl acetate (3×20 mL) . The combined organic phase was dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc =3/2 to 1/9) to give the title compound 64g (240 mg, 85%) .
MS m/z (ESI) : 283 [M+1]
Step 7. 7-Cyclopropyl-6- (4-hydroxytetrahydro-2H-pyran-4-yl) -2-methylquinazolin-4-ol (64h)
To a solution of 64g (240 mg, 0.71 mmol) and PhSiH
3 (230 mg, 2.13 mmol) in isopropanol (9 mL) and DCM (1 mL) was added Mn (dpm)
3 (43 mg, 0.07 mmol) . The mixture was stirred overnight and concentrated to dryness. The residue was purified by silica gel column chromatography (PE/EtOAc =2/3 to 0/100) to give the title compound 64h (180 mg, 85%) .
MS m/z (ESI) : 301 [M+1]
Step 8. 7-Cyclopropyl-6- (4-fluorotetrahydro-2H-pyran-4-yl) -2-methylquinazolin-4-ol (64i)
To a solution of 64h (180 mg, 0.60 mmol) in dichloromethane (5 mL) was added DAST (193 mg, 1.20 mmol) . The resulting mixture was stirred for 1 h and added with sodium bicarbonate aqueous solution (10 mL) . The mixture was extracted with EtOAc (3×10 mL) . The combined organic phase was dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/0 to 19/1) to give the title compound 64i (150 mg, 82%) .
MS m/z (ESI) : 303 [M+1]
Step 9. 7-Cyclopropyl-6- (4-methoxytetrahydro-2H-pyran-4-yl) -2-methylquinazolin-4-ol (64j)
To a solution of 64i (150 mg, 0.50 mmol) in methanol (5 mL) was added sodium methoxide (268 mg, 4.96 mmol) . The resulting mixture was heated to 80℃ and stirred overnight. After cooling to room temperature, the mixture was concentrated to dryness and the residue was purified by silica gel column chromatography (dichloromethane/methanol =49/1 to 19/1) to give the title compound 64j (130 mg, 83%) .
MS m/z (ESI) : 315 [M+1]
Step 10. 7-Cyclopropyl-6- (4-methoxytetrahydro-2H-pyran-4-yl) -2-methylquinazolin-4-yl 2, 4, 6-triisopropylbenzenesulfonate (64k)
To a solution of 64j (130 mg, 0.41 mmol) , 2, 4, 6-triisopropylbenzenesulfonyl chloride (150 mg, 0.50 mmol) and DIPEA (107 mg, 0.83 mmol) in dichloromethane (10 mL) was added DMAP (5 mg, 0.04 mmol) . The reaction was stirred overnight and concentrated to dryness. The residue was purified by silica gel column chromatography (PE/EtOAc =2/3 to 0/100) to give the title compound 64k (180 mg, 76%) .
MS m/z (ESI) : 581 [M+1]
Step 11. (R) -N- (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-cyclopropyl-6- (4-methoxytetrahydro-2H-pyran-4-yl) -2-methylquinazolin-4-amine (64)
To a solution of 64k (180 mg, 0.31 mmol) and 15k (72 mg, 0.31 mmol) in DMSO (1 mL) was added DIPEA (120 mg, 0.93 mmol) . The mixture was heated to 100℃ and stirred overnight. After cooling to room temperature, the mixture was purified by prep-HPLC to give the title compound (2.0 mg, 23%) .
MS m/z (ESI) : 527 [M+1]
1H NMR (400 MHz, CD
3OD) δ 8.00 (s, 1H) , 7.05 (s, 1H) , 6.93 (s, 1H) , 6.89 (s, 1H) , 6.73 (s, 1H) , 5.65 (q, J = 6.9 Hz, 1H) , 3.98 (t, J = 11.0 Hz, 2H) , 3.84 (d, J = 11.2 Hz, 2H) , 3.76 (t, J = 13.3 Hz, 2H) , 3.33 (s, 3H) , 3.11 (ddd, J = 8.4, 6.9, 4.3 Hz, 1H) , 3.05 (s, 3H) , 2.53 (s, 1H) , 2.49 (s, 1H) , 2.45 (s, 3H) , 2.25 –2.13 (m, 2H) , 1.64 (d, J = 7.1 Hz, 3H) , 1.10 (dd, J = 8.4, 2.0 Hz, 2H) , 0.95 –0.82 (m, 2H) .
Intermediate 59e was synthesized according to the procedures of Steps 6 to 10 for Compound 64, except that a different compound was used instead of 64f.
Intermediate 68d was synthesized according to the procedures of Steps 6 to 9 for Compound 64, except that a different compound was used instead of 64f.
Intermediates 70a and 72a were synthesized according to the procedures of Steps 4 to 6 for Compound 64, except that different compounds were used instead of 64d.
Example 34. (R) - (4- ( (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-6- (4-methoxytetrahydro-2H-pyran-4-yl) quinazolin-2-yl) methanol (Compound 65)
Step 1. Methyl 2- (2- (benzyloxy) acetamido) -5-bromo-4-methoxybenzoate (65a)
To a solution of 1i (2.6 g, 10 mmol) and TEA (3.03 g, 30 mmol) in dichloromethane (50 mL) was added 2- (benzyloxy) acetyl chloride (3.69 g, 20 mmol) and the resulting mixture was heated to 40℃ and stirred for 5 h. After cooling to room temperature, the mixture was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EA = 100/1 to 1/1) to give the title compound 65a (3.75 g, 90%) .
MS m/z (ESI) : 408, 410 [M+1]
Step 2. 2- ( (Benzyloxy) methyl) -6-bromo-7-methoxyquinazolin-4-ol (65b)
A mixture of 65a (3.7 g, 9.1 mmol) , ammonium hydroxide (20 mL) and isopropanol (50 mL) was heated to 50℃ and stirred for 15 h. After cooling to room temperature, the mixture was concentrated to dryness and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 20: 1) to give the crude product. The crude product was then dissolved in DMF (30 mL) and methanol (30 mL) , stirred for 0.5 and filtered. The solid was washed with methanol (10 mL) and dried under reduced pressure to give the title compound 65b (1.7 g, 50%) .
MS m/z (ESI) : 375, 377 [M+1]
Step 3. 2- ( (Benzyloxy) methyl) -6-bromo-4-chloro-7-methoxyquinazoline (65c)
To a mixture of 65b (1.7 g, 4.5 mmol) , POCl
3 (15 mL) and MeCN (20 mL) was added DIPEA (5 mL) . The resulting mixture was heated to 60℃ and stirred for 3 h. After cooling to room temperature, the mixture was concentrated to dryness and the residue was dissolved in dichloromethane (200 mL) . The resulting solution was washed with saturated sodium bicarbonate aqueous solution (2×60 mL) and water (60 mL) , dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc = 100/1 to 20/1 then to 5/1) to give the title compound 65c (1.4 g, 79%) .
MS m/z (ESI) : 393, 395 [M+1]
Step 4. 2- ( (Benzyloxy) methyl) -6-bromo-7-methoxy-4- (2, 2, 2-trifluoroethoxy) quinazoline (65d)
A mixture of 65c (1.4 g, 3.56 mmol) , 2, 2, 2-trifluoroethan-1-ol (1.78 g, 17.8 mmol) , K
2CO
3 (0.98 g, 7.12 mmol) and acetonitrile (20 mL) was heated to 90℃ and stirred for 5 h. After cooling to room temperature, the mixture was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EA = 50/1 to 1/1) to give the title compound 65d (1.4 g, 86%) .
MS m/z (ESI) : 457, 459 [M+1]
Step 5. 2- ( (Benzyloxy) methyl) -6- (3, 6-dihydro-2H-pyran-4-yl) -7-methoxy-4- (2, 2, 2-trifluoroethoxy) quinazoline (65e)
A mixture of 65d (1.4 g, 3.06 mmol) , 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (835 mg, 3.98 mmol) , K
2CO
3 (844 mg, 6.12 mmol) , Pd (dppf) Cl
2 (220 mg, 0.3 mmol) , 1, 4-dioxane (16 mL) and water (4 mL) was degassed and refilled with nitrogen gas. The mixture was heated to 100℃ and stirred for 15 h. After cooling to room temperature, the mixture was diluted with EtOAc (100 mL) , washed with saturated brine (60 mL) and concentrated to dryness. The residue was purified by silica gel column chromtography (PE/EA = 100/1 to 1/1) to give the title compound 65e (1.4 g, 99%) .
MS m/z (ESI) : 461 [M+1]
Step 6. 4- (2- ( (Benzyloxy) methyl) -7-methoxy-4- (2, 2, 2-trifluoroethoxy) quinazolin-6-yl) tetrahydro-2H-pyran-4-ol (65f)
To a solution of 65e (1.4 g, 3 mmol) and phenylsilane (973 mg, 9 mmol) in isopropanol (50 mL) and dichloromethane (10 mL) was added Mn (dpm)
3 (181 mg, 0.3 mmol) . The resulting mixture was stirred for 15 h and concentrated to dryness. The residue was purified by silica gel column chromatography (PE/EtOAc = 50/1 to 1/1) to give the title compound 65f (750 mg, 52%) .
MS m/z (ESI) : 479 [M+1]
Step 7. 2- ( (Benzyloxy) methyl) -7-methoxy-6- (4-methoxytetrahydro-2H-pyran-4-yl) -4- (2, 2, 2-trifluoroethoxy) quinazoline (65g)
To a solution of 65f (750 mg, 1.57 mmol) and iodomethane (1.34 g, 9.42 mmol) in DMF at 0℃ (6 mL) was added NaH (60%in mineral oil, 125 mg, 3.13 mmol) . The resulting mixture was stirred at 0℃ for 6 h, added with water (20mL) and extracted with EtOAc (3×50 mL) . The organic phase was washed with saturated brine (60 mL) and concentrated to dryness. The residue was purified by silica gel column chromatography (PE/EtOAc = 50/1 to 1/1) to give the title compound 65g (450 mg, 58%) .
MS m/z (ESI) : 493 [M+1]
Step 8. 2- ( (Benzyloxy) methyl) -7-methoxy-6- (4-methoxytetrahydro-2H-pyran-4-yl) quinazolin-4-ol (65h)
A mixture of 65g (450 mg, 0.9 mmol) , LiOH aqueous solution (1 N, 8 mL) and THF (10 mL) was heated to 70℃ and stirred for 48 h. After cooling to room temperature, the mixture was concentrated to dryness and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/1 to 20/1) to give the title compound 65h (220 mg, 59%) .
MS m/z (ESI) : 411 [M+1]
Step 9. 2- ( (Benzyloxy) methyl) -4-chloro-7-methoxy-6- (4-methoxytetrahydro-2H-pyran-4-yl) quinazoline (65i)
To a mixture of 65h (220 mg, 0.54 mmol) , POCl
3 (3 mL) and acetonitrile (3 mL) was added DIPEA (1 mL) . The resulting mixture was heated to 60℃ and stirred for 3 h. After cooling to room temperature, the mixture was concentrated to dryness and the residue was suspended in dichloromethane (100 mL) . The mixture was washed with saturated sodium bicarbonate (2×30 mL) and water (30 mL) , dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc =50/1 to 5/1) to give the title compound 65i (120 mg, 52%) .
MS m/z (ESI) : 429 [M+1]
Step 10. (R) -2- ( (benzyloxy) methyl) -N- (1- (3- (1, 1-difluoro-2-methoxyethyl) -5-nitrophenyl) ethyl) -7-methoxy-6- (4-methoxytetrahydro-2H-pyran-4-yl) quinazolin-4-amine (65j)
A mixture of 65i (40 mg, 0.093 mmol) , 15j (24 mg, 0.093 mmol) , DIPEA (36 mg, 0.28 mmol) and DMSO (2 mL) was heated to 110℃ and stirred for 4 h. The reaction was purified by prep-HPLC to give the title compound 65j (55 mg, 91%) .
MS m/z (ESI) : 653 [M+1]
Step 11. (R) - (4- ( (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -7-methoxy-6- (4-methoxytetrahydro-2H-pyran-4-yl) quinazolin-2-yl) methanol (65)
A mixture of 65j (55 mg, 0.084 mmol) , ammonium formate (53 mg, 0.84 mmol) , and 10%Pd/C (55 mg) in MeOH (10 mL) was heated to reflux and stirred for 2h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by prep-HPLC to give the title compound 65 (22 mg, 48%) .
MS m/z (ESI) : 533 [M+1]
1H NMR (400 MHz, CD
3OD) δ 8.12 (s, 1H) , 7.16 (s, 1H) , 6.93 (s, 1H) , 6.90 (s, 1H) , 6.72 (s, 1H) , 5.64 (d, J = 7.0 Hz, 1H) , 4.52 (s, 2H) , 3.98 –3.87 (m, 5H) , 3.84 –3.70 (m, 4H) , 3.33 (s, 3H) , 3.03 (s, 3H) , 2.37 (d, J = 14.8 Hz, 2H) , 2.29 –2.20 (m, 2H) , 1.65 (d, J = 7.1 Hz, 3H) .
Compound 78 was prepared according to the procedures of Step 10 to 11 for Compound 65, except that a different compound was used instead of 15j in Step 10.
1H NMR data of Compound 78 are shown below:
Intermediate 66 was synthesized according to the procedures of Steps 3 to 9 for Compound 65, except that a different compound was used instead of 65b.
Example 35. (R) - (4- ( (1- (3- (1, 1-difluoro-2-methoxyethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-6- (4-methoxytetrahydro-2H-pyran-4-yl) quinazolin-2-yl) methanol (Compound 68)
Step 1. Methyl 4-chloro-7-methoxy-6- (4-methoxytetrahydro-2H-pyran-4-yl) quinazoline-2-carboxylate (68e)
To a solution of 68d (100 mg, 0.287 mmol) in dichloromethane (5 mL) was added POCl
3 (130 mg, 0861 mmol) . The resulting mixture was heated to 40℃ and stirred for 2 h. The mixture was added with sodium bicarbonate aqueous solution (10 mL) and extracted with EtOAc (3×10 mL) . The combined organic phase was dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc = 2/3 to 1/4) to give the title compound 68e (80 mg, 76%) .
MS m/z (ESI) : 367 [M+1]
Step 2. Methyl (R) -4- ( (1- (3- (1, 1-difluoro-2-methoxyethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-6- (4-methoxytetrahydro-2H-pyran-4-yl) quinazoline-2-carboxylate (68f)
To a solution of 68e (19 mg, 0.05 mmol) and 8i (14 mg, 0.05 mmol) in DMSO (1 mL) was added DIPEA (20 mg, 0.15 mmol) . The resulting mixture was heated to 100℃ and stirred overnight. After cooling to room temperature, the mixture was added with water (10 mL) and extracted with EtOAc (3×10 mL) . The combined organic phase was dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 49/1 to 19/1) to give the title compound 68f (18 mg, 64%) .
MS m/z (ESI) : 564 [M+1]
Step 3. (R) - (4- ( (1- (3- (1, 1-difluoro-2-methoxyethyl) -2-fluorophenyl) ethyl) amino) -7-methoxy-6- (4-methoxytetrahydro-2H-pyran-4-yl) quinazolin-2-yl) methanol (68)
To a solution of 68f (18 mg, 0.032 mmol) in methanol (2 mL) was added NaBH
4 (12 mg, 0.319 mmol) . The resulting mixture was stirred for 1 h and quenched with Na
2SO
4·10H
2O (50 mg) . The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by prep-HPLC to give the title compound (2.0 mg, 12%) .
MS m/z (ESI) : 536 [M+1]
1H NMR (400 MHz, CD
3OD) δ 8.17 (d, J = 2.9 Hz, 1H) , 7.61 (t, J = 6.7 Hz, 1H) , 7.43 (t, J = 6.3 Hz, 1H) , 7.19 (dd, J = 15.3, 4.0 Hz, 2H) , 5.94 –5.79 (m, 1H) , 4.47 (t, J = 2.9 Hz, 2H) , 4.06 –3.88 (m, 7H) , 3.83 (d, J = 7.4 Hz, 2H) , 3.38 (d, J = 2.8 Hz, 3H) , 3.05 (d, J = 3.1 Hz, 3H) , 2.38 (d, J = 14.9 Hz, 2H) , 2.30 –2.16 (m, 2H) , 1.69 (dd, J = 6.8, 2.6 Hz, 3H) .
Compound 67 was prepared according to the procedures for Compound 68, except that a different compound was used instead of 8i in Step 2.
1H NMR data of Compound 47 are shown below:
Example 36. (R) -N- (1- (4-amino-6- (1, 1-difluoro-2-methoxyethyl) pyridin-2-yl) ethyl) -7-methoxy-6- (4-methoxytetrahydro-2H-pyran-4-yl) -2-methylquinazolin-4-amine (Compound 69)
Step 1. 2, 6-Dibromo-N, N-bis (4-methoxybenzyl) pyridin-4-amine (69c)
To a solution of 2, 6-dibromopyridin-4-amine 69b (2.50 g, 10 mmol) in DMF (20 mL) at 0℃ was added NaH (60%in mineral oil, 1.2 g, 30 mmol) . After stirring for 0.5 h, the mixture was added with p-methoxybenzyl chloride (4.7 g, 30 mmol) . The resulting mixture was stirred for 2 h, quenched with ammonium chloride aqueous solution (30 mL) and extracted with EtOAc (3×30 mL) . The combined organic phase was dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc = 9/1 to 4/1) to give the title compound 69c (3.0 g, 61%) .
MS m/z (ESI) : 491, 493, 495 [M+1]
Step 2. Ethyl 2- (4- (bis (4-methoxybenzyl) amino) -6-bromopyridin-2-yl) -2, 2-difluoroacetate (69d)
To a solution of 69c (3.0 g, 6.1 mmol) and ethyl 2-bromo-2, 2-difluoroacetate (1.48 g, 7.32 mmol) in DMSO (100 mL) was added copper powder (1.98 g, 30.5 mmol) . The resulting mixture was heated to 60℃ and stirred for 18 h. After cooling to room temperature, the mixture was added with water (100 mL) and extracted with EtOAc (3×100 mL) . The combined organic phase was dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc = 19/1 to 9/1) to give the title compound 69d (2.0 g, 62%) .
MS m/z (ESI) : 535, 537 [M+1]
Step 3. 2- (4- (Bis (4-methoxybenzyl) amino) -6-bromopyridin-2-yl) -2, 2-difluoroethan-1-ol (69e)
To a solution of 69d (2.0 g, 3.7 mmol) in methanol (20 mL) was added NaBH
4 (206 mg, 18.7 mmol) . The mixture was stirred overnight and quenched with Na
2SO
4·10H
2O (50 mg) . The resulting mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (PE/EtOAc = 4/1 to 3/2) to give the title compound 69e (1.7 g, 92%) .
MS m/z (ESI) : 493, 495 [M+1]
Step 4. 2-Bromo-6- (1, 1-difluoro-2-methoxyethyl) -N, N-bis (4-methoxybenzyl) pyridin-4-amine (69f)
To a solution of 69e (1.7 g, 3.45 mmol) in DMF (10 mL) at 0℃ was added NaH (60%in mineral oil, 165 mg, 4.14 mmol) . The mixture was stirred at 0℃ for 1 h and added with iodomethane (587 mg, 4.14 mmol) . The mixture was stirred at room temperature for 2 h, quenched with water (20 mL) and extracted with EtOAc (3×30 mL) . The combined organic phase was dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc =17/3 to 4/1) to give the title compound 69f (1.5 g, 86%) .
MS m/z (ESI) : 507, 509 [M+1]
Step 5. 1- (4- (Bis (4-methoxybenzyl) amino) -6- (1, 1-difluoro-2-methoxyethyl) pyridin-2-yl) ethan-1-one (69g)
To a solution of 69f (1.5 g, 3.0 mmol) , tributyl (1-ethoxyvinyl) stannane (1.6 g, 4.4 mmol) , TEA (0.93 g, 8.9 mmol) and Pd (PPh
3)
2Cl
2 (210 mg, 0.30 mmol) in THF (10 mL) at 80℃ was stirred overnight. After cooling to room temperature, the mixture was added with hydrochloric acid (2 N, 7.4 mL) . After stirring for 2 h, the mixture was added with water (20 mL) and extracted with EtOAc (3×10 mL) . The combined organic phase was dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc = 4/1 to 7/3) to give the title compound 69g (500 mg, 36%) .
MS m/z (ESI) : 471 [M+1]
Step 6. (R) -N- ( (R) -1- (4- (bis (4-methoxybenzyl) amino) -6- (1, 1-difluoro-2-methoxyethyl) pyridin-2-yl) ethyl) -2-methylpropane-2-sulfinamide (69h)
To a solution of 69g (500 mg, 1.06 mmol) and (R) -2-methylpropane-2-sulfinamide (167 mg, 1.38 mmol) in THF (10 mL) was added Ti (OEt)
4 (485 mg, 2.13 mmol) . The mixture was heated to 80℃ and stirred overnight. After cooling to room temperature, the mixture was added with methanol (5 mL) , followed by NaBH
4 (121 mg, 3.19 mmol) . The mixture was stirred for 1 h, quenched with water (20 mL) and extracted with EtOAc (3×20 mL) . The combined organic phase was dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 49/1 to 19/1) to give the title compound 69h (250 mg, 41%) .
MS m/z (ESI) : 576 [M+1]
Step 7. (R) -2- (1-aminoethyl) -6- (1, 1-difluoro-2-methoxyethyl) pyridin-4-amine (69i)
A solution of 69h (150 mg, 0.226 mmol) in TFA (5 mL) was heated to 80℃ and stirred for 2 h. After cooling to room temperature, the mixture was concentrated to dryness and the residue was purified by prep-HPLC to give the title compound 69i (25 mg, 48%) .
MS m/z (ESI) : 232 [M+1]
Step 8. (R) -N- (1- (4-amino-6- (1, 1-difluoro-2-methoxyethyl) pyridin-2-yl) ethyl) -7-methoxy-6- (4-methoxytetrahydro-2H-pyran-4-yl) -2-methylquinazolin-4-amine (69)
To a solution of 69i (25 mg, 0.11 mmol) and 69a (42 mg, 1.3 mmol) in DMSO (2 mL) was added DIPEA (28 mg, 0.22 mmol) . The mixture was heated to 100℃ and stirred overnight. After cooling to room temperature, the mixture was purified by prep-HPLC to give the title compound 69 (6.0 mg, 11%) .
MS m/z (ESI) : 518 [M+1]
1H NMR (400 MHz, CD
3OD) δ 8.04 (s, 1H) , 7.07 (s, 1H) , 6.76 (d, J = 2.1 Hz, 1H) , 6.65 (d, J = 1.9 Hz, 1H) , 5.50 (dd, J = 13.9, 6.9 Hz, 1H) , 4.03 –3.79 (m, 9H) , 3.32 (s, 3H) , 3.06 (s, 3H) , 2.46 (s, 3H) , 2.39 –2.22 (m, 4H) , 1.61 (d, J = 7.0 Hz, 3H) .
Example 37. (R) -N- (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-chloro-6- (4-methoxytetrahydro-2H-pyran-4-yl) -2-methylquinazolin-4-amine (Compound 70)
Step 1. 7-Chloro-6- (3, 6-dihydro-2H-pyran-4-yl) -2-methyl-3, 4-dihydroquinazolin-4-yl 2, 4, 6-triisopropylbenzenesulfonate (70b)
To a solution of 70a (1 g, 3.6 mmol) , 2, 4, 6-triisopropylbenzenesulfonyl chloride (1.1 g, 3.6 mmol) and TEA (732 mg, 7.3 mmol) in dichloromethane was added DMAP (45 mg, 0.36 mmol) . The mixture was stirred for 18h and concentrated to dryness. The residue was purified by silica gel column chromatography (PE/EtOAc = 100/1 to 1/1) to give the title compound 70b (400 mg, 20%) .
MS m/z (ESI) : 543 [M+1]
Step 2. (R) -7-chloro-N- (1- (3- (1, 1-difluoro-2-methoxyethyl) -5-nitrophenyl) ethyl) -6- (3, 6-dihydro-2H-pyran-4-yl) -2-methylquinazolin-4-amine (70c)
To a solution of 70b (400 mg, 0.74 mmol) and DIPEA (191 mg, 1.5 mmol) in DMSO (2 mL) , was added 15j (192 mg, 0.74 mmol) . The mixture was heated to 90℃ and stirred for 3 h. After cooling to room temperature, the mixture was concentrated to dryness. The residue was purified by silica gel column chromatography (PE/EtOAc = 100/1 to 1/100) to give the title compound 70c (200 mg, 52%) .
MS m/z (ESI) : 519 [M+1]
Step 3 through Step 5. (R) -7-chloro-N- (1- (3- (1, 1-difluoro-2-methoxyethyl) -5- nitrophenyl) ethyl) -6- (4-methoxytetrahydro-2H-pyran-4-yl) -2-methylquinazolin-4-amine (70f)
70f was prepared according to the procedures of Step 4 to 6 for the preparation of 77 by replacing 77d with 70c.
MS m/z (ESI) : 551 [M+1]
Step 6. (R) -N- (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -7-chloro-6- (4-methoxytetrahydro-2H-pyran-4-yl) -2-methylquinazolin-4-amine (70)
To a solution of 70f (80 mg, 0.15 mmol) and ammonium chloride (24 mg, 0.44 mmol) in ethanol (10 mL) and H
2O (2 mL) was added iron dust (82 mg, 1.5 mmol) . The mixture was stirred at 70℃ for 3 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (PE/EtOAc = 100/1 to 1/100) to give the title compound (30 mg, 40%) .
MS m/z (ESI) : 521 [M+1]
1H NMR (400 MHz, CD
3OD) δ 8.18 (s, 1H) , 7.66 (s, 1H) , 6.93 (s, 1H) , 6.89 (s, 1H) , 6.73 (s, 1H) , 5.66 (dd, J = 14.0, 7.0 Hz, 1H) , 3.94 (t, J = 10.8 Hz, 2H) , 3.87 -3.81 (m, 2H) , 3.76 (t, J = 13.3 Hz, 2H) , 3.33 (s, 3H) , 3.00 (s, 3H) , 2.55 -2.49 (m, 2H) , 2.48 (s, 3H) , 2.20 -2.11 (m, 2H) , 1.65 (d, J = 7.1 Hz, 3H) .
Compound 72 was prepared according to the procedures for Compound 70, except that a different compound was used instead of 70a in Step 1.
1H NMR data of Compound 72 are shown below:
Example 38. (R) -N- (1- (6-amino-4- (1, 1-difluoro-2-methoxyethyl) pyridin-2-yl) ethyl) -7-methoxy-6- (4-methoxytetrahydro-2H-pyran-4-yl) -2-methylquinazolin-4-amine (Compound 71)
Step 1. Ethyl 2- (2, 6-dichloropyridin-4-yl) -2, 2-difluoroacetate (71b)
A mixture of 4-bromo-2, 6-dichloropyridine 71a (1.3 g, 50 mmol) , ethyl 2-bromo-2, 2-difluoroacetate (11.16 g, 55 mmol) , copper dust (9.5 g, 150 mmol) and DMSO (50 mL) was degassed and refilled with nitrogen gas. The mixture was heated to 45℃ and stirred for 5 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was diluted with water (200 mL) and then extracted with EtOAc (3×150 mL) . The combined organic phase was washed with water (150 mL) and saturated brine (150 mL) , dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc = 100/1 to 10/1) to give the title compound 71b (6.5 g, 48%) .
MS m/z (ESI) : 270 [M+1]
Step 2. 2- (2, 6-Dichloropyridin-4-yl) -2, 2-difluoroethan-1-ol (71c)
To a solution of 71b (6.5 g, 24 mmol) in ethanol (80 mL) at 0℃ was added NaBH
4 (910 mg, 24 mmol) . The resulting mixture was stirred at 0℃ for 2 h and concentrated to dryness. The residue was dissolved in a mixture of dichloromethane and methanol (100: 1, 300 mL) and washed with water (100 mL) . The organic phase was then concentrated to dryness. The residue was purified by silica gel column chromatography (PE/EtOAc = 100/1 to 3/1) to give the title compound 71c (5.2 g, 95%) .
MS m/z (ESI) : 228 [M+1]
Step 3. 2, 6-Dichloro-4- (1, 1-difluoro-2-methoxyethyl) pyridine (71d)
To a solution of 71c (5.2 g, 23 mmol) and iodomethane (16.2 g, 114 mmol) in THF (40 mL) at 0℃ was added NaH (60%in mineral oil, 1.82 g, 45.6 mmol) . The mixture was stirred at 0℃ for 0.5 h and added with DMF (40 mL) . The resulting mixture was stirred at 0℃ for another 0.5 h and then added with water (120 mL) . The mixture was extracted with EtOAc (3×150 mL) . The combined organic phase was washed with water (150 mL) and saturated brine (150 mL) , dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc = 100/1 to 10/1) to give the title compound 71d (4.2 g, 76%) .
MS m/z (ESI) : 242 [M+1]
Step 4. 6-Chloro-4- (1, 1-difluoro-2-methoxyethyl) pyridin-2-amine (71e)
A mixture of 71d (4.2 g, 7.4 mmol) and ammonium hydroxide (30%, 80 mL) was heated to 120℃ and stirred for 15 h. After cooling to room temperature, the mixture was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc = 50/1 to 1/1) to give the title compound 71e (3.2 g, 82%) .
MS m/z (ESI) : 223 [M+1]
Step 5. 6-Chloro-4- (1, 1-difluoro-2-methoxyethyl) -N, N-bis (4-methoxybenzyl) pyridin-2-amine (71f)
To a solution of 71e (1.11 g, 5 mmol) in DMF (10 mL) at 0℃ was added NaH (60%in mineral oil, 500 mg, 12.5 mmol) . The resulting mixture was stirred at 0℃ for 1h and added with 1- (chloromethyl) -4-methoxybenzene (1.72 g, 11 mmol) . The resulting mixture was stirred at 0℃ for another 1 h, added with water (30 mL) and extracted with EtOAc (3×50 mL) . The combined organic phase was washed with water (150 mL) and saturated brine (150 mL) , dried over anhydrous and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc = 100/1 to 10/1) to give the title compound 71f (1.8 g, 78%) .
MS m/z (ESI) : 463 [M+1]
Step 6. 1- (6- (Bis (4-methoxybenzyl) amino) -4- (1, 1-difluoro-2-methoxyethyl) pyridin-2-yl) ethan-1-one (71g)
A mixture of 71f (1.8 g, 3.9 mmol) , 1-ethoxyvinyltri-n-butyltin (2.1 g, 5.9 mmol) , TEA (1.18 g, 11.7 mmol) , Pd (PPh
3)
2Cl
2 (273 mg, 0.39 mmol) and 1, 4-dioxane (50 mL) was degassed and refilled with nitrogen gas. The mixture heated to 105℃ and stirred for 15 h under nitrogen atmosphere. After cooling to 0℃, the mixture was added with hydrochloric acid (5 M, 30 mL) and stirred at 0℃ for 0.5 h. The mixture was then extracted with EtOAc (2×100 mL) . The combined organic phase was washed with water (80 mL) and saturated brine (80 mL) , dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc = 50/1 to 5/1) to give the title compound 71g (1.5 g, 82%) .
MS m/z (ESI) : 471 [M+1]
Step 7. (R, Z) -N- (1- (6- (bis (4-methoxybenzyl) amino) -4- (1, 1-difluoro-2-methoxyethyl) pyridin-2-yl) ethylidene) -2-methylpropane-2-sulfinamide (71h)
A solution of 1- (6- (bis (4-methoxybenzyl) amino) -4- (1, 1-difluoro-2-methoxyethyl) pyridin-2-yl) ethan-1-one (1 g, 2.1 mmol) , Ti (OEt)
4 (2.87 g, 12.6 mmol) and (R) -2-methylpropane-2-sulfinamide (1.28 g, 10.6 mmol) in THF (30 mL) was heated to 125℃ and stirred for 3 h. After cooling to 0℃, the mixture was added with saturated sodium bicarbonate aqueous solution (100 mL) and extracted with EtOAc (2×100 mL) . The combined organic phase was washed with saturated brine (80 mL) , dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc = 100/1 to 5/1) to give the title compound 71h (220 mg, 18%) .
MS m/z (ESI) : 574 [M+1]
Step 8. (R) -N- ( (R) -1- (6- (bis (4-methoxybenzyl) amino) -4- (1, 1-difluoro-2-methoxyethyl) pyridin-2-yl) ethyl) -2-methylpropane-2-sulfinamide (71i)
To a solution of 71h (220 mg, 0.38 mmol) in THF (16 mL) and methanol (4 mL) was added NaBH
4 (14 mg, 0.38 mmol) and the resulting mixture was stirred at 0℃ for 1 h. The mixture was concentrated to dryness and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/1 to 20/1) to give the title compound 71i (150 mg, impure, 41%) .
MS m/z (ESI) : 576 [M+1]
Step 9. (R) -6- (1-aminoethyl) -4- (1, 1-difluoro-2-methoxyethyl) pyridin-2-amine (71j)
To a solution of 71i (150 mg, 0.26 mmol) in dichloromethane (2 mL) was added TFA (10 mL) . The resulting solution was heated to 60℃ and stirred for 7h. After cooling to room temperature, the mixture was concentrated to dryness and the residue was purified by pre- HPLC to give the title compound 71j (20 mg, 33%) .
MS m/z (ESI) : 232 [M+1]
Step 10. (R) -N- (1- (6-amino-4- (1, 1-difluoro-2-methoxyethyl) pyridin-2-yl) ethyl) -7-methoxy-6- (4-methoxytetrahydro-2H-pyran-4-yl) -2-methylquinazolin-4-amine (71)
A mixture of 69a (36 mg, 0.11 mmol) , 71j (20 mg, 0.086 mmol) , DIPEA (33 mg, 0.26 mmol) and DMSO (1.5 mL) was heated to 110℃ and stirred for 4h. After cooling to room temperature, the mixture was purified by prep-HPLC to give the title compound 71 (18.7 mg, 33%) .
MS m/z (ESI) : 518 [M+1]
1H NMR (400 MHz, CD
3OD) δ 8.08 (s, 1H) , 7.08 (s, 1H) , 6.75 (d, J = 1.0 Hz, 1H) , 6.56 (s, 1H) , 5.50 (q, J = 7.0 Hz, 1H) , 3.99 –3.87 (m, 5H) , 3.82 (dd, J = 10.2, 5.2 Hz, 2H) , 3.75 (t, J = 13.0 Hz, 2H) , 3.30 (s, 3H) , 3.06 (s, 3H) , 2.44 (s, 3H) , 2.31 (dt, J = 11.2, 9.4 Hz, 4H) , 1.62 (d, J = 7.0 Hz, 3H) .
Example 39. (R) -4- ( (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -6- (4-methoxytetrahydro-2H-pyran-4-yl) -2-methylquinazoline-8-carbonitrile (Compound 75)
Step 1. 2-Amino-3-chlorobenzoic acid (75b)
To a solution of 2-amino-3-chlorobenzoic acid 75a (10 g, 58 mmol) in dichloromethane (100 mL) was added NBS (10 g, 57 mmol) . The solution was stirred at room temperature for 8 hours and filtered. The filter cake was washed with dichloromethane and dried to give the title compound 75b (12 g, 82%) .
MS m/z (ESI) : 250, 252 [M+1]
Step 2. Methyl 2-amino-5-bromo-3-chlorobenzoate (75c)
To a solution of 75b (14 g, 56 mmol) in methanol (100 mL) was added H
2SO
4 (10 mL) . The resulting solution was heated to 100℃ and stirred for 48 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with water (200 mL) and adjusted to pH = 10 with saturated sodium bicarbonate aqueous solution. The resulting solution was extracted with ethyl acetate (200 mL) . The combined organic phase was washed with saturated brine (100 mL) , dried over aqueous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure to give the title compound 75c (10 g, 66%) .
MS m/z (ESI) : 264, 266, 268 [M+1]
Step 3. 6-Bromo-8-chloro-2-methylquinazolin-4-ol (75d)
To a solution of 75c (12 g, 48 mmol) in acetonitrile (120 mL) was added a solution of HCl in 1, 4-dioxane (2M, 30 mL) . The resulting mixture was heated to 100℃ and stirred for 72 hours. After cooling to room temperature, the mixture was filtered and the filter cake was washed with acetonitrile (50mL) and dried to give the title compound 75d (14 g, 93%) .
MS m/z (ESI) : 273, 275, 277 [M+1]
Step 4. 6-Bromo-4, 8-dichloro-2-methylquinazoline (75e)
To a solution of 75d (4g, 14.4 mmol) in POCl
3 (120 mL) was added DIPEA until all solid was fully dissolved. The resulting solution was heated to 90℃ and stirred for 3 hours. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure. The residue was diluted with ethyl acetate (100 mL) and washed with saturated sodium bicarbonate aqueous solution (200 mL) and saturated brine (100 mL) in sequence. The organic phase was concentrated to dryness and the residue was purified with silica gel column chromatography (PE/EtOAc =100/0 to 3/2) to give the title compound 75e (1.7 g, 40%) .
MS m/z (ESI) : 291, 293 [M+1]
Step 5. 4- (4, 8-Dichloro-2-methylquinazolin-6-yl) oxan-4-ol (75f)
To a solution of 75e (1 g, 3.5 mmol) in THF (15 mL) at -78℃ was added n-BuLi (2.5 M in hexane, 1.4 mL, 3.5 mmol) . The solution was warmed to -40℃ and stirred for 0.6 h. The mixture was cooled to -78℃ again and added with oxan-4-one (580 mg, 5.6 mmol) . The solution was slowly warmed to room temperature and stirred for 12 h. The solution was quenched with acetic acid (0.7 mL) and concentrated to dryness under reduced pressure. The residue was purified with by silica gel column chromatography (PE/EtOAc = 100/0 to 3/7) to give the title compound 75f (460 mg, 42%) .
MS m/z (ESI) : 313, 315 [M+1]
Step 6. (R) -4- (4- ( (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -8-chloro-2-methylquinazolin-6-yl) tetrahydro-2H-pyran-4-ol (75g)
To a solution of 15k (200 mg, 0.83 mmol) and 75f (250 mg, 0.83 mmol) in DMSO (5 mL) and DMF (5 mL) was added DIPEA (226 mg, 1.66 mmol) . The resulting solution was stirred at 90℃ for 12 h. The solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL) . The organic phase was washed with saturated brine (30 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure and the residue was purified with silica gel column chromatography (PE/EtOAc = 100/0-3/7) to give the title compound 75g (170 mg, 40%) .
MS m/z (ESI) : 507, 509 [M+1]
Step 7. (R) -N- (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -8-chloro-6- (4-fluorotetrahydro-2H-pyran-4-yl) -2-methylquinazolin-4-amine (75h)
To a solution of 75g (180 mg, 0.36 mmol) in dichloromethane (5 mL) at 0℃ was added DAST (116 mg, 0.72 mmol) . The solution was stirred at 0℃ for 10 min. The solution was quenched with saturated sodium bicarbonate aqueous solution (3 mL) , diluted with dichloromethane (20 mL) and washed with saturated brine (30 mL) . The separated organic phase was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (PE/EtOAc = 100/0 to 3/7) to give the title compound 75h (150 mg, 88%) .
MS m/z (ESI) : 509, 511 [M+1]
Step 8. (R) -N- (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -8-chloro-6- (4-methoxytetrahydro-2H-pyran-4-yl) -2-methylquinazolin-4-amine (75i)
To a solution of 75h (170 mg, 0.33 mmol) in methanol (3 mL) was added a solution of sodium methoxide in methanol (30%wt, 0.3 mL) . The resulting mixture was heated to 90℃ and stirred for 12 h. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure. The residue was purified with silica gel column chromatography (PE/EtOAc = 100/0 to 3/7) to give the title compound 75i (27 mg, 54%) .
MS m/z (ESI) : 521, 523 [M+1]
Step 9. (R) -4- ( (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) amino) -6- (4-methoxytetrahydro-2H-pyran-4-yl) -2-methylquinazoline-8-carbonitrile (75)
To a mixture of 75i (150 mg, 0.29 mmol) , Zn (CN)
2 (20 mg, 0.17 mmol) , Pd (dppf) Cl
2 (20 mg, 0.029 mmol) and DMA (5 mL) was added zinc dust (20 mg, 0.29 mmol) . The resulting mixture was degassed with N
2, heated to 130℃ and stirred for 12 h. After cooling to room temperature, the mixture was purified with prep-HPLC to give the title compound 75i (30 mg, 20%) .
MS m/z (ESI) : 512 [M+1]
1H NMR (400 MHz, DMSO-d
6) δ 8.81 (d, J = 7.9 Hz, 1H) , 8.64 (d, J = 1.8 Hz, 1H) , 8.22 (d, J = 1.8 Hz, 1H) , 6.74 (d, J = 14.4 Hz, 2H) , 6.58 (s, 1H) , 5.67 –5.55 (m, 1H) , 5.33 (s, 2H) , 3.85 –3.64 (m, 6H) , 3.29 (s, 3H) , 2.92 (s, 3H) , 2.47 (s, 3H) , 2.13 –1.96 (m, 4H) , 1.57 (d, J =7.0 Hz, 3H) .
Compound 73 was synthesized according to the procedures of Steps for Compound 75, except that a different compound was used instead of 75i.
Compound 74 was synthesized according to the procedures of Steps 1 to 8 for Compound 75, except that a different compound was used instead of 75a.
1H NMR data of Compounds 73 and 74 are shown below:
Example 40. N- ( (R) -1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -2- (difluoromethyl) -7-methoxy-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine (Compound 76)
Step 1. 2- (2, 2-Difluoroacetamido) -4, 5-dimethoxybenzamide
To a solution of 2-amino-4, 5-dimethoxybenzamide 76a (2.80 g, 14.3 mmol) in DMF (14 mL) were added 2, 2-difluoroacetic acid (2.74 g, 28.5 mmol) , TEA (4.33 g, 42.8 mmol) and HATU (6.51 g, 17.1 mmol) in sequence. The mixture was stirred for 1 h, diluted with water (100 mL) and extracted with EtOAc (3×100 mL) . The combined organic phase was washed with water (2×100 mL) and saturated brine (100 mL) and dried over anhydrous sodium sulphate. The mixture was filtered and the filtrated was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (CH
2Cl
2/EtOAc = 100/0 to 0/100) to give the title compound 76b (2.80 g, 72%) .
MS m/z (ESI) : 275 [M+1]
Step 2. 2- (Difluoromethyl) -6, 7-dimethoxyquinazolin-4 (3H) -one (76c)
To a solution of 76b (2.80 g, 10.2 mmol) in methanol (40 mL) was added sodium methoxide solution (5.51 g, 30%in methanol, 30.6 mmol) . The mixture was stirred for 17 h and concentrated to dryness. The residue was purified by silica gel column chromatography (CH
2Cl
2/methanol = 100/0 to 9/1) to give the title compound 76c (2.26 g, 86%) .
MS m/z (ESI) : 257 [M+1]
Step 3. 2- (Difluoromethyl) -6-hydroxy-7-methoxyquinazolin-4 (3H) -one (76d)
To a solution of 76c (1.60 g, 6.24 mmol) in CH
3SO
3H (12.5 mL) was added DL-methionine (1.86 g, 12.5 mmol) . The mixture was heated to 80℃, stirred for 46 h and then cooled to room temperature. The above operation was repeated and both batches were combined. The mixture was added with additional DL-methionine (730 mg) and stirred at 80℃ for another 24 h. After cooling to room temperature, the mixture was diluted with cold water (60 mL) , cooled with an ice/water bath and neutralized with solid NaOH to pH = 6-7. The resulting mixture was extracted with EtOAc (5×100 mL) and the combined organic phase was dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (CH
2Cl
2/EtOAc = 100/0 to 0/100 then CH
2Cl
2/methanol (with 10%NH
4OH) = 100/0 to 9/1) to give the title compound 76d (1.74 g, 73%) .
MS m/z (ESI) : 243 [M+1]
Step 4. (S) -2- (difluoromethyl) -7-methoxy-6- ( (tetrahydrofuran-3-yl) oxy) quinazolin-4 (3H) -one (76e)
To a solution of 76d (1.74 g, 7.18 mmol) in DMF (17 mL) were added 3e (1.74 g, 7.18 mmol) and Cs
2CO
3 (3.51 g, 10.77 mmol) . The resulting mixture was heated to 80℃ and stirred for 18 h. After cooling to room temperature, the mixture was concentrated to dryness and the residue was purified by silica gel column chromatography (CH
2Cl
2/methanol = 100/0 to 9/1) to give the title compound 76e (480 mg, 21%) .
MS m/z (ESI) : 313 [M+1]
Step 5. (S) -2- (difluoromethyl) -7-methoxy-6- ( (tetrahydrofuran-3-yl) oxy) quinazolin-4-yl 2, 4, 6-triisopropylbenzenesulfonate (76f)
To a solution of 76e (480 mg, 1.54 mmol) in dichloromethane (10 mL) were added 2, 4, 6- triisopropylbenzenesulfonyl chloride (559 mg, 1.84 mmol) , DIPEA (597 mg, 4.62 mmol) and DMAP (38 mg, 0.31 mmol) . The mixture was stirred for 1 h and concentrated to dryness. The residue was purified by silica gel column chromatography (PE/EtOAc = 100/0 to 7/3) to give the title compound 76f (665 mg, 76%) .
MS m/z (ESI) : 579 [M+1]
Step 6. N- ( (R) -1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -2- (difluoromethyl) -7-methoxy-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine (76)
To a solution of 76f (285 mg, 0.5 mmol) in DMSO (5 mL) were added 15k (115 mg, 0.5 mmo) and DIPEA (194 mg, 1.5 mmol) . The resulting mixture was stirred at 80℃ for 16 h, cooled to room temperature and concentrated to dryness. The residue was purified by prep-HPLC to give the title compound 76 (49.2 mg, 19%) .
MS m/z (ESI) : 525 [M+1]
1H NMR (400 MHz, DMSO-d
6) δ 8.35 (d, J = 8.1 Hz, 1H) , 7.79 (s, 1H) , 7.24 (s, 1H) , 6.77 (s, 1H) , 6.75 –6.45 (m, 3H) , 5.60 (p, J = 6.9 Hz, 1H) , 5.32 (s, 2H) , 5.22 (s, 1H) , 4.00 (dd, J = 10.2, 4.5 Hz, 1H) , 3.92 (s, 3H) , 3.90 –3.71 (m, 5H) , 3.29 (s, 3H) , 2.34 (td, J = 14.3, 8.1 Hz, 1H) , 2.03 (dd, J = 12.8, 5.9 Hz, 1H) , 1.58 (d, J = 7.0 Hz, 3H) .
Intermediate 77a was synthesized according to the procedures of Steps 1 to 2 for Compound 76, except that a different compound was used instead of 76a.
Example 41. (R) -N- (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -2- (difluoromethyl) -7-methoxy-6- (4-methoxytetrahydro-2H-pyran-4-yl) quinazolin-4-amine (Compound 77)
Step 1. 6-Bromo-4-chloro-2- (difluoromethyl) -7-methoxyquinazoline (77b)
To a solution of 6-bromo-2- (difluoromethyl) -7-methoxyquinazolin-4 (3H) -one 77a (3.30 g, 10.8 mmol) in POCl
3 (48 mL) was added with three drops of DMF. The resulting mixture was heated to 100℃ and stirred for 1 h. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure. The residue was redissolved in dichloromethane (200 mL) and added slowly with saturated sodium bicarbonate solution (200 mL) while stirring. The organic layer was separated, dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (dichloromethane/EtOAc = 100/0 to 4/1) to give the title compound 77b (3.20 g, 91%) .
Step 2. (R) -6-bromo-N- (1- (3- (1, 1-difluoro-2-methoxyethyl) -5-nitrophenyl) ethyl) -2- (difluoromethyl) -7-methoxyquinazolin-4-amine (77c)
To a solution of 77b (704 mg, 2.18 mmol) dissolved in DMSO (5 mL) were added 15j (566 mg, 2.18 mmo) and DIPEA (845 mg, 6.54 mmol) . The mixture was heated to 80℃, stirred for 1 h and cooled to room temperature. The above operation was repeated twice and all three batches of reaction mixture were combined. The mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL) . The combined organic phase was washed with water (2×50 mL) , dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc = 100/0 to 3/2) to give the title compound 77c (1.15 g, 82%) .
MS m/z (ESI) : 547 [M+1]
Step 3. (R) -N- (1- (3- (1, 1-difluoro-2-methoxyethyl) -5-nitrophenyl) ethyl) -2- (difluoromethyl) -6- (3, 6-dihydro-2H-pyran-4-yl) -7-methoxyquinazolin-4-amine (77d)
To a solution of 77c (1.15 g, 2.10 mmol) in 1, 4-dioxane (40 mL) were added water (2 mL) , 2- (3, 6-dihydro-2H-pyran-4-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (883 mg, 4.20 mmol) , K
2CO
3 (1.16 g, 8.40 mmol) and Pd (dppf) Cl
2 (154 mg, 0.21 mmol) . The resulting mixture was heated to 100℃ and stirred for 2 h. After cooling to room temperature, the mixture was dried over anhydrous sodium sulphate and filtered through a pad of celite. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (PE/EtOAc = 100/0 to 2/3) to give the title compound 77d (993 mg, 86%) .
MS m/z (ESI) : 551 [M+1]
Step 4. (R) -4- (4- ( (1- (3- (1, 1-difluoro-2-methoxyethyl) -5-nitrophenyl) ethyl) amino) -2- (difluoromethyl) -7-methoxyquinazolin-6-yl) tetrahydro-2H-pyran-4-ol (77e)
To a solution of 77d (898 mg, 1.63 mmol) in isopropanol/dichloromethane (40 mL/8 mL) were added PhSiH
3 (530 mg, 4.89 mmol) and Mn (dpm)
3 (197 mg, 0.33 mmol) . The resulting mixture was stirred for 20 h and concentrated to dryness. The residue was purified by silica gel column chromatography (CH
2Cl
2/EtOAc = 100/0 to 0/100) to give the title compound 77e (411 mg, 44%) .
MS m/z (ESI) : 569 [M+1]
Step 5. (R) -N- (1- (3- (1, 1-difluoro-2-methoxyethyl) -5-nitrophenyl) ethyl) -2- (difluoromethyl) -6- (4-fluorotetrahydro-2H-pyran-4-yl) -7-methoxyquinazolin-4-amine (77f)
To a solution of 77e (411 mg, 0.72 mmol) in dichloromethane (6 mL) at 0℃ was added a solution of DAST (291 mg, 1.81 mmol) in dichloromethane (4 mL) dropwise. The mixture was stirred at 0℃ for 1 h, added with saturated sodium bicarbonate aqueous solution (20 mL) and extracted with dichloromethane (3×20 mL) . The combined organic phase was washed with saturated brine (20 mL) , dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (CH
2Cl
2/EtOAc = 100/0 to 3/2) to give the title compound 77f (338 mg, 82%) .
MS m/z (ESI) : 571 [M+1]
Step 6. (R) -N- (1- (3- (1, 1-difluoro-2-methoxyethyl) -5-nitrophenyl) ethyl) -2- (difluoromethyl) -7-methoxy-6- (4-methoxytetrahydro-2H-pyran-4-yl) quinazolin-4-amine (77g)
To a solution of 77f (338 mg, 0.59 mmol) in methanol (6 mL) was added a solution of sodium methoxide (320 mg, 30%in methanol, 1.78 mmol) . The resulting mixture was heated to 70℃ and stirred for 40 h. After cooling to room temperature, the mixture was added with a saturated ammonium chloride aqueous solution (20 mL) and extracted with EtOAc (3×20 mL) . The combined organic phase was dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness and the residue was purified by silica gel column chromatography (dichloromethane/methanol = 100/0 to 9/1) to give the title compound 77g (100 mg, 29%) .
MS m/z (ESI) : 583 [M+1]
Step 7. (R) -N- (1- (3-amino-5- (1, 1-difluoro-2-methoxyethyl) phenyl) ethyl) -2- (difluoromethyl) -7-methoxy-6- (4-methoxytetrahydro-2H-pyran-4-yl) quinazolin-4-amine (77)
To solution of 77g (100 mg, 0.17 mmol) in methanol (5 mL) was added 5%Pt/C (100 mg) . The resulting mixture was stirred under hydrogen atmosphere for 30 min and filtered. The filtrate was concentrated to dryness and the residue was purified by prep-HPLC to give the title compound 77 (19.2 mg, 20%) .
MS m/z (ESI) : 553 [M+1]
1H NMR (400 MHz, CD
3OD) δ 8.17 (s, 1H) , 7.25 (s, 1H) , 6.95 (s, 1H) , 6.91 (s, 1H) , 6.73 (s, 1H) , 6.45 (t, J = 55.1 Hz, 1H) , 5.67 (q, J = 7.0 Hz, 1H) , 3.96 (s, 3H) , 3.92 (t, J = 10.8 Hz, 2H) , 3.82 (d, J = 6.9 Hz, 2H) , 3.75 (t, J = 13.3 Hz, 2H) , 3.33 (s, 3H) , 3.04 (s, 3H) , 2.36 (d, J =14.0 Hz, 2H) , 2.30 –2.20 (m, 2H) , 1.66 (d, J = 7.0 Hz, 3H) .
Example 42. N- ( (R) -1- (5-amino-3- (1, 1-difluoro-2-methoxyethyl) -2-methylphenyl) ethyl) -7-methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine (Compound 79)
Step 1. 1-Bromo-3- (1, 1-difluoro-2-methoxyethyl) -2-methyl-5-nitrobenzene (79a)
To a solution of 78c (3.1 g, 12 mmol) in concentrated sulfuric acid (5 mL) at 0℃ was added nitric acid (1.48 g, 23 mmol) . The mixture was stirred at 0℃ for 1 h and added to ice water (100 mL) . The resulting mixture was extracted with EtOAc (3×20 mL) . The combined organic phase was dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated to dryness to give the title compound 79a (2 g, 55%) .
Step 2 to Step 5. (R) -1- (3- (1, 1-difluoro-2-methoxyethyl) -2-methyl-5-nitrophenyl) ethan-1-amine hydrochloride (79e)
79e was synthesized according to the procedures of Step 6 to Step 9 for Intermediate 15k, except that in Step 6, 79a was used instead of 15f.
MS m/z (ESI) : 275 [M+1]
Step 6 to Step 7. N- ( (R) -1- (5-amino-3- (1, 1-difluoro-2-methoxyethyl) -2-methylphenyl) ethyl) -7-methoxy-2-methyl-6- ( ( (S) -tetrahydrofuran-3-yl) oxy) quinazolin-4-amine (79)
79 was synthesized according to the procedures of Step 10 to Step 11 for Compound 65, except that in Step 10, 79e was used instead of 15j and 3g was used instead of 65i, respectively.
MS m/z (ESI) : 503 [M+1]
1H NMR (400 MHz, CD
3OD) δ 7.71 (s, 1H) , 7.03 (s, 1H) , 6.94 (d, J = 2.3 Hz, 1H) , 6.82 (d, J = 2.4 Hz, 1H) , 5.77 (dd, J = 13.8, 6.9 Hz, 1H) , 5.21 -5.17 (m, 1H) , 4.05 -3.99 (m, 3H) , 3.99 -3.82 (m, 7H) , 3.40 (s, 3H) , 2.47 -2.41 (m, 5H) , 2.31 -2.27 (m, 1H) , 2.22 -2.18 (m, 1H) , 1.59 (d, J = 6.9 Hz, 3H) .
Biological experiments
Example 43. KRAS
G12C /SOS1 binding assay
Interference of the compound of the present invention on the interaction between SOS1 and KRAS
G12C was assessed via detecting the binding affinity between two proteins using a biochemical method in the HTRF assay format (Table 1) .
The experimental method is generally described as below:
An assay buffer contained the following components: 25 mM HEPES, 10 mM MgCl
2, 5 mM EDTA, 1 mM DTT, 0.01%BSA, 0.01%Triton X-100 and 0.04%Brij35. A KRAS
G12C protein solution contained 20 nM human recombinant GDP-bound KRAS
G12C protein with a His-tag (produced by Tsinghua University’s protein purification facility) in the assay buffer. A detection solution contained 20 nM human recombinant SOS1 protein with a GST-tag (produced by Tsinghua University’s protein purification facility) , 90 ng/mL Eu
3+-labeled anti-His antibody (Cisbio, Cat. No. 61HI2KLA) and 1.2 μg/mL d2-labeled anti-GST antibody (Cisbio, Cat. No. 61GSTDLF) in the assay buffer.
The test compound was dissolved to 400 or 1000 μM in DMSO, followed by a serial 4-fold dilution with DMSO to a minimum concentration of 24 or 61 nM. Each concentration was further diluted 50 folds with the assay buffer.
To a 384-well assay plate (Corning, Cat. No. 4512) were added 5 μL of compound solution and 5 μL of KRAS
G12C protein solution, and the mixture was incubated at room temperature for 30 min. The mixture was then added with an equal volume of 10 μL detection solution and allowed to stand at room temperature for 40 min. The absorbances of the mixture at 620 nm and 665 nm were measured using an Envision plate reader (Perkin Elmer) and the ratio of two was positively correlated with the binding affinity between KRAS
G12C and SOS1. In the experiment, a group with 10 μM BI-3406 was treated as 100%inhibition group, and a group without the test compound was treated as 0%inhibition group. The inhibition curve was plotted and the corresponding IC
50 value of the test compound was calculated using XLfit software (ID Business Solutions Ltd., UK) .
Example 44. Antiproliferative cell assays
Inhibition of the compound of the present invention on K562 and MIA-PaCa-2 cell proliferations was assessed using a Cell Titer-Glo kit (Table 1) .
The experimental method is generally described as below:
The test compound was dissolved to 2.5, 5 mM or 10 mM in DMSO, followed by a serial 4-fold dilution with DMSO to a minimum concentration of 155, 310 or 620 nM. Each concentration was further diluted 50 folds with the respective cell culture medium for each cell line.
K562 (Cobioer, Cat. No. CBP60529, a human myelogenous leukemia cell line with a wild type of KRAS) and MIA-PaCa-2 (Cobioer, Cat. No. CBP60544, a human pancreatic cancer cell line with a KRAS G12C mutation) were grown in RPMI 1640 medium (Gibco, Cat. No. 72400047) and DMEM medium (Gibco, Cat. No. 11995065) , respectively. All cell culture media were supplemented with 10%FBS (GBICO, Cat. No 10099-141) and 1%penicillin-streptomycin (Gibco, Cat. No. 15070063) . K562 and MIA-PaCa-2 cells were seeded in a 384-well and a 96-well cell culture plate at a density of 400 cells/well, respectively, and the plates were incubated overnight at 37℃/5%CO
2 in a humidity-controlled incubator. 3 μL (for well with K562 cells) or 10 μL (for well with MIA-PaCa-2 cells) of the test compound solution was added to each well and mixed gently, and the plates were continuously incubated at 37℃/5%CO
2 for 4-5 days. Cell proliferation was then assessed using a Cell Titer-Glo kit (Promega, Cat. No G7572 for K562 cells and G9683) by adding 15 μL (for well with K562 cells) or 50 μL (for well with MIA-PaCa-2 cells) of CTG reagent into each well, shaking for 20 min, and then settling for 10 min at room temperature. The luminescence signals were measured by an Envision plate reader (Perkin Elmer) . In this experiment, the group with 10 μM BI-3406 was treated as 100%inhibition group, and the group with 0.02%DMSO but without the test compound was treated as 0%inhibition group. The inhibition curve was plotted and the corresponding IC
50 value of the test compound was calculated using XLfit software (ID Business Solutions Ltd., UK) .
Table 1
Claims (16)
- A compound of Formula (I) , or a pharmaceutically acceptable salt thereof, or a stable isotope thereof, or a stereoisomer thereof,wherein:A is CR 3 or N;X 1 and X 2 are independently CH or N;X 3 is CR 6 or N;R 1 is C 1-6 alkyl or H, where one or more hydrogens of the alkyl are optionally substituted by D, halogen, -OR 4b or -NR 4bR 4c;R 2 is H, cyano, halogen, -OR 4b, C 1-6 alkyl, C 3-8 cycloalkyl or 4-10 membered heterocyclyl, where one or more hydrogens of the alkyl, cycloalkyl and heterocyclyl are optionally substituted by D, halogen, -OR 4b or -NR 4bR 4c;R 3 is -OR 4b, H, halogen, cyano, -NR 4bR 4c, C 1-6 alkyl, C 3-8 cycloalkyl or 4-10 membered heterocyclyl, where one or more hydrogens of the alkyl, cycloalkyl and heterocyclyl are optionally substituted by D, halogen, -OR 4b or -NR 4bR 4c;R 4 is 4-10 membered heterocyclyl, halogen, cyano, -OR 4a, -NR 4bR 4c, -COOR 4b, -C (O) R 4b, -C (O) NR 4bR 4c, -NR 4bC (O) R 4c, -NR 4bS (O) 2R 4c, -S (O) 2NR 4bR 4c, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-12 aryl or 5-12 membered heteroaryl, where one or more hydrogens of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by R 4’;R 5 is NH 2 or H;R 6 is H, halogen or C 1-6 alkyl;R 7 is C 1-6 alkyl, C 3-8 cycloalkyl or 4-10 membered heterocyclyl, where one or more hydrogens of the alkyl, cycloalkyl and heterocyclyl are optionally substituted by D or halogen;L is C 1-6 alkylene, where one or more hydrogens of the alkylene are optionally substituted by D or halogen;R 4a is C 1-6 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, where one or more hydrogens of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by C 1-6 alkyl, fluorinated C 1-6 alkyl, C 3-8 cycloalkyl, -C (O) C 1-6 alkyl, -C (O) C 3-8 cycloalkyl or 4-10 membered heterocyclyl;R 4’ is -OR 4b, halogen, oxo, -NR 4bR 4c, -COOR 4b, -C (O) R 4b, -C (O) NR 4bR 4c, -NR 4bC (O) R 4c, C 1-6 alkyl or C 3-8 cycloalkyl, where one or more hydrogens of the alkyl are optionally substituted by D, halogen, -OR 4b or -NR 4bR 4c; andR 4b and R 4c are independently selected from C 1-6 alkyl, H, C 3-8 cycloalkyl or 4-10 membered heterocyclyl, where one or more hydrogens of the alkyl, cycloalkyl and heterocyclyl are optionally substituted by D, halogen, and C 1-6 alkyl.
- The compound of Claim 2, where R 1 is -CH 3, -CHF 2, - (CH 2) 1-2OH, or – (CH 2) 1-2OCH 3, preferably -CH 3.
- The compound of Claim 2 or 3, where R 2 is H, halogen, cyano, -CH 3, -OCH 3, -CH 2OH, or -CH 2OCH 3, preferably H or -CH 3.
- The compound of Claim 2, 3, or 4, where R 3 is -OCH 3, halogen, cyano, -CH 3, or H.
- The compound of Claim 2, 3, 4, or 5 where R 4 is -OR 4a; and R 4a is C 1-6 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, where one or more hydrogens of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by C 1-6 alkyl, fluorinated C 1-6 alkyl, C 3-8 cycloalkyl, -C (O) C 1-6 alkyl, -C (O) C 3-8 cycloalkyl, or 4-10 membered heterocyclyl.
- The compound of Claim 6, wherein R 4 is C 3-8 cycloalkyl or 4-10 membered heterocyclyl, where one or more hydrogens of the cycloalkyl and heterocyclyl are optionally substituted by D, halogen, oxo, -OH, -COOH, -OC 1-2 alkyl, -C (O) C 1-2 alkyl, -C (O) C 3-6 cycloalkyl, or -C (O) C 4-6 heterocyclyl.
- The compound of Claim 6, wherein R 4 is C 6-12 aryl or 5-12 membered heteroaryl, where one or more hydrogens of the aryl and heteroaryl are optionally substituted by C 1-2 alkyl.
- A pharmaceutical composition comprising the compound of any one of Claims 1-14 and a pharmaceutically acceptable carrier or excipient thereof.
- A method for preventing or treating cancers mediated by SOS1, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of any one of claims 1-14.
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