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WO2024051763A1 - Dérivé hétérocyclique de quinazoline d'inhibiteur de mutation kras pour le traitement du cancer - Google Patents

Dérivé hétérocyclique de quinazoline d'inhibiteur de mutation kras pour le traitement du cancer Download PDF

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WO2024051763A1
WO2024051763A1 PCT/CN2023/117379 CN2023117379W WO2024051763A1 WO 2024051763 A1 WO2024051763 A1 WO 2024051763A1 CN 2023117379 W CN2023117379 W CN 2023117379W WO 2024051763 A1 WO2024051763 A1 WO 2024051763A1
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methoxy
methyl
fluoro
ethynyl
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朱程刚
高凯
张朝春
杨铉
包丽茗
李诗语
徐良亮
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Shenzhen Forward Pharmaceuticals Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • 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
    • C07D403/12—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention provides a class of inhibitors with a quinazoline heterocyclic structure targeting KRAS mutations.
  • the present invention relates to the structure and chemical synthesis method of quinazoline heterocyclic derivatives.
  • the quinazoline heterocyclic derivatives are mainly used as small molecule inhibitors of KRAS mutations for the treatment of various diseases caused by mutations, including cancer, such as pancreatic cancer. , colorectal cancer, and lung cancer.
  • Kirsten rat sarcoma viral oncogene homolog (Kristen rat sarcoma viral oncogene homolog, KRAS) is a membrane-bound protein located on the inner side of the cell membrane. Its function is similar to the molecular switch of GTPase, by binding to guanosine diphosphate (GDP).
  • GDP guanosine diphosphate
  • guanosine triphosphate respectively inactivate or activate the KRAS protein, thereby regulating the signaling pathways inside the cell and participating in the normal life activities of the cell; when KRAS mutations lead to abnormalities in the encoded protein, the mutant protein will activate The downstream RAF-MEK-ERK, PI3K-AKT-mTOR and RAL-NF-Kb signaling pathways overactivate cell proliferation, differentiation, survival, etc., which in turn leads to the occurrence and spread of tumors.
  • GTP guanosine triphosphate
  • KRAS As a member of the Ras oncogene family, compared with NRAS and HRAS, oncogenic mutations in KRAS account for 85% of the entire Ras oncogenic mutations, and KRAS mutations are present in approximately 22% of cancer patients, including lung cancer (17%), colorectal Cancer (33%) and pancreatic cancer (61%); KRAS gene mutations mostly occur at codons 12, 13 and 61.
  • KRAS mutations are widely prevalent in human cancers, mainly in pancreatic cancer, lung cancer and colorectal cancer. Among them, KRAS mutations are in G12A, G12C, G12D, G12R, G12S, G12V, G13D, Y96C, H95Q, R68S, Q61H and Q99L. The occurrence rate is higher, and at the G12 position, mutations such as G12C, G12D, G12V, and G12S are more common.
  • KRAS G12C Since cysteine at position 12 can serve as a covalent binding anchor and form a strong specific binding with covalent inhibitors, research on G12C targets has made significant progress in the past 8 years.
  • MRTX849, AMG510, etc. have entered phase II or phase III clinical trials and have achieved certain effects in inhibiting G12C.
  • KRAS G12D mutations there has been no breakthrough in the development of small molecule inhibitors for a long time.
  • KRAS G12D inhibitors such as MRTX1133 have low activity and cannot meet clinical needs.
  • inhibitors targeting G12S or G12V alone are even rarer, and there are no small molecule inhibitors in the existing technology that can inhibit multiple mutations at the same time (especially multiple mutations such as G12C, G12D, G12S and G12V). agent.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof:
  • Ring A is selected from substituted or unsubstituted, saturated or unsaturated C 4-14 N-containing cyclic, spirocyclic or bridged ring compounds, and Ring A contains at least one other heteroatom from O, S or N;
  • n 1, 2 or 3;
  • R 2 is selected from C 6-10 aryl, C 5-9 heteroaryl, C 6-10 aryl-C 1-6 alkylene, C 5-9 heteroaryl-C 1-6 alkylene, wherein said alkyl, aryl, heteroaryl or heterocyclyl is optionally one or more independently selected from halogen, cyano, amino, hydroxyl, nitro, C 1-6 alkyl, C 1- 6 alkoxy, C 1-6 alkylamino, C 2-4 alkynyl, C 2-4 alkenyl, C 1-4 alkylcyano, C 3-6 cycloalkyl , di-C 1-6 Substituted by alkylamino, C 1-6 haloalkyl, aminoacyl, C 1-6 alkylaminoacyl or di-C 1-6 alkylaminoacyl substituents;
  • R 4 is selected from hydrogen, C 1-3 alkyl, C 1-3 haloalkyl.
  • Ring A is an optionally substituted 4-14 membered heterocyclyl, wherein preferably, the structure of Ring A is as follows:
  • R 1 When two R 1 are connected to the same atom, it is preferably a spirocyclic structure composed of a C 3-6 cycloalkyl group or a 3 to 6-membered heterocyclyl group and ring A.
  • the spirocyclic ring can be composed of single or multiple rings respectively.
  • R 5 or R 6 are further substituted;
  • R 1 When two R 1 are connected to adjacent atoms, it is preferred to form a bond with ring A by a C 3-6 cycloalkyl group, a 3 to 6-membered heterocyclyl group, an aryl group or a heteroaryl group or to form a fused ring structure,
  • the bond or fused ring may be further substituted by single or multiple R 5 or R 6 ;
  • R 1 When two R 1 are on non-adjacent atoms, they preferentially form a bridged ring structure composed of 1 to 3 carbon atoms in ring A, and the bridged ring structure can be further substituted by R 1 ;
  • n 0 ⁇ 9
  • o 1 to 9.
  • the compound described in the present application or a pharmaceutically acceptable salt or stereoisomer thereof is a compound of general formula (I), wherein:
  • ring A is a single ring, it is preferably selected from substituted or unsubstituted:
  • R 1 When two R 1 are on non-adjacent atoms, they preferentially form a bridged ring structure composed of 1 to 3 carbon atoms in ring A:
  • o is selected from 0 to 8.
  • p is selected from 0, 1, 2 or 3;
  • q is selected from 0, 1, 2 or 3;
  • r is selected from 1, 2 or 3;
  • t is selected from 0 to 6;
  • W and U are respectively selected from: a single bond or a double bond composed of C or N;
  • n is selected from 0 to 9;
  • X, R 5 and R 6 are as defined herein.
  • Ring A (together with the substituents thereon) may be selected from the following structures:
  • ring A is selected from
  • C 1-6 alkyl preferably methyl), -OH; and/or
  • the ring A and the C 3-6 heterocycloalkyl group form a spiro ring structure.
  • Ring A (together with the substituents thereon) is selected from:
  • R 2 (together with substituents thereon) may be selected from the following groups:
  • R 2 (together with the substituents thereon) is selected from the following groups:
  • R 2 (together with the substituents thereon) is selected from the following groups:
  • R 2 (together with the substituents thereon) is selected from the following groups:
  • R 2 is (together with the substituents thereon) selected from the following groups:
  • L is selected from oxygen, sulfur, -NH-; preferably, L is selected from oxygen, -NH-; more preferably, L is oxygen.
  • R3 is selected from the following groups:
  • R3 is pyrrolizinylmethyl optionally substituted by halogen, preferably fluorine.
  • R 3 is selected from the following groups:
  • R 3 is selected from C 3-6 cycloalkyl-C 1-6 alkyl- (preferably cyclopropylmethyl), which is optionally one or more independently selected from - Substituted with (CH 2 ) n -N(R 4 ) 2 (preferably -(CH 2 ) n -N(CH 3 ) 2 ) and halogen (preferably fluorine) substituents (preferably, the substitution position is on a ring atom) ;
  • R 3 is the following group
  • R 5 is independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, 3 to 6 membered heterocyclyl, -(CH 2 ) n -N(R 4 ) 2 , -(CH 2 ) n -3 to 6-membered heterocyclyl, -N(R 4 ) 2 , halogen, preferably halogen,
  • fluorine More preferred is fluorine; p is 0, 1, 2 or 3.
  • R 3 is the following group
  • the use of the above-mentioned compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof in the preparation of a KRAS mutation inhibitor in another aspect of the invention, there is provided the use of the above-mentioned compound of the invention or a pharmaceutically acceptable salt or stereoisomer thereof in the preparation of a medicament for the treatment or prevention of diseases involving KRAS mutations, which involves KRAS Mutated diseases are, for example, cancer, such as lung cancer or pancreatic cancer.
  • the present invention provides a pharmaceutical composition, which contains the above-mentioned compound, its pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, and its pharmaceutically acceptable carriers.
  • pharmaceutically acceptable salts refers to compounds prepared in situ during the final isolation and purification of the above compounds, or purified as the free acid or free base, respectively, and mixed with an appropriate acid or base. Compounds prepared by reaction.
  • aryl alone or in combination with another radical means a carbocyclic aromatic monocyclic radical containing 6 to 10 carbon atoms, which may be further combined with a radical that may be aromatic, saturated or not. Saturated one or more 5- or 6-membered carbocyclic groups are fused.
  • heteroaryl refers to an aromatic monocyclic, bicyclic or tricyclic ring system, which may contain 1-4 selected from N, O and S heteroatoms. In the case of bicyclic or tricyclic ring systems, “heterocyclyl” may be in fused, bridged or spiro form. “Heterocyclyl” may be optionally substituted with one or more substituents.
  • heterocyclyl refers to a saturated or unsaturated monocyclic, bicyclic or tricyclic ring system in which at least one ring is a non-aromatic ring and which may contain 1 to 4 heteroatoms selected from N, O and S. In the case of bicyclic or tricyclic ring systems, “heterocyclyl” may be in fused, bridged or spiro form. “Heterocyclyl” may be optionally substituted with one or more substituents.
  • halogen or halogen includes fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • asymmetric atoms such as carbon atoms
  • they may be enantiomers, diastereomers, or any ratio of enantiomers or diastereomers.
  • the composition may exist in the form of a racemate (e.g., racemate).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) as described above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • methods of treating diseases including, but not limited to, cancer, such as pancreatic cancer, colorectal cancer, and lung cancer, are also provided with compounds or pharmaceutical compositions of the invention.
  • a compound of the present invention in the preparation of a medicament for the treatment of diseases, including but not limited to cancer, such as pancreatic cancer, colorectal cancer, and lung cancer.
  • the compounds in the present invention can be prepared using commercially available reagents using the synthesis methods and reactions shown below, or using other reagents and conventional methods well known to skilled persons.
  • the compounds of the present invention can be prepared by a variety of methods, including standard chemical methods. Illustrative general synthetic methods are listed below, and compounds of formula (I) can be prepared by methods known in the art of organic synthesis. When referring to the methods of the examples described below, it should be understood that part of the substituents can be substituted with groups well known in the art to obtain similar derivatives without departing from the gist of the invention. If necessary, use protecting groups for sensitive or reactive groups according to general principles or chemical methods. Protective groups are handled according to standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 3rd ed., Wiley, New York 1999). These groups are removed at a convenient stage in the synthesis of the compounds using methods well known to those skilled in the art. The method chosen, as well as the reaction conditions and the sequence of their treatment, should be consistent with the preparation of the compounds of formula (I).
  • the present invention includes possible stereoisomers and includes both racemic compounds and individual enantiomers.
  • the desired compound is a single enantiomer, it can be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of final products, intermediates or starting materials can be achieved by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-interscience, 1994).
  • the compounds of formula (I) according to the present invention may be selected from the following compounds:
  • Example 1 6-((S)-(4-((1R,5S)-8-oxo-3-azabicyclo[3.2.1]octane-3-yl)-6,8-difluoro -2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-( Trifluoromethyl)pyridin-2-amine (compound 1):
  • Step 1 Synthesis of (R)-1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol
  • Step 4 (3R)-1-(7-(8-chloro-3-(methoxymethoxy)naphthalene-1-yl)-6,8-difluoro-2-(((2R,7aS) Synthesis of -2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol
  • Step 5 (3R)-1-(7-(8-chloro-3-hydroxynaphthalene-1-yl)-6,8-difluoro-2-((2R,7aS)-2-fluorotetrahydro- Synthesis of 1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol
  • Step 1 to Step 5 Referring to the synthetic route of Intermediate 1, the reaction can be carried out by conventional methods in the art using the reactants shown in the figure to obtain Intermediate No. 7 compound in the figure above.
  • Step 8 (3R)-3-methyl-1-(2,6,8-trifluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropyl) Synthesis of silyl)ethynyl)naphth-1-yl)quinazolin-4-yl)piperidin-3-ol
  • Step 9 (3R)-1-(6,8-difluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene -1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3- Synthesis of methylpiperidin-3-ol
  • Step 10 (3R)-1-(7-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-6,8-difluoro-2-(( (2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-quinazolin-4-yl)-3-methylpiperidin-3-ol synthesis
  • Step 11 (3R)-1-(7-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-6,8-difluoro-2-( ((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-quinazolin-4-yl)-3-methylpiperidin-3-ol Synthesis
  • Step 12 (3R)-1-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)- Synthesis of 2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol
  • Step 1 3(R)-1-(6,8-difluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl) -2-(((2R,7aS)-2-fluoro-tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidine -Synthesis of 3-alcohols
  • reaction solution was concentrated and purified through silica gel column to obtain 3(R )-1-(6,8-difluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-((( 2R,7aS)-2-fluoro-tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol (473 mg ,Crude).
  • Step 2 (3R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-6,8-difluoro-2-(((2R,7aS)-2 -Synthesis of fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidin-3-ol
  • Example 8 (3R,6R)-1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS )-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-4-methylpiperidin-3-ol (compound 8):
  • Example 9 7-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrakis) Hydrogen-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (Compound 9):
  • reaction solution is concentrated and beaten with petroleum ether/ethyl acetate (1/1, 20mL) Purified to obtain 7-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (3.30g, 6.60mmol, yield 69.0%, purity 89.3%).
  • Step 2 Synthesis of 7-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decen-2,4-one
  • Step 3 7-(2,6,8-trifluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene- Synthesis of 1-yl)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decene-2,4-dione
  • Step 4 7-(6,8-difluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1- base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7 -Synthesis of triazaspiro[4.5]decene-2,4-dione
  • reaction solution was then added dropwise to 7-(2,6,8-trifluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triiso) dissolved in 3 mL of tetrahydrofuran solution Propylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decene-2,4-dione (160 mg, 217 ⁇ mol ), the reaction was carried out at 20°C for 30 minutes.
  • Step six 7-(6,8-difluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(( (2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5 ]Synthesis of decene-2,4-dione
  • Step 7 7-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydrogen) -1H-Pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decene-2,4-dione synthesis
  • Example 10 4-(4-(3-(1H-pyrazol-1-yl)piperidin-1-yl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolizine- 7a(5H)-yl)methoxy)quinazolin-7-yl)-5-chloronaphthalene-2-phenol (compound 10):
  • Example 11 7-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrakis) Hydrogen-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one (compound 11 ):
  • Step 1 Synthesis of 7-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one
  • reaction solution was quenched with water at -78°C, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure and purified by a fast silica gel column to obtain 7-(7-bromo -2-Chloro-6,8-difluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one (2.10g, 4.85mmol, 43.8% yield ).
  • Step 2 Synthesis of 7-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2-one become
  • Step 3 7-(2,6,8-trifluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene- Synthesis of 1-yl)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one
  • reaction solution was reacted at 90°C for 2 hours, and LCMS and TLC monitored the completion of the reaction.
  • the reaction was carried out three times in parallel, and the reaction solution was concentrated under reduced pressure and purified by a fast silica gel column to obtain 7-(2,6,8-trifluoro-7-(7-fluoro-3-(methoxymethoxy)-8-( (Triisopropylsilyl)ethynyl)naphth-1-yl)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one (320 mg, 443umol ,12.3% yield).
  • Step 4 7-(6,8-difluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl) )-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7- Synthesis of triazaspiro[4.5]decan-2-one
  • Step five 7-(6,8-difluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(( (2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5 ]Synthesis of Decan-2-one
  • reaction solution was concentrated under reduced pressure to obtain 7-(6,8-difluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)- 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazo Heterospiro[4.5]decan-2-one (200 mg, crude product).
  • Step 6 7-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydrogen) Synthesis of -1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decan-2-one
  • Example 12 6-(7-(8-chloro-3-hydroxynaphthalen-1-yl)-2-((1,3-dimethylimidazolin-2-yl)methoxy)-6,8 -Difluoroquinazolin-4-yl)-1,6-diazaspiro[3.5]nonan-2-one (compound 12):
  • Example 13 7-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrakis) Hydrogen-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-thi-1,3,7-triazaspiro[4.5]decane-2, 2-Dioxide (compound 13):
  • Example 15 7-((S)-7-(3-amino-4-fluoroisoquinolin-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluoro Tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[4.5]decan-3-one (compound Object 15):
  • Example 16 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrakis) Hydrogen-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-2-thi-1,3,7-triazaspiro[4.5]decane 2,2 - Dioxide (compound 16):
  • Example 17 4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrakis) Hydrogen-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1-oxa-4-azepan-6-ol (compound 17):
  • Step 1 4-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-6-methyl-1-oxa-4-azepan-6-ol synthesis
  • reaction solution was concentrated and purified by column chromatography to obtain a light yellow solid 4-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-6-methyl-1-oxa-4- Azepan-6-ol (1.00g, yield 57.7%).
  • Step 2 Synthesis of 4-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-6-methyl-1-oxa-4-azepan-6-ol
  • Step 3 6-methyl-4-(2,6,8-trifluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)) Synthesis of ethynyl)naphthalen-1-yl)quinazolin-4-yl)-1-oxa-4-azepan-6-ol
  • Step 4 4-(6,8-difluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1- base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl- Synthesis of 1-oxa-4-azepan-6-ol
  • 6-methyl-4-(2,6,8-trifluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylmethylsilyl) yl)ethynyl)naphth-1-yl)quinazolin-4-yl)-1-oxa-4-azepan-6-ol (520 mg, 745umol) and stirred for 30 minutes.
  • LCMS monitored the reaction to completion. The reaction solution was quenched with water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated.
  • Step five 4-(6,8-difluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(( (2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1-oxa-4- Synthesis of azepan-6-ol
  • Step 6 4-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydrogen) Synthesis of -1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1-oxa-4-azepan-6-ol
  • Example 18 4-(7-(8-chloro-7-fluoro-3-hydroxynaphthalene-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydrogen) -1H-Pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1-oxa-4-azepan-6-ol (compound 18 ):
  • Example 20 5-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrakis) Hydrogen-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyridine Azolo[1,5-a][1,4]diazepine-2-carboxamide (compound 20):
  • the total synthetic route of compound 20 is as follows:
  • Step 1 5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H- Synthesis of Pyrazolo[1,5-a][1,4]diazepine-2-carboxamide
  • reaction solution was concentrated and separated and purified through a reversed-phase silica gel column to obtain 5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-N,N-di Methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (1g, 2.06mmol, yield 64.6%).
  • reaction solution was concentrated and separated and purified through a reversed-phase silica gel column to obtain 5-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-N ,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (800mg, 1.70 mmol, yield 82.8%).
  • Step 3 N,N-dimethyl-5-(2,6,8-trifluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylmethyl) Silyl)ethynyl)naphth-1-yl)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]di Synthesis of azepane-2-carboxamide
  • Step 4 5-(6,8-difluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1- base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-N, N-di Synthesis of methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide
  • Step five 5-(6,8-difluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(( (2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6, Synthesis of 7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide
  • Step six 5-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydrogen) -1H-Pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazole Synthesis of [1,5-a][1,4]diazepine-2-carboxamide
  • Example 21 5-(7-(8-chloro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolizine-7a(5H)-yl) )methoxy)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazoline[1,5-a][1,4] Diaza-2-carboxamide (compound 21):
  • Example 22 4-(7-(8-chloronaphth-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a (5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1-oxa-4-azepan-6-ol (compound 22):
  • Example 23 6-(7-(7,8-difluoro-3-hydroxynaphthalen-1-yl)-6,8-bisfluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-azabicyclo[3.2.1]octane-3-ol (compound 23):
  • Example 24 5-(7-(8-ethylnaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine- 7a(5H)-yl)methoxy)quinazolin-4-yl)tetrahydropyrrole[3,4-c]pyrrole-1,3(2H,3H)-dione (compound 24):
  • Example 25 5-chloro-4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy )-4-(6-(hydroxymethyl)-1-oxa-4-azepan-4-yl)quinazolin-7-yl)naphthalen-2-ol (compound 25):
  • Example 26 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrakis) Hydrogen-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-2,7-diazaspiro[4.5]decan-3-one (compound 26):
  • Example 27 7-(7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrakis) Hydrogen-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-1,3,7-triazaspiro[4.5]decane-2,4-dione (Compound 27):
  • Example 28 (5-(7-(8-chloro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazoline[1,5-a][1, 4] Diaza-2-yl)(morpholinyl)methanone (compound 28):
  • Example 29 5-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrakis) Hydrogen-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-fluoro-N,N-dimethyl-5,6,7,8-tetrahydro -4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (compound 29):
  • Step 1 5-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-fluoro-N,N-dimethyl-5,6,7,8-tetrahydrofuran Synthesis of Hydrogen-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide
  • Step three 3-fluoro-N,N-dimethyl-5-(2,6,8-trifluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((tri Isopropylsilyl)ethynyl)naphth-1-yl)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1 ,4] Synthesis of diazepane-2-carboxamide
  • Step 4 5-(6,8-difluoro-7-(7-fluoro-3-(methoxymethoxy)8-((triisopropylsilyl)ethynyl)naphthalene-1-yl) )-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-fluoro-N, Synthesis of N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2carboxamide
  • reaction solution was then added dropwise to 3-fluoro-N,N-dimethyl-5-(2,6,8-trifluoro-7-(7-fluoro-3-(methoxy methylmethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyra
  • Azolo[1,5-a][1,4]diazepine-2-carboxamide (440 mg, 556umol) was added to the reaction solution at 20°C for 30 minutes.
  • Step five 5-(6,8-difluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(( (2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-fluoro-N,N-dimethyl- Synthesis of 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2carboxamide
  • Step six 5-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydrogen) -1H-Pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-fluoro-N,N-dimethyl-5,6,7,8-tetrahydro- Synthesis of 4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide
  • Example 30 5-(7-(8-chloro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole) Riazine-7a(5H)-yl)methoxy)quinazolin-4-yl)-N,N,3-trimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[ 1,5-a][1,4]diazepine-2-carboxamide (compound 30):
  • Example 31 5-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolizine-7a (5H)-yl)methoxy)quinazolin-4-yl)-3-fluoro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a][1,4]diazepine-2-carboxamide (compound 31):
  • the route of compound 31 can be referred to compound 29.
  • the synthetic route of compound 31 is as follows:
  • Step 1 5-(6,8-difluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1- base)-2-((tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-fluoro-N,N-dimethyl-5, Synthesis of 6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide
  • reaction solution was then added dropwise to 3-fluoro-N,N-dimethyl-5-(2,6,8-trifluoro-7-(7-fluoro-3-(methoxy methylmethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyra
  • Azolo[1,5-a][1,4]diazepine-2-carboxamide (440 mg, 556umol) was added to the reaction solution at 20°C for 30 minutes.
  • Step 2 5-(6,8-difluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(( Tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-fluoro-N,N-dimethyl-5,6,7,8-tetrahydro Synthesis of Hydrogen-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide
  • Step 3 5-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthyl-1-yl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolizine-7a( 5H)-yl)methoxy)quinazolin-4-yl)-3-fluoro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5 -Synthesis of a][1,4]diazepine-2-carboxamide
  • Example 32 4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6,8-difluoro-2-(((2R,7aS) -2-Fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxepan-6- Synthesis of alcohol (compound 32):
  • Step 1 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)-2,6,8-trifluoroquinazoline-4- Synthesis of 6-methyl-1,4-oxepan-6-ol
  • Step 2 4-(7-(6-(bis(4-methoxybenzyl)amino)-3-iodo-4-methylpyridin-2-yl)-2,6,8-trifluoroquinazole Synthesis of lin-4-yl)-6-methyl-1,4-oxepan-6-ol
  • Step 3 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,6,8 -Synthesis of trifluoroquinazolin-4-yl)-6-methyl-1,4-oxepan-6-ol
  • Step 4 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6,8-di Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1 ,Synthesis of 4-oxepan-6-ol
  • This reaction liquid was then added dropwise to 4-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl) dissolved in 10.0 mL of tetrahydrofuran solution) Pyridin-2-yl)-2,6,8-trifluoroquinazolin-4-yl)-6-methyl-1,4-oxepan-6-ol (450.00 mg, 618.39 ⁇ mol) , the reaction was carried out at 25°C for 1 hour.
  • Step five 4-(7-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-6,8-difluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxepan-6-ol synthesis of synthesis
  • Example 33 5-(7-(8-ethynyl-7-fluoronaphthyl-1-yl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolizine-7a(5H)- (yl)methoxy)quinazolin-4-yl)-3-fluoro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a] [1,4]Diazepine-2-carboxamide (compound 33):
  • the synthetic route of compound 33 can be referred to compound 29.
  • the synthetic route of compound 33 is as follows:
  • Step 1 3-fluoro-N,N-dimethyl-5-(2,6,8-trifluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene) -1-yl)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2 -Synthesis of formamide
  • Step 2 5-(6,8-difluoro-7-(7-fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-((tetrahydro-1H -Pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-fluoro-N,N-dimethyl-5,6,7,8-tetrahydro-4H- Synthesis of Pyrazolo[1,5-a][1,4]diazepine-2-carboxamide
  • Step 4 5-(7-(8-ethynyl-7-fluoronaphthyl-1-yl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolizine-7a(5H)-yl) )methoxy)quinazolin-4-yl)-3-fluoro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][ Synthesis of 1,4]diazepine-2-carboxamide
  • Example 34 5-(7-(8-ethynylnaphthalen-1-yl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy yl)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diaza Cycloheptane-2-carboxamide (compound 34):
  • the synthetic route of compound 34 can be referred to compound 20. Starting from the common intermediate 20C, the synthetic route of compound 34 is as follows:
  • Step 1 N,N-dimethyl-5-(2,6,8-trifluoro-7-(8-((triisopropylsilyl)ethynyl)naphth-1-yl)quinazoline Synthesis of -4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide
  • reaction solution was concentrated and separated and purified through a reversed-phase silica gel column to obtain N,N-dimethyl-5-(2,6,8-trifluoro -7-(8-((triisopropylsilyl)ethynyl)naphth-1-yl)quinazolin-4-yl)-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a][1,4]diazepine-2-carboxamide (350 mg, yield 58.9%).
  • Step 2 5-(6,8-difluoro-2-((tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-7-(8-((triisopropylmethyl) Silyl)ethynyl)naphth-1-yl)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- Synthesis of a][1,4]diazepine-2-carboxamide
  • Step 3 5-(7-(8-ethylnaphthyl-1-yl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy )quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazacyclo Synthesis of heptane-2-carboxamide
  • Example 35 4-(7-(3-amino-8-ethynylisoquinolin-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxepan-6-ol (compound 35):
  • reaction solution was extracted with water and ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated, and purified by column chromatography to obtain a yellow oily compound 1-(tert-butoxy)-N,N-bis(4-methoxy).
  • Benzyl)isoquinolin-3-amine (11.0 g, 21.5 mmol, 67.6% yield, 89.0.% purity).
  • Step 4 Synthesis of 3-(bis(4-methoxybenzyl)amino)-8-((triisopropylsilyl)ethynyl)isoquinolin-1-ol
  • Step 5 Synthesis of 3-(bis(4-methoxybenzyl)amino)-8-((triisopropylsilyl)ethynyl)isoquinolin-1-yl triflate
  • Step six 1-(4-(tert-butoxy)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl )methoxy)quinazolin-7-yl)-N,N-bis(4-methoxybenzyl)-8-((triisopropylsilyl)ethynyl)isoquinoline-3- Synthesis of amines
  • Step 7 7-(3-(bis(4-methoxybenzyl)amino)-8-((triisopropylsilyl)ethynyl)isoquinolin-1-yl)-6,8- Synthesis of difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-ol
  • Step 8 4-(7-(3-(bis(4-methoxybenzyl)amino)-8-((triisopropylsilyl)ethynyl)isoquinolin-1-yl)-6 ,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6- Synthesis of methyl-1,4-oxepan-6-ol
  • Step 9 4-(7-(3-amino-8-((triisopropylsilyl)ethynyl)isoquinolin-1-yl)-6,8-difluoro-2-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxepane -Synthesis of 6-alcohol
  • Step 10 4-(7-(3-amino-8-ethynylisoquinolin-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H) -Synthesis of pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxepan-6-ol
  • Example 36 4-(7-(8-chloro-3-hydroxynaphthyl-1-yl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolizine-7a(5H)-yl) )methoxy)quinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol (compound 36):
  • Step 1 4-(7-(8-chloro-3-(methoxymethoxy)naphthyl-1-yl)-2,6,8-trifluoroquinazolin-4-yl)-6-methyl Synthesis of 1,4-oxaazepan-6-ol
  • Step 2 4-(7-(8-chloro-3-(methoxymethoxy)naphthyl-1-yl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolizine- Synthesis of 7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol
  • Step 3 4-(7-(8-chloro-3-hydroxynaphthalene-1-yl)-6,8-difluoro-2-((tetrahydro-1H-pyrrolizine-7a(5H)-yl) Synthesis of methoxy)quinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol
  • Example 37 4-(7-(6-chloro-5-methyl-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrazol) Hydrogen-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol (compound 37):
  • Step 1 4-(7-(6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2,6,8- Synthesis of trifluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol
  • Step 2 4-(7-(6-chloro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-6,8-difluoro -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1, Synthesis of 4-oxaazepine-6-ol
  • Step 3 4-(7-(6-chloro-5-methyl-1H-indazol-4-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydrogen) Synthesis of -1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol
  • Example 38 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrakis) Hydrogen-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-diazepan-6-ol (compound 38 ):
  • Step 1 4-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-6-hydroxy-6-methyl-1,4-diazepan-1 -Synthesis of tert-butyl formate
  • reaction solution was diluted with water, extracted with dichloromethane, washed with brine, dried, concentrated under reduced pressure and purified by a fast silica gel column to obtain 4-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl) -6-Hydroxy-6-methyl-1,4-diazepine-1-carboxylic acid tert-butyl ester (1.41 g, 2.78 mmol, 91.3% yield).
  • Step 2 4-(7-bromo-2,6,8-difluoroquinazolin-4-yl)-6-hydroxy-6-methyl-1,4-diazepan-1-carboxylic acid Synthesis of tert-butyl ester
  • reaction solution was diluted with water, extracted with ethyl acetate, washed with brine, dried, concentrated under reduced pressure and purified by a fast silica gel column to obtain 4-(7-bromo-2,6,8-difluoroquinazolin-4-yl)-6 -Hydroxy-6-methyl-1,4-diazepan-1-carboxylic acid tert-butyl ester (0.69 g, 1.40 mmol, 50.9% yield).
  • Step 3 6-hydroxy-6-methyl-4-(2,6,8-trifluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropyl) Synthesis of tert-butyl ester of silyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-1,4-azepan-1-carboxylate
  • reaction solution was reacted at 90°C for 2 hours.
  • LCMS monitored the reaction to completion.
  • the reaction solution was concentrated under reduced pressure and purified by a flash silica gel column to obtain 6-hydroxy-6-methyl-4-(2,6,8-trifluoro-7-(7-fluoro-3-(methoxymethoxy)- 8-((Triisopropylsilyl)ethynyl)naphth-1-yl)quinazolin-4-yl)-1,4-azepan-1-carboxylic acid tert-butyl ester (820 mg, 588 ⁇ mol, 48.1% yield).
  • Step 4 4-(6,8-difluoro-7-(7-fluoro-3-(methoxymethoxy)-8-(triisopropylsilyl)ethynyl)naphthalene-1-yl) -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-hydroxy-6-methyl Synthesis of 1,4-diazepine-1-carboxylic acid tert-butyl ester
  • Step 6 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydrogen) Synthesis of -1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-diazepan-6-ol
  • Example 39 4-(4-(3-amino-3-methylpiperidin-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H) -Pyrrolizine-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol (compound 39):
  • Step 1 Synthesis of (1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-yl)carbamic acid tert-butyl ester
  • Step 2 (1-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3-methylpiperidin-3-yl)carbamic acid tert-butyl ester
  • Step 3 (3-methyl-1-(2,6,8-trifluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) )Synthesis of ethynyl)naphthyl-1-yl)quinazolin-4-yl)piperidin-3-yl)carbamate tert-butyl ester
  • Step 4 (1-(6,8-difluoro-7-(7-fluoro-3-(methoxymethyl)-8-((triisopropylsilyl)ethynyl)naphthalene-1- base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperdine Synthesis of tert-butylcarbamic acid
  • Step five 4-(4-(3-amino-3-methylpiperidin-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Pyrrolizine-7a(5H)-yl)methoxy)quinazolin-7-yl)-6-fluoro-5-((triisopropylsilyl)ethynyl)naphthalene -Synthesis of 2-alcohol
  • Step six 4-(4-(3-amino-3-methylpiperidin-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- Synthesis of pyrrolizine-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol
  • Example 40 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrakis) Hydrogen-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidine-3-carboxylic acid (compound 40):
  • Step 1 Synthesis of methyl 1-(7-bromo-2-chloro-6,8-difluoroquinazolin-4-yl)-3-methylpiperidine-3-carboxylate
  • Step 2 Synthesis of 1-(7-bromo-2,6,8-trifluoroquinazolin-4-yl)-3-methylpiperidine-3-carboxylic acid methyl ester
  • Step 3 3-methyl-1-(2,6,8-trifluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)) Synthesis of ethynyl)naphthalen-1-yl)quinazolin-4-yl)piperidine-3-carboxylic acid methyl ester
  • Step 4 1-(6,8-difluoro-7-(7-fluoro-3-(methoxy-methoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1 -yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methyl Synthesis of piperidine-3-carboxylic acid methyl ester
  • Step 5 1-(6,8-difluoro-7-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalene-1- base)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperdine Synthesis of pyridine-3-carboxylic acid
  • Step six 1-(6,8-difluoro-7-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-2-(( Synthesis of (2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidine-3-carboxylic acid
  • Step 7 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydrogen) Synthesis of -1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidine-3-carboxylic acid
  • reaction solution was filtered and purified by prep-HPLC to obtain a white solid 1-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1-yl)-6,8-difluoro-2-(((2R,7aS )-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-3-methylpiperidine-3-carboxylic acid (150 mg, yield 53.1 %).
  • Example 41 4-(7-(1-ethynyl-6-hydroxyisoquinolin-8-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxaazepine-6-ol (compound 41) :
  • the synthesis of compound 41 is mainly divided into the synthesis of fragment 41k and the synthesis of compound 41 itself.
  • the specific route is as follows:
  • 8-Bromo-6-methoxyisoquinoline (5.60g, 23.5mmol) was dissolved in aqueous hydrobromic acid solution (50mL) and reacted at 120°C for 24 hours. LCMS monitored the reaction to completion. After the reaction solution was concentrated, 8-bromoisoquinoline-6-phenol (7.00 g, yield 97.6%, HBr salt) was obtained.
  • Step 8 Synthesis of 8-bromo-6-[(2,2-dimethylpropionyl)oxo]isoquinoline nitrogen oxide
  • Step 10 Synthesis of 8-bromo-1-((triisopropylsilyl)ethynyl)isoquinolin-6-yl pivalate
  • reaction solution was extracted with water and dichloromethane, and the organic phase was washed with saturated brine, dried, filtered, concentrated and purified through a silica gel column to obtain 8-bromo-1-((triisopropylsilyl)ethynyl)isoquinoline-6. -yl pivalate (660 mg, yield 11.6%).
  • Step 11 8-(4-(tert-butoxy)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)- Synthesis of methyl)methoxy)quinazolin-7-yl)-1-((triisopropylsilyl)ethynyl)isoquinolin-6-yl pivalate
  • reaction solution was extracted with water and ethyl acetate, the organic phase was washed with saturated brine, dried, filtered, and concentrated to obtain 8-(4-(tert-butoxy)-6,8-difluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-7-yl)-1-((triisopropylsilyl)ethynyl)isoquinoline -6-yl pivalate (600 mg, yield 73.8%).
  • Step 12 8-(4-(tert-butoxy)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)- Synthesis of methyl)methoxy)quinazolin-7-yl)-1-((triisopropylsilyl)ethynyl)isoquinolin-6-ol
  • reaction solution was concentrated and purified by column chromatography to obtain 8-(4-(tert-butoxy)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine) -7a(5H)-yl)methoxy)quinazolin-7-yl)-1-((triisopropylsilyl)ethynyl)isoquinolin-6-ol (180 mg, yield 30.0% ).
  • Step 13 6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-7-(6- Synthesis of hydroxy-1-((triisopropylsilyl)ethynyl)isoquinolin-8-yl)quinazolin-4-ol
  • reaction solution was extracted with water and ethyl acetate, and the organic phase was concentrated and purified by column chromatography to obtain 6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a( 5H)-yl)methoxy)-7-(6-hydroxy-1-((triisopropylsilyl)ethynyl)isoquinolin-8-yl)quinazolin-4-ol (202 mg, Yield 73.0%).
  • Step 14 8-(4-chloro-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy Synthesis of )quinazolin-7-yl)-1-((triisopropylsilyl)ethynyl)isoquinolin-6-ol
  • Step 15 4-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-7- (6-hydroxy-1-((triisopropylsilyl)ethynyl)isoquinolin-8-yl)quinazolin-4-yl)-6-methyl-1,4-oxaazepine Synthesis of cycloheptane-6-ol
  • Step 16 4-(7-(1-ethynyl-6-hydroxyisoquinolin-8-yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro- Synthesis of 1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol
  • reaction solution was separated by high performance liquid chromatography to obtain 4-(7-(1-ethynyl-6-hydroxyisoquinolin-8-yl)-6,8-difluoro-2-(((2R,7aS)-2 -Fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxaazepine-6- Alcohol (18.0 mg, yield 11%).
  • Example 42 4-(7-(3-amino-8-ethynyl-7-fluoroisoquinolin-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol (Compound 42):
  • Step 4 Synthesis of 1-(tert-butoxy)-7fluoro-N,N-bis(4-methoxybenzyl)isoquinolin-3-amine
  • Step 6 Synthesis of 3-(bis(4-methoxybenzyl)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)isoquinolin-1-ol
  • Step 7 3-(bis(4-methoxybenzyl)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)isoquinolin-1-yl trifluoromethanesulfonic acid Synthesis of esters
  • Step 11 4-(tert-butoxy)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methyl Synthesis of oxy)quinazoline
  • Step 12 1-(4-(tert-butoxy)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)- yl)methoxy)quinazolin-7-yl)-7-fluoro-N,N-bis(4-methoxybenzyl)-8-((triisopropylsilane Synthesis of ethynyl)isoquinolin-3-amine
  • Step 13 7-(3-(bis(4-methoxybenzyl)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)isoquinolin-1-yl) Synthesis of -6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-ol
  • Step 14 4-(7-(3-(bis(4-methoxybenzyl)amino)-7-fluoro-8-((triisopropylsilyl)ethynyl)isoquinoline-1 -yl)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazoline-4- Synthesis of 6-methyl-1,4-oxaazepan-6-ol
  • Step 15 4-(7-(3-amino-7-fluoro-8-((triisopropylsilyl)ethynyl)isoquinolin-1-yl)-6,8-difluoro-2 -(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4- Synthesis of oxazepan-6-ol
  • Step 16 4-(7-(3-amino-8-ethynyl-7-fluoroisoquinolin-1-yl)-6,8-difluoro-2-(((2R,7aS)-2- Fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)quinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol Synthesis
  • Example 43 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1 -(yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (compound 43):
  • Step 1 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoro-7-(7-fluoro-3-(methoxy) Methoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-6-methyl-1,4-oxaazepine Synthesis of Alkane-6-ol
  • Step 2 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoro-7-(7-fluoro-3-hydroxy-8- Synthesis of ((triisopropylsilyl)ethynyl)naphth-1-yl)quinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol
  • the reaction solution was concentrated at low temperature to obtain 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoro-7-(7-fluoro-3-hydroxy- 8-((triisopropylsilyl)ethynyl)naphth-1-yl)quinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol (480mg, crude product).
  • Step 3 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- Synthesis of 6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepine-6-ol
  • reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography to obtain 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7) -Fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol (15.0 mg, yield 6.04%).
  • Example 44 4-(2-((1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro -3-Hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol (Compound 44) :
  • Step 1 Synthesis of: (1-((acetoxy)methyl)-2,2-difluorocyclopropyl)methylacetate
  • Step 3 (R)-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)methanol and (S)-(1-((benzyloxy)methyl)-2 ,Synthesis of 2-difluorocyclopropyl)methanol
  • Step 5 Synthesis of (R)-1-(1-((benzyloxy)methyl)-2,2-difluorocyclopropyl)-N,N-dimethylmethylamine
  • Fragment 44g-II can refer to the synthesis method of 44g-I. Repeat steps four to six to obtain (S)–(1-((dimethylamino)methyl)-2,2-difluorocyclopropyl) Methanol.
  • Step 7 4-(2-(((R)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-6,8-difluoro-7 -(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-6-methyl Synthesis of 1,4-oxaazepan-6-ol
  • Step 8 4-(2-(((R)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-6,8-difluoro-7 -(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-6-methyl-1,4-oxy Synthesis of azepine-6-ol
  • Step 9 4-(2-(((R)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-7-(8-ethynyl- 7-Fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol synthesis
  • Example 45 5-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1 -yl)-6,8-difluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a] [1,4]Diazepine-2-carboxamide (compound 45):
  • Step 1 5-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoro-7-(7-fluoro-3-(methoxy methylmethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)quinazolin-4-yl)-N,N-dimethyl-5,6,7, Synthesis of 8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide
  • Step 2 5-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-6,8-difluoro-7-(7-fluoro-3-hydroxy-8 -((triisopropylsilyl)ethynyl)naphthalen-1-yl)quinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H- Synthesis of Pyrazolo[1,5-a][1,4]diazepine-2-carboxamide
  • Step 3 5-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1- (base)-6,8-difluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][ Synthesis of 1,4]diazepine-2-carboxamide
  • Example 46 1-(2-((1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro -3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-3-methylpiperidin-3-ol (compound 46):
  • Example 47 5-(2-((1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-7-(8-ethynyl-7-fluoro -3-Hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a][1,4]diazepine-2-carboxamide (compound 47):
  • Example 48 4-(2-((1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-7-(8-ethyl-7-fluoro -3-Hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxepan-6-ol (compound 48):
  • Compound 48 can be obtained by reducing compound 44 as follows:
  • the reaction solution is filtered, and the filtrate is purified by high-performance liquid phase preparative chromatography and chiral separation to obtain 4-(2-((1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy )-7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxa Cycloheptan-6-ol (30.0 mg, yield 48.7%).
  • Example 49 7-(2-(((R)-1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-7-(8-ethynyl -7-Fluoro-3-hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-1,3,7-triazaspiro[4.5]decene-2,4- Dione (compound 49):
  • Example 50 4-(2-((1-((dimethylamino)methyl)cyclopropyl)methoxy)-7-(8-ethynyl-2-fluoro-3-hydroxynaphthalene-1 -(yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (compound 50):
  • Example 51 4-(2-((1-((dimethylamino)methyl)-2,2-difluorocyclopropyl)methoxy)-7-(8-ethynyl-2-fluoro -3-Hydroxynaphthalen-1-yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol (Compound 51) :
  • Example 52 4-(7-(2-chloro-8-ethynyl-3-hydroxynaphthalen-1-yl)-2-((1-((dimethylamino)methyl)cyclopropyl)methyl Oxy)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol (compound 52):
  • Example 53 4-(7-(2-chloro-8-ethynyl-3-hydroxynaphthalen-1-yl)-2-((1-((dimethylamino)methyl)-2,2- Difluorocyclopropyl)methoxy)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol (Compound 53) :
  • Example 54 4-(7-(3-amino-8-ethynyl-7-fluoroisoquinolin-1-yl)-2-((1-((dimethylamino)methyl)cyclopropyl) )methoxy)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol (compound 54):
  • Example 55 4-(7-(3-amino-8-ethynyl-7-fluoroisoquinolin-1-yl)-2-((1-((dimethylamino)methyl)-2, 2-Difluorocyclopropyl)methoxy)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol (compound 55):
  • Example 56 4-(7-(3-amino-8-ethyl-7-fluoroisoquinolin-1-yl)-2-((1-((dimethylamino)methyl)-2, 2-Difluorocyclopropyl)methoxy)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol (compound 56):
  • Example 57 4-(7-(2-amino-5-ethynyl-6-fluoroisoquinolin-4-yl)-2-((1-((dimethylamino)methyl)cyclopropyl) )methoxy)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol (compound 57):
  • Example 58 4-(7-(2-amino-5-ethynyl-6-fluoroisoquinolin-4-yl)-2-((1-((dimethylamino)methyl)-2, 2-Difluorocyclopropyl)methoxy)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxaazepan-6-ol (compound 58):
  • Example 59 4-(2-((1-((dimethylamino)methyl)cyclobutyl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1 -(yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (compound 59):
  • Example 60 4-(2-((1-((dimethylamino)methyl)cyclopentyl)methoxy)-7-(8-ethynyl-7-fluoro-3-hydroxynaphthalene-1 -(yl)-6,8-difluoroquinazolin-4-yl)-6-methyl-1,4-oxazepan-6-ol (compound 60):
  • the compound according to claim 1 or its pharmaceutically acceptable salt or stereoisomer is selected from the compounds in the following table:
  • Test Example 1 NCI-H358 cell proliferation test
  • the human lung cancer cell line NCI-H358 (ATCC, CRL-5807) is a KRAS G12C mutant cell line. NCI-H358 cells were cultured in RPMI 1640 medium containing 10% fetal calf serum and placed in a humidified incubator with 5% CO2 for growth at 37°C.
  • the number of viable cells in the culture was determined following the protocol described in Promega's Cell Titer-Glo Luminescent cell Viability Assay (Promega catalog #G7570).
  • 90 ⁇ L of cells (8,000 cells/well) were cultured in growth medium in Corning black clear bottom 96-well plates and cultured overnight at 37°C in a 5% CO2 humidified incubator.
  • Serially diluted compounds in 100% DMSO were added to the cells using a pipette, and cells were incubated for an additional 72 hours.
  • IC50 value is determined by calculating the concentration of compound required to obtain 50% inhibition.
  • Test Example 2 LS513 cell proliferation test
  • the human colorectal cancer cell line LS513 (ATCC, CRL-2134) is a KRAS G12D mutant cell line. LS513 cells were cultured in RPMI 1640 medium containing 10% fetal calf serum and placed in a humidified incubator with 5% CO2 for growth at 37°C.
  • the number of viable cells in the culture was determined following the protocol described in Promega's Cell Titer-Glo Luminescent cell Viability Assay (Promega catalog #G7570).
  • 90 ⁇ L of cells (8,000 cells/well) were cultured in growth medium in Corning black clear bottom 96-well plates and cultured overnight at 37°C in a 5% CO2 humidified incubator. Use a pipette to add 100% DMSO to the Further dilutions of compound were added to the cells, and the cells were incubated for an additional 72 hours.
  • IC50 value is determined by calculating the concentration of compound required to obtain 50% inhibition.
  • the human colorectal cancer cell line SW480 (ATCC, CCL-228) is a KRAS G12V mutant cell line.
  • SW480 cells were cultured in RPMI 1640 medium containing 10% fetal calf serum and placed in a humidified incubator with 5% CO2 for growth at 37°C.
  • the number of viable cells in the culture was determined following the protocol described in Promega's Cell Titer-Glo Luminescent cell Viability Assay (Promega catalog #G7570).
  • 90 ⁇ L of cells (8,000 cells/well) were cultured in growth medium in Corning black clear bottom 96-well plates and cultured overnight at 37°C in a 5% CO2 humidified incubator.
  • Serially diluted compounds in 100% DMSO were added to the cells using a pipette, and cells were incubated for an additional 72 hours.
  • IC50 value is determined by calculating the concentration of compound required to obtain 50% inhibition.
  • Test Example 4 A549 cell proliferation test
  • the human lung cancer cell line A549 (ATCC, CCL-185) is a KRAS G12S mutant cell line.
  • A549 cells were cultured in RPMI 1640 medium containing 10% fetal calf serum and placed in a humidified incubator with 5% CO2 for growth at 37°C.
  • the number of viable cells in the culture was determined following the protocol described in Promega's Cell Titer-Glo Luminescent cell Viability Assay (Promega catalog #G7570).
  • 90 ⁇ L of cells (8,000 cells/well) were cultured in growth medium in Corning black clear bottom 96-well plates and cultured overnight at 37°C in a 5% CO2 humidified incubator.
  • Serially diluted compounds in 100% DMSO were added to the cells using a pipette, and cells were incubated for an additional 72 hours.
  • IC50 value is determined by calculating the concentration of compound required to obtain 50% inhibition.
  • Test Example 1 The activity data of each compound obtained in Test Example 1, Test Example 2, Test Example 3 and Test Example 4 for inhibiting KRAS G12C, KRAS G12D, KRAS G12V and KRAS G12S are shown in Table 1.

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Abstract

La présente invention concerne un inhibiteur ayant une structure hétérocyclique de quinazoline pour le traitement du cancer. Plus particulièrement, la présente invention concerne un dérivé ayant une structure hétérocyclique de quinazoline telle que représentée dans la formule (I) et un sel pharmaceutiquement acceptable de celui-ci. Le composé ou le sel de celui-ci peut inhiber au moins un mutant dans la protéine KRAS, et peut ainsi être utilisé pour traiter diverses maladies provoquées par une mutation, y compris le cancer. La présente invention concerne la structure d'un dérivé inhibiteur ayant la structure hétérocyclique de quinazoline et un procédé de préparation. La présente invention concerne également une composition pharmaceutique contenant le composé ou le sel de celui-ci, et une méthode thérapeutique pour traiter des maladies médiées par KRAS à l'aide du composé et du sel de celui-ci.
PCT/CN2023/117379 2022-09-08 2023-09-07 Dérivé hétérocyclique de quinazoline d'inhibiteur de mutation kras pour le traitement du cancer Ceased WO2024051763A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

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WO2022258974A1 (fr) * 2021-06-10 2022-12-15 Redx Pharma Plc Dérivés de quinazoline utiles en tant qu'inhibiteurs de ras
WO2023020519A1 (fr) * 2021-08-18 2023-02-23 Jacobio Pharmaceuticals Co., Ltd. Dérivés de 1, 4-oxazépane et leurs utilisations
WO2023061294A1 (fr) * 2021-10-13 2023-04-20 再鼎医药(上海)有限公司 Régulateur dérivé hétérocyclique contenant de l'azote, son procédé de préparation et son utilisation
WO2023097227A1 (fr) * 2021-11-24 2023-06-01 Merck Sharp & Dohme Llc Petites molécules inhibitrices de protéines à mutation kras
WO2023150284A2 (fr) * 2022-02-03 2023-08-10 Mirati Therapeutics, Inc. Inhibiteurs de pan-kras de quinazoline
WO2023159087A1 (fr) * 2022-02-16 2023-08-24 Amgen Inc. Composés quinazoline et leur utilisation en tant qu'inhibiteurs de protéines kras mutantes

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CN107849022A (zh) * 2015-04-10 2018-03-27 亚瑞克西斯制药公司 取代的喹唑啉化合物和其使用方法
WO2022258974A1 (fr) * 2021-06-10 2022-12-15 Redx Pharma Plc Dérivés de quinazoline utiles en tant qu'inhibiteurs de ras
WO2023020519A1 (fr) * 2021-08-18 2023-02-23 Jacobio Pharmaceuticals Co., Ltd. Dérivés de 1, 4-oxazépane et leurs utilisations
WO2023061294A1 (fr) * 2021-10-13 2023-04-20 再鼎医药(上海)有限公司 Régulateur dérivé hétérocyclique contenant de l'azote, son procédé de préparation et son utilisation
WO2023097227A1 (fr) * 2021-11-24 2023-06-01 Merck Sharp & Dohme Llc Petites molécules inhibitrices de protéines à mutation kras
WO2023150284A2 (fr) * 2022-02-03 2023-08-10 Mirati Therapeutics, Inc. Inhibiteurs de pan-kras de quinazoline
WO2023159087A1 (fr) * 2022-02-16 2023-08-24 Amgen Inc. Composés quinazoline et leur utilisation en tant qu'inhibiteurs de protéines kras mutantes

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

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