WO2023051495A1 - Isoquinolinone and quinazolinone compounds, and composition and use thereof - Google Patents

Isoquinolinone and quinazolinone compounds, and composition and use thereof Download PDF

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WO2023051495A1
WO2023051495A1 PCT/CN2022/121567 CN2022121567W WO2023051495A1 WO 2023051495 A1 WO2023051495 A1 WO 2023051495A1 CN 2022121567 W CN2022121567 W CN 2022121567W WO 2023051495 A1 WO2023051495 A1 WO 2023051495A1
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alkyl
deuterated
haloalkyl
independently
alkoxy
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French (fr)
Chinese (zh)
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吴双
孙明明
许世民
习宁
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中山医诺维申新药研发有限公司
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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Definitions

  • the present invention belongs to the field of medicine, and in particular relates to a new class of isoquinolinone and quinazolinone compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions containing said compounds, and the use of said compounds and their pharmaceutical combinations Use of the substance in the preparation of medicines for preventing, treating, treating, and/or alleviating PI3-kinase abnormality-related diseases, disorders, and/or conditions.
  • the phosphoinositide 3-kinase (PI3K) pathway is an intracellular signaling pathway with regulatory roles in cell survival, proliferation and differentiation.
  • the phosphoinositide 3-kinase (PI3K) enzyme family is a central regulator of growth, proliferation, migration and metabolism in many cells and tissues.
  • PI3Ks are lipid kinases that generate the lipid second messenger phosphatidylinositol-3,4,5-triphosphate (PIP3), which is used downstream of cell surface receptors to regulate growth, metabolism, survival and differentiation.
  • PIP3 is produced by four distinct class I PI3K catalytic isoforms, grouped into two groups: class IA (p110 ⁇ , p110 ⁇ , and p110 ⁇ ) and class IB (p110 ⁇ ).
  • Class I PI3Ks are constitutively associated with regulatory subunits, the main difference between class IA and class IB PI3Ks is that they are associated with unique regulatory subunits.
  • Class IA PI3Ks (PI3K ⁇ , PI3K ⁇ , and PI3K ⁇ ) are heterodimers composed of the catalytic subunit p110 (p110 ⁇ , p110 ⁇ , and p110 ⁇ , respectively) and the regulatory subunit p85 (e.g., p85 ⁇ , p85 ⁇ , p55 ⁇ , p55 ⁇ , and p50 ⁇ ) Complex). These signaling responses are often transmitted through receptor tyrosine kinases (RTKs).
  • RTKs receptor tyrosine kinases
  • GPCRs G protein-coupled receptors
  • PI3K/mTOR pathway In normal cells, the PI3K/mTOR pathway has regulatory roles in cell survival, proliferation and differentiation. However, aberrant activation of this pathway has been linked to a variety of human diseases, including cancer, immunodeficiency, inflammation and developmental disorders.
  • Various inhibitors targeting key nodes within the PI3K pathway are in various stages of clinical development for the treatment of various human diseases. (“Small-molecule inhibitors of the PI3K signaling network.” Future MedChem. 2011, 3(5), 549-565).
  • the expression patterns of two isoforms of PI3K ⁇ and PI3K ⁇ are ubiquitous, while two isoforms of PI3K ⁇ and PI3K ⁇ are mainly expressed in leukocytes.
  • the relatively restricted expression pattern of PI3K ⁇ and PI3K ⁇ suggests an important role for these two isoforms in the adaptive and innate immune system (J. Med. Chem. 2012, 55(20), 8559–8581).
  • PI3K ⁇ isoforms are associated with angiogenesis and glucose homeostasis.
  • the PI3K/mTOR pathway is frequently dysregulated in cancer, often because of activating mutations or amplification of PIK3CA.
  • Gain-of-function mutations in PIK3CA (the gene encoding the PI3K p110 ⁇ catalytic subunit) are among the most common somatic alterations in solid tumors.
  • PI3K ⁇ is predominantly expressed in cells of the hematopoietic lineage and is activated by cytokine receptors, antigen receptors, growth factor receptors, and costimulatory receptors. PI3K ⁇ is important in the development and activation of T and B cells. Blockade of PI3K ⁇ signaling increases gene instability. Gain-of-function (GOF) mutations in PI3K ⁇ lead to a range of developmental and functional defects in B and T cells, thereby compromising host defense. Loss-of-function (LOF) mutations lead to more severe B-cell lymphopenia and agammaglobulinemia but not T-cell senescence.
  • GAF Gain-of-function
  • the class IB PI3K catalytic subunit p110 ⁇ is a master regulator of immune cell function, and p110 ⁇ plays a key role in immune signaling.
  • p110 ⁇ is a key factor in inflammatory diseases and has been identified as a therapeutic target in cancer due to its immunomodulatory effects.
  • PI3K ⁇ plays an important role in the regulation of myeloid (macrophages, mast cells, neutrophils) and lymphoid (T cells, B cells, and natural killer cells)-derived immune cells. It regulates immune cell chemotaxis, cytokine release and production of reactive oxygen species.
  • PI3K ⁇ The ability of PI3K ⁇ to mediate a variety of immune cell functions is controlled by its activation downstream of numerous cell surface receptors, including G protein-coupled receptors (GPCRs), IgE/antigen receptors, receptor tyrosine kinases (RTKs) and Toll-like receptors (TLRs).
  • GPCRs G protein-coupled receptors
  • IgE/antigen receptors IgE/antigen receptors
  • RTKs receptor tyrosine kinases
  • TLRs Toll-like receptors
  • genetic or pharmacological deletion of PI3K ⁇ is protective against a variety of inflammatory diseases, including cardiovascular disease, arthritis, lupus, asthma, lung inflammation and fibrosis, and metabolic syndrome.
  • PI3K ⁇ is also a driver of pancreatic ductal adenocarcinoma progression through immunomodulatory effects.
  • the PI3K pathway has been the focus of drug development research over the past two decades.
  • the PI3K ⁇ inhibitor idelalisib Zydelig; Gilead Sciences
  • the pan-class I PI3K inhibitor copanlisib (Aliqopa; Bayer) was approved in 2017, and the dual PI3K ⁇ /PI3K ⁇ inhibitor duvelisib (Copiktra; Verastem, now Secura Bio) was approved in 2018 for the same indication.
  • PI3K ⁇ inhibitor alpelisib (Piqray; Novartis) was the first and only FDA-approved drug in May 2019 in combination with the estrogen receptor (ER) down-regulator fulvestrant for the treatment of advanced PIK3CA-mutant HER2/ER+ metastases.
  • PI3K ⁇ inhibitors in breast cancer were the first and only FDA-approved drug in May 2019 in combination with the estrogen receptor (ER) down-regulator fulvestrant for the treatment of advanced PIK3CA-mutant HER2/ER+ metastases.
  • preferred compounds should bind potently to PI3K receptors while exhibiting little affinity for other receptors and exhibit functional activity as agonists.
  • the compound should be fully absorbed by the gastrointestinal tract, stable in metabolism and have good pharmacokinetic properties. They freely cross the blood-brain barrier when targeting receptors in the central nervous system and should not cross the blood-brain barrier when selectively targeting receptors in the peripheral nervous system. They should be non-toxic and show few side effects.
  • the ideal drug candidate should be in a stable, non-hygroscopic and easily formulated physical form.
  • Compounds of the invention exhibit specific levels of selectivity against different paralogs of PI3K alpha, beta, gamma and delta. In particular, a certain level of selectivity against PI3K ⁇ was shown.
  • the present invention provides a class of compounds capable of inhibiting, regulating and/or modulating the activity of PI3-kinase for treating and/or preventing diseases, disorders, and/or conditions related to PI3-kinase abnormality.
  • the compound of the present invention has better pharmacological activity, specifically, the compound of the present invention shows excellent inhibitory activity to PI3-kinase, and has high selectivity to PI3K ⁇ , and liver microsomes are stable It has obvious advantages in sex, and has good pharmacokinetic properties and higher bioavailability. Therefore, the compounds of the present invention have very good development prospects.
  • Stereoisomers refer to compounds that have the same chemical structure, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • the compounds of the present invention can be optionally substituted by one or more substituents, such as the general formula compounds of the present invention, or as specific examples, subclasses in the embodiments, and included in the present invention a class of compounds.
  • substituted means that one or more hydrogen atoms in a given structure, whether attached to C or N or otherwise, have been replaced by a particular substituent.
  • substituents Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted by one or more substituents selected from a particular group, then the substituents can be substituted at each position the same or differently.
  • C 1 -C 6 alkyl specifically refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl.
  • alkyl or "alkyl group” used in the present invention means a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group can be optionally substituted by one or more of the substituents described herein. Unless otherwise specified, an alkyl group contains 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1 - 4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms. The alkyl group may be optionally substituted with one or more substituents described herein.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CH 3 )
  • alkenyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one site of unsaturation, that is, there is a carbon-carbon sp2 double bond, which includes “cis” and " The positioning of "anti”, or the positioning of "E” and "Z".
  • an alkenyl group contains 2-8 carbon atoms; in another embodiment, an alkenyl group contains 2-6 carbon atoms; in yet another embodiment, an alkenyl group contains 2 - 4 carbon atoms.
  • the alkenyl group can be optionally substituted with one or more substituents described herein.
  • alkynyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one site of unsaturation, ie, a carbon-carbon sp triple bond.
  • the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 - 4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl ( -CH2C ⁇ CH ), 1-propynyl (-C ⁇ C- CH3 ), and the like .
  • the alkynyl group can be optionally substituted with one or more substituents described herein.
  • alkoxy denotes an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning set forth herein. Unless specified otherwise, the alkoxy groups contain 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group Groups contain 1-3 carbon atoms. The alkoxy groups may be optionally substituted with one or more substituents described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butane Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ),
  • haloalkyl or “haloalkoxy” means that an alkyl or alkoxy group is substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl (-CF 3 ), Trifluoromethoxy (-OCF 3 ), difluoroethyl (-CH 2 CHF 2 , -CF 2 CH 3 , -CHFCH 2 F), trifluoroethyl (-CH 2 CF 3 , -CF 2 CH 2 F, -CFHCHF 2 ), -CF(CH 3 ) 2 and so on.
  • halogen atoms examples of which include, but are not limited to, trifluoromethyl (-CF 3 ), Trifluoromethoxy (-OCF 3 ), difluoroethyl (-CH 2 CHF 2 , -CF 2 CH 3 , -CHFCH 2 F), trifluoroethyl (-CH 2 CF 3 , -CF 2 CH 2 F,
  • deuteroalkyl means an alkyl , alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are substituted with one or more D atoms, examples of which include, but are not limited to, monodeuteromethyl (-CH 2 D), Dideuteromethyl (-CHD 2 ), Trideuteromethyl (-CD 3 ), One Deuteriomethoxy (-OCH 2 D), Dideuuteriomethoxy (-OCHD 2 ), Trideuteriomethoxyl (-OCD 3 ), Dideuuterioethyl (-CH 2 CHD 2 , -CD 2 CH 3 , -CHDCH 2 D), Pentadeuterioethyl (-CD 2 CD 3 ), Deuterium Substituted cyclopropy
  • deuterium (D)-containing group means that one or more H atoms on the group or part of the group described in the present invention are replaced by D, but do not include a single D group, such groups include , but not limited to, C 1-6 deuterated alkyl, C 3-8 deuterated cycloalkyl, C 2-9 deuterated heterocyclyl, C 6-10 deuterated aryl, C 1-9 deuterated hetero Aryl, etc., each of which has the definition described in the present invention, wherein each of the groups is independently and optionally replaced by one or more of H, D, F, Cl, Br, I, -OH, -CN, -NO 2 , -NR e R f , C 1-6 alkyl and C 1-6 deuterated alkyl are substituted, wherein both R e and R f have the definitions described in the present invention.
  • hydroxyalkyl or "hydroxy-substituted alkyl” and “hydroxyalkoxy” or “hydroxy-substituted alkoxy” denote respectively an alkyl or alkoxy group, as the case may be, surrounded by one or more hydroxy groups, where “hydroxyalkyl” and “hydroxyalkyl” are used interchangeably, such examples include, but are not limited to, hydroxymethyl (-CH 2 OH), 2-hydroxyethyl ( -CH 2 CH 2 OH), 1-hydroxyethyl (-CH(OH)CH 3 ), 2-hydroxypropan-2-yl (-COH(CH 3 ) 2 ), 2-hydroxy-2-methylpropane (-CH 2 COH(CH 3 ) 2 ), 3-hydroxypropyl (-CH 2 CH 2 CH 2 OH), 2-hydroxypropyl (-CH 2 CH(OH)CH 3 ), 2-hydroxy- 2-methylpropyl (-CH 2 CH(OH)(CH 3 )CH 3 ), hydroxymethoxy (-OCH 2 OH) and
  • cyano-substituted alkyl or “cyanoalkyl” includes C 1-10 straight or branched chain alkyl groups substituted with one or more cyano groups.
  • cyanoalkyl is C 1-6 "lower cyanoalkyl” substituted with one or more cyano groups, and in other embodiments, cyanoalkyl is C 1-4 "lower cyanoalkyl” substituted with one or more cyano groups, examples of which include, but are not limited to, CNCH 2 -, CNCH 2 CH 2 -, CNCH 2 CH 2 CH 2 -, CNCH 2 CHCNCH 2 -, etc.
  • alkylamino includes “N-alkylamino” and "N,N-dialkylamino", wherein the amino groups are each independently substituted with one or two alkyl groups.
  • alkylamino is a lower alkylamino group with one or two C 1-6 alkyl groups attached to a nitrogen atom.
  • the alkylamino is a C 1-3 lower alkylamino group.
  • Suitable alkylamino groups may be mono- or di-alkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N- -Diethylamino and the like.
  • aminoalkyl includes C 1-10 straight or branched chain alkyl groups substituted with one or more amino groups.
  • the aminoalkyl group is a C 1-6 "lower aminoalkyl” substituted with one or more amino groups, and in other embodiments, the aminoalkyl group is substituted with one or more C 1-4 "lower aminoalkyl” substituted with an amino group, examples of which include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.
  • cycloalkyl denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms.
  • Bicyclic cycloalkyls include spirobicycloalkyls, fused bicycloalkyls and bridged bicycloalkyls.
  • cycloalkyl groups contain 3-12 carbon atoms; in other embodiments, cycloalkyl groups contain 3-10 carbon atoms; in other embodiments, cycloalkyl groups contain 3-8 carbon atoms Atom; In other embodiments, cycloalkyl contains 3-7 carbon atoms; In other embodiments, cycloalkyl contains 3-6 carbon atoms; Still in some embodiments, cycloalkyl is C 7 -C 12 cycloalkyl, which includes C 7 -C 12 monocycloalkyl, C 7 -C 12 bicycloalkyl (such as C 7 -C 12 spirobicycloalkyl, C 7 -C 12 fused bicycloalkyl and C 7 -C 12 bridged bicycloalkyl) or C 7 -C 12 tricycloalkyl.
  • the cycloalkyl groups can be independently unsubstituted or substituted with one or more substituents described herein.
  • the term "monocyclic cycloalkyl” or “monocycloalkyl” refers to a cycloalkyl group of a monocyclic ring system, wherein said cycloalkyl group has the definition as previously stated, and said monocyclic cycloalkyl group can be independently Unsubstituted or substituted with one or more substituents described herein.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclo Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl , cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.
  • cycloalkylalkyl includes cycloalkyl substituted alkyl groups.
  • a cycloalkylalkyl group refers to a "lower cycloalkylalkyl” group, ie, a cycloalkyl group attached to a C 1-6 alkyl group.
  • a cycloalkylalkyl group refers to a C 1-3 alkyl-containing "phenylalkylene.” Specific examples thereof include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentylethyl, cyclohexylethyl, and the like.
  • the cycloalkyl group on the cycloalkylalkyl group may be further substituted with one or more substituents described herein.
  • heterocyclyl and “heterocycle” are used interchangeably herein, and both refer to monovalent or multivalent, saturated or partially unsaturated, non-aromatic monocyclic, Bicyclic or tricyclic ring systems wherein at least one ring atom is selected from nitrogen, oxygen and sulfur atoms.
  • a heterocyclyl or heterocycle contains 4-12 ring atoms.
  • a heterocyclyl or heterocycle contains 5-12 ring atoms.
  • a heterocyclyl or heterocycle contains 4-8 ring atoms.
  • a heterocyclyl or heterocycle contains 3-10 ring atoms.
  • a heterocyclyl or heterocycle contains 3-8 ring atoms. In some embodiments, a heterocyclyl or heterocycle contains 3-6 ring atoms. In some embodiments, a heterocyclyl or heterocycle contains 4-7 ring atoms.
  • the heterocyclic group includes a saturated heterocyclic group (heterocycloalkyl group) and a partially unsaturated heterocyclic group.
  • Said heterocyclyl has one or more points of attachment to the rest of the molecule.
  • heterocyclic groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazole Alkyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolyl, dithiocyclopentyl, tetrahydropyranyl , Dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidiny
  • Examples of oxidized sulfur atoms in heterocyclic groups include, but are not limited to, sulfolane, 1,1-dioxothiomorpholinyl.
  • Said heterocyclyl groups may be optionally substituted with one or more substituents described herein.
  • the heterocyclic group is a heterocyclic group composed of 4-7 atoms, which refers to a monovalent or polyvalent, saturated or partially unsaturated non-aromatic monocyclic ring containing 4-7 ring atoms Or bicyclic, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms.
  • Ring sulfur atoms can optionally be oxidized to S-oxides.
  • Ring nitrogen atoms can optionally be oxidized to N-oxygen compounds.
  • the 4-7 atom heterocyclic group has one or more points of attachment to the rest of the molecule.
  • examples of monocyclic heterocyclic groups composed of 4-7 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl , pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, dihydrothiophenyl, tetrahydropyranyl, dihydropyranyl, 2H -pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, 1,2-oxaziny
  • heterocyclylalkyl includes heterocyclyl substituted alkyl, wherein both heterocyclyl and alkyl have the meanings described herein, such examples include, but are not limited to tetrahydrofuranylmethyl, pyrrole- 2-ylmethyl, morpholin-4-ylethyl, piperazin-4-ylethyl, piperidin-4-ylethyl and the like.
  • aryl denotes monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic family in which each ring system contains rings of 3-7 atoms and has one or more points of attachment to the rest of the molecule.
  • aryl is used interchangeably with the term “aromatic ring”. Examples of aryl groups may include phenyl, naphthyl and anthracenyl. The aryl groups may be independently optionally substituted with one or more substituents described herein.
  • arylalkyl or “aralkyl” includes aryl-substituted alkyl groups.
  • an arylalkyl group refers to a "lower arylalkyl” group, ie, an aryl group attached to a C 1-6 alkyl group.
  • an arylalkyl group refers to a C 1-3 alkyl-containing "phenylalkylene.” Specific examples thereof include, but are not limited to, benzyl, diphenylmethyl, phenethyl and the like.
  • the aryl group on the arylalkyl group may be further substituted with one or more substituents described herein.
  • heteroaryl denotes monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein all rings are aromatic, and At least one aromatic ring contains one or more heteroatoms, wherein each ring system contains rings of 5-7 atoms and has one or more points of attachment to the rest of the molecule.
  • heteroaryl may be used interchangeably with the terms “heteroaryl” or “heteroaromatic”.
  • the heteroaryl group is a 5-12 atom heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • the heteroaryl group is a 5-10 atom heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In another embodiment, the heteroaryl group is a 5-6 atom heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • the heteroaryl group is optionally substituted with one or more substituents described herein.
  • heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-thi
  • heteroarylalkyl means that an alkyl group is substituted by one or more heteroaryl groups, wherein both heteroaryl and alkyl groups have the meanings described herein, examples of which include, but are not Limited to, pyridine-2-methyl, imidazol-2-methyl, furan-2-ethyl, indole-3-methyl and the like.
  • halogen refers to F, Cl, Br or I.
  • connection points in the ring system connected to the rest of the molecule there are two connection points in the ring system connected to the rest of the molecule, as shown in formula (a1), which means that either the E end or the E' end is connected to the rest of the molecule, that is, the two ends of the Connection methods can be interchanged.
  • substituents are bonded to a central ring to form a ring system (shown below) meaning that substituents can be substituted at any substitutable position on either ring.
  • formula b represents that any position that may be substituted on ring A or ring B can be substituted, such as formula c, d, e, f, g, h, i, j, k, l, m, n, o, Shown by p, q, etc.
  • the "pharmaceutically acceptable salt” used in the present invention refers to organic and inorganic salts of the compounds of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods such as ion exchange methods recorded in books and literature these salts.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3 - Phenylpropionate,
  • Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates the quaternary ammonium salts of any compound containing an N group.
  • Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed as counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1 -8 sulfonates and aromatic sulfonates.
  • a “solvate” of the present invention refers to an association of one or more solvent molecules with a compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to an association of solvent molecules with water.
  • the invention discloses a novel class of pyrimidine amine compounds, which can be used as inhibitors of PI3-kinase activity, especially PI3K- ⁇ activity, for preventing, treating, treating, and/or alleviating PI3-kinase abnormality-related diseases, disorders, and/or conditions such as respiratory disease, viral infection, non-viral respiratory infection, allergic disease, autoimmune disease, inflammatory disease, cardiovascular disease, hematologic malignancy, neurodegenerative disease, pancreatitis, multiorgan failure, Kidney disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, lung damage or pain, etc.
  • PI3-kinase abnormality-related diseases, disorders, and/or conditions such as respiratory disease, viral infection, non-viral respiratory infection, allergic disease, autoimmune disease, inflammatory disease, cardiovascular disease, hematologic malignancy, neurodegenerative disease, pancreatitis, multiorgan failure, Kidney disease, platelet aggregation, cancer, sperm mot
  • the compound of the present invention Compared with existing similar compounds, the compound of the present invention has better pharmacological activity, specifically, the compound of the present invention shows excellent inhibitory activity to PI3-kinase and has high selectivity to PI3K ⁇ , and pharmacokinetic Significant advantages in academics. Therefore, the compounds of the present invention have very good development prospects.
  • the compounds disclosed in the present invention can show strong inhibitory activity on PI3-kinase, especially PI3K- ⁇ .
  • the present invention provides a kind of isoquinolones and quinazolinones compound, it has the structure shown in formula (I):
  • X is -C(R c )-, or N;
  • Z 1 and Z 2 are each independently -C(R 4d )- or N;
  • R a , R b and R c are each independently H, D, F, Cl, C 1-3 alkyl, C 1-6 deuterated alkyl, C 1-3 alkoxy, C 1-3 haloalkyl , C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, C 1-3 cyanoalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkyl substituted by 1 to 5 deuteriums , a C 1-6 hydroxyalkyl group substituted by 1 to 5 deuteriums, a C 3-8 cycloalkyl group substituted by 1 to 5 deuteriums, or a C 1-9 heteroaryl group substituted by 1 to 5 deuteriums;
  • R 3 is H, D, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkane Base, C 3-8 deuterated cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein R 3 is optionally replaced by 0, 1, 2, 3 , 4 or 5 R 6 substitutions;
  • R e , R f , R 7 and R 7a are independently H, D, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 2-9 heterocyclyl, C 2-9 heterocyclyl C 1-6 alkyl , C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each C 1 -6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-9 heterocyclyl, C 2-9 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C
  • n 0, 1, 2, or 3;
  • the present invention provides a kind of isoquinolones and quinazolinones compound, it has the structure shown in formula (Ib):
  • X is -C(R c )-, or N;
  • Z 1 and Z 2 are each independently -C(R 4d )- or N;
  • R a , R b and R c are each independently H, D, F, Cl, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 alkoxy, C 1-3 haloalkyl , C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, or C 1-3 cyanoalkyl;
  • R 3 is H, D, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkane Base, C 3-8 deuterated cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein R 3 is optionally replaced by 0, 1, 2, 3 , 4 or 5 R 6 substitutions;
  • R e , R f , R 7 and R 7a are independently H, D, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 2-9 heterocyclyl, C 2-9 heterocyclyl C 1-6 alkyl , C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each C 1 -6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-9 heterocyclyl, C 2-9 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C
  • n 0, 1, 2, or 3;
  • the compound shown in formula (I) has the structure shown in formula (Ia):
  • R is phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, thiazolyl, imidazolyl, oxazolyl, thiazolyl oxadiazolyl,
  • Y 1 is O, S, or -NH-;
  • Y 6 is O, or -NH-
  • t3 and t4 are each independently 1, 2, 3 or 4;
  • R is optionally substituted by 0, 1, 2, 3 or 4 R 5 ;
  • R 1 is When, wherein R 1 is optionally substituted by 0, 1, 2, 3 or 4 R 5 , then at least one of each R 2 , R 4a , R 4b and R 4c is independently F, Cl, -CN, C 1-3 alkoxy, C 1-3 deuterated alkyl, C 1-3 deuterated alkoxy, C 1-3 haloalkyl substituted by 1 to 5 deuteriums, substituted by 1 to 5 deuteriums C 1-3 hydroxyalkyl, C 3-6 cycloalkyl substituted by 1 to 5 deuteriums, or C 1-9 heteroaryl substituted by 1 to 5 deuteriums; 2) when R 1 is phenyl, Pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, thiazolyl, imidazolyl, oxazolyl, thiadiazolyl, , wherein R 1 is optionally substituted by 0, 1, 2, 3 or 4 R
  • R is phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, thiazolyl, imidazolyl, oxazolyl, thiazolyl oxadiazolyl,
  • Y 1 is O, S, or -NH-;
  • Y 6 is O, or -NH-
  • t3 and t4 are each independently 1, 2, 3 or 4;
  • R is optionally substituted by 0, 1, 2, 3 or 4 R 5 ;
  • R 1 is , then at least one of R 2 , R 4a , R 4b and R 4c is independently F, Cl, or a deuterium-containing group; 2) when R 1 is phenyl, pyridyl, pyridazinyl, pyridyl Azinyl, pyrimidinyl, triazinyl, thiazolyl, imidazolyl, oxazolyl, thiadiazolyl, , then at least one of R a , R b , R c , R 2 , R 3 , R 4a , R 4b , R 4c and R 4d is independently D (deuterium), or a deuterium-containing group.
  • R 4a , R 4b , R 4c and R 4d are each independently H, F, Cl, D, -CN, -OCH 3 , - OCH2CH3 ,
  • X is -C(R c )-, or N;
  • W is C 3-10 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein W is optionally replaced by 0, 1, 2, 3 or 4 R 4 replaces;
  • R a , R b and R c are each independently H, D, F, Cl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, or C 1-6 cyanoalkyl;
  • Y 2 and Y 3 are each independently -(CH 2 ) t1 -, -(CH 2 ) t1 -L-, -(CH 2 ) t1 -L-(CH 2 ) t2 -, O, or -NH- ;
  • Y 5 is -CH-, or N
  • Y 6 is O, or -NH-
  • Y 7 is O, or -NH-
  • each occurrence of t1, t2 and t3 is independently 1, 2, 3 or 4;
  • R is optionally substituted by 0, 1, 2, 3 or 4 R 5 ;
  • R 3 is H, D, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkane Base, C 3-8 deuterated cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein R 3 is optionally replaced by 0, 1, 2, 3 , 4 or 5 R 6 substitutions;
  • R e , R f , R 7 and R 7a are independently H, D, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 2-9 heterocyclyl, C 2-9 heterocyclyl C 1-6 alkyl , C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each C 1 -6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-9 heterocyclyl, C 2-9 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C
  • n 0, 1, 2, or 3.
  • W is C 3-8 cycloalkyl, C 3-8 heterocyclyl
  • Z 1 , Z 2 and Z 3 are each independently -CH-, or N;
  • W is optionally substituted by 0, 1, 2, 3 or 4 R 4 .
  • the compound shown in formula (II) has the structure shown in formula (IIa):
  • n 0, 1, 2 or 3.
  • R is wherein R 1 is optionally substituted by 0, 1, 2, 3 or 4 R 5 .
  • R 3 is cyclopropyl, pyridyl, or phenyl; wherein R 3 is optionally replaced by 0, 1, 2, 3, 4 or 5 independently selected from H, D, F, Cl, Br, I, -OH, -CN, -NO 2 , -NR e R f , C 1-3 alkyl, C 1 -3 alkoxy, C 1-3 deuterated alkyl and C 1-3 haloalkyl group substitution.
  • R a , R b and R c are each independently H, D, F, -CN, -NO 2 , -NR e R f , methyl, ethyl, isopropyl, -CD 3 , -CHD 2 , -CH 2 D, methoxy, ethoxy, halomethyl, haloethyl, or -CH 2 CH 2 OH.
  • R e , R f , R 7 and R 7a are independently H , D, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-4 alkyl, C 3-6 heterocyclyl, C 3-6 heterocyclyl C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, C 1 -9 heteroaryl, or C 1-9 heteroaryl C 1-4 alkyl; wherein each C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 1 -4 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-4 alkyl, C 3-6 heterocycly
  • R e , R f , R 7 and R 7a are independently H , D, C 1-2 alkyl, C 1-2 deuterated alkyl, C 1-2 haloalkyl, phenyl, or cyclopropyl.
  • the compound is a compound having one of the following structures:
  • the compound is a compound having one of the following structures:
  • the compounds disclosed herein may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms.
  • the present invention intends to make all stereoisomeric forms of compounds shown in formula (I), (Ia), (Ib), (II) or (IIa), including but not limited to diastereoisomers, enantiomers isomers, atropisomers and geometric (or conformational) isomers, as well as mixtures thereof, such as racemic mixtures, form part of the present invention.
  • stereochemistry of any particular chiral atom when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers of the structure are contemplated and included in the present invention as disclosed compounds .
  • stereochemistry is indicated by a solid wedge or a dashed line indicating a particular configuration, then the stereoisomers of that structure are identified and defined.
  • the compound represented by formula (I), (Ia), (Ib), (II) or (IIa) may exist in the form of a salt.
  • the salt refers to a pharmaceutically acceptable salt.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or with the mammal being treated therewith.
  • the salt is not necessarily a pharmaceutically acceptable salt, but may be used for preparing and/or purifying the salt shown in formula (I), (Ia), (Ib), (II) or (IIa).
  • the present invention relates to intermediates for the preparation of compounds represented by formula (I), (Ia), (Ib), (II) or (IIa).
  • the present invention relates to methods for preparing, isolating and purifying compounds represented by formula (I), (Ia), (Ib), (II) or (IIa).
  • the present invention provides a pharmaceutical composition comprising a compound of the present invention.
  • the pharmaceutical composition of the present invention further includes a pharmaceutically acceptable adjuvant, diluent or carrier, or a combination thereof.
  • the pharmaceutical composition may be in liquid, solid, semi-solid, gel or spray form.
  • compositions described herein further comprise additional therapeutic agents.
  • the present invention relates to a method for preventing, treating, treating, and/or alleviating PI3-kinase-mediated diseases, disorders, and and/or a condition, or use in a drug that inhibits PI3-kinase activity.
  • the PI3-kinase-mediated disease, disorder, and/or condition is selected from respiratory disease, viral infection, non-viral respiratory infection, allergic disease, autoimmune disease, inflammatory disease, cardiovascular disease , hematological malignancy, neurodegenerative disease, pancreatitis, multiple organ failure, renal disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, lung injury, or pain.
  • the PI3-kinase-mediated disease, disorder, and/or condition is selected from asthma, chronic obstructive pulmonary disease (COPD), viral respiratory infection, exacerbation of viral respiratory disease, aspergillosis, leishmaniasis disease, allergic rhinitis, allergic dermatitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, thrombosis, atherosclerosis, hematological malignancy, neurodegenerative disease, pancreatitis, multiple organ failure, kidney disease , platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, lung injury, pain associated with rheumatoid arthritis or osteoarthritis, back pain, systemic inflammatory pain, retrohepatic neuralgia, diabetic neuropathy , inflammatory neuropathic pain (trauma), trigeminal neuralgia or central pain.
  • COPD chronic obstructive pulmonary disease
  • viral respiratory infection exacerbation of viral
  • the cancer is selected from acute myelogenous leukemia, myelodysplastic syndrome, myeloproliferative disorder, chronic myelogenous leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, non-Hodgkin's lymphoma , B-cell lymphoma, solid tumor, or breast cancer.
  • PI3-kinase is PI3K- ⁇ .
  • the present invention provides a pharmaceutical composition, which comprises the compounds disclosed in the present invention, or the compounds listed in the examples, or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites or pharmaceutically an acceptable salt; and a pharmaceutically acceptable adjuvant, diluent, carrier, vehicle or a combination thereof.
  • the amount of the compound in the pharmaceutical composition disclosed in the present invention refers to the amount that can effectively detect and inhibit the protein kinase in biological samples or patients.
  • compositions of the invention may exist in free form for use in therapy or, if appropriate, as a pharmaceutically acceptable derivative thereof.
  • pharmaceutically acceptable derivatives include pharmaceutically acceptable salts, esters, salts of these esters, or compounds that provide, directly or indirectly, the compounds of the present invention or their derivatives when administered to a patient in need thereof. Any additional adducts or derivatives of metabolites or residues.
  • compositions provided by the present invention can be formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.
  • the compounds of the invention are inhibitors of kinase activity, especially inhibitors of PI3-kinase activity.
  • Compounds that are PI3-kinase inhibitors are useful in the treatment of disorders in which the underlying pathology is attributable (at least in part) to inappropriate PI3-kinase activity, such as asthma, chronic obstructive pulmonary disease (COPD), viral infections, non-viral respiratory infections, Allergic disease, autoimmune disease, inflammatory disease, cardiovascular disease, hematologic malignancy, neurodegenerative disease, pancreatitis, multiorgan failure, renal disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, Lung damage or pain, etc.
  • COPD chronic obstructive pulmonary disease
  • Inappropriate PI3-kinase activity refers to any PI3-kinase activity that deviates from the normal PI3-kinase activity expected in a particular patient.
  • An inappropriate PI3-kinase can take the form, for example, of an abnormal increase in activity, or an aberration or malfunction of the PI3-kinase. These inappropriate activities may result, for example, from overexpression or mutations of protein kinases that result in inappropriate or uncontrolled activation. Accordingly, in another aspect, the invention relates to methods of treating said diseases or conditions.
  • Such diseases or conditions include, but are not limited to, respiratory diseases, including asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis (IPF); viral infections, including viral respiratory infections and viral respiratory disease exacerbations, Examples include asthma and COPD; nonviral respiratory infections, including aspergillosis and leishmaniasis; allergic diseases, including allergic rhinitis and atopic dermatitis; autoimmune diseases, including rheumatoid arthritis and multiple sclerosis; Inflammatory disease, including inflammatory bowel disease; cardiovascular disease, including thrombosis and atherosclerosis; hematological malignancies; neurodegenerative disease; pancreatitis; multiple organ failure; renal disease; platelet aggregation; cancer; sperm motility ; transplant rejection; graft rejection; lung injury; and pain, including pain associated with rheumatoid arthritis or osteoarthritis, back pain, systemic inflammatory pain, retrohepatic neuralgia, diabetic neuropathy, inflammatory
  • such disorders include, respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD); allergic diseases, including allergic rhinitis and atopic dermatitis; autoimmune diseases, including rheumatoid arthritis inflammation and multiple sclerosis; inflammatory diseases, including inflammatory bowel disease; cardiovascular disease, including thrombosis and atherosclerosis; hematological malignancies; neurodegenerative diseases; pancreatitis; multiple organ failure; renal disease; platelets Aggregation; cancer; sperm motility; transplant rejection; Neuropathy, inflammatory neuropathic pain (trauma), trigeminal neuralgia, and central pain.
  • respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD); allergic diseases, including allergic rhinitis and atopic dermatitis; autoimmune diseases, including rheumatoid arthritis inflammation and multiple sclerosis; inflammatory diseases, including inflammatory bowel disease; cardiovascular disease, including thrombosis and atherosclerosis; hematological malignancies;
  • the cancer is selected from acute myelogenous leukemia, myelodysplastic syndrome, myeloproliferative disorder, chronic myelogenous leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, non-Hodgkin Gold lymphoma, B-cell lymphoma, solid tumor, or breast cancer.
  • the treatment method of the present invention comprises administering a safe and effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof to a patient in need.
  • Various embodiments of the present invention include methods for treating any of the disorders or diseases mentioned in the present invention by administering a safe and effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof to a patient in need.
  • the compounds of the present invention may be administered as the sole active agent, or may be administered in combination with other therapeutic agents, including other compounds that have the same or similar therapeutic activity and are determined to be safe and effective for such combination administration.
  • the present invention provides a method for treating, preventing or ameliorating a disease or condition, comprising administering a safe and effective amount of a combination drug comprising a compound disclosed in the present invention and one or more therapeutically active agents.
  • the combination comprises one or two other therapeutic agents.
  • therapeutic agents include, but are not limited to: anti-cancer agents, including chemotherapeutics and anti-proliferative agents; anti-inflammatory agents; and immunomodulators or immunosuppressants.
  • the invention provides a product comprising a compound of the invention and at least one other therapeutic agent, prepared as a combination for simultaneous, separate or sequential administration in therapy.
  • the treatment is for a disease or condition mediated by the activity of one or more protein kinases, such as PI3k-kinase.
  • Products provided by combination preparations include compositions comprising a compound disclosed herein and an additional therapeutic agent in the same pharmaceutical composition, or in different forms, eg, a kit.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed herein and one or more additional therapeutic agents.
  • the pharmaceutical composition may comprise pharmaceutically acceptable excipients as described above.
  • the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound disclosed herein.
  • the kit includes means for individually maintaining the compositions, such as containers, divided bottles, or divided foil boxes.
  • An example of such a kit is a blister pack, which is commonly used for packaging tablets, capsules and the like.
  • Compounds disclosed herein may be administered as the sole active ingredient or co-administered with other therapeutic agents, eg, as adjuvants.
  • such additional therapeutic agents include, for example, immunosuppressants, immunomodulators, or other anti-inflammatory agents for the treatment or prevention of acute or chronic rejection of allograft or xenograft, or inflammatory, or autoimmune disease drugs, or chemotherapeutic agents, such as antiproliferative agents for malignant tumor cells.
  • the compound represented by the formula (I) of the present invention is used together with other immunosuppressants/immunomodulators, anti-inflammatory agents, chemotherapeutic agents or anti-infective agents, wherein immunosuppressants/immunomodulators, anti-inflammatory agents, chemotherapeutic agents Or the dose of anti-infective agent co-administration depends on the type of co-administration, whether it is a steroid compound or a calcineurin inhibitor, and the specific drug being used for treatment and the treatment situation.
  • anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAIDs).
  • NSAIDs include cromolyn sodium, nedocromil sodium, phosphodiesterase (PDE) inhibitors (such as theophylline, PDE4 inhibitors, or mixed PDE3/PDE4 inhibitors), leukotriene antagonists , leukotriene synthesis inhibitors (eg, montelukast), iNOS inhibitors, trypsin and elastase inhibitors, beta-2 integrin antagonists, and adenosine receptor agonists or antagonists (eg, adenosine 2 ⁇ receptor agonists), cytokine antagonists (such as chemokine receptor antagonists, including CCR3 antagonists), cytokine synthesis inhibitors, or 5-lipoxygenase inhibitors.
  • PDE phosphodiesterase
  • the compounds of formula (I) may also advantageously be used in combination with other compounds, or in combination with other therapeutic agents, especially antiproliferative agents.
  • antiproliferative agents include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule activating agents; alkylating agents; histone deacetylation Enzyme inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platinum compounds; compounds that target/reduce protein or lipid kinase activity and other anti- Angiogenic compounds; Compounds that target, decrease, or inhibit protein or lipid phosphatase activity; Gonadorelin-like agonists; Antiandrogens; Methionine aminopeptidase inhibitors; Bisphosphonates; Biological response modifiers ; antiproliferative antibodies; heparanase inhibitors
  • Combination means a fixed combination in single dosage unit form or a kit of parts for combined administration wherein the compound disclosed herein and the combination partner may be administered independently at the same time or may be administered separately at intervals , especially to make joint partners exhibit cooperation, such as synergy.
  • co-administration or “combination administration” and the like as used herein are intended to encompass the administration of selected combination partners to a single individual (e.g. patient) in need thereof, and are intended to include where the substances do not necessarily have to be administered by the same route of administration or Concomitant treatment regimens.
  • the methods of treatment disclosed herein comprise administering to a patient in need thereof a safe and effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
  • Various embodiments disclosed herein include methods of treating the diseases or conditions described herein by administering to a patient in need thereof a safe and effective amount of a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein.
  • a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein may be administered at one time, or several times at different time intervals within a specified period of time according to a dosing regimen. For example, once, twice, three or four times per day. In one embodiment, the administration is once daily. In yet another embodiment, the administration is twice daily. Administration can be until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for compounds disclosed herein or pharmaceutical compositions comprising compounds disclosed herein depend on the pharmacokinetic properties of the compound, such as dilution, distribution and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens for compounds disclosed herein or pharmaceutical compositions comprising compounds disclosed herein including the duration for which such regimens are carried out, depend on the disease being treated, the severity of the disease being treated, the age and Physical condition, medical history of the patient being treated, nature of concurrent therapy, desired therapeutic effect, etc., are factors within the knowledge and experience of the skilled person. It will also be understood by those skilled in the art that the response of an individual patient to the dosing regimen, or as the individual patient's needs change over time, may require adjustment of the appropriate dosing regimen.
  • the pharmaceutical composition or combination/combination of the present invention may be about 1-1000 mg active ingredient, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1 - a unit dose of 50 mg of active ingredient.
  • Therapeutically effective dosages of the compounds, pharmaceutical compositions or combinations thereof depend on the individual's species, body weight, age and individual disease, disorder or condition or severity being treated. A physician, clinician or veterinarian of ordinary skill in the art can readily determine the effective amount of each active ingredient for preventing, treating or inhibiting the progression of a disease or condition.
  • the dosage properties cited above have been demonstrated in in vitro and in vivo experiments using mammals, eg, mice, rats, dogs, monkeys, or isolated organs, tissues and specimens thereof, advantageously.
  • the compounds of the present invention can be administered in vitro in the form of solutions, eg, aqueous solutions, and in vivo in the form of suspensions or aqueous solutions enterally, parenterally and preferably intravenously.
  • a therapeutically effective amount in vivo ranges depending on the route of administration and is between about 0.01-500 mg/kg, or between about 1-100 mg/kg.
  • a compound disclosed herein may be administered simultaneously with, prior to, or subsequent to, one or more other therapeutic agents.
  • the compound of the present invention can be administered separately with other therapeutic agents through the same or different routes of administration, or in the form of the same pharmaceutical composition.
  • the compounds of the present invention can be prepared by the methods described in the present invention, unless there are further instructions, wherein the substituents are defined as formula (I), (Ia), (Ib), (II) or (IIa) shown.
  • the following reaction schemes and examples serve to further illustrate the present invention.
  • Anhydrous THF, dioxane, DCM, toluene and DMF were purchased from commercial suppliers such as Energy chemical company and Aldrich chemical company.
  • EtOAc, PE, CH3CN , NMP and DMSO were all treated with anhydrous Na2SO4 before use.
  • reaction vials were fitted with suitable rubber stoppers, and the substrate was introduced by syringe. Glassware is dried.
  • the chromatographic column is a silica gel column.
  • Silica gel 300-400 mesh was purchased from Qingdao Ocean Chemical Factory.
  • 1 H NMR spectra and 13 C/2D data were collected on a Bruker Avance III 400 MHz.
  • 1 H NMR spectrum uses CDC1 3 , DMSO-d 6 , CD 3 OD or acetone-d 6 as the solvent (in ppm), and TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard.
  • LC/MS was performed on an Agilent 1260 (binary pump/DAD detector) coupled to an Agilent 6120/6125 mass spectrometer.
  • MeCN aqueous solution (0.1% HCOOH), flow rate: 20ml/min, 50ml/min, column 30x250mm, 10 ⁇ m; wavelength: 210-400nm. Samples were injected into DMSO (+ optional formic acid and water) and eluted with a linear gradient from 10% to 95% MeCN over 10 minutes.
  • Aqueous solution of MeCN (0.1% trifluoroacetic acid), flow rate: 20ml/min, 50ml/min, column 30x250mm, 10 ⁇ m; wavelength: 210-400nm. Samples were injected into DMSO (+ optional formic acid and water) and eluted with a linear gradient from 10% to 95% MeCN over 10 minutes.
  • Aqueous solution of MeCN (0.1% NH 3 -H 2 O/10 mM NH 4 AC), flow rate: 20 ml/min, 50 ml/min, column 30x250 mm, 10 ⁇ m; wavelength: 210-400 nm.
  • Samples were injected into DMSO (+ optional formic acid and water) and eluted with a linear gradient from 10% to 95% MeCN over 10 minutes.
  • R 1 , R 2 , R 3 , R 4a , R 4b , R 4c , R a , R b , X, Z 1 , Z 2 , W and n all have the definitions as described in the present invention.
  • the compound of the present invention having the structure shown in formula (6) can be prepared by the general synthesis method described in Synthesis Scheme 1, and the specific steps can be referred to the examples.
  • compound (1) can be synthesized by purchasing commercial reagents or referring to literature (WO2016149160A1).
  • Compound (1) is coupled with a terminal alkyne substituted with R 1 under the catalysis of a suitable palladium salt or copper salt to obtain compound (3).
  • the Boc protecting group is removed under acidic conditions to obtain the derivative of compound (4).
  • Compound (4) and compound (5) react under suitable alkaline conditions or in the presence of a condensing agent to obtain the target kinase inhibitor (6).
  • the compound of the present invention having the structure shown in formula (8) can be prepared by the general synthesis method described in Synthesis Scheme 2, and the specific steps can be referred to the examples.
  • Synthesis Scheme 2 amine derivatives (4) and carboxylic acid derivatives (7) are condensed in the presence of a suitable condensing agent to obtain the target kinase inhibitor (8).
  • the alkyne derivatives with the structure shown in formula (2) can be prepared by the general synthesis method described in Fragment Synthesis Scheme 1, and the specific steps can be referred to the examples.
  • compound (2-a) is under suitable basic conditions (such as potassium carbonate, cesium carbonate and potassium phosphate, etc.), and trimethylethynyl silicon is under the catalysis of suitable palladium salt and copper salt Coupling affords compound (2-b).
  • suitable basic conditions such as potassium carbonate, cesium carbonate and potassium phosphate, etc.
  • trimethylethynyl silicon is under the catalysis of suitable palladium salt and copper salt Coupling affords compound (2-b).
  • the TMS protecting group was removed by TBAF to obtain the alkyne derivative (2).
  • R substituted aldehyde derivatives (2-c) under suitable basic conditions, and (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester at low temperature reaction to give alkyne Class derivatives (2).
  • the carboxylic acid derivative having the structure shown in formula (5) can be prepared by the general synthesis method described in Fragment Synthesis Scheme 2, and the specific steps can be referred to the examples.
  • Synthesis Scheme 3 compound (5-a) is deethylated under suitable basic conditions to obtain carboxylic acid derivative (5-b).
  • Compound (5-b) and compound (4) are condensed in the presence of a condensing agent (such as EDCI or HATU) to obtain the target kinase inhibitor (6).
  • a condensing agent such as EDCI or HATU
  • Compound (5-b) and N-hydroxysuccinimide are condensed in the presence of a condensing agent to obtain compound (5-c). Under suitable alkaline conditions, compound (5-c) reacts with compound (4) to obtain target kinase inhibitor (6).
  • deuterium-containing synthetic building blocks used in the synthesis of compounds of the present invention include commercial reagents, and can be synthesized through references (such as WO2017161116A1), specifically including but not limited to the following structures:
  • EDCI (279.8 mg, 1.46 mmol) and 1-hydroxypyrrolidine-2,5-dione (168 mg, 1.46 mmol) were added to 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid ( 200 mg, 1.12 mmol) in DMF (10 mL), the mixture was stirred at room temperature for 16 h. After the reaction was completed, it was diluted with water (30ml), and extracted three times with ethyl acetate (30mL x 3).
  • Step 8) (S)-2-amino-N-(1-(8-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)ethynyl)- 1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-5,7-D2-3-carboxamide
  • the mixture was cooled to room temperature, concentrated under reduced pressure to remove solvent, and diluted with dichloromethane (30 mL). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure.
  • Step 5 3-((1S)-1-aminoethyl)-8-(2-(1-((2,4-dimethoxyphenyl)methyl)-5-oxopyrrolidine-3 -yl)ethynyl)-2-phenylisoquinolin-1-one
  • the mixture was heated at 80°C for 5 hours, and after cooling down to room temperature, the mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate (30 mL), the mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrate under reduced pressure.
  • n-butyllithium (2.4N n-hexane solution, 5.9mL, 14.3mmol) dropwise to a solution of diisopropylamine (1.38g, 13.6mmol) in tetrahydrofuran (30mL). Stir for 1 hour. Then the mixture was cooled to -70°C, a solution of 4-(1-bromovinyl)dihydrofuran-2(3H)-one (650mg, 3.4mmol) in tetrahydrofuran (3mL) was added, stirred at -10°C for 2 hours .
  • Step 3 3-((S)-1-aminoethyl)-8-((5-oxotetrahydrofuran-3-yl)ethynyl)-2-phenylisoquinolin-1(2H)-one
  • Step 2) 3-((S)-1-aminoethyl)-8-((3-hydroxyoxetan-3-yl)ethynyl)-2-phenylnaphthalene-1(2H)-one
  • Step 2 Tert-butyl (S)-(4-(3-chloro-2-(cyclopropylcarbamoyl)phenyl)-3-oxobutan-2-yl)carbamate
  • Step 6 (S)-2-amino-N-(1-(8-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)ethynyl)-1- Oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
  • Step 2) 7-Bromo-2,3-dihydropyrazolo[5,1-b]oxazole
  • Step 6) (S)-2-amino-N-(1-(8-((2,3-dihydropyrazolo[5,1-b]oxazol-7-yl)ethynyl)-1- Oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
  • Step 2 (S)-2-amino-N-(1-(5-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)ethynyl)- 4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
  • Step 2) (S)-2-amino-N-(1-(7-fluoro-8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2- Phenyl-1,2-dihydroisoquinolin-3-yl))ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
  • Step 6) (S)-2-amino-N-(1-(8-((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3- Base) ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
  • the mixture was diluted with DCM (50 mL) and washed with brine (30 mL x 2). The layers were separated, and the organic phase was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo.
  • Step 7) (S)-2-amino-N-(1-(6-fluoro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-3- Phenyl-3,4-dihydroquinazolin)-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
  • Example 29 2-Amino-N-((1S)-1-(8-(2-(1-methyl-5-oxopyrrolidin-3-yl)ethynyl)-1-oxo-2 -phenylisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; and
  • Example 30 6-(3-((S)-1-(2 -aminopyrazolo[1,5-a]pyrimidine-3-carboxamido)ethyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-8-yl)-4 -Hydroxy-hex-5-ynoic acid methyl ester
  • Step 3 3-((1S)-1-aminoethyl)-8-(2-(5-oxooxolan-2-yl)ethynyl)-2-phenylisoquinoline-1 - Ketone; 6-(3-((S)-1-aminoethyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-8-yl)-4-hydroxy-hexyl -5-ynoic acid methyl ester
  • Step 4) 2-amino-N-((1S)-1-(8-(2-(1-methyl-5-oxopyrrolidin-3-yl)ethynyl)-1-oxo-2- phenylisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; 6-(3-((S)-1-(2-aminopyrazolo[ 1,5-a]pyrimidine-3-carboxamido)ethyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-8-yl)-4-hydroxy-hexan-5 -Methyl alkynoate
  • Step 2) 4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-5-carbaldehyde
  • Step 7) (S)-2-amino-N-(1-(8-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3- Base) ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
  • Step 1) (S)-2-(1-aminoethyl)-5-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)ethynyl)-6- Fluoro-3-phenylquinazolin-4(3H)-one
  • 6-ethynyl-2,3-dihydropyrazolo[5,1-b]oxazole (50mg, 0.14mmol) and 2-ethynyl-5H,6H-pyrazolo[3 ,2-b][1,3]oxazole (18.5 mg, 0.14 mmol) in acetonitrile (20 mL) was added Pd 2 (dba) 3 (32 mg, 0.034 mmol), X-phos (33 mg, 0.07 mmol) and K 3 PO 4 (88mg, 0.41mmol), the mixture was warmed up to 80°C and stirred for 4h. After cooling to room temperature, it was concentrated in vacuo.
  • Step 2 (S)-2-amino-N-(1-(5-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)ethynyl)-6- Fluoro-4-oxo-3-phenyl)-3,4-dihydroquinazolin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
  • Step 9) 3-((S)-1-Aminoethyl)-8-(((R)-5-Hydroxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole- 3-yl)ethynyl)-2-phenylisoquinolin-1(2H)-one
  • Step 2) (S)-tert-butyl(4-(3-chloro-4-fluoro-2-((phenyl-d5)carbamoyl)phenyl)-3-oxobutan-2-yl)carbamate ester
  • Step 6 (S)-2-amino-N-(1-(7-fluoro-8-((1-methyl-1H-pyrazol-4-yl-5-d)ethynyl)-1-oxo Substitute-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
  • nitric acid (4.1 g, 0.064 mol, 2.6 mL) was added dropwise to a solution of 2-chloro-6-methylbenzoic acid (10 g, 0.0586 mol) in sulfuric acid (100 mL), and the mixture was stirred for 30 minutes, then transferred To room temperature, stirred for 16h. The mixture was slowly poured into ice water (260 mL) and stirring was continued for 1 h. After filtration, the filter cake was washed with water (50 mL) and dried in vacuo to obtain 6-chloro-2-methyl-3-nitrobenzoic acid (12.5 g, yield 98%) as a white solid.
  • LCMS MS (ESI) m/z 214.4 [MH] - .
  • Step 8) (S)-2-Amino-N-(1-(5-fluoro-8-((1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-1-oxo Substitute-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
  • Step 2) (S)-2-Amino-5-(methoxy-d3)-N-(1-(8-((1-(methyl-d3)-1H-pyrazol-4-yl)acetylene Base)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
  • Step 6 (S)-2-Amino-5-bromo-N-(1-(8-((1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-1-oxo Substitute-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide
  • Kinase Activity Assay The activity of the compounds of the present invention as PI3K and mTOR kinase inhibitors can be evaluated by the following assays.
  • Kinase assays are performed by detecting myelin basic protein (MBP) incorporation of [gamma]-33P-ATP. Prepare 20 ⁇ g/mL of MBP (Sigma#M-1891) tris-buffered saline (TBS; 50 mM Tris pH 8.0, 138 mM NaCl, 2.7 mM KCl), and coat a high-binding white 384-well plate (Greiner ), 60 ⁇ L per well. Incubate at 4°C for 24 hours.
  • MBP myelin basic protein
  • kinase reactions were performed in a total volume of 34 ⁇ L of kinase buffer (5 mM Hepes pH 7.6, 15 mM NaCl, 0.01% bovine serum albumin (Sigma #I-5506), 10 mM MgCl 2 , 1 mM DTT, 0.02% TritonX-100).
  • kinase buffer 5 mM Hepes pH 7.6, 15 mM NaCl, 0.01% bovine serum albumin (Sigma #I-5506), 10 mM MgCl 2 , 1 mM DTT, 0.02% TritonX-100.
  • Compounds were dissolved in DMSO and added to the wells at a final concentration of 1% DMSO. Each data was measured twice, and the determination of each compound was carried out at least twice. For example, the final concentration of the enzyme is 10 nM or 20 nM.
  • the reaction was started by adding unlabeled ATP (10 ⁇ M) and ⁇ -33P-labeled ATP (2 ⁇ 10 6 cpm per well, 3000Ci/mmole). The reaction was carried out with shaking at room temperature for 1 hour. The 384-well plate was washed with 7x PBS, and then 50 ⁇ L of scintillation fluid was added to each well. A Wallac Trilux meter can also be used.
  • IC50 of inhibition and/or inhibition constant Ki can be obtained by the above test method.
  • IC50 is defined as the concentration of compound that inhibits 50% of the enzyme activity under the assay conditions.
  • Use a 1/2 log dilution to generate a curve containing 10 concentration points to estimate the IC50 value (for example, make a typical curve through the following compound concentrations: 10 ⁇ M, 3 ⁇ M, 1 ⁇ M, 0.3 ⁇ M, 0.1 ⁇ M, 0.03 ⁇ M, 0.01 ⁇ M, 0.003 ⁇ M, 0.001 ⁇ M and 0 ⁇ M).
  • HTRF homogeneous time-resolved fluorescence
  • the cellular activity of the compounds of the present invention as PI3K kinase inhibitors can be evaluated by the following tests.
  • PI3K- ⁇ , ⁇ subtypes First the compounds were diluted to 5 mM from stock concentration with 100% DMSO. In the second step, 5 mM compound was used as the first point and diluted 10 points by 4 times with 100% DMSO. In the third step, it is diluted 250-fold with serum-free medium, and the concentration of DMSO at this time is 0.4%. Then transfer 50 ⁇ L of the compound that has been diluted with medium to a 50 ⁇ L cell plate.
  • the concentration of DMSO is 0.2%, and the final concentration of the compound is 10000nM, 2500nM, 625nM, 156.25nM, 39.06nM, 9.77nM, 2.44nM, 0.61nM, 0.15nM, 0.04nM.
  • PI3K-beta, delta isoforms Compounds were first diluted from stock concentration to 1.25 mM in 100% DMSO. In the second step, 1.25 mM compound was used as the first point and diluted 10 points by 4 times with 100% DMSO.
  • the third step is to dilute 35.714 times with serum-free medium, then transfer 2.5 ⁇ L of the compound that has been diluted with the medium to a 30 ⁇ L cell plate, incubate in the incubator for 1 hour, and then add 2.5 ⁇ L anti-IgM at this time
  • the concentration of DMSO was 0.2%, and the final concentrations of the compounds were 2500nM, 625nM, 156.25nM, 39.06nM, 9.77nM, 2.44nM, 0.61nM, 0.15nM, 0.04nM, 0.01nM.
  • SKOV-3 cells were seeded into a 96-well plate of cell culture level at a density of 60,000 cells/50 ⁇ L/well, and the cell culture medium was RPMI-1640 without serum. Cultivated overnight in a 5% CO2 incubator at 37°C. Add 50 ⁇ L/well of the test compound to the cells and incubate for 60 minutes at 37°C in a 5% CO2 incubator with a final DMSO concentration of 0.2%. Aspirate the medium and add 50 ⁇ L of 1x lysis solution to each well. Shake at room temperature for 45 minutes.
  • 786-O cells were seeded into a 96-well plate of cell culture level at a density of 30,000 cells/50 ⁇ L/well, and the cell culture medium was RPMI-1640 without serum. Cultured overnight in a 5% CO2 incubator at 37°C. Add 50 ⁇ L/well of the test compound to the cells and incubate for 60 minutes at 37°C in a 5% CO2 incubator with a final DMSO concentration of 0.2%. Aspirate the medium and add 50 ⁇ L of 1x lysis solution to each well. Shake at room temperature for 45 minutes. Transfer 16 ⁇ L of the lysate to a 384 plate, and add 4 ⁇ L of premixed antibody from Cisbio’s Phospho-AKT (Ser473) kit. Centrifuge at 1000rpm/min for one minute, incubate at 22°C for 4 hours and read with Envision (665nm/615nm).
  • Raji cells were cultured in 96-well plates at 30 ⁇ L per well, 50,000 cells, and the cell culture medium was RPMI-1640 without serum. Cells were incubated overnight in a 5% CO2 incubator at 37°C. After 18 hours of serum-free starvation, 2.5 ⁇ L of compound (14X) was added to the cells and incubated for 60 minutes in the incubator. Then 2.5 ⁇ L (14X, diluted with serum medium) of anti-human IgM (Jackson Immuno Research) was added and placed in the incubator to stimulate for 30 minutes (final concentration was 10 ⁇ g/mL). Add 11.5 ⁇ L of 4x Lysis Buffer to each well. Shake at room temperature for 45 minutes.
  • RAW264.7 cells were resuspended in serum-free DMEM medium, and 60,000 cells/45 ⁇ L of cell suspension were added to each well of a 96-well plate. Cells were incubated overnight in a 5% CO2, 37°C incubator. After 18 hours of serum-free starvation, 50 ⁇ L of the compound was added and incubated in the incubator for 60 minutes. Then, 5 ⁇ L of 25 nM C5a (R&D Systems, diluted with serum medium) was added to stimulate for 5 min. Aspirate the medium and add 50 ⁇ L of 1x Lysis Buffer to each well. Shake at room temperature for 45 minutes.
  • the kinase test in the present invention is completed by BaoDuo Biotechnology (Jiangsu) Co., Ltd., and the test results are shown in Table 2, wherein, +: >500nM; ++: 100-500nM; +++: 50-100nM; ++++: ⁇ 50nM.
  • test results show that the compound of the present invention has significant inhibitory activity on PI3K ⁇ , and has very obvious selectivity on other PI3K subtypes.
  • the compound of the present invention has higher selectivity than the positive drug IPI-549.
  • the metabolic stability of the compounds of the present invention as PI3K kinase inhibitors can be evaluated by the following assay.
  • liver microsomal stability assay
  • test compound was co-incubated with human liver microsomes, and NADPH was added to start the reaction. At 0, 5, 15, 30 and 60 minutes, 30 microliters were withdrawn and transferred to 300 microliters of acetonitrile containing an internal standard to stop the reaction. This was followed by vigorous vortexing for 1 minute and centrifugation at 4000 rpm for 15 minutes below 4°C. After protein precipitation, 100 microliters of the supernatant was taken out, diluted with 100 microliters of distilled water and analyzed by LC-MS/MS method. Calculate the intrinsic clearance rate in vitro according to the elimination half-life of the test compound in the incubation system. Verapamil was used as a control compound, and both were incubated in parallel for 5 minutes.
  • the percent remaining (%Remaining) was calculated from the ratio of the peak area of the test compound in the non-zero time point sample to the zero time point sample.
  • the elimination half-life (T 1/2 , min) and in vitro intrinsic clearance (C Lint , ⁇ L.min -1 .mg -1 ) of the test compound are obtained by the following equation:
  • Table 3 shows the parameters related to the stability of human liver microsomes of the compounds of the examples of the present invention and IPI-549.
  • Example 16 and Example 28 of the present invention when the hydrogen of the methyl group on pyrazole is replaced by deuterium, the stability of human liver microsomes is significantly improved; similarly, comparing Example 21 and Example 37 of the present invention, the After the hydrogen of the methyl group was replaced by deuterium, the stability of human liver microsomes was also significantly improved.
  • PI3K kinase inhibitors The pharmacokinetic studies of the compounds of the present invention as PI3K kinase inhibitors can be evaluated by the following tests.

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Abstract

The present invention relates to isoquinolinone and quinazolinone compounds as represented by formula (I) or (II), a pharmaceutical composition containing the compounds, and the use of the compounds and the pharmaceutical composition thereof in the preparation of a drug for preventing, processing, treating and/or alleviating PI3-kinase-mediated diseases, disorders and/or conditions, or for inhibiting a PI3-kinase activity. The compounds show an excellent inhibitory activity and kinase selectivity for a target kinase, and have good pharmacokinetic properties and higher bioavailability.

Description

异喹啉酮类及喹唑啉酮类化合物及其组合物和用途Isoquinolones and quinazolinones and their compositions and uses 发明领域field of invention
本发明属于药物领域，具体涉及一类新的异喹啉酮类及喹唑啉酮类化合物、其药学上可接受的盐和包含所述化合物的药物组合物以及使用所述化合物及其药物组合物在制备预防、处理、治疗、和/或减轻PI3-激酶异常相关疾病、病症和/或病况的药物中的用途。The present invention belongs to the field of medicine, and in particular relates to a new class of isoquinolinone and quinazolinone compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions containing said compounds, and the use of said compounds and their pharmaceutical combinations Use of the substance in the preparation of medicines for preventing, treating, treating, and/or alleviating PI3-kinase abnormality-related diseases, disorders, and/or conditions.
发明背景Background of the invention
磷酸肌醇3-激酶(PI3K)通路是一种细胞内信号通路，在细胞存活、增殖和分化中具有调节作用。磷酸肌醇3-激酶(PI3K)酶家族是许多细胞和组织中生长、增殖、迁移和代谢的中心调节剂。PI3K是产生脂质第二信使磷脂酰肌醇-3,4,5-三磷酸(PIP3)的脂质激酶，PIP3在细胞表面受体的下游被用来调节生长、代谢、存活和分化。PIP3由四种不同的I类PI3K催化异构体产生，分为两组：IA类(p110α、p110β和p110δ)和IB类(p110γ)。所有I类PI3K都与调节亚基组成性相关，IA类和IB类PI3K之间的主要区别在于它们与独特的调节亚基相关。IA类PI3Ks(PI3Kα,PI3Kβ和PI3Kδ)是由催化亚单位p110(分别是p110α，p110β和p110δ)和调节亚单位p85(例如：p85α，p85β，p55δ，p55α和p50α)组成的异源二聚体复合物)。这些信号响应通常是通过受体酪氨酸激酶(RTKs)传递的。IB类的PI3Kγ的信号是通过G蛋白偶联受体(GPCRs)传递的，由催化亚基p110γ组成。在正常细胞中，PI3K/mTOR通路在细胞存活、增殖和分化中具有调节作用。然而，该途径的异常激活与多种人类疾病有关，包括癌症、免疫缺陷、炎症和发育障碍。针对PI3K通路内关键节点的多种抑制剂处于临床开发的不同阶段，用于治疗多种人类疾病。(“Small-molecule inhibitors of the PI3K signaling network.”Future MedChem.2011,3(5),549-565)。The phosphoinositide 3-kinase (PI3K) pathway is an intracellular signaling pathway with regulatory roles in cell survival, proliferation and differentiation. The phosphoinositide 3-kinase (PI3K) enzyme family is a central regulator of growth, proliferation, migration and metabolism in many cells and tissues. PI3Ks are lipid kinases that generate the lipid second messenger phosphatidylinositol-3,4,5-triphosphate (PIP3), which is used downstream of cell surface receptors to regulate growth, metabolism, survival and differentiation. PIP3 is produced by four distinct class I PI3K catalytic isoforms, grouped into two groups: class IA (p110α, p110β, and p110δ) and class IB (p110γ). All class I PI3Ks are constitutively associated with regulatory subunits, the main difference between class IA and class IB PI3Ks is that they are associated with unique regulatory subunits. Class IA PI3Ks (PI3Kα, PI3Kβ, and PI3Kδ) are heterodimers composed of the catalytic subunit p110 (p110α, p110β, and p110δ, respectively) and the regulatory subunit p85 (e.g., p85α, p85β, p55δ, p55α, and p50α) Complex). These signaling responses are often transmitted through receptor tyrosine kinases (RTKs). Class IB PI3Kγ signaling is transmitted through G protein-coupled receptors (GPCRs), consisting of the catalytic subunit p110γ. In normal cells, the PI3K/mTOR pathway has regulatory roles in cell survival, proliferation and differentiation. However, aberrant activation of this pathway has been linked to a variety of human diseases, including cancer, immunodeficiency, inflammation and developmental disorders. Various inhibitors targeting key nodes within the PI3K pathway are in various stages of clinical development for the treatment of various human diseases. (“Small-molecule inhibitors of the PI3K signaling network.” Future MedChem. 2011, 3(5), 549-565).
PI3Kα和PI3Kβ两种亚型的表达方式是普遍存在的，而PI3Kδ和PI3Kγ这两种亚型主要在白细胞中表达。PI3Kδ和PI3Kγ相对受限的表达方式表明这两个亚型在适应性和先天免疫系统中的重要作用(J.Med.Chem.2012,55(20),8559–8581)。The expression patterns of two isoforms of PI3Kα and PI3Kβ are ubiquitous, while two isoforms of PI3Kδ and PI3Kγ are mainly expressed in leukocytes. The relatively restricted expression pattern of PI3Kδ and PI3Kγ suggests an important role for these two isoforms in the adaptive and innate immune system (J. Med. Chem. 2012, 55(20), 8559–8581).
PI3Kα亚型与血管生成和葡萄糖稳态有关。PI3K/mTOR通路在癌症中经常失调，通常是因为PIK3CA的激活突变或扩增。PIK3CA(是编码PI3K p110α催化亚基的基因)的功能获得突变是实体瘤中最常见的体细胞改变之一。PI3Kα isoforms are associated with angiogenesis and glucose homeostasis. The PI3K/mTOR pathway is frequently dysregulated in cancer, often because of activating mutations or amplification of PIK3CA. Gain-of-function mutations in PIK3CA (the gene encoding the PI3K p110α catalytic subunit) are among the most common somatic alterations in solid tumors.
PI3Kδ主要在造血谱系细胞中表达，并被细胞因子受体、抗原受体、生长因子受体和共刺激受体激活。PI3Kδ在T和B细胞的发育和激活中很重要。PI3Kδ信号通路的阻断可增加基因不稳定性。PI3Kδ中的功能获得(GOF)突变导致B和T细胞的一系列发育和功能缺陷，从而危及宿主防御。功能丧失(LOF)突变导致更严重的B细胞淋巴细胞减少和无丙种球蛋白血症，但不会导致T细胞衰老。PI3Kδ is predominantly expressed in cells of the hematopoietic lineage and is activated by cytokine receptors, antigen receptors, growth factor receptors, and costimulatory receptors. PI3Kδ is important in the development and activation of T and B cells. Blockade of PI3Kδ signaling increases gene instability. Gain-of-function (GOF) mutations in PI3Kδ lead to a range of developmental and functional defects in B and T cells, thereby compromising host defense. Loss-of-function (LOF) mutations lead to more severe B-cell lymphopenia and agammaglobulinemia but not T-cell senescence.
IB类PI3K催化亚基p110γ是免疫细胞功能的主要调节因子，p110γ在免疫信号传导中起关键作用。p110γ是炎症性疾病的关键因素，由于其免疫调节作用，已被确定为癌症的治疗靶点。PI3Kγ在调节骨髓(巨噬细胞、肥大细胞、中性粒细胞)和淋巴(T细胞、B细胞和自然杀伤细胞)衍生的免疫细胞中发挥重要作用。它调节免疫细胞趋化性、细胞因子释放和活性氧物种的产生。PI3Kγ介导多种免疫细胞功能的能力受其在众多细胞表面受体下游的激活控制，包括G蛋白偶联受体(GPCR)、IgE/抗原受体、受体酪氨酸激酶(RTKs)和Toll样受体(TLRs)。在小鼠模型中，PI3Kγ在遗传或药理学上的缺失对多种炎症性疾病具有保护作用，包括心血管疾病、关节炎、狼疮、哮喘、肺部炎症和纤维化、以及代谢综合征。PI3Kγ也是通过免疫调节作用导致胰腺导管腺癌进展的驱动因素。在免疫系统中靶向PI3Kγ与检查点抑制剂联合已在临床癌症治疗研究中显示出前景(Eganelisib，Infinity Pharmaceuticals News Release，2021)。(Henau OD,Rausch M,Winkler D et al.Nature 539(7629),443–447(2016)；Kaneda MM,Messer KS,Ralainirina N et al.Nature 539(7629),437–442(2016).)The class IB PI3K catalytic subunit p110γ is a master regulator of immune cell function, and p110γ plays a key role in immune signaling. p110γ is a key factor in inflammatory diseases and has been identified as a therapeutic target in cancer due to its immunomodulatory effects. PI3Kγ plays an important role in the regulation of myeloid (macrophages, mast cells, neutrophils) and lymphoid (T cells, B cells, and natural killer cells)-derived immune cells. It regulates immune cell chemotaxis, cytokine release and production of reactive oxygen species. The ability of PI3Kγ to mediate a variety of immune cell functions is controlled by its activation downstream of numerous cell surface receptors, including G protein-coupled receptors (GPCRs), IgE/antigen receptors, receptor tyrosine kinases (RTKs) and Toll-like receptors (TLRs). In mouse models, genetic or pharmacological deletion of PI3Kγ is protective against a variety of inflammatory diseases, including cardiovascular disease, arthritis, lupus, asthma, lung inflammation and fibrosis, and metabolic syndrome. PI3Kγ is also a driver of pancreatic ductal adenocarcinoma progression through immunomodulatory effects. Targeting PI3Kγ in the immune system in combination with checkpoint inhibitors has shown promise in clinical cancer therapy research (Eganelisib, Infinity Pharmaceuticals News Release, 2021). (Henau OD, Rausch M, Winkler D et al. Nature 539(7629), 443–447(2016); Kaneda MM, Messer KS, Ralainirina N et al. Nature 539(7629), 437–442(2016).)
鉴于其在癌症和免疫中的关键作用，PI3K通路一直是过去二十年药物开发研究的重点。2014年，PI3Kδ抑制剂idelalisib(Zydelig；Gilead Sciences)成为第一个被批准用于特定B细胞噁性肿瘤的PI3K抑制剂。随后，泛I类PI3K抑制剂copanlisib(Aliqopa；拜耳)于2017年获批，2018年PI3Kδ/PI3Kγ双重抑制剂duvelisib(Copiktra；Verastem，现为Secura Bio)获批用于相同适应症。PI3Kα抑制剂alpelisib(Piqray； 诺华)是第一个也是唯一一个于2019年5月被FDA批准与雌激素受体(ER)下调剂氟维司群联合用于治疗PIK3CA突变型HER2/ER+转移晚期乳腺癌的PI3Kα抑制剂。Given its critical role in cancer and immunity, the PI3K pathway has been the focus of drug development research over the past two decades. In 2014, the PI3Kδ inhibitor idelalisib (Zydelig; Gilead Sciences) became the first PI3K inhibitor approved for specific B-cell malignancies. Subsequently, the pan-class I PI3K inhibitor copanlisib (Aliqopa; Bayer) was approved in 2017, and the dual PI3Kδ/PI3Kγ inhibitor duvelisib (Copiktra; Verastem, now Secura Bio) was approved in 2018 for the same indication. The PI3Kα inhibitor alpelisib (Piqray; Novartis) was the first and only FDA-approved drug in May 2019 in combination with the estrogen receptor (ER) down-regulator fulvestrant for the treatment of advanced PIK3CA-mutant HER2/ER+ metastases. PI3Kα inhibitors in breast cancer.
需要提供新的，良好的候选药物PI3K抑制剂。具体而言，优选的化合物应当与PI3K受体有力结合，同时对其它受体几乎不显示出亲和性，并且显示出作为激动剂的功能活性。该化合物应由胃肠道充分吸收，代谢稳定且具有良好药代动力学性质。当靶向于中枢神经系统中的受体时，它们可自由地穿越血脑屏障，并且当选择性靶向于外周神经系统中的受体时，它们应不会穿越血脑屏障。它们应无毒性并且显示极少副作用。此外，所述理想的候选药物应以稳定、非吸湿性和容易配制的物理形式存在。本发明化合物显示出特定水平的针对不同的共生同源(paralogs)的PI3Kα，β，γ和δ的选择性。特别是，显示出特定水平的针对ΡΙ3Kγ的选择性。There is a need to provide new, good drug candidates for PI3K inhibitors. In particular, preferred compounds should bind potently to PI3K receptors while exhibiting little affinity for other receptors and exhibit functional activity as agonists. The compound should be fully absorbed by the gastrointestinal tract, stable in metabolism and have good pharmacokinetic properties. They freely cross the blood-brain barrier when targeting receptors in the central nervous system and should not cross the blood-brain barrier when selectively targeting receptors in the peripheral nervous system. They should be non-toxic and show few side effects. Furthermore, the ideal drug candidate should be in a stable, non-hygroscopic and easily formulated physical form. Compounds of the invention exhibit specific levels of selectivity against different paralogs of PI3K alpha, beta, gamma and delta. In particular, a certain level of selectivity against PI3Kγ was shown.
本发明描述的化合物、组合物和方法直接对应上述这些需要和其他目的。具体地，本发明提供了一类可抑制、调节和/或调控PI3-激酶活性的化合物，用于治疗和/或预防PI3-激酶异常相关疾病、病症、和/或病况。与已有的同类化合物相比，本发明的化合物具有更好的药理活性，具体而言，本发明化合物对PI3-激酶显示出优异的抑制活性，并对PI3Kγ具有高度选择性，肝微粒体稳定性表现出明显优势，并且具有良好的药代动力学性质，生物利用度更高。因此，本发明化合物具有非常好的开发前景。The compounds, compositions and methods described in this invention directly respond to these above-mentioned needs and other objectives. Specifically, the present invention provides a class of compounds capable of inhibiting, regulating and/or modulating the activity of PI3-kinase for treating and/or preventing diseases, disorders, and/or conditions related to PI3-kinase abnormality. Compared with the existing similar compounds, the compound of the present invention has better pharmacological activity, specifically, the compound of the present invention shows excellent inhibitory activity to PI3-kinase, and has high selectivity to PI3Kγ, and liver microsomes are stable It has obvious advantages in sex, and has good pharmacokinetic properties and higher bioavailability. Therefore, the compounds of the present invention have very good development prospects.
发明内容Contents of the invention
术语定义Definition of Terms
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在所附权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本发明所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本发明所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。Certain embodiments of the invention are now described in detail, examples of which are illustrated by the accompanying Structural and Chemical Formulas. The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are included within the scope of the present invention as defined by the appended claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including, but not limited to, defined terms, term usage, described techniques, etc.), this Application shall prevail.
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。"Stereoisomers" refer to compounds that have the same chemical structure, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如本发明的通式化合物，或者像实施例里面特殊的例子、子类，以及本发明所包含的一类化合物。As described in the present invention, the compounds of the present invention can be optionally substituted by one or more substituents, such as the general formula compounds of the present invention, or as specific examples, subclasses in the embodiments, and included in the present invention a class of compounds.
应了解术语“任选取代的”与术语“取代或未取代的”可以交换使用。一般而言，术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代，无论此氢原子是连在C上或N上或者其他原子上。“任选地”除非其他方面表明，一个任选的取代基团可以在所述基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" are used interchangeably. In general, the term "substituted" means that one or more hydrogen atoms in a given structure, whether attached to C or N or otherwise, have been replaced by a particular substituent. "Optionally" Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted by one or more substituents selected from a particular group, then the substituents can be substituted at each position the same or differently.
术语“任选地被……所取代”，可以与术语“未取代或被……所取代”交换使用，即所述结构是未取代的或者被一个或多个本发明所述的取代基所取代，本发明所述的取代基包括，但不限于H、D、氧代(＝O)、F、Cl、Br、I、-OH、-CN、-NO 2、-NR eR f、-C(＝O)R 7、-OC(＝O)R 7、-C(＝O)OR 7a、-S(＝O) 0-2R 7、-OS(＝O) 1-2R 7、-S(＝O) 1-2OR 7a、-N(R 8a)C(＝O)R 8、-C(＝O)NR 8aR 8、-OC(＝O)NR 8aR 8、-N(R 8a)S(＝O) 1-2R 8、-S(＝O) 1-2NR 8aR 8、-N(R 8a)C(＝O)NR 8aR 8、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 1-6烷氧基、C 1-6烷基氨基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中各取代基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-6氘代烷基、C 1-6烷基和C 1-6烷氧基的基团取代等等。其中，R e、R f、R 9、R 9a、R 10和R 10a具有如本发明所述定义。 The term "optionally substituted" may be used interchangeably with the term "unsubstituted or substituted", that is, the structure is either unsubstituted or substituted with one or more of the substituents described herein Substitution, the substituents described in the present invention include, but not limited to, H, D, oxo (=O), F, Cl, Br, I, -OH, -CN, -NO 2 , -NR e R f , - C(=O)R 7 , -OC(=O)R 7 , -C(=O)OR 7a , -S(=O) 0-2 R 7 , -OS(=O) 1-2 R 7 , -S(=O) 1-2 OR 7a , -N(R 8a )C(=O)R 8 , -C(=O)NR 8a R 8 , -OC(=O)NR 8a R 8 , -N (R 8a )S(=O) 1-2 R 8 , -S(=O) 1-2 NR 8a R 8 , -N(R 8a )C(=O)NR 8a R 8 , C 1-6 alkane C 1-6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1 -6 cyanoalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-6 alkyl, C 2-7 hetero Cyclic group, C 2-7 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 Heteroaryl C 1-6 alkyl; wherein each substituent is independently and optionally 0, 1, 2, 3 or 4 independently selected from H, D, oxo (=O), F, Cl, Br, -OH, -NH 2 , -CN, -NO 2 , C 1-6 deuterated alkyl, C 1-6 alkyl and C 1-6 alkoxy group substitution, and the like. Wherein, R e , R f , R 9 , R 9a , R 10 and R 10a have the definitions as described in the present invention.
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1-C 6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。 In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the type or range of the group. It is specifically intended that the invention includes each individual subcombination of individual members of these radical classes and ranges. For example, the term "C 1 -C 6 alkyl" specifically refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl.
本发明使用的术语“烷基”或“烷基基团”，表示含有1至20个碳原子，饱和的直链或支链一价烃基基团，其中，所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外详细说明，烷基基团 含有1-20个碳原子。在一实施方案中，烷基基团含有1-12个碳原子；在另一实施方案中，烷基基团含有1-6个碳原子；在又一实施方案中，烷基基团含有1-4个碳原子；还在一实施方案中，烷基基团含有1-3个碳原子。所述烷基基团可任选地被一个或多个本发明描述的取代基所取代。The term "alkyl" or "alkyl group" used in the present invention means a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group can be optionally substituted by one or more of the substituents described herein. Unless otherwise specified, an alkyl group contains 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1 - 4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms. The alkyl group may be optionally substituted with one or more substituents described herein.
烷基基团的实例包含，但并不限于，甲基(Me、-CH 3)，乙基(Et、-CH 2CH 3)，正丙基(n-Pr、-CH 2CH 2CH 3)，异丙基(i-Pr、-CH(CH 3) 2)，正丁基(n-Bu、-CH 2CH 2CH 2CH 3)，异丁基(i-Bu、-CH 2CH(CH 3) 2)，仲丁基(s-Bu、-CH(CH 3)CH 2CH 3)，叔丁基(t-Bu、-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)，正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)，2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)，3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))，2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)，3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)，4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)，3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)，2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)，2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)，3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)，正庚基，正辛基，等等。 Examples of alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-1- Butyl (-CH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH(CH 3 )CH(CH 3 )CH 2 CH 3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 ) CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH (CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), n-heptyl, n-octyl, and the like.
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp 2双键，其包括“顺”和“反”的定位，或者“E”和“Z”的定位。在一实施方案中，烯基基团包含2-8个碳原子；在另一实施方案中，烯基基团包含2-6个碳原子；在又一实施方案中，烯基基团包含2-4个碳原子。烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH 2)、烯丙基(-CH 2CH＝CH 2)等等。所述烯基基团可以任选地被一个或多个本发明描述的取代基所取代。 The term "alkenyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one site of unsaturation, that is, there is a carbon-carbon sp2 double bond, which includes "cis" and " The positioning of "anti", or the positioning of "E" and "Z". In one embodiment, an alkenyl group contains 2-8 carbon atoms; in another embodiment, an alkenyl group contains 2-6 carbon atoms; in yet another embodiment, an alkenyl group contains 2 - 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl (-CH= CH2 ), allyl ( -CH2CH = CH2 ), and the like. The alkenyl group can be optionally substituted with one or more substituents described herein.
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp三键。在一实施方案中，炔基基团包含2-8个碳原子；在另一实施方案中，炔基基团包含2-6个碳原子；在又一实施方案中，炔基基团包含2-4个碳原子。炔基基团的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH 2C≡CH)、1-丙炔基(-C≡C-CH 3)等等。所述炔基基团可以任选地被一个或多个本发明描述的取代基所取代。 The term "alkynyl" means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one site of unsaturation, ie, a carbon-carbon sp triple bond. In one embodiment, the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 - 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl ( -CH2C≡CH ), 1-propynyl (-C≡C- CH3 ), and the like . The alkynyl group can be optionally substituted with one or more substituents described herein.
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的定义。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一实施方案中，烷氧基基团含有1-6个碳原子；在另一实施方案中，烷氧基基团含有1-4个碳原子；在又一实施方案中，烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。The term "alkoxy" denotes an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning set forth herein. Unless specified otherwise, the alkoxy groups contain 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group Groups contain 1-3 carbon atoms. The alkoxy groups may be optionally substituted with one or more substituents described herein.
烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH 3)，乙氧基(EtO、-OCH 2CH 3)，1-丙氧基(n-PrO、n-丙氧基、-OCH 2CH 2CH 3)，2-丙氧基(i-PrO、i-丙氧基、-OCH(CH 3) 2)，1-丁氧基(n-BuO、n-丁氧基、-OCH 2CH 2CH 2CH 3)，2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH 2CH(CH 3) 2)，2-丁氧基(s-BuO、s-丁氧基、-OCH(CH 3)CH 2CH 3)，2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH 3) 3)，1-戊氧基(n-戊氧基、-OCH 2CH 2CH 2CH 2CH 3)，2-戊氧基(-OCH(CH 3)CH 2CH 2CH 3)，3-戊氧基(-OCH(CH 2CH 3) 2)，2-甲基-2-丁氧基(-OC(CH 3) 2CH 2CH 3)，3-甲基-2-丁氧基(-OCH(CH 3)CH(CH 3) 2)，3-甲基-l-丁氧基(-OCH 2CH 2CH(CH 3) 2)，2-甲基-l-丁氧基(-OCH 2CH(CH 3)CH 2CH 3)，等等。 Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butane Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyloxy (-OCH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyloxy (-OCH(CH 2 CH 3 ) 2 ), 2-methyl-2-butoxy (-OC(CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butoxy (-OCH(CH 3 )CH(CH 3 ) 2 ), 3-methyl-l-butoxy (-OCH 2 CH 2 CH(CH 3 ) 2 ), 2-methyl-l-butoxy ( -OCH2CH ( CH3 ) CH2CH3 ), and so on .
术语“卤代烷基”或“卤代烷氧基”表示烷基或烷氧基基团被一个或多个卤素原子所取代，此类实例包含，但并不限于，三氟甲基(-CF 3)、三氟甲氧基(-OCF 3)、二氟乙基(-CH 2CHF 2,-CF 2CH 3,-CHFCH 2F)、三氟乙基(-CH 2CF 3,-CF 2CH 2F,-CFHCHF 2)、-CF(CH 3) 2等。 The term "haloalkyl" or "haloalkoxy" means that an alkyl or alkoxy group is substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl (-CF 3 ), Trifluoromethoxy (-OCF 3 ), difluoroethyl (-CH 2 CHF 2 , -CF 2 CH 3 , -CHFCH 2 F), trifluoroethyl (-CH 2 CF 3 , -CF 2 CH 2 F, -CFHCHF 2 ), -CF(CH 3 ) 2 and so on.
术语“氘代烷基”、“氘代烷氧基”、“氘代环烷基”、“氘代杂环基”、“氘代芳基”、或“氘代杂芳基”表示烷基、烷氧基、环烷基、杂环基、芳基或杂芳基基团被一个或多个D原子所取代，此类实例包含，但并不限于，一氘代甲基(-CH 2D)、二氘代甲基(-CHD 2)、三氘代甲基(-CD 3)、一氘代甲氧基(-OCH 2D)、二氘代甲氧基(-OCHD 2)、三氘代甲氧基(-OCD 3)、二氘代乙基(-CH 2CHD 2,-CD 2CH 3,-CHDCH 2D)、五氘代乙基(-CD 2CD 3)、氘代环丙基、氘代环己基、五氘代苯基等。 The term "deuteroalkyl", "deuteroalkoxy", "deuterocycloalkyl", "deuteroheterocyclyl", "deuteroaryl", or "deuteroheteroaryl" means an alkyl , alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups are substituted with one or more D atoms, examples of which include, but are not limited to, monodeuteromethyl (-CH 2 D), Dideuteromethyl (-CHD 2 ), Trideuteromethyl (-CD 3 ), One Deuteriomethoxy (-OCH 2 D), Dideuuteriomethoxy (-OCHD 2 ), Trideuteriomethoxyl (-OCD 3 ), Dideuuterioethyl (-CH 2 CHD 2 , -CD 2 CH 3 , -CHDCH 2 D), Pentadeuterioethyl (-CD 2 CD 3 ), Deuterium Substituted cyclopropyl, deuterated cyclohexyl, pentadeuterated phenyl, etc.
术语“含氘(D)的基团”是指本发明所述的基团或基团部分上的一个或多个H原子被D取代，但不包含单独的D基团，此类基团包含，但不限于，C 1-6氘代烷基、C 3-8氘代环烷基、C 2-9氘代杂环基、C 6-10氘代芳基、C 1-9氘代杂芳基等，其各自具有本发明所述定义，其中所述各基团独立任选地被一个或多个H、D、F、Cl、Br、I、-OH、-CN、-NO 2、-NR eR f、C 1-6烷基和C 1-6氘代烷基的基团所取代，其中R e和R f均具有本发明所述定义。 The term "deuterium (D)-containing group" means that one or more H atoms on the group or part of the group described in the present invention are replaced by D, but do not include a single D group, such groups include , but not limited to, C 1-6 deuterated alkyl, C 3-8 deuterated cycloalkyl, C 2-9 deuterated heterocyclyl, C 6-10 deuterated aryl, C 1-9 deuterated hetero Aryl, etc., each of which has the definition described in the present invention, wherein each of the groups is independently and optionally replaced by one or more of H, D, F, Cl, Br, I, -OH, -CN, -NO 2 , -NR e R f , C 1-6 alkyl and C 1-6 deuterated alkyl are substituted, wherein both R e and R f have the definitions described in the present invention.
术语“羟基烷基”或“羟基取代的烷基”和“羟基烷氧基”或“羟基取代的烷氧基”分别表示烷基或烷氧基基团，视情况而定，被一个或多个羟基基团所取代，其中，“羟基烷基”与“羟烷基”可以交换使用，此类实例包含，但并不限于，羟甲基(-CH 2OH)、2-羟乙基(-CH 2CH 2OH)、1-羟乙基(-CH(OH)CH 3)、2-羟基丙-2-基(-COH(CH 3) 2)、2-羟基-2-甲基丙基(-CH 2COH(CH 3) 2)、3-羟丙基(-CH 2CH 2CH 2OH)、2-羟丙基(-CH 2CH(OH)CH 3)、2-羟基-2甲基丙基(-CH 2CH(OH)(CH 3)CH 3)、羟基甲氧基(-OCH 2OH)等。 The terms "hydroxyalkyl" or "hydroxy-substituted alkyl" and "hydroxyalkoxy" or "hydroxy-substituted alkoxy" denote respectively an alkyl or alkoxy group, as the case may be, surrounded by one or more hydroxy groups, where "hydroxyalkyl" and "hydroxyalkyl" are used interchangeably, such examples include, but are not limited to, hydroxymethyl (-CH 2 OH), 2-hydroxyethyl ( -CH 2 CH 2 OH), 1-hydroxyethyl (-CH(OH)CH 3 ), 2-hydroxypropan-2-yl (-COH(CH 3 ) 2 ), 2-hydroxy-2-methylpropane (-CH 2 COH(CH 3 ) 2 ), 3-hydroxypropyl (-CH 2 CH 2 CH 2 OH), 2-hydroxypropyl (-CH 2 CH(OH)CH 3 ), 2-hydroxy- 2-methylpropyl (-CH 2 CH(OH)(CH 3 )CH 3 ), hydroxymethoxy (-OCH 2 OH) and the like.
术语“氰基取代烷基”或“氰基烷基”包括被一个或多个氰基所取代的C 1-10直链或支链烷基基团。其中一些实施例是，氰基烷基是被一个或多个氰基基团所取代的C 1-6“较低级的氰基烷基”，另一些实施例是，氰基烷基是被一个或多个氰基基团所取代的C 1-4“较低级的氰基烷基”，此类实例包括，但并不限于，CNCH 2-、CNCH 2CH 2-、CNCH 2CH 2CH 2-、CNCH 2CHCNCH 2-等。 The term "cyano-substituted alkyl" or "cyanoalkyl" includes C 1-10 straight or branched chain alkyl groups substituted with one or more cyano groups. In some embodiments, cyanoalkyl is C 1-6 "lower cyanoalkyl" substituted with one or more cyano groups, and in other embodiments, cyanoalkyl is C 1-4 "lower cyanoalkyl" substituted with one or more cyano groups, examples of which include, but are not limited to, CNCH 2 -, CNCH 2 CH 2 -, CNCH 2 CH 2 CH 2 -, CNCH 2 CHCNCH 2 -, etc.
术语“烷氨基”包括“N-烷基氨基”和“N,N-二烷基氨基”，其中氨基基团分别独立地被一个或两个烷基基团所取代。其中一些实施例是，烷基氨基是一个或两个C 1-6烷基连接到氮原子上的较低级的烷基氨基基团。另外一些实施例是，烷基氨基是C 1-3的较低级的烷基氨基基团。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基，此类实例包括，但并不限于，N-甲氨基，N-乙氨基，N,N-二甲氨基，N,N-二乙氨基等等。 The term "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino groups are each independently substituted with one or two alkyl groups. In some embodiments, alkylamino is a lower alkylamino group with one or two C 1-6 alkyl groups attached to a nitrogen atom. In some other embodiments, the alkylamino is a C 1-3 lower alkylamino group. Suitable alkylamino groups may be mono- or di-alkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N- -Diethylamino and the like.
术语“氨基烷基”包括被一个或多个氨基所取代的C 1-10直链或支链烷基基团。其中一些实施例是，氨基烷基是被一个或多个氨基基团所取代的C 1-6“较低级的氨基烷基”，另一些实施例是，氨基烷基是被一个或多个氨基基团所取代的C 1-4“较低级的氨基烷基”，此类实例包括，但并不限于，氨甲基，氨乙基，氨丙基，氨丁基和氨己基。 The term "aminoalkyl" includes C 1-10 straight or branched chain alkyl groups substituted with one or more amino groups. In some embodiments, the aminoalkyl group is a C 1-6 "lower aminoalkyl" substituted with one or more amino groups, and in other embodiments, the aminoalkyl group is substituted with one or more C 1-4 "lower aminoalkyl" substituted with an amino group, examples of which include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.
术语“环烷基”表示含有3-12个碳原子的，单价或多价的饱和单环，双环或三环体系。双环环烷基包含螺双环烷基、稠合双环烷基和桥双环烷基。在一些实施方案，环烷基包含3-12个碳原子；在另一些实施方案中，环烷基包含3-10个碳原子；在另一些实施方案中，环烷基包含3-8个碳原子；在另一些实施方案中，环烷基包含3-7个碳原子；在另一些实施方案中，环烷基包含3-6个碳原子；还在一些实施方案，环烷基为C 7-C 12环烷基，其包含C 7-C 12单环烷基、C 7-C 12双环烷基(如C 7-C 12螺双环烷基、C 7-C 12稠合双环烷基和C 7-C 12桥双环烷基)或C 7-C 12三环烷基。所述环烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。术语“单环环烷基”或“单环烷基”表示单环体系的环烷基，其中所述环烷基具有如前所述的定义，所述单环环烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。环烷基基团的实例包括，但不限于，环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-1-烯基、1-环己基-2-烯基、1-环己基-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基，等等。 The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Bicyclic cycloalkyls include spirobicycloalkyls, fused bicycloalkyls and bridged bicycloalkyls. In some embodiments, cycloalkyl groups contain 3-12 carbon atoms; in other embodiments, cycloalkyl groups contain 3-10 carbon atoms; in other embodiments, cycloalkyl groups contain 3-8 carbon atoms Atom; In other embodiments, cycloalkyl contains 3-7 carbon atoms; In other embodiments, cycloalkyl contains 3-6 carbon atoms; Still in some embodiments, cycloalkyl is C 7 -C 12 cycloalkyl, which includes C 7 -C 12 monocycloalkyl, C 7 -C 12 bicycloalkyl (such as C 7 -C 12 spirobicycloalkyl, C 7 -C 12 fused bicycloalkyl and C 7 -C 12 bridged bicycloalkyl) or C 7 -C 12 tricycloalkyl. The cycloalkyl groups can be independently unsubstituted or substituted with one or more substituents described herein. The term "monocyclic cycloalkyl" or "monocycloalkyl" refers to a cycloalkyl group of a monocyclic ring system, wherein said cycloalkyl group has the definition as previously stated, and said monocyclic cycloalkyl group can be independently Unsubstituted or substituted with one or more substituents described herein. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclo Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl , cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.
术语“环烷基烷基”包括环烷基取代的烷基基团。在一些实施方案，环烷基烷基基团是指“较低级的环烷基烷基”基团，即环烷基基团连接到C 1-6的烷基基团上。在另一些实施方案，环烷基烷基基团是指含C 1-3的烷基的“苯烷撑”。其中具体实例包括，但不限于，环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、环戊基乙基、环己基乙基等。环烷基烷基上的环烷基可进一步被一个或多个本发明所描述的取代基所取代。 The term "cycloalkylalkyl" includes cycloalkyl substituted alkyl groups. In some embodiments, a cycloalkylalkyl group refers to a "lower cycloalkylalkyl" group, ie, a cycloalkyl group attached to a C 1-6 alkyl group. In other embodiments, a cycloalkylalkyl group refers to a C 1-3 alkyl-containing "phenylalkylene." Specific examples thereof include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentylethyl, cyclohexylethyl, and the like. The cycloalkyl group on the cycloalkylalkyl group may be further substituted with one or more substituents described herein.
术语“杂环基”和“杂环”在此处可交换使用，都是指包含3-12个环原子的，单价或多价的，饱和或部分不饱和的，非芳香性的单环、双环或三环体系，其中至少一个环原子选自氮、氧和硫原子。在一些实施方案，杂环基或杂环包含4-12个环原子。在一些实施方案，杂环基或杂环包含5-12个环原子。在一些实施方案，杂环基或杂环包含4-8个环原子。在一些实施方案，杂环基或杂环包含3-10个环原子。在一些实施方案，杂环基或杂环包含3-8个环原子。在一些实施方案，杂环基或杂环包含3-6个环原子。在一些实施方案，杂环基或杂环包含4-7个环原子。除非另外说明，杂环基可以是碳基或氮基，且-CH 2-基团可以任选地被-C(＝O)-替代，环的硫原子可以任选地被氧化成S-氧化物，环的氮原子可以任选地被氧化成N-氧化合物。杂环基包含饱和的杂环基(杂环烷基)和部分不饱和的杂环基。所述的杂环基具有一个或多个连接点与分子的其余部分相连。杂环基的实例包括，但不限于：环氧乙烷基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡咯啉基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氮单杂环庚烷、氧氮杂
Figure PCTCN2022121567-appb-000001
基(如，1,4-氧氮杂
Figure PCTCN2022121567-appb-000002
基、1,2-氧氮杂
Figure PCTCN2022121567-appb-000003
基)、二氮杂
Figure PCTCN2022121567-appb-000004
基(如，1,4-二氮杂
Figure PCTCN2022121567-appb-000005
基、1,2-二氮杂
Figure PCTCN2022121567-appb-000006
基)、二氧杂
Figure PCTCN2022121567-appb-000007
基(如，1,4-二氧杂
Figure PCTCN2022121567-appb-000008
基、1,2-二氧杂
Figure PCTCN2022121567-appb-000009
基)、硫氮杂
Figure PCTCN2022121567-appb-000010
基(如1,4-硫氮杂
Figure PCTCN2022121567-appb-000011
基、1,2-硫氮杂
Figure PCTCN2022121567-appb-000012
基)、吲哚啉基、1,2,3,4-四氢异喹啉基、1,3-苯并二噁茂基、2-氧杂-5-氮杂双环[2.2.1]庚-5-基、2-氮杂螺[4.4]壬烷基、1,6-二氧杂螺[4.4]壬烷基、2-氮杂螺[4.5]癸烷基、8-氮杂螺[4.5]癸烷基、7-氮杂螺[4.5]癸烷基、3-氮杂螺[5.5]十一烷基、2-氮杂螺[5.5]十一烷基、八氢-1H-异吲哚基、八氢环戊烷并[c]吡咯基、二氢吲哚基、1,2,3,4-四氢异喹啉基、六氢呋喃并[3,2-b]呋喃基和十二氢异喹啉基，等。杂环基中-CH2-基团被-C(＝O)-替代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基和3,5-二氧代哌啶基。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、1,1-二氧代硫代吗啉基。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。 The terms "heterocyclyl" and "heterocycle" are used interchangeably herein, and both refer to monovalent or multivalent, saturated or partially unsaturated, non-aromatic monocyclic, Bicyclic or tricyclic ring systems wherein at least one ring atom is selected from nitrogen, oxygen and sulfur atoms. In some embodiments, a heterocyclyl or heterocycle contains 4-12 ring atoms. In some embodiments, a heterocyclyl or heterocycle contains 5-12 ring atoms. In some embodiments, a heterocyclyl or heterocycle contains 4-8 ring atoms. In some embodiments, a heterocyclyl or heterocycle contains 3-10 ring atoms. In some embodiments, a heterocyclyl or heterocycle contains 3-8 ring atoms. In some embodiments, a heterocyclyl or heterocycle contains 3-6 ring atoms. In some embodiments, a heterocyclyl or heterocycle contains 4-7 ring atoms. Unless otherwise stated, the heterocyclyl group can be carbon- or nitrogen-based, and the -CH2- group can optionally be replaced by -C(=O)-, and the sulfur atom of the ring can be optionally oxidized to S-oxide species, the nitrogen atom of the ring can be optionally oxidized to the N-oxygen compound. The heterocyclic group includes a saturated heterocyclic group (heterocycloalkyl group) and a partially unsaturated heterocyclic group. Said heterocyclyl has one or more points of attachment to the rest of the molecule. Examples of heterocyclic groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazole Alkyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolyl, dithiocyclopentyl, tetrahydropyranyl , Dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithia Alkyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, azacycloheptane, oxazepine
Figure PCTCN2022121567-appb-000001
groups (e.g., 1,4-oxazepine
Figure PCTCN2022121567-appb-000002
base, 1,2-oxazepine
Figure PCTCN2022121567-appb-000003
base), diazepine
Figure PCTCN2022121567-appb-000004
groups (e.g., 1,4-diazepine
Figure PCTCN2022121567-appb-000005
base, 1,2-diazepine
Figure PCTCN2022121567-appb-000006
base), dioxa
Figure PCTCN2022121567-appb-000007
group (e.g., 1,4-dioxa
Figure PCTCN2022121567-appb-000008
group, 1,2-dioxa
Figure PCTCN2022121567-appb-000009
base), thiazepines
Figure PCTCN2022121567-appb-000010
group (such as 1,4-thiazepine
Figure PCTCN2022121567-appb-000011
base, 1,2-thiazepine
Figure PCTCN2022121567-appb-000012
base), indolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl- 5-yl, 2-azaspiro[4.4]nonyl, 1,6-dioxaspiro[4.4]nonyl, 2-azaspiro[4.5]decyl, 8-azaspiro[4.5 ]decyl, 7-azaspiro[4.5]decyl, 3-azaspiro[5.5]undecyl, 2-azaspiro[5.5]undecyl, octahydro-1H-isoindyl Indolyl, octahydrocyclopenta[c]pyrrolyl, indolinyl, 1,2,3,4-tetrahydroisoquinolyl, hexahydrofuro[3,2-b]furyl and dodecahydroisoquinolinyl, etc. Examples of -CH2- groups in heterocyclic groups replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinone and 3,5-dioxopiperidinyl. Examples of oxidized sulfur atoms in heterocyclic groups include, but are not limited to, sulfolane, 1,1-dioxothiomorpholinyl. Said heterocyclyl groups may be optionally substituted with one or more substituents described herein.
还在一实施方案中，杂环基为4-7个原子组成的杂环基，是指包含4-7个环原子的单价或多价的，饱和或部分不饱和的非芳香性的单环或双环，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，4-7个原子组成的杂环基可以是碳基或氮基，且-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。所述4-7个原子组成的杂环基具有一个或多个连接点与分子的其余部分相连。其中，4-7个原子组成的单环杂环基的实例包括，但不限于：氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、吡咯烷基、吡咯啉基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂
Figure PCTCN2022121567-appb-000013
基(1,4-氧氮杂
Figure PCTCN2022121567-appb-000014
基、1,2-氧氮杂
Figure PCTCN2022121567-appb-000015
基)、二氮杂
Figure PCTCN2022121567-appb-000016
基(1,4-二氮杂
Figure PCTCN2022121567-appb-000017
基、1,2-二氮杂
Figure PCTCN2022121567-appb-000018
基)和硫氮杂
Figure PCTCN2022121567-appb-000019
基(1,4-硫氮杂
Figure PCTCN2022121567-appb-000020
基、1,2-硫氮杂
Figure PCTCN2022121567-appb-000021
基)等；4-7个原子组成的双环杂环基的实例包括，但不限于：3-氮杂双环[3,2,0]庚烷、3-氧代双环[3,2,0]庚烷等；4-7个原子组成的杂环基中-CH 2-基团被-C(＝O)-替代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基和3,5-二氧代哌啶基；4-7个原子组成的杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、1,1-二氧代四氢噻吩、1,1-二氧代四氢噻喃、1,1-二氧代硫代吗啉基。所述的4-7个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。 In another embodiment, the heterocyclic group is a heterocyclic group composed of 4-7 atoms, which refers to a monovalent or polyvalent, saturated or partially unsaturated non-aromatic monocyclic ring containing 4-7 ring atoms Or bicyclic, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise stated, a heterocyclyl group of 4-7 atoms may be carbonyl or nitrogenyl, and a -CH2- group may optionally be replaced by -C(=O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. Ring nitrogen atoms can optionally be oxidized to N-oxygen compounds. The 4-7 atom heterocyclic group has one or more points of attachment to the rest of the molecule. Among them, examples of monocyclic heterocyclic groups composed of 4-7 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl , pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, dihydrothiophenyl, tetrahydropyranyl, dihydropyranyl, 2H -pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine
Figure PCTCN2022121567-appb-000013
group (1,4-oxazepine
Figure PCTCN2022121567-appb-000014
base, 1,2-oxazepine
Figure PCTCN2022121567-appb-000015
base), diazepine
Figure PCTCN2022121567-appb-000016
base (1,4-diazepine
Figure PCTCN2022121567-appb-000017
base, 1,2-diazepine
Figure PCTCN2022121567-appb-000018
base) and thiazepines
Figure PCTCN2022121567-appb-000019
base (1,4-thiazepine
Figure PCTCN2022121567-appb-000020
base, 1,2-thiazepine
Figure PCTCN2022121567-appb-000021
base) etc.; examples of bicyclic heterocyclyl groups consisting of 4-7 atoms include, but are not limited to: 3-azabicyclo[3,2,0]heptane, 3-oxobicyclo[3,2,0] Heptane, etc.; in a heterocyclic group consisting of 4-7 atoms, the -CH 2 - group is replaced by -C(=O)- Examples include, but are not limited to, 2-oxopyrrolidinyl, oxo-1 ,3-thiazolidinyl, 2-piperidinonyl, and 3,5-dioxopiperidinyl; examples of oxidized sulfur atoms in heterocyclic groups consisting of 4-7 atoms include, but are not limited to, sulfolane , 1,1-dioxotetrahydrothiophene, 1,1-dioxotetrahydrothiopyran, 1,1-dioxothiomorpholinyl. The heterocyclyl group consisting of 4-7 atoms can be optionally substituted by one or more substituents described in the present invention.
术语“杂环基烷基”包括杂环基取代的烷基，其中杂环基和烷基均具有如本发明所述的含义，此类实例包括，但并不限于四氢呋喃基甲基、吡咯-2-基甲基、吗啉-4-基乙基、哌嗪-4-基乙基、哌啶-4-基乙基等。The term "heterocyclylalkyl" includes heterocyclyl substituted alkyl, wherein both heterocyclyl and alkyl have the meanings described herein, such examples include, but are not limited to tetrahydrofuranylmethyl, pyrrole- 2-ylmethyl, morpholin-4-ylethyl, piperazin-4-ylethyl, piperidin-4-ylethyl and the like.
术语“芳基”表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子组成的环，且有一个或多个连接点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用。芳基基团的实例可以包括苯基、萘基和蒽基。所述芳基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。The term "aryl" denotes monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic family in which each ring system contains rings of 3-7 atoms and has one or more points of attachment to the rest of the molecule. The term "aryl" is used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, naphthyl and anthracenyl. The aryl groups may be independently optionally substituted with one or more substituents described herein.
术语“芳基烷基”或“芳烷基”包括芳基取代的烷基基团。在一些实施方案，芳基烷基基团是指“较低级的芳基烷基”基团，即芳基基团连接到C 1-6的烷基基团上。在另一些实施方案，芳基烷基基团是指含C 1-3的烷基的“苯烷撑”。其中具体实例包括，但不限于，苄基、二苯基甲基、苯乙基等。芳基烷基上的芳基可进一步被一个或多个本发明所描述的取代基所取代。 The term "arylalkyl" or "aralkyl" includes aryl-substituted alkyl groups. In some embodiments, an arylalkyl group refers to a "lower arylalkyl" group, ie, an aryl group attached to a C 1-6 alkyl group. In other embodiments, an arylalkyl group refers to a C 1-3 alkyl-containing "phenylalkylene." Specific examples thereof include, but are not limited to, benzyl, diphenylmethyl, phenethyl and the like. The aryl group on the arylalkyl group may be further substituted with one or more substituents described herein.
术语“杂芳基”表示含有5-12个环原子，或5-10个环原子，或5-6个环原子的单环、双环和三环体系，其中所有环均是芳香族的，且至少一个芳香环包含一个或多个杂原子，其中每一个环体系包含5-7个原子组成的环，且有一个或多个连接点与分子其余部分相连。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。在一实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-12个原子组成的杂芳基。在另一实施案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-10个原子组成的杂芳基。在另一实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-6个原子组成的杂芳基。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein all rings are aromatic, and At least one aromatic ring contains one or more heteroatoms, wherein each ring system contains rings of 5-7 atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl" or "heteroaromatic". In one embodiment, the heteroaryl group is a 5-12 atom heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In another embodiment, the heteroaryl group is a 5-10 atom heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In another embodiment, the heteroaryl group is a 5-6 atom heteroaryl group comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. The heteroaryl group is optionally substituted with one or more substituents described herein.
杂芳基基团的实例包括，但并不限于，2-呋喃基、3-呋喃基、N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噁唑基、4-噁唑基、5-噁唑基、N-吡咯基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基、哒嗪基(如3-哒嗪基)、2-噻唑基、4-噻唑基、5-噻唑基、四唑基(如5-四唑基)、三唑基(如2-三唑基和5-三唑基)、2-噻吩基、3-噻吩基、吡唑基(如2-吡唑基)、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、 1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)、异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基，等等。Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3- Triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5- Triazinyl; also includes, but is by no means limited to, the following bicyclic rings: benzimidazolyl, benzofuryl, benzothienyl, indolyl (eg 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazole And[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazole And[1,5-a]pyridyl, etc.
术语“杂芳基烷基”表示烷基基团被一个或多个杂芳基所取代，其中杂芳基和烷基基团均具有本发明所述的含义，此类实例包括，但并不限于，吡啶-2-甲基、咪唑-2-甲基、呋喃-2-乙基、吲哚-3-甲基等。The term "heteroarylalkyl" means that an alkyl group is substituted by one or more heteroaryl groups, wherein both heteroaryl and alkyl groups have the meanings described herein, examples of which include, but are not Limited to, pyridine-2-methyl, imidazol-2-methyl, furan-2-ethyl, indole-3-methyl and the like.
术语“卤素”是指F，Cl，Br或I。The term "halogen" refers to F, Cl, Br or I.
如本发明所描述的，环体系中有两个连接点与分子其余部分相连，如式(a1)所示，表示既可以是E端也可以是E’端与分子其余部分相连，即两端的连接方式可以互换。As described in the present invention, there are two connection points in the ring system connected to the rest of the molecule, as shown in formula (a1), which means that either the E end or the E' end is connected to the rest of the molecule, that is, the two ends of the Connection methods can be interchanged.
E-(CH 2)t 1-L-E′  (a1) E-(CH 2 )t 1- LE′ (a1)
像本发明所描述的，取代基画一个键连接到中心的环上形成的环体系(如下所示)代表取代基可在任一环上任何可取代的位置取代。例如，式b代表A环或B环上任何可能被取代的位置均可被取代，如式c、d、e、f、g、h、i、j、k、l、m、n、o、p、q等所示。As described herein, substituents are bonded to a central ring to form a ring system (shown below) meaning that substituents can be substituted at any substitutable position on either ring. For example, formula b represents that any position that may be substituted on ring A or ring B can be substituted, such as formula c, d, e, f, g, h, i, j, k, l, m, n, o, Shown by p, q, etc.
Figure PCTCN2022121567-appb-000022
Figure PCTCN2022121567-appb-000022
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N +(C 1-4烷基) 4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物， C 1-8磺酸化物和芳香磺酸化物。 The "pharmaceutically acceptable salt" used in the present invention refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods such as ion exchange methods recorded in books and literature these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3 - Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts. The present invention also contemplates the quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed as counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1 -8 sulfonates and aromatic sulfonates.
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules with water.
本发明化合物的描述DESCRIPTION OF THE COMPOUNDS OF THE INVENTION
本发明公开了一类新颖的嘧啶胺化合物，可作为PI3-激酶活性，特别是PI3K-γ活性的抑制剂，用于预防、处理、治疗、和/或减轻PI3-激酶异常相关疾病、病症、和/或病况，例如呼吸道疾病，病毒感染，非病毒呼吸道感染，过敏性疾病，自身免疫性疾病，炎性疾病，心血管疾病，恶性血液病，神经退行性疾病，胰腺炎，多器官衰竭，肾病，血小板聚集，癌症，精子活力，移植排斥，移植物排斥，肺损伤或疼痛等。与已有的同类化合物相比，本发明的化合物具有更好的药理活性，具体而言，本发明化合物对PI3-激酶显示出优异的抑制活性并对PI3Kγ具有高度选择性，并且在药代动力学方面表现出明显优势。因此，本发明化合物具有非常好的开发前景。The invention discloses a novel class of pyrimidine amine compounds, which can be used as inhibitors of PI3-kinase activity, especially PI3K-γ activity, for preventing, treating, treating, and/or alleviating PI3-kinase abnormality-related diseases, disorders, and/or conditions such as respiratory disease, viral infection, non-viral respiratory infection, allergic disease, autoimmune disease, inflammatory disease, cardiovascular disease, hematologic malignancy, neurodegenerative disease, pancreatitis, multiorgan failure, Kidney disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, lung damage or pain, etc. Compared with existing similar compounds, the compound of the present invention has better pharmacological activity, specifically, the compound of the present invention shows excellent inhibitory activity to PI3-kinase and has high selectivity to PI3Kγ, and pharmacokinetic Significant advantages in academics. Therefore, the compounds of the present invention have very good development prospects.
本发明公开化合物可显示对PI3-激酶，特别是PI3K-γ表现出较强的抑制活性。一方面，本发明提供了一种异喹啉酮类及喹唑啉酮类化合物，其具有式(I)所示结构：The compounds disclosed in the present invention can show strong inhibitory activity on PI3-kinase, especially PI3K-γ. On the one hand, the present invention provides a kind of isoquinolones and quinazolinones compound, it has the structure shown in formula (I):
Figure PCTCN2022121567-appb-000023
Figure PCTCN2022121567-appb-000023
或其立体异构体、互变异构体、氘代物、氮氧化物、溶剂化物、或药学上可接受的盐；Or its stereoisomers, tautomers, deuterated substances, nitrogen oxides, solvates, or pharmaceutically acceptable salts;
其中，in,
X是-C(R c)-、或N； X is -C(R c )-, or N;
Z 1和Z 2各自独立地为-C(R 4d)-或N； Z 1 and Z 2 are each independently -C(R 4d )- or N;
R a、R b和R c各自独立地为H、D、F、Cl、C 1-3烷基、C 1-6氘代烷基、C 1-3烷氧基、C 1-3卤代烷基、C 1-3羟基烷基、C 1-3氨基烷基、C 1-3氰基烷基、C 1-6氘代烷氧基、被1至5个氘取代的C 1-6卤代烷基、被1至5个氘取代的C 1-6羟基烷基、被1至5个氘取代的C 3-8环烷基、或被1至5个氘取代的C 1-9杂芳基； R a , R b and R c are each independently H, D, F, Cl, C 1-3 alkyl, C 1-6 deuterated alkyl, C 1-3 alkoxy, C 1-3 haloalkyl , C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, C 1-3 cyanoalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkyl substituted by 1 to 5 deuteriums , a C 1-6 hydroxyalkyl group substituted by 1 to 5 deuteriums, a C 3-8 cycloalkyl group substituted by 1 to 5 deuteriums, or a C 1-9 heteroaryl group substituted by 1 to 5 deuteriums;
R 1是H、D、-C 1-6烷基-NR eR f、-C(＝O)R 7、-C(＝O)OR 7a、-C(＝O)NR 7R 7a、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 3-8环烷基、C 2-9杂环基、C 6-10芳基、或C 1-9杂芳基；其中R 1任选地被0、1、2、3或4个R 5取代； R 1 is H, D, -C 1-6 alkyl-NR e R f , -C(=O)R 7 , -C(=O)OR 7a , -C(=O)NR 7 R 7a , C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl, or C 1-9 Heteroaryl; wherein R is optionally substituted by 0, 1, 2, 3 or 4 R 5 ;
R 2在每次出现时，分别独立地为H、D、F、Cl、Br、I、-OH、-CN、-NO 2、-NR eR f、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基、或C 1-9杂芳基；其中R 2在每次出现时，独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基和C 1-6卤代烷基的基团取代； Each occurrence of R 2 is independently H, D, F, Cl, Br, I, -OH, -CN, -NO 2 , -NR e R f , C 1-6 alkyl, C 1- 6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2-9 heterocyclyl, C 3-8 cycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein R, at each occurrence, is independently optionally 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH , -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy and C 1-6 haloalkyl;
R 3是H、D、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8氘代环烷基、C 2-9杂环基、C 6-10芳基、或C 1-9杂芳基；其中R 3任选地被0、1、2、3、4或5个R 6取代； R 3 is H, D, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkane Base, C 3-8 deuterated cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein R 3 is optionally replaced by 0, 1, 2, 3 , 4 or 5 R 6 substitutions;
R 4a、R 4b、R 4c和R 4d各自独立地为H、D、F、Cl、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基、或C 1-9杂芳基；其中R 4a、R 4b、R 4c和R 4d各自独立任选地被0、1、2、3、4或5个独立选自H、 D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基、C 1-6氘代烷氧基、C 1-6卤代烷基和C 1-6卤代氘代烷基的基团取代； R 4a , R 4b , R 4c and R 4d are each independently H, D, F, Cl, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2-9 hetero Cyclic group, C 3-8 cycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein R 4a , R 4b , R 4c and R 4d are each independently optionally replaced by 0, 1, 2 , 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 deuterated alkyl group, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkyl group and C 1-6 halodeuteroalkyl group substitution;
R 5和R 6，在每次出现时，分别独立地为H、D、氧代(＝O)、F、Cl、Br、I、-OH、-CN、-NO 2、-NR eR f、-C(＝O)R 7、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基、或C 1-9杂芳基；其中所述各-NR eR f、-C(＝O)R 7、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基和C 1-9杂芳基独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基和C 1-6卤代烷基的基团取代； R 5 and R 6 , at each occurrence, are independently H, D, oxo (=O), F, Cl, Br, I, -OH, -CN, -NO 2 , -NR e R f , -C(=O)R 7 , C 1-6 alkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1 -6 haloalkyl, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2-9 heterocyclyl, C 3-8 Cycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein each of -NR e R f , -C(=O)R 7 , C 1-6 alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2-9 heterocyclyl, C 3-8 cycloalkyl, C 6-10 aryl and C 1-9 heteroaryl are independently optional 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 alkoxy group and C 1-6 haloalkyl group substitution;
R e、R f、R 7和R 7a，在每次出现时，分别独立地为H、D、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-9杂环基、C 2-9杂环基C 1-6烷基、C 6-10芳基、C 6-10芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-9杂环基、C 2-9杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基和C 1-6卤代烷基的基团取代；和 R e , R f , R 7 and R 7a , at each occurrence, are independently H, D, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 2-9 heterocyclyl, C 2-9 heterocyclyl C 1-6 alkyl , C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each C 1 -6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-9 heterocyclyl, C 2-9 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl and C 1-9 heteroaryl C 1-6 alkyl groups are independently optionally selected from 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy and C 1-6 haloalkyl group substitution; and
n是0、1、2、或3；n is 0, 1, 2, or 3;
条件是：1)当R 1是吡唑基时、其中R 1任选地被0、1、2、3或4个R 5取代，则各R 2、R 4a、R 4b和R 4c中的至少一个独立地为F、Cl、-CN、C 1-6烷氧基、C 1-6氘代烷基、C 1-6氘代烷氧基、被1至5个氘取代的C 1-6卤代烷基、被1至5个氘取代的C 1-6羟基烷基、被1至5个氘取代的C 3-8环烷基、或被1至5个氘取代的C 1-9杂芳基；或者2)当R 1是H、D、-C 1-6烷基-NR eR f、-C(＝O)R 7、-C(＝O)OR 7a、-C(＝O)NR 7R 7a、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 3-8环烷基、C 2-9杂环基、C 6-10芳基、或除吡唑基以外的C 1-9杂芳基时、其中R 1任选地被0、1、2、3或4个R 5取代，则各R a、R b、R c、R 2、R 3、R 4a、R 4b、R 4c和R 4d中的至少一个独立地为D(氘)、C 1-6氘代烷基、C 1-6氘代烷氧基、被1至5个氘取代的C 1-6卤代烷基、被1至5个氘取代的C 1-6羟基烷基、被1至5个氘取代的C 3-8环烷基、或被1至5个氘取代的C 1-9杂芳基。 Provided that: 1) when R 1 is pyrazolyl, wherein R 1 is optionally substituted by 0, 1, 2, 3 or 4 R 5 , then each of R 2 , R 4a , R 4b and R 4c At least one is independently F, Cl, -CN, C 1-6 alkoxy, C 1-6 deuterated alkyl, C 1-6 deuterated alkoxy, C 1- substituted by 1 to 5 deuteriums 6 haloalkyl, C 1-6 hydroxyalkyl substituted by 1 to 5 deuterium, C 3-8 cycloalkyl substituted by 1 to 5 deuterium, or C 1-9 heteroalkyl substituted by 1 to 5 deuterium Aryl; or 2) when R 1 is H, D, -C 1-6 alkyl-NR e R f , -C(=O)R 7 , -C(=O)OR 7a , -C(=O )NR 7 R 7a , C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl When C 1-9 heteroaryl group or C 1-9 heteroaryl group other than pyrazolyl, wherein R 1 is optionally substituted by 0, 1, 2, 3 or 4 R 5 , then each R a , R b , R c , At least one of R 2 , R 3 , R 4a , R 4b , R 4c and R 4d is independently D (deuterium), C 1-6 deuterated alkyl, C 1-6 deuterated alkoxy, 1 C 1-6 haloalkyl substituted by 1 to 5 deuterium, C 1-6 hydroxyalkyl substituted by 1 to 5 deuterium, C 3-8 cycloalkyl substituted by 1 to 5 deuterium, or 1 to 5 deuterium-substituted C 1-9 heteroaryl.
另一方面，本发明提供了一种异喹啉酮类及喹唑啉酮类化合物，其具有式(Ib)所示结构：On the other hand, the present invention provides a kind of isoquinolones and quinazolinones compound, it has the structure shown in formula (Ib):
Figure PCTCN2022121567-appb-000024
Figure PCTCN2022121567-appb-000024
或其立体异构体、互变异构体、氘代物、氮氧化物、溶剂化物、或药学上可接受的盐；Or its stereoisomers, tautomers, deuterated substances, nitrogen oxides, solvates, or pharmaceutically acceptable salts;
其中，in,
X是-C(R c)-、或N； X is -C(R c )-, or N;
Z 1和Z 2各自独立地为-C(R 4d)-或N； Z 1 and Z 2 are each independently -C(R 4d )- or N;
R a、R b和R c各自独立地为H、D、F、Cl、C 1-3烷基、C 1-3氘代烷基、C 1-3烷氧基、C 1-3卤代烷基、C 1-3羟基烷基、C 1-3氨基烷基、或C 1-3氰基烷基； R a , R b and R c are each independently H, D, F, Cl, C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 alkoxy, C 1-3 haloalkyl , C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, or C 1-3 cyanoalkyl;
R 1是H、D、-C 1-6烷基-NR eR f、-C(＝O)R 7、-C(＝O)OR 7a、-C(＝O)NR 7R 7a、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 3-8环烷基、C 2-9杂环基、C 6-10芳基、或C 1-9杂芳基；其中R 1任选地被0、1、2、3或4个R 5取代； R 1 is H, D, -C 1-6 alkyl-NR e R f , -C(=O)R 7 , -C(=O)OR 7a , -C(=O)NR 7 R 7a , C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl, or C 1-9 Heteroaryl; wherein R is optionally substituted by 0, 1, 2, 3 or 4 R 5 ;
R 2在每次出现时，分别独立地为H、D、F、Cl、Br、I、-OH、-CN、-NO 2、-NR eR f、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基、或C 1-9杂芳基；其中各R 2独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基和C 1-6卤代烷基的基团取代； Each occurrence of R 2 is independently H, D, F, Cl, Br, I, -OH, -CN, -NO 2 , -NR e R f , C 1-6 alkyl, C 1- 6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2-9 heterocyclyl, C 3-8 cycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein each R 2 is independently optionally selected from 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy and C 1-6 haloalkyl group substitution;
R 3是H、D、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8氘代环烷基、C 2-9杂环基、C 6-10芳基、或C 1-9杂芳基；其中R 3任选地被0、1、2、3、4或5个R 6取代； R 3 is H, D, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkane Base, C 3-8 deuterated cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein R 3 is optionally replaced by 0, 1, 2, 3 , 4 or 5 R 6 substitutions;
R 4a、R 4b、R 4c和R 4d各自独立地为H、D、F、Cl、含氘的基团、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基、或C 1-9杂芳基；其中R 4a、R 4b、R 4c和R 4d各自独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基、C 1-6氘代烷氧基、C 1-6卤代烷基和C 1-6卤代氘代烷基的基团取代； R 4a , R 4b , R 4c and R 4d are each independently H, D, F, Cl, a deuterium-containing group, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2 -9 heterocyclyl, C 3-8 cycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein R 4a , R 4b , R 4c and R 4d are each independently optionally replaced by 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-6 Alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, C 1-6 haloalkyl and C 1-6 halodeuteroalkyl groups replace;
R 5和R 6，在每次出现时，分别独立地为H、D、氧代(＝O)、F、Cl、Br、I、-OH、-CN、-NO 2、-NR eR f、-C(＝O)R 7、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基、或C 1-9杂芳基；其中所述各-NR eR f、-C(＝O)R 7、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基和C 1-9杂芳基独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基和C 1-6卤代烷基的基团取代； R 5 and R 6 , at each occurrence, are independently H, D, oxo (=O), F, Cl, Br, I, -OH, -CN, -NO 2 , -NR e R f , -C(=O)R 7 , C 1-6 alkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1 -6 haloalkyl, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2-9 heterocyclyl, C 3-8 Cycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein each of -NR e R f , -C(=O)R 7 , C 1-6 alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2-9 heterocyclyl, C 3-8 cycloalkyl, C 6-10 aryl and C 1-9 heteroaryl are independently optional 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 alkoxy group and C 1-6 haloalkyl group substitution;
R e、R f、R 7和R 7a，在每次出现时，分别独立地为H、D、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-9杂环基、C 2-9杂环基C 1-6烷基、C 6-10芳基、C 6-10芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-9杂环基、C 2-9杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基和C 1-6卤代烷基的基团取代；和 R e , R f , R 7 and R 7a , at each occurrence, are independently H, D, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 2-9 heterocyclyl, C 2-9 heterocyclyl C 1-6 alkyl , C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each C 1 -6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-9 heterocyclyl, C 2-9 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl and C 1-9 heteroaryl C 1-6 alkyl groups are independently optionally selected from 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy and C 1-6 haloalkyl group substitution; and
n是0、1、2、或3；n is 0, 1, 2, or 3;
条件是：1)当R 1是吡唑基时，则R 2、R 4a、R 4b和R 4c中的至少一个独立地为F、Cl、或含氘的基团；或者2)当R 1是H、D、-C 1-6烷基-NR eR f、-C(＝O)R 7、-C(＝O)OR 7a、-C(＝O)NR 7R 7a、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 3-8环烷基、C 2-9杂环基、C 6-10芳基、或除吡唑基以外的C 1-9杂芳基时，R a、R b、R c、R 2、R 3、R 4a、R 4b、R 4c和R 4d中的至少一个独立地为D(氘)、或含氘的基团。 The conditions are: 1) when R 1 is pyrazolyl, at least one of R 2 , R 4a , R 4b and R 4c is independently F, Cl, or a deuterium-containing group; or 2) when R 1 is H, D, -C 1-6 alkyl-NR e R f , -C(=O)R 7 , -C(=O)OR 7a , -C(=O)NR 7 R 7a , C 1- 6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl, or other than pyrazolyl When C 1-9 heteroaryl, at least one of R a , R b , R c , R 2 , R 3 , R 4a , R 4b , R 4c and R 4d is independently D (deuterium), or contains deuterium group.
在一些实施方案，式(I)所示化合物具有式(Ia)所示结构：In some embodiments, the compound shown in formula (I) has the structure shown in formula (Ia):
Figure PCTCN2022121567-appb-000025
Figure PCTCN2022121567-appb-000025
或其立体异构体、互变异构体、氘代物、氮氧化物、溶剂化物、或药学上可接受的盐。Or a stereoisomer, tautomer, deuterated substance, nitrogen oxide, solvate, or a pharmaceutically acceptable salt thereof.
在式(I)或(Ia)的一些实施方案中，R 1是苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、三嗪基、噻唑 基、咪唑基、噁唑基、噻二唑基、
Figure PCTCN2022121567-appb-000026
Figure PCTCN2022121567-appb-000027
In some embodiments of formula (I) or (Ia), R is phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, thiazolyl, imidazolyl, oxazolyl, thiazolyl oxadiazolyl,
Figure PCTCN2022121567-appb-000026
Figure PCTCN2022121567-appb-000027
其中Y 1是O、S、或-NH-； Wherein Y 1 is O, S, or -NH-;
Y 6是O、或-NH-； Y 6 is O, or -NH-;
t3和t4各自独立地为1、2、3或4；和t3 and t4 are each independently 1, 2, 3 or 4; and
其中R 1任选地被0、1、2、3或4个R 5取代； wherein R is optionally substituted by 0, 1, 2, 3 or 4 R 5 ;
条件是：1)R 1为
Figure PCTCN2022121567-appb-000028
时、其中R 1任选地被0、1、2、3或4个R 5取代，则各R 2、R 4a、R 4b和R 4c中的至少一个独立地为F、Cl、-CN、C 1-3烷氧基、C 1-3氘代烷基、C 1-3氘代烷氧基、被1至5个氘取代的C 1-3卤代烷基、被1至5个氘取代的C 1-3羟基烷基、被1至5个氘取代的C 3-6环烷基、或被1至5个氘取代的C 1-9杂芳基；2)当R 1为苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、三嗪基、噻唑基、咪唑基、噁唑基、噻二唑基、
Figure PCTCN2022121567-appb-000029
时、其中R 1任选地被0、1、2、3或4个R 5取代，则各R a、R b、R c、R 2、R 3、R 4a、R 4b、R 4c和R 4d中的至少一个独立地为D(氘)、C 1-3氘代烷基、C 1-3氘代烷氧基、被1至5个氘取代的C 1-3卤代烷基、被1至5个氘取代的C 1-3羟基烷基、被1至5个氘取代的C 3-6环烷基、或被1至5个氘取代的C 1-9杂芳基。 The conditions are: 1) R 1 is
Figure PCTCN2022121567-appb-000028
When, wherein R 1 is optionally substituted by 0, 1, 2, 3 or 4 R 5 , then at least one of each R 2 , R 4a , R 4b and R 4c is independently F, Cl, -CN, C 1-3 alkoxy, C 1-3 deuterated alkyl, C 1-3 deuterated alkoxy, C 1-3 haloalkyl substituted by 1 to 5 deuteriums, substituted by 1 to 5 deuteriums C 1-3 hydroxyalkyl, C 3-6 cycloalkyl substituted by 1 to 5 deuteriums, or C 1-9 heteroaryl substituted by 1 to 5 deuteriums; 2) when R 1 is phenyl, Pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, thiazolyl, imidazolyl, oxazolyl, thiadiazolyl,
Figure PCTCN2022121567-appb-000029
, wherein R 1 is optionally substituted by 0, 1, 2, 3 or 4 R 5 , then each of R a , R b , R c , R 2 , R 3 , R 4a , R 4b , R 4c and R At least one of 4d is independently D (deuterium), C 1-3 deuterated alkyl, C 1-3 deuterated alkoxy, C 1-3 haloalkyl substituted by 1 to 5 deuterium, 1 to 3 C 1-3 hydroxyalkyl substituted with 5 deuteriums, C 3-6 cycloalkyl substituted with 1 to 5 deuteriums, or C 1-9 heteroaryl substituted with 1 to 5 deuteriums.
在式(I)或(Ib)的一些实施方案中，R 1是苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、三嗪基、噻唑基、咪唑基、噁唑基、噻二唑基、
Figure PCTCN2022121567-appb-000030
Figure PCTCN2022121567-appb-000031
In some embodiments of formula (I) or (Ib), R is phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, thiazolyl, imidazolyl, oxazolyl, thiazolyl oxadiazolyl,
Figure PCTCN2022121567-appb-000030
Figure PCTCN2022121567-appb-000031
其中Y 1是O、S、或-NH-； Wherein Y 1 is O, S, or -NH-;
Y 6是O、或-NH-； Y 6 is O, or -NH-;
t3和t4各自独立地为1、2、3或4；和t3 and t4 are each independently 1, 2, 3 or 4; and
其中R 1任选地被0、1、2、3或4个R 5取代； wherein R is optionally substituted by 0, 1, 2, 3 or 4 R 5 ;
条件是：1)R 1为
Figure PCTCN2022121567-appb-000032
时，则R 2、R 4a、R 4b和R 4c中的至少一个独立地为F、Cl、或含氘的基团；；2)当R 1为苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、三嗪基、噻唑基、咪唑基、噁唑基、噻二唑基、
Figure PCTCN2022121567-appb-000033
Figure PCTCN2022121567-appb-000034
时，则R a、R b、R c、R 2、R 3、R 4a、R 4b、R 4c和R 4d中的至少一个独立地为D(氘)、或含氘的基团。 The conditions are: 1) R 1 is
Figure PCTCN2022121567-appb-000032
, then at least one of R 2 , R 4a , R 4b and R 4c is independently F, Cl, or a deuterium-containing group; 2) when R 1 is phenyl, pyridyl, pyridazinyl, pyridyl Azinyl, pyrimidinyl, triazinyl, thiazolyl, imidazolyl, oxazolyl, thiadiazolyl,
Figure PCTCN2022121567-appb-000033
Figure PCTCN2022121567-appb-000034
, then at least one of R a , R b , R c , R 2 , R 3 , R 4a , R 4b , R 4c and R 4d is independently D (deuterium), or a deuterium-containing group.
在式(I)或(Ia)的一些实施方案中，R 4a、R 4b、R 4c和R 4d各自独立地为H、D、F、Cl、C 1-3烷基、C 1-3氘代烷基、C 1-3烷氧基、C 1-3卤代烷基、C 1-3卤代烷氧基、C 1-3羟基烷基、C 1-3氨基烷基、C 1-3氰基烷基、C 3-6杂环基、C 3-6氘代杂环基、C 3-6环烷基、C 3-6氘代环烷基、苯基、或5-6个原子组成的杂芳基；其中R 4a、R 4b、R 4c和R 4d各自独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-3烷基、C 1-3氘代烷基、C 1-3烷氧基、C 1-3氘代烷氧基、C 1-3卤代烷基和C 1-3卤代氘代烷基的基团取代。 In some embodiments of formula (I) or (Ia), R 4a , R 4b , R 4c and R 4d are each independently H, D, F, Cl, C 1-3 alkyl, C 1-3 deuterium Substituted alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, C 1-3 cyanoalkane group, C 3-6 heterocyclyl, C 3-6 deuterated heterocyclyl, C 3-6 cycloalkyl, C 3-6 deuterated cycloalkyl, phenyl, or hetero Aryl; wherein R 4a , R 4b , R 4c and R 4d are each independently optionally 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl , Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 alkoxy, C 1-3 deuterated alkane Oxygen, C 1-3 haloalkyl and C 1-3 halodeuteroalkyl are substituted.
在式(I)、(Ia)或(Ib)的一些实施方案中，R 4a、R 4b、R 4c和R 4d各自独立地为H，F，Cl，D，-CN，-OCH 3，-OCH 2CH 3，
Figure PCTCN2022121567-appb-000035
Figure PCTCN2022121567-appb-000036
In some embodiments of formula (I), (Ia) or (Ib), R 4a , R 4b , R 4c and R 4d are each independently H, F, Cl, D, -CN, -OCH 3 , - OCH2CH3 ,
Figure PCTCN2022121567-appb-000035
Figure PCTCN2022121567-appb-000036
另一方面，本发明还提供了式(II)所示化合物：On the other hand, the present invention also provides the compound shown in formula (II):
Figure PCTCN2022121567-appb-000037
Figure PCTCN2022121567-appb-000037
或其立体异构体、互变异构体、氘代物、氮氧化物、溶剂化物、或药学上可接受的盐；Or its stereoisomers, tautomers, deuterated substances, nitrogen oxides, solvates, or pharmaceutically acceptable salts;
其中，in,
X是-C(R c)-、或N； X is -C(R c )-, or N;
W是C 3-10环烷基、C 2-9杂环基、C 6-10芳基、或C 1-9杂芳基；其中W任选地被0、1、2、3或4个R 4取代； W is C 3-10 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein W is optionally replaced by 0, 1, 2, 3 or 4 R 4 replaces;
R a、R b和R c各自独立地为H、D、F、Cl、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、或C 1-6氰基烷基； R a , R b and R c are each independently H, D, F, Cl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, or C 1-6 cyanoalkyl;
R 1是-C 1-3羟基烷基-C(＝O)OR 7a，-C(＝O)OR 7a，-C(＝O)NR 7R 7a，
Figure PCTCN2022121567-appb-000038
Figure PCTCN2022121567-appb-000039
R 1 is -C 1-3 hydroxyalkyl-C(=O)OR 7a , -C(=O)OR 7a , -C(=O)NR 7 R 7a ,
Figure PCTCN2022121567-appb-000038
Figure PCTCN2022121567-appb-000039
其中Y 2和Y 3各自独立地为-(CH 2) t1-、-(CH 2) t1-L-、-(CH 2) t1-L-(CH 2) t2-、O、或-NH-； wherein Y 2 and Y 3 are each independently -(CH 2 ) t1 -, -(CH 2 ) t1 -L-, -(CH 2 ) t1 -L-(CH 2 ) t2 -, O, or -NH- ;
Y 4是-(CH 2) t1-、-(CH 2) t1-L-、-(CH 2) t1-L-(CH 2) t2-、-C(＝O)-、O、S、或-NH-； Y 4 is -(CH 2 ) t1 -, -(CH 2 ) t1 -L-, -(CH 2 ) t1 -L-(CH 2 ) t2 -, -C(=O)-, O, S, or -NH-;
Y 5是-CH-、或N； Y 5 is -CH-, or N;
Y 6是O、或-NH-； Y 6 is O, or -NH-;
Y 7是O、或-NH-； Y 7 is O, or -NH-;
L是-C(＝O)-、O、S、或-NH-；L is -C(=O)-, O, S, or -NH-;
t1、t2和t3在每次出现时，各自独立地为1、2、3或4；each occurrence of t1, t2 and t3 is independently 1, 2, 3 or 4;
t4是1；t5是1或2；和t4 is 1; t5 is 1 or 2; and
Figure PCTCN2022121567-appb-000040
代表单键或双键；和
Figure PCTCN2022121567-appb-000040
represents a single or double bond; and
其中R 1任选地被0、1、2、3或4个R 5取代； wherein R is optionally substituted by 0, 1, 2, 3 or 4 R 5 ;
R 2在每次出现时，分别独立地为H、D、F、Cl、Br、I、-OH、-CN、-NO 2、-NR eR f、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基、或C 1-9杂芳基；其中R 2在每次出现时，独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基和C 1-6卤代烷基的基团取代； Each occurrence of R 2 is independently H, D, F, Cl, Br, I, -OH, -CN, -NO 2 , -NR e R f , C 1-6 alkyl, C 1- 6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2-9 heterocyclyl, C 3-8 cycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein R, at each occurrence, is independently optionally 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH , -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy and C 1-6 haloalkyl;
R 3是H、D、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8氘代环烷基、C 2-9杂环基、C 6-10芳基、或C 1-9杂芳基；其中R 3任选地被0、1、2、3、4或5个R 6取代； R 3 is H, D, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkane Base, C 3-8 deuterated cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein R 3 is optionally replaced by 0, 1, 2, 3 , 4 or 5 R 6 substitutions;
R 4在每次出现时，分别独立地为H、D、F、Cl、Br、I、-OH、-CN、-NO 2、-NR eR f、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基、或C 1-9杂芳基；其中R 4在每次出现时，独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基和C 1-6卤代烷基的基团取代； Each occurrence of R 4 is independently H, D, F, Cl, Br, I, -OH, -CN, -NO 2 , -NR e R f , C 1-6 alkyl, C 1- 6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2-9 heterocyclyl, C 3-8 cycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein R is , at each occurrence, independently optionally 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH , -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy and C 1-6 haloalkyl;
R 5和R 6，在每次出现时，分别独立地为H、D、氧代(＝O)、F、Cl、Br、I、-OH、-CN、-NO 2、-NR eR f、-C(＝O)R 7、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基、或C 1-9杂芳基；其中所述各-NR eR f、-C(＝O)R 7、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基和C 1-9杂芳基独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基和C 1-6卤代烷基的基团取代； R 5 and R 6 , at each occurrence, are independently H, D, oxo (=O), F, Cl, Br, I, -OH, -CN, -NO 2 , -NR e R f , -C(=O)R 7 , C 1-6 alkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1 -6 haloalkyl, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2-9 heterocyclyl, C 3-8 Cycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein each of -NR e R f , -C(=O)R 7 , C 1-6 alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2-9 heterocyclyl, C 3-8 cycloalkyl, C 6-10 aryl and C 1-9 heteroaryl are independently optional 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 alkoxy group and C 1-6 haloalkyl group substitution;
R 5a是-C(＝O)R 7、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基、或C 1-9杂芳基；其中所述各-C(＝O)R 7、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基和C 1-9杂芳基独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基和C 1-6卤代烷基的基团取代； R 5a is -C(=O)R 7 , C 1-6 alkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl , C 2-9 heterocyclyl, C 3 -8 cycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein each of -C(=O)R 7 , C 1-6 alkyl, C 1-6 deuterated alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 cyanoalkyl, C 2-9 heterocyclyl, C 3-8 cycloalkyl, C 6-10 aryl and C 1-9 heteroaryl are independently optionally replaced by O, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-6 Alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy and C 1-6 haloalkyl group substitution;
R e、R f、R 7和R 7a，在每次出现时，分别独立地为H、D、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-9杂环基、C 2-9杂环基C 1-6烷基、C 6-10芳基、C 6-10芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-9杂环基、C 2-9杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基和C 1-6卤代烷基的基团取代；和 R e , R f , R 7 and R 7a , at each occurrence, are independently H, D, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 2-9 heterocyclyl, C 2-9 heterocyclyl C 1-6 alkyl , C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each C 1 -6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-9 heterocyclyl, C 2-9 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl and C 1-9 heteroaryl C 1-6 alkyl groups are independently optionally selected from 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy and C 1-6 haloalkyl group substitution; and
n是0、1、2、或3。n is 0, 1, 2, or 3.
在式(II)的一些实施方案中，W是C 3-8环烷基、C 3-8杂环基、
Figure PCTCN2022121567-appb-000041
Figure PCTCN2022121567-appb-000042
In some embodiments of formula (II), W is C 3-8 cycloalkyl, C 3-8 heterocyclyl,
Figure PCTCN2022121567-appb-000041
Figure PCTCN2022121567-appb-000042
其中Z 1、Z 2和Z 3各自独立地为-CH-、或N；和 wherein Z 1 , Z 2 and Z 3 are each independently -CH-, or N; and
其中W任选地被0、1、2、3或4个R 4取代。 wherein W is optionally substituted by 0, 1, 2, 3 or 4 R 4 .
在一些实施方案，式(II)所示化合物具有式(IIa)所示结构：In some embodiments, the compound shown in formula (II) has the structure shown in formula (IIa):
Figure PCTCN2022121567-appb-000043
Figure PCTCN2022121567-appb-000043
或其立体异构体、互变异构体、氘代物、氮氧化物、溶剂化物、或药学上可接受的盐；Or its stereoisomers, tautomers, deuterated substances, nitrogen oxides, solvates, or pharmaceutically acceptable salts;
其中，m是0、1、2或3。wherein m is 0, 1, 2 or 3.
在式(II)或(IIa)的一些实施方案中，R 1是
Figure PCTCN2022121567-appb-000044
Figure PCTCN2022121567-appb-000045
Figure PCTCN2022121567-appb-000046
其中R 1任选地被0、1、2、3或4个R 5取代。 In some embodiments of formula (II) or (IIa), R is
Figure PCTCN2022121567-appb-000044
Figure PCTCN2022121567-appb-000045
Figure PCTCN2022121567-appb-000046
wherein R 1 is optionally substituted by 0, 1, 2, 3 or 4 R 5 .
在式(II)或(IIa)的一些实施方案中，R 4在每次出现时，分别独立地为H、D、F、Cl、Br、I、-OH、-CN、-NO 2、-NH 2、C 1-3烷基、C 1-3烷氧基、C 1-3卤代烷基、C 1-3卤代烷氧基、C 1-3羟基烷基、C 1-3氨基烷基、C 1-3氰基烷基、C 3-6杂环基、C 3-6环烷基、苯基、或5-6个原子组成的杂芳基；其中R 4在每次出现时，分别独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-3烷基、C 1-3氘代烷基、C 1-3烷氧基和C 1-3卤代烷基的基团取代。 In some embodiments of formula (II) or (IIa), each occurrence of R 4 is independently H, D, F, Cl, Br, I, -OH, -CN, -NO 2 , - NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, C 1-3 cyanoalkyl, C 3-6 heterocyclyl, C 3-6 cycloalkyl, phenyl, or heteroaryl consisting of 5-6 atoms; wherein R 4 is independently Optionally 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, -NH2 , -CN, -NO 2. Substitution by C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 alkoxy and C 1-3 haloalkyl.
在式(II)或(IIa)的一些实施方案中，R 4在每次出现时，分别独立地为R 4在每次出现时，分别独立地为H、D、F、Cl、Br、I、-OH、-CN、-NO 2、-NH 2、甲基、乙基、异丙基、甲氧基、乙氧基、氟代甲基、-CD 3、-CHD 2、-CH 2D、环丙基、苯基、或5-6个原子组成的杂芳基；其中各R 4独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-3烷基、C 1-3氘代烷基、C 1-3烷氧基和C 1-3卤代烷基的基团取代。 In some embodiments of formula (II) or (IIa), each occurrence of R 4 is, independently, each occurrence of R 4 , each independently H, D, F, Cl, Br, I , -OH, -CN, -NO 2 , -NH 2 , methyl, ethyl, isopropyl, methoxy, ethoxy, fluoromethyl, -CD 3 , -CHD 2 , -CH 2 D , cyclopropyl, phenyl, or heteroaryl consisting of 5-6 atoms; wherein each R 4 is independently and optionally 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 alkoxy and C 1-3 haloalkyl group substitution.
在式(II)或(IIa)的一些实施方案中，R 5a是-C(＝O)R 7、C 1-4烷基、C 1-4氘代烷基、C 2-4烯基、C 2-4炔 基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4羟基烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 3-6杂环基、C 3-6环烷基、C 6-10芳基、或C 1-9杂芳基；其中所述各-C(＝O)R 7、C 1-4烷基、C 1-4氘代烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4羟基烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 3-6杂环基、C 3-6环烷基、C 6-10芳基和C 1-9杂芳基独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-4氘代烷基、C 1-4烷氧基和C 1-4卤代烷基的基团取代。 In some embodiments of formula (II) or (IIa), R 5a is -C(=O)R 7 , C 1-4 alkyl, C 1-4 deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl , C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 Cyanoalkyl, C 3-6 heterocyclyl, C 3-6 cycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein each -C(=O)R 7 , C 1-4 alkyl, C 1-4 deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkane Oxygen, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-6 heterocyclyl, C 3-6 cycloalkyl, C 6-10 aryl and C 1-9 heteroaryl are independently optionally selected from 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, Group substitution by -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-4 deuterated alkyl, C 1-4 alkoxy and C 1-4 haloalkyl.
在式(II)或(IIa)的一些实施方案中，R 5a是甲基、乙基、异丙基、环丙基、-CF 3、-CH 2CH 2OH、-C(＝O)CH 3、-C(＝O)CH 2CH 3、或-CH 2CH 2OCH 3。 In some embodiments of formula (II) or (IIa), R 5a is methyl, ethyl, isopropyl, cyclopropyl, -CF 3 , -CH 2 CH 2 OH, -C(=O)CH 3. -C(=O)CH 2 CH 3 , or -CH 2 CH 2 OCH 3 .
在式(I)、(Ia)、(Ib)、(II)或(IIa)的一些实施方案中，R 3是环丙基、吡啶基、或苯基；其中R 3任选地被0、1、2、3、4或5个独立选自H、D、F、Cl、Br、I、-OH、-CN、-NO 2、-NR eR f、C 1-3烷基、C 1-3烷氧基、C 1-3氘代烷基和C 1-3卤代烷基的基团取代。 In some embodiments of formula (I), (Ia), (Ib), (II) or (IIa), R 3 is cyclopropyl, pyridyl, or phenyl; wherein R 3 is optionally replaced by 0, 1, 2, 3, 4 or 5 independently selected from H, D, F, Cl, Br, I, -OH, -CN, -NO 2 , -NR e R f , C 1-3 alkyl, C 1 -3 alkoxy, C 1-3 deuterated alkyl and C 1-3 haloalkyl group substitution.
在式(I)、(Ia)、(Ib)、(II)或(IIa)的一些实施方案中，R 5和R 6在每次出现时，分别独立地为H、D、氧代(＝O)、F、Cl、Br、I、-OH、-CN、-NO 2、-NR eR f、-C(＝O)R 7、C 1-3烷基、C 1-6氘代烷基、C 1-3烷氧基、C 1-3卤代烷基、C 1-3羟基烷基、C 3-6环烷基、苯基、或5-6个原子组成的杂芳基；其中所述各-NR eR f、-C(＝O)R 7、C 1-3烷基、C 1-6氘代烷基、C 1-3烷氧基、C 1-3卤代烷基、C 1-3羟基烷基、C 3-6环烷基、苯基和5-6个原子组成的杂芳基独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-3烷基、C 1-3氘代烷基、C 1-3烷氧基和C 1-3卤代烷基的基团取代。 In some embodiments of formula (I), (Ia), (Ib), (II) or (IIa), each occurrence of R and R is independently H, D, oxo (= O), F, Cl, Br, I, -OH, -CN, -NO 2 , -NR e R f , -C(=O)R 7 , C 1-3 alkyl, C 1-6 deuterated alkanes C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, phenyl , or heteroaryl consisting of 5-6 atoms; -NR e R f , -C(=O)R 7 , C 1-3 alkyl, C 1-6 deuterated alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1 -3 hydroxyalkyl, C 3-6 cycloalkyl, phenyl and heteroaryl consisting of 5-6 atoms are independently and optionally 0, 1, 2, 3, 4 or 5 independently selected from H, D , oxo (=O), F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 Alkoxy and C 1-3 haloalkyl group substitution.
在式(I)、(Ia)、(Ib)、(II)或(IIa)的一些实施方案中，R 5和R 6在每次出现时，分别独立地为H、D、F、Cl、Br、I、-OH、-CN、-NO 2、-NR eR f、甲基、乙基、异丙基、环丙基、-CD 3、-OCD 3、-CF 3、-CH 2CH 2OH、-C(＝O)CH 3、-C(＝O)CH 2CH 3、或-CH 2CH 2OCH 3。 In some embodiments of formula (I), (Ia), (Ib), (II) or (IIa), each occurrence of R and R is independently H, D, F, Cl, Br, I, -OH, -CN, -NO 2 , -NR e R f , methyl, ethyl, isopropyl, cyclopropyl, -CD 3 , -OCD 3 , -CF 3 , -CH 2 CH 2 OH, -C(=O)CH 3 , -C(=O)CH 2 CH 3 , or -CH 2 CH 2 OCH 3 .
在式(I)、(Ia)、(II)或(IIa)的一些实施方案中，R a、R b和R c各自独立地为H、D、F、-CN、-NO 2、-NR eR f、甲基、乙基、异丙基、-CD 3、-CHD 2、-CH 2D、甲氧基、乙氧基、卤代甲基、卤代乙基、或-CH 2CH 2OH。 In some embodiments of formula (I), (Ia), (II) or (IIa), R a , R b and R c are each independently H, D, F, -CN, -NO 2 , -NR e R f , methyl, ethyl, isopropyl, -CD 3 , -CHD 2 , -CH 2 D, methoxy, ethoxy, halomethyl, haloethyl, or -CH 2 CH 2 OH.
在式(I)、(Ia)、(Ib)、(II)或(IIa)的一些实施方案中，R e、R f、R 7和R 7a，在每次出现时，分别独立地为H、D、C 1-4烷基、C 1-4氘代烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 3-6杂环基、C 3-6杂环基C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-4烷基；其中所述各C 1-4烷基、C 1-4氘代烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 3-6杂环基、C 3-6杂环基C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基和C 1-9杂芳基C 1-4烷基独立任选地被0、1、2、3、4或5个独立地选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-4烷基、C 1-4氘代烷基、C 1-4烷氧基和C 1-4卤代烷基的基团取代。 In some embodiments of formula (I), (Ia), (Ib), (II) or (IIa), R e , R f , R 7 and R 7a , at each occurrence, are independently H , D, C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-4 alkyl, C 3-6 heterocyclyl, C 3-6 heterocyclyl C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, C 1 -9 heteroaryl, or C 1-9 heteroaryl C 1-4 alkyl; wherein each C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 1 -4 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-4 alkyl, C 3-6 heterocyclyl, C 3-6 heterocyclyl C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, C 1-9 heteroaryl and C 1-9 heteroaryl C 1-4 alkyl are independently optionally replaced by 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-4 alkane The group substitution of radical, C 1-4 deuterated alkyl, C 1-4 alkoxy and C 1-4 haloalkyl.
在式(I)、(Ia)、(Ib)、(II)或(IIa)的一些实施方案中，R e、R f、R 7和R 7a，在每次出现时，分别独立地为H、D、C 1-2烷基、C 1-2氘代烷基、C 1-2卤代烷基、苯基、或环丙基。 In some embodiments of formula (I), (Ia), (Ib), (II) or (IIa), R e , R f , R 7 and R 7a , at each occurrence, are independently H , D, C 1-2 alkyl, C 1-2 deuterated alkyl, C 1-2 haloalkyl, phenyl, or cyclopropyl.
在式(I)、(Ia)或(Ib)的一些实施方案中，所述化合物为具有以下结构之一的化合物：In some embodiments of Formula (I), (Ia) or (Ib), the compound is a compound having one of the following structures:
Figure PCTCN2022121567-appb-000047
Figure PCTCN2022121567-appb-000047
Figure PCTCN2022121567-appb-000048
Figure PCTCN2022121567-appb-000048
Figure PCTCN2022121567-appb-000049
Figure PCTCN2022121567-appb-000049
或其立体异构体、互变异构体、氘代物、氮氧化物、溶剂化物、或药学上可接受的盐。Or a stereoisomer, tautomer, deuterated substance, nitrogen oxide, solvate, or a pharmaceutically acceptable salt thereof.
在式(II)或(IIa)的一些实施方案中，所述化合物为具有以下结构之一的化合物：In some embodiments of formula (II) or (IIa), the compound is a compound having one of the following structures:
Figure PCTCN2022121567-appb-000050
Figure PCTCN2022121567-appb-000050
Figure PCTCN2022121567-appb-000051
Figure PCTCN2022121567-appb-000051
或其立体异构体、互变异构体、氮氧化物、溶剂化物、或药学上可接受的盐。Or a stereoisomer, tautomer, nitrogen oxide, solvate, or a pharmaceutically acceptable salt thereof.
除非另有说明，式(I)、(Ia)、(Ib)、(II)或(IIa)所示化合物的立体异构体、互变异构体、溶剂化物、代谢产物或药学上可接受的盐均包含在本发明范围内。Unless otherwise stated, stereoisomers, tautomers, solvates, metabolites or pharmaceutically acceptable All salts are included within the scope of the present invention.
本发明公开化合物可含有不对称或手性中心，因此可以不同的立体异构体形式存在。本发明旨在使式(I)、(Ia)、(Ib)、(II)或(IIa)所示化合物的所有立体异构体形式，包括但不限于非对映异构体、对映 异构体、阻转异构体和几何(或构象)异构体，以及它们的混合物如外消旋混合物，成为本发明的组成部分。The compounds disclosed herein may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. The present invention intends to make all stereoisomeric forms of compounds shown in formula (I), (Ia), (Ib), (II) or (IIa), including but not limited to diastereoisomers, enantiomers isomers, atropisomers and geometric (or conformational) isomers, as well as mixtures thereof, such as racemic mixtures, form part of the present invention.
在本发明公开的结构中，当任意特定的手性原子的立体化学未指明时，则该结构的所有立体异构体均考虑在本发明之内，并且作为本发明公开化合物包括在本发明中。当立体化学被表示特定构型的实楔形线(solid wedge)或虚线指明时，则该结构的立体异构体就此明确和定义。In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers of the structure are contemplated and included in the present invention as disclosed compounds . When stereochemistry is indicated by a solid wedge or a dashed line indicating a particular configuration, then the stereoisomers of that structure are identified and defined.
式(I)、(Ia)、(Ib)、(II)或(IIa)所示化合物可以盐的形式存在。在一实施方案，所述盐是指药学上可接受的盐。术语“药学上可接受的”是指物质或组合物必须与包含制剂的其它成分和/或用其治疗的哺乳动物化学上和/或毒理学上相容。在另一实施方案，所述盐不一定是药学上可接受的盐，可以是用于制备和/或提纯式(I)、(Ia)、(Ib)、(II)或(IIa)所示化合物和/或用于分离本式(I)、(Ia)、(II)或(IIa)所示化合物的对映体的中间体。The compound represented by formula (I), (Ia), (Ib), (II) or (IIa) may exist in the form of a salt. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or with the mammal being treated therewith. In another embodiment, the salt is not necessarily a pharmaceutically acceptable salt, but may be used for preparing and/or purifying the salt shown in formula (I), (Ia), (Ib), (II) or (IIa). Compounds and/or intermediates used to separate enantiomers of compounds represented by formula (I), (Ia), (II) or (IIa).
另一方面，本发明涉及制备式(I)、(Ia)、(Ib)、(II)或(IIa)所示化合物的中间体。In another aspect, the present invention relates to intermediates for the preparation of compounds represented by formula (I), (Ia), (Ib), (II) or (IIa).
另一方面，本发明涉及式(I)、(Ia)、(Ib)、(II)或(IIa)所示化合物的制备、分离和纯化的方法。In another aspect, the present invention relates to methods for preparing, isolating and purifying compounds represented by formula (I), (Ia), (Ib), (II) or (IIa).
另一方面，本发明提供一种药物组合物，所述药物组合物包含本发明化合物。在一实施方案中，本发明所述药物组合物，更进一步包括药学上可接受的辅料、稀释剂或载体、或其组合。在另一实施方案，所述药物组合物可以是液体、固体、半固体、凝胶或喷雾剂型。In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention. In one embodiment, the pharmaceutical composition of the present invention further includes a pharmaceutically acceptable adjuvant, diluent or carrier, or a combination thereof. In another embodiment, the pharmaceutical composition may be in liquid, solid, semi-solid, gel or spray form.
在一些实施方案，本发明所述药物组合物进一步包含附加治疗剂。In some embodiments, the pharmaceutical compositions described herein further comprise additional therapeutic agents.
另一方面，本发明涉及一种使用本发明所述的化合物或本发明所述的药物组合物在制备用于预防、处理、治疗、和/或减轻PI3-激酶介导的疾病、病症、和/或病况，或抑制PI3-激酶活性的药物中的用途。In another aspect, the present invention relates to a method for preventing, treating, treating, and/or alleviating PI3-kinase-mediated diseases, disorders, and and/or a condition, or use in a drug that inhibits PI3-kinase activity.
在一些实施方案，所述PI3-激酶介导的疾病、病症、和/或病况选自呼吸道疾病，病毒感染，非病毒呼吸道感染，过敏性疾病，自身免疫性疾病，炎性疾病，心血管疾病，恶性血液病，神经退行性疾病，胰腺炎，多器官衰竭，肾病，血小板聚集，癌症，精子活力，移植排斥，移植物排斥，肺损伤或疼痛。In some embodiments, the PI3-kinase-mediated disease, disorder, and/or condition is selected from respiratory disease, viral infection, non-viral respiratory infection, allergic disease, autoimmune disease, inflammatory disease, cardiovascular disease , hematological malignancy, neurodegenerative disease, pancreatitis, multiple organ failure, renal disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, lung injury, or pain.
在一些实施方案，所述PI3-激酶介导的疾病、病症、和/或病况选自哮喘，慢性阻塞性肺病(COPD)，病毒性呼吸道感染，病毒性呼吸道疾病恶化，曲霉病，利什曼病，过敏性鼻炎，过敏性皮肤炎，风湿性关节炎，多发性硬化，炎性肠病，血栓症，动脉粥样硬化，恶性血液病，神经退行性疾病，胰腺炎，多器官衰竭，肾病，血小板聚集，癌症，精子活力，移植排斥，移植物排斥，肺损伤，与类风湿性关节炎或骨关节炎相关的疼痛，背痛，全身炎症性疼痛，肝后神经痛，糖尿病性神经病变，炎症性神经性疼痛(外伤)，三叉神经痛或中枢性疼痛。In some embodiments, the PI3-kinase-mediated disease, disorder, and/or condition is selected from asthma, chronic obstructive pulmonary disease (COPD), viral respiratory infection, exacerbation of viral respiratory disease, aspergillosis, leishmaniasis disease, allergic rhinitis, allergic dermatitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, thrombosis, atherosclerosis, hematological malignancy, neurodegenerative disease, pancreatitis, multiple organ failure, kidney disease , platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, lung injury, pain associated with rheumatoid arthritis or osteoarthritis, back pain, systemic inflammatory pain, retrohepatic neuralgia, diabetic neuropathy , inflammatory neuropathic pain (trauma), trigeminal neuralgia or central pain.
在一些实施方案，所述癌症选自急性骨髓性白血病，脊髓发育异常综合征，骨髓增生病，慢性骨髓性白血病，T细胞急性淋巴细胞白血病，B细胞急性淋巴细胞白血病，非霍奇金淋巴瘤，B细胞淋巴瘤，实体瘤，或乳腺癌。In some embodiments, the cancer is selected from acute myelogenous leukemia, myelodysplastic syndrome, myeloproliferative disorder, chronic myelogenous leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, non-Hodgkin's lymphoma , B-cell lymphoma, solid tumor, or breast cancer.
在一些实施方案，其中所述PI3-激酶是PI3K-γ。In some embodiments, wherein the PI3-kinase is PI3K-γ.
本发明化合物的药物组合物、制剂和给药Pharmaceutical Compositions, Formulations and Administration of Compounds of the Invention
本发明提供了一种药物组合物，其包含本发明公开化合物，或实施例中所列化合物，或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物或药学上可接受的盐；和药学上可接受的辅料、稀释剂、载体、溶媒或其组合。本发明公开的药物组合物中化合物的量是指能有效检测到抑制生物样本或患者体内蛋白激酶的量。The present invention provides a pharmaceutical composition, which comprises the compounds disclosed in the present invention, or the compounds listed in the examples, or their stereoisomers, tautomers, nitrogen oxides, solvates, metabolites or pharmaceutically an acceptable salt; and a pharmaceutically acceptable adjuvant, diluent, carrier, vehicle or a combination thereof. The amount of the compound in the pharmaceutical composition disclosed in the present invention refers to the amount that can effectively detect and inhibit the protein kinase in biological samples or patients.
也应认识到，本发明的某些化合物可以以游离形式存在用于治疗，或者如果适当可以以其药学上可接受的衍生物的形式存在。药学上可接受衍生物的一些非限制性的实施方案包括药学上可接受的盐、酯、这些酯的盐、或者对有需要的患者给药时能直接或间接提供本发明所述化合物或其代谢产物或残余物的任何另外的加合物或衍生物。It will also be recognized that some of the compounds of the invention may exist in free form for use in therapy or, if appropriate, as a pharmaceutically acceptable derivative thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable salts, esters, salts of these esters, or compounds that provide, directly or indirectly, the compounds of the present invention or their derivatives when administered to a patient in need thereof. Any additional adducts or derivatives of metabolites or residues.
在文献例如Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York中披露了用于配置药学上可接受的组合物的各种载体，和用于其制备的公知技术，这些文献各自的内容通过引用并入本发明。除任何诸如因产生任何不期望的生物作用，或以有害方式与药学上可接受组合物中的任何其它成分发生相互作用而与本发明公开化合物不相容的任何常用载体外，关注其应用属于本发明的范围。In literature such as Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy, Lippincott Williams&Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Various carriers for formulating pharmaceutically acceptable compositions, and well known techniques for their preparation are disclosed in York, the contents of each of which are incorporated herein by reference. Concerned about the use of any of the compounds disclosed herein, except for any commonly used carriers that are incompatible with the compounds disclosed herein, such as by producing any undesired biological effects, or by interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition scope of the invention.
本发明提供的药物组合物可以与不会损害预期治疗作用的其它活性成分共同配制，或者与补充预期作用的物质共同配制。The pharmaceutical compositions provided by the present invention can be formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.
本发明化合物和组合物的用途Uses of the compounds and compositions of the invention
本发明化合物是激酶活性的抑制剂，特别是PI3-激酶活性的抑制剂。作为PI3-激酶抑制剂的化合物可用于治疗其中潜在病理(至少有一部分)归因于不当的PI3-激酶活性的紊乱，例如哮喘，慢性阻塞性肺病(COPD)，病毒感染，非病毒呼吸道感染，过敏性疾病，自身免疫性疾病，炎性疾病，心血管疾病，恶性血液病，神经退行性疾病，胰腺炎，多器官衰竭，肾病，血小板聚集，癌症，精子活力，移植排斥，移植物排斥，肺损伤或疼痛等。“不当的PI3-激酶活性”指的是与在具体的患者中期望的正常PI3-激酶活性有偏离的任何PI3-激酶活性。不当的PI3-激酶可采取，例如，活性的异常增加，或PI3-激酶畸变或控制失常的形式。这些不当的活性可起因于，例如导致不当的或未受控制被激活的蛋白激酶的过表达或突变。因此，在另一方面，本发明涉及治疗所述疾病或病症的方法。The compounds of the invention are inhibitors of kinase activity, especially inhibitors of PI3-kinase activity. Compounds that are PI3-kinase inhibitors are useful in the treatment of disorders in which the underlying pathology is attributable (at least in part) to inappropriate PI3-kinase activity, such as asthma, chronic obstructive pulmonary disease (COPD), viral infections, non-viral respiratory infections, Allergic disease, autoimmune disease, inflammatory disease, cardiovascular disease, hematologic malignancy, neurodegenerative disease, pancreatitis, multiorgan failure, renal disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, Lung damage or pain, etc. "Inappropriate PI3-kinase activity" refers to any PI3-kinase activity that deviates from the normal PI3-kinase activity expected in a particular patient. An inappropriate PI3-kinase can take the form, for example, of an abnormal increase in activity, or an aberration or malfunction of the PI3-kinase. These inappropriate activities may result, for example, from overexpression or mutations of protein kinases that result in inappropriate or uncontrolled activation. Accordingly, in another aspect, the invention relates to methods of treating said diseases or conditions.
此类疾病或病症包含，但并不仅仅限于，呼吸系统疾病，包括哮喘、慢性阻塞性肺病和特发性肺纤维化(IPF)；病毒感染，包括病毒性呼吸道感染和病毒性呼吸道疾病恶化，例如哮喘和COPD；非病毒性呼吸道感染，包括曲霉病和利什曼病；过敏性疾病，包括过敏性鼻炎和特应性皮炎；自身免疫性疾病，包括类风湿性关节炎和多发性硬化；炎症性疾病，包括炎症性肠病；心血管疾病，包括血栓症和动脉粥样硬化；恶性血液病；神经退行性疾病；胰腺炎；多器官功能衰竭；肾脏疾病；血小板聚集；癌症；精子活力；移植排斥；移植物排斥；肺损伤；以及疼痛，包括与类风湿性关节炎或骨关节炎相关的疼痛、背痛、全身炎症性疼痛、肝后神经痛、糖尿病性神经病变、炎症性神经性疼痛(外伤)、三叉神经痛和中枢性疼痛。在一实施例中，此类紊乱包含，呼吸系统疾病，包括哮喘和慢性阻塞性肺病(COPD)；过敏性疾病，包括过敏性鼻炎和特应性皮炎；自身免疫性疾病，包括类风湿性关节炎和多发性硬化；炎症性疾病，包括炎症性肠病；心血管疾病，包括血栓症和动脉粥样硬化；恶性血液病；神经退行性疾病；胰腺炎；多器官功能衰竭；肾脏疾病；血小板聚集；癌症；精子活力；移植排斥；移植物排斥；肺损伤；以及疼痛，包括与类风湿性关节炎或骨关节炎相关的疼痛、背痛、全身炎症性疼痛、肝后神经痛、糖尿病性神经病变、炎症性神经性疼痛(外伤)、三叉神经痛和中枢性疼痛。Such diseases or conditions include, but are not limited to, respiratory diseases, including asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis (IPF); viral infections, including viral respiratory infections and viral respiratory disease exacerbations, Examples include asthma and COPD; nonviral respiratory infections, including aspergillosis and leishmaniasis; allergic diseases, including allergic rhinitis and atopic dermatitis; autoimmune diseases, including rheumatoid arthritis and multiple sclerosis; Inflammatory disease, including inflammatory bowel disease; cardiovascular disease, including thrombosis and atherosclerosis; hematological malignancies; neurodegenerative disease; pancreatitis; multiple organ failure; renal disease; platelet aggregation; cancer; sperm motility ; transplant rejection; graft rejection; lung injury; and pain, including pain associated with rheumatoid arthritis or osteoarthritis, back pain, systemic inflammatory pain, retrohepatic neuralgia, diabetic neuropathy, inflammatory neuropathy Sexual pain (trauma), trigeminal neuralgia and central pain. In one example, such disorders include, respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD); allergic diseases, including allergic rhinitis and atopic dermatitis; autoimmune diseases, including rheumatoid arthritis inflammation and multiple sclerosis; inflammatory diseases, including inflammatory bowel disease; cardiovascular disease, including thrombosis and atherosclerosis; hematological malignancies; neurodegenerative diseases; pancreatitis; multiple organ failure; renal disease; platelets Aggregation; cancer; sperm motility; transplant rejection; Neuropathy, inflammatory neuropathic pain (trauma), trigeminal neuralgia, and central pain.
在此类疾病或病症中，所述癌症选自急性骨髓性白血病，脊髓发育异常综合征，骨髓增生病，慢性骨髓性白血病，T细胞急性淋巴细胞白血病，B细胞急性淋巴细胞白血病，非霍奇金淋巴瘤，B细胞淋巴瘤，实体瘤，或乳腺癌。In such diseases or conditions, the cancer is selected from acute myelogenous leukemia, myelodysplastic syndrome, myeloproliferative disorder, chronic myelogenous leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, non-Hodgkin Gold lymphoma, B-cell lymphoma, solid tumor, or breast cancer.
本发明的治疗方法包括给予有需要的患者以安全和有效量的式(I)所示化合物或其药学上可接受的盐。本发明的各个实施例包括通过给予有需要的患者以安全和有效量的式(I)所示化合物或其药学上可接受的盐，治疗本发明提到的任一种紊乱或疾病的方法。The treatment method of the present invention comprises administering a safe and effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof to a patient in need. Various embodiments of the present invention include methods for treating any of the disorders or diseases mentioned in the present invention by administering a safe and effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof to a patient in need.
联合治疗combination therapy
本发明化合物可作为单独的活性剂给药，或者可与其它治疗剂联合给药，包括具有相同或相似治疗活性并且对于此类联合给药确定为安全且有效的其它化合物。The compounds of the present invention may be administered as the sole active agent, or may be administered in combination with other therapeutic agents, including other compounds that have the same or similar therapeutic activity and are determined to be safe and effective for such combination administration.
一方面，本发明提供治疗、预防或改善疾病或病症的方法，包括施用安全有效量的包含本发明公开化合物与一种或多种治疗活性剂的联合药物。在一些实施方案，联合药物包含一种或两种其他治疗剂。In one aspect, the present invention provides a method for treating, preventing or ameliorating a disease or condition, comprising administering a safe and effective amount of a combination drug comprising a compound disclosed in the present invention and one or more therapeutically active agents. In some embodiments, the combination comprises one or two other therapeutic agents.
其它治疗剂的实例包括包括但不限于：抗癌剂，包括化疗剂和抗增殖剂；抗炎剂；和免疫调节剂或免疫抑制剂。Examples of other therapeutic agents include, but are not limited to: anti-cancer agents, including chemotherapeutics and anti-proliferative agents; anti-inflammatory agents; and immunomodulators or immunosuppressants.
另一方面，本发明提供了包括本发明化合物和至少一种其它治疗剂的产品，可制备成在治疗中同时、分别或顺序施用的组合。在一些实施方案，治疗是针对由一种或多种蛋白激酶，如PI3k-激酶活性介导的疾病或病征的治疗。联合制备提供的产品包括存在于同一药物组合物中、并包含本发明公开化合物和其他治疗剂的组合物，或以不同形式存在的本发明公开化合物和其他治疗剂，例如，药盒。In another aspect, the invention provides a product comprising a compound of the invention and at least one other therapeutic agent, prepared as a combination for simultaneous, separate or sequential administration in therapy. In some embodiments, the treatment is for a disease or condition mediated by the activity of one or more protein kinases, such as PI3k-kinase. Products provided by combination preparations include compositions comprising a compound disclosed herein and an additional therapeutic agent in the same pharmaceutical composition, or in different forms, eg, a kit.
另一方面，本发明提供了一种包含本发明公开化合物和另外一种或多种治疗剂的药物组合物。在一些实施方案，药物组合物可包含如上所述的药学上可接受的辅料。In another aspect, the invention provides a pharmaceutical composition comprising a compound disclosed herein and one or more additional therapeutic agents. In some embodiments, the pharmaceutical composition may comprise pharmaceutically acceptable excipients as described above.
另一方面，本发明提供了包含两种或两种以上的单独药物组合物的药盒，其中至少一种药物组合物包含本发明公开化合物。在一些实施方案，药盒包括单独保持所述组合物的工具，例如容器、分开的瓶或分 开的箔盒。这类药盒的实例是泡罩包装，其通常用于包装片剂、胶囊剂等。In another aspect, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound disclosed herein. In some embodiments, the kit includes means for individually maintaining the compositions, such as containers, divided bottles, or divided foil boxes. An example of such a kit is a blister pack, which is commonly used for packaging tablets, capsules and the like.
本发明公开化合物可以作为单一活性组分施用或作为例如佐剂，与其它治疗剂共同施用。Compounds disclosed herein may be administered as the sole active ingredient or co-administered with other therapeutic agents, eg, as adjuvants.
在一些实施方案，所述其它治疗剂包括，例如免疫抑制剂、免疫调节剂或其他抗炎剂、用于治疗或预防同种或异种移植急性或慢性排斥反应、或炎症、或自身免疫性疾病的药物，或化学治疗剂，如恶性肿瘤细胞抗增殖剂。In some embodiments, such additional therapeutic agents include, for example, immunosuppressants, immunomodulators, or other anti-inflammatory agents for the treatment or prevention of acute or chronic rejection of allograft or xenograft, or inflammatory, or autoimmune disease drugs, or chemotherapeutic agents, such as antiproliferative agents for malignant tumor cells.
本发明式(I)所示化合物与其他的免疫抑制剂/免疫调节剂，抗炎剂，化学治疗剂或抗感染剂共同用药，其中免疫抑制剂/免疫调节剂，抗炎剂，化学治疗剂或抗感染剂共同用药的剂量取决于联合用药的类型，是甾体类化合物还是钙调磷酸酶抑制剂，及正在用于治疗的具体药物和治疗情况等。The compound represented by the formula (I) of the present invention is used together with other immunosuppressants/immunomodulators, anti-inflammatory agents, chemotherapeutic agents or anti-infective agents, wherein immunosuppressants/immunomodulators, anti-inflammatory agents, chemotherapeutic agents Or the dose of anti-infective agent co-administration depends on the type of co-administration, whether it is a steroid compound or a calcineurin inhibitor, and the specific drug being used for treatment and the treatment situation.
抗炎剂的实例包括非甾体抗炎药物(NSAID)。NSAID的实例包括色甘酸钠，奈多罗米钠(nedocromil sodium)，磷酸二酯酶(PDE)抑制剂(如茶碱、PDE4抑制剂，或混合型PDE3/PDE4抑制剂)，白三烯拮抗剂，白三烯合成抑制剂(如孟鲁司特)，iNOS抑制剂，胰蛋白酶和弹性蛋白酶抑制剂，β-2整联蛋白拮抗剂和腺苷受体激动剂或拮抗剂(如，腺苷2α受体激动剂)，细胞因子拮抗剂(如趋化因子受体拮抗剂，包括CCR3拮抗剂)，细胞因子合成抑制剂，或5-脂氧化酶抑制剂。Examples of anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAIDs). Examples of NSAIDs include cromolyn sodium, nedocromil sodium, phosphodiesterase (PDE) inhibitors (such as theophylline, PDE4 inhibitors, or mixed PDE3/PDE4 inhibitors), leukotriene antagonists , leukotriene synthesis inhibitors (eg, montelukast), iNOS inhibitors, trypsin and elastase inhibitors, beta-2 integrin antagonists, and adenosine receptor agonists or antagonists (eg, adenosine 2α receptor agonists), cytokine antagonists (such as chemokine receptor antagonists, including CCR3 antagonists), cytokine synthesis inhibitors, or 5-lipoxygenase inhibitors.
式(I)化合物也可有利地用于与其他化合物的组合，或与其他治疗剂，尤其是抗增殖剂的组合中。此类抗增殖剂包括，但不限于，芳香酶抑制剂；抗雌激素；拓扑异构酶I抑制剂；拓扑异构酶II抑制剂；微管活性剂；烷化剂；组蛋白去乙酰化酶抑制剂；诱导细胞分化过程的化合物；环氧合酶抑制剂；MMP抑制剂；mTOR抑制剂；抗肿瘤抗代谢药；铂化合物；靶向/降低蛋白或脂质激酶活性的化合物和其他抗血管生成的化合物；靶向、降低或抑制蛋白或脂质磷酸酯酶活性的化合物；戈那瑞林类激动剂；抗雄激素；蛋氨酸氨肽酶抑制剂；双膦酸盐；生物反应调节剂；抗增殖抗体；乙酰肝素酶抑制剂；Ras致癌亚型抑制剂；端粒酶抑制剂；蛋白酶体抑制剂；治疗血液肿瘤的药剂；靶向、降低或抑制Flt-3活性的化合物；Hsp90抑制剂；替莫唑胺和亚叶酸钙。The compounds of formula (I) may also advantageously be used in combination with other compounds, or in combination with other therapeutic agents, especially antiproliferative agents. Such antiproliferative agents include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule activating agents; alkylating agents; histone deacetylation Enzyme inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platinum compounds; compounds that target/reduce protein or lipid kinase activity and other anti- Angiogenic compounds; Compounds that target, decrease, or inhibit protein or lipid phosphatase activity; Gonadorelin-like agonists; Antiandrogens; Methionine aminopeptidase inhibitors; Bisphosphonates; Biological response modifiers ; antiproliferative antibodies; heparanase inhibitors; Ras oncogenic isoform inhibitors; telomerase inhibitors; Inhibitors; Temozolomide and Leucovorin.
“联合”表示在单个剂量单位形式中的固定联合或用于联合给药的部分的药盒，其中本发明公开的化合物和联合伴侣可在同一时间独立施用或者可在一定的时间间隔内分别施用，特别是使联合伴侣表现出合作、例如协同作用。如本发明所用的术语“共同给药”或“联合给药”等意欲囊括将所选的联合伴侣施用于需要其的单个个体(例如患者)，并且意欲包括其中物质不必通过相同给药途径或同时给药的治疗方案。"Combination" means a fixed combination in single dosage unit form or a kit of parts for combined administration wherein the compound disclosed herein and the combination partner may be administered independently at the same time or may be administered separately at intervals , especially to make joint partners exhibit cooperation, such as synergy. The terms "co-administration" or "combination administration" and the like as used herein are intended to encompass the administration of selected combination partners to a single individual (e.g. patient) in need thereof, and are intended to include where the substances do not necessarily have to be administered by the same route of administration or Concomitant treatment regimens.
治疗方法treatment method
在一些实施方案，本发明公开的治疗方法包括对有需要的患者施用安全有效量的本发明化合物或包含本发明化合物的药物组合物。本发明公开的各实施方案包括通过对有需要的患者给予安全有效量的本发明公开化合物或包含本发明公开化合物的药物组合物，来治疗本发明所述疾病或病症的方法。In some embodiments, the methods of treatment disclosed herein comprise administering to a patient in need thereof a safe and effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention. Various embodiments disclosed herein include methods of treating the diseases or conditions described herein by administering to a patient in need thereof a safe and effective amount of a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein.
在一些实施方案，本发明公开化合物或包含本发明公开化合物的药物组合物可以一次性给药，或者根据给药方案，在指定时间段内，在不同的时间间隔给药若干次。例如，每天给药一次、两次、三次或四次。在其中一个实施方案，每天给药一次。在又一实施方案，每天给药两次。可以给药直至达到想要的治疗效果或无限期地维持想要的治疗效果。本发明公开化合物或包含本发明公开化合物的药物组合物的合适给药方案取决于所述化合物的药代动力学性质，例如稀释、分布和半衰期，这些可由技术人员测定。此外，本发明公开化合物或包含本发明公开化合物的药物组合物的合适给药方案，包括实施该方案的持续时间，取决于被治疗的疾病、被治疗疾病的严重程度、被治疗患者的年龄和身体状况、被治疗患者的医疗史、同时疗法的性质、想要的治疗效果等那些在技术人员知识和经验范围内的因素。所述领域技术人员还应理解，对于个体患者对给药方案的反应，或随着时间推移个体患者需要变化时，可要求调整适宜的给药方案。In some embodiments, a compound disclosed herein or a pharmaceutical composition comprising a compound disclosed herein may be administered at one time, or several times at different time intervals within a specified period of time according to a dosing regimen. For example, once, twice, three or four times per day. In one embodiment, the administration is once daily. In yet another embodiment, the administration is twice daily. Administration can be until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for compounds disclosed herein or pharmaceutical compositions comprising compounds disclosed herein depend on the pharmacokinetic properties of the compound, such as dilution, distribution and half-life, which can be determined by the skilled artisan. Furthermore, suitable dosing regimens for compounds disclosed herein or pharmaceutical compositions comprising compounds disclosed herein, including the duration for which such regimens are carried out, depend on the disease being treated, the severity of the disease being treated, the age and Physical condition, medical history of the patient being treated, nature of concurrent therapy, desired therapeutic effect, etc., are factors within the knowledge and experience of the skilled person. It will also be understood by those skilled in the art that the response of an individual patient to the dosing regimen, or as the individual patient's needs change over time, may require adjustment of the appropriate dosing regimen.
本发明的药物组合物或组合/联合对于约50-70kg的个体可以是约1-1000mg活性成分，或约1-500mg或约1-250mg或约1-150mg或约0.5-100mg、或约1-50mg的活性成分的单位剂量。化合物、药物组合物或其组合的治疗有效剂量取决于个体的物种、体重、年龄和个体疾病、病症或病况或待治疗的严重度。本领域普通技能医师、临床医生或兽医能够很容易地确定用于预防、治疗或抑制疾病或病症进展的各活性成分的有效量。以上所引用的剂量特性已在采用有利的哺乳动物，例如小鼠、大鼠、狗、猴、或离体器官、组织及其标本的体外和体内试验中证实。本发明的化合物能以溶液的形式在体外使用，例如水溶液，也可呈混悬液或水溶液的形式经肠、肠胃外和宜经的静脉在体内使用。体内治疗有效量的范围取决于给药途径，其在约0.01-500mg/kg之间，或约在1-100mg/kg之间。The pharmaceutical composition or combination/combination of the present invention may be about 1-1000 mg active ingredient, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1 - a unit dose of 50 mg of active ingredient. Therapeutically effective dosages of the compounds, pharmaceutical compositions or combinations thereof depend on the individual's species, body weight, age and individual disease, disorder or condition or severity being treated. A physician, clinician or veterinarian of ordinary skill in the art can readily determine the effective amount of each active ingredient for preventing, treating or inhibiting the progression of a disease or condition. The dosage properties cited above have been demonstrated in in vitro and in vivo experiments using mammals, eg, mice, rats, dogs, monkeys, or isolated organs, tissues and specimens thereof, advantageously. The compounds of the present invention can be administered in vitro in the form of solutions, eg, aqueous solutions, and in vivo in the form of suspensions or aqueous solutions enterally, parenterally and preferably intravenously. A therapeutically effective amount in vivo ranges depending on the route of administration and is between about 0.01-500 mg/kg, or between about 1-100 mg/kg.
本发明公开化合物可与一种或多种其它治疗剂同时、或在其之前或之后进行给药。本发明化合物可以与其他治疗剂通过相同或不同给药途径分别进行给药，或与之以同一药物组合物形式给药。A compound disclosed herein may be administered simultaneously with, prior to, or subsequent to, one or more other therapeutic agents. The compound of the present invention can be administered separately with other therapeutic agents through the same or different routes of administration, or in the form of the same pharmaceutical composition.
一般合成方案General Synthetic Scheme
为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。In order to describe the present invention, examples are listed below. However, it should be understood that the present invention is not limited to these examples, but only provides a method of practicing the present invention.
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)、(Ia)、(Ib)、(II)或(IIa)所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless there are further instructions, wherein the substituents are defined as formula (I), (Ia), (Ib), (II) or (IIa) shown. The following reaction schemes and examples serve to further illustrate the present invention.
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。试剂购自商品供应商，例如Aldrich Chemical Company，Alfa Chemical Company，上海韶远试剂有限公司，SAIN化学技术(上海)有限公司，上海拜德制药技术有限公司，上海浩宏生物医学技术有限公司，除非另有说明，否则本发明所使用的试剂无需进一步纯化即可使用。常用溶剂购自北京海之源伟业科技有限公司等商品供应商。In the examples described below, unless indicated otherwise, all temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers, such as Aldrich Chemical Company, Alfa Chemical Company, Shanghai Shaoyuan Reagent Co., Ltd., SAIN Chemical Technology (Shanghai) Co., Ltd., Shanghai Baide Pharmaceutical Technology Co., Ltd., Shanghai Haohong Biomedical Technology Co., Ltd., unless Otherwise, the reagents used in the present invention were used without further purification. Commonly used solvents were purchased from commodity suppliers such as Beijing Haizhiyuan Weiye Technology Co., Ltd.
无水THF、二氧六环、DCM、甲苯和DMF均购自商品供应商，例如安耐吉公司(Energy chemical company)和Aldrich化学公司。EtOAc、PE、CH 3CN、NMP和DMSO在使用前均用无水Na 2SO 4处理。 Anhydrous THF, dioxane, DCM, toluene and DMF were purchased from commercial suppliers such as Energy chemical company and Aldrich chemical company. EtOAc, PE, CH3CN , NMP and DMSO were all treated with anhydrous Na2SO4 before use.
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿都是干燥过的。The following reactions were generally carried out under a positive pressure of nitrogen or argon or over anhydrous solvents with a dry tube (unless otherwise indicated), the reaction vials were fitted with suitable rubber stoppers, and the substrate was introduced by syringe. Glassware is dried.
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory.
1H NMR谱和 13C/2D数据是在Bruker Avance III 400MHz上收集得到。 1H NMR谱以CDC1 3、DMSO-d 6、CD 3OD或丙酮-d 6为溶剂(以ppm为单位)，用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)、d(doublet，双峰)、t(triplet，三重峰)、m(multiplet，多重峰)、br(broadened，宽峰)、brs(broadened singlet，宽单峰)、dd(doublet of doublets，双二重峰)、dt(doublet of triplets，双三重峰)。偶合常数，用赫兹(Hz)表示。 1 H NMR spectra and 13 C/2D data were collected on a Bruker Avance III 400 MHz. 1 H NMR spectrum uses CDC1 3 , DMSO-d 6 , CD 3 OD or acetone-d 6 as the solvent (in ppm), and TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. When multiplets appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broadened) peak), brs (broadened singlet, broad singlet), dd (doublet of doublets, double doublet), dt (doublet of triplets, double triplet). Coupling constants are expressed in Hertz (Hz).
LC/MS是在与Agilent 6120/6125质谱仪耦合的Agilent 1260(二元泵/DAD检测器)上进行。LC/MS was performed on an Agilent 1260 (binary pump/DAD detector) coupled to an Agilent 6120/6125 mass spectrometer.
方法1：method 1:
柱：HALO C18 2.7μm，4.6mm×30mm，流动相：MeCN(0.05％HCOOH)-Water(0.05％HCOOH)；Column: HALO C18 2.7μm, 4.6mm×30mm, mobile phase: MeCN (0.05% HCOOH)-Water (0.05% HCOOH);
梯度：从5％至95％的MeCN，洗脱0.8min，保持0.8min，总运行时间是2.0min；流速：1.8mL/min；Gradient: from 5% to 95% MeCN, elution 0.8min, hold 0.8min, total running time is 2.0min; flow rate: 1.8mL/min;
柱温：45℃；Column temperature: 45°C;
方法2：Method 2:
柱：HALO C18 2.7μm，4.6mm×50mm，流动相：MeCN(0.025％三氟乙酸)-水(0.025％三氟乙酸)；梯度：从5％至95％的MeCN，洗脱1.0min，保持1.0min，总运行时间是2.5min；流速：Column: HALO C18 2.7μm, 4.6mm×50mm, mobile phase: MeCN (0.025% trifluoroacetic acid)-water (0.025% trifluoroacetic acid); gradient: from 5% to 95% MeCN, elution 1.0min, hold 1.0min, the total running time is 2.5min; flow rate:
1.8mL/min；柱温：45℃。1.8mL/min; Column temperature: 45°C.
由RP-HPLC进行纯度测试：Purity test by RP-HPLC:
在RP-HPLC上进行化合物纯度测试(Shimadzu 2010/2030)Compound purity testing on RP-HPLC (Shimadzu 2010/2030)
方法1：method 1:
柱：Gemini 4.6×150mm 5um；流动相：H 2O(0.05％三氟乙酸)-MeCN(0.05％三氟乙酸)。梯度： Column: Gemini 4.6×150mm 5um; mobile phase: H 2 O (0.05% trifluoroacetic acid)-MeCN (0.05% trifluoroacetic acid). gradient:
从10％至100％的MeCN，洗脱8分钟，保持2分钟。流速：1.2mL/min，柱温：35℃/40℃。From 10% to 100% MeCN, 8 min elution, 2 min hold. Flow rate: 1.2mL/min, column temperature: 35°C/40°C.
方法2：Method 2:
柱：XBRIDGE 2.1×50mm，3.5um；流动相：H 2O(0.05％三氟乙酸)-MeCN(0.05％三氟乙酸)。梯度：从10％至100％的MeCN，洗脱7分钟，保持1分钟。流速：0.8mL/min，柱温：35℃/40℃。 Column: XBRIDGE 2.1×50mm, 3.5um; mobile phase: H 2 O (0.05% trifluoroacetic acid)-MeCN (0.05% trifluoroacetic acid). Gradient: From 10% to 100% MeCN, 7 min elution, 1 min hold. Flow rate: 0.8mL/min, column temperature: 35°C/40°C.
由SFC进行化合物纯化：Compound purification by SFC:
在配备UV检测器的Thar P80上进行SFC纯化。SFC purification was performed on a Thar P80 equipped with UV detector.
方法：柱CHIRALPAK AD-H 250mm，20mm，5μm，改性剂：30％EtOH(0.2％NH 4OH)。 Method: Column CHIRALPAK AD-H 250 mm, 20 mm, 5 μm, Modifier: 30% EtOH (0.2% NH 4 OH).
由RP-HPLC进行化合物纯化：Compound purification by RP-HPLC:
在Gilson纯化系统(322或306泵和GX-281馏分收集器)，Shimadzu LC20Ap和Waters MS触发纯化系统上进行RP-HPLC纯化；RP-HPLC purification on Gilson purification system (322 or 306 pump and GX-281 fraction collector), Shimadzu LC20Ap and Waters MS trigger purification system;
方法1：method 1:
柱Gemini C18 21x150mm，5μm Xbrige C18 19x150mm，5μm，Spolar C18 20x150mm和Ultimate AQ-C18 30x250mm，10μmColumn Gemini C18 21x150mm, 5μm Xbrige C18 19x150mm, 5μm, Spolar C18 20x150mm and Ultimate AQ-C18 30x250mm, 10μm
流动相：mobile phase:
1.MeCN的水溶液(0.1％HCOOH)，流速：20ml/min，50ml/min，柱30x250mm，10μm；波长：210-400nm。将样品注入DMSO(+任选的甲酸和水)中，从10％至95％MeCN的线性梯度，洗脱10分钟。1. MeCN aqueous solution (0.1% HCOOH), flow rate: 20ml/min, 50ml/min, column 30x250mm, 10μm; wavelength: 210-400nm. Samples were injected into DMSO (+ optional formic acid and water) and eluted with a linear gradient from 10% to 95% MeCN over 10 minutes.
2.MeCN的水溶液(0.1％三氟乙酸)，流速：20ml/min，50ml/min，柱30x250mm，10μm；波长：210-400nm。将样品注入DMSO(+任选的甲酸和水)中，从10％至95％MeCN的线性梯度，洗脱10分钟。2. Aqueous solution of MeCN (0.1% trifluoroacetic acid), flow rate: 20ml/min, 50ml/min, column 30x250mm, 10μm; wavelength: 210-400nm. Samples were injected into DMSO (+ optional formic acid and water) and eluted with a linear gradient from 10% to 95% MeCN over 10 minutes.
3.MeCN的水溶液(0.1％NH 3-H 2O/10mM NH 4AC)，流速：20ml/min，50ml/min，柱30x250mm，10μm；波长：210-400nm。将样品注入DMSO(+任选的甲酸和水)中，从10％至95％MeCN的线性梯度，洗脱10分钟。 3. Aqueous solution of MeCN (0.1% NH 3 -H 2 O/10 mM NH 4 AC), flow rate: 20 ml/min, 50 ml/min, column 30x250 mm, 10 μm; wavelength: 210-400 nm. Samples were injected into DMSO (+ optional formic acid and water) and eluted with a linear gradient from 10% to 95% MeCN over 10 minutes.
制备本发明公开化合物的典型合成步骤如以下合成方案所示。除非另外说明，R 1、R 2、R 3、R 4a、R 4b、R 4c、R a、R b、X、Z 1、Z 2、W和n均具有如本发明所述的定义。 Typical synthetic procedures for the preparation of the compounds disclosed herein are shown in the following synthetic schemes. Unless otherwise specified, R 1 , R 2 , R 3 , R 4a , R 4b , R 4c , R a , R b , X, Z 1 , Z 2 , W and n all have the definitions as described in the present invention.
合成方案1：Synthesis Scheme 1:
Figure PCTCN2022121567-appb-000052
Figure PCTCN2022121567-appb-000052
具有如式(6)所示结构的本发明化合物可以通过合成方案1描述的一般合成方法制备得到，具体步骤可参考实施例。在合成方案1中，化合物(1)可通过购买商用试剂，或者参照文献(WO2016149160A1)合成得到。化合物(1)和带有R 1取代的端基炔在合适的钯盐和铜盐催化下偶联得到化合物(3)。在酸性条件下脱除Boc保护基，得到化合物(4)的衍生物。化合物(4)和化合物(5)在合适的碱性条件下，或在缩合剂存在下反应得到目标激酶抑制剂(6)。 The compound of the present invention having the structure shown in formula (6) can be prepared by the general synthesis method described in Synthesis Scheme 1, and the specific steps can be referred to the examples. In Synthesis Scheme 1, compound (1) can be synthesized by purchasing commercial reagents or referring to literature (WO2016149160A1). Compound (1) is coupled with a terminal alkyne substituted with R 1 under the catalysis of a suitable palladium salt or copper salt to obtain compound (3). The Boc protecting group is removed under acidic conditions to obtain the derivative of compound (4). Compound (4) and compound (5) react under suitable alkaline conditions or in the presence of a condensing agent to obtain the target kinase inhibitor (6).
合成方案2：Synthesis Scheme 2:
Figure PCTCN2022121567-appb-000053
Figure PCTCN2022121567-appb-000053
具有如式(8)所示结构的本发明化合物可通过合成方案2描述的一般合成方法制备得到，具体步骤可参考实施例。在合成方案2中，胺类衍生物(4)和羧酸衍生物(7)在合适的缩合剂存在下缩合得到目标激酶抑制剂(8)。The compound of the present invention having the structure shown in formula (8) can be prepared by the general synthesis method described in Synthesis Scheme 2, and the specific steps can be referred to the examples. In Synthesis Scheme 2, amine derivatives (4) and carboxylic acid derivatives (7) are condensed in the presence of a suitable condensing agent to obtain the target kinase inhibitor (8).
片段合成方案1：Fragment Synthesis Scheme 1:
Figure PCTCN2022121567-appb-000054
Figure PCTCN2022121567-appb-000054
具有如式(2)所示结构的炔类衍生物可通过片段合成方案1描述的一般合成方法制备得到，具体步骤可参考实施例。在合成方案2中，化合物(2-a)在合适的碱性条件下(如碳酸钾、碳酸铯和磷酸钾等)，和三甲基乙炔基硅在合适的钯盐和铜盐的催化下偶联得到化合物(2-b)。采用TBAF脱去TMS保护基得到炔类衍生物(2)。或者使用R 1取代的醛基衍生物(2-c)，在合适的碱性条件下，和(1-重氮基-2-氧代丙基)膦酸二甲酯在低温下反应得到炔类衍生物(2)。 The alkyne derivatives with the structure shown in formula (2) can be prepared by the general synthesis method described in Fragment Synthesis Scheme 1, and the specific steps can be referred to the examples. In Synthesis Scheme 2, compound (2-a) is under suitable basic conditions (such as potassium carbonate, cesium carbonate and potassium phosphate, etc.), and trimethylethynyl silicon is under the catalysis of suitable palladium salt and copper salt Coupling affords compound (2-b). The TMS protecting group was removed by TBAF to obtain the alkyne derivative (2). Or use R substituted aldehyde derivatives (2-c), under suitable basic conditions, and (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester at low temperature reaction to give alkyne Class derivatives (2).
片段合成方案2：Fragment Synthesis Scheme 2:
Figure PCTCN2022121567-appb-000055
Figure PCTCN2022121567-appb-000055
具有如式(5)所示结构的羧酸衍生物可通过片段合成方案2描述的一般合成方法制备得到，具体步骤可参考实施例。在合成方案3中，化合物(5-a)在合适的碱性条件下脱去乙基，得到羧酸衍生物(5-b)。化合物(5-b)和化合物(4)在缩合剂(如EDCI或HATU)存在下缩合得到目标激酶抑制剂(6)。化合物(5-b)和N-羟基丁二酰亚胺在缩合剂存在下缩合得到化合物(5-c)。在合适的碱性条件下，化合物(5-c)和化合物(4)反应得到目标激酶抑制剂(6)。The carboxylic acid derivative having the structure shown in formula (5) can be prepared by the general synthesis method described in Fragment Synthesis Scheme 2, and the specific steps can be referred to the examples. In Synthesis Scheme 3, compound (5-a) is deethylated under suitable basic conditions to obtain carboxylic acid derivative (5-b). Compound (5-b) and compound (4) are condensed in the presence of a condensing agent (such as EDCI or HATU) to obtain the target kinase inhibitor (6). Compound (5-b) and N-hydroxysuccinimide are condensed in the presence of a condensing agent to obtain compound (5-c). Under suitable alkaline conditions, compound (5-c) reacts with compound (4) to obtain target kinase inhibitor (6).
氘代片段示例1：Deuterated Fragment Example 1:
本发明合成化合物所使用的带氘合成砌块包括商用试剂，以及可通过参考文献(如WO2017161116A1)合成得到，具体包括但不限于以下结构：The deuterium-containing synthetic building blocks used in the synthesis of compounds of the present invention include commercial reagents, and can be synthesized through references (such as WO2017161116A1), specifically including but not limited to the following structures:
Figure PCTCN2022121567-appb-000056
Figure PCTCN2022121567-appb-000056
实施例Example
中间体1 2,5-二氧代吡咯-1-基2-氨基吡唑并[1,5-a]嘧啶-3-羧酸酯-5,7-D2Intermediate 1 2,5-dioxopyrrol-1-yl 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylate-5,7-D2
Figure PCTCN2022121567-appb-000057
Figure PCTCN2022121567-appb-000057
步骤1)2-氨基吡唑并[1,5-a]嘧啶-3-羧酸乙酯-5,7-D2Step 1) Ethyl 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylate-5,7-D2
向3,5-二氨基-1H-吡唑-4-羧酸乙酯(1g，5.9mmol)的乙酸(30mL)溶液中加入1,1,3,3-四乙氧基丙烷-1,3-D 2(1313.3mg，5.9mmol)。混合物升温至120℃搅拌16h，冷却至室温，减压浓缩，残余物用丙酮(30mL)稀释，抽滤后得到2-氨基吡唑并[1,5-a]嘧啶-3-羧酸乙酯-5,7-D2(1.2g，93.21％收率)。MS(ESI):209.1[M+H] +。 To a solution of ethyl 3,5-diamino-1H-pyrazole-4-carboxylate (1 g, 5.9 mmol) in acetic acid (30 mL) was added 1,1,3,3-tetraethoxypropane-1,3 -D 2 (1313.3 mg, 5.9 mmol). The mixture was heated to 120°C and stirred for 16h, cooled to room temperature, concentrated under reduced pressure, the residue was diluted with acetone (30mL), and filtered with suction to obtain ethyl 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylate -5,7-D2 (1.2 g, 93.21% yield). MS (ESI): 209.1 [M+H] + .
步骤2)2-氨基吡唑并[1,5-a]嘧啶-3-羧酸-5,7-D2Step 2) 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid-5,7-D2
向2-氨基吡唑并[1,5-a]嘧啶-3-羧酸乙酯(1.2g，5.8mmol)的MeOH/H 2O(50mL/10mL)溶液中加入LiOH(1.22g，29mmol)。混合物在60℃下搅拌4h，减压除去溶剂，残余物用1N HCl调pH至5。抽滤，滤渣干燥后得到2-氨基吡唑并[1,5-a]嘧啶-3-羧酸-5,7-D2(785mg，72.41％收率)为黄色固体。MS(ESI):181.0[M+H] +。 To a solution of ethyl 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylate (1.2 g, 5.8 mmol) in MeOH/H 2 O (50 mL/10 mL) was added LiOH (1.22 g, 29 mmol) . The mixture was stirred at 60 °C for 4 h, the solvent was removed under reduced pressure, and the pH of the residue was adjusted to 5 with 1N HCl. After suction filtration, the filter residue was dried to obtain 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid-5,7-D2 (785 mg, 72.41% yield) as a yellow solid. MS (ESI): 181.0 [M+H] + .
步骤3)2,5-二氧代吡咯-1-基2-氨基吡唑并[1,5-a]嘧啶-3-羧酸酯-5,7-D2Step 3) 2,5-dioxopyrrol-1-yl 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylate-5,7-D2
将EDCI(279.8mg，1.46mmol)和1-羟基吡咯烷-2,5-二酮(168mg，1.46mmol)加入到2-氨基吡唑并[1,5-a]嘧啶-3-羧酸(200mg，1.12mmol)的DMF(10mL)溶液中，混合物于室温下搅拌16h。反应完毕后，用水(30ml)稀释，并用乙酸乙酯(30mL x 3)萃取三次。合并的有机相用饱和食盐水洗(40mL x 2)，经无水硫酸钠干燥，减压浓缩，得到2,5-二氧代吡咯烷-1-基2-氨基吡唑并[1,5-a]嘧啶-3-羧酸酯-5,7-D2(238mg，69.32％收率)为黄色固体。MS(ESI):277.9[M+H] +。 EDCI (279.8 mg, 1.46 mmol) and 1-hydroxypyrrolidine-2,5-dione (168 mg, 1.46 mmol) were added to 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid ( 200 mg, 1.12 mmol) in DMF (10 mL), the mixture was stirred at room temperature for 16 h. After the reaction was completed, it was diluted with water (30ml), and extracted three times with ethyl acetate (30mL x 3). The combined organic phases were washed with saturated brine (40mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2,5-dioxopyrrolidin-1-yl 2-aminopyrazolo[1,5- a] Pyrimidine-3-carboxylate-5,7-D2 (238 mg, 69.32% yield) as a yellow solid. MS (ESI): 277.9 [M+H] + .
中间体2(S)-3-(1-氨乙基)-8-氯-2-苯基异喹啉-1(2H)-酮Intermediate 2(S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one
Figure PCTCN2022121567-appb-000058
Figure PCTCN2022121567-appb-000058
步骤1)(S)-(1-(甲氧基(甲基)氨基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯Step 1) tert-butyl (S)-(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate
向(叔丁氧基羰基)-L-丙氨酸(8.0g，0.042mol)的DCM(200mL)溶液中加入CDI(8.92g，0.055mmol)。混合物在室温下搅拌1h，然后加入N,O-二甲基羟胺(4.95g，0.051mol)和TEA(17.1g，0.17mol)，混合物在25℃下搅拌16h。混合物用H 2O(20mL)稀释，然后用DCM(50mL×3)萃取。合并的有机层用盐水(40mL x 2)洗，经Na 2SO 4干燥，减压下浓缩。残余物经快速色谱法(DCM/MeOH＝98/2)纯化，得到(S)-(1-(甲氧基(甲基)氨基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(6.8g，62.17％收率)为白色固体。MS(ESI):254.9[M+Na] +。 To a solution of (tert-butoxycarbonyl)-L-alanine (8.0 g, 0.042 mol) in DCM (200 mL) was added CDI (8.92 g, 0.055 mmol). The mixture was stirred at room temperature for 1 h, then N,O-dimethylhydroxylamine (4.95 g, 0.051 mol) and TEA (17.1 g, 0.17 mol) were added, and the mixture was stirred at 25° C. for 16 h. The mixture was diluted with H 2 O (20 mL), then extracted with DCM (50 mL×3). The combined organic layers were washed with brine (40 mL x 2), dried over Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM/MeOH=98/2) to afford tert-butyl (S)-(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate The ester (6.8 g, 62.17% yield) was a white solid. MS (ESI): 254.9 [M+Na] + .
步骤2)2-氯-6-甲基-N-苯基苯甲酰胺Step 2) 2-Chloro-6-methyl-N-phenylbenzamide
在0℃下，向2-氯-6-甲基苯甲酸(5.0g，0.029mol)和DMF(210mg，0.29mmol)的DCM(50mL)溶液中滴加草酰氯(4.83g，0.038mol)，混合物于0℃下搅拌2h。在0℃下，向苯胺(2.73g，0.029mol)和TEA(8.88g，0.088mol)的DCM(50mL)溶液中加入上述反应混合物。将混合物在室温下搅拌5小时。混合物用H 2O(30ml)稀释，用DCM(50mL×3)萃取。合并的有机层用盐水(40mL x 2)洗，经Na 2SO 4干燥，减压浓缩。残余物经快速色谱法(PE/EA＝3/1)纯化，得到2-氯-6-甲基-N-苯基苯甲酰胺(5.66g，70.65％收率)为黄色固体。MS(ESI):245.9[M+H] +。 To a solution of 2-chloro-6-methylbenzoic acid (5.0 g, 0.029 mol) and DMF (210 mg, 0.29 mmol) in DCM (50 mL) was added dropwise oxalyl chloride (4.83 g, 0.038 mol) at 0 °C, The mixture was stirred at 0 °C for 2 h. To a solution of aniline (2.73 g, 0.029 mol) and TEA (8.88 g, 0.088 mol) in DCM (50 mL) was added the above reaction mixture at 0°C. The mixture was stirred at room temperature for 5 hours. The mixture was diluted with H 2 O (30 ml), extracted with DCM (50 mL×3). The combined organic layers were washed with brine (40 mL x 2), dried over Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified by flash chromatography (PE/EA=3/1) to give 2-chloro-6-methyl-N-phenylbenzamide (5.66 g, 70.65% yield) as a yellow solid. MS (ESI): 245.9 [M+H] + .
步骤3)(S)-(4-(3-氯-2-(苯基氨基甲酰基)苯基)-3-氧代丁烷-2-基)氨基甲酸叔丁酯Step 3) Tert-butyl (S)-(4-(3-chloro-2-(phenylcarbamoyl)phenyl)-3-oxobutan-2-yl)carbamate
在-30℃下，在氮气下，在10分钟内向搅拌的2-氯-6-甲基-N-苯基苯甲酰胺(1g，4.1mmol)的THF(20mL)溶液中滴加n-BuLi(4.3ml，10.2mmol)溶液，反应混合物在-30℃搅拌1小时。在-30℃和氮气下，向搅拌的(S)-(1-(甲氧基(甲基)氨基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(1.43g，6.15mmol)的THF(20mL) 溶液中在10min内滴加i-PrMgCl(9.5ml，12.3mmol)溶液，反应混合物在-30℃下搅拌1h。然后将所得溶液缓慢加入上述反应混合物中。混合物在室温下搅拌3小时。混合物用NH 4Cl(30mL)淬灭，然后用EtOAc(30mL x 3)萃取。合并的有机层用盐水(10mL x 2)洗，经Na 2SO 4干燥，减压浓缩。残余物经快速色谱法(PE/EA＝3/1)纯化，得到(S)-(4-(3-氯-2-(苯基氨基甲酰基)苯基)-3-氧代丁烷-2-基)氨基甲酸叔丁酯(1.45g，75.61％收率)为黄色固体。MS(ESI):438.8[M+Na] +。 To a stirred solution of 2-chloro-6-methyl-N-phenylbenzamide (1 g, 4.1 mmol) in THF (20 mL) was added n-BuLi dropwise over 10 min at -30 °C under nitrogen (4.3ml, 10.2mmol) solution, and the reaction mixture was stirred at -30°C for 1 hour. To stirred tert-butyl (S)-(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (1.43 g, 6.15 mmol) at -30°C under nitrogen ) in THF (20 mL) was added dropwise i-PrMgCl (9.5 ml, 12.3 mmol) within 10 min, and the reaction mixture was stirred at -30°C for 1 h. The resulting solution was then slowly added to the above reaction mixture. The mixture was stirred at room temperature for 3 hours. The mixture was quenched with NH 4 Cl (30 mL), then extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified by flash chromatography (PE/EA=3/1) to give (S)-(4-(3-chloro-2-(phenylcarbamoyl)phenyl)-3-oxobutane- 2-yl) tert-butyl carbamate (1.45 g, 75.61% yield) was a yellow solid. MS (ESI): 438.8 [M+Na] + .
步骤4)(S)-3-(1-氨乙基)-8-氯-2-苯基异喹啉-1(2H)-酮Step 4) (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one
在室温下，向(S)-(4-(3-氯-2-(苯基氨基甲酰基)苯基)-3-氧代丁烷-2-基)氨基甲酸叔丁酯(1.4g，3.4mmol)的MeOH(30mL)溶液中加入浓盐酸(2.8mL)，将混合物在80℃下搅拌2小时。混合物减压浓缩，残余物用H 2O(10mL)稀释，并用NaHCO 3溶液调节pH至7-8。混合物用DCM(30mL x 3)萃取，合并的有机层用盐水(20mL x 2)洗，经Na 2SO 4干燥，减压浓缩。残余物经快速色谱法(DCM/MeOH＝95/5)纯化，得到(S)-3-(1-氨乙基)-8-氯-2-苯基异喹啉-1(2H)-酮(830mg，73.53％收率)为黄色固体。MS(ESI):298.9[M+H] +。 To (S)-(4-(3-chloro-2-(phenylcarbamoyl)phenyl)-3-oxobutan-2-yl)carbamate tert-butyl ester (1.4 g, 3.4 mmol) in MeOH (30 mL) was added concentrated hydrochloric acid (2.8 mL), and the mixture was stirred at 80°C for 2 hours. The mixture was concentrated under reduced pressure, the residue was diluted with H 2 O (10 mL), and the pH was adjusted to 7-8 with NaHCO 3 solution. The mixture was extracted with DCM (30 mL x 3), the combined organic layers were washed with brine (20 mL x 2), dried over Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM/MeOH=95/5) to give (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (830 mg, 73.53% yield) as a yellow solid. MS (ESI): 298.9 [M+H] + .
中间体3 2-氨基-5-甲基吡唑并[1,5-a]嘧啶-3-羧酸Intermediate 3 2-Amino-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid
Figure PCTCN2022121567-appb-000059
Figure PCTCN2022121567-appb-000059
步骤1)2-氨基-5-甲基吡唑并[1,5-a]嘧啶-3-羧酸乙酯Step 1) Ethyl 2-amino-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate
向溶于DMF(10mL)的3,5-二氨基-1H-吡唑-4-羧酸乙酯(1g，6.0mmol)的溶液中加入4,4-二甲氧基-2-丁酮(1.6g，12.0mmol))，将反应在110℃下加热1小时，然后加入CH 3COOH(361mg，6.0mmol)，并将反应加热2小时。冷却至室温后，混合物用饱和碳酸氢钠中和，并用水(30mL)稀释。混合物用EtOAc(40mL x 3)萃取。合并的有机层用盐水(60mL x 2)洗，经无水Na 2SO 4干燥，过滤，浓缩。残余物经柱色谱法(DCM/MeOH＝20/1)纯化，得到2-氨基-5-甲基吡唑并[1,5-a]嘧啶-3-羧酸乙酯(940mg，71％)为白色固体。MS(ESI)m/z 224.1[M+H] +。 To a solution of ethyl 3,5-diamino-1H-pyrazole-4-carboxylate (1 g, 6.0 mmol) in DMF (10 mL) was added 4,4-dimethoxy-2-butanone ( 1.6 g, 12.0 mmol)), the reaction was heated at 110 °C for 1 hour, then CH3COOH (361 mg, 6.0 mmol) was added and the reaction was heated for 2 hours. After cooling to room temperature, the mixture was neutralized with saturated sodium bicarbonate and diluted with water (30 mL). The mixture was extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (60 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated . The residue was purified by column chromatography (DCM/MeOH=20/1) to give ethyl 2-amino-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (940mg, 71%) It is a white solid. MS (ESI) m/z 224.1 [M+H] + .
步骤2)2-氨基-5-甲基吡唑并[1,5-a]嘧啶-3-羧酸Step 2) 2-Amino-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid
向2-氨基-5-甲基吡唑并[1,5-a]嘧啶-3-羧酸乙酯(940mg，4.3mmol)的MeOH/H 2O(20mL/4mL)溶液中加入NaOH(854mg，21.4mmol)，然后将混合物在60℃下搅拌16小时。混合物减压浓缩，残余物用水(20mL)稀释。混合物用1N HCl酸化至pH＝3-4，然后混合物用EtOAc(200mL)萃取。分离的有机层用盐水(100mL)洗，经Na 2SO 4干燥，真空浓缩，得到2-氨基-5-甲基吡唑并[1,5-a]嘧啶-3-羧酸(450mg，53％)，为黄色固体。MS(ESI)m/z 196.0[M+H] +。 To a solution of ethyl 2-amino-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (940 mg, 4.3 mmol) in MeOH/H 2 O (20 mL/4 mL) was added NaOH (854 mg , 21.4 mmol), and then the mixture was stirred at 60 °C for 16 hours. The mixture was concentrated under reduced pressure, and the residue was diluted with water (20 mL). The mixture was acidified with 1N HCl to pH=3-4, then the mixture was extracted with EtOAc (200 mL). The separated organic layer was washed with brine (100 mL), dried over Na 2 SO 4 , and concentrated in vacuo to give 2-amino-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (450 mg, 53 %), as a yellow solid. MS (ESI) m/z 196.0 [M+H] + .
实施例1(S)-2-氨基-N-(1-(8-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-2-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-5,7-D2-3-甲酰胺Example 1 (S)-2-amino-N-(1-(8-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)ethynyl)- 1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-5,7-D2-3-carboxamide
Figure PCTCN2022121567-appb-000060
Figure PCTCN2022121567-appb-000060
步骤1)亚硝基脯氨酸Step 1) Nitrosoproline
在0℃下，向吡咯烷-2-羧酸和NaNO 2(4.19g，0.061mmol)的水(10mL)溶液中加入浓盐酸(5mL)。混合物于室温下搅拌16h后，加入水(20mL)稀释，并用乙酸乙酯(30mL x 3)萃取三次。合并的有机相用食盐水洗(40mL x 2)，无水硫酸钠干燥，浓缩除去溶剂，得到亚硝基脯氨酸(5.5g，83％收率)为白色固体。MS(ESI):145.1[M+H] +。 1H NMR(400MHz,DMSO)δ6.50(d,J＝8.6Hz,1H),5.81-5.67(m,1H),5.07-4.90(m,2H), 4.64-4.54(m,1H),3.44-3.37(m,1H),2.31-2.19(m,1H),2.07-1.96(m,1H),1.41-1.33(m,9H)。 To a solution of pyrrolidine-2-carboxylic acid and NaNO2 (4.19 g, 0.061 mmol) in water (10 mL) was added concentrated hydrochloric acid (5 mL) at 0 °C. After the mixture was stirred at room temperature for 16 h, it was diluted with water (20 mL), and extracted three times with ethyl acetate (30 mL x 3). The combined organic phases were washed with brine (40 mL x 2), dried over anhydrous sodium sulfate, and concentrated to remove the solvent to give nitrosoproline (5.5 g, 83% yield) as a white solid. MS (ESI): 145.1 [M+H] + . 1 H NMR(400MHz,DMSO)δ6.50(d,J=8.6Hz,1H),5.81-5.67(m,1H),5.07-4.90(m,2H), 4.64-4.54(m,1H),3.44 -3.37 (m, 1H), 2.31-2.19 (m, 1H), 2.07-1.96 (m, 1H), 1.41-1.33 (m, 9H).
步骤2)5,6-二氢-4H-吡咯并[1,2-c][1,2,3]噁二唑-7-氮鎓-3-内盐Step 2) 5,6-Dihydro-4H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-azonium-3-inner salt
在0℃下，向亚硝基脯氨酸(2g，0.014mol)的乙腈(6mL)溶液中加入TFAA(3.8g，0.018mol)，继续搅拌3h。混合物用碳酸钾淬灭(3.1g，0.022mol)，加入水稀释(20mL)。混合物用乙酸乙酯萃取三次(20mL x3)。合并的有机相经无水硫酸钠干燥，减压浓缩，残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到5,6-二氢-4H-吡咯[1,2-c][1,2,3]噁二唑-7-氮鎓-3-内盐(1.5g，77％收率)为棕色油状物。MS(ESI):252.8[2M+H] +。 1H NMR(400MHz,CDCl 3)δ4.44-4.39(m,2H),2.94-2.90(m,2H),2.81-2.74(m,2H)。 To a solution of nitrosoproline (2 g, 0.014 mol) in acetonitrile (6 mL) was added TFAA (3.8 g, 0.018 mol) at 0° C., and stirring was continued for 3 h. The mixture was quenched with potassium carbonate (3.1 g, 0.022 mol) and diluted with water (20 mL). The mixture was extracted three times with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain 5,6-dihydro-4H-pyrrole[1,2-c ][1,2,3]Oxadiazol-7-azonium-3-inner salt (1.5 g, 77% yield) as a brown oil. MS (ESI): 252.8 [2M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 4.44-4.39 (m, 2H), 2.94-2.90 (m, 2H), 2.81-2.74 (m, 2H).
步骤3)5,6-二氢-4H-吡咯并[1,2-b]吡唑-2-羧酸乙酯Step 3) Ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate
将5,6-二氢-4H-吡咯[1,2-c][1,2,3]噁二唑-7-氮鎓-3-内盐(0.5g，4mmol)和丙-2-炔酸甲酯(1.18g，12mmol)的二甲苯溶液(10mL)升温至140℃并搅拌16h。冷却至室温，浓缩。残余物用EtOAc(30mL)稀释并用饱和食盐水洗(20mL)，有机相用饱和硫酸钠干燥，减压浓缩。所得残余物经硅胶柱色谱分离，得到5,6-二氢-4H-吡咯[1,2-b]吡唑-2-羧酸乙酯(0.23g，30％收率)为棕色油状物。MS(ESI):181.1[M+H] +。 1H NMR(400MHz,CDCl 3)δ6.55(s,1H),4.39(q,J＝7.2Hz,2H),4.25-4.16(m,2H),2.99-2.87(m,2H),2.69-2.56(m, 5,6-Dihydro-4H-pyrrole[1,2-c][1,2,3]oxadiazol-7-azonium-3-inner salt (0.5g, 4mmol) and prop-2-yne A solution of methyl ester (1.18 g, 12 mmol) in xylene (10 mL) was warmed to 140° C. and stirred for 16 h. Cool to room temperature and concentrate. The residue was diluted with EtOAc (30 mL) and washed with saturated brine (20 mL). The organic phase was dried over saturated sodium sulfate and concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography to obtain ethyl 5,6-dihydro-4H-pyrrole[1,2-b]pyrazole-2-carboxylate (0.23 g, 30% yield) as a brown oil. MS (ESI): 181.1 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ6.55(s, 1H), 4.39(q, J=7.2Hz, 2H), 4.25-4.16(m, 2H), 2.99-2.87(m, 2H), 2.69- 2.56(m,
2H),1.40(t,J＝7.2Hz,3H)。2H), 1.40 (t, J=7.2Hz, 3H).
步骤4)(5,6-二氢-4H-吡咯并[1,2-b]吡唑-2-基)甲醇Step 4) (5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methanol
在0℃下，向5,6-二氢-4H-吡咯[1,2-b]吡唑-2-羧酸乙酯(230mg，1.27mmol)的四氢呋喃溶液(10mL)中加入LiAlH 4(48mg，1.27mmol)，混合物保持在0℃下搅拌2h。混合物用10％NaOH的水溶液(2mL)淬灭，过滤。滤液用乙酸乙酯(20mL x 3)萃取三次,合并有机相，经无水硫酸钠干燥，减压浓缩除去溶剂，得到(5,6-二氢-4H-吡咯[1,2-b]吡唑-2-基)甲醇(200mg，90％收率)为无色油状物。MS(ESI):139.1[M+H] +。 1H NMR(400MHz,CDCl 3)δ5.99(s,1H),5.09(s,1H),4.65(d,J＝1.6Hz,2H),4.16-4.12(m,2H),2.88(t,J＝7.2Hz,2H),2.62–2.58(m,2H)。 To a solution of ethyl 5,6-dihydro-4H-pyrrole[1,2-b]pyrazole-2-carboxylate (230 mg, 1.27 mmol) in tetrahydrofuran (10 mL) was added LiAlH 4 (48 mg , 1.27mmol), the mixture was kept stirring at 0°C for 2h. The mixture was quenched with 10% NaOH in water (2 mL) and filtered. The filtrate was extracted three times with ethyl acetate (20mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain (5,6-dihydro-4H-pyrrole[1,2-b]pyrrole Azol-2-yl)methanol (200 mg, 90% yield) was a colorless oil. MS (ESI): 139.1 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ5.99(s, 1H), 5.09(s, 1H), 4.65(d, J=1.6Hz, 2H), 4.16-4.12(m, 2H), 2.88(t, J=7.2Hz, 2H), 2.62–2.58(m, 2H).
步骤5)5,6-二氢-4H-吡咯并[1,2-b]吡唑-2-甲醛Step 5) 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carbaldehyde
向(5,6-二氢-4H-吡咯[1,2-b]吡唑-2-基)甲醇(50mg，0.36mmol)的氯仿(20mL)溶液中加入MnO 2(157mg，1.8mmol)，混合物升温至60℃，搅拌16h。混合物过滤，滤液浓缩后得到5,6-二氢-4H-吡咯并[1,2-b]吡唑-2-甲醛(30mg，58％收率)为无色油状物。MS(ESI):137.1[M+H] +。 1H NMR(400MHz,CDCl 3)δ9.92(s,1H),6.53(s,1H),4.23(t,J＝7.2Hz,2H),2.99-2.95(m,2H),2.72-2.62(m,2H)。 To a solution of (5,6-dihydro-4H-pyrrole[1,2-b]pyrazol-2-yl)methanol (50 mg, 0.36 mmol) in chloroform (20 mL) was added MnO 2 (157 mg, 1.8 mmol), The mixture was warmed to 60 °C and stirred for 16 h. The mixture was filtered and the filtrate was concentrated to give 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carbaldehyde (30 mg, 58% yield) as a colorless oil. MS (ESI): 137.1 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ9.92(s, 1H), 6.53(s, 1H), 4.23(t, J=7.2Hz, 2H), 2.99-2.95(m, 2H), 2.72-2.62( m,2H).
步骤6)2-乙炔基-5,6-二氢-4H-吡咯并[1,2-b]吡唑Step 6) 2-ethynyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole
向5,6-二氢-4H-吡咯[1,2-b]吡唑-2-甲醛(30mg，0.22mmol)和碳酸钾(61mg，0.44mmol)的甲醇(5mL)溶液中加入(1-重氮基-2-氧代丙基)膦酸二甲酯(63mg，0.33mmol)，混合物在室温下搅拌16h。浓缩除去溶剂，残余物用乙酸乙酯稀释(30mL)。混合物用饱和食盐水洗(20mL)，无水硫酸钠干燥，经硅胶柱色谱分离，得到2-乙炔基-5,6-二氢-4H-吡咯并[1,2-b]吡唑(22mg，61.8％收率)为无色油状物。MS(ESI):133.2To a solution of 5,6-dihydro-4H-pyrrole[1,2-b]pyrazole-2-carbaldehyde (30 mg, 0.22 mmol) and potassium carbonate (61 mg, 0.44 mmol) in methanol (5 mL) was added (1- Dimethyl diazo-2-oxopropyl)phosphonate (63mg, 0.33mmol), and the mixture was stirred at room temperature for 16h. The solvent was removed by concentration, and the residue was diluted with ethyl acetate (30 mL). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and separated by silica gel column chromatography to obtain 2-ethynyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (22 mg, 61.8% yield) as a colorless oil. MS(ESI):133.2
[M+H] +。 1H NMR(400MHz,CDCl 3)δ6.19(s,1H),4.28-4.17(m,2H),3.13(s,1H),2.96-2.87(m,2H),2.67-2.60(m,2H)。 [M+H] + . 1 H NMR (400MHz, CDCl 3 )δ6.19(s,1H),4.28-4.17(m,2H),3.13(s,1H),2.96-2.87(m,2H),2.67-2.60(m,2H ).
步骤7)(S)-3-(1-氨乙基)-8-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-2-基)乙炔基)-2-苯基异喹啉-1(2H)-酮Step 7) (S)-3-(1-aminoethyl)-8-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)ethynyl)- 2-Phenylisoquinolin-1(2H)-one
氮气气氛下，向(S)-3-(1-氨乙基)-8-氯-2-苯基异喹啉-1(2H)-酮(40mg，0.13mmol)和2-乙炔基-5,6-二氢-4H-吡咯并[1,2-b]吡唑(21.2mg，0.16mmol)的乙腈溶液(30mL)中加入X-Phos(31.9mg，0.067mmol)、Pd 2(dba) 3(30.6mg，0.033mmol)和K 3PO 4(85.3mg，0.40mmol)，抽真空置换气体三次，混合物升温至80℃并搅拌5h。冷却至室温，减压浓缩除去溶剂。残余物用乙酸乙酯(30mL)稀释。混合物用饱和食盐水(20mL)洗，减压浓缩除去溶剂，残余物经快速硅胶柱色谱分离(DCM/MeOH＝91/9)，得到(S)-3-(1-氨乙基)-8-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-2-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(60mg，90.9％收率)为黄色油状物。MS(ESI):395.1[M+H] +。 Under nitrogen atmosphere, (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (40mg, 0.13mmol) and 2-ethynyl-5 , 6-dihydro-4H-pyrrolo[1,2-b]pyrazole (21.2mg, 0.16mmol) in acetonitrile solution (30mL) was added X-Phos (31.9mg, 0.067mmol), Pd 2 (dba) 3 (30.6mg, 0.033mmol) and K 3 PO 4 (85.3mg, 0.40mmol), the gas was evacuated three times, and the mixture was heated to 80°C and stirred for 5h. Cool to room temperature, and concentrate under reduced pressure to remove the solvent. The residue was diluted with ethyl acetate (30 mL). The mixture was washed with saturated brine (20 mL), concentrated under reduced pressure to remove the solvent, and the residue was separated by flash silica gel column chromatography (DCM/MeOH=91/9) to obtain (S)-3-(1-aminoethyl)-8 -((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)ethynyl)-2-phenylisoquinolin-1(2H)-one (60mg, 90.9 % yield) as a yellow oil. MS (ESI): 395.1 [M+H] + .
步骤8)(S)-2-氨基-N-(1-(8-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-2-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-5,7-D2-3-甲酰胺Step 8) (S)-2-amino-N-(1-(8-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)ethynyl)- 1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-5,7-D2-3-carboxamide
在室温下，将DIEA(63.8mg，0.49mmol)加入到(S)-3-(1-氨乙基)-8-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-2-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(60mg，0.16mmol)和2,5-二氧代吡咯烷-1-基2-氨基吡唑并[1,5-a]嘧啶-3-羧酸酯-5,7-D2(59mg，0.21mmol)的乙腈溶液(10mL)中，混合物升温至80℃，搅拌16h。混合物冷却 至室温，减压浓缩除去溶剂，用二氯甲烷(30mL)稀释。混合物用饱和食盐水(20mL)洗，经无水硫酸钠干燥，减压除去溶剂。残余物经制备型HPLC(Gemini-C18 150x21.2mm,5um ACN--H2O(0.1％FA)45-50)纯化，得到(S)-2-氨基-N-(1-(8-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-2-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-5,7-D2-3-甲酰胺(5.3mg，5.8％收率)为白色固体。MS(ESI):556.8[M+H] +。 1H NMR(400MHz,DMSO)δ8.93(dd,J＝6.7,1.6Hz,1H),8.56(dd,J＝4.5,1.6Hz,1H),8.01(d,J＝6.7Hz,1H),7.66(d,J＝4.5Hz,2H),7.63-7.55(m,2H),7.53-7.46(m,3H),7.41-7.36(m,1H),7.02(dd,J＝6.7,4.5Hz,1H),6.76(s,1H),6.44(s,2H),6.17(s,1H),4.56(t,J＝6.8Hz,1H),4.09-4.02(m,2H),2.82(t,J＝7.3Hz,2H),2.54(d,J＝7.7Hz,1H),1.35(d,J＝6.8Hz,3H)。 DIEA (63.8 mg, 0.49 mmol) was added to (S)-3-(1-aminoethyl)-8-((5,6-dihydro-4H-pyrrolo[1,2-b ]pyrazol-2-yl)ethynyl)-2-phenylisoquinolin-1(2H)-one (60mg, 0.16mmol) and 2,5-dioxopyrrolidin-1-yl 2-aminopyridine Azolo[1,5-a]pyrimidine-3-carboxylate-5,7-D2 (59mg, 0.21mmol) in acetonitrile solution (10mL), the mixture was heated to 80°C and stirred for 16h. The mixture was cooled to room temperature, concentrated under reduced pressure to remove solvent, and diluted with dichloromethane (30 mL). The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (Gemini-C18 150x21.2mm, 5um ACN--H2O(0.1%FA) 45-50) to give (S)-2-amino-N-(1-(8-((5 ,6-Dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinoline-3- yl)ethyl)pyrazolo[1,5-a]pyrimidine-5,7-D2-3-carboxamide (5.3 mg, 5.8% yield) as a white solid. MS (ESI): 556.8 [M+H] + . 1 H NMR (400MHz, DMSO) δ8.93 (dd, J = 6.7, 1.6Hz, 1H), 8.56 (dd, J = 4.5, 1.6Hz, 1H), 8.01 (d, J = 6.7Hz, 1H), 7.66(d, J=4.5Hz, 2H), 7.63-7.55(m, 2H), 7.53-7.46(m, 3H), 7.41-7.36(m, 1H), 7.02(dd, J=6.7, 4.5Hz, 1H),6.76(s,1H),6.44(s,2H),6.17(s,1H),4.56(t,J=6.8Hz,1H),4.09-4.02(m,2H),2.82(t,J =7.3Hz, 2H), 2.54(d, J=7.7Hz, 1H), 1.35(d, J=6.8Hz, 3H).
实施例2(S)-2-氨基-5-甲基-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 2 (S)-2-amino-5-methyl-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2 -Phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000061
Figure PCTCN2022121567-appb-000061
步骤1)1-甲基-4-((三甲基硅烷基)乙炔基)-1H-吡唑Step 1) 1-Methyl-4-((trimethylsilyl)ethynyl)-1H-pyrazole
将三甲基乙炔基硅(2.8g，28.8mmol)、CuI(366.24mg，1.923mmol)和二(三苯基膦)二氯化钯(II)(1.3g，1.9mmol)加入到4-碘-1-甲基吡唑(4g，19.2mmol)的三乙胺(30mL)溶液中，升温至90℃搅拌16h。冷却至室温后,减压浓缩除去溶剂。残余物用DCM(300mL)溶解，用水(150mL)稀释，饱和食盐水(150mL x 2)洗。有机相用无水硫酸钠干燥，浓缩，残余物经硅胶柱色谱分离(DCM/MEOH＝10/1)，得到1-甲基-4-((三甲基硅烷基)乙炔基)-1H-吡唑(2.5g，72.9％收率)为棕色油状物。MS(ESI):179.1[M+H] +。 Add silicon trimethylethynyl (2.8 g, 28.8 mmol), CuI (366.24 mg, 1.923 mmol) and bis(triphenylphosphine)palladium(II) dichloride (1.3 g, 1.9 mmol) to 4-iodo - In a solution of 1-methylpyrazole (4g, 19.2mmol) in triethylamine (30mL), warm up to 90°C and stir for 16h. After cooling to room temperature, it was concentrated under reduced pressure to remove the solvent. The residue was dissolved in DCM (300 mL), diluted with water (150 mL), and washed with saturated brine (150 mL x 2). The organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was separated by silica gel column chromatography (DCM/MEOH=10/1) to obtain 1-methyl-4-((trimethylsilyl)ethynyl)-1H- Pyrazole (2.5 g, 72.9% yield) was a brown oil. MS (ESI): 179.1 [M+H] + .
步骤2)4-乙炔基-1-甲基-1H-吡唑Step 2) 4-ethynyl-1-methyl-1H-pyrazole
在室温下，向1-甲基-4-((三甲基甲硅烷基)乙炔基)-1H-吡唑(2.3g，7.291mmol)的THF(20mL)溶液中加入四丁基氟化铵(14.6mL，14.6mmol，1N的THF溶液)。将反应在室温下搅拌1小时。反应用EtOAc(300mL)稀释，然后用盐水(150mL×2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经色谱法(PE:EA＝10:1)纯化，得到4-乙炔基-1-甲基-1H-吡唑(0.9g，65％收率)为透明油状物。MS(ESI):107.0[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.60(s,1H),7.52(s,1H),3.88(s,3H),3.01(s,1H)。 To a solution of 1-methyl-4-((trimethylsilyl)ethynyl)-1H-pyrazole (2.3 g, 7.291 mmol) in THF (20 mL) was added tetrabutylammonium fluoride at room temperature (14.6 mL, 14.6 mmol, 1 N in THF). The reaction was stirred at room temperature for 1 hour. The reaction was diluted with EtOAc (300 mL), then washed with brine (150 mL×2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (PE:EA=10:1) to give 4-ethynyl-1-methyl-1H-pyrazole (0.9 g, 65% yield) as a transparent oil. MS (ESI): 107.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.60 (s, 1H), 7.52 (s, 1H), 3.88 (s, 3H), 3.01 (s, 1H).
步骤3)(S)-3-(1-氨乙基)-8-((1-甲基-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮Step 3) (S)-3-(1-aminoethyl)-8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2-phenylisoquinoline-1(2H )-ketone
在室温、氮气氛下，向(S)-3-(1-氨乙基)-8-氯-2-苯基异喹啉-1(2H)-酮(400mg，1.34mmol)和4-乙炔基-1-甲基-1H-吡唑(213.1mg，2.00mmol)的CH 3CN(30mL)混合物中加入X-Phos(319.1mg，0.67mmol)、Pd 2(dba) 3(306.5mg，0.33mmol)和K 3PO 4(852.5mg，4.02mmol)，将混合物在80℃下搅拌5h。冷却至室温后，将混合物真空浓缩，残余物用EtOAc(130mL)稀释。混合物用盐水(50mL)洗，经Na 2SO 4干燥，真空浓缩。残余物经快速色谱法(DCM/MeOH＝91/9)纯化，得到(S)-3-(1-氨乙基)-8-((1-甲基-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(460mg，83.93％收率)为黄色油状物。MS(ESI):369.1[M+H] +。 To (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (400mg, 1.34mmol) and 4-ethyne X-Phos ( 319.1 mg, 0.67 mmol), Pd 2 (dba) 3 (306.5 mg, 0.33 mmol) and K 3 PO 4 (852.5mg, 4.02mmol), the mixture was stirred at 80°C for 5h. After cooling to room temperature, the mixture was concentrated in vacuo, and the residue was diluted with EtOAc (130 mL). The mixture was washed with brine (50 mL), dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash chromatography (DCM/MeOH=91/9) to give (S)-3-(1-aminoethyl)-8-((1-methyl-1H-pyrazol-4-yl) Ethynyl)-2-phenylisoquinolin-1(2H)-one (460 mg, 83.93% yield) was a yellow oil. MS (ESI): 369.1 [M+H] + .
步骤4)(S)-2-氨基-5-甲基-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 4) (S)-2-amino-5-methyl-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2 -Phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向(S)-3-(1-氨乙基)-8-((1-甲基-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(60mg，0.16mmol)和2-氨基-5-甲基吡唑并[1,5-a]嘧啶-3-羧酸(31.31mg，0.16mmol)的DCM(20mL)溶液中加入DIEA(84.1mg，0.65mmol)、EDCI(46.8mg，0.24mmol)、HOAT(39.4mg，0.24mmol)。混合物在40℃下搅拌16小时。混合物用DCM(30mL)稀释，然后用盐水(20mL)洗，经Na 2SO 4干燥，真空浓缩。残余物经制备型HPLC(Gemini-C18 150x21.2mm,5um ACN--H2O(0.1％FA)30-70)纯化，得到(S)-2-氨基-5-甲基-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(28.8mg，32.47％收率)为白色固体。MS(ESI):545.9[M+H] +。 1H NMR(400MHz,DMSO)δ8.78(d,J＝6.9Hz,1H), 8.17(d,J＝6.6Hz,1H),8.01(s,1H),7.66-7.45(m,8H),7.40(d,J＝7.6Hz,1H),6.91(d,J＝6.9Hz,1H),6.73(s,1H),6.32(s,2H),4.526-4.49(m,1H),3.82(s,3H),2.57(s,3H),1.35(d,J＝6.8Hz,3H)。 To (S)-3-(1-aminoethyl)-8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2-phenylisoquinoline-1(2H)- To a solution of ketone (60 mg, 0.16 mmol) and 2-amino-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (31.31 mg, 0.16 mmol) in DCM (20 mL) was added DIEA (84.1 mg, 0.65mmol), EDCI (46.8mg, 0.24mmol), HOAT (39.4mg, 0.24mmol). The mixture was stirred at 40°C for 16 hours. The mixture was diluted with DCM (30 mL), then washed with brine (20 mL), dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by preparative HPLC (Gemini-C18 150x21.2mm, 5um ACN--H2O(0.1%FA) 30-70) to give (S)-2-amino-5-methyl-N-(1-( 8-((1-Methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyridine Azolo[1,5-a]pyrimidine-3-carboxamide (28.8 mg, 32.47% yield) was a white solid. MS (ESI): 545.9 [M+H] + . 1 H NMR (400MHz, DMSO) δ8.78(d, J=6.9Hz, 1H), 8.17(d, J=6.6Hz, 1H), 8.01(s, 1H), 7.66-7.45(m, 8H), 7.40(d, J=7.6Hz, 1H), 6.91(d, J=6.9Hz, 1H), 6.73(s, 1H), 6.32(s, 2H), 4.526-4.49(m, 1H), 3.82(s , 3H), 2.57(s, 3H), 1.35(d, J=6.8Hz, 3H).
实施例3 2-氨基-N-((1S)-1-(1-氧代-8-(2-(5-氧代吡咯烷-3-基)乙炔基)-2-苯基异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 3 2-amino-N-((1S)-1-(1-oxo-8-(2-(5-oxopyrrolidin-3-yl)ethynyl)-2-phenylisoquinoline -3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000062
Figure PCTCN2022121567-appb-000062
步骤1)1-(2,4-二甲氧基苄基)-5-氧代吡咯烷-3-羧酸Step 1) 1-(2,4-Dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid
将(2,4-二甲氧基苯基)甲胺(2.0g，11.9mmol)和2-亚甲基丁二酸(1.55g，11.9mmol)的甲苯(50mL)溶液升温至100℃，搅拌16h。混合物加入水(20mL)稀释，然后用EtOAc(150mL)萃取。合并有机相用饱和食盐水洗(40mL x 2)，无水硫酸钠干燥，减压浓缩，残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到1-(2,4-二甲氧基苄基)-5-氧代吡咯烷-3-羧酸(3.2g，91％收率)为无色油状液体。MS(ESI):280.1[M+H] +。 A solution of (2,4-dimethoxyphenyl)methanamine (2.0g, 11.9mmol) and 2-methylenesuccinic acid (1.55g, 11.9mmol) in toluene (50mL) was warmed to 100°C, stirred 16h. The mixture was diluted with water (20 mL), then extracted with EtOAc (150 mL). The combined organic phases were washed with saturated brine (40mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain 1-(2,4-di Methoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (3.2 g, 91% yield) was a colorless oily liquid. MS (ESI): 280.1 [M+H] + .
步骤2)1-[(2,4-二甲氧基苯基)甲基]-4-(羟甲基)吡咯烷-2-酮Step 2) 1-[(2,4-dimethoxyphenyl)methyl]-4-(hydroxymethyl)pyrrolidin-2-one
在0℃下，向1-(2,4-二甲氧基苄基)-5-氧代吡咯烷-3-羧酸(3.2g，11.4mmol)的THF(50mL)溶液中加入BH3.THF(13mL，1moL/L)，然后升温至常温，搅拌16h。混合物用MeOH(20mL)淬灭，减压浓缩。将残余物溶于EtOAc(200mL)，用饱和食盐水(40mL x 2)洗。有机相经无水Na 2SO 4干燥，减压浓缩。残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到1-[(2,4-二甲氧基苯基)甲基]-4-(羟甲基)吡咯烷-2-酮(2.0g，59％收率)为无色油状液体。MS(ESI):266.1[M+H] +。 To a solution of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (3.2 g, 11.4 mmol) in THF (50 mL) at 0°C was added BH3.THF (13mL, 1moL/L), then warmed up to room temperature and stirred for 16h. The mixture was quenched with MeOH (20 mL) and concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL), washed with saturated brine (40 mL x 2). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to give 1-[(2,4-dimethoxyphenyl)methyl]-4-(hydroxymethyl)pyrrolidine-2- The ketone (2.0 g, 59% yield) was a colorless oily liquid. MS (ESI): 266.1 [M+H] + .
步骤3)1-[(2,4-二甲氧基苯基)甲基]-5-氧代吡咯烷-3-甲醛Step 3) 1-[(2,4-dimethoxyphenyl)methyl]-5-oxopyrrolidine-3-carbaldehyde
在20℃下，向1-[(2,4-二甲氧基苯基)甲基]-4-(羟甲基)吡咯烷-2-酮(1.6g，6.03mmol)的DCM(50mL)溶液中加入戴斯-马丁高碘烷(Dess-Martin periodinane，3.1g，6mmol)，保温搅拌16h。向混合物中加入DCM(250mL)，过滤。滤液用Na 2SO 3水溶液(50mL)和NaHCO 3水溶液(50mL)洗。有机相经无水Na 2SO 4干燥，减压浓缩得到1-[(2,4-二甲氧基苯基)甲基]-5-氧代吡咯烷-3-甲醛(1.6g，80％收率)为无色油状液体。MS(ESI):264.1[M+H] +。 To 1-[(2,4-dimethoxyphenyl)methyl]-4-(hydroxymethyl)pyrrolidin-2-one (1.6 g, 6.03 mmol) in DCM (50 mL) at 20 °C Add Dess-Martin periodinane (Dess-Martin periodinane, 3.1 g, 6 mmol) into the solution, and keep stirring for 16 h. DCM (250 mL) was added to the mixture and filtered. The filtrate was washed with aqueous Na 2 SO 3 (50 mL) and aqueous NaHCO 3 (50 mL). The organic phase was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain 1-[(2,4-dimethoxyphenyl)methyl]-5-oxopyrrolidine-3-carbaldehyde (1.6 g, 80% yield) was a colorless oily liquid. MS (ESI): 264.1 [M+H] + .
步骤4)1-[(2,4-二甲氧基苯基)甲基]-4-乙炔基吡咯烷-2-酮Step 4) 1-[(2,4-dimethoxyphenyl)methyl]-4-ethynylpyrrolidin-2-one
在20℃下，向1-[(2,4-二甲氧基苯基)甲基]-5-氧代吡咯烷-3-甲醛(1.6g，6.1mmol)和K 2CO 3(2.5g，18mmol)的MeOH(100mL)溶液中加入(1-重氮基-2-氧代丙基)膦酸二甲酯(1.38g，7.3mmol)，保温继续搅拌4h。混合物经EtOAc(250mL)稀释后，用饱和食盐水洗(50mL x 2)。有机相经无水Na 2SO 4干燥，减压浓缩得到1-[(2,4-二甲氧基苯基)甲基]-4-乙炔基吡咯烷-2-酮(1.1g，62％收率)为无色油状液体。MS(ESI):260.1[M+H] +。 At 20°C, 1-[(2,4-dimethoxyphenyl)methyl]-5-oxopyrrolidine-3-carbaldehyde (1.6g, 6.1mmol) and K 2 CO 3 (2.5g , 18 mmol) in MeOH (100 mL) was added (1-diazo-2-oxopropyl) dimethyl phosphonate (1.38 g, 7.3 mmol) and kept stirring for 4 h. The mixture was diluted with EtOAc (250 mL), and washed with saturated brine (50 mL x 2). The organic phase was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to obtain 1-[(2,4-dimethoxyphenyl)methyl]-4-ethynylpyrrolidin-2-one (1.1 g, 62% yield) was a colorless oily liquid. MS (ESI): 260.1 [M+H] + .
步骤5)3-((1S)-1-氨基乙基)-8-(2-(1-((2,4-二甲氧基苯基)甲基)-5-氧代吡咯烷-3-基)乙炔基)-2-苯基异喹啉-1-酮Step 5) 3-((1S)-1-aminoethyl)-8-(2-(1-((2,4-dimethoxyphenyl)methyl)-5-oxopyrrolidine-3 -yl)ethynyl)-2-phenylisoquinolin-1-one
在氮气气氛下，向1-[(2,4-二甲氧基苯基)甲基]-4-乙炔基吡咯烷-2-酮(208mg，0.8mmol)和(S)-3-(1-氨乙基)-8-氯-2-苯基异喹啉-1(2H)-酮(160mg,0.53mmol)的乙腈(50mL)溶液中加入K 3PO 4(341mg，1.6mmol)、x-Phos(2-二环己基磷-2',4',6'-三异丙基联苯，102mg，0.21mmol)和Pd 2(dba) 3(98mg，0.1mmol)。混合物升温至80℃并搅拌16h。反应完全后，冷却至室温，减压浓缩。残余物经EtOAc(200mL)稀释后，用饱和食盐水洗(100mL)，有机相经无水Na 2SO 4干燥，减压浓缩。残余物经硅胶柱色谱法(DCM/MeOH＝20/1)纯化，得到3-((1S)-1-氨基乙基)-8-(2-(1-((2,4-二甲氧基苯基)甲基)-5-氧代吡咯烷-3-基)乙炔基)-2-苯基异喹啉-1-酮(280mg，89％收率)为棕色固体。MS(ESI):522.2[M+H] +。 Under nitrogen atmosphere, 1-[(2,4-dimethoxyphenyl)methyl]-4-ethynylpyrrolidin-2-one (208mg, 0.8mmol) and (S)-3-(1 -Aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (160mg, 0.53mmol) in acetonitrile (50mL) was added K 3 PO 4 (341mg, 1.6mmol), x - Phos (2-dicyclohexylphosphonium-2',4',6'-triisopropylbiphenyl, 102 mg, 0.21 mmol) and Pd 2 (dba) 3 (98 mg, 0.1 mmol). The mixture was warmed to 80 °C and stirred for 16 h. After the reaction was complete, it was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc (200 mL), washed with brine (100 mL), and the organic phase was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to give 3-((1S)-1-aminoethyl)-8-(2-(1-((2,4-dimethoxy phenyl)methyl)-5-oxopyrrolidin-3-yl)ethynyl)-2-phenylisoquinolin-1-one (280 mg, 89% yield) as a brown solid. MS (ESI): 522.2 [M+H] + .
步骤6)2-氨基-N-((1S)-1-(8-(2-(1-((2,4-二甲氧基苯基)甲基)-5-氧代吡咯烷-3-基)乙炔基)-1-氧代-2-苯基异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 6) 2-amino-N-((1S)-1-(8-(2-(1-((2,4-dimethoxyphenyl)methyl)-5-oxopyrrolidine-3 -yl)ethynyl)-1-oxo-2-phenylisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
在室温下，向2-氨基吡唑并[1,5-a]嘧啶-3-羧酸(95mg，0.53mmol)、HOAt(109mg，0.8mmol)、3-((1S)-1-氨基乙基)-8-(2-(1-((2,4-二甲氧基苯基)甲基)-5-氧代吡咯烷-3-基)乙炔基)-2-苯基异喹啉-1-酮(280mg，0.53mmol)和EDCI(154mg，0.80mmol)的DCM(10mL)溶液中加入DIEA(208mg，1.6mmol)。混合物升温至40℃，继续搅拌16h。向混合物中加入DCM(60mL)稀释，再用饱和食盐水洗(50mL)。有机相经无水Na 2SO 4干燥，减压浓缩，残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到2-氨基-N-((1S)-1-(8-(2-(1-((2,4-二甲氧基苯基)甲基)-5-氧代吡咯烷-3-基)乙炔基)-1-氧代-2-苯基异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(320mg，78％收率)为棕色固体。MS(ESI):682.3[M+H] +。 To 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (95 mg, 0.53 mmol), HOAt (109 mg, 0.8 mmol), 3-((1S)-1-aminoethyl Base)-8-(2-(1-((2,4-dimethoxyphenyl)methyl)-5-oxopyrrolidin-3-yl)ethynyl)-2-phenylisoquinoline - To a solution of 1-one (280 mg, 0.53 mmol) and EDCI (154 mg, 0.80 mmol) in DCM (10 mL) was added DIEA (208 mg, 1.6 mmol). The mixture was warmed to 40 °C and stirring was continued for 16 h. DCM (60 mL) was added to the mixture for dilution, and washed with saturated brine (50 mL). The organic phase was dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to obtain 2-amino-N-((1S)-1-(8- (2-(1-((2,4-dimethoxyphenyl)methyl)-5-oxopyrrolidin-3-yl)ethynyl)-1-oxo-2-phenylisoquinoline -3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (320 mg, 78% yield) as a brown solid. MS (ESI): 682.3 [M+H] + .
步骤7)2-氨基-N-((1S)-1-(1-氧代-8-(2-(5-氧代吡咯烷-3-基)乙炔基)-2-苯基异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 7) 2-Amino-N-((1S)-1-(1-oxo-8-(2-(5-oxopyrrolidin-3-yl)ethynyl)-2-phenylisoquinoline -3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
将2-氨基-N-((1S)-1-(8-(2-(1-((2,4-二甲氧基苯基)甲基)-5-氧代吡咯烷-3-基)乙炔基)-1-氧代-2-苯基异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(150mg，0.22mmol)加至6N HCl(10mL)中，升温至80℃搅拌1h。减压浓缩，残余物经制备型HPLC(CAN-H 2O，0.1％FA，梯度20％至50％)纯化，得到2-氨基-N-((1S)-1-(1-氧代-8-(2-(5-氧代吡咯烷-3-基)乙炔基)-2-苯基异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(3.7mg，3.1％收率)为白色固体。MS(ESI):532.2[M+H] +。 1H NMR(400MHz,CD 3OD)δ8.72(d,J＝6.8Hz,1H),8.52(s,1H),8.43(t,J＝6.4Hz,1H),8.26(t,J＝7.2Hz,1H),8.12(d,J＝7.2Hz,1H),8.04(d,J＝8.0Hz,1H),8.00(s,1H),7.93(d,J＝8.0Hz,1H),7.80-7.71(m,3H),7.02-6.98(m,1H),6.72(d,J＝8.8Hz,1H),5.09-5.05(m,1H),3.66-3.52(m,3H),2.56-2.48(m,1H),2.35-2.30(m,1H),1.65-1.57(m,3H)。 2-Amino-N-((1S)-1-(8-(2-(1-((2,4-dimethoxyphenyl)methyl)-5-oxopyrrolidin-3-yl )ethynyl)-1-oxo-2-phenylisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (150mg, 0.22mmol) was added to 6N In HCl (10 mL), warm up to 80 °C and stir for 1 h. Concentrated under reduced pressure, the residue was purified by preparative HPLC (CAN-H 2 O, 0.1% FA, gradient 20% to 50%) to give 2-amino-N-((1S)-1-(1-oxo- 8-(2-(5-oxopyrrolidin-3-yl)ethynyl)-2-phenylisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3- Formamide (3.7 mg, 3.1% yield) was a white solid. MS (ESI): 532.2 [M+H] + . 1 H NMR (400MHz, CD 3 OD) δ8.72(d, J=6.8Hz, 1H), 8.52(s, 1H), 8.43(t, J=6.4Hz, 1H), 8.26(t, J=7.2 Hz,1H),8.12(d,J=7.2Hz,1H),8.04(d,J=8.0Hz,1H),8.00(s,1H),7.93(d,J=8.0Hz,1H),7.80- 7.71(m,3H),7.02-6.98(m,1H),6.72(d,J＝8.8Hz,1H),5.09-5.05(m,1H),3.66-3.52(m,3H),2.56-2.48( m,1H), 2.35-2.30(m,1H), 1.65-1.57(m,3H).
实施例4 2-氨基-N-((1S)-1-(8-(2-(1-甲基-5-氧代吡咯烷-3-基)乙炔基)-1-氧代-2-苯基异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 4 2-amino-N-((1S)-1-(8-(2-(1-methyl-5-oxopyrrolidin-3-yl)ethynyl)-1-oxo-2- Phenylisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000063
Figure PCTCN2022121567-appb-000063
步骤1)4-(羟甲基)-1-甲基吡咯烷-2-酮Step 1) 4-(Hydroxymethyl)-1-methylpyrrolidin-2-one
在0℃下，将NaBH 4(481mg，12.7mmol)加至1-甲基-5-氧代吡咯烷-3-羧酸甲酯(1g，6.3mmol)的MeOH(50mL)溶液中。混合物升温至常温，搅拌16h后，减压浓缩，残余物用MeOH/DCM＝1/20(200mL)溶解，再抽滤。滤液经无水Na 2SO 4干燥，减压浓缩，残余物经柱色谱法分离(MeOH/DCM＝1/20)，得到4-(羟甲基)-1-甲基吡咯烷-2-酮(900mg，98.57％收率)为无色油状液体。MS(ESI):130.1[M+H] +。 1H NMR(400MHz,CDCl 3)δ3.62-3.57(m,2H),3.50(dd,J＝10.0,8.0Hz,1H),3.26(dd,J＝10.0,5.0Hz,1H),2.84(s,3H),2.63-2.55(m,1H),2.55-2.49(m,1H),2.22(dd,J＝16.4,5.2Hz,1H)。 NaBH 4 (481 mg, 12.7 mmol) was added to a solution of methyl 1-methyl-5-oxopyrrolidine-3-carboxylate (1 g, 6.3 mmol) in MeOH (50 mL) at 0°C. The mixture was warmed up to room temperature, stirred for 16 h, concentrated under reduced pressure, and the residue was dissolved in MeOH/DCM=1/20 (200 mL), and filtered with suction. The filtrate was dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure, and the residue was separated by column chromatography (MeOH/DCM=1/20) to obtain 4-(hydroxymethyl)-1-methylpyrrolidin-2-one (900 mg, 98.57% yield) was a colorless oily liquid. MS (ESI): 130.1 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ3.62-3.57 (m, 2H), 3.50 (dd, J = 10.0, 8.0Hz, 1H), 3.26 (dd, J = 10.0, 5.0Hz, 1H), 2.84 ( s, 3H), 2.63-2.55 (m, 1H), 2.55-2.49 (m, 1H), 2.22 (dd, J=16.4, 5.2Hz, 1H).
步骤2)1-甲基-5-氧代吡咯烷-3-甲醛Step 2) 1-Methyl-5-oxopyrrolidine-3-carbaldehyde
在20℃下，向4-(羟甲基)-1-甲基吡咯烷-2-酮(420mg，3.2mmol)的DCM(50mL)溶液中加入戴斯-马丁高碘烷(Dess-Martin periodinane，2.7g，6.5mmol)，保温搅拌16h。向混合物中加入DCM(100mL)，过滤。滤液用Na 2SO 3水溶液(50mL)和NaHCO 3水溶液(50mL)洗。有机相经无水Na 2SO 4干燥，减压浓缩，残余物经柱色谱法分离(MeOH/DCM＝1/20)，得到1-甲基-5-氧代吡咯烷-3-甲醛(280mg，67.72％收率)为无色油状液体。MS(ESI):128.1[M+H] +。 To a solution of 4-(hydroxymethyl)-1-methylpyrrolidin-2-one (420 mg, 3.2 mmol) in DCM (50 mL) at 20°C was added Dess-Martin periodinane , 2.7g, 6.5mmol), kept stirring for 16h. DCM (100 mL) was added to the mixture and filtered. The filtrate was washed with aqueous Na 2 SO 3 (50 mL) and aqueous NaHCO 3 (50 mL). The organic phase was dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure, and the residue was separated by column chromatography (MeOH/DCM=1/20) to obtain 1-methyl-5-oxopyrrolidine-3-carbaldehyde (280mg , 67.72% yield) was a colorless oily liquid. MS (ESI): 128.1 [M+H] + .
步骤3)4-乙炔基-1-甲基吡咯烷-2-酮Step 3) 4-ethynyl-1-methylpyrrolidin-2-one
在20℃下，向1-甲基-5-氧代吡咯烷-3-甲醛(400mg，3.1mmol)和K 2CO 3(1.3g，9.4mmol)的MeOH(30mL)溶液中加入(1-重氮基-2-氧代丙基)膦酸二甲酯(718mg，3.78mmol)，保温继续搅拌4h。混合物经H 2O(10mL)稀释后，用饱和食盐水洗(40mL x 2)。有机相经无水Na 2SO 4干燥，减压浓缩，残余物经柱色谱法分离(MeOH/DCM＝1/30)，得到4-乙炔基-1-甲基吡咯烷-2-酮(180mg，37.17％收率)为无色油状液体。MS(ESI):124.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ3.70-3.55(m,2H),3.27(dd,J＝9.1,6.3Hz,1H),2.71(s,3H), 2.56(dd,J＝16.3,8.6Hz,1H),2.22(dd,J＝16.3,7.1Hz,1H)。 To a solution of 1-methyl-5-oxopyrrolidine-3-carbaldehyde (400 mg, 3.1 mmol) and K 2 CO 3 (1.3 g, 9.4 mmol) in MeOH (30 mL) was added (1- Dimethyl diazo-2-oxopropyl)phosphonate (718mg, 3.78mmol), keep stirring for 4h. The mixture was diluted with H 2 O (10 mL), and washed with saturated brine (40 mL x 2). The organic phase was dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure, and the residue was separated by column chromatography (MeOH/DCM=1/30) to obtain 4-ethynyl-1-methylpyrrolidin-2-one (180mg , 37.17% yield) was a colorless oily liquid. MS (ESI): 124.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ3.70-3.55 (m, 2H), 3.27 (dd, J = 9.1, 6.3 Hz, 1H), 2.71 (s, 3H), 2.56 (dd, J = 16.3 , 8.6Hz, 1H), 2.22 (dd, J = 16.3, 7.1Hz, 1H).
步骤4)3-((1S)-1-氨基乙基)-8-(2-(1-甲基-5-氧代吡咯烷-3-基)乙炔基)-2-苯基异喹啉-1-酮Step 4) 3-((1S)-1-aminoethyl)-8-(2-(1-methyl-5-oxopyrrolidin-3-yl)ethynyl)-2-phenylisoquinoline -1-one
在氮气气氛下，向4-乙炔基-1-甲基吡咯烷-2-酮(37.1mg，0.3mmol)和(S)-3-(1-氨乙基)-8-氯-2-苯基异喹啉-1(2H)-酮(60mg，0.2mmol)的乙腈(20mL)溶液中加入K 3PO 4(128mg，0.6mmol)、x-Phos(38mg，0.08mmol)和Pd 2(dba) 3(37mg，0.04mmol)。混合物升温到80℃并搅拌4h。反应完全后，冷却至室温，减压浓缩。残余物经EtOAc(60mL)稀释后，用饱和食盐水洗(30mL x 2)，有机相经无水Na 2SO 4干燥，减压浓缩。残余物经硅胶柱色谱法纯化(DCM/MeOH＝20/1)，得到3-((1S)-1-氨基乙基)-8-(2-(1-甲基-5-氧代吡咯烷-3-基)乙炔基)-2-苯基异喹啉-1-酮(30mg，35.0％收率)为黄色固体。MS(ESI):473.0[M+H] +。 Under nitrogen atmosphere, 4-ethynyl-1-methylpyrrolidin-2-one (37.1 mg, 0.3 mmol) and (S)-3-(1-aminoethyl)-8-chloro-2-benzene K 3 PO 4 (128 mg, 0.6 mmol), x-Phos (38 mg, 0.08 mmol) and Pd 2 (dba ) 3 (37 mg, 0.04 mmol). The mixture was warmed to 80 °C and stirred for 4 h. After the reaction was complete, it was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc (60 mL), washed with saturated brine (30 mL x 2), and the organic phase was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH=20/1) to give 3-((1S)-1-aminoethyl)-8-(2-(1-methyl-5-oxopyrrolidine -3-yl)ethynyl)-2-phenylisoquinolin-1-one (30 mg, 35.0% yield) was a yellow solid. MS (ESI): 473.0 [M+H] + .
步骤5)2-氨基-N-((1S)-1-(8-(2-(1-甲基-5-氧代吡咯烷-3-基)乙炔基)-1-氧代-2-苯基异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 5) 2-amino-N-((1S)-1-(8-(2-(1-methyl-5-oxopyrrolidin-3-yl)ethynyl)-1-oxo-2- Phenylisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
在室温下，向2-氨基吡唑并[1,5-a]嘧啶-3-羧酸(15mg，0.08mmol)、HOAt(16mg，0.12mmol)、3-((1S)-1-氨基乙基)-8-(2-(1-甲基-5-氧代吡咯烷-3-基)乙炔基)-2-苯基异喹啉-1-酮(30mg，0.08mmol)和EDCI(22mg，0.12mmol)的DCM(10mL)溶液中加入DIEA(30mg，0.23mmol)。混合物升温至40℃，继续搅拌16h。向混合物中加入DCM(60mL)稀释，再用饱和食盐水洗(40mL)。有机相经无水Na 2SO 4干燥，减压浓缩，残余物经制备型HPLC(CAN-H 2O 0.1FA，梯度30％至60％)分离，得到2-氨基-N-((1S)-1-(8-(2-(1-甲基-5-氧代吡咯烷-3-基)乙炔基)-1-氧代-2-苯基异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(18.0mg，42.42％收率)为白色固体。MS(ESI):546.2[M+H] +。 1H NMR(400MHz,CDCl 3)δ8.47(d,J＝6.8Hz,1H),8.42(d,J＝4.5Hz,1H),7.94-7.89(m,1H),7.53(d,J＝1.7Hz,1H),7.51(d,J＝7.5Hz,1H),7.47(d,J＝1.3Hz,3H),7.42(s,1H),7.35(d,J＝8.0Hz,1H),6.82(dd,J＝6.6,4.5Hz,1H),6.62(s,1H),4.84-4.78(m,1H),3.63(dd,J＝12.8,5.0Hz,1H),3.57-3.51(m,1H),3.51-3.43(m,1H),2.84(s,3H),2.78-2.71(m,1H),2.63(s,1H),1.40(d,J＝6.8Hz,3H)。 To 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (15 mg, 0.08 mmol), HOAt (16 mg, 0.12 mmol), 3-((1S)-1-aminoethyl Base)-8-(2-(1-methyl-5-oxopyrrolidin-3-yl)ethynyl)-2-phenylisoquinolin-1-one (30mg, 0.08mmol) and EDCI (22mg , 0.12 mmol) in DCM (10 mL) was added DIEA (30 mg, 0.23 mmol). The mixture was warmed to 40 °C and stirring was continued for 16 h. DCM (60 mL) was added to the mixture for dilution, and washed with saturated brine (40 mL). The organic phase was dried over anhydrous Na2SO4 , concentrated under reduced pressure, and the residue was separated by preparative HPLC (CAN- H2O 0.1FA, gradient 30% to 60%) to give 2-amino-N-((1S) -1-(8-(2-(1-methyl-5-oxopyrrolidin-3-yl)ethynyl)-1-oxo-2-phenylisoquinolin-3-yl)ethyl) Pyrazolo[1,5-a]pyrimidine-3-carboxamide (18.0 mg, 42.42% yield) was a white solid. MS (ESI): 546.2 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ8.47(d, J=6.8Hz, 1H), 8.42(d, J=4.5Hz, 1H), 7.94-7.89(m, 1H), 7.53(d, J= 1.7Hz, 1H), 7.51(d, J=7.5Hz, 1H), 7.47(d, J=1.3Hz, 3H), 7.42(s, 1H), 7.35(d, J=8.0Hz, 1H), 6.82 (dd, J=6.6,4.5Hz,1H),6.62(s,1H),4.84-4.78(m,1H),3.63(dd,J=12.8,5.0Hz,1H),3.57-3.51(m,1H ), 3.51-3.43 (m, 1H), 2.84 (s, 3H), 2.78-2.71 (m, 1H), 2.63 (s, 1H), 1.40 (d, J=6.8Hz, 3H).
实施例5(S)-2-氨基-N-(1-(8-((5,6-二氢-4H-吡咯[1,2-b]吡唑-3-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 5 (S)-2-amino-N-(1-(8-((5,6-dihydro-4H-pyrrole[1,2-b]pyrazol-3-yl)ethynyl)-1 -Oxo-2-phenyl-1,2-dihydroisoquinolin-3-ylethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000064
Figure PCTCN2022121567-appb-000064
步骤1)5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-甲醛Step 1) 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carbaldehyde
在-78℃下，向3-溴-4H,5H,6H-吡咯并[1,2-b]吡唑(200mg，1.07mmol)的四氢呋喃(10mL)溶液中慢慢加入正丁基锂(2.4M的正己烷溶液，0.49mL，1.18mmol)，混合物在-70℃搅拌1小时后加入N,N-二甲基甲酰胺(156mg，2.1mmol)的四氢呋喃(1mL)溶液，将混合物在0℃搅拌2小时。混合物用氯化铵水溶液(10mL)淬灭并用乙酸乙酯(20mL x 3)萃取。合并的有机层用饱和食盐水(10mL x 2)洗，经无水硫酸钠干燥，过滤，滤液减压浓缩。粗品通过硅胶色谱法(EA/PE＝1/3)纯化，得到5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-甲醛(100mg，65％收率)为白色固体。MS(ESI):137.1[M+H] +。 1H NMR(400MHz,CDCl 3)δ9.81(s,1H),7.95(s,1H),4.25-4.16(m,2H),3.18-3.10(m,2H),2.75-2.63(m,2H)。 To a solution of 3-bromo-4H,5H,6H-pyrrolo[1,2-b]pyrazole (200mg, 1.07mmol) in THF (10mL) was slowly added n-butyllithium (2.4 N-hexane solution of M, 0.49mL, 1.18mmol), the mixture was stirred at -70°C for 1 hour, and N,N-dimethylformamide (156mg, 2.1mmol) in tetrahydrofuran (1mL) was added, and the mixture was heated at 0°C Stir for 2 hours. The mixture was quenched with aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (EA/PE=1/3) to give 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carbaldehyde (100 mg, 65% yield) as white solid. MS (ESI): 137.1 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ9.81(s,1H),7.95(s,1H),4.25-4.16(m,2H),3.18-3.10(m,2H),2.75-2.63(m,2H ).
步骤2)3-乙炔基-5,6-二氢-4H-吡咯并[1,2-b]吡唑Step 2) 3-ethynyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole
向5,6-二氢-4H-吡咯[1,2-b]吡唑-3-甲醛(100mg，0.73mmol)和碳酸钾(203mg，1.47mmol)的甲醇(10mL)溶液中加入(1-重氮-2-氧丙基)膦酸二甲酯(212mg，1.1mmol)，混合物在25℃下搅拌16小时，减压浓缩，残余物用乙酸乙酯(40mL)稀释。有机层用饱和食盐水(20mL x 2)洗，经无水硫酸钠干燥，过滤，滤液减压浓缩，得到3-乙炔基-5,6-二氢-4H-吡咯并[1,2-b]吡唑(80mg，70％收率)为无色油状。MS(ESI):133.1[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.61(s,1H),4.16-4.11(m,2H),3.03(s,1H),3.00-2.92(m,2H),2.67-2.60(m,2H)。 To a solution of 5,6-dihydro-4H-pyrrole[1,2-b]pyrazole-3-carbaldehyde (100 mg, 0.73 mmol) and potassium carbonate (203 mg, 1.47 mmol) in methanol (10 mL) was added (1- Dimethyldiazo-2-oxopropyl)phosphonate (212mg, 1.1mmol), the mixture was stirred at 25°C for 16 hours, concentrated under reduced pressure, and the residue was diluted with ethyl acetate (40mL). The organic layer was washed with saturated brine (20mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 3-ethynyl-5,6-dihydro-4H-pyrrolo[1,2-b ] Pyrazole (80 mg, 70% yield) as a colorless oil. MS (ESI): 133.1 [M+H] + . 1 H NMR (400MHz, CDCl 3 )δ7.61(s,1H),4.16-4.11(m,2H),3.03(s,1H),3.00-2.92(m,2H),2.67-2.60(m,2H ).
步骤3)(S)-3-(1-氨基乙基)-8-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)乙炔基)-2-苯基异喹啉-1(2H)-酮Step 3) (S)-3-(1-aminoethyl)-8-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)ethynyl)- 2-Phenylisoquinolin-1(2H)-one
在氮气环境下，向(S)-3-(1-氨基乙基)-8-氯-2-苯基异喹啉-1(2H)-酮(60mg，0.20mmol)和3-乙炔基-5,6-二氢-4H-吡咯并[1,2-b]吡唑(40mg，0.30mmol)的乙腈(30mL)溶液中加入X-Phos(48mg，0.10mmol)、Pd 2(dba) 3(46mg，0.05mmol)和磷酸钾(128mmol，0.60mmol)。将混合物在80℃下加热5小时，降至室温后，减压浓缩混合物，残余物用乙酸乙酯(30mL)稀释，混合物用饱和食盐水(20mL)洗，无水硫酸钠干燥,过滤，滤液减压浓缩。粗品通过硅胶色谱法(DCM/MeOH＝91/9)纯化，得到(S)-3-(1-氨基乙基)-8-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(35mg，39.8％收率)为黄色油状物。MS(ESI):394.9[M+H] +。 Under nitrogen atmosphere, (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (60mg, 0.20mmol) and 3-ethynyl- 5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazole (40mg, 0.30mmol) in acetonitrile (30mL) was added X-Phos (48mg, 0.10mmol), Pd 2 (dba) 3 (46mg, 0.05mmol) and potassium phosphate (128mmol, 0.60mmol). The mixture was heated at 80°C for 5 hours, and after cooling down to room temperature, the mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate (30 mL), the mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrate under reduced pressure. The crude product was purified by silica gel chromatography (DCM/MeOH=91/9) to give (S)-3-(1-aminoethyl)-8-((5,6-dihydro-4H-pyrrolo[1,2 -b] pyrazol-3-yl)ethynyl)-2-phenylisoquinolin-1(2H)-one (35 mg, 39.8% yield) as a yellow oil. MS (ESI): 394.9 [M+H] + .
步骤4)(S)-2-氨基-N-(1-(8-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 4) (S)-2-amino-N-(1-(8-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)ethynyl)- 1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-ylethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
在室温下，向(S)-3-(1-氨基乙基)-8-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-吡唑基-3-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(37mg，0.09mmol)和2-氨基-5-甲基吡唑并[1,5-a]嘧啶-3-羧酸(18mg，0.10mmol)的二氯甲烷(20mL)溶液中加入N,N'-二异丙基乙基胺(36mg，0.28mmol)、1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(27mg，0.14mmol)和1-羟基-7-氮杂苯并三氮唑(19mg，0.14mmol)。将混合物在40℃下搅拌16小时，然后用二氯甲烷(30mL)稀释，用饱和食盐水(20mL)洗，经无水硫酸钠干燥，过滤，滤液减压浓缩。粗品通过高效制备液相(Gemini-C18 150x21.2mm,5um ACN-H 2O(0.1％FA)30-70)纯化，得到(S)-2-氨基-N-(1-(8-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-乙基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(9.3mg，17.70％收率)为白色固体。MS(ESI):554.8[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.93(dd,J＝6.7,1.6Hz,1H),8.55(dd,J＝4.5,1.6Hz,1H),8.00(d,J＝6.7Hz,1H),7.66-7.53(m,5H),7.52-7.46(m,3H),7.42-7.34(m,1H),7.02(dd,J＝6.7,4.5Hz,1H),6.73(s,1H),6.44(s,2H),4.55(q,J＝6.7Hz,1H),4.07(t,J＝7.2Hz,2H),2.93-2.80(m,2H),2.58-2.53(m,1H),1.35(d,J＝6.8Hz,3H)。 At room temperature, to (S)-3-(1-aminoethyl)-8-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-pyrazolyl- 3-yl)ethynyl)-2-phenylisoquinolin-1(2H)-one (37mg, 0.09mmol) and 2-amino-5-methylpyrazolo[1,5-a]pyrimidine-3 -To a solution of carboxylic acid (18mg, 0.10mmol) in dichloromethane (20mL) was added N,N'-diisopropylethylamine (36mg, 0.28mmol), 1-ethyl-(3-dimethylamino Propyl)carbodiimide hydrochloride (27mg, 0.14mmol) and 1-hydroxy-7-azabenzotriazole (19mg, 0.14mmol). The mixture was stirred at 40°C for 16 hours, then diluted with dichloromethane (30 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC (Gemini-C18 150x21.2mm, 5um ACN-H 2 O(0.1%FA) 30-70) to give (S)-2-amino-N-(1-(8-(( 5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinoline-3 -Ethyl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (9.3 mg, 17.70% yield) as a white solid. MS (ESI): 554.8 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.93(dd, J=6.7,1.6Hz,1H),8.55(dd,J=4.5,1.6Hz,1H),8.00(d,J=6.7Hz, 1H),7.66-7.53(m,5H),7.52-7.46(m,3H),7.42-7.34(m,1H),7.02(dd,J＝6.7,4.5Hz,1H),6.73(s,1H) ,6.44(s,2H),4.55(q,J=6.7Hz,1H),4.07(t,J=7.2Hz,2H),2.93-2.80(m,2H),2.58-2.53(m,1H), 1.35 (d, J=6.8Hz, 3H).
实施例6 2-氨基-N-((1S)-1-(1-氧代-8-((5-氧代四氢呋喃-3-基)乙炔基)-2-苯基-1,2-二氢异喹啉-3-烷基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 6 2-amino-N-((1S)-1-(1-oxo-8-((5-oxotetrahydrofuran-3-yl)ethynyl)-2-phenyl-1,2-di Hydroisoquinoline-3-alkyl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000065
Figure PCTCN2022121567-appb-000065
步骤1)4-(1-溴乙烯基)二氢呋喃-2(3H)-酮Step 1) 4-(1-Bromovinyl)dihydrofuran-2(3H)-one
在0℃下，向4-乙烯基氧杂环-2-酮(500mg，4.46mmol)的二氯甲烷(40mL)溶液中加入液溴(784mg，4.9mmol)，混合物在0℃下搅拌2小时后，减压浓缩混合物，将残余物溶于乙腈(20mL)。在0℃下，向混合物中加入1,8-二氮杂二环十一碳-7-烯(1.35g，8.9mmol)，并在25℃搅拌16小时。混合物用乙酸乙酯(50mL)稀释并用饱和食盐水(30mL x 2)洗。将分离的有机层用无水硫酸钠干燥，过滤，减压浓缩。粗品通过硅胶色谱法纯化(EA/PE＝1/4)，得到4-(1-溴乙烯基)二氢呋喃-2(3H)-酮(600mg，31.7％收率)为棕色油状物。MS(ESI):191.0,193.0[M+H] +。 1H NMR(400MHz,CDCl3)δ5.80(dd,J＝2.4,0.8Hz,1H),5.58(d,J＝2.4Hz,1H),4.45-4.39(m,1H),4.25-4.20(m,1H),3.55-3.46(m,1H),2.71-2.66(m,2H)。 Add liquid bromine (784mg, 4.9mmol) to a solution of 4-vinyloxetan-2-one (500mg, 4.46mmol) in dichloromethane (40mL) at 0°C, and the mixture was stirred at 0°C for 2 hours Afterwards, the mixture was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (20 mL). To the mixture was added 1,8-diazabicycloundec-7-ene (1.35 g, 8.9 mmol) at 0°C and stirred at 25°C for 16 hours. The mixture was diluted with ethyl acetate (50 mL) and washed with saturated brine (30 mL x 2). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (EA/PE=1/4) to give 4-(1-bromovinyl)dihydrofuran-2(3H)-one (600 mg, 31.7% yield) as a brown oil. MS (ESI): 191.0, 193.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ5.80 (dd, J = 2.4, 0.8Hz, 1H), 5.58 (d, J = 2.4Hz, 1H), 4.45-4.39 (m, 1H), 4.25-4.20 (m ,1H), 3.55-3.46(m,1H), 2.71-2.66(m,2H).
步骤2)4-乙基二氢呋喃-2(3H)-酮Step 2) 4-Ethyldihydrofuran-2(3H)-one
在-70℃下，向二异丙胺(1.38g，13.6mmol)的四氢呋喃(30mL)溶液中慢慢滴加正丁基锂(2.4N正己烷溶液，5.9mL，14.3mmol)，于-30℃搅拌1小时。然后将混合物冷却至-70℃，加入4-(1-溴乙烯基)二氢呋喃-2(3H)-酮(650mg，3.4mmol)的四氢呋喃(3mL)溶液，在-10℃下搅拌2小时。混合物用氯化铵水溶液(30mL)淬灭，并用乙酸乙酯(30mL x 3)提取。合并的有机层用饱和食盐水(50mL)洗，将分离的有机层用无水硫酸钠干燥，过滤，减压浓缩。粗品通过硅胶色谱法纯化(EA/PE＝1/4)，得到4-乙炔基二氢呋喃-2(3H)-酮(250mg，43.4％收率)为无色油状物。 1H NMR(400MHz,CDCl 3)δ4.51(dd,J＝8.8,7.6Hz,1H),4.22(dd,J＝8.8, 7.6Hz,1H),3.45-3.33(m,1H),2.81(dd,J＝17.4,8.8Hz,1H),2.63(dd,J＝17.4,8.8Hz,1H),2.25(d,J＝2.4Hz,1H)。 At -70°C, slowly add n-butyllithium (2.4N n-hexane solution, 5.9mL, 14.3mmol) dropwise to a solution of diisopropylamine (1.38g, 13.6mmol) in tetrahydrofuran (30mL). Stir for 1 hour. Then the mixture was cooled to -70°C, a solution of 4-(1-bromovinyl)dihydrofuran-2(3H)-one (650mg, 3.4mmol) in tetrahydrofuran (3mL) was added, stirred at -10°C for 2 hours . The mixture was quenched with aqueous ammonium chloride (30 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (50 mL), and the separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (EA/PE=1/4) to give 4-ethynyldihydrofuran-2(3H)-one (250 mg, 43.4% yield) as a colorless oil. 1 H NMR (400MHz, CDCl 3 ) δ4.51(dd, J=8.8, 7.6Hz, 1H), 4.22(dd, J=8.8, 7.6Hz, 1H), 3.45-3.33(m, 1H), 2.81( dd, J = 17.4, 8.8 Hz, 1H), 2.63 (dd, J = 17.4, 8.8 Hz, 1H), 2.25 (d, J = 2.4 Hz, 1H).
步骤3)3-((S)-1-氨基乙基)-8-((5-氧代四氢呋喃-3-基)乙炔基)-2-苯基异喹啉-1(2H)-酮Step 3) 3-((S)-1-aminoethyl)-8-((5-oxotetrahydrofuran-3-yl)ethynyl)-2-phenylisoquinolin-1(2H)-one
在氮气环境下，向(S)-3-(1-氨基乙基)-8-氯-2-苯基异喹啉-1(2H)-酮(50mg，0.17mmol)和4-乙炔基二氢呋喃-2(3H)-酮(37mg，0.33mmol)的乙腈(30mL)溶液中加入X-Phos(40mg，0.083mmol)、Pd 2(dba) 3(38mg，0.042mmol)以及磷酸钾(107mg，0.50mmol)，混合物在80℃加热5小时。降至室温后，混合物减压浓缩，残余物用乙酸乙酯(30mL)稀释。混合物用饱和食盐水(20mL)洗，将分离的有机层用无水硫酸钠干燥，过滤，减压浓缩。粗品通过硅胶色谱法(DCM/MeOH＝91/9)纯化得到3-((S)-1-氨基乙基)-8-((5-氧代四氢呋喃-3-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(48mg，收率69.30％)为黄色油状物。MS(ESI):373.0[M+H] +。 Under nitrogen atmosphere, (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (50mg, 0.17mmol) and 4-ethynyldi Add X-Phos (40mg, 0.083mmol), Pd 2 (dba) 3 (38mg, 0.042mmol) and potassium phosphate (107mg , 0.50 mmol), and the mixture was heated at 80°C for 5 hours. After cooling down to room temperature, the mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (30 mL). The mixture was washed with saturated brine (20 mL), and the separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (DCM/MeOH=91/9) to give 3-((S)-1-aminoethyl)-8-((5-oxotetrahydrofuran-3-yl)ethynyl)-2- Phenylisoquinolin-1(2H)-one (48 mg, yield 69.30%) was a yellow oil. MS (ESI): 373.0 [M+H] + .
步骤4)2-氨基-N-((1S)-1-(1-氧代-8-((5-氧代四氢呋喃-3-基)乙炔基)-2-苯基-1,2-二氢异喹啉-3-烷基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 4) 2-Amino-N-((1S)-1-(1-oxo-8-((5-oxotetrahydrofuran-3-yl)ethynyl)-2-phenyl-1,2-di Hydroisoquinoline-3-alkyl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向3-((S)-1-氨基乙基)-8-((5-氧代四氢呋喃-3-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(48mg，0.13mmol)和2,5-二氧代吡咯烷-1-基2-氨基吡唑并[1.5-a]嘧啶-3-羧酸酯(35.5mg，0.13mmol)的乙腈(10mL)混合物中加入N,N'-二异丙基乙基胺(50mg，0.39mmol)，将混合物在80℃下搅拌16小时。降至室温后，混合物减压浓缩，残余物用二氯甲烷(30mL)稀释，用饱和食盐水(20mL)洗，将分离的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物(Gemini-C18 150x21.2mm.2mm.5um ACN-H 2O(0.1％FA)40-55)纯化得到2-氨基-N-((1S)-1-(1-氧代-8-((5-氧代四氢呋喃-3-基)乙炔基)-2-苯基-1,2-二氢异喹啉-3-乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(14.8mg，21.1％收率)为白色固体。MS(ESI):532.8[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.93(dd,J＝6.7,1.6Hz,1H),8.55(dd,J＝4.5,1.6Hz,1H),7.99(d,J＝6.7Hz,1H),7.67-7.42(m,7H),7.37(dd,J＝5.7,3.5Hz,1H),7.01(dd,J＝6.7,4.5Hz,1H),6.74(s,1H),6.43(s,2H),4.59-4.47(m,2H),4.20(dd,J＝8.3,6.9Hz,1H),3.77-3.68(m,1H),2.86(dd,J＝17.0,8.6Hz,1H),2.61(dd,J＝17.0,7.8Hz,1H),1.34(d,J＝6.8Hz,3H)。 To 3-((S)-1-aminoethyl)-8-((5-oxotetrahydrofuran-3-yl)ethynyl)-2-phenylisoquinolin-1(2H)-one (48mg, 0.13mmol) and 2,5-dioxopyrrolidin-1-yl 2-aminopyrazolo[1.5-a]pyrimidine-3-carboxylate (35.5mg, 0.13mmol) in acetonitrile (10mL) mixture was added N,N'-Diisopropylethylamine (50mg, 0.39mmol), the mixture was stirred at 80°C for 16 hours. After cooling down to room temperature, the mixture was concentrated under reduced pressure, the residue was diluted with dichloromethane (30 mL), washed with saturated brine (20 mL), the separated organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue 2 -amino-N-((1S)-1-(1-oxo-8-( (5-Oxotetrahydrofuran-3-yl)ethynyl)-2-phenyl-1,2-dihydroisoquinoline-3-ethyl)pyrazolo[1,5-a]pyrimidine-3-methyl Amide (14.8 mg, 21.1% yield) was a white solid. MS (ESI): 532.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ8.93 (dd, J=6.7, 1.6 Hz ,1H),8.55(dd,J=4.5,1.6Hz,1H),7.99(d,J=6.7Hz,1H),7.67-7.42(m,7H),7.37(dd,J=5.7,3.5Hz, 1H), 7.01(dd, J=6.7, 4.5Hz, 1H), 6.74(s, 1H), 6.43(s, 2H), 4.59-4.47(m, 2H), 4.20(dd, J=8.3, 6.9Hz ,1H),3.77-3.68(m,1H),2.86(dd,J=17.0,8.6Hz,1H),2.61(dd,J=17.0,7.8Hz,1H),1.34(d,J=6.8Hz, 3H).
实施例7(S)-2-氨基-N-(1-(8-((3-羟基氧杂环丁烷-3-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-烷基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 7 (S)-2-amino-N-(1-(8-((3-hydroxyl oxetane-3-yl)ethynyl)-1-oxo-2-phenyl-1, 2-Dihydroisoquinoline-3-alkyl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000066
Figure PCTCN2022121567-appb-000066
步骤1)3-乙炔基氧杂环丁烷-3-醇Step 1) 3-Ethynyloxetan-3-ol
在-78℃、氮气保护下，向3-氧杂环丁酮(750mg，10.41mmol)的四氢呋喃(20mL)溶液中慢慢滴加乙炔基溴化镁(25mL，12.50mmol，0.5mmol的THF溶液)，混合物在室温下搅拌2小时。反应用氯化铵水溶液(20mL)淬灭，用乙酸乙酯(50mL x 3)萃取。合并的有机层用饱和食盐水(50mL)洗，经无水硫酸钠干燥，过滤，浓缩。粗品通过快速硅胶色谱法(DCM/MeOH＝30/1)纯化，得到3-乙炔基氧杂环丁烷-3-醇(485mg，42.75％收率)为黄色油状物。 1H NMR(400MHz,CDCl 3)δ4.83(dd,J＝6.7,0.9Hz,2H),4.68(dd,J＝6.6,0.9Hz,2H),3.52(s,1H),2.71(s,1H)。 Under the protection of nitrogen at -78°C, ethynylmagnesium bromide (25 mL, 12.50 mmol, 0.5 mmol in THF) was slowly added dropwise to a solution of 3-oxetanone (750 mg, 10.41 mmol) in tetrahydrofuran (20 mL). ), and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with aqueous ammonium chloride (20 mL), extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash silica gel chromatography (DCM/MeOH=30/1) to give 3-ethynyloxetan-3-ol (485 mg, 42.75% yield) as a yellow oil. 1 H NMR (400MHz, CDCl 3 )δ4.83(dd, J=6.7,0.9Hz,2H),4.68(dd,J=6.6,0.9Hz,2H),3.52(s,1H),2.71(s, 1H).
步骤2)3-((S)-1-氨基乙基)-8-((3-羟基氧杂环丁烷-3-基)乙炔基)-2-苯基萘-1(2H)-酮Step 2) 3-((S)-1-aminoethyl)-8-((3-hydroxyoxetan-3-yl)ethynyl)-2-phenylnaphthalene-1(2H)-one
向(S)-3-(1-氨基乙基)-8-氯-2-苯基异喹啉-1(2H)-酮(60mg，0.20mmol)和3-乙炔氧烷-3-醇(29mg，0.30mmol)的乙腈(10mL)溶液中加入X-Phos(48mg，0.10mmol)、Pd 2(dba) 3(37mg，0.04mmol)以及磷酸钾(128mg，0.60mmol)，混合物在80℃加热5小时。降至室温后，混合物减压浓缩，残余物用乙酸乙酯(60mL)稀释。混合物用饱和食盐水(40mL)洗，将分离的有机层用无水硫酸钠干燥，过滤，减压浓缩。粗品通过硅胶色谱法(DCM/MeOH＝91/9)纯化，得到3-((S)-1-氨基乙基)-8-((3-羟基氧杂环丁烷-3-基)乙炔基)-2-苯基萘-1(2H)-酮(50mg，收率62.20％)为黄色固体。MS(ESI):361.0[M+H] +。 To (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (60 mg, 0.20 mmol) and 3-ethynyloxyalkan-3-ol ( 29mg, 0.30mmol) in acetonitrile (10mL) was added X-Phos (48mg, 0.10mmol), Pd 2 (dba) 3 (37mg, 0.04mmol) and potassium phosphate (128mg, 0.60mmol), and the mixture was heated at 80°C 5 hours. After cooling down to room temperature, the mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (60 mL). The mixture was washed with saturated brine (40 mL), and the separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (DCM/MeOH=91/9) to give 3-((S)-1-aminoethyl)-8-((3-hydroxyoxetan-3-yl)ethynyl )-2-phenylnaphthalen-1(2H)-one (50 mg, yield 62.20%) was a yellow solid. MS (ESI): 361.0 [M+H] + .
步骤3)(S)-2-氨基-N-(1-(8-((3-羟基氧杂环丁烷-3-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-烷基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 3) (S)-2-amino-N-(1-(8-((3-hydroxyoxetane-3-yl)ethynyl)-1-oxo-2-phenyl-1, 2-Dihydroisoquinoline-3-alkyl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向3-((S)-1-氨基乙基)-8-((3-羟基氧杂环丁烷-3-基)乙炔基)-2-苯基萘-1(2H)-酮(25mg，0.07mmol)和2-氨基吡唑并[1.5-a]嘧啶-3-羧酸(12mg，0.07mmol)的二氯甲烷(20mL)溶液中加入N,N'-二异丙基乙基胺(27mg，0.21mmol)、1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(20mg，0.10mmol)和1-羟基-7-氮杂苯并三氮唑(14mg，0.10mmol)。将混合物在40℃下搅拌16小时，然后混合物用二氯甲烷(60mL)稀释，用饱和食盐水(40mL)洗，经无水硫酸钠干燥，过滤，滤液减压浓缩。粗品通过高效制备液相(-Gemini-C18 150x21.2mm，5um:ACN-H 2O(0.1％FA),40-60)纯化，得到(S)-2-氨基-N-(1-(8-((3-羟基氧杂环丁烷-3-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(4.1mg，11.24％)为黄色固体。MS(ESI):520.9[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.93(dd,J＝6.7,1.6Hz,1H),8.55(dd,J＝4.5,1.6Hz,1H),8.00(d,J＝6.7Hz,1H),7.70-7.63(m,2H),7.60-7.54(m,2H),7.53-7.45(m,3H),7.41-7.35(m,1H),7.02(dd,J＝6.7,4.5Hz,1H),6.75(s,1H),6.58-6.35(m,3H),4.73(d,J＝6.3Hz,2H),4.55(t,J＝6.1Hz,3H),1.35(d,J＝6.8Hz,3H)。 To 3-((S)-1-aminoethyl)-8-((3-hydroxyoxetan-3-yl)ethynyl)-2-phenylnaphthalene-1(2H)-one (25mg , 0.07mmol) and 2-aminopyrazolo[1.5-a]pyrimidine-3-carboxylic acid (12mg, 0.07mmol) in dichloromethane (20mL) solution was added N,N'-diisopropylethylamine (27mg, 0.21mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (20mg, 0.10mmol) and 1-hydroxy-7-azabenzotriazole ( 14 mg, 0.10 mmol). The mixture was stirred at 40°C for 16 hours, then the mixture was diluted with dichloromethane (60 mL), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC (-Gemini-C18 150x21.2mm, 5um:ACN- H2O (0.1%FA), 40-60) to obtain (S)-2-amino-N-(1-(8 -((3-Hydroxyoxetane-3-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinoline-3-ethyl)pyrazolo[1 ,5-a]pyrimidine-3-carboxamide (4.1 mg, 11.24%) is a yellow solid. MS (ESI): 520.9[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.93 ( dd,J=6.7,1.6Hz,1H),8.55(dd,J=4.5,1.6Hz,1H),8.00(d,J=6.7Hz,1H),7.70-7.63(m,2H),7.60-7.54 (m,2H),7.53-7.45(m,3H),7.41-7.35(m,1H),7.02(dd,J＝6.7,4.5Hz,1H),6.75(s,1H),6.58-6.35(m , 3H), 4.73 (d, J=6.3Hz, 2H), 4.55 (t, J=6.1Hz, 3H), 1.35 (d, J=6.8Hz, 3H).
实施例8 2-氨基-N-((1S)-1-(8-(2-(1,2-二甲基-5-氧代吡唑-3-基)乙炔基)-1-氧代-2-苯基异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 8 2-amino-N-((1S)-1-(8-(2-(1,2-dimethyl-5-oxopyrazol-3-yl)ethynyl)-1-oxo -2-phenylisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000067
Figure PCTCN2022121567-appb-000067
步骤1)1,2-二甲基-5-氧代吡唑-3-甲酸甲酯Step 1) Methyl 1,2-Dimethyl-5-oxopyrazole-3-carboxylate
在0℃下，向2-甲基-5-氧代-1H-吡唑-3-甲酸甲酯(1g，6.4mmol)的DMF(20mL)溶液中加入NaH(184mg，7.7mmol)，混合物继续搅拌0.5h。然后加入MeI(1.3g，9.6mmol)，随后搅拌4h。混合物用水淬灭，NH 4Cl溶液(50mL)稀释，并用EtOAc(50mL x 3)萃取。合并的有机层用盐水(100mL x 2)洗，经Na 2SO 4干燥，真空浓缩。残余物经硅胶色谱法(EA:PE＝1:2)纯化，得到1,2-二甲基-5-氧代吡唑-3-甲酸甲酯(1.05g，91.5％收率)为棕色固体。MS(ESI):171.1[M+H] +。 To a solution of methyl 2-methyl-5-oxo-1H-pyrazole-3-carboxylate (1 g, 6.4 mmol) in DMF (20 mL) was added NaH (184 mg, 7.7 mmol) at 0 °C and the mixture continued Stir for 0.5h. MeI (1.3 g, 9.6 mmol) was then added followed by stirring for 4 h. The mixture was quenched with water, diluted with NH 4 Cl solution (50 mL), and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na 2 SO 4 , concentrated in vacuo. The residue was purified by silica gel chromatography (EA:PE=1:2) to give methyl 1,2-dimethyl-5-oxopyrazole-3-carboxylate (1.05 g, 91.5% yield) as a brown solid . MS (ESI): 171.1 [M+H] + .
步骤2)5-(羟甲基)-1,2-二甲基吡唑-3-酮Step 2) 5-(Hydroxymethyl)-1,2-dimethylpyrazol-3-one
在0℃下，向1,2-二甲基-5-氧代吡唑-3-甲酸甲酯(1g，5.9mmol)的THF(50mL)溶液中加入LiAlH 4(446mg，11.7mmol)，保温搅拌2h。混合物加入10％NaOH(0.5mL)和水(1mL)淬灭，过滤。滤饼用EtOAc(40mL)洗，滤液经Na 2SO 4干燥，真空浓缩，得到粗制5-(羟甲基)-1,2-二甲基吡唑-3-酮(740mg，收率88％)，为无色油状物。MS(ESI):143.1[M+H] +。 Add LiAlH 4 (446 mg, 11.7 mmol) to a solution of methyl 1,2-dimethyl-5-oxopyrazole-3-carboxylate (1 g, 5.9 mmol) in THF (50 mL) at 0°C and keep warm Stir for 2h. The mixture was quenched with 10% NaOH (0.5 mL) and water (1 mL), and filtered. The filter cake was washed with EtOAc (40 mL), the filtrate was dried over Na 2 SO 4 , and concentrated in vacuo to give crude 5-(hydroxymethyl)-1,2-dimethylpyrazol-3-one (740 mg, yield 88 %), as a colorless oil. MS (ESI): 143.1 [M+H] + .
步骤3)1,2-二甲基-5-氧代吡唑-3-甲醛Step 3) 1,2-Dimethyl-5-oxopyrazole-3-carbaldehyde
在20℃下，向5-(羟甲基)-1,2-二甲基吡唑-3-酮(740mg，5.2mmol)的DCM(100mL)溶液中加入戴斯-马丁试剂(4.4g，10.4mmol)，混合物搅拌16小时。混合物用DCM(100mL)稀释，过滤。滤液用水(50mL)和盐水(50mL)洗，经Na 2SO 4干燥，真空浓缩。残余物经硅胶色谱法(EA/PE＝1/1)纯化，得到1,2-二甲基-5-氧代吡唑-3-甲醛(710mg，87.5％收率)为黄色油状物。MS(ESI):141.1[M+H] +。 To a solution of 5-(hydroxymethyl)-1,2-dimethylpyrazol-3-one (740 mg, 5.2 mmol) in DCM (100 mL) was added Dess-Martin reagent (4.4 g, 10.4 mmol), and the mixture was stirred for 16 hours. The mixture was diluted with DCM (100 mL) and filtered. The filtrate was washed with water (50 mL) and brine (50 mL), dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel chromatography (EA/PE=1/1) to give 1,2-dimethyl-5-oxopyrazole-3-carbaldehyde (710 mg, 87.5% yield) as a yellow oil. MS (ESI): 141.1 [M+H] + .
步骤4)5-乙炔基-1,2-二甲基吡唑-3-酮Step 4) 5-ethynyl-1,2-dimethylpyrazol-3-one
向1,2-二甲基-5-氧代吡唑-3-甲醛(710mg，5.1mmol)和K 2CO 3(2.1g，15mmol)的MeOH(50mL)溶液中加入二甲基(1-重氮-2-氧代丙基)膦酸盐(1.7g，6.1mmol)，混合物常温搅拌16小时。混合物真空浓缩后，用EtOAc(100mL)稀释；然后用盐水(100mL)洗，经Na 2SO 4干燥，真空浓缩。残余物经硅胶色谱法(EA:PE＝1:1)纯化，得到5-乙炔基-1,2-二甲基吡唑-3-酮(540mg，70.4％收率)为无色油状物。MS(ESI):137.1[M+H] +。 To a solution of 1,2-dimethyl-5-oxopyrazole-3-carbaldehyde (710 mg, 5.1 mmol) and K 2 CO 3 (2.1 g, 15 mmol) in MeOH (50 mL) was added dimethyl (1- Diazo-2-oxopropyl)phosphonate (1.7g, 6.1mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, diluted with EtOAc (100 mL); then washed with brine (100 mL), dried over Na2SO4 , and concentrated in vacuo . The residue was purified by silica gel chromatography (EA:PE=1:1) to give 5-ethynyl-1,2-dimethylpyrazol-3-one (540 mg, 70.4% yield) as a colorless oil. MS (ESI): 137.1 [M+H] + .
步骤5)3-((1S)-1-氨基乙基)-8-(2-(1,2-二甲基-5-氧代吡唑-3-基)乙炔基)-2-苯基异喹啉-1-酮Step 5) 3-((1S)-1-Aminoethyl)-8-(2-(1,2-Dimethyl-5-oxopyrazol-3-yl)ethynyl)-2-phenyl Isoquinolin-1-one
将5-乙炔基-1,2-二甲基吡唑-3-酮(9.6mg，0.07mmol)、3-[(1S)-1-氨基乙基]-8-氯-2-苯基异喹啉-1-酮(13.1mg，0.044mmol)、K 3PO 4(28mg，0.13mmol)、X-phos(8.4mg，0.02mmol)和Pd 2(dba) 3(8.1mg，0.01mmol)的CH 3CN(10mL)溶液升温至80℃，搅拌16小时。冷却至室温，真空浓缩，残余物用EtOAc(50mL)稀释。混合物用盐水(20mL)洗，经Na 2SO 4干燥，真空浓缩。残余物经硅胶色谱法(MeOH/DCM＝1/20)纯化，得到3-((1S)-1-氨基乙基)-8-(2-(1,2-二甲基-5-氧代吡唑-3-基)乙炔基)-2-苯基异喹啉-1-酮(120mg，95％收率)为棕色固体。MS(ESI):399.2[M+H] +。 5-Ethynyl-1,2-dimethylpyrazol-3-one (9.6mg, 0.07mmol), 3-[(1S)-1-aminoethyl]-8-chloro-2-phenyliso Quinolin-1-one (13.1mg, 0.044mmol), K 3 PO 4 (28mg, 0.13mmol), X-phos (8.4mg, 0.02mmol) and Pd 2 (dba) 3 (8.1mg, 0.01mmol) The CH 3 CN (10 mL) solution was warmed to 80° C. and stirred for 16 hours. Cooled to room temperature, concentrated in vacuo, and the residue was diluted with EtOAc (50 mL). The mixture was washed with brine (20 mL), dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM=1/20) to give 3-((1S)-1-aminoethyl)-8-(2-(1,2-dimethyl-5-oxo Pyrazol-3-yl)ethynyl)-2-phenylisoquinolin-1-one (120 mg, 95% yield) was a brown solid. MS (ESI): 399.2 [M+H] + .
步骤6)2-氨基-N-((1S)-1-(8-(2-(1,2-二甲基-5-氧代吡唑-3-基)乙炔基)-1-氧代-2-苯基异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 6) 2-amino-N-((1S)-1-(8-(2-(1,2-dimethyl-5-oxopyrazol-3-yl)ethynyl)-1-oxo -2-phenylisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向2-氨基吡唑并[1,5-a]嘧啶-3-羧酸(54mg，0.3mmol)和HOAT(61.5mg，0.45mmol)、EDCI(86.6mg，0.45mmol)、DIEA(117mg,0.9mmol)的DCM(20mL)溶液中加入3-((1S)-1-氨基乙基)-8-(2-(1,2-二甲基-5-氧代吡唑-3-基)乙炔基)-2-苯基异喹啉-1-酮(120mg，0.30mmol)，混合物升温至40℃搅拌16h。冷却至室温后，混合物用DCM(60mL)稀释。混合物用盐水(50mL)洗，经Na 2SO 4干燥，真空浓缩。残余物经制备型HPLC(ACN-H 2O 0.1％FA，梯度30％至50％)纯化，得到2-氨基-N-((1S)-1-(8-(2-(1,2-二甲基)-5-氧代吡唑-3-基)乙炔基)-1-氧代-2-苯基异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(56mg，32.6％收率)为白色固体。MS(ESI):559.2[M+H] +。 1H NMR(400MHz,CDCl 3)δ8.49(dd,J＝6.8,1.6Hz,1H),8.44(dd,J＝4.4,1.6Hz,1H),7.97(d,J＝6.8Hz,1H),7.66(dd,J＝7.6,1.2Hz,1H),7.60-7.56(m,1H),7.55-7.48(m,4H),7.38-7.33(m,1H),6.86-6.82(m,1H),6.67(s,1H),5.88(s,1H),4.86-4.81(m,1H),3.93(s,3H),3.91(s,3H),1.42(d,J＝6.8Hz,3H)。 To 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (54mg, 0.3mmol) and HOAT (61.5mg, 0.45mmol), EDCI (86.6mg, 0.45mmol), DIEA (117mg, 0.9 mmol) in DCM (20mL) was added 3-((1S)-1-aminoethyl)-8-(2-(1,2-dimethyl-5-oxopyrazol-3-yl)acetylene yl)-2-phenylisoquinolin-1-one (120mg, 0.30mmol), and the mixture was heated to 40°C and stirred for 16h. After cooling to room temperature, the mixture was diluted with DCM (60 mL). The mixture was washed with brine (50 mL), dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by preparative HPLC (ACN- H2O 0.1% FA, gradient 30% to 50%) to give 2-amino-N-((1S)-1-(8-(2-(1,2- Dimethyl)-5-oxopyrazol-3-yl)ethynyl)-1-oxo-2-phenylisoquinolin-3-yl)ethyl)pyrazolo[1,5-a] Pyrimidine-3-carboxamide (56 mg, 32.6% yield) was a white solid. MS (ESI): 559.2 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ8.49(dd, J=6.8,1.6Hz,1H),8.44(dd,J=4.4,1.6Hz,1H),7.97(d,J=6.8Hz,1H) ,7.66(dd,J＝7.6,1.2Hz,1H),7.60-7.56(m,1H),7.55-7.48(m,4H),7.38-7.33(m,1H),6.86-6.82(m,1H) , 6.67 (s, 1H), 5.88 (s, 1H), 4.86-4.81 (m, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 1.42 (d, J=6.8Hz, 3H).
实施例9(S)-2-氨基-N-(1-(8-((6,7-二氢-5H-吡咯并[1,2-a]咪唑-2-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 9 (S)-2-amino-N-(1-(8-((6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)ethynyl)-1 -Oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000068
Figure PCTCN2022121567-appb-000068
步骤1)2-((三异丙基甲硅烷基)乙炔基)-6,7-二氢-5H-吡咯并[1,2-a]咪唑Step 1) 2-((triisopropylsilyl)ethynyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole
向2-溴-5H,6H,7H-吡咯并[1,2-a]咪唑(300mg，1.6mmol)、乙炔基三异丙基硅烷(439mg，2.4mmol)、醋酸钯(36mg，0.16mmol)的DMF(10mL)溶液中加入K 2CO 3(443mg，3.2mmol)和X-phos(76mg，0.16mmol)，混合物升温至80℃，搅拌16h。冷却至室温后，混合物用EtOAc(50mL)稀释，并用盐水(30mL×2)洗。有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝20/1)分离纯化，得到产物(200mg，41％收率)为黄色固体。MS(ESI):289.2[M+H] +。 To 2-bromo-5H,6H,7H-pyrrolo[1,2-a]imidazole (300mg, 1.6mmol), ethynyltriisopropylsilane (439mg, 2.4mmol), palladium acetate (36mg, 0.16mmol) K 2 CO 3 (443 mg, 3.2 mmol) and X-phos (76 mg, 0.16 mmol) were added to a solution of DMF (10 mL), and the mixture was heated to 80° C. and stirred for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc (50 mL), and washed with brine (30 mL×2). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was separated and purified by column chromatography (DCM/MeOH=20/1) to obtain the product (200 mg, 41% yield) as a yellow solid. MS (ESI): 289.2 [M+H] + .
步骤2)2-((三异丙基甲硅烷基)乙炔基)-6,7-二氢-5H-吡咯并[1,2-a]咪唑Step 2) 2-((triisopropylsilyl)ethynyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole
向2-(2-(三异丙基甲硅烷基)乙炔基)-5H,6H,7H-吡咯并[1,2-a]咪唑(150mg，0.52mmol)的THF(5mL)溶液中加入四丁基氟化铵(0.8mL,0.8mmol,1M的THF溶液)，混合物升温至25℃搅拌2小时。混合物用EtOAc(50mL)稀释，并用盐水(30mL)洗。有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱(DCM/MeOH＝15/1)分离，得到2-乙炔基-6,7-二氢-5H-吡咯并[1,2-a]咪唑(60mg，收率78％)为白色固体。MS(ESI):133.0[M+H] +。 To a solution of 2-(2-(triisopropylsilyl)ethynyl)-5H,6H,7H-pyrrolo[1,2-a]imidazole (150 mg, 0.52 mmol) in THF (5 mL) was added tetrakis Butylammonium fluoride (0.8mL, 0.8mmol, 1M solution in THF), the mixture was warmed to 25°C and stirred for 2 hours. The mixture was diluted with EtOAc (50 mL), and washed with brine (30 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was separated by column chromatography (DCM/MeOH=15/1) to obtain 2-ethynyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (60 mg, yield 78%) as white solid. MS (ESI): 133.0 [M+H] + .
步骤3)(S)-3-(1-氨基乙基)-8-((6,7-二氢-5H-吡咯并[1,2-a]咪唑-2-基)乙炔基)-2-苯基异喹啉-1(2H)-酮Step 3) (S)-3-(1-aminoethyl)-8-((6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)ethynyl)-2 -Phenylisoquinolin-1(2H)-one
在氮气气氛下，向(S)-3-(1-氨基乙基)-8-氯-2-苯基异喹啉-1(2H)-酮(60mg，0.20mmol)和2-乙炔基-6,7-二氢-5H-吡咯并[1,2-a]咪唑(34.5mg，0.26mmol)的MeCN(50mL)溶液中加入X-Phos(38mg，0.08mmol)、Pd 2(dba) 3(37mg，0.04mmol)和K 3PO 4(128mg，0.60mmol)。混合物升温至80℃，搅拌5h。冷却至室温 后，将混合物真空浓缩，残余物用EtOAc(130mL)稀释，并用盐水(50mL×2)洗。有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝91/9)纯化，得到(S)-3-(1-氨基乙基)-8-((6,7-二氢-5H-吡咯并[1,2-a]咪唑-2-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(50mg，57％收率)为黄色油状物。MS(ESI):394.9[M+H] +。 Under nitrogen atmosphere, (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (60 mg, 0.20 mmol) and 2-ethynyl- To a solution of 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (34.5mg, 0.26mmol) in MeCN (50mL) was added X-Phos (38mg, 0.08mmol), Pd 2 (dba) 3 (37 mg, 0.04 mmol) and K 3 PO 4 (128 mg, 0.60 mmol). The mixture was warmed to 80 °C and stirred for 5 h. After cooling to room temperature, the mixture was concentrated in vacuo, the residue was diluted with EtOAc (130 mL), and washed with brine (50 mL×2). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=91/9) to give (S)-3-(1-aminoethyl)-8-((6,7-dihydro-5H-pyrrolo[1, 2-a] Imidazol-2-yl)ethynyl)-2-phenylisoquinolin-1(2H)-one (50 mg, 57% yield) as a yellow oil. MS (ESI): 394.9 [M+H] + .
步骤4)(S)-2-氨基-N-(1-(8-((6,7-二氢-5H-吡咯并[1,2-a]咪唑-2-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 4) (S)-2-amino-N-(1-(8-((6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)ethynyl)-1 -Oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向(S)-3-(1-氨基乙基)-8-((6,7-二氢-5H-吡咯并[1,2-a]咪唑-2-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(50mg，0.13mmol)和2-氨基吡唑并[1,5-a]嘧啶-3-羧酸(25mg，0.14mmol)的DCM(20mL)溶液中加入DIEA(65mg，0.51mmol)、EDCI(36mg，0.19mmol)和HOAT(26mg，0.19mmol)。混合物升温至40℃，搅拌16h。冷却至室温后，混合物用DCM(100mL)稀释，并用盐水(50mL x 2)洗。有机相经Na 2SO 4干燥，真空浓缩。残余物经制备型HPLC(-Xbridge-C18 150x 19mm,5um,ACN-H 2O(0.05％NH 4OH),15％-40％)纯化，得到(S)-2-氨基-N-(1-(8-((6,7-二氢-5H-吡咯并[1,2-a]咪唑-2-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(13.4mg，19.01％收率)为白色固体。MS(ESI):554.8[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.94(dd,J＝6.7,1.6Hz,1H),8.56(dd,J＝4.5,1.6Hz,1H),8.02(d,J＝6.6Hz,1H),7.89(s,1H),7.79-7.65(m,3H),7.61-7.46(m,4H),7.43-7.38(m,1H),7.02(dd,J＝6.7,4.5Hz,1H),6.81(s,1H),6.43(s,2H),4.60-4.52(m,1H),4.17-4.09(m,2H),3.04(t,J＝7.6Hz,2H),2.66-2.55(m,2H),1.36(d,J＝6.8Hz,3H)。 To (S)-3-(1-aminoethyl)-8-((6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)ethynyl)-2-benzene 1-isoquinolin-1(2H)-one (50 mg, 0.13 mmol) and 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (25 mg, 0.14 mmol) in DCM (20 mL) DIEA (65 mg, 0.51 mmol), EDCI (36 mg, 0.19 mmol) and HOAT (26 mg, 0.19 mmol) were added. The mixture was warmed to 40 °C and stirred for 16 h. After cooling to room temperature, the mixture was diluted with DCM (100 mL), and washed with brine (50 mL x 2). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (-Xbridge-C18 150x 19mm, 5um, ACN-H 2 O (0.05% NH 4 OH), 15%-40%) to give (S)-2-amino-N-(1 -(8-((6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydro Isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (13.4 mg, 19.01% yield) was a white solid. MS (ESI): 554.8 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.94(dd, J=6.7,1.6Hz,1H),8.56(dd,J=4.5,1.6Hz,1H),8.02(d,J=6.6Hz, 1H),7.89(s,1H),7.79-7.65(m,3H),7.61-7.46(m,4H),7.43-7.38(m,1H),7.02(dd,J＝6.7,4.5Hz,1H) ,6.81(s,1H),6.43(s,2H),4.60-4.52(m,1H),4.17-4.09(m,2H),3.04(t,J＝7.6Hz,2H),2.66-2.55(m , 2H), 1.36 (d, J=6.8Hz, 3H).
实施例10 2-氨基-5-(氟甲基-d)-N-((S)-1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 10 2-amino-5-(fluoromethyl-d)-N-((S)-1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 -Oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000069
Figure PCTCN2022121567-appb-000069
步骤1)2-氨基-5-甲基吡唑并[1,5-a]嘧啶-3-甲酸乙酯Step 1) Ethyl 2-amino-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate
向3,5-二氨基-1H-吡唑-4-甲酸乙酯(2g，11.7mmol)的DMF(20mL)溶液中加入4,4-二甲氧基丁-2-酮(3.1g，23.5mmol)。混合物升温至110℃，搅拌1h，然后加入乙酸(2.8g，47.0mmol)，继续搅拌16h。冷却至室温，真空浓缩。将残余物溶于EtOAc(200mL)和盐水(100mL×3)，分液，有机相经无Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(PE:EA＝3:1)纯化，得到2-氨基-5-甲基吡唑并[1,5-a]嘧啶-3-甲酸乙酯(2.2g，85％收率)为黄色固体。LCMS:MS(ESI)m/z 221.2[M+H] +。 To a solution of ethyl 3,5-diamino-1H-pyrazole-4-carboxylate (2 g, 11.7 mmol) in DMF (20 mL) was added 4,4-dimethoxybutan-2-one (3.1 g, 23.5 mmol). The mixture was warmed to 110 °C and stirred for 1 h, then acetic acid (2.8 g, 47.0 mmol) was added and stirring was continued for 16 h. Cool to room temperature and concentrate in vacuo. The residue was dissolved in EtOAc (200 mL) and brine (100 mL×3), separated, the organic phase was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography (PE:EA=3:1) to obtain ethyl 2-amino-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (2.2 g, 85% yield rate) as a yellow solid. LCMS: MS (ESI) m/z 221.2 [M+H] + .
步骤2)5-甲基-2-(2,2,2-三氟乙酰胺)吡唑并[1,5-a]嘧啶-3-羧酸乙酯Step 2) Ethyl 5-methyl-2-(2,2,2-trifluoroacetamide)pyrazolo[1,5-a]pyrimidine-3-carboxylate
在0℃下，向2-氨基-5-甲基吡唑并[1,5-a]嘧啶-3-甲酸乙酯(2g，9.0mmol)和DIEA(2.3g，18mmol)的DCM(30mL)溶液中加入三氟乙酸酐(3.8g，18mmol)。混合物转移至室温，搅拌16小时。将混合物用DCM(100mL)稀释，用盐水(50mL x 2)洗。分液，有机相经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法(DCM/MeOH＝10/1)纯化，得到5-甲基-2-(2,2,2-三氟乙酰胺)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(1.5g，47％收率)为黄色固体。LCMS:MS(ESI)m/z 316.9[M+H] +。 Ethyl 2-amino-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (2 g, 9.0 mmol) and DIEA (2.3 g, 18 mmol) in DCM (30 mL) were dissolved at 0°C Trifluoroacetic anhydride (3.8 g, 18 mmol) was added to the solution. The mixture was transferred to room temperature and stirred for 16 hours. The mixture was diluted with DCM (100 mL), washed with brine (50 mL x 2). The layers were separated, and the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=10/1) to give 5-methyl-2-(2,2,2-trifluoroacetamide)pyrazolo[1,5-a]pyrimidine-3 - Ethyl formate (1.5 g, 47% yield) as a yellow solid. LCMS: MS (ESI) m/z 316.9 [M+H] + .
步骤3)5-甲酰基-2-(2,2,2-三氟乙酰胺)吡唑并[1,5-a]嘧啶-3-甲酸乙酯Step 3) Ethyl 5-formyl-2-(2,2,2-trifluoroacetamide)pyrazolo[1,5-a]pyrimidine-3-carboxylate
向5-甲基-2-(2,2,2-三氟乙酰胺)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(600mg，1.9mmol)的1,4-二氧六环(30mL)溶液中加入二氧化硒(421mg，3.8mmol)。将混合物升温至100℃，搅拌36小时。冷却至室温后，过滤，滤液真空浓缩。将残余物溶于EtOAc(200mL)，用盐水(100mL x 2)洗。分液，有机相经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法(PE/EA＝2/1)纯化，得到5-甲酰基-2-(2,2,2-三氟乙酰胺)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(270mg，43％收率)为黄色固体。LCMS:MS(ESI)m/z 349.0[M+H] +。 To 5-methyl-2-(2,2,2-trifluoroacetamide)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester (600mg, 1.9mmol) To the solution of hexacyclic (30 mL) was added selenium dioxide (421 mg, 3.8 mmol). The mixture was warmed to 100°C and stirred for 36 hours. After cooling to room temperature, it was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (200 mL), washed with brine (100 mL x 2). The layers were separated, and the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=2/1) to give 5-formyl-2-(2,2,2-trifluoroacetamide)pyrazolo[1,5-a]pyrimidine-3 - Ethyl formate (270 mg, 43% yield) as a yellow solid. LCMS: MS (ESI) m/z 349.0 [M+H] + .
步骤4)5-(羟甲基-d)-2-(2,2,2-三氟乙酰胺)吡唑并[1,5-a]嘧啶-3-甲酸乙酯Step 4) Ethyl 5-(hydroxymethyl-d)-2-(2,2,2-trifluoroacetamide)pyrazolo[1,5-a]pyrimidine-3-carboxylate
在0℃下，向5-甲酰基-2-(2,2,2-三氟乙酰胺)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(200mg，0.6mmol)的THF(3 mL)溶液中加入氘代硼氢化钠(11mg，0.3mmol)。混合物转移至室温，搅拌16小时。将混合物用10％柠檬酸(30mL)淬灭，用EtOAc(50mL×2)萃取。合并的有机层用盐水(30mL x 2)洗，经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法(PE/EA＝5/1)纯化，得到5-(羟甲基-d)-2-(2,2,2-三氟乙酰胺)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(60mg，29％收率)为黄色固体。LCMS:MS(ESI)m/z 334.0[M+H] +。 To 5-formyl-2-(2,2,2-trifluoroacetamide)pyrazolo[1,5-a]pyrimidine-3-carboxylate ethyl ester (200mg, 0.6mmol) in THF at 0°C (3 mL) solution was added sodium deuterated borohydride (11 mg, 0.3 mmol). The mixture was transferred to room temperature and stirred for 16 hours. The mixture was quenched with 10% citric acid (30 mL), extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=5/1) to give 5-(hydroxymethyl-d)-2-(2,2,2-trifluoroacetamide)pyrazolo[1,5- a] Ethyl pyrimidine-3-carboxylate (60 mg, 29% yield) as a yellow solid. LCMS: MS (ESI) m/z 334.0 [M+H] + .
步骤5)5-(氟甲基-d)-2-(2,2,2-三氟乙酰胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯Step 5) Ethyl 5-(fluoromethyl-d)-2-(2,2,2-trifluoroacetamido)pyrazolo[1,5-a]pyrimidine-3-carboxylate
在0℃下，向5-(羟甲基)-2-(2,2,2-三氟乙酰胺)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(50mg，0.15mmol)的DCM(10mL)溶液中加入DAST(48mg，0.3mmol)。将混合物转移至室温，搅拌1小时。混合物用DCM(50mL)稀释，并用盐水(30mL x 2)洗。分液，有机相经无水Na 2SO 4干燥，过滤，真空浓缩，得到5-(氟甲基-d)-2-(2,2,2-三氟乙酰胺基)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(40mg，80％收率)为黄色油状物。LCMS:MS(ESI)m/z 336.1[M+H] +。 At 0°C, ethyl 5-(hydroxymethyl)-2-(2,2,2-trifluoroacetamide)pyrazolo[1,5-a]pyrimidine-3-carboxylate (50mg, 0.15mmol ) in DCM (10 mL) was added DAST (48 mg, 0.3 mmol). The mixture was transferred to room temperature and stirred for 1 hour. The mixture was diluted with DCM (50 mL) and washed with brine (30 mL x 2). The layers were separated, and the organic phase was dried over anhydrous Na2SO4 , filtered, and concentrated in vacuo to give 5-(fluoromethyl-d)-2-(2,2,2-trifluoroacetamido)pyrazolo[1 ,5-a] Ethyl pyrimidine-3-carboxylate (40 mg, 80% yield) as a yellow oil. LCMS: MS (ESI) m/z 336.1 [M+H] + .
步骤6)2-氨基-5-(氟甲基-d)吡唑并[1,5-a]嘧啶-3-羧酸Step 6) 2-Amino-5-(fluoromethyl-d)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
向5-(氟甲基)-2-(2,2,2-三氟乙酰胺)吡唑并[1,5-a]嘧啶-3-甲酸乙酯(40mg，0.12mmol)的EtOH(4mL)和H 2O(1mL)溶液中加入氢氧化钠(10mg，0.24mmol)。将混合物转移至室温，搅拌16h。混合物用1M HCl调节至pH＝6-7，用EtOAc(30mL x 3)萃取。合并有机相经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法(DCM/MeOH＝10/1)纯化，得到2-氨基-5-(氟甲基-d)吡唑并[1,5-a]嘧啶-3-羧酸(20mg，收率80％)为黄色固体。LCMS:MS(ESI)m/z 212.1[M+H] +。 To ethyl 5-(fluoromethyl)-2-(2,2,2-trifluoroacetamide)pyrazolo[1,5-a]pyrimidine-3-carboxylate (40mg, 0.12mmol) in EtOH (4mL ) and H2O (1 mL) was added sodium hydroxide (10 mg, 0.24 mmol). The mixture was transferred to room temperature and stirred for 16h. The mixture was adjusted to pH=6-7 with 1M HCl, extracted with EtOAc (30 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=10/1) to obtain 2-amino-5-(fluoromethyl-d)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (20 mg, Yield 80%) as a yellow solid. LCMS: MS (ESI) m/z 212.1 [M+H] + .
步骤7)2-氨基-5-(氟甲基-d)-N-((S)-1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 7) 2-amino-5-(fluoromethyl-d)-N-((S)-1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 -Oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向(S)-3-(1-氨基乙基)-8-((1-甲基-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(20mg，0.05mmol)的DCM(15mL)溶液中加入2-氨基-5-(氟甲基-d)吡唑并[1,5-a]嘧啶-3-羧酸(14mg，0.06mmol)、HOAt(11mg，0.08mmol)、EDCI(13mg，0.08mmol)和DIEA(21mg，0.16mmol)。混合物升温至40℃，搅拌16h。冷却至室温后，将混合物用DCM(50mL)稀释，并用盐水(30mL x 2)洗。分离的有机层经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法(DCM/MeOH＝15/1)纯化，得到2-氨基-5-(氟甲基-d)-N-((S)-1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(0.8mg，2.6％收率)为白色固体。LCMS:MS(ESI)m/z 562.0[M+H] +。 1H NMR(400MHz,CD 3OD)δ8.67(d,J＝7.0Hz,1H),7.77(s,1H),7.59(s,1H),7.58-7.48(m,4H),7.47-7.39(m,3H),7.35(d,J＝8.8Hz,1H),7.01(d,J＝7.0Hz,1H),6.80(s,1H),5.39(d,J＝2.3Hz,1H),4.67(d,J＝6.9Hz,1H),3.79(s,3H),1.38(d,J＝6.8Hz,3H)。 To (S)-3-(1-aminoethyl)-8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2-phenylisoquinoline-1(2H)- To a solution of ketone (20 mg, 0.05 mmol) in DCM (15 mL) was added 2-amino-5-(fluoromethyl-d)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (14 mg, 0.06 mmol) , HOAt (11 mg, 0.08 mmol), EDCI (13 mg, 0.08 mmol) and DIEA (21 mg, 0.16 mmol). The mixture was warmed to 40 °C and stirred for 16 h. After cooling to room temperature, the mixture was diluted with DCM (50 mL), and washed with brine (30 mL x 2). The separated organic layer was dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=15/1) to give 2-amino-5-(fluoromethyl-d)-N-((S)-1-(8-((1-methyl -1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a ] Pyrimidine-3-carboxamide (0.8 mg, 2.6% yield) as a white solid. LCMS: MS (ESI) m/z 562.0 [M+H] + . 1 H NMR (400MHz, CD 3 OD) δ8.67 (d, J = 7.0Hz, 1H), 7.77 (s, 1H), 7.59 (s, 1H), 7.58-7.48 (m, 4H), 7.47-7.39 (m,3H),7.35(d,J=8.8Hz,1H),7.01(d,J=7.0Hz,1H),6.80(s,1H),5.39(d,J=2.3Hz,1H),4.67 (d, J = 6.9Hz, 1H), 3.79 (s, 3H), 1.38 (d, J = 6.8Hz, 3H).
实施例11(S)-2-氨基-N-(1-(2-环丙基-8-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-2-基)乙炔基)-1-氧代-1,2-二氢异喹啉-3-基)乙基)-5-甲基吡唑并[1,5-a]嘧啶-3-甲酰胺Example 11 (S)-2-amino-N-(1-(2-cyclopropyl-8-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2- Base) ethynyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)ethyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000070
Figure PCTCN2022121567-appb-000070
步骤1)2-氯-N-环丙基-6-甲基苯甲酰胺Step 1) 2-Chloro-N-cyclopropyl-6-methylbenzamide
在0℃下，向2-氯-6-甲基苯甲酸(1.0g，5.9mmol)的DCM(50mL)和DMF(40mg)溶液中滴加草酰氯(970mg，7.67mmol)。将混合物在0℃下继续搅拌2h，减压浓缩。向环丙胺(340mg，5.9mmol)和TEA(1.79g，17.7mmol)的DCM(50mL)溶液中加入上述酰氯的DCM(10mL)溶液，混合物在室温下搅拌5小时。将混合物用H 2O(30mL)稀释，用DCM(50mL x 3)萃取。合并的有机相用盐水(40mL x 2)洗，经Na 2SO 4干燥，减压浓缩。残余物经柱色谱法(PE/EA＝3/1)纯化，得到2-氯-N-环丙基-6-甲基苯甲酰胺(1.2g，88％收率)为黄色固体。MS(ESI):210.01[M+H] +。 To a solution of 2-chloro-6-methylbenzoic acid (1.0 g, 5.9 mmol) in DCM (50 mL) and DMF (40 mg) was added oxalyl chloride (970 mg, 7.67 mmol) dropwise at 0°C. The mixture was continued to be stirred at 0 °C for 2 h, concentrated under reduced pressure. To a solution of cyclopropylamine (340 mg, 5.9 mmol) and TEA (1.79 g, 17.7 mmol) in DCM (50 mL) was added a solution of the above acid chloride in DCM (10 mL), and the mixture was stirred at room temperature for 5 hours. The mixture was diluted with H 2 O (30 mL), extracted with DCM (50 mL x 3). The combined organic phases were washed with brine (40 mL x 2), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA=3/1) to give 2-chloro-N-cyclopropyl-6-methylbenzamide (1.2 g, 88% yield) as a yellow solid. MS (ESI): 210.01 [M+H] + .
步骤2)(S)-(4-(3-氯-2-(环丙基氨基甲酰基)苯基)-3-氧代丁-2-基)氨基甲酸叔丁酯Step 2) Tert-butyl (S)-(4-(3-chloro-2-(cyclopropylcarbamoyl)phenyl)-3-oxobutan-2-yl)carbamate
在氮气气氛中，于-30℃下，向2-氯-N-环丙基-6-甲基苯甲酰胺(300mg，1.43mmol)的THF(20mL) 溶液中加入n-BuLi(1.6mL，3.72mmol)。将混合物保温搅拌1小时。于氮气气氛中，在-30℃下，向(S)-(1-(甲氧基(甲基)氨基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(498mg，2.15mmol)的THF(20mL)溶液中缓慢滴加i-PrMgCl(3.5mL，4.58mmol)溶液，混合物搅拌1小时。然后将该溶液缓慢加至上述混合物中，转移至室温，搅拌3h。混合物用NH 4Cl(30mL)的水溶液淬灭，并用EtOAc(50mL x 3)萃取。合并的有机相用盐水(10mL x 2)洗，经Na 2SO 4干燥，减压浓缩。残余物经柱色谱法(PE/EA＝3/1)纯化，得到(S)-(4-(3-氯-2-(环丙基氨基甲酰基)苯基)-3-氧代丁-2-基)氨基甲酸叔丁酯(463mg，收率81％)为黄色固体。MS(ESI):402.9[M+Na] +。 To a solution of 2-chloro-N-cyclopropyl-6-methylbenzamide (300 mg, 1.43 mmol) in THF (20 mL) was added n-BuLi (1.6 mL, 3.72 mmol). The mixture was stirred at temperature for 1 hour. In a nitrogen atmosphere, at -30 ° C, to (S)-(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate tert-butyl ester (498mg, 2.15mmol ) in THF (20 mL) was slowly added dropwise with i-PrMgCl (3.5 mL, 4.58 mmol), and the mixture was stirred for 1 hour. This solution was then slowly added to the above mixture, transferred to room temperature, and stirred for 3 h. The mixture was quenched with an aqueous solution of NH4Cl (30 mL), and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (10 mL x 2), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA=3/1) to give (S)-(4-(3-chloro-2-(cyclopropylcarbamoyl)phenyl)-3-oxobutane- 2-yl)tert-butyl carbamate (463 mg, yield 81%) was a yellow solid. MS (ESI): 402.9 [M+Na] + .
步骤3)(S)-3-(1-氨基乙基)-8-氯-2-环丙基异喹啉-1(2H)-酮Step 3) (S)-3-(1-aminoethyl)-8-chloro-2-cyclopropylisoquinolin-1(2H)-one
向(S)-(4-(3-氯-2-(环丙基氨基甲酰基)苯基)-3-氧代丁-2-基)氨基甲酸叔丁酯(200mg，0.53mmol)的MeOH(10mL)溶液中加入HCl(2.0mL)，混合物升温至80℃搅拌2h。冷却至室温后，将混合物减压浓缩。残余物用H 2O(10mL)稀释，用NaHCO 3水溶液将pH值调节至7-8，然后用DCM(30mL x 3)萃取，合并有机相用盐水(30mL x 2)洗，经Na 2SO 4干燥，减压浓缩。残余物经柱色谱法纯化(DCM/MeOH＝95/5)，得到(S)-3-(1-氨基乙基)-8-氯-2-环丙基异喹啉-1(2H)-酮(130mg，85％收率)为黄色固体。MS(ESI):263.0[M+H] +。 To (S)-tert-butyl(4-(3-chloro-2-(cyclopropylcarbamoyl)phenyl)-3-oxobut-2-yl)carbamate (200 mg, 0.53 mmol) in MeOH (10 mL) was added HCl (2.0 mL), and the mixture was warmed to 80° C. and stirred for 2 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with H 2 O (10 mL), adjusted to pH 7-8 with aqueous NaHCO 3 , then extracted with DCM (30 mL x 3), the combined organic phases were washed with brine (30 mL x 2), washed over Na 2 SO 4 was dried and concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=95/5) to give (S)-3-(1-aminoethyl)-8-chloro-2-cyclopropylisoquinoline-1(2H)- The ketone (130 mg, 85% yield) was a yellow solid. MS (ESI): 263.0 [M+H] + .
步骤4)(S)-3-(1-氨基乙基)-2-环丙基-8-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-2-基)乙炔基)异喹啉-1(2H)-酮Step 4) (S)-3-(1-aminoethyl)-2-cyclopropyl-8-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2- Base) ethynyl) isoquinolin-1(2H)-one
在氮气气氛下，向(S)-3-(1-氨基乙基)-8-氯-2-环丙基异喹啉-1(2H)-酮(50mg，0.19mmol)和2-乙炔基-5,6-二氢-4H-吡咯并[1,2-b]吡唑(33mg，0.25mmol)的MeCN(20mL)溶液中加入X-Phos(45mg，0.09mmol),Pd 2(dba) 3(43mg，0.05mmol)和K 3PO 4(121mg，0.57mmol)，混合物升温至80℃，搅拌5h。冷却至室温后，将混合物真空浓缩。残余物用EtOAc(100mL)稀释，用盐水(50mL×2)洗。分液，有机相经Na  2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝91/9)纯化，得到(S)-3-(1-氨基乙基)-2-环丙基-8-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-2-基)乙炔基)异喹啉-1(2H)-酮(33mg，45.3％收率)为黄色油状物。MS(ESI):359.0[M+H] +。 Under nitrogen atmosphere, (S)-3-(1-aminoethyl)-8-chloro-2-cyclopropylisoquinolin-1(2H)-one (50mg, 0.19mmol) and 2-ethynyl -5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (33mg, 0.25mmol) in MeCN (20mL) solution was added X-Phos (45mg, 0.09mmol), Pd 2 (dba) 3 (43mg, 0.05mmol) and K 3 PO 4 (121mg, 0.57mmol), the mixture was heated to 80°C and stirred for 5h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (100 mL), washed with brine (50 mL×2). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=91/9) to give (S)-3-(1-aminoethyl)-2-cyclopropyl-8-((5,6-dihydro-4H -pyrrolo[1,2-b]pyrazol-2-yl)ethynyl)isoquinolin-1(2H)-one (33 mg, 45.3% yield) as a yellow oil. MS (ESI): 359.0 [M+H] + .
步骤5)(S)-2-氨基-N-(1-(2-环丙基-8-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-2-基)乙炔基)-1-氧代-1,2-二氢异喹啉-3-基)乙基)-5-甲基吡唑并[1,5-a]嘧啶-3-甲酰胺Step 5) (S)-2-amino-N-(1-(2-cyclopropyl-8-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2- Base) ethynyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)ethyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide
向(S)-3-(1-氨基乙基)-2-环丙基-8-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-2-基)乙炔基)异喹啉-1(2H)-酮(33mg，0.09mmol)和2-氨基-5-甲基吡唑并[1,5-a]嘧啶-3-甲酸(18mg，0.09mmol)的DCM(20mL)溶液中加入DIEA(36mg，0.28mmol)、EDCI(26mg，0.14mmol)和HOAT(19mg，0.14mmol)，混合物升温至40℃，搅拌16小时。冷却至室温后，将混合物用DCM(100mL)稀释，用盐水(40mL x 2)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经制备型HPLC(-Gemini-C18 150x 21.2mm,5um:ACN--H 2O(0.1％FA),40％-60％)纯化，得到(S)-2-氨基-N-(1-(2-环丙基-8-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-2-基)乙炔基)-1-氧代-1,2-二氢异喹啉-3-基)乙基)-5-甲基吡唑并[1,5-a]嘧啶-3-甲酰胺(5.5mg，11％收率)为白色固体。MS(ESI):532.9[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.79(d,J＝6.9Hz,1H),8.22(d,J＝7.2Hz,1H),7.60-7.53(m,3H),6.91(d,J＝6.9Hz,1H),6.62(s,1H),6.38(s,2H),6.26(s,1H),5.84-5.78(m,1H),4.22(t,J＝6.6Hz,1H),4.14-4.08(m,2H),3.01(s,1H),2.90-2.84(m,2H),2.56(s,3H),2.54(s,1H),1.58(d,J＝6.7Hz,3H),1.11-1.03(m,2H),0.91(t,J＝7.4Hz,1H),0.86-0.76(m,2H)。 To (S)-3-(1-aminoethyl)-2-cyclopropyl-8-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl) Ethynyl)isoquinolin-1(2H)-one (33mg, 0.09mmol) and 2-amino-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (18mg, 0.09mmol) DIEA (36mg, 0.28mmol), EDCI (26mg, 0.14mmol) and HOAT (19mg, 0.14mmol) were added to DCM (20mL) solution, and the mixture was heated to 40°C and stirred for 16 hours. After cooling to room temperature, the mixture was diluted with DCM (100 mL), washed with brine (40 mL x 2). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (-Gemini-C18 150x 21.2mm, 5um:ACN-- H2O (0.1%FA), 40%-60%) to give (S)-2-amino-N-(1 -(2-cyclopropyl-8-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)ethynyl)-1-oxo-1,2- Dihydroisoquinolin-3-yl)ethyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide (5.5 mg, 11% yield) was a white solid. MS (ESI): 532.9 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.79(d, J=6.9Hz, 1H), 8.22(d, J=7.2Hz, 1H), 7.60-7.53(m, 3H), 6.91(d, J=6.9Hz,1H),6.62(s,1H),6.38(s,2H),6.26(s,1H),5.84-5.78(m,1H),4.22(t,J=6.6Hz,1H), 4.14-4.08(m,2H),3.01(s,1H),2.90-2.84(m,2H),2.56(s,3H),2.54(s,1H),1.58(d,J＝6.7Hz,3H) , 1.11-1.03 (m, 2H), 0.91 (t, J=7.4Hz, 1H), 0.86-0.76 (m, 2H).
实施例12(S)-2-氨基-N-(1-(8-((6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑-2-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 12 (S)-2-amino-N-(1-(8-((6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2 -yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000071
Figure PCTCN2022121567-appb-000071
步骤1)4-氯-N'-(二苯基亚甲基)丁酰肼Step 1) 4-Chloro-N'-(diphenylmethylene)butanohydrazide
在0℃下，向(二苯基亚甲基)肼(3.9g，20mmol)和吡啶(1.58g，20mmol)的DCM(60mL)溶液中滴加4-氯丁酰氯(2.8g，20mmol)，将混合物在室温下搅拌16小时。混合物用DCM(200mL)稀释，并用盐水(100mL x 2)洗，分液，有机相经无水Na 2SO 4干燥，过滤，浓缩，得到4-氯-N'-(二苯基亚甲基)丁酰肼(6.8g，粗品)为白色固体。MS(ESI):301.0[M+H] +。 To a solution of (diphenylmethylene)hydrazine (3.9 g, 20 mmol) and pyridine (1.58 g, 20 mmol) in DCM (60 mL) was added dropwise 4-chlorobutyryl chloride (2.8 g, 20 mmol) at 0 °C, The mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM (200 mL), washed with brine (100 mL x 2), separated, the organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated to give 4-chloro-N'-(diphenylmethylene ) butyrhydrazide (6.8 g, crude product) was a white solid. MS (ESI): 301.0 [M+H] + .
步骤2)1-((二苯基亚甲基)氨基)吡咯烷-2-酮Step 2) 1-((Diphenylmethylene)amino)pyrrolidin-2-one
在0℃下，向4-氯-N'-(二苯基亚甲基)丁酰肼(905mg，3.0mmol)的THF(20mL)溶液中缓慢加入NaH(73mg，3.0mmol)，混合物在室温下搅拌16小时。混合物用EtOAc(60mL)稀释，用盐水(30mL×2)洗，分液，有机层经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(PE/EA＝2/1)纯化，得到1-((二苯基亚甲基)氨基)吡咯烷-2-酮(768mg，92％收率)为白色固体。MS(ESI):265.0[M+H] +。 At 0°C, NaH (73 mg, 3.0 mmol) was slowly added to a solution of 4-chloro-N'-(diphenylmethylene) butanohydrazide (905 mg, 3.0 mmol) in THF (20 mL), and the mixture was Stirring was continued for 16 hours. The mixture was diluted with EtOAc (60 mL), washed with brine (30 mL×2), separated, and the organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=2/1) to give 1-((diphenylmethylene)amino)pyrrolidin-2-one (768 mg, 92% yield) as a white solid. MS (ESI): 265.0 [M+H] + .
步骤3)1-氨基吡咯烷-2-酮盐酸盐Step 3) 1-aminopyrrolidin-2-one hydrochloride
向1-((二苯基亚甲基)氨基)吡咯烷-2-酮(503mg，1.9mmol)的H 2O(10mL)溶液中加入2N HCl(5mL)，转移至室温，搅拌16h。混合物用DCM(30mL)萃取，分液，将水相真空浓缩，得到1-氨基吡咯烷-2-酮盐酸盐(330mg，粗品)为白色固体。MS(ESI):101.1[M+H] +。 To a solution of 1-((diphenylmethylene)amino)pyrrolidin-2-one (503 mg, 1.9 mmol) in H 2 O (10 mL) was added 2N HCl (5 mL), transferred to room temperature, and stirred for 16 h. The mixture was extracted with DCM (30 mL), the layers were separated, and the aqueous phase was concentrated in vacuo to give 1-aminopyrrolidin-2-one hydrochloride (330 mg, crude) as a white solid. MS (ESI): 101.1 [M+H] + .
步骤4)2-亚氨基-2-((2-氧代吡咯烷-1-基)氨基)乙酸乙酯Step 4) Ethyl 2-imino-2-((2-oxopyrrolidin-1-yl)amino)acetate
向1-氨基吡咯烷-2-酮盐酸盐(330mg，2.4mmol)的EtOH(20mL)溶液中加入2-乙氧基-2-亚氨基乙酸乙酯(351mg，2.4mmol)，混合物在40℃下搅拌16小时。将混合物真空浓缩，得到2-亚氨基-2-((2-氧代吡咯烷-1-基)氨基)乙酸乙酯(450mg，粗品)为白色固体。MS(ESI):200.0[M+H] +。 To a solution of 1-aminopyrrolidin-2-one hydrochloride (330 mg, 2.4 mmol) in EtOH (20 mL) was added ethyl 2-ethoxy-2-iminoacetate (351 mg, 2.4 mmol), and the mixture was stirred at 40 Stir at °C for 16 hours. The mixture was concentrated in vacuo to afford ethyl 2-imino-2-((2-oxopyrrolidin-1-yl)amino)acetate (450 mg, crude) as a white solid. MS (ESI): 200.0 [M+H] + .
步骤5)6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑-2-甲酸乙酯Step 5) Ethyl 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate
将2-亚氨基-2-((2-氧代吡咯烷-1-基)氨基)乙酸乙酯(450mg，2.3mmol)和POCl 3(10mL)的混合物在110℃搅拌16h。冷却至室温后，真空浓缩。残余物用EtOAc(50mL)和碳酸氢钠水溶液(30mL)稀释。分液，有机相用盐水(30mL x 2)洗，经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝20/1)纯化，得到6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑-2-甲酸乙酯(100mg，25％收率)为白色固体。MS(ESI):182.0[M+H] +。 A mixture of ethyl 2-imino-2-((2-oxopyrrolidin-1-yl)amino)acetate (450 mg, 2.3 mmol) and POCl 3 (10 mL) was stirred at 110° C. for 16 h. After cooling to room temperature, it was concentrated in vacuo. The residue was diluted with EtOAc (50 mL) and aqueous sodium bicarbonate (30 mL). The layers were separated, and the organic phase was washed with brine (30 mL x 2), dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=20/1) to give ethyl 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate The ester (100 mg, 25% yield) was a white solid. MS (ESI): 182.0 [M+H] + .
步骤6)(6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑-2-基)甲醇Step 6) (6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanol
在0℃下，将LiAlH 4(21mg，0.55mmol)缓慢加至6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑-2-甲酸乙酯(100mg，0.55mmol)的THF(10mL)溶液中，混合物在室温下搅拌16h，用10％NaOH(0.1mL)和水(5mL)淬灭，然后用EtOAc(30mL x 2)萃取，合并的有机相用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，真空浓缩，得到(6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑-2-基)甲醇(80mg，粗品)为白色固体。MS(ESI):140.1[M+H] +。 LiAlH 4 (21 mg, 0.55 mmol) was slowly added to ethyl 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carboxylate at 0°C (100 mg, 0.55 mmol) in THF (10 mL), the mixture was stirred at room temperature for 16 h, quenched with 10% NaOH (0.1 mL) and water (5 mL), then extracted with EtOAc (30 mL x 2), the combined organic The phase was washed with brine (50 mL), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo to give (6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]tri Azol-2-yl)methanol (80 mg, crude) was a white solid. MS (ESI): 140.1 [M+H] + .
步骤7)6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑-2-甲醛Step 7) 6,7-Dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbaldehyde
向(6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑-2-基)甲醇(50mg，0.36mmol)的CHCl 3(20mL)溶液中加入MnO 2(157mg，1.8mmol)，混合物升温至70℃，搅拌16h。冷却至室温后，过滤，滤液真空浓缩，得到6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑-2-甲醛(40mg，粗品)为白色固体。MS(ESI):138.0[M+H] +。 To a solution of (6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)methanol (50 mg, 0.36 mmol) in CHCl 3 (20 mL) was added MnO 2 (157mg, 1.8mmol), the mixture was warmed up to 70°C and stirred for 16h. After cooling to room temperature, it was filtered and the filtrate was concentrated in vacuo to give 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbaldehyde (40mg, crude product) as white solid. MS (ESI): 138.0 [M+H] + .
步骤8)2-乙炔基-6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑Step 8) 2-ethynyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole
向6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑-2-甲醛(40mg，0.30mmol)的MeOH(10mL)溶液中加入(1-重氮-2-氧代丙基)膦酸二甲酯(85mg，0.44mmol)和K 2CO 3(81mg，0.58mmol)，将混合物在室温下搅拌16小时，真空浓缩。残余物用EtOAc(50mL)稀释，用盐水(30mL×2)洗。有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱(DCM/MeOH＝20/1)纯化，得到2-乙炔基-6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑(18mg，45％收率)为白色固体。MS(ESI):156.1[M+Na] +。 To a solution of 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2-carbaldehyde (40 mg, 0.30 mmol) in MeOH (10 mL) was added (1-fold Nitro-2-oxopropyl)phosphonic acid dimethyl ester (85 mg, 0.44 mmol) and K 2 CO 3 (81 mg, 0.58 mmol), the mixture was stirred at room temperature for 16 hours and concentrated in vacuo. The residue was diluted with EtOAc (50 mL), washed with brine (30 mL×2). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=20/1) to give 2-ethynyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole ( 18 mg, 45% yield) as a white solid. MS (ESI): 156.1 [M+Na] + .
步骤9)(S)-3-(1-氨基乙基)-8-((6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑-2-基)乙炔基)-2-苯基异喹啉-1(2H)-酮Step 9) (S)-3-(1-aminoethyl)-8-((6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2 -yl)ethynyl)-2-phenylisoquinolin-1(2H)-one
在氮气气氛下，向(S)-3-(1-氨基乙基)-8-氯-2-苯基异喹啉-1(2H)-酮(40mg，0.13mmol)的CH 3CN(20mL)溶液中加入2-乙炔基-6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑(27mg，0.20mmol)、K 3PO 4(57mg，0.27mmol)、Pd 2(dba) 3(31mg，0.03mmol)和X-Phos(32mg，0.07mmol)，混合物升温至80℃，搅拌16h。冷却至室温后，真空浓缩。将残余物用EtOAc(50mL)稀释，用盐水(30mL x 3)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝20/1)纯化，得到(S)-3-(1-氨基乙基)-8-((6,7-二氢-5H-吡咯并 [1,2-b][1,2,4]三唑-2-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(25mg，45％收率)为白色固体。MS(ESI):395.9[M+H] +。 To (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (40 mg, 0.13 mmol) in CH 3 CN (20 mL) under nitrogen atmosphere ) solution was added 2-ethynyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (27mg, 0.20mmol), K 3 PO 4 (57mg, 0.27mmol), Pd 2 (dba) 3 (31mg, 0.03mmol) and X-Phos (32mg, 0.07mmol), the mixture was heated to 80°C and stirred for 16h. After cooling to room temperature, it was concentrated in vacuo. The residue was diluted with EtOAc (50 mL), washed with brine (30 mL x 3). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=20/1) to give (S)-3-(1-aminoethyl)-8-((6,7-dihydro-5H-pyrrolo[1, 2-b][1,2,4]Triazol-2-yl)ethynyl)-2-phenylisoquinolin-1(2H)-one (25 mg, 45% yield) as a white solid. MS (ESI): 395.9 [M+H] + .
步骤10)(S)-2-氨基-N-(1-(8-((6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑-2-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 10) (S)-2-amino-N-(1-(8-((6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole-2 -yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向(S)-3-(1-氨基乙基)-8-((6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑-2-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(25mg，0.06mmol)的DCM(20mL)溶液中加入2-氨基吡唑并[1,5-a]嘧啶-3-羧酸(12mg，0.06mmol)、EDCI(19mg，0.09mmol)、HOAT(13mg，0.09mmol)和DIEA(25mg，0.19mmol)，混合物升温至40℃，搅拌16h。冷却至室温后，将混合物用DCM(40mL)稀释，用盐水(30mL x 2)洗。分液，有机相经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经制备型HPLC(Gemini-C18 150x 21.2mm，5um,ACN--H2O(0.1％FA)20％-30％)纯化，得到(S)-2-氨基-N-(1-(8-((6,7-二氢-5H-吡咯并[1,2-b][1,2,4]三唑-2-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(16.1mg，收率45％)为白色固体。MS(ESI):555.9[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.93(dd,J＝6.7,1.6Hz,1H),8.56(dd,J＝4.5,1.6Hz,1H),8.02(d,J＝6.7Hz,1H),7.75-7.66(m,3H),7.58-7.46(m,4H),7.41-7.37(m,1H),7.02(dd,J＝6.7,4.5Hz,1H),6.78(s,1H),6.44(s,2H),4.60-4.55(m,1H),4.11-4.06(m,2H),2.85-2.80(m,2H),2.65-2.58(m,2H),1.36(d,J＝6.8Hz,3H)。 To (S)-3-(1-aminoethyl)-8-((6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl )ethynyl)-2-phenylisoquinolin-1(2H)-one (25 mg, 0.06 mmol) in DCM (20 mL) was added 2-aminopyrazolo[1,5-a]pyrimidine-3- Carboxylic acid (12mg, 0.06mmol), EDCI (19mg, 0.09mmol), HOAT (13mg, 0.09mmol) and DIEA (25mg, 0.19mmol), the mixture was heated to 40°C and stirred for 16h. After cooling to room temperature, the mixture was diluted with DCM (40 mL), washed with brine (30 mL x 2). The layers were separated, and the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Gemini-C18 150x 21.2mm, 5um, ACN--H2O(0.1%FA) 20%-30%) to give (S)-2-amino-N-(1-(8- ((6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-2-yl)ethynyl)-1-oxo-2-phenyl-1, 2-Dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (16.1 mg, yield 45%) was a white solid. MS (ESI): 555.9 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.93(dd, J=6.7,1.6Hz,1H),8.56(dd,J=4.5,1.6Hz,1H),8.02(d,J=6.7Hz, 1H),7.75-7.66(m,3H),7.58-7.46(m,4H),7.41-7.37(m,1H),7.02(dd,J＝6.7,4.5Hz,1H),6.78(s,1H) ,6.44(s,2H),4.60-4.55(m,1H),4.11-4.06(m,2H),2.85-2.80(m,2H),2.65-2.58(m,2H),1.36(d,J= 6.8Hz, 3H).
实施例13(S)-2-氨基-N-(1-(8-((2,3-二氢吡唑并[5,1-b]噁唑-6-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 13 (S)-2-amino-N-(1-(8-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)ethynyl)-1- Oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000072
Figure PCTCN2022121567-appb-000072
步骤1)2,3-二氢吡唑并[5,1-b]噁唑-6-甲酸乙酯Step 1) Ethyl 2,3-dihydropyrazolo[5,1-b]oxazole-6-carboxylate
向5-羟基-1H-吡唑-3-甲酸乙酯(2g，12.8mmol)的CH 3CN(10mL)溶液中加入1,2-二溴乙烷(6g，32mmol)和碳酸钾(2.5g，17.68mmol)，将混合物在65℃搅拌36h。冷却至室温后，将混合物真空浓缩。残余物用EtOAc(200mL)稀释，分别用水(100mL)和盐水(100mL)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝10/1)纯化，得到2,3-二氢吡唑并[5,1-b]噁唑-6-甲酸乙酯(1.8g，77％收率)为白色固体。LCMS:MS(ESI)m/z 183.1[M+H] +。 To a solution of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (2 g, 12.8 mmol) in CH3CN (10 mL) was added 1,2-dibromoethane (6 g, 32 mmol) and potassium carbonate (2.5 g , 17.68mmol), the mixture was stirred at 65°C for 36h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (200 mL), washed with water (100 mL) and brine (100 mL), respectively. The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=10/1) to obtain ethyl 2,3-dihydropyrazolo[5,1-b]oxazole-6-carboxylate (1.8 g, 77% yield ) is a white solid. LCMS: MS (ESI) m/z 183.1 [M+H] + .
步骤2)(2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲醇Step 2) (2,3-Dihydropyrazolo[5,1-b]oxazol-6-yl)methanol
在0℃下，向2,3-二氢吡唑并[5,1-b]噁唑-6-甲酸乙酯(100mg，0.55mmol)的THF(10mL)溶液中加入LiAlH 4(31mg，0.82mmol)，混合物转移至室温搅拌2h。混合物用10％的NaOH(0.3mL)和水(1mL)淬灭，然后用乙酸乙酯(100mL)稀释，分液，用盐水(50mL)洗，有机相经无水Na 2SO 4干燥，过滤，浓缩，得到(2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲醇(60mg，收率78％)为白色固体。LCMS:MS(ESI)m/z141.2[M+H] +。 To a solution of ethyl 2,3-dihydropyrazolo[5,1-b]oxazole-6-carboxylate (100 mg, 0.55 mmol) in THF (10 mL) was added LiAlH 4 (31 mg, 0.82 mmol), the mixture was transferred to room temperature and stirred for 2h. The mixture was quenched with 10% NaOH (0.3 mL) and water (1 mL), then diluted with ethyl acetate (100 mL), separated, washed with brine (50 mL), and the organic phase was dried over anhydrous Na2SO4 and filtered , concentrated to give (2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methanol (60 mg, yield 78%) as a white solid. LCMS: MS (ESI) m/z 141.2 [M+H] + .
步骤3)2,3-二氢吡唑并[5,1-b]噁唑-6-甲醛Step 3) 2,3-Dihydropyrazolo[5,1-b]oxazole-6-carbaldehyde
向(2,3-二氢吡唑并[5,1-b]噁唑-6-基)甲醇(50mg，0.36mmol)的氯仿(10mL)溶液中加入MnO 2(155mg，1.78mmol)，混合物升温至62℃，搅拌36h。冷却至室温后，过滤。滤饼用DCM(10mL)洗两次，滤液真空浓缩，得到2,3-二氢吡唑并[5,1-b]噁唑-6-甲醛(40mg，81％收率)为白色固体。LCMS:MS(ESI)m/z 139.1[M+H] +。 To a solution of (2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)methanol (50 mg, 0.36 mmol) in chloroform (10 mL) was added MnO 2 (155 mg, 1.78 mmol), and the mixture Raise the temperature to 62°C and stir for 36h. After cooling to room temperature, filter. The filter cake was washed twice with DCM (10 mL), and the filtrate was concentrated in vacuo to give 2,3-dihydropyrazolo[5,1-b]oxazole-6-carbaldehyde (40 mg, 81% yield) as a white solid. LCMS: MS (ESI) m/z 139.1 [M+H] + .
步骤4)6-乙炔基-2,3-二氢吡唑并[5,1-b]噁唑Step 4) 6-ethynyl-2,3-dihydropyrazolo[5,1-b]oxazole
向2,3-二氢吡唑并[5,1-b]噁唑-6-甲醛(40mg，0.29mmol)的MeOH(10mL)溶液中加入(1-重氮-2-氧代丙基)膦酸二甲酯(83mg，0.43mmol)和碳酸钾(81mg，0.58mmol)，混合物于室温下搅拌16h。混合物减压浓缩。将残余物溶于EtOAc(100mL)，用盐水(50mL)洗。分液，有机相经无水Na 2SO 4干燥，过滤，真空浓 缩，得到6-乙炔基-2,3-二氢吡唑并[5,1-b]噁唑(20mg，收率52％)为黄色固体。LCMS:MS(ESI)m/z 135.2[M+H] +。 To a solution of 2,3-dihydropyrazolo[5,1-b]oxazole-6-carbaldehyde (40 mg, 0.29 mmol) in MeOH (10 mL) was added (1-diazo-2-oxopropyl) Dimethyl phosphonate (83mg, 0.43mmol) and potassium carbonate (81mg, 0.58mmol), the mixture was stirred at room temperature for 16h. The mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with brine (50 mL). Separation, the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to obtain 6-ethynyl-2,3-dihydropyrazolo[5,1-b]oxazole (20mg, yield 52% ) is a yellow solid. LCMS: MS (ESI) m/z 135.2 [M+H] + .
步骤5)(S)-3-(1-氨基乙基)-8-((2,3-二氢吡唑并[5,1-b]噁唑-6-基)乙炔基)-2-苯基异喹啉-1(2H)-酮Step 5) (S)-3-(1-aminoethyl)-8-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)ethynyl)-2- Phenylisoquinolin-1(2H)-one
向(S)-3-(1-氨基乙基)-8-氯-2-苯基异喹啉-1(2H)-酮(30mg，0.1mmol)的CH 3CN(10mL)溶液中加入6-乙炔基-2,3-二氢吡唑并[5,1-b]噁唑(20mg，0.15mmol)、Pd 2(dba) 3(9mg，0.01mmol)、X-phos(5mg，0.01mmol)和K 3PO 4(32mg,0.15mmol)，混合物升温至80℃，搅拌4h。冷却至室温后，混合物真空浓缩。将残余物溶于DCM(50mL)，用盐水(30mL)洗。分液，有机相经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱(DCM/MeOH＝10/1)纯化，得到(S)-3-(1-氨基乙基)-8-((2,3-二氢吡唑并[5,1-b]噁唑-6-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(20mg，50％收率)为黄色固体。LCMS:MS(ESI)m/z 396.8[M+H] +。 To a solution of (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (30 mg, 0.1 mmol) in CH 3 CN (10 mL) was added 6 -Ethynyl-2,3-dihydropyrazolo[5,1-b]oxazole (20mg, 0.15mmol), Pd 2 (dba) 3 (9mg, 0.01mmol), X-phos (5mg, 0.01mmol ) and K 3 PO 4 (32mg, 0.15mmol), the mixture was heated to 80°C and stirred for 4h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was dissolved in DCM (50 mL), washed with brine (30 mL). The layers were separated, and the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=10/1) to obtain (S)-3-(1-aminoethyl)-8-((2,3-dihydropyrazolo[5,1-b ]oxazol-6-yl)ethynyl)-2-phenylisoquinolin-1(2H)-one (20 mg, 50% yield) as a yellow solid. LCMS: MS (ESI) m/z 396.8 [M+H] + .
步骤6)(S)-2-氨基-N-(1-(8-((2,3-二氢吡唑并[5,1-b]噁唑-6-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 6) (S)-2-amino-N-(1-(8-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)ethynyl)-1- Oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向(S)-3-(1-氨基乙基)-8-((2,3-二氢吡唑并[5,1-b]噁唑-6-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(20mg，0.05mmol)和2-氨基吡唑并[1,5-a]嘧啶-3-羧酸(11mg，0.06mmol)的DCM(20mL)溶液中加入HOAt(10mg，0.07mmol)、EDCI(15mg，0.07mmol)和DIEA(20mg，0.15mmol)，混合物升温至40℃，搅拌16h。冷却至室温后，混合物用DCM(50mL)稀释，并用盐水(30mL)洗。分液，有机相经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱(DCM:MeOH＝10:1)纯化，得到(S)-2-氨基-N-(1-(8-((2,3-二氢吡唑并[5,1-b]噁唑-6-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(9.5mg，33％收率)为白色固体。LCMS:MS(ESI)m/z 556.9[M+H] +。 1H NMR(400MHz,CD 3OD)δ8.69(dd,J＝6.8,1.6Hz,1H),8.50(dd,J＝4.5,1.6Hz,1H),8.21(d,J＝7.0Hz,1H),7.63(dd,J＝14.4,8.2,6.9,2.0Hz,4H),7.53-7.38(m,4H),6.96(dd,J＝6.8,4.5Hz,1H),6.88(s,1H),5.68(s,1H),5.10-5.02(m,2H),4.76(q,J＝6.8Hz,1H),4.32-4.24(m,2H),1.46(d,J＝6.8Hz,3H)。 To (S)-3-(1-aminoethyl)-8-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)ethynyl)-2-phenyl To a solution of isoquinolin-1(2H)-one (20mg, 0.05mmol) and 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (11mg, 0.06mmol) in DCM (20mL) was added HOAt (10mg, 0.07mmol), EDCI (15mg, 0.07mmol) and DIEA (20mg, 0.15mmol), the mixture was warmed to 40°C and stirred for 16h. After cooling to room temperature, the mixture was diluted with DCM (50 mL), and washed with brine (30 mL). The layers were separated, and the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography (DCM:MeOH=10:1) to obtain (S)-2-amino-N-(1-(8-((2,3-dihydropyrazolo[5,1-b ]oxazol-6-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine -3-Carboxamide (9.5 mg, 33% yield) was a white solid. LCMS: MS (ESI) m/z 556.9 [M+H] + . 1 H NMR (400MHz, CD 3 OD) δ8.69 (dd, J = 6.8, 1.6Hz, 1H), 8.50 (dd, J = 4.5, 1.6Hz, 1H), 8.21 (d, J = 7.0Hz, 1H ),7.63(dd,J=14.4,8.2,6.9,2.0Hz,4H),7.53-7.38(m,4H),6.96(dd,J=6.8,4.5Hz,1H),6.88(s,1H), 5.68 (s, 1H), 5.10-5.02 (m, 2H), 4.76 (q, J=6.8Hz, 1H), 4.32-4.24 (m, 2H), 1.46 (d, J=6.8Hz, 3H).
实施例14(S)-2-氨基-N-(1-(8-((2,3-二氢吡唑并[5,1-b]噁唑-7-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 14 (S)-2-amino-N-(1-(8-((2,3-dihydropyrazolo[5,1-b]oxazol-7-yl)ethynyl)-1- Oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000073
Figure PCTCN2022121567-appb-000073
步骤1)2,3-二氢吡唑并[5,1-b]噁唑Step 1) 2,3-Dihydropyrazolo[5,1-b]oxazole
向1,2-二氢吡唑-3-酮(2.0g，0.02mol)的CH 3CN(20mL)溶液中加入1,2-二溴乙烷(19g，0.09mol)和K 2CO 3(6.58g，0.047mol)，混合物升温至80℃，搅拌16h。冷却至室温后，过滤，滤液真空浓缩。残余物用DCM(100mL)稀释，用盐水(50mL)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱分离(DCM/MeOH＝20/1)纯化，得到2,3-二氢吡唑并[5,1-b]噁唑(1.0g，34.45％收率)为黄色油状。MS(ESI):111.2[M+H] +。 To a solution of 1,2-dihydropyrazol-3-one (2.0 g, 0.02 mol) in CH 3 CN (20 mL) was added 1,2-dibromoethane (19 g, 0.09 mol) and K 2 CO 3 ( 6.58g, 0.047mol), the mixture was heated to 80°C and stirred for 16h. After cooling to room temperature, it was filtered and the filtrate was concentrated in vacuo. The residue was diluted with DCM (100 mL), washed with brine (50 mL). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=20/1) to obtain 2,3-dihydropyrazolo[5,1-b]oxazole (1.0 g, 34.45% yield) as a yellow oil. MS (ESI): 111.2 [M+H] + .
步骤2)7-溴-2,3-二氢吡唑并[5,1-b]噁唑Step 2) 7-Bromo-2,3-dihydropyrazolo[5,1-b]oxazole
向2,3-二氢吡唑并[5,1-b]噁唑(450mg，4.09mmol)的CH 3CN(10mL)溶液中加入NBS(873mg，4.9mmol)，混合物搅拌5小时。混合物用水(20mL)稀释，然后用DCM(30mL×3)萃取。合并的有机相用盐水(30mL x 2)洗，经Na 2SO 4干燥，真空浓缩。残余物经柱色谱分离(PE:EtOAc＝2:1)纯化，得到7-溴-2,3-二氢吡唑并[5,1-b]噁唑(500mg，51.79％收率)为白色固体。MS(ESI):189.1[M+H] +。 To a solution of 2,3-dihydropyrazolo[5,1-b]oxazole (450 mg, 4.09 mmol) in CH 3 CN (10 mL) was added NBS (873 mg, 4.9 mmol), and the mixture was stirred for 5 hours. The mixture was diluted with water (20 mL), then extracted with DCM (30 mL×3). The combined organic phases were washed with brine (30 mL x 2), dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=2:1) to give 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole (500 mg, 51.79% yield) as white solid. MS (ESI): 189.1 [M+H] + .
步骤3)7-((三异丙基甲硅烷基)乙炔基)-2,3-二氢吡唑并[5,1-b]噁唑Step 3) 7-((triisopropylsilyl)ethynyl)-2,3-dihydropyrazolo[5,1-b]oxazole
在氮气气氛下，向7-溴-2,3-二氢吡唑并[5,1-b]噁唑(600mg，3.17mmol)的CH 3CN(20mL)溶液中加入乙炔基三异丙基硅烷(695mg，3.8mmol)、磷酸三钾(2g,9.5mmol)、三(二亚苄基丙酮)二钯(581mg，0.64mmol)和X-phos(302mg，0.64mmol)，混合物升温至80℃，搅拌16小时。冷却至室温后，真空 浓缩。将残余物用DCM(60mL)稀释，并用盐水(30mL x 2)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(PE:EtOAc＝2:1)纯化，得到7-((三异丙基甲硅烷基)乙炔基)-2,3-二氢吡唑并[5,1-b]噁唑(300mg，收率26.03％)为黄色油状物。MS(ESI):291.1[M+H] +。 To a solution of 7-bromo-2,3-dihydropyrazolo[5,1-b]oxazole (600 mg, 3.17 mmol) in CH3CN (20 mL) was added ethynyltriisopropyl Silane (695mg, 3.8mmol), tripotassium phosphate (2g, 9.5mmol), tris(dibenzylideneacetone)dipalladium (581mg, 0.64mmol) and X-phos (302mg, 0.64mmol), the mixture was warmed to 80°C , stirred for 16 hours. After cooling to room temperature, it was concentrated in vacuo. The residue was diluted with DCM (60 mL) and washed with brine (30 mL x 2). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=2:1) to give 7-((triisopropylsilyl)ethynyl)-2,3-dihydropyrazolo[5,1-b] Oxazole (300 mg, yield 26.03%) was a yellow oil. MS (ESI): 291.1 [M+H] + .
步骤4)7-乙炔基-2,3-二氢吡唑并[5,1-b]噁唑Step 4) 7-ethynyl-2,3-dihydropyrazolo[5,1-b]oxazole
向7-((三异丙基甲硅烷基)乙炔基)-2,3-二氢吡唑并[5,1-b]噁唑(300mg，1.03mmol)的THF(20mL)溶液中加入TBAF(1mL，1M THF溶液)，混合物搅拌2h。混合物用EtOAc(30mL)稀释，用盐水(20mL×2)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM:MeOH＝10:1)纯化，得到7-乙炔基-2,3-二氢吡唑并[5,1-b]噁唑(60mg,34.64％收率)为无色油状物。MS(ESI):135.1[M+H] +。 To a solution of 7-((triisopropylsilyl)ethynyl)-2,3-dihydropyrazolo[5,1-b]oxazole (300 mg, 1.03 mmol) in THF (20 mL) was added TBAF (1 mL, 1M in THF), and the mixture was stirred for 2 h. The mixture was diluted with EtOAc (30 mL), washed with brine (20 mL×2). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM:MeOH=10:1) to give 7-ethynyl-2,3-dihydropyrazolo[5,1-b]oxazole (60 mg, 34.64% yield) as Colorless oil. MS (ESI): 135.1 [M+H] + .
步骤5)(S)-3-(1-氨基乙基)-8-((2,3-二氢吡唑并[5,1-b]噁唑-7-基)乙炔基)-2-苯基异喹啉-1(2H)-酮Step 5) (S)-3-(1-aminoethyl)-8-((2,3-dihydropyrazolo[5,1-b]oxazol-7-yl)ethynyl)-2- Phenylisoquinolin-1(2H)-one
在氮气气氛下，向(S)-3-(1-氨基乙基)-8-氯-2-苯基异喹啉-1(2H)-酮(30mg，0.1mmol)和7-乙炔基-2,3-二氢吡唑并[5,1-b]噁唑(20mg，0.15mmol)的乙腈(5mL)溶液中加入三(二亚苄基丙酮)二钯(9mg，0.01mmol)、X-phos(5mg，0.01mmol)和K 3PO 4(43mg，0.2mmol)，混合物升温至80℃，搅拌16h。冷却至室温后，真空浓缩。残余物用DCM(30mL)稀释，并用盐水(30mL)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝10:1)纯化，得到(S)-3-(1-氨基乙基)-8-((2,3-二氢吡唑并[5,1-b]噁唑-7-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(23mg，60.0％收率)为黄色固体。MS(ESI):398.0[M+H] +。 Under nitrogen atmosphere, (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (30 mg, 0.1 mmol) and 7-ethynyl- 2,3-Dihydropyrazolo[5,1-b]oxazole (20mg, 0.15mmol) in acetonitrile (5mL) was added tris(dibenzylideneacetone)dipalladium (9mg, 0.01mmol), X -phos (5mg, 0.01mmol) and K 3 PO 4 (43mg, 0.2mmol), the mixture was heated to 80°C and stirred for 16h. After cooling to room temperature, it was concentrated in vacuo. The residue was diluted with DCM (30 mL) and washed with brine (30 mL). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=10:1) to obtain (S)-3-(1-aminoethyl)-8-((2,3-dihydropyrazolo[5,1- b] oxazol-7-yl)ethynyl)-2-phenylisoquinolin-1(2H)-one (23 mg, 60.0% yield) as a yellow solid. MS (ESI): 398.0 [M+H] + .
步骤6)(S)-2-氨基-N-(1-(8-((2,3-二氢吡唑并[5,1-b]噁唑-7-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 6) (S)-2-amino-N-(1-(8-((2,3-dihydropyrazolo[5,1-b]oxazol-7-yl)ethynyl)-1- Oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向(S)-3-(1-氨基乙基)-8-((2,3-二氢吡唑并[5,1-b]噁唑-7-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(20mg，0.05mmol)和2-氨基吡唑并[1,5-a]嘧啶-3-羧酸(11mg，0.06mmol)的DCM(5mL)溶液中加入HOAT(10mg，0.075mmol)、EDCI(14mg，0.075mmol)和DIEA(13mg，0.1mmol)，混合物升温至40℃，搅拌6h。冷却至室温后，混合物用DCM(40mL)稀释，并用盐水(20mL)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱分离(DCM/MeOH＝10/1)纯化，得到(S)-2-氨基-N-(1-(8-((2,3-二氢吡唑并[5,1-b]噁唑-7-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(5.3mg，18.49％收率)为黄色固体。MS(ESI):557.0[M+H] +。 1H NMR(400MHz,)δ8.89(dd,J＝6.7,1.6Hz,1H),8.51(dd,J＝4.5,1.6Hz,1H),7.96(d,J＝6.7Hz,1H),7.61-7.51(m,3H),7.49-7.43(m,3H),7.43-7.39(m,2H),7.35-7.30(m,1H),6.98(dd,J＝6.7,4.5Hz,1H),6.68(s,1H),6.40(s,2H),5.14-5.07(m,2H),4.53-4.48(m,1H),4.29-4.22(m,2H),1.30(t,J＝3.4Hz,3H)。 To (S)-3-(1-aminoethyl)-8-((2,3-dihydropyrazolo[5,1-b]oxazol-7-yl)ethynyl)-2-phenyl To a solution of isoquinolin-1(2H)-one (20 mg, 0.05 mmol) and 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (11 mg, 0.06 mmol) in DCM (5 mL) was added HOAT (10mg, 0.075mmol), EDCI (14mg, 0.075mmol) and DIEA (13mg, 0.1mmol), the mixture was heated to 40°C and stirred for 6h. After cooling to room temperature, the mixture was diluted with DCM (40 mL), and washed with brine (20 mL). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=10/1) to obtain (S)-2-amino-N-(1-(8-((2,3-dihydropyrazolo[5,1- b] oxazol-7-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a] Pyrimidine-3-carboxamide (5.3 mg, 18.49% yield) was a yellow solid. MS (ESI): 557.0 [M+H] + . 1 H NMR (400MHz,) δ8.89 (dd, J = 6.7, 1.6Hz, 1H), 8.51 (dd, J = 4.5, 1.6Hz, 1H), 7.96 (d, J = 6.7Hz, 1H), 7.61 -7.51(m,3H),7.49-7.43(m,3H),7.43-7.39(m,2H),7.35-7.30(m,1H),6.98(dd,J＝6.7,4.5Hz,1H),6.68 (s,1H),6.40(s,2H),5.14-5.07(m,2H),4.53-4.48(m,1H),4.29-4.22(m,2H),1.30(t,J＝3.4Hz,3H ).
实施例15(S)-2-氨基-N-(1-(5-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)乙炔基)-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 15 (S)-2-amino-N-(1-(5-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)ethynyl)- 4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000074
Figure PCTCN2022121567-appb-000074
步骤1)(S)-2-(1-氨基乙基)-5-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)乙炔基)-3-苯基喹唑啉-4(3H)-酮Step 1) (S)-2-(1-aminoethyl)-5-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)ethynyl)- 3-Phenylquinazolin-4(3H)-one
在氮气气氛下，向(S)-2-(1-氨基乙基)-5-溴-3-苯基喹唑啉-4(3H)-酮(50mg，0.15mmol)和3-乙炔基-5,6-二氢-4H-吡咯并[1,2-b]吡唑(29mg，0.22mmol)的CH 3CN(20mL)溶液中加入K 3PO 4(62mg，0.3mmol)、Pd 2(dba) 3(34mg，0.03mmol)和X-Phos(35mg，0.08mmol)，混合物升温至80℃搅拌16h。冷却至室温后，真空浓缩。残余物用EtOAc(50mL)稀释，用盐水(30mL x 3)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法分离(DCM/MeOH＝20/1)纯化，得到(S)-2-(1-氨基乙基)-5-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)乙炔基)-3-苯基喹唑啉-4(3H)-酮(20mg，35％收率)为白色固体。MS(ESI):395.9[M+H] +。 Under nitrogen atmosphere, (S)-2-(1-aminoethyl)-5-bromo-3-phenylquinazolin-4(3H)-one (50mg, 0.15mmol) and 3-ethynyl- K 3 PO 4 (62 mg, 0.3 mmol), Pd 2 ( dba) 3 (34mg, 0.03mmol) and X-Phos (35mg, 0.08mmol), the mixture was heated to 80°C and stirred for 16h. After cooling to room temperature, it was concentrated in vacuo. The residue was diluted with EtOAc (50 mL), washed with brine (30 mL x 3). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=20/1) to obtain (S)-2-(1-aminoethyl)-5-((5,6-dihydro-4H-pyrrolo[1 ,2-b]pyrazol-3-yl)ethynyl)-3-phenylquinazolin-4(3H)-one (20 mg, 35% yield) as a white solid. MS (ESI): 395.9 [M+H] + .
步骤2)(S)-2-氨基-N-(1-(5-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)乙炔基)-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 2) (S)-2-amino-N-(1-(5-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)ethynyl)- 4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向(S)-2-(1-氨基乙基)-5-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)乙炔基)-3-苯基喹唑啉-4(3H)-酮(20mg，0.05mmol)和2-氨基吡唑并[1,5-a]嘧啶-3-羧酸(10mg，0.05mmol)的DCM(20mL)溶液中加入EDCI(15mg，0.07mmol))、HOAT(11mg，0.07mmol)和DIEA(20mg，0.15mmol)，混合物升温至40℃，搅拌16h。混合物用DCM(50mL)稀释，并用盐水(30mL x 2)洗，分液，有机相经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经制备型-HPLC(Gemini-C18 150x 21.2mm，5um,ACN--H 2O(0.1％FA),梯度20％-30％)纯化，得到(S)-2-氨基-N-(1-(5-((5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)乙炔基)-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(6.2mg，收率23％)为白色固体。MS(ESI):555.8[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.92(dd,J＝6.7,1.7Hz,1H),8.72(d,J＝7.4Hz,1H),8.65(dd,J＝4.5,1.6Hz,1H),7.79(d,J＝7.6Hz,1H),7.69(dd,J＝8.1,1.2Hz,1H),7.65-7.58(m,6H),7.53(d,J＝7.5Hz,1H),7.04-7.01(m,1H),6.49-6.42(m,2H),4.74(t,J＝7.0Hz,1H),4.08(t,J＝7.2Hz,2H),2.88(t,J＝7.2Hz,2H),2.57-2.54(m,2H),1.32(d,J＝6.6Hz,3H)。 To (S)-2-(1-aminoethyl)-5-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)ethynyl)-3- Phenylquinazolin-4(3H)-one (20 mg, 0.05 mmol) and 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (10 mg, 0.05 mmol) in DCM (20 mL) EDCI (15mg, 0.07mmol)), HOAT (11mg, 0.07mmol) and DIEA (20mg, 0.15mmol) were added, and the mixture was warmed to 40°C and stirred for 16h. The mixture was diluted with DCM (50 mL), washed with brine (30 mL x 2), separated, and the organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by preparative-HPLC (Gemini-C18 150x 21.2mm, 5um, ACN--H 2 O (0.1% FA), gradient 20%-30%) to obtain (S)-2-amino-N-( 1-(5-((5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)ethynyl)-4-oxo-3-phenyl-3,4- Dihydroquinazolin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (6.2 mg, yield 23%) was a white solid. MS (ESI): 555.8 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.92(dd, J=6.7,1.7Hz,1H),8.72(d,J=7.4Hz,1H),8.65(dd,J=4.5,1.6Hz, 1H), 7.79(d, J=7.6Hz, 1H), 7.69(dd, J=8.1, 1.2Hz, 1H), 7.65-7.58(m, 6H), 7.53(d, J=7.5Hz, 1H), 7.04-7.01(m,1H),6.49-6.42(m,2H),4.74(t,J=7.0Hz,1H),4.08(t,J=7.2Hz,2H),2.88(t,J=7.2Hz , 2H), 2.57-2.54 (m, 2H), 1.32 (d, J=6.6Hz, 3H).
实施例16(S)-2-氨基-N-(1-(7-氟-8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基))乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 16 (S)-2-amino-N-(1-(7-fluoro-8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2- Phenyl-1,2-dihydroisoquinolin-3-yl))ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000075
Figure PCTCN2022121567-appb-000075
步骤1)(S)-3-(1-氨基乙基)-7-氟-8-((1-甲基-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮Step 1) (S)-3-(1-aminoethyl)-7-fluoro-8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2-phenylisoquinoline -1(2H)-one
在氮气气氛下，向(S)-3-(1-氨基乙基)-8-氯-7-氟-2-苯基异喹啉-1(2H)-酮(304mg，0.96mmol)和4-乙炔基-1-甲基-1H-吡唑(153mg，1.44mmol)的MeCN(50mL)溶液中加入X-Phos(183mg，0.38mmol)、Pd 2(dba) 3(176mg，0.20mmol)和K 3PO 4(611mg，2.88mmol)，混合物升温至80℃，搅拌5h。冷却至室温后，真空浓缩。将残余物用EtOAc(130mL)稀释，用盐水(60mL x 2)洗，分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝91/9)纯化，得到(S)-3-(1-氨基乙基)-7-氟-8-((1-甲基-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(210mg，53.8％收率)为黄色油状物。MS(ESI):386.9[M+H] +。 Under nitrogen atmosphere, (S)-3-(1-aminoethyl)-8-chloro-7-fluoro-2-phenylisoquinolin-1(2H)-one (304mg, 0.96mmol) and 4 -Ethynyl-1-methyl-1H-pyrazole (153 mg, 1.44 mmol) in MeCN (50 mL) was added X-Phos (183 mg, 0.38 mmol), Pd 2 (dba) 3 (176 mg, 0.20 mmol) and K 3 PO 4 (611mg, 2.88mmol), the mixture was warmed up to 80°C and stirred for 5h. After cooling to room temperature, it was concentrated in vacuo. The residue was diluted with EtOAc (130 mL), washed with brine (60 mL x 2), separated, and the organic phase was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=91/9) to give (S)-3-(1-aminoethyl)-7-fluoro-8-((1-methyl-1H-pyrazole- 4-yl)ethynyl)-2-phenylisoquinolin-1(2H)-one (210 mg, 53.8% yield) as a yellow oil. MS (ESI): 386.9 [M+H] + .
步骤2)(S)-2-氨基-N-(1-(7-氟-8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基))乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 2) (S)-2-amino-N-(1-(7-fluoro-8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2- Phenyl-1,2-dihydroisoquinolin-3-yl))ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向(S)-3-(1-氨基乙基)-7-氟-8-((1-甲基-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(120mg，0.31mmol)和2-氨基-5-甲基吡唑并[1,5-a]嘧啶-3-羧酸(61mg，0.34mmol)的DCM(20mL)溶液中加入DIEA(160mg，1.24mmol)、EDCI(89mg，0.47mmol)和HOAT(63mg，0.47mmol)，混合物升温至40℃，搅拌16h。冷却至室温后，将混合物用DCM(100mL)稀释，并用盐水(60mL x 2)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经制备型HPLC(-Xbridge-C18 150x 19mm,5um,ACN-H 2O(0.05％NH 4OH),40％-45％)纯化，得到(S)-2-氨基-N-(1-(7-氟-8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基))乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(55mg，32.4％收率)为白色固体。MS(ESI):546.8[M+H] +。 1H NMR(400MHz,DMSO)δ8.93(dd,J＝6.7,1.6Hz,1H),8.55(dd,J＝4.5,1.6Hz,1H),8.05(s,1H),7.99(d,J＝6.6Hz,1H),7.75-7.65(m,2H),7.63-7.55(m,2H),7.53-7.46(m,3H),7.41-7.36(m,1H),7.02(dd,J＝6.7,4.5Hz,1H),6.79(s,1H),6.43(s,2H),4.54(t,J＝6.7Hz,1H),3.82(s,3H),1.35(d,J＝6.8Hz,3H)。 To (S)-3-(1-aminoethyl)-7-fluoro-8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2-phenylisoquinoline-1 (2H)-Kone (120 mg, 0.31 mmol) and 2-amino-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (61 mg, 0.34 mmol) in DCM (20 mL) were added DIEA (160mg, 1.24mmol), EDCI (89mg, 0.47mmol) and HOAT (63mg, 0.47mmol), the mixture was warmed to 40°C and stirred for 16h. After cooling to room temperature, the mixture was diluted with DCM (100 mL), and washed with brine (60 mL x 2). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (-Xbridge-C18 150x 19mm, 5um, ACN-H 2 O (0.05% NH 4 OH), 40%-45%) to give (S)-2-amino-N-(1 -(7-fluoro-8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinoline-3- yl))ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (55 mg, 32.4% yield) as a white solid. MS (ESI): 546.8 [M+H] + . 1 H NMR (400MHz, DMSO) δ8.93 (dd, J = 6.7, 1.6 Hz, 1H), 8.55 (dd, J = 4.5, 1.6 Hz, 1H), 8.05 (s, 1H), 7.99 (d, J =6.6Hz,1H),7.75-7.65(m,2H),7.63-7.55(m,2H),7.53-7.46(m,3H),7.41-7.36(m,1H),7.02(dd,J=6.7 ,4.5Hz,1H),6.79(s,1H),6.43(s,2H),4.54(t,J＝6.7Hz,1H),3.82(s,3H),1.35(d,J＝6.8Hz,3H ).
实施例17(S)-2-氨基-6-氟-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 17 (S)-2-amino-6-fluoro-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2- Phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000076
Figure PCTCN2022121567-appb-000076
步骤1)(E)-2-氟代-3-羟基丙烯醛Step 1) (E)-2-fluoro-3-hydroxyacrolein
向四甲氧基丙烷(2.0g，0.01mol)的水(10mL)溶液中加PTSA(2.1g，0.01mol)，混合物于室温搅拌2h。向混合物中加入选择性氟试剂(Selectflour，5.9g，0.02mol)，继续搅拌16h。所得溶液直接用于下一步骤。MS(ESI):91.1[M+H] +。 To a solution of tetramethoxypropane (2.0 g, 0.01 mol) in water (10 mL) was added PTSA (2.1 g, 0.01 mol), and the mixture was stirred at room temperature for 2 h. A selective fluorine reagent (Selectflour, 5.9 g, 0.02 mol) was added to the mixture, and stirring was continued for 16 h. The resulting solution was used directly in the next step. MS (ESI): 91.1 [M+H] + .
步骤2)2-氨基-6-氟吡唑并[1,5-a]嘧啶-3-甲酸乙酯Step 2) Ethyl 2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate
向(E)-2-氟代-3-羟基丙烯醛(2mL)的溶液中缓慢加入DMSO(10mL)。混合物搅拌10分钟后，加入3,5-二氨基-1H-吡唑-4-甲酸乙酯(283mg，1.67mmol)。混合物升温至85℃，搅拌4h。冷却至室温后，混合物用EtOAc(30mL x 3)萃取。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝20:1)纯化，得到2-氨基-6-氟吡唑并[1,5-a]嘧啶-3-甲酸乙酯(100mg，40.3％收率)为黄色固体。MS(ESI):225.0[M+H]+。 To a solution of (E)-2-fluoro-3-hydroxypropenal (2 mL) was slowly added DMSO (10 mL). After the mixture was stirred for 10 minutes, ethyl 3,5-diamino-1H-pyrazole-4-carboxylate (283 mg, 1.67 mmol) was added. The mixture was warmed to 85 °C and stirred for 4 h. After cooling to room temperature, the mixture was extracted with EtOAc (30 mL x 3). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=20:1) to give ethyl 2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate (100 mg, 40.3% yield) It is a yellow solid. MS (ESI): 225.0 [M+H]+.
步骤3)2-氨基-6-氟吡唑并[1,5-a]嘧啶-3-羧酸Step 3) 2-Amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylic acid
向2-氨基-6-氟吡唑并[1,5-a]嘧啶-3-甲酸乙酯(100mg，0.45mmol)的MeOH(5mL)溶液中加入NaOH(89mg，2.23mmol)的H 2O(2mL)溶液，混合物升温至40℃，搅拌8h。冷却至室温后，真空浓缩。混合物用1N HCl酸化至pH＝5-6，过滤，滤饼用水(5mL)洗。滤液真空浓缩，得到2-氨基-6-氟吡唑并[1,5-a]嘧啶-3-羧酸(60mg，54.67％收率)为黄色固体。MS(ESI):197.1[M+H] +。 To a solution of ethyl 2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate (100 mg, 0.45 mmol) in MeOH (5 mL) was added NaOH (89 mg, 2.23 mmol) in H2O (2 mL) solution, the mixture was warmed to 40°C and stirred for 8h. After cooling to room temperature, it was concentrated in vacuo. The mixture was acidified with 1N HCl to pH=5-6, filtered, and the filter cake was washed with water (5 mL). The filtrate was concentrated in vacuo to afford 2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (60 mg, 54.67% yield) as a yellow solid. MS (ESI): 197.1 [M+H] + .
步骤4)(S)-2-氨基-6-氟-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 4) (S)-2-amino-6-fluoro-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2- Phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向2-氨基-6-氟吡唑并[1,5-a]嘧啶-3-甲酸(42mg，0.21mmol)和(S)-3-(1-氨基乙基)-8-((1-甲基-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(95mg，0.26mmol)的DCM(5mL)溶液中加入HOAT(5mg，0.32mmol)、EDCI(62mg，0.32mmol)和DIEA(55mg，0.43mmol)，混合物升温至40℃，搅拌16h。混合物用DCM(20mL)稀释，并用盐水(20mL)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经制备型HPLC(ACN--H 2O(0.1％FA)梯度：40％-70％)纯化，得到(S)-2-氨基-6-氟-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(16mg，14.11％收率)为黄色固体。MS(ESI):547.0[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ9.41(dd,J＝4.8,2.6Hz,1H),8.78(d,J＝2.4Hz,1H),8.00(s,1H),7.84(d,J＝6.8Hz,1H),7.68-7.55(m,5H),7.53-7.44(m,3H),7.39-7.35(m,1H),6.75(s,1H),6.50(s,2H),4.59-4.52(m,1H),3.82(s,3H),1.35(d,J＝6.8Hz,3H)。 To 2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (42 mg, 0.21 mmol) and (S)-3-(1-aminoethyl)-8-((1- To a solution of methyl-1H-pyrazol-4-yl)ethynyl)-2-phenylisoquinolin-1(2H)-one (95 mg, 0.26 mmol) in DCM (5 mL) was added HOAT (5 mg, 0.32 mmol ), EDCI (62mg, 0.32mmol) and DIEA (55mg, 0.43mmol), the mixture was heated to 40°C and stirred for 16h. The mixture was diluted with DCM (20 mL) and washed with brine (20 mL). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (ACN-- H2O (0.1% FA) gradient: 40%-70%) to give (S)-2-amino-6-fluoro-N-(1-(8-( (1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[ 1,5-a]pyrimidine-3-carboxamide (16 mg, 14.11% yield) was a yellow solid. MS (ESI): 547.0 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ9.41(dd, J=4.8, 2.6Hz, 1H), 8.78(d, J=2.4Hz, 1H), 8.00(s, 1H), 7.84(d, J＝6.8Hz,1H),7.68-7.55(m,5H),7.53-7.44(m,3H),7.39-7.35(m,1H),6.75(s,1H),6.50(s,2H),4.59 -4.52 (m, 1H), 3.82 (s, 3H), 1.35 (d, J=6.8Hz, 3H).
实施例18(S)-N-(1-(8-((1-乙酰氮杂环丁烷-3-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)-2-氨基吡唑并[1,5-a]嘧啶-3-甲酰胺Example 18 (S)-N-(1-(8-((1-acetylazetidin-3-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydro Isoquinolin-3-yl)ethyl)-2-aminopyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000077
Figure PCTCN2022121567-appb-000077
步骤1)3-乙炔基氮杂环丁烷-1-羧酸叔丁酯Step 1) tert-butyl 3-ethynylazetidine-1-carboxylate
向3-甲酰氮杂环丁烷-1-甲酸叔丁酯(200mg，1.07mmol)的MeOH(10mL)溶液中加入K 2CO 3(370mg，2.69mmol)和(1-重氮-2-氧代丙基)膦酸二甲酯(309mg，1.61mmol)，混合物转移至室温，搅拌16h。将混合物真空浓缩，用EtOAc(100mL)稀释，用盐水(40ml×2)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MEOH＝20/1)分离纯化，得到3-乙炔基氮杂环丁烷-1-羧酸叔丁酯(180mg，83％收率)为棕色油状物。MS(ESI):126.0[M-55] +。 To a solution of tert-butyl 3-formylazetidine-1-carboxylate (200 mg, 1.07 mmol) in MeOH (10 mL) was added K 2 CO 3 (370 mg, 2.69 mmol) and (1-diazo-2- Oxopropyl) dimethyl phosphonate (309mg, 1.61mmol), the mixture was transferred to room temperature and stirred for 16h. The mixture was concentrated in vacuo, diluted with EtOAc (100 mL), washed with brine (40 ml x 2). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was separated and purified by column chromatography (DCM/MEOH=20/1) to obtain tert-butyl 3-ethynylazetidine-1-carboxylate (180 mg, 83% yield) as a brown oil. MS (ESI): 126.0 [M-55] + .
步骤2)3-乙炔基氮杂环丁烷Step 2) 3-Ethynylazetidine
向3-乙炔基氮杂环丁烷-1-甲酸叔丁酯(180mg，0.99mmol)的DCM(10mL)溶液中加入TFA(5mL)，混合物于室温搅拌2h。将混合物真空浓缩，得到3-乙炔基氮杂环丁烷(100mg，99.8％收率)为棕色油状物。MS(ESI):82.1[M+H] +。 To a solution of tert-butyl 3-ethynylazetidine-1-carboxylate (180 mg, 0.99 mmol) in DCM (10 mL) was added TFA (5 mL), and the mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to afford 3-ethynylazetidine (100 mg, 99.8% yield) as a brown oil. MS (ESI): 82.1 [M+H] + .
步骤3)1-(3-乙炔基氮杂环丁烷-1-基)乙烷-1-酮Step 3) 1-(3-ethynylazetidin-1-yl)ethan-1-one
在0℃下，向3-乙炔基氮杂环丁烷(118mg，1.45mmol)和DIEA(1.8g，14.5mmol)的DCM(20mL)溶液中加入乙酰氯(228mg，2.91mmol)，混合物于室温下搅拌3小时。混合物用DCM(50mL)稀释，并用盐水(20mL x 2)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝20/1)分离纯化，得到1-(3-乙炔基氮杂环丁烷-1-基)乙烷-1-酮(150mg，75.36％收率)为黄色油状物。MS(ESI):124.1[M+H] +。 To a solution of 3-ethynylazetidine (118 mg, 1.45 mmol) and DIEA (1.8 g, 14.5 mmol) in DCM (20 mL) was added acetyl chloride (228 mg, 2.91 mmol) at 0 °C, and the mixture was Stirring was continued for 3 hours. The mixture was diluted with DCM (50 mL) and washed with brine (20 mL x 2). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was separated and purified by column chromatography (DCM/MeOH=20/1) to obtain 1-(3-ethynylazetidin-1-yl)ethan-1-one (150 mg, 75.36% yield) For the yellow oil. MS (ESI): 124.1 [M+H] + .
步骤4)(S)-8-((1-乙酰氮杂环丁烷-3-基)乙炔基)-3-(1-氨基乙基)-2-苯基异喹啉-1(2H)-酮Step 4) (S)-8-((1-acetylazetidin-3-yl)ethynyl)-3-(1-aminoethyl)-2-phenylisoquinoline-1(2H) -ketone
向(S)-3-(1-氨基乙基)-8-氯-2-苯基异喹啉-1(2H)-酮(60mg，0.20mmol)和1-(3-乙炔基氮杂环丁烷-1-基)乙烷-1-酮(37mg，0.30mmol)的MeCN(30mL)溶液中加入X-Phos(38mg，0.08mmol)、Pd 2(dba) 3(37mg，0.04mmol)和K 3PO 4(128mg，0.60mmol))，混合物升温至80℃，搅拌5h。冷却至室温后，混合物真空浓缩。将残余物用EtOAc(100mL)稀释，用盐水(50mL×2)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱分离(DCM/MeOH＝91/9)纯化，得到(S)-8-((1-乙酰氮杂环丁烷-3-基)乙炔基)-3-(1-氨基乙基)-2-苯基异喹啉-1(2H)-酮(47mg，54.6％收率)为黄色油状物。MS(ESI):386.0[M+H] +。 To (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (60mg, 0.20mmol) and 1-(3-ethynyl nitrogen heterocycle Butan-1-yl)ethan-1-one (37 mg, 0.30 mmol) in MeCN (30 mL) was added X-Phos (38 mg, 0.08 mmol), Pd 2 (dba) 3 (37 mg, 0.04 mmol) and K 3 PO 4 (128mg, 0.60mmol)), the mixture was heated to 80°C and stirred for 5h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (100 mL), washed with brine (50 mL×2). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=91/9) to obtain (S)-8-((1-acetylazetidin-3-yl)ethynyl)-3-(1-aminoethane yl)-2-phenylisoquinolin-1(2H)-one (47 mg, 54.6% yield) as a yellow oil. MS (ESI): 386.0 [M+H] + .
步骤5)(S)-N-(1-(8-((1-乙酰氮杂环丁烷-3-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)-2-氨基吡唑并[1,5-a]嘧啶-3-甲酰胺Step 5) (S)-N-(1-(8-((1-acetylazetidin-3-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydro Isoquinolin-3-yl)ethyl)-2-aminopyrazolo[1,5-a]pyrimidine-3-carboxamide
向(S)-8-((1-乙酰氮杂环丁烷-3-基)乙炔基)-3-(1-氨基乙基)-2-苯基异喹啉-1(2H)-酮和2-氨基吡唑并[1,5-a]嘧啶-3-甲酸(22mg，0.12mmol)的DCM(20mL)溶液中加入DIEA(47mg，0.37mmol)、EDCI(35mg，0.18mmol)和HOAT(25mg，0.18mmol)，混合物升温至40℃，搅拌16h。冷却至室温后，将混合物用DCM(30mL)稀释，用盐水(20mL x 2)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经制备型HPLC纯化(Gemini-C18 150x21.2mm,5um ACN--H 2O(0.1％FA)35％-50％)，得到(S)-N-(1-(8-((1-乙酰氮杂环丁烷-3-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)-2-氨基吡唑并[1,5-a]嘧啶-3-甲酰胺(13.1mg，19.7％收率)为白色固体。MS(ESI):546.0[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.93(dd,J＝6.7,1.6Hz,1H),8.55(dd,J＝4.5,1.6Hz,1H),8.00(d,J＝6.6Hz,1H),7.64(dd,J＝7.0,4.3Hz,2H),7.60-7.53(m,2H),7.53-7.48(m,2H),7.45(d,J＝7.8Hz,1H),7.37(dd,J＝5.7,3.5Hz,1H),7.02(dd,J＝6.7,4.5Hz,1H),6.74(s,1H),6.43(s,2H),4.54(q,J＝6.6Hz,1H),4.38(t,J＝8.4Hz,1H),4.15-4.08(m,2H),3.79(dd,J＝8.8,6.3Hz,1H),3.68(dd,J＝8.9,6.2Hz,1H),1.73(s,3H),1.34(d,J＝6.8Hz,3H)。 To (S)-8-((1-acetylazetidin-3-yl)ethynyl)-3-(1-aminoethyl)-2-phenylisoquinolin-1(2H)-one and 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (22 mg, 0.12 mmol) in DCM (20 mL) were added DIEA (47 mg, 0.37 mmol), EDCI (35 mg, 0.18 mmol) and HOAT (25mg, 0.18mmol), the mixture was warmed to 40°C and stirred for 16h. After cooling to room temperature, the mixture was diluted with DCM (30 mL), washed with brine (20 mL x 2). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (Gemini-C18 150x21.2mm, 5um ACN-- H2O (0.1%FA) 35%-50%) to give (S)-N-(1-(8-((1 -Acetazetidin-3-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)-2-aminopyrazolo [1,5-a]pyrimidine-3-carboxamide (13.1 mg, 19.7% yield) was a white solid. MS (ESI): 546.0 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.93(dd, J=6.7,1.6Hz,1H),8.55(dd,J=4.5,1.6Hz,1H),8.00(d,J=6.6Hz, 1H), 7.64(dd, J＝7.0, 4.3Hz, 2H), 7.60-7.53(m, 2H), 7.53-7.48(m, 2H), 7.45(d, J＝7.8Hz, 1H), 7.37(dd ,J=5.7,3.5Hz,1H),7.02(dd,J=6.7,4.5Hz,1H),6.74(s,1H),6.43(s,2H),4.54(q,J=6.6Hz,1H) ,4.38(t,J=8.4Hz,1H),4.15-4.08(m,2H),3.79(dd,J=8.8,6.3Hz,1H),3.68(dd,J=8.9,6.2Hz,1H), 1.73 (s, 3H), 1.34 (d, J=6.8Hz, 3H).
实施例19 2-氨基-N-((1S)-1-(2-(2-甲基-5-氧代氧杂环戊烷-2-基)乙炔基)-1-氧代-2-苯基异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 19 2-amino-N-((1S)-1-(2-(2-methyl-5-oxooxolane-2-yl)ethynyl)-1-oxo-2- Phenylisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000078
Figure PCTCN2022121567-appb-000078
步骤1)4-氧代-6-(三甲基甲硅烷基)己-5-炔酸甲酯Step 1) Methyl 4-oxo-6-(trimethylsilyl)hex-5-ynoate
在0℃下，向4-氯-4-氧代丁酸甲酯(100mg，0.66mmol)和三甲基(2-(三甲基甲硅烷基)乙炔基)硅烷(113mg，0.66mmol)的DCM(10mL)溶液中加入AlCl 3(133mg，0.99mmol)，混合物搅拌1小时。混合物用1N HCl(4mL)淬灭，并用DCM(50mL)稀释。混合物用盐水(30mL x 2)洗，经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法纯化(EA/PE＝1/3)，得到4-氧代-6-(三甲基甲硅烷基)己-5-炔酸甲酯(96.0mg，68.1％收率)为无色油状物。MS(ESI):213.1[M+H] +。 At 0°C, 4-chloro-4-oxobutanoic acid methyl ester (100mg, 0.66mmol) and trimethyl(2-(trimethylsilyl)ethynyl)silane (113mg, 0.66mmol) AlCl 3 (133 mg, 0.99 mmol) was added to DCM (10 mL) solution, and the mixture was stirred for 1 hour. The mixture was quenched with 1N HCl (4 mL) and diluted with DCM (50 mL). The mixture was washed with brine (30 mL x 2), dried over Na 2 SO 4 , concentrated in vacuo. The residue was purified by column chromatography (EA/PE=1/3) to give methyl 4-oxo-6-(trimethylsilyl)hex-5-ynoate (96.0 mg, 68.1% yield) It is a colorless oil. MS (ESI): 213.1 [M+H] + .
步骤2)5-甲基-5-(2-(三甲基甲硅烷基)乙炔基)氧杂环戊烷-2-酮Step 2) 5-Methyl-5-(2-(trimethylsilyl)ethynyl)oxolan-2-one
在-20℃下，向4-氧代-6-(三甲基甲硅烷基)己-5-炔酸甲酯(120mg，0.56mmol)的THF(10mL)溶液中加入MeMgCl(0.18mL，0.56mmol，3mol/L)，混合物于室温搅拌16h。混合物用NH 4Cl溶液(5mL)淬灭，用EtOAc(50mL)萃取。分液，有机相用盐水(30mL)洗，经Na 2SO 4干燥，真空浓缩，得到粗品5-甲基-5-[2-(三甲基甲硅烷基)乙炔基]氧杂环戊烷-2-酮(105mg，94.62％收率)为无色油状物。MS(ESI):143.1[M+H] +。 To a solution of methyl 4-oxo-6-(trimethylsilyl)hex-5-ynoate (120 mg, 0.56 mmol) in THF (10 mL) was added MeMgCl (0.18 mL, 0.56 mmol, 3mol/L), the mixture was stirred at room temperature for 16h. The mixture was quenched with NH4Cl solution (5 mL), extracted with EtOAc (50 mL). The layers were separated, the organic phase was washed with brine (30 mL), dried over Na2SO4 , and concentrated in vacuo to give crude 5-methyl-5-[2-(trimethylsilyl)ethynyl]oxolane -2-one (105 mg, 94.62% yield) was a colorless oil. MS (ESI): 143.1 [M+H] + .
步骤3)5-乙炔基-5-甲基氧杂环戊烷-2-酮Step 3) 5-ethynyl-5-methyloxolan-2-one
在-10℃下，向5-甲基-5-(2-(三甲基甲硅烷基)乙炔基)氧杂环戊烷-2-酮(92mg，0.47mmol)的THF(10mL)溶液中加入TBAF(0.25mL，1M)，混合物于室温搅拌1小时。混合物用EtOAc(50mL)稀释，并用盐水(30mL)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(EA/PE＝1/1)纯化，得到5-乙炔基-5-甲基氧杂环戊烷-2-酮(25mg，41.25％收率)为棕色油状物。 1H NMR(400MHz,CDCl 3)δ2.85-2.75(m,1H),2.63-2.49(m,2H),2.59(s,1H),2.23-2.15(m,1H),1.72(s,3H)。 To a solution of 5-methyl-5-(2-(trimethylsilyl)ethynyl)oxolan-2-one (92mg, 0.47mmol) in THF (10mL) at -10°C TBAF (0.25 mL, 1M) was added and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc (50 mL), and washed with brine (30 mL). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EA/PE=1/1) to give 5-ethynyl-5-methyloxolan-2-one (25 mg, 41.25% yield) as a brown oil. 1 H NMR (400MHz, CDCl 3 ) δ2.85-2.75(m,1H),2.63-2.49(m,2H),2.59(s,1H),2.23-2.15(m,1H),1.72(s,3H ).
步骤4)3-((1S)-1-氨基乙基)-8-(2-(2-甲基-5-氧代氧杂环戊烷-2-基)乙炔基)-2-苯基异喹啉-1-酮Step 4) 3-((1S)-1-aminoethyl)-8-(2-(2-methyl-5-oxooxolan-2-yl)ethynyl)-2-phenyl Isoquinolin-1-one
在氮气气氛下，向3-((1S)-1-氨基乙基)-8-氯-2-苯基异喹啉-1-酮(60mg，0.2mmol)和5-乙炔基-5-甲基氧杂环戊烷-2-酮(30mg，0.24mmol)的CH 3CN溶液中加入K 3PO 4(128mg，0.6mmol)、X-phos(38mg，0.08mmol)和Pd 2(dba) 3(37mg，0.04mmol)，混合物升温至80℃，搅拌16h。冷却至室温后，将混合物真空浓缩。残余物用EtOAc(100mL)稀释，用盐水(30mL x 2)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱(MeOH/DCM＝1/20)纯化，得到3-((1S)-1-氨基乙基)-8-(2-(2-甲基-5-氧代氧杂环戊烷-2-基)乙炔基)-2-苯基异喹啉-1-酮(37mg，74％收率)为黄色固体。MS(ESI):387.1[M+H] +。 Under nitrogen atmosphere, 3-((1S)-1-aminoethyl)-8-chloro-2-phenylisoquinolin-1-one (60 mg, 0.2 mmol) and 5-ethynyl-5-methanol K 3 PO 4 (128 mg, 0.6 mmol), X-phos (38 mg, 0.08 mmol) and Pd 2 (dba) 3 were added to a solution of oxolan-2-one (30 mg, 0.24 mmol) in CH 3 CN (37mg, 0.04mmol), the mixture was warmed up to 80°C and stirred for 16h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (100 mL), washed with brine (30 mL x 2). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (MeOH/DCM=1/20) to give 3-((1S)-1-aminoethyl)-8-(2-(2-methyl-5-oxooxolane Alk-2-yl)ethynyl)-2-phenylisoquinolin-1-one (37 mg, 74% yield) was a yellow solid. MS (ESI): 387.1 [M+H] + .
步骤5)2-氨基-N-((1S)-1-(2-(2-甲基-5-氧代氧杂环戊烷-2-基)乙炔基)-1-氧代-2-苯基异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 5) 2-amino-N-((1S)-1-(2-(2-methyl-5-oxooxolan-2-yl)ethynyl)-1-oxo-2- Phenylisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向2-氨基吡唑并[1,5-a]嘧啶-3-羧酸(25mg，0.14mmol)、HOAt(26mg，0.19mmol)、EDCI(37mg，0.19mmol)和DIEA(50mg，0.39mmol)的DCM(10mL)溶液中加入3-((1S)-1-氨基乙基)-8-(2-(1-甲基-5-氧代吡咯烷-3-基)乙炔基)-2-苯基异喹啉-1-酮(50mg，0.13mmol)，混合物升温至40℃，搅拌16h。冷却至室温后，将混合物用DCM(50mL)稀释，并用盐水(30mL x 2)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经制备型HPLC(ACN–H 2O 0.1％FA，梯度30％至60％)纯化，得到2-氨基-N-((1S)-1-(2-(2-甲基-5-氧代氧杂环戊烷-2-基)乙炔基)-1-氧代-2-苯基异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(3.1mg，4.25％收率)为白色固体。MS(ESI):547.2[M+H] +。 1H NMR(400MHz,CD 3OD)δ8.72(d,J＝6.8Hz,1H),8.53(d,J＝4.1Hz,1H),8.25(s,1H),7.66(d,J＝4.4Hz,2H),7.64(d,J＝1.7Hz,1H),7.61(d,J＝8.6Hz,1H),7.51(d,J＝7.1Hz,1H),7.48(s,1H),7.43(d,J＝8.0Hz,1H),6.99(dd,J＝6.7,4.9Hz,1H),6.90(s,1H),4.79-4.74(m,1H),2.86(d,J＝5.1Hz,1H),2.66-2.56(m,2H),2.28(dd,J＝8.8,2.8Hz,1H),1.77(s,3H),1.48(dd,J＝6.8,1.5Hz,3H)。 To 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (25mg, 0.14mmol), HOAt (26mg, 0.19mmol), EDCI (37mg, 0.19mmol) and DIEA (50mg, 0.39mmol) 3-((1S)-1-aminoethyl)-8-(2-(1-methyl-5-oxopyrrolidin-3-yl)ethynyl)-2- Phenylisoquinolin-1-one (50mg, 0.13mmol), the mixture was warmed up to 40°C and stirred for 16h. After cooling to room temperature, the mixture was diluted with DCM (50 mL), and washed with brine (30 mL x 2). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (ACN–H 2 O 0.1% FA, gradient 30% to 60%) to give 2-amino-N-((1S)-1-(2-(2-methyl-5- Oxooxolan-2-yl)ethynyl)-1-oxo-2-phenylisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3- Formamide (3.1 mg, 4.25% yield) was a white solid. MS (ESI): 547.2 [M+H] + . 1 H NMR (400MHz, CD 3 OD) δ8.72(d, J=6.8Hz, 1H), 8.53(d, J=4.1Hz, 1H), 8.25(s, 1H), 7.66(d, J=4.4 Hz, 2H), 7.64(d, J=1.7Hz, 1H), 7.61(d, J=8.6Hz, 1H), 7.51(d, J=7.1Hz, 1H), 7.48(s, 1H), 7.43( d,J=8.0Hz,1H),6.99(dd,J=6.7,4.9Hz,1H),6.90(s,1H),4.79-4.74(m,1H),2.86(d,J=5.1Hz,1H ), 2.66-2.56 (m, 2H), 2.28 (dd, J=8.8, 2.8Hz, 1H), 1.77 (s, 3H), 1.48 (dd, J=6.8, 1.5Hz, 3H).
实施例20(S)-2-氨基-N-(1-(8-((6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 20 (S)-2-amino-N-(1-(8-((6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)ethynyl)-1 -Oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000079
Figure PCTCN2022121567-appb-000079
步骤1)6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-甲醛Step 1) 6,7-Dihydro-5H-pyrrolo[1,2-a]imidazole-3-carbaldehyde
在-78℃下，向6,7-二氢-5H-吡咯并[1,2-a]咪唑(200mg，1.85mmol)的THF(10mL)溶液中加入n-BuLi(0.88mL，2.22mmol)，混合物升温至-5℃，搅拌1小时。将混合物冷却至-75℃，加入N,N-二甲基甲酰胺(202mg，2.77mmol)，升温至20℃，搅拌2小时。冷却至0-5℃，反应用饱和NH 4Cl水溶液(40mL)淬灭，用EtOAc(60mL×2)萃取。合并的有机层用盐水(50mL x 2)洗，经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱(DCM/MeOH＝20/1)纯化，得到6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-甲醛(200mg，收率79％)为黄色油状物。LCMS:MS(ESI)m/z 137.0[M+H] +。 To a solution of 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (200 mg, 1.85 mmol) in THF (10 mL) was added n-BuLi (0.88 mL, 2.22 mmol) at -78 °C , the mixture was warmed to -5°C and stirred for 1 hour. The mixture was cooled to -75°C, N,N-dimethylformamide (202 mg, 2.77 mmol) was added, the temperature was raised to 20°C, and stirred for 2 hours. Cooled to 0-5°C, the reaction was quenched with saturated aqueous NH 4 Cl (40 mL), extracted with EtOAc (60 mL×2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=20/1) to obtain 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carbaldehyde (200 mg, yield 79%) as yellow Oil. LCMS: MS (ESI) m/z 137.0 [M+H] + .
步骤2)3-乙炔基-6,7-二氢-5H-吡咯并[1,2-a]咪唑Step 2) 3-ethynyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole
向6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-甲醛(200mg，1.47mmol)的MeOH(10mL)溶液中加入(1-重氮-2-氧代丙基)膦酸二甲酯(423mg，2.2mmol)和碳酸钾(412mg，2.94mmol)，混合物于室温搅拌16h。将混合物真空浓缩，残余物用EtOAc(100mL)稀释，并用盐水(50mL)洗。分液，有机相经无水Na 2SO 4干燥，过滤，真空浓缩，得到3-乙炔基-6,7-二氢-5H-吡咯并[1,2-a]咪唑(130mg，67％收率)为黄色固体。LCMS:MS(ESI)m/z 133.1[M+H] +。 To a solution of 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carbaldehyde (200 mg, 1.47 mmol) in MeOH (10 mL) was added (1-diazo-2-oxopropyl ) dimethyl phosphonate (423mg, 2.2mmol) and potassium carbonate (412mg, 2.94mmol), the mixture was stirred at room temperature for 16h. The mixture was concentrated in vacuo, the residue was diluted with EtOAc (100 mL), and washed with brine (50 mL). The liquid was separated, and the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to obtain 3-ethynyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (130 mg, 67% yield rate) as a yellow solid. LCMS: MS (ESI) m/z 133.1 [M+H] + .
步骤3)(S)-3-(1-氨基乙基)-8-((6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)乙炔基)-2-苯基异喹啉-1(2H)-酮Step 3) (S)-3-(1-aminoethyl)-8-((6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)ethynyl)-2 -Phenylisoquinolin-1(2H)-one
向(S)-3-(1-氨基乙基)-8-氯-2-苯基异喹啉-1(2H)-酮(30mg，0.1mmol)和3-乙炔基-6,7-二氢-5H-吡咯并[1,2-a]咪唑(20mg，0.15mmol)的CH 3CN(10mL)溶液中加入Pd 2(dba) 3(9mg，0.01mmol)、X-phos(5mg，0.01mmol)和K 3PO 4(32mg，0.15mmol)，混合物升温至80℃，搅拌4h。冷却至室温后，真空浓缩。将残余物溶于DCM(50mL)，用盐水(30mL)洗。分液，有机相经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法纯化(DCM/MeOH＝10/1)，得到(S)-3-(1-氨基乙基)-8-((6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(40mg，99％收率)为黄色固体。LCMS:MS(ESI)m/z 395.2[M+H] +。 To (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (30mg, 0.1mmol) and 3-ethynyl-6,7-di Hydrogen-5H-pyrrolo[1,2-a]imidazole (20mg, 0.15mmol) in CH 3 CN (10mL) solution was added Pd 2 (dba) 3 (9mg, 0.01mmol), X-phos (5mg, 0.01 mmol) and K 3 PO 4 (32mg, 0.15mmol), the mixture was heated to 80°C and stirred for 4h. After cooling to room temperature, it was concentrated in vacuo. The residue was dissolved in DCM (50 mL), washed with brine (30 mL). The layers were separated, and the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=10/1) to give (S)-3-(1-aminoethyl)-8-((6,7-dihydro-5H-pyrrolo[1, 2-a] Imidazol-3-yl)ethynyl)-2-phenylisoquinolin-1(2H)-one (40 mg, 99% yield) as a yellow solid. LCMS: MS (ESI) m/z 395.2 [M+H] + .
步骤4)(S)-2-氨基-N-(1-(8-((6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 4) (S)-2-amino-N-(1-(8-((6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)ethynyl)-1 -Oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向(S)-3-(1-氨基乙基)-8-((6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(40mg，0.1mmol)和2-氨基吡唑并[1,5-a]嘧啶-3-羧酸(18mg，0.1mmol)的DCM(20mL)溶液中加入HOAt(21mg，0.15mmol)、EDCI(24mg，0.15mmol)和DIEA(39mg，0.3mmol)，混合物升温至40℃，搅拌16h。冷却至室温后，将混合物用DCM(50mL)稀释，并用盐水(30mL x 2)洗。分液，有机相经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法(DCM/MeOH＝10/1)纯化，得到(S)-2-氨基-N-(1-(8-((6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(10.1mg，18％收率)为白色固体。LCMS:MS(ESI)m/z 555.0[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.93(dd,J＝6.7,1.6Hz,1H),8.55(dd,J＝4.5,1.6Hz,1H),8.01(d,J＝6.7Hz,1H),7.70-7.64(m,2H),7.64-7.55(m,2H),7.54-7.46(m,3H),7.43-7.37(m,1H),7.21(s,1H),7.02(dd,J＝6.7,4.5Hz,1H),6.76(s,1H),6.43(s,2H),4.56(t,J＝6.7Hz,1H),3.97(t,J＝7.0Hz,2H),2.79(t,J＝7.4Hz,2H),2.55(d,J＝7.5Hz,2H),1.35(d,J＝6.8Hz,3H)。 To (S)-3-(1-aminoethyl)-8-((6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)ethynyl)-2-benzene 1-isoquinolin-1(2H)-one (40 mg, 0.1 mmol) and 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (18 mg, 0.1 mmol) in DCM (20 mL) HOAt (21mg, 0.15mmol), EDCI (24mg, 0.15mmol) and DIEA (39mg, 0.3mmol) were added, the mixture was warmed to 40°C and stirred for 16h. After cooling to room temperature, the mixture was diluted with DCM (50 mL), and washed with brine (30 mL x 2). The layers were separated, and the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=10/1) to give (S)-2-amino-N-(1-(8-((6,7-dihydro-5H-pyrrolo[1, 2-a]imidazol-3-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a ] Pyrimidine-3-carboxamide (10.1 mg, 18% yield) as a white solid. LCMS: MS (ESI) m/z 555.0 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.93(dd, J=6.7,1.6Hz,1H),8.55(dd,J=4.5,1.6Hz,1H),8.01(d,J=6.7Hz, 1H),7.70-7.64(m,2H),7.64-7.55(m,2H),7.54-7.46(m,3H),7.43-7.37(m,1H),7.21(s,1H),7.02(dd, J=6.7,4.5Hz,1H),6.76(s,1H),6.43(s,2H),4.56(t,J=6.7Hz,1H),3.97(t,J=7.0Hz,2H),2.79( t, J=7.4Hz, 2H), 2.55(d, J=7.5Hz, 2H), 1.35(d, J=6.8Hz, 3H).
实施例21(S)-2-氨基-5-(甲氧基-d3)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 21 (S)-2-amino-5-(methoxy-d3)-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 -Oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000080
Figure PCTCN2022121567-appb-000080
向(S)-3-(1-氨基乙基)-8-((1-甲基-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(30mg，0.08mmol)和2-氨基-5-(甲氧基-d3)吡唑并[1,5-a]嘧啶-3-羧酸(17mg，0.08mmol)的DCM(20mL)溶液中加入DIEA(31mg，0.24mmol)、EDCI(23mg，0.12mmol)和HOAT(17mg，0.12mmol)，混合物在40℃搅拌24小时。冷却至室温后，混合物用DCM(100mL)稀释，用盐水(40mL x 2)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经制备型HPLC(-Xbridge-C18 150x 19mm,5um,ACN-H 2O(0.1％TFA)40％-60％)纯化，得到(S)-2-氨基-5-(甲氧基-d3)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(19.1mg，41.3％收率)为白色固体。MS(ESI):561.8[M+H] +。 1H NMR(400MHz,DMSO)δ8.74-8.64(m,1H),8.01(s,1H),7.88(d,J＝6.4Hz,1H),7.68-7.44(m,8H),7.39(d,J＝6.9Hz,1H),6.79(s,1H),6.47(d,J＝7.3Hz,1H),6.14(s,2H),4.52-4.41(m,1H),3.82(s,3H),1.36(d,J＝6.6Hz,3H)。 To (S)-3-(1-aminoethyl)-8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2-phenylisoquinoline-1(2H)- Ketone (30mg, 0.08mmol) and 2-amino-5-(methoxy-d3)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (17mg, 0.08mmol) in DCM (20mL) DIEA (31 mg, 0.24 mmol), EDCI (23 mg, 0.12 mmol) and HOAT (17 mg, 0.12 mmol) were added, and the mixture was stirred at 40°C for 24 hours. After cooling to room temperature, the mixture was diluted with DCM (100 mL), washed with brine (40 mL x 2). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (-Xbridge-C18 150x 19mm, 5um, ACN-H 2 O (0.1% TFA) 40%-60%) to give (S)-2-amino-5-(methoxy- d3)-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinoline -3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (19.1 mg, 41.3% yield) was a white solid. MS (ESI): 561.8 [M+H] + . 1 H NMR (400MHz, DMSO) δ8.74-8.64(m, 1H), 8.01(s, 1H), 7.88(d, J=6.4Hz, 1H), 7.68-7.44(m, 8H), 7.39(d ,J=6.9Hz,1H),6.79(s,1H),6.47(d,J=7.3Hz,1H),6.14(s,2H),4.52-4.41(m,1H),3.82(s,3H) , 1.36 (d, J=6.6Hz, 3H).
实施例22(S)-2-氨基-N-(1-(8-((6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 22 (S)-2-amino-N-(1-(8-((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3- Base) ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000081
Figure PCTCN2022121567-appb-000081
步骤1)6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪Step 1) 6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine
向2,4-二氢-3H-吡唑-3-酮(2.5g，30mmol)的DMF(50mL)溶液中加入1,3-二溴丙烷(9.1g，45mmol)和K 2CO 3(6.2g，45mmol)，混合物升温至130℃，搅拌16h。冷却至室温后，混合物用H 2O(30mL)稀释，并用EtOAc(50mL x 3)萃取。合并有机相，用盐水(30mL x 2)洗，经无水Na 2SO 4干燥，过滤，真空浓缩，得到6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪(1.9g，粗品)为白色固体。MS(ESI):125.1[M+H] +。 To a solution of 2,4-dihydro-3H-pyrazol-3-one (2.5 g, 30 mmol) in DMF (50 mL) was added 1,3-dibromopropane (9.1 g, 45 mmol) and K 2 CO 3 (6.2 g, 45mmol), the mixture was warmed up to 130°C and stirred for 16h. After cooling to room temperature, the mixture was diluted with H 2 O (30 mL), and extracted with EtOAc (50 mL x 3). The organic phases were combined, washed with brine (30 mL x 2), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo to give 6,7-dihydro-5H-pyrazolo[5,1-b][1, 3] Oxazine (1.9 g, crude product) was a white solid. MS (ESI): 125.1 [M+H] + .
步骤2)3-溴-6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪Step 2) 3-Bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine
在20℃下，向6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪(1.9g，15.3mmol)的DCM(40mL)溶液中加入NBS(2.7g，15.3mmol)，混合物搅拌16小时。混合物用DCM(50mL)稀释，并用盐水(20mL x 2)洗。分液，有机相经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法(PE/EA＝1/1)纯化，得到3-溴-6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪(1.7g，53％收率)为白色固体。MS(ESI):202.9[M+H] +。 To a solution of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (1.9 g, 15.3 mmol) in DCM (40 mL) was added NBS (2.7 g, 15.3 mmol), and the mixture was stirred for 16 hours. The mixture was diluted with DCM (50 mL) and washed with brine (20 mL x 2). The layers were separated, and the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=1/1) to give 3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (1.7 g, 53% yield) as a white solid. MS (ESI): 202.9 [M+H] + .
步骤3)3-((三异丙基甲硅烷基)乙炔基)-6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪Step 3) 3-((triisopropylsilyl)ethynyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine
在氮气气氛下，向3-溴-6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪(780mg，3.84mmol)的CH 3CN(20mL)溶液中加入乙炔基三异丙基硅烷(1.05g，5.76mmol)、K 3PO 4(1.6g，7.68mmol)、Pd 2(dba) 3(880mg，0.96mmol)和X-Phos(916mg，1.92mmol)，混合物升温至80℃，搅拌16h。冷却至室温，真空浓缩。残余物用EtOAc(50mL)稀释，并用盐水(30mL x 3)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝20/1)纯化，得到3-((三异丙基甲硅烷基)乙炔基)-6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪(450mg，38％收率)为白色固体。MS(ESI):305.0[M+H] +。 To a solution of 3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (780 mg, 3.84 mmol) in CH 3 CN (20 mL) under nitrogen atmosphere Added ethynyltriisopropylsilane (1.05g, 5.76mmol), K 3 PO 4 (1.6g, 7.68mmol), Pd 2 (dba) 3 (880mg, 0.96mmol) and X-Phos (916mg, 1.92mmol ), the mixture was warmed to 80°C and stirred for 16h. Cool to room temperature and concentrate in vacuo. The residue was diluted with EtOAc (50 mL), and washed with brine (30 mL x 3). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=20/1) to give 3-((triisopropylsilyl)ethynyl)-6,7-dihydro-5H-pyrazolo[5,1 -b] [1,3]oxazine (450 mg, 38% yield) as a white solid. MS (ESI): 305.0 [M+H] + .
步骤4)3-乙炔基-6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪Step 4) 3-ethynyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine
向3-((三异丙基甲硅烷基)乙炔基)-6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪(450mg，1.48mmol)的THF(10mL)溶液中加入TBAF(3.0mL，1M的THF溶液)，然后将混合物在室温下搅拌1小时。混合物用EtOAc(60 mL)萃取，并用盐水(40mL×2)洗。分液，有机相经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法(PE/EA＝1/1)纯化，得到3-乙炔基-6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪(200mg，88％收率)为棕色固体。MS(ESI):149.0[M+H] +。 To 3-((triisopropylsilyl)ethynyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (450mg, 1.48mmol) To a solution in THF (10 mL) was added TBAF (3.0 mL, 1M in THF), and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with EtOAc (60 mL), and washed with brine (40 mL×2). The layers were separated, and the organic phase was dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=1/1) to give 3-ethynyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine ( 200 mg, 88% yield) as a brown solid. MS (ESI): 149.0 [M+H] + .
步骤5)(S)-3-(1-氨基乙基)-8-((6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)乙炔基)-2-苯基异喹啉-1(2H)-酮Step 5) (S)-3-(1-aminoethyl)-8-((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3- Base) ethynyl) -2-phenylisoquinolin-1(2H)-one
在氮气气氛下，向3-乙炔基-6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪(37.2mg，0.25mmol)和(S)-3-(1-氨基乙基)-8-氯-2-苯基异喹啉-1(2H)-酮(50mg，0.16mmol)的CH 3CN(20mL)溶液中加入K 3PO 4(72mg，0.34mmol)、Pd 2(dba) 3(16mg，0.01mmol)和X-Phos(16mg，0.03mmol)，混合物升温至80℃，搅拌16h。冷却至室温后，将混合物真空浓缩。残余物用EtOAc(50mL)稀释，并用盐水(30mL x 3)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝20/1)纯化，得到(S)-3-(1-氨基乙基)-8-((6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(30mg，43％收率)为白色固体。MS(ESI):410.9[M+H] +。 Under nitrogen atmosphere, 3-ethynyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (37.2mg, 0.25mmol) and (S)-3 To a solution of -(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (50 mg, 0.16 mmol) in CH 3 CN (20 mL) was added K 3 PO 4 (72 mg, 0.34mmol), Pd 2 (dba) 3 (16mg, 0.01mmol) and X-Phos (16mg, 0.03mmol), the mixture was heated to 80°C and stirred for 16h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (50 mL), and washed with brine (30 mL x 3). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=20/1) to give (S)-3-(1-aminoethyl)-8-((6,7-dihydro-5H-pyrazolo[5 ,1-b][1,3]oxazin-3-yl)ethynyl)-2-phenylisoquinolin-1(2H)-one (30 mg, 43% yield) as a white solid. MS (ESI): 410.9 [M+H] + .
步骤6)(S)-2-氨基-N-(1-(8-((6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 6) (S)-2-amino-N-(1-(8-((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3- Base) ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向(S)-3-(1-氨基乙基)-8-((6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(30mg，0.07mmol)和2-氨基吡唑并[1,5-a]嘧啶-3-羧酸(14mg，0.07mmol)的DCM(20mL)溶液中加入EDCI(22mg，0.10mmol)、HOAT(15mg，0.10mmol)和DIEA(29mg，0.21mmol)，混合物升温至40℃，搅拌16h。混合物用DCM(50mL)稀释，并用盐水(30mL x 2)洗。分液，有机相用盐水(50mL)洗，经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法(DCM/MeOH＝20/1)纯化，得到(S)-2-氨基-N-(1-(8-((6,7-二氢-5H-吡唑并[5,1-b][1,3]噁嗪-3-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(27.8mg，66％收率)为白色固体。MS(ESI):570.8[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.93(dd,J＝6.7,1.6Hz,1H),8.55(dd,J＝4.5,1.6Hz,1H),8.00(d,J＝6.8Hz,1H),7.63-7.55(m,3H),7.52-7.45(m,4H),7.41(s,1H),7.39-7.35(m,1H),7.02(dd,J＝6.7,4.5Hz,1H),6.72(s,1H),6.44(s,2H),4.57-4.52(m,1H),4.38-4.34(m,2H),4.07(t,J＝6.1Hz,2H),2.21-2.13(m,2H),1.35(d,J＝6.8Hz,3H)。 To (S)-3-(1-aminoethyl)-8-((6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl) Ethynyl)-2-phenylisoquinolin-1(2H)-one (30mg, 0.07mmol) and 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (14mg, 0.07mmol) EDCI (22mg, 0.10mmol), HOAT (15mg, 0.10mmol) and DIEA (29mg, 0.21mmol) were added to a solution of DCM (20mL), and the mixture was heated to 40°C and stirred for 16h. The mixture was diluted with DCM (50 mL) and washed with brine (30 mL x 2). The layers were separated, and the organic phase was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=20/1) to give (S)-2-amino-N-(1-(8-((6,7-dihydro-5H-pyrazolo[5 ,1-b][1,3]oxazin-3-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazole And[1,5-a]pyrimidine-3-carboxamide (27.8 mg, 66% yield) was a white solid. MS (ESI): 570.8 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.93(dd, J=6.7,1.6Hz,1H),8.55(dd,J=4.5,1.6Hz,1H),8.00(d,J=6.8Hz, 1H),7.63-7.55(m,3H),7.52-7.45(m,4H),7.41(s,1H),7.39-7.35(m,1H),7.02(dd,J＝6.7,4.5Hz,1H) ,6.72(s,1H),6.44(s,2H),4.57-4.52(m,1H),4.38-4.34(m,2H),4.07(t,J＝6.1Hz,2H),2.21-2.13(m , 2H), 1.35 (d, J=6.8Hz, 3H).
实施例23(S)-2-氨基-5-(甲氧基-d3)-N-(1-(5-((1-甲基-1H-吡唑-4-基)乙炔基)-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 23 (S)-2-amino-5-(methoxy-d3)-N-(1-(5-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4 -Oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000082
Figure PCTCN2022121567-appb-000082
步骤1)(S)-2-(1-氨基乙基)-5-((1-甲基-1H-吡唑-4-基)乙炔基)-3-苯基喹唑啉-4(3H)-酮Step 1) (S)-2-(1-aminoethyl)-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)-3-phenylquinazoline-4(3H )-ketone
在2-((1S)-1-氨基乙基)-5-溴-3-苯基喹唑啉-4-酮(200mg，0.58mmol)和4-乙炔基-1-甲基吡唑(93mg，0.87mmol)的CH 3CN(30mL)溶液中加入K 3PO 4(247mg，1.2mmol)、Pd 2(dba) 3(53mg，0.058mmol)和X-phos(55mg，0.12mmol)，混合物升温至80℃，加热5h。混合物冷却至室温，真空浓缩。将残余物用EtOAc(60mL)稀释，并用盐水(40mL x 2)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法纯化 In 2-((1S)-1-aminoethyl)-5-bromo-3-phenylquinazolin-4-one (200mg, 0.58mmol) and 4-ethynyl-1-methylpyrazole (93mg , 0.87mmol) in CH 3 CN (30mL) was added K 3 PO 4 (247mg, 1.2mmol), Pd 2 (dba) 3 (53mg, 0.058mmol) and X-phos (55mg, 0.12mmol), the mixture was heated To 80 ℃, heating 5h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with EtOAc (60 mL), and washed with brine (40 mL x 2). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography
(DCM/MeOH＝20/1)，得到(S)-2-(1-氨基乙基)-5-((1-甲基-1H-吡唑-4-基)乙炔基)-3-苯基喹唑啉-4(3H)-酮(130mg，54.5％收率)为黄色固体。MS(ESI):370.1[M+H] +。 (DCM/MeOH=20/1) to give (S)-2-(1-aminoethyl)-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)-3-benzene Quinazolin-4(3H)-one (130 mg, 54.5% yield) was a yellow solid. MS (ESI): 370.1 [M+H] + .
步骤2)2-氨基-5-(甲氧基-d3)吡唑并[1,5-a]嘧啶-3-羧酸Step 2) 2-Amino-5-(methoxy-d3)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
将Na(29mg，1.24mmol)加至CD 3OD(3mL)中，并将混合物在20℃搅拌1小时。然后加入2-氨基-5-氯吡唑并[1,5-a]嘧啶-3-甲酸乙酯(100mg，0.41mmol)。混合物继续搅拌2h。混合物用H 2O(1mL)淬灭，升温至40℃，加热16h。将混合物真空浓缩，残余物用水(5mL)稀释，然后用1N HCl酸化至pH＝4-5。过滤，滤饼用水(2mL)洗，滤液减压浓缩，得到2-氨基-5-(甲氧基-d3)吡唑并[1,5-a]嘧啶-3-羧酸(90mg， 92.3％收率)为浅色固体。MS(ESI):237.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.66-8.56(m,1H),6.49-6.37(m,1H),6.15(s,2H)。 Na (29 mg, 1.24 mmol) was added to CD 3 OD (3 mL), and the mixture was stirred at 20° C. for 1 hr. Then ethyl 2-amino-5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (100 mg, 0.41 mmol) was added. The mixture was stirred for an additional 2h. The mixture was quenched with H2O (1 mL), warmed to 40 °C and heated for 16 h. The mixture was concentrated in vacuo, the residue was diluted with water (5 mL), then acidified with 1N HCl to pH=4-5. Filter, wash the filter cake with water (2mL), and concentrate the filtrate under reduced pressure to obtain 2-amino-5-(methoxy-d3)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (90mg, 92.3% yield) was a light-colored solid. MS (ESI): 237.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.66-8.56 (m, 1H), 6.49-6.37 (m, 1H), 6.15 (s, 2H).
步骤3)(S)-2-氨基-5-(甲氧基-d3)-N-(1-(5-((1-甲基-1H-吡唑-4-基)乙炔基)-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 3) (S)-2-amino-5-(methoxy-d3)-N-(1-(5-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4 -Oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向2-((1S)-1-氨基乙基)-5-(2-(1-甲基吡唑-4-基)乙炔基)-3-苯基喹唑啉-4-酮(30mg，0.08mmol)和2-氨基-5-甲氧基吡唑并[1,5-a]嘧啶-3-羧酸(17mg，0.08mmol)的DCM(20mL)溶液中加入HOAt(13mg，0.097mmol)、DIEA(32mg，0.24mmol)和EDCI(23mg，0.12mmol)，混合物升温至40℃，加热16h。冷却至室温后，混合物用DCM(30mL)稀释，并用盐水(30mL)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝15/1)纯化，得到(S)-2-氨基-5-(甲氧基-d3)-N-(1-(5-((1-甲基-1H-吡唑-4-基)乙炔基)-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(14.1mg，28.7％收率)为白色固体。MS(ESI):563.2[M+H] +。 1H NMR(400MHz,CD 3OD)δ8.44-8.41(m,1H),7.88(s,1H),7.79(t,J＝8.0Hz,1H),7.69-7.61(m,5H),7.59-7.56(m,1H),7.53-7.50(m,1H),6.45(d,J＝7.2Hz,1H),4.93-4.91(m,1H),3.89(s,3H),1.51(d,J＝6.8Hz,3H)。 To 2-((1S)-1-aminoethyl)-5-(2-(1-methylpyrazol-4-yl)ethynyl)-3-phenylquinazolin-4-one (30mg, 0.08mmol) and 2-amino-5-methoxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid (17mg, 0.08mmol) in DCM (20mL) was added HOAt (13mg, 0.097mmol) , DIEA (32mg, 0.24mmol) and EDCI (23mg, 0.12mmol), the mixture was warmed up to 40°C and heated for 16h. After cooling to room temperature, the mixture was diluted with DCM (30 mL), and washed with brine (30 mL). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=15/1) to give (S)-2-amino-5-(methoxy-d3)-N-(1-(5-((1-methyl -1H-pyrazol-4-yl)ethynyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)pyrazolo[1,5-a ] Pyrimidine-3-carboxamide (14.1 mg, 28.7% yield) as a white solid. MS (ESI): 563.2 [M+H] + . 1 H NMR (400MHz, CD 3 OD) δ8.44-8.41 (m, 1H), 7.88 (s, 1H), 7.79 (t, J = 8.0Hz, 1H), 7.69-7.61 (m, 5H), 7.59 -7.56(m,1H),7.53-7.50(m,1H),6.45(d,J＝7.2Hz,1H),4.93-4.91(m,1H),3.89(s,3H),1.51(d,J =6.8Hz, 3H).
实施例24(S)-2-氨基-N-(1-(6-氟-5-((1-甲基-1H-吡唑-4-基)乙炔基)-4-氧代-3-苯基-3,4-二氢喹唑啉)-2-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 24 (S)-2-amino-N-(1-(6-fluoro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-3- Phenyl-3,4-dihydroquinazolin)-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000083
Figure PCTCN2022121567-appb-000083
步骤1)2-溴-3-氟-6-硝基苯甲酸Step 1) 2-Bromo-3-fluoro-6-nitrobenzoic acid
在0℃下，向2-溴-3-氟苯甲酸(3.0g，13.7mmol)的H 2SO 4(15mL)的溶液中滴加HNO 3(3.54g，20.55mmol)，混合物于室温下搅拌3小时。将混合物用冰水(100mL)稀释，并用DCM(100mL x 3)萃取。合并的有机相经Na 2SO 4干燥，真空浓缩，得到2-溴-3-氟-6-硝基苯甲酸(3.35g，收率83.21％)为黄色固体。MS(ESI):263.9[M+H] +。 To a solution of 2-bromo-3-fluorobenzoic acid (3.0 g, 13.7 mmol) in H 2 SO 4 (15 mL) was added HNO 3 (3.54 g, 20.55 mmol) dropwise at 0° C., and the mixture was stirred at room temperature 3 hours. The mixture was diluted with ice water (100 mL), and extracted with DCM (100 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give 2-bromo-3-fluoro-6 - nitrobenzoic acid (3.35 g, 83.21% yield) as a yellow solid. MS (ESI): 263.9 [M+H] + .
步骤2)2-溴-3-氟-6-硝基-N-苯基苯甲酰胺Step 2) 2-Bromo-3-fluoro-6-nitro-N-phenylbenzamide
将2-溴-3-氟-6-硝基苯甲酸(3.35g，12.7mmol)加至SOCl 2(30mL)，混合物升温至80℃，搅拌16小时。然后将混合物减压浓缩，得到酰氯。在0℃下，向苯胺(1.16g，12.5mmol)和TEA(8.1g，62.5mol)的DCM(50mL)溶液中加入上述酰氯。将混合物在室温下搅拌5小时，然后用H 2O(100mL)稀释，并用DCM(150mL x 3)萃取。合并的有机层用盐水(70mL x 2)洗，经Na 2SO 4干燥，减压浓缩。残余物经柱色谱法(PE/EA＝3/1)纯化，得到2-溴-3-氟-6-硝基-N-苯基苯甲酰胺(2.0g，43.2％收率)为黄色固体。MS(ESI):338.8[M+H] +。 2-Bromo-3-fluoro-6-nitrobenzoic acid (3.35 g, 12.7 mmol) was added to SOCl 2 (30 mL), and the mixture was warmed to 80° C. and stirred for 16 hours. The mixture was then concentrated under reduced pressure to afford the acid chloride. To a solution of aniline (1.16 g, 12.5 mmol) and TEA (8.1 g, 62.5 mol) in DCM (50 mL) was added the above acid chloride at 0°C. The mixture was stirred at room temperature for 5 hours, then diluted with H 2 O (100 mL), and extracted with DCM (150 mL x 3). The combined organic layers were washed with brine (70 mL x 2), dried over Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA=3/1) to give 2-bromo-3-fluoro-6-nitro-N-phenylbenzamide (2.0 g, 43.2% yield) as a yellow solid . MS (ESI): 338.8 [M+H] + .
步骤3)6-氨基-2-溴-3-氟-N-苯基苯甲酰胺Step 3) 6-Amino-2-bromo-3-fluoro-N-phenylbenzamide
向2-溴-3-氟-6-硝基-N-苯基苯甲酰胺(400mg，1.2mmol)和饱和氯化铵水溶液(10mL)中加入Fe(660.0mg，12.0mmol)，混合物于室温下搅拌16h。过滤，滤液用H 2O(100mL)稀释，并用EtOAc(50mL×3)萃取。合并的有机层用盐水(40mL x 2)洗，经Na 2SO 4干燥，减压浓缩，得到6-氨基-2-溴-3-氟-N-苯基苯甲酰胺(366mg，90.34％收率)为黄色固体。MS(ESI):310.9[M+H] +。 Add Fe (660.0 mg, 12.0 mmol) to 2-bromo-3-fluoro-6-nitro-N-phenylbenzamide (400 mg, 1.2 mmol) and saturated aqueous ammonium chloride solution (10 mL), and the mixture is Under stirring for 16h. After filtration, the filtrate was diluted with H 2 O (100 mL), and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (40 mL x 2), dried over Na 2 SO 4 , and concentrated under reduced pressure to give 6-amino-2-bromo-3-fluoro-N-phenylbenzamide (366 mg, 90.34% yield rate) as a yellow solid. MS (ESI): 310.9 [M+H] + .
步骤4)(S)-(1-((3-溴-4-氟-2-(苯基氨基甲酰基)苯基)氨基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯Step 4) tert-butyl (S)-(1-((3-bromo-4-fluoro-2-(phenylcarbamoyl)phenyl)amino)-1-oxopropan-2-yl)carbamate
向6-氨基-2-溴-3-氟-N-苯基苯甲酰胺(366mg，1.18mmol)的DCM(50mL)溶液中加入(叔丁氧羰基)-L-丙氨酸(224mg，1.18mmol)、DIEA(611mg，4.74mmol)和HATU(675mg，1.78mmol)，混合物于室温下搅拌16h。将混合物用H 2O(30mL)稀释，并用DCM(50mL x 3)萃取。合并的有机层用盐水(30mL x 2)洗，经Na 2SO 4干燥，减压浓缩。残余物经柱色谱法(PE/EA＝3/1)纯化，得到(S)-(1-((3-溴-4-氟-2-(苯基氨基甲酰基)苯基)氨基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(448mg，收率70.75％)为黄色固体。MS(ESI):501.8[M+Na] +。 To a solution of 6-amino-2-bromo-3-fluoro-N-phenylbenzamide (366 mg, 1.18 mmol) in DCM (50 mL) was added (tert-butoxycarbonyl)-L-alanine (224 mg, 1.18 mmol), DIEA (611 mg, 4.74 mmol) and HATU (675 mg, 1.78 mmol), the mixture was stirred at room temperature for 16 h. The mixture was diluted with H 2 O (30 mL), and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried over Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA=3/1) to give (S)-(1-((3-bromo-4-fluoro-2-(phenylcarbamoyl)phenyl)amino)- tert-butyl 1-oxopropan-2-yl)carbamate (448 mg, yield 70.75%) was a yellow solid. MS (ESI): 501.8 [M+Na] + .
步骤5)(S)-2-(1-氨基乙基)-5-溴-6-氟-3-苯基喹唑啉-4(3H)-酮Step 5) (S)-2-(1-aminoethyl)-5-bromo-6-fluoro-3-phenylquinazolin-4(3H)-one
向(S)-(1-((3-溴-4-氟-2-(苯基氨基甲酰基)苯基)氨基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(448mg，0.93mmol)的DCM(30mL)溶液中加入HMDS(451mg，2.79mmol)和I 2(472mg，1.86mmol)，混合物升温至45℃，搅拌16h。冷却至室温后，混合物用Na 2SO 3(20mL)水溶液稀释，然后用DCM(30mL x 3)萃取。合并的有机层用盐水(50mL x 2)洗，经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝95/5)纯化，得到(S)-2-(1-氨基乙基)-5-溴-6-氟-3-苯基喹唑啉-4(3H)-酮(267mg，71.3％收率)为黄色固体。MS(ESI):361.8[M+H] +。 To (S)-(1-((3-bromo-4-fluoro-2-(phenylcarbamoyl)phenyl)amino)-1-oxopropan-2-yl)carbamate tert-butyl ester (448mg , 0.93mmol) in DCM (30mL) were added HMDS (451mg, 2.79mmol) and I 2 (472mg, 1.86mmol), the mixture was heated to 45°C and stirred for 16h. After cooling to room temperature, the mixture was diluted with aqueous Na 2 SO 3 (20 mL), then extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na 2 SO 4 , concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=95/5) to give (S)-2-(1-aminoethyl)-5-bromo-6-fluoro-3-phenylquinazoline-4( 3H)-one (267 mg, 71.3% yield) was a yellow solid. MS (ESI): 361.8 [M+H] + .
步骤6)(S)-2-(1-氨基乙基)-6-氟-5-((1-甲基-1H-吡唑-4-基)乙炔基)-3-苯基喹唑啉-4(3H)-酮Step 6) (S)-2-(1-aminoethyl)-6-fluoro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)-3-phenylquinazoline -4(3H)-one
向(S)-2-(1-氨乙基)-5-溴-6-氟-3-苯基喹唑啉-4(3H)-酮(60mg，0.17mmol)和4-乙炔基-1-甲基-1H-吡唑(23mg，0.22mmol)的CH 3CN(20mL)溶液中的加入X-Phos(39mg，0.083mmol)、Pd 2(dba) 3(38mg，0.041mmol)和K 3PO 4(105mg，0.50mmol)，混合物升温至80℃，搅拌5h。冷却至室温后，将混合物真空浓缩。残余物用EtOAc(60mL)稀释，并用盐水(30mL x 2)洗，经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法纯化(DCM/MeOH＝91/9)，得到(S)-2-(1-氨基乙基)-6-氟-5-((1-甲基-1H-吡唑-4-基)乙炔基)-3-苯基喹唑啉-4(3H)-酮(49mg，69％收率)为黄色油状物。MS(ESI):388.0[M+H] +。 To (S)-2-(1-aminoethyl)-5-bromo-6-fluoro-3-phenylquinazolin-4(3H)-one (60mg, 0.17mmol) and 4-ethynyl-1 - To a solution of methyl-1H-pyrazole (23 mg, 0.22 mmol) in CH 3 CN (20 mL) was added X-Phos (39 mg, 0.083 mmol), Pd 2 (dba) 3 (38 mg, 0.041 mmol) and K 3 PO 4 (105mg, 0.50mmol), the mixture was warmed up to 80°C and stirred for 5h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (60 mL), washed with brine (30 mL x 2), dried over Na 2 SO 4 , concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=91/9) to give (S)-2-(1-aminoethyl)-6-fluoro-5-((1-methyl-1H-pyrazole- 4-yl)ethynyl)-3-phenylquinazolin-4(3H)-one (49 mg, 69% yield) as a yellow oil. MS (ESI): 388.0 [M+H] + .
步骤7)(S)-2-氨基-N-(1-(6-氟-5-((1-甲基-1H-吡唑-4-基)乙炔基)-4-氧代-3-苯基-3,4-二氢喹唑啉)-2-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 7) (S)-2-amino-N-(1-(6-fluoro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-3- Phenyl-3,4-dihydroquinazolin)-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向(S)-2-(1-氨基乙基)-6-氟-5-((1-甲基-1H-吡唑-4-基)乙炔基)-3-苯基喹唑啉-4(3H)-酮(49mg，0.13mmol)和2-氨基-5-甲基吡唑并[1,5-a]嘧啶-3-羧酸(25mg，0.14mmol)的DCM(20mL)溶液中加入DIEA(65mg，0.51mmol)、EDCI(36mg，0.19mmol)和HOAT(26mg，0.19mmol)，混合物升温至40℃，搅拌16h。冷却至室温后，将混合物用DCM(70mL)稀释，并用盐水(40mL x 2)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经制备型HPLC(-Gemini-C18 150x 21.2mm,5um:ACN--H 2O(0.1％FA),30％-60％)纯化，得到(S)-2-氨基-N-(1-(6-氟-5-((1-甲基-1H-吡唑-4-基)乙炔基)-4-氧代-3-苯基-3,4-二氢喹唑啉)-2-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(2.95mg，4.27％收率)为白色固体。MS(ESI):547.8[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.92(dd,J＝6.7,1.6Hz,1H),8.70(d,J＝7.4Hz,1H),8.64(dd,J＝4.5,1.6Hz,1H),8.09(s,1H),7.85-7.74(m,2H),7.67-7.57(m,5H),7.54(d,J＝7.9Hz,1H),7.03(dd,J＝6.7,4.5Hz,1H),6.45(s,2H),4.79-4.69(m,1H),3.83(s,3H),1.32(d,J＝6.7Hz,3H)。 To (S)-2-(1-aminoethyl)-6-fluoro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)-3-phenylquinazoline-4 (3H)-Kone (49 mg, 0.13 mmol) and 2-amino-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (25 mg, 0.14 mmol) in DCM (20 mL) were added DIEA (65mg, 0.51mmol), EDCI (36mg, 0.19mmol) and HOAT (26mg, 0.19mmol), the mixture was warmed to 40°C and stirred for 16h. After cooling to room temperature, the mixture was diluted with DCM (70 mL), and washed with brine (40 mL x 2). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (-Gemini-C18 150x 21.2mm, 5um:ACN-- H2O (0.1%FA), 30%-60%) to give (S)-2-amino-N-(1 -(6-fluoro-5-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline)-2 -yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (2.95 mg, 4.27% yield) as a white solid. MS (ESI): 547.8 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.92(dd, J=6.7,1.6Hz,1H),8.70(d,J=7.4Hz,1H),8.64(dd,J=4.5,1.6Hz, 1H), 8.09(s, 1H), 7.85-7.74(m, 2H), 7.67-7.57(m, 5H), 7.54(d, J=7.9Hz, 1H), 7.03(dd, J=6.7, 4.5Hz , 1H), 6.45 (s, 2H), 4.79-4.69 (m, 1H), 3.83 (s, 3H), 1.32 (d, J=6.7Hz, 3H).
实施例25(S)-2-氨基-N-(1-(5-((6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)乙炔基)-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 25 (S)-2-amino-N-(1-(5-((6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)ethynyl)-4 -Oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000084
Figure PCTCN2022121567-appb-000084
步骤1)6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-甲醛Step 1) 6,7-Dihydro-5H-pyrrolo[1,2-a]imidazole-3-carbaldehyde
在-78℃下，向6,7-二氢-5H-吡咯并[1,2-a]咪唑(200mg，1.85mmol)的THF(10mL)溶液中加入n-BuLi(0.9mL，2.22mmol，2.4M的THF溶液)，混合物升温至-10℃，搅拌1小时。然后将混合物冷却至-75℃，加入N,N-二甲基甲酰胺(203mg，2.8mmol)，转移至室温，搅拌2小时。在0-5℃下，加入饱和NH 4Cl水溶液(20mL)淬灭反应。混合物用EtOAc(50mL x 2)萃取，合并的有机层用盐水(50mL x 2)洗，经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱(DCM/MeOH＝10/1)纯化，得到6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-甲醛(200mg，收率79％)为黄色油状物。LCMS:MS(ESI)m/z 137.0[M+H] +。 To a solution of 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (200 mg, 1.85 mmol) in THF (10 mL) at -78 °C was added n-BuLi (0.9 mL, 2.22 mmol, 2.4M THF solution), the mixture was warmed to -10°C and stirred for 1 hour. Then the mixture was cooled to -75°C, N,N-dimethylformamide (203 mg, 2.8 mmol) was added, transferred to room temperature, and stirred for 2 hours. The reaction was quenched by adding saturated aqueous NH4Cl (20 mL) at 0-5 °C. The mixture was extracted with EtOAc (50 mL x 2), the combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=10/1) to obtain 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carbaldehyde (200 mg, yield 79%) as yellow Oil. LCMS: MS (ESI) m/z 137.0 [M+H] + .
步骤2)3-乙炔基-6,7-二氢-5H-吡咯并[1,2-a]咪唑Step 2) 3-ethynyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole
向6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-甲醛(200mg，1.47mmol)的MeOH(10mL)溶液中加入(1-重氮-2-氧代丙基)膦酸二甲酯(423mg，2.2mmol)和K 2CO 3(412mg，2.94mmol)，混合物于室温下搅拌16小时。 将混合物真空浓缩，用EtOAc(100mL)溶解，并用盐水(50mL x 2)洗。分离的有机层经无水Na 2SO 4干燥，过滤，真空浓缩，得到3-乙炔基-6,7-二氢-5H-吡咯并[1,2-a]咪唑(130mg，67％收率)为黄色固体。LCMS:MS(ESI)m/z 133.1[M+H] +。 To a solution of 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carbaldehyde (200 mg, 1.47 mmol) in MeOH (10 mL) was added (1-diazo-2-oxopropyl ) dimethyl phosphonate (423 mg, 2.2 mmol) and K 2 CO 3 (412 mg, 2.94 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, dissolved with EtOAc (100 mL), and washed with brine (50 mL x 2). The separated organic layer was dried over anhydrous Na2SO4 , filtered and concentrated in vacuo to give 3-ethynyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (130 mg, 67% yield ) is a yellow solid. LCMS: MS (ESI) m/z 133.1 [M+H] + .
步骤3)(S)-2-(1-氨基乙基)-5-((6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)乙炔基)-3-苯基喹唑啉-4(3H)-酮Step 3) (S)-2-(1-aminoethyl)-5-((6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)ethynyl)-3 -Phenylquinazolin-4(3H)-one
向(S)-2-(1-氨基乙基)-5-溴-3-苯基喹唑啉-4(3H)-酮(50mg，0.15mmol)的CH 3CN(10mL)溶液中加入3-乙炔基-6,7-二氢-5H-吡咯并[1,2-a]咪唑(38mg，0.29mmol)、Pd 2(dba) 3(13mg，0.015mmol)、X-phos(7mg，0.015mmol)和K 3PO 4(46mg，0.22mmol)，混合物升温至70℃，搅拌3h。冷却至室温后，混合物真空浓缩。将残余物溶于DCM(50mL)，并用盐水(30mL x 2)洗。分离的有机层经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法纯化(DCM/MeOH＝10/1)，得到(S)-2-(1-氨基乙基)-5-((6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)乙炔基)-3-苯基喹唑啉-4(3H)-酮(30mg，52％收率)为黄色固体。LCMS:MS(ESI)m/z 396.2[M+H] +。 To a solution of (S)-2-(1-aminoethyl)-5-bromo-3-phenylquinazolin-4(3H)-one (50 mg, 0.15 mmol) in CH3CN (10 mL) was added 3 -Ethynyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (38mg, 0.29mmol), Pd 2 (dba) 3 (13mg, 0.015mmol), X-phos (7mg, 0.015 mmol) and K 3 PO 4 (46mg, 0.22mmol), the mixture was heated to 70°C and stirred for 3h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was dissolved in DCM (50 mL) and washed with brine (30 mL x 2). The separated organic layer was dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=10/1) to give (S)-2-(1-aminoethyl)-5-((6,7-dihydro-5H-pyrrolo[1, 2-a] Imidazol-3-yl)ethynyl)-3-phenylquinazolin-4(3H)-one (30 mg, 52% yield) was a yellow solid. LCMS: MS (ESI) m/z 396.2 [M+H] + .
步骤4)(S)-2-氨基-N-(1-(5-((6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)乙炔基)-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 4) (S)-2-amino-N-(1-(5-((6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)ethynyl)-4 -Oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向(S)-2-(1-氨基乙基)-5-((6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)乙炔基)-3-苯基喹唑啉-4(3H)-酮(30mg，0.08mmol)的DCM(15mL)溶液中加入2-氨基吡唑并[1,5-a]嘧啶-3-羧酸(14mg，0.08mmol)、[1,2,3]三唑并[4,5-b]吡啶-3-醇(16mg，0.11mmol)、EDCI(18mg，0.11mmol)和DIEA(30mg，0.23mmol)，混合物升温至40℃，搅拌16h。冷却至室温后，将混合物用DCM(50mL)稀释，并用盐水(30mL x 2)洗。分离的有机层经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法(DCM/MeOH＝10/1)纯化，得到(S)-2-氨基-N-(1-(5-((6,7-二氢-5H-吡咯并[1,2-a]咪唑-3-基)乙炔基)-4-氧代-3-苯基-3,4-二氢喹唑啉-2-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(6.5mg，15％收率)为白色固体。LCMS:MS(ESI)m/z 556.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.92(dd,J＝6.7,1.6Hz,1H),8.72(d,J＝7.4Hz,1H),8.65(dd,J＝4.5,1.6Hz,1H),7.82(d,J＝7.7Hz,1H),7.74(d,J＝1.2Hz,1H),7.67(dd,J＝7.5,1.2Hz,1H),7.63(s,2H),7.61(s,3H),7.25(s,1H),7.03(dd,J＝6.7,4.5Hz,1H),6.45(s,2H),4.78-4.71(m,1H),3.96(s,2H),2.76(d,J＝7.6Hz,2H),2.54(s,2H),1.32(d,J＝6.7Hz,3H)。 To (S)-2-(1-aminoethyl)-5-((6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)ethynyl)-3-benzene To a solution of quinazolin-4(3H)-one (30 mg, 0.08 mmol) in DCM (15 mL) was added 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (14 mg, 0.08 mmol) , [1,2,3]triazolo[4,5-b]pyridin-3-ol (16mg, 0.11mmol), EDCI (18mg, 0.11mmol) and DIEA (30mg, 0.23mmol), the mixture was warmed to 40 °C, stirred for 16h. After cooling to room temperature, the mixture was diluted with DCM (50 mL), and washed with brine (30 mL x 2). The separated organic layer was dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=10/1) to give (S)-2-amino-N-(1-(5-((6,7-dihydro-5H-pyrrolo[1, 2-a]imidazol-3-yl)ethynyl)-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)pyrazolo[1,5-a ] Pyrimidine-3-carboxamide (6.5 mg, 15% yield) as a white solid. LCMS: MS (ESI) m/z 556.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.92(dd, J=6.7,1.6Hz,1H),8.72(d,J=7.4Hz,1H),8.65(dd,J=4.5,1.6Hz, 1H), 7.82(d, J=7.7Hz, 1H), 7.74(d, J=1.2Hz, 1H), 7.67(dd, J=7.5, 1.2Hz, 1H), 7.63(s, 2H), 7.61( s,3H),7.25(s,1H),7.03(dd,J＝6.7,4.5Hz,1H),6.45(s,2H),4.78-4.71(m,1H),3.96(s,2H),2.76 (d, J = 7.6Hz, 2H), 2.54 (s, 2H), 1.32 (d, J = 6.7Hz, 3H).
实施例26(S)-2-氨基-N-(1-(7-氟-8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉)-3-基)乙基)-5-(甲氧基-d3)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 26 (S)-2-amino-N-(1-(7-fluoro-8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2- Phenyl-1,2-dihydroisoquinolin)-3-yl)ethyl)-5-(methoxy-d3)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000085
Figure PCTCN2022121567-appb-000085
向(S)-3-(1-氨基乙基)-7-氟-8-((1-甲基-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(49mg，0.38mmol)和2-氨基-5-(甲氧基-d3)吡唑并[1,5-a]嘧啶-3-羧酸(20mg，0.10mmol)的DCM(20mL)溶液中加入DIEA(49mg，0.38mmol)、EDCI(27mg，0.14mmol)和HOAT(20mg，0.14mmol)，混合物在40℃搅拌16h。冷却至室温后，将混合物用DCM(50mL)稀释，并用盐水(30mL x 2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经制备型HPLC(-Xbridge-C18 150x 19mm,5um,ACN-H 2O(0.1％TFA))纯化，得到(S)-2-氨基-N-(1-(7-氟-8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉)-3-基)乙基)-5-(甲氧基-d3)吡唑并[1,5-a]嘧啶-3-甲酰胺(27.3mg，50.0％收率)为白色固体。MS(ESI):579.8[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.74-8.67(m,1H),8.05(s,1H),7.88(d,J＝6.5Hz,1H),7.75-7.65(m,2H),7.61-7.46(m,5H),7.39(d,J＝7.5Hz,1H),6.83(s,1H),6.51-6.45(m,1H),6.13(s,2H),4.52-4.41(m,1H),3.83(s,3H),1.35(d,J＝6.7Hz,3H)。 To (S)-3-(1-aminoethyl)-7-fluoro-8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2-phenylisoquinoline-1 (2H)-Kone (49 mg, 0.38 mmol) and 2-amino-5-(methoxy-d3)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (20 mg, 0.10 mmol) in DCM ( 20 mL) solution was added DIEA (49 mg, 0.38 mmol), EDCI (27 mg, 0.14 mmol) and HOAT (20 mg, 0.14 mmol), and the mixture was stirred at 40° C. for 16 h. After cooling to room temperature, the mixture was diluted with DCM (50 mL), and washed with brine (30 mL x 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (-Xbridge-C18 150x 19mm, 5um, ACN-H 2 O (0.1% TFA)) to give (S)-2-amino-N-(1-(7-fluoro-8- ((1-Methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolinyl)-3-yl)ethyl)-5 -(Methoxy-d3)pyrazolo[1,5-a]pyrimidine-3-carboxamide (27.3 mg, 50.0% yield) as a white solid. MS (ESI): 579.8 [M+H] + . 1 H NMR (400MHz,DMSO-d 6 )δ8.74-8.67(m,1H),8.05(s,1H),7.88(d,J=6.5Hz,1H),7.75-7.65(m,2H), 7.61-7.46(m,5H),7.39(d,J＝7.5Hz,1H),6.83(s,1H),6.51-6.45(m,1H),6.13(s,2H),4.52-4.41(m, 1H), 3.83(s, 3H), 1.35(d, J=6.7Hz, 3H).
实施例27(S)-2-氨基-N-(1-(7-氟-8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉)-3-基)乙基)吡唑并[1,5-a]嘧啶-5,7-d2-3-甲酰胺Example 27 (S)-2-amino-N-(1-(7-fluoro-8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2- Phenyl-1,2-dihydroisoquinolin)-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-5,7-d2-3-carboxamide
Figure PCTCN2022121567-appb-000086
Figure PCTCN2022121567-appb-000086
步骤1)N 1,N 3-二甲氧基-N 1,N 3-二甲基丙二酰胺 Step 1) N 1 , N 3 -dimethoxy-N 1 , N 3 -dimethylmalonamide
在0℃下，向甲氧基(甲基)胺(1.08g，17.7mmol)和DIEA(4.59g，35.5mmol)的DCM(20mL)溶液中加入丙二酰氯(1g，7.1mmol)，混合物于室温搅拌16h。混合物用DCM(50mL)稀释，并用盐水(30mL x 3)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(EA/PE＝1/8)纯化，得到N 1,N 3-二甲氧基-N 1,N 3-二甲基丙二酰胺(700mg，收率31％)为无色油状物。MS(ESI):191.1[M+H] +。 To a solution of methoxy(methyl)amine (1.08 g, 17.7 mmol) and DIEA (4.59 g, 35.5 mmol) in DCM (20 mL) was added malonyl chloride (1 g, 7.1 mmol) at 0 °C, and the mixture was Stir at room temperature for 16h. The mixture was diluted with DCM (50 mL) and washed with brine (30 mL x 3). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EA/PE=1/8) to give N 1 ,N 3 -dimethoxy-N 1 ,N 3 -dimethylmalonamide (700 mg, yield 31%) as Colorless oil. MS (ESI): 191.1 [M+H] + .
步骤2)丙二醛-1,3-d2Step 2) Malondialdehyde-1,3-d2
在0℃下，向N 1,N 3-二甲氧基-N 1,N 3-二甲基丙二酰胺(500mg，2.63mmol)的THF(15mL)溶液中分批加入LiAlD4(220mg，5.24mmol)，混合物搅拌2h。然后混合物用1N氘代盐酸(5mmol，溶于D 2O(5mL))淬灭，用EtOAc(10mL)萃取，水相不经进一步纯化即可用于下一步骤。MS(ESI):75.2[M+H] +。 To a solution of N 1 ,N 3 -dimethoxy-N 1 ,N 3 -dimethylmalonamide (500 mg, 2.63 mmol) in THF (15 mL) was added LiAlD4 (220 mg, 5.24 mmol), the mixture was stirred for 2h. The mixture was then quenched with 1N deuterated hydrochloric acid (5 mmol, dissolved in D2O (5 mL)), extracted with EtOAc (10 mL), and the aqueous phase was used in the next step without further purification. MS (ESI): 75.2 [M+H] + .
步骤3)2-氨基-5,7-d2-吡唑并[1,5-a]嘧啶-3-甲酸乙酯Step 3) Ethyl 2-amino-5,7-d2-pyrazolo[1,5-a]pyrimidine-3-carboxylate
向3,5-二氨基-1H-吡唑-4-甲酸乙酯(250mg，0.29mmol)的HOAc(20mL)溶液中加入上一步的丙二醛-1,3-d2水溶液，混合物升温至90℃，搅拌2h。冷却至室温后，将混合物真空浓缩。残余物用EtOAc(60mL)稀释，并分别用NaHCO 3水溶液(40mL)和盐水(40mL)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(EA/PE＝1/1)纯化，得到2-氨基-5,7-d2-吡唑并[1,5-a]嘧啶-3-甲酸乙酯(110mg，34％收率)为黄色固体。MS(ESI):210.2[M+H] +。 To a solution of ethyl 3,5-diamino-1H-pyrazole-4-carboxylate (250 mg, 0.29 mmol) in HOAc (20 mL) was added the aqueous solution of malondialdehyde-1,3-d2 from the previous step, and the mixture was warmed to 90 ℃, stirred for 2h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (60 mL), and washed with aqueous NaHCO 3 (40 mL) and brine (40 mL), respectively. The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EA/PE=1/1) to give ethyl 2-amino-5,7-d2-pyrazolo[1,5-a]pyrimidine-3-carboxylate (110mg, 34% yield) as a yellow solid. MS (ESI): 210.2 [M+H] + .
步骤4)2-氨基-5,7-d2-吡唑并[1,5-a]嘧啶-3-羧酸Step 4) 2-Amino-5,7-d2-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
向2-氨基-5,7-d2-吡唑并[1,5-a]嘧啶-3-甲酸乙酯(120mg，0.58mmol)的MeOH(20mL)加入NaOH(115mg，2.9mmol)和H 2O(5mL)，混合物升温至40℃，搅拌16h。冷却至室温后，将混合物真空浓缩。残余物用水(10mL)稀释，并用1N FA调至pH 5-6。过滤，滤饼用水洗，真空干燥，得到2-氨基-5,7-d2-吡唑并[1,5-a]嘧啶-3-羧酸(60mg，54.9％收率)为黄色的固体。MS(ESI):180.9[M+H] +。 To ethyl 2-amino-5,7-d2-pyrazolo[1,5-a]pyrimidine-3-carboxylate (120 mg, 0.58 mmol) in MeOH (20 mL) was added NaOH (115 mg, 2.9 mmol) and H2 O (5 mL), the mixture was warmed to 40 °C and stirred for 16 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with water (10 mL) and adjusted to pH 5-6 with 1N FA. After filtration, the filter cake was washed with water and dried in vacuo to obtain 2-amino-5,7-d2-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (60 mg, 54.9% yield) as a yellow solid. MS (ESI): 180.9 [M+H] + .
步骤5)(S)-2-氨基-N-(1-(7-氟-8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉)-3-基)乙基)吡唑并[1,5-a]嘧啶-5,7-d2-3-甲酰胺Step 5) (S)-2-amino-N-(1-(7-fluoro-8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2- Phenyl-1,2-dihydroisoquinolin)-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-5,7-d2-3-carboxamide
向3-((1s)-1-氨基乙基)-7-氟-8-(2-(1-甲基吡唑-4-基)乙基乙基)-2-苯基甲喹啉-1-酮(43mg，0.11mmol)和2-氨基-5,7-d2-吡唑并[1,5-a]嘧啶-3-羧酸(20mg，0.11mmol)的DCM(30mL)溶液中加入HOAt(18mg，0.13mmol)、EDCI(32mg，0.17mmol)和DIEA(43mg，0.33mmol)，混合物升温至40℃，搅拌15h。冷却至室温后，将混合物用DCM(40mL)稀释，并用盐水(30mL x 2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝15/1)纯化，得到(S)-2-氨基-N-(1-(7-氟-8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉)-3-基)乙基)吡唑并[1,5-a]嘧啶-5,7-d2-3-甲酰胺(26.9mg，44％收率)为淡黄色固体。MS(ESI):549.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.95-8.91(m,1H),8.04(s,1H),7.99(d,J＝6.4Hz,1H),7.74-7.64(m,2H),7.61(s,1H),7.59-7.55(m,1H),7.53-7.45(m,3H),7.40-7.36(m,1H),6.79(s,1H),6.42(s,2H),4.59-4.50(m,1H),3.82(s,1H),1.35(d,J＝6.8Hz,3H)。 To 3-((1s)-1-aminoethyl)-7-fluoro-8-(2-(1-methylpyrazol-4-yl)ethylethyl)-2-phenylmethylquinoline- To a solution of 1-keto (43 mg, 0.11 mmol) and 2-amino-5,7-d2-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (20 mg, 0.11 mmol) in DCM (30 mL) was added HOAt (18mg, 0.13mmol), EDCI (32mg, 0.17mmol) and DIEA (43mg, 0.33mmol), the mixture was heated to 40°C and stirred for 15h. After cooling to room temperature, the mixture was diluted with DCM (40 mL), and washed with brine (30 mL x 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=15/1) to give (S)-2-amino-N-(1-(7-fluoro-8-((1-methyl-1H-pyrazole- 4-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin)-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-5, 7-d2-3-Carboxamide (26.9 mg, 44% yield) was a pale yellow solid. MS (ESI): 549.1 [M+H] + . 1 H NMR (400MHz,DMSO-d 6 )δ8.95-8.91(m,1H),8.04(s,1H),7.99(d,J=6.4Hz,1H),7.74-7.64(m,2H), 7.61(s,1H),7.59-7.55(m,1H),7.53-7.45(m,3H),7.40-7.36(m,1H),6.79(s,1H),6.42(s,2H),4.59- 4.50 (m, 1H), 3.82 (s, 1H), 1.35 (d, J=6.8Hz, 3H).
实施例28(S)-2-氨基-N-(1-(7-氟-8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 28 (S)-2-amino-N-(1-(7-fluoro-8-((1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-1-oxo Substitute-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000087
Figure PCTCN2022121567-appb-000087
步骤1)4-碘-1-(甲基-d3)-1H-吡唑Step 1) 4-iodo-1-(methyl-d3)-1H-pyrazole
在0℃下，向4-碘-1H-吡唑(2g，10mmol)的DMF(10mL)溶液中加入氢化钠(297mg，12.3mmol)，混合物搅拌0.5h。然后加入碘甲烷-d3(1.8g，12.3mmol)，转移至室温，搅拌16小时。混合物用冰水(20mL)淬灭，并用EtOAc(50mL×3)萃取。合并的有机层用盐水(50mL x 3)洗，经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法(PE/EA＝2/1)纯化，得到4-碘-1-(甲基-d3)-1H-吡唑(2g，91％收率)为黄色油状物。LCMS:MS(ESI)m/z 212.0[M+H] +。 To a solution of 4-iodo-1H-pyrazole (2 g, 10 mmol) in DMF (10 mL) was added sodium hydride (297 mg, 12.3 mmol) at 0° C., and the mixture was stirred for 0.5 h. Then iodomethane-d3 (1.8 g, 12.3 mmol) was added, transferred to room temperature, and stirred for 16 hours. The mixture was quenched with ice water (20 mL), and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=2/1) to give 4-iodo-1-(methyl-d3)-1H-pyrazole (2 g, 91% yield) as a yellow oil. LCMS: MS (ESI) m/z 212.0 [M+H] + .
步骤2)1-(甲基-d3)-4-((三甲基甲硅烷基)乙炔基)-1H-吡唑Step 2) 1-(Methyl-d3)-4-((trimethylsilyl)ethynyl)-1H-pyrazole
向4-碘-1-(甲基-d3)-1H-吡唑(2g，9.6mmol)的TEA(30mL)溶液中加入乙炔基三甲基硅烷(1.4g，14.4mmol)、CuI(183mg，0.96mmol)、双(三苯基膦)氯化钯(II)(675mg，0.96mmol)和三乙胺(9.7g，96mmol)，混合物升温至90℃，搅拌4h。冷却至室温后，真空浓缩。将残余物溶于DCM(50mL)，用水(30mL)和盐水(30mL)洗。分离的有机层经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法纯化(PE/EA＝3/1)，得到1-(甲基-d3)-4-((三甲基甲硅烷基)乙炔基)-1H-吡唑(1.2g，收率70％)为棕色油状物。LCMS:MS(ESI)m/z182.1[M+H] +。 To a solution of 4-iodo-1-(methyl-d3)-1H-pyrazole (2 g, 9.6 mmol) in TEA (30 mL) was added ethynyltrimethylsilane (1.4 g, 14.4 mmol), CuI (183 mg, 0.96mmol), bis(triphenylphosphine)palladium(II) chloride (675mg, 0.96mmol) and triethylamine (9.7g, 96mmol), the mixture was heated to 90°C and stirred for 4h. After cooling to room temperature, it was concentrated in vacuo. The residue was dissolved in DCM (50 mL), washed with water (30 mL) and brine (30 mL). The separated organic layer was dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=3/1) to give 1-(methyl-d3)-4-((trimethylsilyl)ethynyl)-1H-pyrazole (1.2 g, Yield 70%) as a brown oil. LCMS: MS (ESI) m/z 182.1 [M+H] + .
步骤3)4-乙炔基-1-(甲基-d3)-1H-吡唑Step 3) 4-ethynyl-1-(methyl-d3)-1H-pyrazole
向1-(甲基-d3)-4-((三甲基甲硅烷基)乙炔基)-1H-吡唑(2.3g，12.7mmol)的THF(20mL)溶液中加入TBAF(13mL，12.7mmol，1N的THF溶液)，混合物于室温搅拌0.5h。将反应混合物用EtOAc(100mL)稀释，并用盐水(30mL x 2)洗。分离的有机层经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法(PE/EA＝10/1)纯化，得到4-乙炔基-1-(甲基-d3)-1H-吡唑(800mg，收率87％)为黄色固体。LCMS:MS(ESI)m/z110.1[M+H] +。 To a solution of 1-(methyl-d3)-4-((trimethylsilyl)ethynyl)-1H-pyrazole (2.3 g, 12.7 mmol) in THF (20 mL) was added TBAF (13 mL, 12.7 mmol) , 1N in THF), and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was diluted with EtOAc (100 mL), and washed with brine (30 mL x 2). The separated organic layer was dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=10/1) to give 4-ethynyl-1-(methyl-d3)-1H-pyrazole (800 mg, yield 87%) as a yellow solid. LCMS: MS (ESI) m/z 110.1 [M+H] + .
步骤4)(S)-3-(1-氨基乙基)-7-氟-8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮Step 4) (S)-3-(1-aminoethyl)-7-fluoro-8-((1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-2-benzene Isoquinolin-1(2H)-one
向(S)-3-(1-氨基乙基)-7-氟-8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(150mg，0.47mmol)和4-乙炔基-1-(甲基-d3)-1H-吡唑(77mg，0.71mmol)的CH 3CN(20mL)溶液中加入Pd 2(dba) 3(87mg，0.095mmol)、X-phos(90mg，0.19mmol)和K 3PO 4(150mg，0.71mmol)，混合物升温至80℃，搅拌4h。冷却至室温后，真空浓缩。将残余物溶于DCM(50mL)，并用盐水(30mL x 2)洗。分离的有机层经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法纯化(DCM/MeOH＝10/1)，得到(S)-3-(1-氨基乙基)-7-氟-8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(120mg，65％收率)为棕色油状物。LCMS:MS(ESI)m/z 390.1[M+H] +。 To (S)-3-(1-aminoethyl)-7-fluoro-8-((1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-2-phenyliso To a solution of quinolin-1(2H)-one (150mg, 0.47mmol) and 4-ethynyl-1-(methyl-d3)-1H-pyrazole (77mg, 0.71mmol) in CH 3 CN (20mL) was added Pd 2 (dba) 3 (87mg, 0.095mmol), X-phos (90mg, 0.19mmol) and K 3 PO 4 (150mg, 0.71mmol), the mixture was heated to 80°C and stirred for 4h. After cooling to room temperature, it was concentrated in vacuo. The residue was dissolved in DCM (50 mL) and washed with brine (30 mL x 2). The separated organic layer was dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=10/1) to give (S)-3-(1-aminoethyl)-7-fluoro-8-((1-(methyl-d3)-1H -pyrazol-4-yl)ethynyl)-2-phenylisoquinolin-1(2H)-one (120 mg, 65% yield) as a brown oil. LCMS: MS (ESI) m/z 390.1 [M+H] + .
步骤5)(S)-2-氨基-N-(1-(7-氟-8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 5) (S)-2-amino-N-(1-(7-fluoro-8-((1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-1-oxo Substitute-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向(S)-3-(1-氨基乙基)-7-氟-8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(90mg，0.23mmol)和2-氨基吡唑并[1,5-a]嘧啶-3-羧酸(41mg，0.23mmol)的DCM(15mL)溶液中加入[1,2,3]三唑[4,5-b]吡啶-3-醇(47mg，0.34mmol)、EDCI(54mg，0.34mmol)和DIEA(90mg，0.69mmol)，混合物升温至40℃，搅拌16h。冷却至室温后，将混合物用DCM(50mL)稀释，并用盐水(30mL x 2)洗。合并的有机层经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经制备型HPLC(DCM/MeOH＝10/1)纯化，得到(S)-2-氨基-N-(1-(7-氟-8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(48.5mg，38％收率)为白色固体。LCMS:MS(ESI)m/z 550.0[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.93(dd,J＝6.7,1.6Hz,1H),8.55(dd,J＝4.5,1.6Hz,1H),8.05(d,J＝0.6Hz,1H),7.99(d,J＝6.6Hz,1H), 7.72-7.68(m,2H),7.64-7.55(m,2H),7.55-7.45(m,3H),7.41-7.36(m,1H),7.02(dd,J＝6.7,4.5Hz,1H),6.79(s,1H),6.43(s,2H),4.54(q,J＝6.8Hz,1H),1.35(d,J＝6.8Hz,3H)。 To (S)-3-(1-aminoethyl)-7-fluoro-8-((1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-2-phenyliso To a solution of quinolin-1(2H)-one (90 mg, 0.23 mmol) and 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (41 mg, 0.23 mmol) in DCM (15 mL) was added [ 1,2,3]triazol[4,5-b]pyridin-3-ol (47mg, 0.34mmol), EDCI (54mg, 0.34mmol) and DIEA (90mg, 0.69mmol), the mixture was heated to 40°C and stirred 16h. After cooling to room temperature, the mixture was diluted with DCM (50 mL), and washed with brine (30 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by preparative HPLC (DCM/MeOH=10/1) to give (S)-2-amino-N-(1-(7-fluoro-8-((1-(methyl-d3)-1H -pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine -3-Carboxamide (48.5 mg, 38% yield) as a white solid. LCMS: MS (ESI) m/z 550.0 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.93(dd, J=6.7,1.6Hz,1H),8.55(dd,J=4.5,1.6Hz,1H),8.05(d,J=0.6Hz, 1H),7.99(d,J＝6.6Hz,1H), 7.72-7.68(m,2H),7.64-7.55(m,2H),7.55-7.45(m,3H),7.41-7.36(m,1H) ,7.02(dd,J=6.7,4.5Hz,1H),6.79(s,1H),6.43(s,2H),4.54(q,J=6.8Hz,1H),1.35(d,J=6.8Hz, 3H).
实施例29：2-氨基-N-((1S)-1-(8-(2-(1-甲基-5-氧代吡咯烷-3-基)乙炔基)-1-氧代-2-苯基异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺；和实施例30：6-(3-((S)-1-(2-氨基吡唑并[1,5-a]嘧啶-3-甲酰胺基)乙基)-1-氧代-2-苯基-1,2-二氢异喹啉-8-基)-4-羟基-己-5-炔酸甲酯Example 29: 2-Amino-N-((1S)-1-(8-(2-(1-methyl-5-oxopyrrolidin-3-yl)ethynyl)-1-oxo-2 -phenylisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; and Example 30: 6-(3-((S)-1-(2 -aminopyrazolo[1,5-a]pyrimidine-3-carboxamido)ethyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-8-yl)-4 -Hydroxy-hex-5-ynoic acid methyl ester
Figure PCTCN2022121567-appb-000088
Figure PCTCN2022121567-appb-000088
步骤1)4-羟基-6-(三甲基甲硅烷基)己-5-炔酸甲酯Step 1) Methyl 4-Hydroxy-6-(trimethylsilyl)hex-5-ynoate
在-20℃下，向4-氧代-6-(三甲基甲硅烷基)己-5-炔酸甲酯(300mg，1.4mmol)的MeOH(10mL)溶液中加入NaBH 4(59mg，1.55mmol)，混合物于室温搅拌16h。然后用NH 4Cl溶液(5mL)淬灭反应，真空浓缩。残余物用EtOAc(50mL)稀释，并用盐水(30mL x 2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩，得到4-羟基-6-(三甲基甲硅烷基)己-5-炔酸甲酯(270mg，收率89％)为无色油状物。MS(ESI):215.2[M+H] +。 To a solution of methyl 4-oxo-6-(trimethylsilyl)hex-5-ynoate (300 mg, 1.4 mmol) in MeOH (10 mL) was added NaBH 4 (59 mg, 1.55 mmol), the mixture was stirred at room temperature for 16h. The reaction was then quenched with NH4Cl solution (5 mL) and concentrated in vacuo. The residue was diluted with EtOAc (50 mL), and washed with brine (30 mL x 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo to give methyl 4-hydroxy-6-(trimethylsilyl)hex-5-ynoate (270 mg, 89% yield) as a colorless oil . MS (ESI): 215.2 [M+H] + .
步骤2)4-羟基-己-5-炔酸甲酯Step 2) 4-Hydroxy-hex-5-ynoic acid methyl ester
在-10℃下，向4-羟基-6-(三甲基甲硅烷基)己-5-壬酸甲酯(250mg，1.17mmol)的THF(10mL)溶液中加入TBAF(1.2mL，1M/L)，混合物于室温搅拌1h。混合物用EtOAc(50mL)稀释，并用盐水(30mL×2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(EA:PE＝1:4)纯化，得到4-羟基-己-5-炔酸甲酯(125mg，60％收率)为无色油状物。 1H NMR(400MHz,CDCl3)δ4.50(td,J＝6.1,2.1Hz,1H),3.70(s,3H),2.65-2.53(m,2H),2.49(d,J＝2.1Hz,1H),2.09-2.04(m,2H)。 To a solution of methyl 4-hydroxy-6-(trimethylsilyl)hex-5-nonanoate (250 mg, 1.17 mmol) in THF (10 mL) was added TBAF (1.2 mL, 1M/ L), the mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc (50 mL), and washed with brine (30 mL×2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EA:PE=1:4) to give methyl 4-hydroxy-hex-5-ynoate (125 mg, 60% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ4.50(td, J=6.1, 2.1Hz, 1H), 3.70(s, 3H), 2.65-2.53(m, 2H), 2.49(d, J=2.1Hz, 1H ), 2.09-2.04(m,2H).
步骤3)3-((1S)-1-氨基乙基)-8-(2-(5-氧代氧杂环戊烷-2-基)乙炔基)-2-苯基异喹啉-1-酮；6-(3-((S)-1-氨基乙基)-1-氧代-2-苯基-1,2-二氢异喹啉-8-基)-4-羟基-己-5-炔酸甲酯Step 3) 3-((1S)-1-aminoethyl)-8-(2-(5-oxooxolan-2-yl)ethynyl)-2-phenylisoquinoline-1 - Ketone; 6-(3-((S)-1-aminoethyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-8-yl)-4-hydroxy-hexyl -5-ynoic acid methyl ester
向3-((1S)-1-氨基乙基)-8-氯-2-苯基异喹啉-1-酮(60mg，0.2mmol)和4-羟基-己-5-炔酸甲酯(28mg，0.2mmol)的CH 3CN(10mL)溶液中加入K 3PO 4(128mg，0.6mmol)、X-phos(38mg，0.08mmol)和Pd 2(dba) 3(37mg，0.04mmol)，混合物升温至80℃，搅拌16h。冷却至室温后，真空浓缩。将残余物用DCM(100mL)稀释，并用盐水(30mL)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(MeOH/DCM＝1/20)纯化，得到3-((1S)-1-氨基乙基)-8-(2-(5-氧代氧杂环戊烷-2-基)乙炔基)-2-苯基异喹啉-1-酮，MS(ESI):373.1[M+H] +；和6-(3-((S)-1-氨基乙基)-1-氧代-2-苯基-1,2-二氢异喹啉-8-基)-4-羟基-己-5-炔酸甲酯的混合物(60mg，60.16％收率)为黄色固体，MS(ESI):405.2[M+H] +。 To 3-((1S)-1-aminoethyl)-8-chloro-2-phenylisoquinolin-1-one (60 mg, 0.2 mmol) and 4-hydroxy-hex-5-ynoic acid methyl ester ( 28mg, 0.2mmol) in CH 3 CN (10mL) was added K 3 PO 4 (128mg, 0.6mmol), X-phos (38mg, 0.08mmol) and Pd 2 (dba) 3 (37mg, 0.04mmol), the mixture Raise the temperature to 80°C and stir for 16h. After cooling to room temperature, it was concentrated in vacuo. The residue was diluted with DCM (100 mL) and washed with brine (30 mL). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (MeOH/DCM=1/20) to give 3-((1S)-1-aminoethyl)-8-(2-(5-oxooxolane-2- base) ethynyl) -2-phenylisoquinolin-1-one, MS (ESI): 373.1[M+H] + ; and 6-(3-((S)-1-aminoethyl)-1 A mixture of -oxo-2-phenyl-1,2-dihydroisoquinolin-8-yl)-4-hydroxy-hex-5-ynoic acid methyl ester (60 mg, 60.16% yield) was a yellow solid, MS (ESI): 405.2 [M+H] + .
步骤4)2-氨基-N-((1S)-1-(8-(2-(1-甲基-5-氧代吡咯烷-3-基)乙炔基)-1-氧代-2-苯基异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺；6-(3-((S)-1-(2-氨基吡唑并[1,5-a]嘧啶-3-甲酰胺基)乙基)-1-氧代-2-苯基-1,2-二氢异喹啉-8-基)-4-羟基-己-5-炔酸甲酯Step 4) 2-amino-N-((1S)-1-(8-(2-(1-methyl-5-oxopyrrolidin-3-yl)ethynyl)-1-oxo-2- phenylisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; 6-(3-((S)-1-(2-aminopyrazolo[ 1,5-a]pyrimidine-3-carboxamido)ethyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-8-yl)-4-hydroxy-hexan-5 -Methyl alkynoate
向3-((1S)-1-氨基乙基)-8-(2-(5-氧代氧杂环戊烷-2-基)乙炔基)-2-苯基异喹啉-1-酮和6-(3-((S)-1-氨基乙基)-1-氧代-2-苯基-1,2-二氢异喹啉-8-基)-4-羟基-己-5-炔酸甲酯的混合物(60mg，0.16mmol)和2-氨基吡唑并[1,5-a]嘧啶-3-羧酸(29mg，0.16mmol)的DCM(10mL)溶液中加入HOAT(33mg，0.24mmol)、EDCI(46mg，0.24mmol)和DIEA(62mg，0.48mmol)，混合物升温至40℃，搅拌16h。混合物用DCM(150mL)稀释，用盐水(50mL x 2)洗。分液，有机相经Na 2SO 4干燥，真空浓缩。残余物经制备型HPLC(ACN-H 2O 0.1％FA,梯度30％至60％)纯化，得到2-氨基-N-((1S)-1-(8-(2-(1-甲基-5-氧代吡咯烷-3-基)乙炔基)-1-氧代-2-苯基异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(8.0mg，11.30％收率)为白色固体，和6-(3-((S)-1-(2-氨基吡唑并[1,5-a]嘧啶-3-甲酰胺基)乙基)-1-氧代-2-苯基-1,2-二氢异喹啉-8-基)-4-羟基-己-5-炔酸甲酯(3.4mg，3.74％收率)为白色固体。 To 3-((1S)-1-aminoethyl)-8-(2-(5-oxooxolan-2-yl)ethynyl)-2-phenylisoquinolin-1-one and 6-(3-((S)-1-aminoethyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-8-yl)-4-hydroxy-hexan-5 - To a mixture of methyl alkynoate (60 mg, 0.16 mmol) and 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (29 mg, 0.16 mmol) in DCM (10 mL) was added HOAT (33 mg , 0.24mmol), EDCI (46mg, 0.24mmol) and DIEA (62mg, 0.48mmol), the mixture was heated to 40°C and stirred for 16h. The mixture was diluted with DCM (150 mL), washed with brine (50 mL x 2). The layers were separated, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (ACN-H 2 O 0.1% FA, gradient 30% to 60%) to give 2-amino-N-((1S)-1-(8-(2-(1-methyl -5-oxopyrrolidin-3-yl)ethynyl)-1-oxo-2-phenylisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3- Formamide (8.0 mg, 11.30% yield) as a white solid, and 6-(3-((S)-1-(2-aminopyrazolo[1,5-a]pyrimidine-3-carboxamido) Ethyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-8-yl)-4-hydroxy-hex-5-ynoic acid methyl ester (3.4 mg, 3.74% yield) It is a white solid.
2-氨基-N-((1S)-1-(8-(2-(1-甲基-5-氧代吡咯烷-3-基)乙炔基)-1-氧代-2-苯基异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺：MS(ESI):533.2[M+H] +。 1H NMR(400MHz,CD 3OD)δ8.71(dd,J＝6.8,1.6Hz,1H),8.54-8.51(m,1H),7.67-7.35(m,8H),6.98(dd,J＝6.8,4.5Hz,1H),6.90(d,J＝4.1Hz,1H),5.47(t,J＝6.4Hz,1H),4.80-4.74(m,1H),4.56(s,1H),2.66-2.41(m,4H),1.48(d,J＝6.7Hz,3H)。 2-Amino-N-((1S)-1-(8-(2-(1-methyl-5-oxopyrrolidin-3-yl)ethynyl)-1-oxo-2-phenyliso Quinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide: MS (ESI): 533.2[M+H] + . 1 H NMR (400MHz, CD 3 OD) δ8.71 (dd, J = 6.8, 1.6 Hz, 1H), 8.54-8.51 (m, 1H), 7.67-7.35 (m, 8H), 6.98 (dd, J = 6.8,4.5Hz,1H),6.90(d,J=4.1Hz,1H),5.47(t,J=6.4Hz,1H),4.80-4.74(m,1H),4.56(s,1H),2.66- 2.41 (m, 4H), 1.48 (d, J=6.7Hz, 3H).
6-(3-((S)-1-(2-氨基吡唑并[1,5-a]嘧啶-3-甲酰胺基)乙基)-1-氧代-2-苯基-1,2-二氢异喹啉-8-基)-4-羟基-己-5-炔酸甲酯：MS(ESI):565.2[M+H] +。 1H NMR(400MHz,CD 3OD)δ8.72(dd,J＝6.8,1.6Hz,1H),8.53(dd,J＝4.5,1.6Hz,1H),7.63-7.61(m,4H),7.54-7.47(m,4H),6.99(dd,J＝6.8,4.5Hz,1H),6.89(s,1H),4.83-4.77(m,1H),4.63-4.60(m,1H),3.64(s,3H),2.56(t,J＝7.7Hz,2H),2.06–2.02(m,2H),1.48(d,J＝6.8Hz,3H)。 6-(3-((S)-1-(2-aminopyrazolo[1,5-a]pyrimidine-3-carboxamido)ethyl)-1-oxo-2-phenyl-1, Methyl 2-dihydroisoquinolin-8-yl)-4-hydroxy-hex-5-ynoate: MS (ESI): 565.2 [M+H] + . 1 H NMR (400MHz, CD 3 OD) δ8.72 (dd, J = 6.8, 1.6Hz, 1H), 8.53 (dd, J = 4.5, 1.6Hz, 1H), 7.63-7.61 (m, 4H), 7.54 -7.47(m,4H),6.99(dd,J＝6.8,4.5Hz,1H),6.89(s,1H),4.83-4.77(m,1H),4.63-4.60(m,1H),3.64(s , 3H), 2.56 (t, J = 7.7Hz, 2H), 2.06–2.02 (m, 2H), 1.48 (d, J = 6.8Hz, 3H).
实施例31(S)-2-氨基-N-(1-(8-((6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪-3-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 31 (S)-2-amino-N-(1-(8-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3- Base) ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000089
Figure PCTCN2022121567-appb-000089
步骤1)4-溴-1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-1H-吡唑Step 1) 4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole
向4-溴-1H-吡唑(2.0g，13.6mmol)和(2-溴乙氧基)(叔丁基)二甲基硅烷(3.58g，149.6mmol)的MeCN(100mL)溶液中加入碳酸铯(8.86g，27.2mmol)，混合物于室温下搅拌16h。将混合物真空浓缩，残余物用EtOAc(130mL)稀释，用盐水(50mL x 2)洗，分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝50/1)纯化，得到4-溴-1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-1H-吡唑(2.5g,70％收率)为黄色油状物。MS(ESI):304.9[M+H] +。 To a solution of 4-bromo-1H-pyrazole (2.0 g, 13.6 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (3.58 g, 149.6 mmol) in MeCN (100 mL) was added carbonic acid Cesium (8.86g, 27.2mmol), the mixture was stirred at room temperature for 16h. The mixture was concentrated in vacuo, the residue was diluted with EtOAc (130 mL), washed with brine (50 mL x 2), the separated organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=50/1) to give 4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole (2.5 g, 70% yield) as a yellow oil. MS (ESI): 304.9 [M+H] + .
步骤2)4-溴-1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-1H-吡唑-5-甲醛Step 2) 4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-5-carbaldehyde
在-78℃下，向4-溴-1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-1H-吡唑(300mg，0.98mmol)的THF(30mL)溶液中加入LDA(0.6mL，1.18mmol)，混合物搅拌1h。然后加入DMF(144mg，1.96mmol)，混合物转移至室温，搅拌1h。混合物用NH 4Cl(20mL)水溶液淬灭，并用EtOAc(50mL x 2)萃取，用盐水(40mL x 2)洗。合并的有机层经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝50/1)纯化，得到4-溴-1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-1H-吡唑-5-甲醛(200mg，66％收率)为黄色油状物。MS(ESI):333.1[M+H] +。 4-Bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole (300mg, 0.98mmol) in THF (30mL) at -78°C LDA (0.6 mL, 1.18 mmol) was added to the solution, and the mixture was stirred for 1 h. Then DMF (144 mg, 1.96 mmol) was added and the mixture was transferred to room temperature and stirred for 1 h. The mixture was quenched with aqueous NH4Cl (20 mL), extracted with EtOAc (50 mL x 2), washed with brine (40 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=50/1) to give 4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole -5-Carboxaldehyde (200 mg, 66% yield) as a yellow oil. MS (ESI): 333.1 [M+H] + .
步骤3)3-溴-6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪Step 3) 3-Bromo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine
在氮气气氛下，在-78℃下，向4-溴-1-(2-((叔丁基二甲基甲硅烷基)氧基)乙基)-1H-吡唑-5-甲醛(200mg，0.60mmol)的DCM(20mL)溶液中滴加Et 3SiH(209mg，1.80mmol)和TMSOTf(800mg，3.60mmol)，混合物转移至室温，搅拌15h。将混合物用NaHCO 3水溶液(20mL)淬灭，并用DCM(50mL x 3)萃取。合并的有机层用盐水(50mL x 2)洗，经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝40/1)纯化，得到3-溴-6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪(100mg，74％收率)为黄色油状物。MS(ESI):203.1[M+H] +。 Under nitrogen atmosphere, at -78°C, 4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-5-carbaldehyde (200mg , 0.60 mmol) in DCM (20 mL) were added dropwise Et 3 SiH (209 mg, 1.80 mmol) and TMSOTf (800 mg, 3.60 mmol), and the mixture was transferred to room temperature and stirred for 15 h. The mixture was quenched with aqueous NaHCO 3 (20 mL), and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na 2 SO 4 , concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=40/1) to obtain 3-bromo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (100mg , 74% yield) as a yellow oil. MS (ESI): 203.1 [M+H] + .
步骤4)3-((三异丙基甲硅烷基)乙炔基)-6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪Step 4) 3-((triisopropylsilyl)ethynyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine
在氮气气氛下，向3-溴-6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪(100mg，0.49mmol)的MeCN(20mL)溶液中加入X-Phos(117mg，0.25mmol)、Pd 2(dba) 3(71mg，0.12mmol)和K 3PO 4(313mg，1.48mmol)，混合物升温至80℃，搅拌5h。冷却至室温后，真空浓缩。将残余物用EtOAc(60mL)稀释，并用盐水(40mL x 2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝50/1)纯化，得到3-((三异丙基甲硅烷基)乙炔基)-6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪(150mg，90％收率)为黄色油状物。MS(ESI):305.2[M+H] +。 To a solution of 3-bromo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (100 mg, 0.49 mmol) in MeCN (20 mL) was added X-Phos (117mg, 0.25mmol), Pd 2 (dba) 3 (71mg, 0.12mmol) and K 3 PO 4 (313mg, 1.48mmol), the mixture was heated to 80°C and stirred for 5h. After cooling to room temperature, it was concentrated in vacuo. The residue was diluted with EtOAc (60 mL), and washed with brine (40 mL x 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=50/1) to give 3-((triisopropylsilyl)ethynyl)-6,7-dihydro-4H-pyrazolo[5,1 -c] [1,4]oxazine (150 mg, 90% yield) as a yellow oil. MS (ESI): 305.2 [M+H] + .
步骤5)3-乙炔基-6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪Step 5) 3-ethynyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine
在0℃下，向3-((三异丙基甲硅烷基)乙炔基)-6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪(150mg，0.49mmol)的THF(10mL)溶液中加入TBAF(1mL，1mmol)，混合物搅拌2h。将混合物用H 2O(30mL)稀释，并用EtOAc(30mL x 3)萃取。合并的有机层用盐水(20mL)洗，经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝30/1)纯化，得到3-乙炔基-6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪(114mg，78％收率)为黄色油状物。MS(ESI):149.0[M+H] +。 At 0°C, 3-((triisopropylsilyl)ethynyl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine (150mg , 0.49 mmol) in THF (10 mL) was added TBAF (1 mL, 1 mmol), and the mixture was stirred for 2 h. The mixture was diluted with H 2 O (30 mL), and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=30/1) to give 3-ethynyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine ( 114 mg, 78% yield) as a yellow oil. MS (ESI): 149.0 [M+H] + .
步骤6)(S)-3-(1-氨基乙基)-8-((6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪-3-基)乙炔基)-2-苯基异喹啉-1(2H)-酮Step 6) (S)-3-(1-aminoethyl)-8-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3- Base) ethynyl) -2-phenylisoquinolin-1(2H)-one
向(S)-3-(1-氨基乙基)-8-氯-2-苯基异喹啉-1(2H)-酮(65mg，0.22mmol)和3-乙炔基-6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪(113mg，0.76mmol)的MeCN(20mL)溶液中加入X-Phos(52mg，0.11mmol)、Pd 2(dba) 3(31mg，0.05mmol)和K 3PO 4(138mg，0.65mmol)，混合物升温至80℃，搅拌5h。冷却至室温后，将混合物真空浓缩。残余物用EtOAc(70mL)稀释，并用盐水(50mL x 2)洗，经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝20/1)纯化，得到(S)-3-(1-氨基乙基)-8-((6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪-3-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(20mg，21％收率)为黄色油状物。MS(ESI):411.1[M+H] +。 To (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (65mg, 0.22mmol) and 3-ethynyl-6,7-di Hydrogen-4H-pyrazolo[5,1-c][1,4]oxazine (113 mg, 0.76 mmol) in MeCN (20 mL) was added X-Phos (52 mg, 0.11 mmol), Pd 2 (dba) 3 (31mg, 0.05mmol) and K 3 PO 4 (138mg, 0.65mmol), the mixture was heated to 80°C and stirred for 5h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with EtOAc (70 mL), washed with brine (50 mL x 2), dried over Na 2 SO 4 , concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=20/1) to give (S)-3-(1-aminoethyl)-8-((6,7-dihydro-4H-pyrazolo[5 ,1-c][1,4]oxazin-3-yl)ethynyl)-2-phenylisoquinolin-1(2H)-one (20 mg, 21% yield) as a yellow oil. MS (ESI): 411.1 [M+H] + .
步骤7)(S)-2-氨基-N-(1-(8-((6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪-3-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 7) (S)-2-amino-N-(1-(8-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine-3- Base) ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向(S)-3-(1-氨基乙基)-8-((6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪-3-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(20mg，0.05mmol)和2-氨基-5-甲基吡唑并[1,5-a]嘧啶-3-羧酸(7mg，0.05mmol)的DCM(10mL)溶液中加入DIEA(17mg，0.15mmol)、EDCI(14mg，0.07mmol)和HOAt(10mg，0.07mmol)，混合物升温至40℃，搅拌16h。混合物用DCM(50mL)稀释，并用盐水(30mL x 2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经制备型HPLC纯化(-Gemini-C18 150x 19mm,5um:ACN--H 2O(0.05％NH3),20-50)，得到(S)-2-氨基-N-(1-(8-((6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪-3-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(6.59mg，23％收率)为黄色固体。MS(ESI):570.8[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.92(dd,J＝6.8,1.6Hz,1H),8.55(dd,J＝4.4,1.6Hz,1H),8.00(d,J＝6.8Hz,1H),7.67-7.55(m,5H),7.55-7.45(m,3H),7.41-7.36(m,1H),7.01(dd,J＝6.8,4.4Hz,1H),6.74(s,1H),6.42(s,2H),4.84(s,2H),4.56(q,J＝6.4Hz,1H),4.13-4.02(m,4H),1.35(d,J＝6.8Hz,3H)。 To (S)-3-(1-aminoethyl)-8-((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl) Ethynyl)-2-phenylisoquinolin-1(2H)-one (20mg, 0.05mmol) and 2-amino-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid ( DIEA (17mg, 0.15mmol), EDCI (14mg, 0.07mmol) and HOAt (10mg, 0.07mmol) were added to a solution of 7mg, 0.05mmol) in DCM (10mL), and the mixture was heated to 40°C and stirred for 16h. The mixture was diluted with DCM (50 mL) and washed with brine (30 mL x 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (-Gemini-C18 150x 19mm, 5um:ACN-- H2O (0.05%NH3), 20-50) to give (S)-2-amino-N-(1-(8 -((6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-yl)ethynyl)-1-oxo-2-phenyl-1, 2-Dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (6.59 mg, 23% yield) was a yellow solid. MS (ESI): 570.8 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ8.92(dd, J=6.8,1.6Hz,1H),8.55(dd,J=4.4,1.6Hz,1H),8.00(d,J=6.8Hz, 1H),7.67-7.55(m,5H),7.55-7.45(m,3H),7.41-7.36(m,1H),7.01(dd,J＝6.8,4.4Hz,1H),6.74(s,1H) , 6.42 (s, 2H), 4.84 (s, 2H), 4.56 (q, J = 6.4Hz, 1H), 4.13-4.02 (m, 4H), 1.35 (d, J = 6.8Hz, 3H).
实施例32(S)-2-氨基-N-(1-(5-((2,3-二氢吡唑并[5,1-b]噁唑-6-基)乙炔基)-6-氟-4-氧代-3-苯基)-3,4-二氢喹唑啉-2-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 32 (S)-2-amino-N-(1-(5-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)ethynyl)-6- Fluoro-4-oxo-3-phenyl)-3,4-dihydroquinazolin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000090
Figure PCTCN2022121567-appb-000090
步骤1)(S)-2-(1-氨基乙基)-5-((2,3-二氢吡唑并[5,1-b]噁唑-6-基)乙炔基)-6-氟-3-苯基喹唑啉-4(3H)-酮Step 1) (S)-2-(1-aminoethyl)-5-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)ethynyl)-6- Fluoro-3-phenylquinazolin-4(3H)-one
在氮气气氛下，向6-乙炔基-2,3-二氢吡唑并[5,1-b]噁唑(50mg，0.14mmol)和2-乙炔基-5H,6H-吡唑并[3,2-b][1,3]噁唑(18.5mg，0.14mmol)的乙腈(20mL)溶液中加入Pd 2(dba) 3(32mg，0.034mmol)、X-phos(33mg，0.07mmol)和K 3PO 4(88mg，0.41mmol)，混合物升温至80℃，搅拌4h。冷却至室温后，真空浓缩。将残余物溶于DCM(50mL)，用水(30ml)和盐水(30mL)洗，真空浓缩。残余物经柱色谱法(DCM/MEOH＝10/1)纯化，得到(S)-2-(1-氨基乙基)-5-((2,3-二氢吡唑并[5,1-b]噁唑-6-基)乙炔基)-6-氟-3-苯基喹唑啉-4(3H)-酮(20mg，30％收率)为白色固体。LCMS:MS(ESI)m/z 416.1[M+H] +。 Under nitrogen atmosphere, 6-ethynyl-2,3-dihydropyrazolo[5,1-b]oxazole (50mg, 0.14mmol) and 2-ethynyl-5H,6H-pyrazolo[3 ,2-b][1,3]oxazole (18.5 mg, 0.14 mmol) in acetonitrile (20 mL) was added Pd 2 (dba) 3 (32 mg, 0.034 mmol), X-phos (33 mg, 0.07 mmol) and K 3 PO 4 (88mg, 0.41mmol), the mixture was warmed up to 80°C and stirred for 4h. After cooling to room temperature, it was concentrated in vacuo. The residue was dissolved in DCM (50 mL), washed with water (30 mL) and brine (30 mL), concentrated in vacuo. The residue was purified by column chromatography (DCM/MEOH=10/1) to obtain (S)-2-(1-aminoethyl)-5-((2,3-dihydropyrazolo[5,1- b] oxazol-6-yl)ethynyl)-6-fluoro-3-phenylquinazolin-4(3H)-one (20 mg, 30% yield) as a white solid. LCMS: MS (ESI) m/z 416.1 [M+H] + .
步骤2)(S)-2-氨基-N-(1-(5-((2,3-二氢吡唑并[5,1-b]噁唑-6-基)乙炔基)-6-氟-4-氧代-3-苯基)-3,4-二氢喹唑啉-2-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 2) (S)-2-amino-N-(1-(5-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)ethynyl)-6- Fluoro-4-oxo-3-phenyl)-3,4-dihydroquinazolin-2-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向(S)-2-(1-氨基乙基)-5-((2,3-二氢吡唑并[5,1-b]噁唑-6-基)乙炔基)-6-氟-3-苯基喹唑啉-4(3H)-酮(20mg，0.048mmol)和2-氨基吡唑并[1,5-a]嘧啶-3-羧酸(8.6mg，0.048mmol)的DCM(15mL)溶液中加入HOAt(10mg，0.072mmol)、EDCI(11mg，0.072mmol)和DIEA(18.6mg，0.14mmol)，混合物升温至40℃，搅拌 16h。冷却至室温后，将混合物加入水(30mL)稀释，并用DCM(30mL x 2)萃取。合并的有机层用盐水(30mL x 2)洗，经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法(DCM/MEOH＝10/1)纯化，得到(S)-2-氨基-N-(1-(5-((2,3-二氢吡唑并[5,1-b]噁唑-6-基)乙炔基)-6-氟-4-氧代-3-苯基)-3,4-二氢喹唑啉-2-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(4.14mg，14％收率)为白色固体。LCMS:MS(ESI)m/z 576.0[M+H] +。 1H NMR(400MHz,CDCl 3)δ8.78(d,J＝6.2Hz,1H),8.54(dd,J＝4.4,1.7Hz,1H),8.42(dd,J＝6.8,1.7Hz,1H),8.29(s,1H),7.72(d,J＝7.4Hz,1H),7.68-7.63(m,1H),7.60-7.58(m,1H),7.56-7.51(m,1H),7.35-7.28(m,1H),6.81(dd,J＝6.8,4.4Hz,1H),5.65(s,1H),5.06-4.99(m,2H),4.88-4.82(m,1H),4.34-4.27(m,2H),1.71(d,J＝6.9Hz,3H)。 To (S)-2-(1-aminoethyl)-5-((2,3-dihydropyrazolo[5,1-b]oxazol-6-yl)ethynyl)-6-fluoro- 3-Phenylquinazolin-4(3H)-one (20 mg, 0.048 mmol) and 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (8.6 mg, 0.048 mmol) in DCM ( 15 mL) solution was added HOAt (10 mg, 0.072 mmol), EDCI (11 mg, 0.072 mmol) and DIEA (18.6 mg, 0.14 mmol), and the mixture was heated to 40°C and stirred for 16 h. After cooling to room temperature, the mixture was diluted with water (30 mL), and extracted with DCM (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM/MEOH=10/1) to obtain (S)-2-amino-N-(1-(5-((2,3-dihydropyrazolo[5,1- b] oxazol-6-yl)ethynyl)-6-fluoro-4-oxo-3-phenyl)-3,4-dihydroquinazolin-2-yl)ethyl)pyrazolo[1 ,5-a]pyrimidine-3-carboxamide (4.14 mg, 14% yield) as a white solid. LCMS: MS (ESI) m/z 576.0 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ8.78(d, J=6.2Hz, 1H), 8.54(dd, J=4.4, 1.7Hz, 1H), 8.42(dd, J=6.8, 1.7Hz, 1H) ,8.29(s,1H),7.72(d,J=7.4Hz,1H),7.68-7.63(m,1H),7.60-7.58(m,1H),7.56-7.51(m,1H),7.35-7.28 (m,1H),6.81(dd,J＝6.8,4.4Hz,1H),5.65(s,1H),5.06-4.99(m,2H),4.88-4.82(m,1H),4.34-4.27(m , 2H), 1.71 (d, J=6.9Hz, 3H).
实施例33 2-氨基-N-((S)-1-(8-(((R)-5-羟基-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 33 2-amino-N-((S)-1-(8-(((R)-5-hydroxyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole- 3-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-methyl Amide
Figure PCTCN2022121567-appb-000091
Figure PCTCN2022121567-appb-000091
步骤1)(2S,4R)-4-(苄氧基)吡咯烷-2-羧酸Step 1) (2S,4R)-4-(Benzyloxy)pyrrolidine-2-carboxylic acid
向(2S,4R)-4-(苄氧基)-1-(叔丁氧基羰基)吡咯烷-2-甲酸(4g，12.4mmol)的DCM(20mL)溶液中加入TFA(4mL)，混合物搅拌2h。将混合物真空浓缩，得到(2S,4R)-4-(苄氧基)吡咯烷-2-羧酸(3g，98.4％收率)为黄色油状物。MS(ESI):222.1[M+H] +。 To a solution of (2S,4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (4 g, 12.4 mmol) in DCM (20 mL) was added TFA (4 mL), and the mixture Stir for 2h. The mixture was concentrated in vacuo to afford (2S,4R)-4-(benzyloxy)pyrrolidine-2-carboxylic acid (3 g, 98.4% yield) as a yellow oil. MS (ESI): 222.1 [M+H] + .
步骤2)(2S,4R)-4-(苄氧基)-1-亚硝基吡咯烷-2-羧酸Step 2) (2S,4R)-4-(Benzyloxy)-1-nitrosopyrrolidine-2-carboxylic acid
在0℃下，向(2S,4R)-4-(苄氧基)吡咯烷-2-羧酸(3g，13.6mmol)的H 2O(10mL)溶液中加入NaNO 2(1.41g，20.4mmol)的H 2O(5mL)溶液，然后加入HOAc(3mL)，将混合物在室温下搅拌16h。过滤，滤饼用水(10mL)洗，真空干燥，得到产物(3.5g，98％收率)为白色固体。MS(ESI):251.1[M+H] +。 To a solution of (2S,4R)-4-(benzyloxy)pyrrolidine-2-carboxylic acid (3 g, 13.6 mmol) in H 2 O (10 mL) was added NaNO 2 (1.41 g, 20.4 mmol) at 0°C ) in H 2 O (5 mL), then HOAc (3 mL) was added, and the mixture was stirred at room temperature for 16 h. After filtration, the filter cake was washed with water (10 mL) and dried in vacuo to give the product (3.5 g, 98% yield) as a white solid. MS (ESI): 251.1 [M+H] + .
步骤3)(R)-5-(苄氧基)-3-氧代-5,6-二氢-3H-吡咯并[1,2-c][1,2,3]噁二唑-7(4H)-铵-3a-内鎓盐Step 3) (R)-5-(Benzyloxy)-3-oxo-5,6-dihydro-3H-pyrrolo[1,2-c][1,2,3]oxadiazole-7 (4H)-Ammonium-3a-ylide
在0℃下，向(2S,4R)-4-(苄氧基)-1-亚硝基吡咯烷-2-羧酸(3.5g，14mmol)的THF(50mL)溶液中加入TFAA(4.41g，21mmol)，混合物于室温搅拌16h。混合物用EtOAc(80mL)稀释，并用盐水(50mL×2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(EA/PE＝1/2)纯化，得到(R)-5-(苄氧基)-3-氧代-5,6-二氢-3H-吡咯并[1,2-c][1,2,3]噁二唑-7(4H)-铵-3a-内鎓盐(1.5g，41.4％收率)为黄色油状物。MS(ESI):233.1[M+H] +。 To a solution of (2S,4R)-4-(benzyloxy)-1-nitrosopyrrolidine-2-carboxylic acid (3.5 g, 14 mmol) in THF (50 mL) was added TFAA (4.41 g , 21mmol), the mixture was stirred at room temperature for 16h. The mixture was diluted with EtOAc (80 mL), and washed with brine (50 mL×2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EA/PE=1/2) to give (R)-5-(benzyloxy)-3-oxo-5,6-dihydro-3H-pyrrolo[1,2 -c] [1,2,3]oxadiazole-7(4H)-ammonium-3a-ylide (1.5 g, 41.4% yield) as a yellow oil. MS (ESI): 233.1 [M+H] + .
步骤4)(R)-5-(苄氧基)-2-(三甲基甲硅烷基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑Step 4) (R)-5-(Benzyloxy)-2-(trimethylsilyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole
将(R)-5-(苄氧基)-3-氧代-5,6-二氢-3H-吡咯并[1,2-c][1,2,3]噁二唑-7(4H)-铵-3a-内鎓盐(1g，4.3mmol)和乙炔基三甲基硅烷(0.84g，8.6mmol)的二甲苯(10mL)混合溶液升温至130℃，加热16h。冷却至室温后，真空浓缩。残余物经柱色谱法(EA/PE＝1/3)纯化，得到(R)-5-(苄氧基)-2-(三甲基甲硅烷基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑(600mg，46.5％收率)为黄色油状物。MS(ESI):287.1[M+H] +。 (R)-5-(Benzyloxy)-3-oxo-5,6-dihydro-3H-pyrrolo[1,2-c][1,2,3]oxadiazole-7(4H )-Ammonium-3a-ylide (1 g, 4.3 mmol) and ethynyltrimethylsilane (0.84 g, 8.6 mmol) in xylene (10 mL) was warmed up to 130° C. and heated for 16 h. After cooling to room temperature, it was concentrated in vacuo. The residue was purified by column chromatography (EA/PE=1/3) to give (R)-5-(benzyloxy)-2-(trimethylsilyl)-5,6-dihydro-4H- Pyrrolo[1,2-b]pyrazole (600 mg, 46.5% yield) was a yellow oil. MS (ESI): 287.1 [M+H] + .
步骤5)(R)-5-(苄氧基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑Step 5) (R)-5-(Benzyloxy)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole
向(R)-5-(苄氧基)-2-(三甲基甲硅烷基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑(700mg，2.44mmol)的THF(5mL)溶液中加入TBAF(24.4mL，24.4mmol)，混合物升温至60℃，加热48h。冷却至室温后，混合物用EtOAc(40mL)稀释，并用盐水(30mL×2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(EA/PE＝1/2)纯化，得到(R)-5-(苄氧基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑(330mg,56.7％收率)为黄色固体。MS(ESI):215.1[M+H] +。 To (R)-5-(benzyloxy)-2-(trimethylsilyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (700mg, 2.44mmol) TBAF (24.4 mL, 24.4 mmol) was added to a THF (5 mL) solution, and the mixture was warmed to 60° C. and heated for 48 h. After cooling to room temperature, the mixture was diluted with EtOAc (40 mL), and washed with brine (30 mL×2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EA/PE=1/2) to give (R)-5-(benzyloxy)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (330 mg, 56.7% yield) as a yellow solid. MS (ESI): 215.1 [M+H] + .
步骤6)(R)-5-(苄氧基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-甲醛Step 6) (R)-5-(Benzyloxy)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carbaldehyde
向(R)-5-(苄氧基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑(330mg，1.54mmol)的DCM(20mL)溶液中加入(氯亚甲基)二甲基铵氯化物(296mg，2.31mmol)，混合物升温至40℃，加热48h。向混合物中加入1N HCl(3mL)， 升温至40℃，加热2h。然后真空浓缩，将残余物用水(5mL)稀释，并用NaHCO 3水溶液(10mL)洗。混合物用EtOAc(30mL x 3)萃取，合并的有机层用盐水(20mL)洗，经Na 2SO 4干燥，真空浓缩，得到(R)-5-(苄氧基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-甲醛(350mg，收率84％)为黄色油状物。MS(ESI):243.1[M+H] +。 To a solution of (R)-5-(benzyloxy)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (330 mg, 1.54 mmol) in DCM (20 mL) was added (chlorohydrin Methyl)dimethylammonium chloride (296mg, 2.31mmol), the mixture was warmed to 40°C and heated for 48h. 1N HCl (3 mL) was added to the mixture, the temperature was raised to 40° C., and heated for 2 h. It was then concentrated in vacuo and the residue was diluted with water (5 mL) and washed with aqueous NaHCO 3 (10 mL). The mixture was extracted with EtOAc (30 mL x 3), the combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 and concentrated in vacuo to afford (R)-5-(benzyloxy)-5,6-dihydro -4H-Pyrrolo[1,2-b]pyrazole-3-carbaldehyde (350 mg, yield 84%) was a yellow oil. MS (ESI): 243.1 [M+H] + .
步骤7)(R)-5-羟基-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-甲醛Step 7) (R)-5-Hydroxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carbaldehyde
将(R)-5-(苄氧基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-甲醛(200mg，0.82mmol)溶于浓HCl(10mL)，升温至70℃，搅拌16h。冷却至室温后，真空浓缩。将残余物用水(3mL)稀释，用碳酸氢钠水溶液(10mL)洗，然后用EtOAc(20mL x 3)萃取，合并的有机层经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(EA/PE＝1/3)纯化，得到(R)-5-羟基-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-甲醛(140mg，89％收率)为黄色固体。MS(ESI):153.1[M+H] +。 1H NMR(400MHz,CDCl 3)δ9.82(s,1H),7.97(s,1H),5.21-5.17(m,1H),4.40(dd,J＝12.4,6.0Hz,1H),4.16(dd,J＝12.4,2.4Hz,1H),3.46(dd,J＝17.6,6.4Hz,1H),3.15(dd,J＝17.6,2.4Hz,1H)。 (R)-5-(Benzyloxy)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carbaldehyde (200 mg, 0.82 mmol) was dissolved in concentrated HCl (10 mL) , warmed up to 70°C, and stirred for 16h. After cooling to room temperature, it was concentrated in vacuo. The residue was diluted with water (3 mL), washed with aqueous sodium bicarbonate (10 mL), then extracted with EtOAc (20 mL x 3), the combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by column chromatography (EA/PE=1/3) to give (R)-5-hydroxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carbaldehyde (140 mg, 89% yield) as a yellow solid. MS (ESI): 153.1 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ9.82(s, 1H), 7.97(s, 1H), 5.21-5.17(m, 1H), 4.40(dd, J=12.4, 6.0Hz, 1H), 4.16( dd, J=12.4, 2.4Hz, 1H), 3.46 (dd, J=17.6, 6.4Hz, 1H), 3.15 (dd, J=17.6, 2.4Hz, 1H).
步骤8)(R)-3-乙炔基-5,6-二氢-4H-吡咯并[1,2-b]吡唑-5-醇Step 8) (R)-3-ethynyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-5-ol
向(R)-5-羟基-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-甲醛(50mg，0.33mmol)和(1-重氮-2-氧代丙基)膦酸二甲酯(95mg，0.49mmol)的MeOH(20mL)溶液中加入K 2CO 3(91mg，0.66mmol)，混合物于室温搅拌16h。将混合物真空浓缩，用EtOAc(60mL)稀释，并用盐水(20mL×2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩，得到(R)-3-乙炔基-5,6-二氢-4H-吡咯并[1,2-b]吡唑-5-醇(45mg，83％收率)为黄色油状物。MS(ESI):148.9[M+H] +。 1HNMR(400MHz,CDCl 3)δ7.62(s,1H),5.15-5.07(m,1H),4.35(dd,J＝12.0,6.0Hz,1H),4.09(dd,J＝12.0,2.8Hz,1H),3.77(d,J＝10.8Hz,1H),3.30(dd,J＝16.8,6.4Hz,1H),3.02(s,1H),2.93(dd,J＝16.8,2.8Hz,1H)。 To (R)-5-hydroxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carbaldehyde (50mg, 0.33mmol) and (1-diazo-2-oxo To a solution of dimethyl propyl)phosphonate (95 mg, 0.49 mmol) in MeOH (20 mL) was added K 2 CO 3 (91 mg, 0.66 mmol), and the mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo, diluted with EtOAc (60 mL), and washed with brine (20 mL×2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo to give (R)-3-ethynyl-5,6-dihydro-4H - pyrrolo[1,2-b]pyrazol-5-ol (45 mg , 83% yield) as a yellow oil. MS (ESI): 148.9 [M+H] + . 1 HNMR (400MHz, CDCl 3 ) δ7.62(s, 1H), 5.15-5.07(m, 1H), 4.35(dd, J＝12.0, 6.0Hz, 1H), 4.09(dd, J＝12.0, 2.8Hz ,1H),3.77(d,J=10.8Hz,1H),3.30(dd,J=16.8,6.4Hz,1H),3.02(s,1H),2.93(dd,J=16.8,2.8Hz,1H) .
步骤9)3-((S)-1-氨基乙基)-8-(((R)-5-羟基-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)乙炔基)-2-苯基异喹啉-1(2H)-酮Step 9) 3-((S)-1-Aminoethyl)-8-(((R)-5-Hydroxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole- 3-yl)ethynyl)-2-phenylisoquinolin-1(2H)-one
在氮气气氛下，向3-((1S)-1-氨基乙基)-8-氯-2-苯基异喹啉-1-酮(50mg，0.17mmol)和4-乙炔基-1-甲基吡唑(37mg，0.25mmol)的CH 3CN(20mL)溶液中加入Pd 2(dba) 3(31mg，0.033mmol)、K 3PO 4(71mg，0.33mmol)和X-phos(32mg，0.067mmol)，混合物升温至80℃，搅拌5h。冷却至室温后，混合物用EtOAc(60mL)稀释，并用盐水(40mL×2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝20/1)纯化，得到3-((S)-1-氨基乙基)-8-(((R)-5-羟基-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(40mg，61％)为黄色固体。MS(ESI):394.0[M+H] +。 Under nitrogen atmosphere, 3-((1S)-1-aminoethyl)-8-chloro-2-phenylisoquinolin-1-one (50 mg, 0.17 mmol) and 4-ethynyl-1-methanol Pd 2 (dba) 3 (31 mg, 0.033 mmol), K 3 PO 4 (71 mg, 0.33 mmol) and X-phos (32 mg, 0.067 mmol), the mixture was warmed up to 80°C and stirred for 5h. After cooling to room temperature, the mixture was diluted with EtOAc (60 mL), and washed with brine (40 mL×2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=20/1) to give 3-((S)-1-aminoethyl)-8-(((R)-5-hydroxy-5,6-dihydro -4H-pyrrolo[1,2-b]pyrazol-3-yl)ethynyl)-2-phenylisoquinolin-1(2H)-one (40 mg, 61%) was a yellow solid. MS (ESI): 394.0 [M+H] + .
步骤10)2-氨基-N-((S)-1-(8-(((R)-5-羟基-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 10) 2-Amino-N-((S)-1-(8-(((R)-5-Hydroxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole- 3-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-methyl Amide
向3-((S)-1-氨基乙基)-8-(((R)-5-羟基-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(40mg，0.1mmol)和2-氨基吡唑并[1,5-a]嘧啶-3-羧酸(19.5mg，0.1mmol)的DCM(20mL)溶液中加入EDCI(31.5mg，0.16mmol)、HOAt(18mg，0.13mmol)和DIEA(43mg，0.32mmol)，混合物升温至40℃，搅拌16h。冷却至室温后，将混合物用DCM(40mL)稀释，并用盐水(20mL x 2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经制备型HPLC(ACN-H 2O，0.1％FA，梯度20％至50％)纯化，得到2-氨基-N-((S)-1-(8-(((R)-5-羟基-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(14.6mg，23％收率)为淡黄色固体。MS(ESI):571.2[M+H] +。 1H NMR(400MHz,CD 3OD)δ8.62(dd,J＝6.8,1.6Hz,1H),8.43(dd,J＝4.4,1.6Hz,1H),8.14(d,J＝6.8Hz,1H),7.61(s,1H),7.57-7.54(m,2H),7.52-7.48(m,2H),7.45-7.33(m,4H),6.89(dd,J＝6.8,4.4Hz,1H),6.80(s,1H),4.93-4.90(m,1H),4.72-4.65(m,1H),4.24(dd,J＝11.6,5.6Hz,1H),3.88(dd,J＝11.6,2.4Hz,1H),3.19(d,J＝6.4Hz,1H),2.82(dd,J＝16.8,2.4Hz,1H),1.39(d,J＝6.8Hz,3H)。 To 3-((S)-1-aminoethyl)-8-(((R)-5-hydroxyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3- base)ethynyl)-2-phenylisoquinolin-1(2H)-one (40mg, 0.1mmol) and 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (19.5mg, 0.1 mmol) in DCM (20 mL) was added with EDCI (31.5 mg, 0.16 mmol), HOAt (18 mg, 0.13 mmol) and DIEA (43 mg, 0.32 mmol), and the mixture was heated to 40°C and stirred for 16 h. After cooling to room temperature, the mixture was diluted with DCM (40 mL), and washed with brine (20 mL x 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (ACN- H2O , 0.1% FA, gradient 20% to 50%) to give 2-amino-N-((S)-1-(8-(((R)-5 -Hydroxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinol Lin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (14.6 mg, 23% yield) was a pale yellow solid. MS (ESI): 571.2 [M+H] + . 1 H NMR (400MHz, CD 3 OD) δ8.62(dd, J=6.8, 1.6Hz, 1H), 8.43(dd, J=4.4, 1.6Hz, 1H), 8.14(d, J=6.8Hz, 1H ),7.61(s,1H),7.57-7.54(m,2H),7.52-7.48(m,2H),7.45-7.33(m,4H),6.89(dd,J＝6.8,4.4Hz,1H), 6.80(s,1H),4.93-4.90(m,1H),4.72-4.65(m,1H),4.24(dd,J=11.6,5.6Hz,1H),3.88(dd,J=11.6,2.4Hz, 1H), 3.19 (d, J=6.4Hz, 1H), 2.82 (dd, J=16.8, 2.4Hz, 1H), 1.39 (d, J=6.8Hz, 3H).
实施例34(S)-2-氨基-N-(1-(7-氟-8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-(苯基-d5)-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 34 (S)-2-amino-N-(1-(7-fluoro-8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2- (Phenyl-d5)-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000092
Figure PCTCN2022121567-appb-000092
步骤1)2-氯-3-氟-6-甲基-N-(苯基-d5)苯甲酰胺Step 1) 2-Chloro-3-fluoro-6-methyl-N-(phenyl-d5)benzamide
在0℃下，向2-氯-3-氟-6-甲基苯甲酸(1.0g，5.3mmol)和DMF(40mg，0.53mmol)的DCM(25mL)溶液中滴加草酰氯(810mg，6.36mmol)，滴毕，混合物搅拌2h。将混合物减压浓缩，得到酰氯混合物。在0℃下，向苯-d5-胺(550mg，5.3mmol)和TEA(1.61g，15.9mol)的DCM(25mL)溶液中加入上述酰氯的DCM(10mL)溶液，混合物升温至室温，搅拌5h。混合物用H 2O(30mL)稀释，并用DCM(30mL x 3)萃取。合并的有机层用盐水(50mL x 2)洗，经Na 2SO 4干燥，减压浓缩。残余物经柱色谱法(PE/EA＝3/1)纯化，得到2-氯-3-氟-6-甲基-N-(苯基-d5)苯甲酰胺(1.01g，64％收率)为黄色固体。MS(ESI):269.1[M+H] +。 To a solution of 2-chloro-3-fluoro-6-methylbenzoic acid (1.0 g, 5.3 mmol) and DMF (40 mg, 0.53 mmol) in DCM (25 mL) was added dropwise oxalyl chloride (810 mg, 6.36 mmol), after dropping, the mixture was stirred for 2h. The mixture was concentrated under reduced pressure to obtain a mixture of acid chlorides. At 0°C, to a solution of phenyl-d5-amine (550 mg, 5.3 mmol) and TEA (1.61 g, 15.9 mol) in DCM (25 mL) was added a solution of the above acid chloride in DCM (10 mL), and the mixture was warmed to room temperature and stirred for 5 h . The mixture was diluted with H 2 O (30 mL), and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA=3/1) to give 2-chloro-3-fluoro-6-methyl-N-(phenyl-d5)benzamide (1.01 g, 64% yield ) is a yellow solid. MS (ESI): 269.1 [M+H] + .
步骤2)(S)-(4-(3-氯-4-氟-2-((苯基-d5)氨基甲酰基)苯基)-3-氧代丁-2-基)氨基甲酸叔丁酯Step 2) (S)-tert-butyl(4-(3-chloro-4-fluoro-2-((phenyl-d5)carbamoyl)phenyl)-3-oxobutan-2-yl)carbamate ester
在氮气气氛下，将2-氯-3-氟-6-甲基-N-(苯基-d5)苯甲酰胺(1.01g，3.8mmol)的THF(25mL)溶液降温至-30℃，加入n-BuLi(4.0mL，9.5mmol)，搅拌1h，得到黄色液体。在-30℃下，向(S)-(1-(甲氧基(甲基)氨基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(1.32g，5.7mmol)的THF(25mL)溶液中加入异丙基氯化镁(8.8mL，11.4mmol)溶液，搅拌1h。然后将混合物缓慢加入到上述黄色混合物中，转移至室温，搅拌3小时。将混合物用NH 4Cl(30mL)水溶液稀释，并用EtOAc(50mL x 3)萃取。合并的有机层用盐水(40mL x 2)洗，经Na 2SO 4干燥，减压浓缩。残余物经柱色谱法(PE/EA＝3/1)纯化，得到(S)-(4-(3-氯-4-氟-2-((苯基-d5)氨基甲酰基)苯基)-3-氧代丁-2-基)氨基甲酸叔丁酯(0.63g，37％收率)为黄色固体。MS(ESI):462.1[M+Na] +。 Under a nitrogen atmosphere, a solution of 2-chloro-3-fluoro-6-methyl-N-(phenyl-d5)benzamide (1.01g, 3.8mmol) in THF (25mL) was cooled to -30°C and added n-BuLi (4.0 mL, 9.5 mmol) was stirred for 1 h to give a yellow liquid. To tert-butyl (S)-(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (1.32 g, 5.7 mmol) in THF ( 25mL) solution was added isopropylmagnesium chloride (8.8mL, 11.4mmol) solution, stirred for 1h. The mixture was then slowly added to the above yellow mixture, transferred to room temperature, and stirred for 3 hours. The mixture was diluted with aqueous NH 4 Cl (30 mL), and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (40 mL x 2), dried over Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified by column chromatography (PE/EA=3/1) to give (S)-(4-(3-chloro-4-fluoro-2-((phenyl-d5)carbamoyl)phenyl) tert-butyl-3-oxobut-2-yl)carbamate (0.63 g, 37% yield) was a yellow solid. MS (ESI): 462.1 [M+Na] + .
步骤3)(S)-3-(1-氨基乙基)-8-氯-7-氟-2-(苯基-d5)异喹啉-1(2H)-酮Step 3) (S)-3-(1-aminoethyl)-8-chloro-7-fluoro-2-(phenyl-d5)isoquinolin-1(2H)-one
向(S)-(4-(3-氯-4-氟-2-((苯基-d5)氨基甲酰基)苯基)-3-氧代丁-2-基)氨基甲酸叔丁酯(0.63g，1.43mmol)的MeOH(30mL)溶液中加入浓HCl(15mL)，混合物升温至80℃，搅拌24h。冷却至室温后，将混合物减压浓缩。残余物用H 2O(10mL)稀释，并用NaHCO 3水溶液将pH值调节至7-8。混合物用DCM(60mL x 3)萃取，并用盐水(50mL x 2)洗。分离的有机层经Na 2SO 4干燥，并减压浓缩。残余物经柱色谱法(DCM/MeOH＝95/5)纯化，得到(S)-3-(1-氨基乙基)-8-氯-7-氟-2-(苯基-d5)异喹啉-1(2H)-酮(160mg，33％收率)为黄色固体。MS(ESI):321.9[M+H] +。 To (S)-(4-(3-chloro-4-fluoro-2-((phenyl-d5)carbamoyl)phenyl)-3-oxobut-2-yl)carbamate tert-butyl ester ( Concentrated HCl (15 mL) was added to a solution of 0.63 g, 1.43 mmol) in MeOH (30 mL), and the mixture was warmed to 80° C. and stirred for 24 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with H2O (10 mL), and the pH was adjusted to 7-8 with aqueous NaHCO3 . The mixture was extracted with DCM (60 mL x 3) and washed with brine (50 mL x 2). The separated organic layer was dried over Na2SO4 , and concentrated under reduced pressure. The residue was purified by column chromatography (DCM/MeOH=95/5) to give (S)-3-(1-aminoethyl)-8-chloro-7-fluoro-2-(phenyl-d5)isoquine Lin-1(2H)-one (160 mg, 33% yield) was a yellow solid. MS (ESI): 321.9 [M+H] + .
步骤4)(S)-3-(1-氨基乙基)-7-氟-8-((1-甲基-1H-吡唑-4-基)乙炔基)-2-(苯基-d5)异喹啉-1(2H)-酮Step 4) (S)-3-(1-aminoethyl)-7-fluoro-8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2-(phenyl-d5 ) isoquinolin-1(2H)-one
向(S)-3-(1-氨基乙基)-8-氯-7-氟-2-(苯基-d5)异喹啉-1(2H)-酮(160mg，0.50mmol)和4-乙炔基-1-甲基-1H-吡唑(79mg，0.75mmol)的MeCN(10mL)溶液中加入X-Phos(118mg，0.25mmol)、Pd 2(dba) 3(72mg，0.12mmol)和K 3PO 4(317mg，1.50mmol)，混合物升温至80℃，搅拌5h。冷却至室温后，真空浓缩。将残余物用EtOAc(80mL)稀释，并用盐水(50mL x 2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝20/1)纯化，得到(S)-3-(1-氨基乙基)-7-氟-8-((1-甲基-1H-吡唑-4-基)乙炔基)-2-(苯基-d5)异喹啉-1(2H)-酮(110mg，53％收率)为黄色油状物。MS(ESI):391.9[M+H] +。 To (S)-3-(1-aminoethyl)-8-chloro-7-fluoro-2-(phenyl-d5)isoquinolin-1(2H)-one (160mg, 0.50mmol) and 4- Ethynyl-1-methyl-1H-pyrazole (79 mg, 0.75 mmol) in MeCN (10 mL) was added with X-Phos (118 mg, 0.25 mmol), Pd 2 (dba) 3 (72 mg, 0.12 mmol) and K 3 PO 4 (317mg, 1.50mmol), the mixture was warmed up to 80°C and stirred for 5h. After cooling to room temperature, it was concentrated in vacuo. The residue was diluted with EtOAc (80 mL), and washed with brine (50 mL x 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=20/1) to give (S)-3-(1-aminoethyl)-7-fluoro-8-((1-methyl-1H-pyrazole- 4-yl)ethynyl)-2-(phenyl-d5)isoquinolin-1(2H)-one (110 mg, 53% yield) as a yellow oil. MS (ESI): 391.9 [M+H] + .
步骤5)(S)-2-氨基-N-(1-(7-氟-8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-(苯基-d5)-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 5) (S)-2-amino-N-(1-(7-fluoro-8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2- (Phenyl-d5)-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向(S)-3-(1-氨基乙基)-7-氟-8-((1-甲基-1H-吡唑-4-基)乙炔基)-2-(苯基-d5)异喹啉-1(2H)-酮(110mg，0.28mmol)和2-氨基-5-甲基吡唑并[1,5-a]嘧啶-3-甲酸(55mg，0.31mmol)的DCM(30mL)溶液中加入DIEA(109mg，0.84mmol)、EDCI(81mg，0.42mmol)和HOAt(57mg，0.42mmol)，混合物升温至40℃，搅拌16h。冷却至室温后，将混合物用DCM(60mL)稀释，并用盐水(40mL x 2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经制备型HPLC(-Gemini-C18 150x 19mm,5um:ACN--H2O(0.05％NH 3),20-50)纯化，得到(S)-2-氨基-N-(1-(7-氟-8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-(苯基-d5)-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(31.8mg，20％收率)为黄色固体。MS(ESI):552.1[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.93(dd,J＝6.8,1.6Hz,1H),8.55(dd,J＝4.4,1.6Hz,1H),8.05(s,1H),8.00(d,J＝6.8Hz,1H), 7.70(ddd,J＝21.2,13.2,7.2Hz,2H),7.61(s,1H),7.02(dd,J＝6.8,4.4Hz,1H),6.79(s,1H),6.43(s,2H),4.58-4.50(m,1H),3.82(s,3H),1.34(d,J＝6.8Hz,3H)。 To (S)-3-(1-aminoethyl)-7-fluoro-8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2-(phenyl-d5)iso Quinolin-1(2H)-one (110 mg, 0.28 mmol) and 2-amino-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (55 mg, 0.31 mmol) in DCM (30 mL) DIEA (109mg, 0.84mmol), EDCI (81mg, 0.42mmol) and HOAt (57mg, 0.42mmol) were added to the solution, and the mixture was heated to 40°C and stirred for 16h. After cooling to room temperature, the mixture was diluted with DCM (60 mL), and washed with brine (40 mL x 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (-Gemini-C18 150x 19mm, 5um:ACN--H2O(0.05% NH3 ), 20-50) to give (S)-2-amino-N-(1-(7- Fluoro-8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-(phenyl-d5)-1,2-dihydroisoquinoline-3- yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (31.8 mg, 20% yield) as a yellow solid. MS (ESI): 552.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.93 (dd, J=6.8, 1.6Hz, 1H), 8.55 (dd, J=4.4, 1.6Hz, 1H), 8.05(s, 1H), 8.00( d,J=6.8Hz,1H), 7.70(ddd,J=21.2,13.2,7.2Hz,2H),7.61(s,1H),7.02(dd,J=6.8,4.4Hz,1H),6.79(s , 1H), 6.43 (s, 2H), 4.58-4.50 (m, 1H), 3.82 (s, 3H), 1.34 (d, J=6.8Hz, 3H).
实施例35(S)-2-氨基-N-(1-(7-氟-8-((1-甲基-1H-吡唑-4-基-5-d)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 35 (S)-2-amino-N-(1-(7-fluoro-8-((1-methyl-1H-pyrazol-4-yl-5-d)ethynyl)-1-oxo Substitute-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000093
Figure PCTCN2022121567-appb-000093
步骤1)1-甲基-1H-吡唑-5-dStep 1) 1-methyl-1H-pyrazole-5-d
在-15℃下，向5-溴-1-甲基-1H-吡唑(2g，12.42mmol)的THF(10mL)溶液中加入i-PrMgCl.LiCl(2.16mg，14.9mmol；1.3M的THF溶液)。混合物升温至-10～0℃，搅拌1h。在-10℃下，向反应混合物中加入甲醇-d4(0.5mL)，室温下搅拌16h。混合物用NH 4Cl水溶液(5mL)和MTBE(50mL)淬灭；分液，有机相用盐水(20mL x 2)洗。分离的有机层经无水Na 2SO 4干燥，过滤，真空浓缩，得到1-甲基-1H-吡唑-5-d(500mg，48％收率)为无色油状物。LCMS:MS(ESI)m/z 84.1[M+H] +。 To a solution of 5-bromo-1-methyl-1H-pyrazole (2 g, 12.42 mmol) in THF (10 mL) at -15°C was added i-PrMgCl.LiCl (2.16 mg, 14.9 mmol; 1.3 M in THF solution). The mixture was warmed to -10~0°C and stirred for 1 h. Methanol-d4 (0.5 mL) was added to the reaction mixture at -10°C, and stirred at room temperature for 16 h. The mixture was quenched with aqueous NH4Cl (5 mL) and MTBE (50 mL); the layers were separated and the organic phase was washed with brine (20 mL x 2). The separated organic layer was dried over anhydrous Na2SO4 , filtered and concentrated in vacuo to afford 1-methyl-1H-pyrazole-5-d (500 mg, 48% yield) as a colorless oil. LCMS: MS (ESI) m/z 84.1 [M+H] + .
步骤2)4-碘-1-甲基-1H-吡唑-5-dStep 2) 4-iodo-1-methyl-1H-pyrazole-5-d
向1-甲基-1H-吡唑-5-d(500mg，6mmol)的水(10mL)溶液中加入单质碘(763mg，3mmol)，混合物于室温搅拌0.5h，然后加入H 2O 2(3mL)，升温至60℃，搅拌1h。冷却至室温后，用亚硫酸钠水溶液(30mL)淬灭反应。混合物用EtOAc(50mL x 2)萃取，合并的有机层用盐水(50mL x 2)洗，经无水Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(PE:EA＝3:1)纯化，得到4-碘-1-甲基-1H-吡唑-5-d(1g，79％收率)为黄色固体。LCMS:MS(ESI)m/z 210.1[M+H] +。 To a solution of 1-methyl-1H-pyrazole-5-d (500mg, 6mmol) in water (10mL) was added elemental iodine (763mg, 3mmol), the mixture was stirred at room temperature for 0.5h, then H 2 O 2 (3mL ), warming up to 60°C and stirring for 1h. After cooling to room temperature, the reaction was quenched with aqueous sodium sulfite (30 mL). The mixture was extracted with EtOAc (50 mL x 2), the combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na 2 SO 4 , and concentrated in vacuo. The residue was purified by column chromatography (PE:EA=3:1) to give 4-iodo-1-methyl-1H-pyrazole-5-d (1 g, 79% yield) as a yellow solid. LCMS: MS (ESI) m/z 210.1 [M+H] + .
步骤3)1-甲基-4-((三甲基甲硅烷基)乙炔基)-1H-吡唑-5-dStep 3) 1-methyl-4-((trimethylsilyl)ethynyl)-1H-pyrazole-5-d
在0℃下，向4-碘-1-甲基-1H-吡唑-5-d(1g，4.78mmol)和乙炔基三甲基硅烷(705mg，7.18mmol)的THF(100mL)溶液中加入CuI(91mg，0.48mmol)、Pd(PPh 3) 2Cl 2(168mg，0.24mmol)和三乙胺(968mg，9.57mmol)，混合物于室温搅拌2小时。残余物用EtOAc(300mL)稀释，并用盐水(200mL x 2)洗。分离的有机层经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法纯化(PE:EA＝3:1))，得到1-甲基-4-((三甲基甲硅烷基)乙炔基)-1H-吡唑-5-d(700mg，81％收率)为黄色油状物。LCMS:MS(ESI)m/z 180.2[M+H] +。 To a solution of 4-iodo-1-methyl-1H-pyrazole-5-d (1 g, 4.78 mmol) and ethynyltrimethylsilane (705 mg, 7.18 mmol) in THF (100 mL) at 0°C was added CuI (91 mg, 0.48 mmol), Pd(PPh 3 ) 2 Cl 2 (168 mg, 0.24 mmol) and triethylamine (968 mg, 9.57 mmol), the mixture was stirred at room temperature for 2 hours. The residue was diluted with EtOAc (300 mL), and washed with brine (200 mL x 2). The separated organic layer was dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (PE:EA=3:1)) to obtain 1-methyl-4-((trimethylsilyl)ethynyl)-1H-pyrazole-5-d (700 mg, 81% yield) as a yellow oil. LCMS: MS (ESI) m/z 180.2 [M+H] + .
步骤4)4-乙炔基-1-甲基-1H-吡唑-5-dStep 4) 4-ethynyl-1-methyl-1H-pyrazole-5-d
向1-甲基-4-((三甲基甲硅烷基)乙炔基)-1H-吡唑-5-d(700mg，3.9mmol)的THF(20mL)溶液中加入TBAF(4mL，4mmol，1M的THF溶液)，混合物于室温搅拌1h。然后混合物用EtOAc(50mL)稀释，并用盐水(30mL x 2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(PE:EA＝3:1)纯化，得到4-乙炔基-1-甲基-1H-吡唑-5-d(200mg，47％收率)为黄色油状。LCMS:MS(ESI)m/z 108.0[M+H] +。 To a solution of 1-methyl-4-((trimethylsilyl)ethynyl)-1H-pyrazole-5-d (700 mg, 3.9 mmol) in THF (20 mL) was added TBAF (4 mL, 4 mmol, 1M THF solution), the mixture was stirred at room temperature for 1 h. Then the mixture was diluted with EtOAc (50 mL) and washed with brine (30 mL x 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (PE:EA=3:1) to give 4-ethynyl-1-methyl-1H-pyrazole-5-d (200 mg, 47% yield) as a yellow oil. LCMS: MS (ESI) m/z 108.0 [M+H] + .
步骤5)(S)-3-(1-氨基乙基)-7-氟-8-((1-甲基-1H-吡唑-4-基-5-d)乙炔基)-2-苯基异喹啉-1(2H)-酮Step 5) (S)-3-(1-aminoethyl)-7-fluoro-8-((1-methyl-1H-pyrazol-4-yl-5-d)ethynyl)-2-benzene Isoquinolin-1(2H)-one
将(S)-3-(1-氨基乙基)-8-氯-7-氟-2-苯基异喹啉-1(2H)-酮(50mg，0.16mmol)和4-乙炔基-1-甲基-1H-吡唑-5-d(25mg，0.24mmol)的MeCN(20mL)溶液中加入Pd 2(dba) 3(29mg，0.032mmol)、X-phos(30mg，0.063mmol)和K 3PO 4(67mg，0.32mmol)，混合物升温至80℃，搅拌4h。冷却至室温后，真空浓缩。残余物用DCM(50mL)稀释，并用盐水(30mL x 2)洗。分离的有机层经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法纯化(DCM:MeOH＝10:1)，得到(S)-3-(1-氨基乙基)-7-氟-8-((1-甲基-1H-吡唑-4-基-5-d)乙炔基)-2-苯基异喹啉-1(2H)-酮(20mg，32％收率)为黄色固体。LCMS:MS(ESI)m/z 388.1[M+H] +。 (S)-3-(1-aminoethyl)-8-chloro-7-fluoro-2-phenylisoquinolin-1(2H)-one (50mg, 0.16mmol) and 4-ethynyl-1 -Methyl-1H-pyrazole-5-d (25 mg, 0.24 mmol) in MeCN (20 mL) was added with Pd 2 (dba) 3 (29 mg, 0.032 mmol), X-phos (30 mg, 0.063 mmol) and K 3 PO 4 (67mg, 0.32mmol), the mixture was warmed up to 80°C and stirred for 4h. After cooling to room temperature, it was concentrated in vacuo. The residue was diluted with DCM (50 mL), and washed with brine (30 mL x 2). The separated organic layer was dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM:MeOH=10:1) to give (S)-3-(1-aminoethyl)-7-fluoro-8-((1-methyl-1H-pyrazole- 4-yl-5-d)ethynyl)-2-phenylisoquinolin-1(2H)-one (20 mg, 32% yield) was a yellow solid. LCMS: MS (ESI) m/z 388.1 [M+H] + .
步骤6)(S)-2-氨基-N-(1-(7-氟-8-((1-甲基-1H-吡唑-4-基-5-d)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 6) (S)-2-amino-N-(1-(7-fluoro-8-((1-methyl-1H-pyrazol-4-yl-5-d)ethynyl)-1-oxo Substitute-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向(S)-3-(1-氨基乙基)-7-氟-8-((1-甲基-1H-吡唑-4-基-5-d)乙炔基)-2-苯基异喹啉-1(2H)-酮(20mg，0.052mmol)和2-氨基吡唑并[1,5-a]嘧啶-3-羧酸(9mg，0.052mmol)的DCM(15mL)溶液中加入HOAt(10mg， 0.078mmol)、EDCI(12mg，0.078mmol)和DIEA(20mg，0.155mmol)，混合物升温至40℃，搅拌16h。冷却至室温后，将混合物用DCM(50mL)稀释，并用盐水(30mL x 2)洗。分离的有机层经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法(DCM:MeOH＝10:1)纯化，得到(S)-2-氨基-N-(1-(7-氟-8-((1-甲基-1H-吡唑-4-基-5-d)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(7.3mg，25％收率)为白色固体。LCMS:MS(ESI)m/z 548.0[M+H] +。 1H NMR(400MHz,CD 3OD)δ8.72(dd,J＝6.8,1.6Hz,1H),8.53(dd,J＝4.4,1.6Hz,1H),7.69(s,1H),7.67-7.60(m,2H),7.59-7.42(m,5H),6.99(dd,J＝6.8,4.4Hz,1H),6.91(s,1H),4.77(q,J＝6.8Hz,1H),3.89(s,3H),1.48(d,J＝6.8Hz,3H)。 To (S)-3-(1-aminoethyl)-7-fluoro-8-((1-methyl-1H-pyrazol-4-yl-5-d)ethynyl)-2-phenyliso To a solution of quinolin-1(2H)-one (20 mg, 0.052 mmol) and 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (9 mg, 0.052 mmol) in DCM (15 mL) was added HOAt (10mg, 0.078mmol), EDCI (12mg, 0.078mmol) and DIEA (20mg, 0.155mmol), the mixture was heated to 40°C and stirred for 16h. After cooling to room temperature, the mixture was diluted with DCM (50 mL), and washed with brine (30 mL x 2). The separated organic layer was dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM:MeOH=10:1) to give (S)-2-amino-N-(1-(7-fluoro-8-((1-methyl-1H-pyrazole- 4-yl-5-d)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine -3-Carboxamide (7.3 mg, 25% yield) was a white solid. LCMS: MS (ESI) m/z 548.0 [M+H] + . 1 H NMR (400MHz, CD 3 OD) δ8.72 (dd, J = 6.8, 1.6Hz, 1H), 8.53 (dd, J = 4.4, 1.6Hz, 1H), 7.69 (s, 1H), 7.67-7.60 (m,2H),7.59-7.42(m,5H),6.99(dd,J=6.8,4.4Hz,1H),6.91(s,1H),4.77(q,J=6.8Hz,1H),3.89( s, 3H), 1.48 (d, J=6.8Hz, 3H).
实施例36(S)-2-氨基-N-(1-(5-氟-8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 36 (S)-2-amino-N-(1-(5-fluoro-8-((1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-1-oxo Substitute-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000094
Figure PCTCN2022121567-appb-000094
步骤1)6-氯-2-甲基-3-硝基苯甲酸Step 1) 6-Chloro-2-methyl-3-nitrobenzoic acid
在0℃下，向2-氯-6-甲基苯甲酸(10g，0.0586mol)的硫酸(100mL)溶液中滴加硝酸(4.1g，0.064mol，2.6mL)，混合物搅拌30分钟后，转移至室温，搅拌16h。将混合物缓慢倒入冰水(260mL)中，继续搅拌1h。过滤，滤饼用水(50mL)洗，真空干燥，得到6-氯-2-甲基-3-硝基苯甲酸(12.5g，收率98％)为白色固体。LCMS:MS(ESI)m/z 214.4[M-H] -。 At 0°C, nitric acid (4.1 g, 0.064 mol, 2.6 mL) was added dropwise to a solution of 2-chloro-6-methylbenzoic acid (10 g, 0.0586 mol) in sulfuric acid (100 mL), and the mixture was stirred for 30 minutes, then transferred To room temperature, stirred for 16h. The mixture was slowly poured into ice water (260 mL) and stirring was continued for 1 h. After filtration, the filter cake was washed with water (50 mL) and dried in vacuo to obtain 6-chloro-2-methyl-3-nitrobenzoic acid (12.5 g, yield 98%) as a white solid. LCMS: MS (ESI) m/z 214.4 [MH] - .
步骤2)6-氯-2-甲基-3-硝基-N-苯基苯甲酰胺Step 2) 6-Chloro-2-methyl-3-nitro-N-phenylbenzamide
在0℃下，向6-氯-2-甲基-3-硝基苯甲酸(11.5g，0.053mol)的DCM(60mL)溶液中加入DMF(1mL)和草酰氯(8.2g，0.064mol)，混合物转移至室温，搅拌2h；将混合物真空浓缩，得到白色固体(13g)。在0℃下，将上述白色固体(13g)溶于DCM(20mL)，加入苯胺(7.5g，0.08mol)、三乙胺(5.4g，0.0533mol)和DCM(60mL)，混合物于室温搅拌16小时。将混合物用水(200mL)淬灭，并用DCM(200mL x 2)萃取。合并的有机层用盐水(200mL x 2)洗，经无水Na 2SO 4干燥，过滤，真空浓缩，得到6-氯-2-甲基-3-硝基-N-苯基苯甲酰胺(14g，89％收率)为黄色固体。LCMS:MS(ESI)m/z 291.0[M+H] +。 To a solution of 6-chloro-2-methyl-3-nitrobenzoic acid (11.5 g, 0.053 mol) in DCM (60 mL) was added DMF (1 mL) and oxalyl chloride (8.2 g, 0.064 mol) at 0 °C , the mixture was transferred to room temperature and stirred for 2 h; the mixture was concentrated in vacuo to give a white solid (13 g). At 0°C, the above white solid (13g) was dissolved in DCM (20mL), aniline (7.5g, 0.08mol), triethylamine (5.4g, 0.0533mol) and DCM (60mL) were added, and the mixture was stirred at room temperature for 16 Hour. The mixture was quenched with water (200 mL), and extracted with DCM (200 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous Na2SO4 , filtered, and concentrated in vacuo to give 6-chloro-2-methyl-3-nitro-N-phenylbenzamide ( 14 g, 89% yield) as a yellow solid. LCMS: MS (ESI) m/z 291.0 [M+H] + .
步骤3)3-氨基-6-氯-2-甲基-N-苯基苯甲酰胺Step 3) 3-Amino-6-chloro-2-methyl-N-phenylbenzamide
向6-氯-2-甲基-3-硝基-N-苯基苯甲酰胺(15g，0.051mol)的MeOH(200mL)溶液中加入SnCl 2(29.7g，0.155mol)，混合物升温至回流，搅拌24h。冷却至室温后，真空浓缩。残余物用NaHCO 3水溶液(200mL)淬灭，并用EtOAc(300mL x 2)萃取。合并的有机层用盐水(200mL x 2)洗，经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法(PE/EA＝3/1))纯化，得到3-氨基-6-氯-2-甲基-N-苯基苯甲酰胺(7g，51％收率)为白色固体。LCMS:MS(ESI)m/z 261.1[M+H] +。 To a solution of 6-chloro-2-methyl-3-nitro-N-phenylbenzamide (15g, 0.051mol) in MeOH (200mL) was added SnCl 2 (29.7g, 0.155mol), and the mixture was warmed to reflux , stirred for 24h. After cooling to room temperature, it was concentrated in vacuo. The residue was quenched with aqueous NaHCO 3 (200 mL), and extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=3/1)) to give 3-amino-6-chloro-2-methyl-N-phenylbenzamide (7 g, 51% yield) as a white solid . LCMS: MS (ESI) m/z 261.1 [M+H] + .
步骤4)6-氯-3-氟-2-甲基-N-苯基苯甲酰胺Step 4) 6-Chloro-3-fluoro-2-methyl-N-phenylbenzamide
在0℃下，向3-氨基-6-氯-2-甲基-N-苯基苯甲酰胺(2g，7.67mmol)的四氟硼酸(48mass％,20mL)溶液中缓慢滴加硝酸钠(1g，15.34mmol)水溶液(5mL)，滴毕，混合物转移至常温，搅拌1h。过滤，用冷水(5mL x 2)冲洗滤饼，真空干燥，得到白色固体状的重氮盐(2g)。将重氮盐在120℃下加热30分钟，冷却至室温后，倒入冰水(50mL)中，然后用乙酸乙酯(50mL×3)萃取。合并的有机层用盐水(50mL x 2)洗，经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法(PE/EA＝10/1))纯化，得到6-氯-3-氟-2-甲基-N-苯基苯甲酰胺(800mg，收率35％)为白色固体。LCMS:MS(ESI)m/z 264.1[M+H] +。 At 0°C, sodium nitrate ( 1 g, 15.34 mmol) aqueous solution (5 mL), after dropping, the mixture was transferred to room temperature and stirred for 1 h. Filtration, rinsing the filter cake with cold water (5 mL x 2) and drying in vacuo afforded the diazonium salt (2 g) as a white solid. The diazonium salt was heated at 120° C. for 30 minutes, cooled to room temperature, poured into ice water (50 mL), and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=10/1)) to give 6-chloro-3-fluoro-2-methyl-N-phenylbenzamide (800 mg, yield 35%) as a white solid . LCMS: MS (ESI) m/z 264.1 [M+H] + .
步骤5)(S)-(4-(3-氯-6-氟-2-(苯基氨基甲酰基)苯基)-3-氧代丁-2-基)氨基甲酸叔丁酯Step 5) Tert-butyl (S)-(4-(3-chloro-6-fluoro-2-(phenylcarbamoyl)phenyl)-3-oxobutan-2-yl)carbamate
在-30℃下，向6-氯-3-氟-2-甲基-N-苯基苯甲酰胺(400mg，1.52mmol)的THF(5mL)溶液中加入n-BuLi(3.8mmol，2.4M/L＝1.58mL)，混合物搅拌2h，得到黄色液体。于氮气气氛下，在-30℃，向N-((1S)-1-(甲 氧基(甲基)氨基甲酰基)乙基)氨基甲酸叔丁酯(528mg，2.27mmol)的THF(10mL)溶液中加入i-PrMgCl.LiCl(4.55mmol，1.3M/L,3.5mL)，混合物搅拌2h。在-40℃向该混合物中加入上述黄色液体，转移至室温，搅拌16h。混合物用NH 4Cl溶液(50mL)淬灭，并用EtOAc(50mL×2)萃取。合并的有机层用盐水(50mL x 2)洗，经无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法(PE/EA＝3/1)纯化，得到(S)-(4-(3-氯-6-氟-2-(苯基氨基甲酰基)苯基)-3-氧代丁-2-基)氨基甲酸叔丁酯(160mg，24％收率)为黄色固体。LCMS:MS(ESI)m/z457.0[M+Na] +。 To a solution of 6-chloro-3-fluoro-2-methyl-N-phenylbenzamide (400 mg, 1.52 mmol) in THF (5 mL) was added n-BuLi (3.8 mmol, 2.4 M /L=1.58mL), the mixture was stirred for 2h to obtain a yellow liquid. Under nitrogen atmosphere, at -30 ℃, add N-((1S)-1-(methoxy(methyl)carbamoyl)ethyl)carbamate tert-butyl ester (528mg, 2.27mmol) in THF (10mL ) solution was added i-PrMgCl.LiCl (4.55mmol, 1.3M/L, 3.5mL), and the mixture was stirred for 2h. The above yellow liquid was added to the mixture at -40 °C, transferred to room temperature, and stirred for 16 h. The mixture was quenched with NH 4 Cl solution (50 mL), and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EA=3/1) to give (S)-(4-(3-chloro-6-fluoro-2-(phenylcarbamoyl)phenyl)-3-oxo tert-Butyl (butan-2-yl)carbamate (160 mg, 24% yield) was a yellow solid. LCMS: MS (ESI) m/z 457.0 [M+Na] + .
步骤6)(S)-3-(1-氨基乙基)-8-氯-5-氟-2-苯基异喹啉-1(2H)-酮Step 6) (S)-3-(1-aminoethyl)-8-chloro-5-fluoro-2-phenylisoquinolin-1(2H)-one
向(S)-(4-(3-氯-6-氟-2-(苯基氨基甲酰基)苯基)-3-氧代丁-2-基)氨基甲酸叔丁酯(150mg，0.345mmol)的MeOH(6mL)溶液中加入浓盐酸(3mL)，混合物升温至70℃，搅拌3h。冷却至室温后，真空浓缩。将残余物倒入水(50mL)中，所得溶液用碳酸氢钠水溶液中和至pH＝8。混合物用EtOAc(50mL x 3)萃取，合并的有机层用盐水(50mL)洗，经无Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法(DCM/MeOH＝95/5)纯化，得到(S)-3-(1-氨基乙基)-8-氯-5-氟-2-苯基异喹啉-1(2H)-酮(50mg，45％收率)为白色固体。LCMS:MS(ESI)m/z 317.0[M+H] +。 To (S)-(4-(3-chloro-6-fluoro-2-(phenylcarbamoyl)phenyl)-3-oxobut-2-yl)carbamate tert-butyl ester (150mg, 0.345mmol ) in MeOH (6 mL) was added concentrated hydrochloric acid (3 mL), and the mixture was warmed to 70 °C and stirred for 3 h. After cooling to room temperature, it was concentrated in vacuo. The residue was poured into water (50 mL), and the resulting solution was neutralized to pH=8 with aqueous sodium bicarbonate. The mixture was extracted with EtOAc (50 mL x 3), the combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=95/5) to give (S)-3-(1-aminoethyl)-8-chloro-5-fluoro-2-phenylisoquinoline-1( 2H)-Kone (50 mg, 45% yield) was a white solid. LCMS: MS (ESI) m/z 317.0 [M+H] + .
步骤7)(S)-3-(1-氨基乙基)-5-氟-8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮Step 7) (S)-3-(1-aminoethyl)-5-fluoro-8-((1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-2-benzene Isoquinolin-1(2H)-one
在氮气气氛下，向(S)-3-(1-氨基乙基)-8-氯-5-氟-2-苯基异喹啉-1(2H)-酮(50mg，0.23mmol)和4-乙炔基-1-甲基吡唑(26mg，0.23mmol)的乙腈(20mL)溶液中加入Pa 2(dba) 3(36mg，0.039mmol)、X-phos(38mg，0.039mmol)和K 3PO 4(67mg，0.32mmol)，混合物升温至80℃，搅拌4h。冷却至室温后，真空浓缩。将残余物溶于DCM(50mL)，并用盐水(30mL)洗。分离的有机层用无水Na 2SO 4干燥，过滤，真空浓缩。残余物经柱色谱法(DCM/MeOH＝10/1)纯化，得到(S)-3-(1-氨基乙基)-5-氟-8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(50mg，80％收率)为黄色固体。LCMS:MS(ESI)m/z 390.1[M+H] +。 Under nitrogen atmosphere, (S)-3-(1-aminoethyl)-8-chloro-5-fluoro-2-phenylisoquinolin-1(2H)-one (50mg, 0.23mmol) and 4 -Ethynyl-1-methylpyrazole (26 mg, 0.23 mmol) in acetonitrile (20 mL) was added Pa 2 (dba) 3 (36 mg, 0.039 mmol), X-phos (38 mg, 0.039 mmol) and K 3 PO 4 (67mg, 0.32mmol), the mixture was warmed up to 80°C and stirred for 4h. After cooling to room temperature, it was concentrated in vacuo. The residue was dissolved in DCM (50 mL) and washed with brine (30 mL). The separated organic layer was dried over anhydrous Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=10/1) to give (S)-3-(1-aminoethyl)-5-fluoro-8-((1-(methyl-d3)-1H -pyrazol-4-yl)ethynyl)-2-phenylisoquinolin-1(2H)-one (50 mg, 80% yield) as a yellow solid. LCMS: MS (ESI) m/z 390.1 [M+H] + .
步骤8)(S)-2-氨基-N-(1-(5-氟-8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 8) (S)-2-Amino-N-(1-(5-fluoro-8-((1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-1-oxo Substitute-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向(S)-3-(1-氨基乙基)-5-氟-8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(50mg，0.13mmol)和2-氨基吡唑并[1,5-a]嘧啶-3-羧酸(23mg，0.13mmol)的DCM(15mL)溶液中加入HOAt(26mg，0.19mmol)、EDCI(30mg，0.19mmol)和DIEA(50mg，0.39mmol)，混合物升温至40℃，搅拌16h。冷却至室温后，将混合物用DCM(50mL)稀释，并用盐水(30mL x 2)洗。分离的有机层经无水Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM:MeOH＝15:1)纯化，得到(S)-2-氨基-N-(1-(5-氟-8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(24.5mg，34％收率)为白色固体。LCMS:MS(ESI)m/z 550.1[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ8.94(dd,J＝6.8,1.6Hz,1H),8.56(dd,J＝4.4,1.6Hz,1H),8.08(d,J＝6.8Hz,1H),8.00(d,J＝0.8Hz,1H),7.62-7.49(m,7H),7.43(d,J＝7.2Hz,1H),7.03(dd,J＝6.8,4.4Hz,1H),6.75(s,1H),6.45(s,2H),4.55(t,J＝6.8Hz,1H),1.36(d,J＝6.8Hz,3H)。 To (S)-3-(1-aminoethyl)-5-fluoro-8-((1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-2-phenyliso To a solution of quinolin-1(2H)-one (50 mg, 0.13 mmol) and 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (23 mg, 0.13 mmol) in DCM (15 mL) was added HOAt (26mg, 0.19mmol), EDCI (30mg, 0.19mmol) and DIEA (50mg, 0.39mmol), the mixture was heated to 40°C and stirred for 16h. After cooling to room temperature, the mixture was diluted with DCM (50 mL), and washed with brine (30 mL x 2). The separated organic layer was dried over anhydrous Na2SO4 , concentrated in vacuo. The residue was purified by column chromatography (DCM:MeOH=15:1) to give (S)-2-amino-N-(1-(5-fluoro-8-((1-(methyl-d3)-1H -pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine -3-Carboxamide (24.5 mg, 34% yield) was a white solid. LCMS: MS (ESI) m/z 550.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.94 (dd, J=6.8, 1.6Hz, 1H), 8.56 (dd, J= 4.4,1.6Hz,1H),8.08(d,J=6.8Hz,1H),8.00(d,J=0.8Hz,1H),7.62-7.49(m,7H),7.43(d,J=7.2Hz, 1H), 7.03(dd, J=6.8, 4.4Hz, 1H), 6.75(s, 1H), 6.45(s, 2H), 4.55(t, J=6.8Hz, 1H), 1.36(d, J=6.8 Hz, 3H).
实施例37(S)-2-氨基-5-(甲氧基-d3)-N-(1-(8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Example 37 (S)-2-amino-5-(methoxy-d3)-N-(1-(8-((1-(methyl-d3)-1H-pyrazol-4-yl)acetylene Base)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
Figure PCTCN2022121567-appb-000095
Figure PCTCN2022121567-appb-000095
步骤1)(S)-3-(1-氨基乙基)-8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮Step 1) (S)-3-(1-aminoethyl)-8-((1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-2-phenylisoquinoline -1(2H)-one
向3-((1S)-1-氨基乙基)-8-氯-2-苯基异喹啉-1-酮(100mg，0.33mmol)和4-乙炔基-1-甲基吡唑(55mg，0.5mmol)的CH 3CN(20mL)溶液中加入Pd 2(dba) 3(61mg，0.067mmol)、K 3PO 4(142mg，0.67mmol)和X-phos (64mg，0.13mmol)，混合物升温至80℃，搅拌5小时。冷却至室温后，混合物用EtOAc(60mL)稀释，并用盐水(40mL×2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝20/1)纯化，得到(S)-3-(1-氨基乙基)-8-((1-(甲基-d3)-1H-吡唑-4-基))乙炔基)-2-苯基异喹啉-1(2H)-酮(80mg，61％)为黄色固体。MS(ESI):371.9[M+H] +。 To 3-((1S)-1-aminoethyl)-8-chloro-2-phenylisoquinolin-1-one (100mg, 0.33mmol) and 4-ethynyl-1-methylpyrazole (55mg , 0.5mmol) in CH 3 CN (20mL) was added Pd 2 (dba) 3 (61mg, 0.067mmol), K 3 PO 4 (142mg, 0.67mmol) and X-phos (64mg, 0.13mmol), the mixture was heated to 80°C and stirred for 5 hours. After cooling to room temperature, the mixture was diluted with EtOAc (60 mL), and washed with brine (40 mL×2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=20/1) to give (S)-3-(1-aminoethyl)-8-((1-(methyl-d3)-1H-pyrazole- 4-yl))ethynyl)-2-phenylisoquinolin-1(2H)-one (80 mg, 61%) as a yellow solid. MS (ESI): 371.9 [M+H] + .
步骤2)(S)-2-氨基-5-(甲氧基-d3)-N-(1-(8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺Step 2) (S)-2-Amino-5-(methoxy-d3)-N-(1-(8-((1-(methyl-d3)-1H-pyrazol-4-yl)acetylene Base)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
向(S)-3-(1-氨基乙基)-8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(40mg，0.1mmol)和2-氨基-5-甲氧基吡唑并[1,5-a]嘧啶-3-羧酸(23mg，0.1mmol)的DCM(20mL)溶液中加入EDCI(31mg，0.16mmol)、HOAt(18mg，0.13mmol)和DIEA(42mg，0.32mmol)，混合物升温至40℃，搅拌16h。冷却至室温后，将混合物用DCM(40mL)稀释，并用盐水(30mL x 2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经制备型HPLC(DCM/MeOH＝15/1)纯化，得到(S)-2-氨基-5-(甲氧基-d3)-N-(1-(8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]嘧啶-3-甲酰胺(19mg，30％收率)为白色固体。MS(ESI):564.8[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.72-8.66(m,1H),8.01(d,J＝0.8Hz,1H),7.88(d,J＝6.8Hz,1H),7.68-7.61(m,2H),7.60(s,1H),7.59-7.50(m,4H),7.46(d,J＝7.6Hz,1H),7.39(d,J＝7.6Hz,1H),6.79(s,1H),6.49-6.44(m,1H),6.14(s,2H),4.49-4.43(m,1H),1.36(d,J＝6.8Hz,3H)。 To (S)-3-(1-aminoethyl)-8-((1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-2-phenylisoquinoline-1 (2H)-Kone (40 mg, 0.1 mmol) and 2-amino-5-methoxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid (23 mg, 0.1 mmol) in DCM (20 mL) EDCI (31 mg, 0.16 mmol), HOAt (18 mg, 0.13 mmol) and DIEA (42 mg, 0.32 mmol) were added, and the mixture was warmed to 40° C. and stirred for 16 h. After cooling to room temperature, the mixture was diluted with DCM (40 mL), and washed with brine (30 mL x 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (DCM/MeOH=15/1) to give (S)-2-amino-5-(methoxy-d3)-N-(1-(8-((1-(methoxy Base-d3)-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1 ,5-a]pyrimidine-3-carboxamide (19 mg, 30% yield) as a white solid. MS (ESI): 564.8 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.72-8.66 (m, 1H), 8.01 (d, J = 0.8Hz, 1H), 7.88 (d, J = 6.8Hz, 1H), 7.68-7.61 ( m,2H),7.60(s,1H),7.59-7.50(m,4H),7.46(d,J=7.6Hz,1H),7.39(d,J=7.6Hz,1H),6.79(s,1H ), 6.49-6.44 (m, 1H), 6.14 (s, 2H), 4.49-4.43 (m, 1H), 1.36 (d, J=6.8Hz, 3H).
实施例38(S)-2-氨基-5-氰基-N-(1-(8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]吡啶-3-甲酰胺Example 38 (S)-2-amino-5-cyano-N-(1-(8-((1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-1- Oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide
Figure PCTCN2022121567-appb-000096
Figure PCTCN2022121567-appb-000096
步骤1)1-氨基-4-溴吡啶-1-鎓Step 1) 1-Amino-4-bromopyridin-1-ium
向4-溴吡啶(1g，6.3mmol)的DCM(10mL)溶液中分批加入氨基二苯基次膦酸盐(4.41g，18.9mmol)，混合物于室温搅拌48h。然后加入氢碘酸(1mL，55％的H 2O溶液)，过滤沉淀，滤饼用DCM(10mL)洗，真空干燥，得到1-氨基-4-溴吡啶-1-鎓(1g，46％收率)为棕色固体。MS(ESI):173.0,175.0[M+H] +。 To a solution of 4-bromopyridine (1 g, 6.3 mmol) in DCM (10 mL) was added aminodiphenylphosphinate (4.41 g, 18.9 mmol) in portions, and the mixture was stirred at room temperature for 48 h. Hydroiodic acid (1 mL, 55% in H2O ) was then added, the precipitate was filtered, the filter cake was washed with DCM (10 mL), and dried in vacuo to give 1-amino-4-bromopyridin-1-ium (1 g, 46% yield) as a brown solid. MS (ESI): 173.0, 175.0 [M+H] + .
步骤2)5-溴吡唑并[1,5-a]吡啶-2,3-二羧酸二甲酯Step 2) Dimethyl 5-bromopyrazolo[1,5-a]pyridine-2,3-dicarboxylate
向1-氨基-4-溴吡啶-1-鎓(800mg，4.6mmol)的DMF(20mL)溶液中加入1,4-二甲基丁二酸(784mg，5.5mmol)和K 2CO 3(953mg，6.89mmol)，混合物于室温搅拌16h。混合物用EtOAc(80mL)稀释，并用盐水(40mL×2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(EA/PE＝1/5)纯化，得到5-溴吡唑并[1,5-a]吡啶-2,3-二羧酸二甲酯(200mg，13％收率)为黄色固体。MS(ESI):313.0,315.0[M+H] +。 To a solution of 1-amino-4-bromopyridin-1-ium (800 mg, 4.6 mmol) in DMF (20 mL) was added 1,4-dimethylsuccinic acid (784 mg, 5.5 mmol) and K 2 CO 3 (953 mg , 6.89mmol), the mixture was stirred at room temperature for 16h. The mixture was diluted with EtOAc (80 mL), and washed with brine (40 mL×2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EA/PE=1/5) to give dimethyl 5-bromopyrazolo[1,5-a]pyridine-2,3-dicarboxylate (200 mg, 13% yield ) is a yellow solid. MS (ESI): 313.0, 315.0 [M+H] + .
步骤3)5-溴-3-(甲氧基羰基)吡唑并[1,5-a]吡啶-2-羧酸Step 3) 5-Bromo-3-(methoxycarbonyl)pyrazolo[1,5-a]pyridine-2-carboxylic acid
向5-溴吡唑并[1,5-a]吡啶-2,3-二羧酸二甲酯(200mg，0.19mmol)的THF(10mL)溶液中加入NaOH(26mg，0.64mmol)的H 2O(3mL)溶液，混合物于室温搅拌16h。将混合物真空浓缩，残余物用水(10mL)稀释，并用1N HCl酸化至pH为4-5。过滤沉淀，滤饼用水洗，真空干燥，得到5-溴-3-(甲氧基羰基)吡唑并[1,5-a]吡啶-2-甲酸(180mg，收率89％)为白色固体。MS(ESI):299.0,301.0[M+H] +。 To a solution of dimethyl 5-bromopyrazolo[1,5-a]pyridine-2,3-dicarboxylate (200 mg, 0.19 mmol) in THF (10 mL) was added NaOH (26 mg, 0.64 mmol) in H2 O (3 mL) solution, the mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo, the residue was diluted with water (10 mL), and acidified to pH 4-5 with 1N HCl. The precipitate was filtered, the filter cake was washed with water, and dried in vacuo to obtain 5-bromo-3-(methoxycarbonyl)pyrazolo[1,5-a]pyridine-2-carboxylic acid (180mg, yield 89%) as a white solid . MS (ESI): 299.0, 301.0 [M+H] + .
步骤4)5-溴-2-((叔丁氧基羰基)氨基)吡唑并[1,5-a]吡啶-3-羧酸甲酯Step 4) Methyl 5-bromo-2-((tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylate
向5-溴-3-(甲氧基羰基)吡唑并[1,5-a]吡啶-2-羧酸(230mg，0.77mmol)的二氧六环(20mL)溶液中加入三乙胺(233mg，2.3mmol)和DPPA(254mg，0.92mmol)，混合物于室温搅拌1h。然后加入t-BuOH(114mg，1.53mmol)，升温至100℃，搅拌16h。冷却至室温后，真空浓缩。将残余物用EtOAc(60mL)稀释，并用盐水(40mL x 2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(EA/PE＝1/5)纯化，得到 5-溴-2-((叔丁氧基羰基)氨基)吡唑并[1,5-a]吡啶-3-羧酸甲酯(150mg,53％收率)和2-氨基-5-溴吡唑并[1,5-a]吡啶-3-羧酸甲酯(50mg，17.5％收率)，均为白色固体。MS(ESI):392.0,394.0[M+H] +,270.0,272.0[M+H] +。 To a solution of 5-bromo-3-(methoxycarbonyl)pyrazolo[1,5-a]pyridine-2-carboxylic acid (230 mg, 0.77 mmol) in dioxane (20 mL) was added triethylamine ( 233mg, 2.3mmol) and DPPA (254mg, 0.92mmol), the mixture was stirred at room temperature for 1h. Then t-BuOH (114mg, 1.53mmol) was added, the temperature was raised to 100°C, and stirred for 16h. After cooling to room temperature, it was concentrated in vacuo. The residue was diluted with EtOAc (60 mL), and washed with brine (40 mL x 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EA/PE=1/5) to give 5-bromo-2-((tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylic acid Methyl ester (150 mg, 53% yield) and methyl 2-amino-5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (50 mg, 17.5% yield), both white solids. MS (ESI): 392.0, 394.0 [M+H] + , 270.0, 272.0 [M+H] + .
步骤5)2-氨基-5-溴吡唑并[1,5-a]吡啶-3-羧酸Step 5) 2-Amino-5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid
向2-氨基-5-溴吡唑并[1,5-a]吡啶-3-羧酸甲酯(50mg，0.18mmol)的MeOH(10mL)溶液中加入NaOH(22mg，0.55mmol)水溶液(2mL)，混合物升温至50℃，搅拌3h。冷却至室温后，将混合物真空浓缩。残余物用水(5mL)稀释，并用1N HCl酸化至pH＝4-5。然后用EtOAc(20mL x 3)萃取，合并的有机层用盐水(20mL x 2)洗，经Na 2SO 4干燥，真空浓缩，得到2-氨基-5-溴吡唑并[1,5-a]吡啶-3-羧酸(45mg，90％收率)为浅色固体。MS(ESI):255.9,257.9[M+H] +。 To a solution of methyl 2-amino-5-bromopyrazolo[1,5-a]pyridine-3-carboxylate (50 mg, 0.18 mmol) in MeOH (10 mL) was added aqueous NaOH (22 mg, 0.55 mmol) (2 mL ), the mixture was warmed up to 50°C and stirred for 3h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with water (5 mL) and acidified to pH=4-5 with 1N HCl. It was then extracted with EtOAc (20 mL x 3), and the combined organic layers were washed with brine (20 mL x 2), dried over Na 2 SO 4 and concentrated in vacuo to give 2-amino-5-bromopyrazolo[1,5-a ] Pyridine-3-carboxylic acid (45 mg, 90% yield) as a pale solid. MS (ESI): 255.9, 257.9 [M+H] + .
步骤6)(S)-2-氨基-5-溴-N-(1-(8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]吡啶-3-甲酰胺Step 6) (S)-2-Amino-5-bromo-N-(1-(8-((1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-1-oxo Substitute-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide
向(S)-3-(1-氨基乙基)-8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(65mg，0.18mmol)和2-氨基-5-溴吡唑并[1,5-a]吡啶-3-羧酸(45mg，0.18mmol)的DCM(30mL)溶液中加入HOAt(32mg，0.23mmol)、EDCI(56mg，0.29mmol)和DIEA(75mg，0.59mmol)，混合物升温至40℃，搅拌16h。冷却至室温后，将混合物用DCM(30mL)稀释，并用盐水(30mL x 2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(DCM/MeOH＝20/1)纯化，得到(S)-2-氨基-5-溴-N-(1-(8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]吡啶-3-甲酰胺(100mg，76％收率)为黄色固体。MS(ESI):609.0[M+H] +。 To (S)-3-(1-aminoethyl)-8-((1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-2-phenylisoquinoline-1 To a solution of (2H)-ketone (65 mg, 0.18 mmol) and 2-amino-5-bromopyrazolo[1,5-a]pyridine-3-carboxylic acid (45 mg, 0.18 mmol) in DCM (30 mL) was added HOAt (32mg, 0.23mmol), EDCI (56mg, 0.29mmol) and DIEA (75mg, 0.59mmol), the mixture was heated to 40°C and stirred for 16h. After cooling to room temperature, the mixture was diluted with DCM (30 mL), and washed with brine (30 mL x 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=20/1) to give (S)-2-amino-5-bromo-N-(1-(8-((1-(methyl-d3)-1H -pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyridine -3-Carboxamide (100 mg, 76% yield) was a yellow solid. MS (ESI): 609.0 [M+H] + .
步骤7)(S)-2-氨基-5-氰基-N-(1-(8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]吡啶-3-甲酰胺Step 7) (S)-2-Amino-5-cyano-N-(1-(8-((1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-1- Oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide
在氮气气氛下，向(S)-2-氨基-5-溴-N-(1-(8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]吡啶-3-甲酰胺(50mg，0.08mmol)的DMF(5mL)溶液中加入Zn(CN) 2(19mg，0.16mmol)、Zn(11mg,0.16mmol)和Pd(dppf)Cl 2.DCM(7mg，0.008mmol)，混合物升温至100℃，搅拌16h。冷却至室温后，混合物用EtOAc(60mL)稀释，并用盐水(30mL×3)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经制备型HPLC(ACN-H 2O,0.1FA,梯度40％-60％)纯化，得到(S)-2-氨基-5-氰基-N-(1-(8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]吡啶-3-甲酰胺(7.8mg，17％收率)为黄色固体。MS(ESI):556.1[M+H] +. 1H NMR(400MHz,CD 3OD)δ8.48(dd,J＝6.8,0.8Hz,1H),8.18(d,J＝0.8Hz,1H),7.87(s,1H),7.69(s,1H),7.67-7.52(m,7H),7.44(d,J＝7.6Hz,1H),7.04(dd,J＝7.2,1.6Hz,1H),6.94(s,1H),4.76(q,J＝6.8Hz,1H),1.50(d,J＝6.8Hz,3H)。 Under nitrogen atmosphere, to (S)-2-amino-5-bromo-N-(1-(8-((1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)- 1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide (50mg, 0.08mmol) Add Zn(CN) 2 (19mg, 0.16mmol), Zn(11mg, 0.16mmol) and Pd(dppf)Cl 2 .DCM (7mg, 0.008mmol) to DMF (5mL) solution, the mixture is heated to 100°C and stirred for 16h . After cooling to room temperature, the mixture was diluted with EtOAc (60 mL), and washed with brine (30 mL×3). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (ACN-H 2 O, 0.1FA, gradient 40%-60%) to give (S)-2-amino-5-cyano-N-(1-(8-((1 -(Methyl-d3)-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazole Ac[1,5-a]pyridine-3-carboxamide (7.8 mg, 17% yield) was a yellow solid. MS(ESI):556.1[M+H] + . 1 H NMR(400MHz,CD 3 OD)δ8.48(dd,J＝6.8,0.8Hz,1H),8.18(d,J＝0.8Hz,1H) ,7.87(s,1H),7.69(s,1H),7.67-7.52(m,7H),7.44(d,J=7.6Hz,1H),7.04(dd,J=7.2,1.6Hz,1H), 6.94 (s, 1H), 4.76 (q, J=6.8Hz, 1H), 1.50 (d, J=6.8Hz, 3H).
实施例39(S)-2-氨基-5-甲氧基-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]吡啶-3-甲酰胺Example 39 (S)-2-amino-5-methoxy-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo- 2-Phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide
Figure PCTCN2022121567-appb-000097
Figure PCTCN2022121567-appb-000097
步骤1)2-((叔丁氧基羰基)氨基)-5-甲氧基吡唑并[1,5-a]吡啶-3-羧酸甲酯Step 1) Methyl 2-((tert-butoxycarbonyl)amino)-5-methoxypyrazolo[1,5-a]pyridine-3-carboxylate
向5-溴-2-((叔丁氧基羰基)氨基)吡唑并[1,5-a]吡啶-3-羧酸甲酯(100mg，0.27mmol)和甲醇钠(44mg，0.81mmol)的二氧六环(10mL)和MeOH(5mL)溶液中加入Pd 2(dba) 3(25mg，0.027mmol)和X-phos(26mg，0.054mmol)，混合物升温至70℃，搅拌16h。冷却至室温后，真空浓缩。残余物用EtOAc(50mL)稀释，用盐水(30mL x 2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经柱色谱法(EA/PE＝1/2)纯化，得到2-((叔丁氧基羰基)氨基)-5-甲氧基吡唑并[1,5-a]吡啶-3-羧酸甲酯(80mg，73.7％收率)为黄色固体。MS(ESI):344.1[M+Na] +。 To 5-bromo-2-((tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyridine-3-carboxylic acid methyl ester (100mg, 0.27mmol) and sodium methoxide (44mg, 0.81mmol) Pd 2 (dba) 3 (25mg, 0.027mmol) and X-phos (26mg, 0.054mmol) were added to a solution of dioxane (10mL) and MeOH (5mL), and the mixture was heated to 70°C and stirred for 16h. After cooling to room temperature, it was concentrated in vacuo. The residue was diluted with EtOAc (50 mL), washed with brine (30 mL x 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EA/PE=1/2) to give 2-((tert-butoxycarbonyl)amino)-5-methoxypyrazolo[1,5-a]pyridine-3- Methyl carboxylate (80 mg, 73.7% yield) was a yellow solid. MS (ESI): 344.1 [M+Na] + .
步骤2)2-氨基-5-甲氧基吡唑并[1,5-a]吡啶-3-羧酸甲酯Step 2) Methyl 2-amino-5-methoxypyrazolo[1,5-a]pyridine-3-carboxylate
向2-((叔丁氧基羰基)氨基)-5-甲氧基吡唑并[1,5-a]吡啶-3-甲酸甲酯(80mg，0.25mmol)的DCM(3mL)溶液中加入TFA(1mL)，混合物于室温搅拌2h。将混合物真空浓缩，得到2-氨基-5-甲氧基吡唑并[1,5-a]吡啶-3-羧酸甲酯(60mg，收率87％)为黄色油状物。MS(ESI):222.1[M+H] +。 To a solution of methyl 2-((tert-butoxycarbonyl)amino)-5-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (80 mg, 0.25 mmol) in DCM (3 mL) was added TFA (1 mL), the mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo to afford methyl 2-amino-5-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (60 mg, yield 87%) as a yellow oil. MS (ESI): 222.1 [M+H] + .
步骤3)2-氨基-5-甲氧基吡唑并[1,5-a]吡啶-3-羧酸Step 3) 2-Amino-5-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid
向2-氨基-5-甲氧基吡唑并[1,5-a]吡啶-3-羧酸甲酯(60mg，0.27mmol)的MeOH(10mL)溶液中加入NaOH(32mg，0.81mmol)水溶液(3mL)，混合物升温至65℃，搅拌48h。冷却至室温后，真空浓缩。残余物用水(3mL)稀释，并用1N HCl酸化至pH＝4-5，过滤收集沉淀。滤饼用水(2mL)洗，真空干燥，得到2-氨基-5-甲氧基吡唑并[1,5-a]吡啶-3-甲酸(50mg，收率53％)为黄色固体。MS(ESI):208.1[M+H] +。 To a solution of methyl 2-amino-5-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (60 mg, 0.27 mmol) in MeOH (10 mL) was added aqueous NaOH (32 mg, 0.81 mmol) (3 mL), the mixture was warmed to 65 °C and stirred for 48 h. After cooling to room temperature, it was concentrated in vacuo. The residue was diluted with water (3 mL) and acidified with 1N HCl to pH = 4-5, and the precipitate was collected by filtration. The filter cake was washed with water (2 mL) and dried in vacuo to obtain 2-amino-5-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid (50 mg, yield 53%) as a yellow solid. MS (ESI): 208.1 [M+H] + .
步骤4)(S)-2-氨基-5-甲氧基-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]吡啶-3-甲酰胺Step 4) (S)-2-Amino-5-methoxy-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo- 2-Phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyridine-3-carboxamide
向(S)-3-(1-氨基乙基)-8-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-2-苯基异喹啉-1(2H)-酮(89mg，0.24mmol)和2-氨基-5-甲氧基吡唑并[1,5-a]吡啶-3-羧酸(50mg，0.24mmol)的DCM(40mL)溶液中加入EDCI(69mg，0.36mmol)、HOAt(49mg，0.36mmol)和DIEA(93mg，0.72mmol)，混合物升温至40℃，搅拌16h。冷却至室温后，将混合物用DCM(50mL)稀释，并用盐水(30mL x 2)洗。分离的有机层经Na 2SO 4干燥，真空浓缩。残余物经制备型HPLC(ACN-H 2O，0.1FA，梯度40％-60％)纯化，得到(S)-2-氨基-5-甲氧基-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1,2-二氢异喹啉-3-基)乙基)吡唑并[1,5-a]吡啶-3-甲酰胺(6.5mg，5％收率)为白色固体。MS(ESI):561.2[M+H] +。 1H NMR(400MHz,CD 3OD)δ8.15(d,J＝7.6Hz,1H),7.86(s,1H),7.69(d,J＝3.2Hz,1H),7.67–7.53(m,7H),7.43(d,J＝7.6Hz,1H),7.10(d,J＝2.4Hz,1H),6.94(s,1H),6.55(dd,J＝7.6,2.7Hz,1H),4.74(q,J＝6.8Hz,1H),3.90(s,3H),1.47(d,J＝6.8Hz,3H)。 To (S)-3-(1-aminoethyl)-8-((1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-2-phenylisoquinoline-1 (2H)-Kone (89 mg, 0.24 mmol) and 2-amino-5-methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid (50 mg, 0.24 mmol) in DCM (40 mL) EDCI (69mg, 0.36mmol), HOAt (49mg, 0.36mmol) and DIEA (93mg, 0.72mmol) were added, the mixture was warmed to 40°C and stirred for 16h. After cooling to room temperature, the mixture was diluted with DCM (50 mL), and washed with brine (30 mL x 2). The separated organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC (ACN- H2O , 0.1FA, gradient 40%-60%) to give (S)-2-amino-5-methoxy-N-(1-(8-(( 1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)pyrazolo[1 ,5-a]pyridine-3-carboxamide (6.5 mg, 5% yield) was a white solid. MS (ESI): 561.2 [M+H] + . 1 H NMR (400MHz, CD 3 OD) δ8.15(d, J=7.6Hz, 1H), 7.86(s, 1H), 7.69(d, J=3.2Hz, 1H), 7.67–7.53(m, 7H ), 7.43(d, J=7.6Hz, 1H), 7.10(d, J=2.4Hz, 1H), 6.94(s, 1H), 6.55(dd, J=7.6, 2.7Hz, 1H), 4.74(q , J=6.8Hz, 1H), 3.90(s, 3H), 1.47(d, J=6.8Hz, 3H).
生物试验biological test
激酶活性试验本发明化合物作为PI3K和mTOR激酶抑制剂的活性可以通过下述试验来进行评价的。激酶试验的一般性描述激酶试验通过检测掺入γ-33P-ATP的髓磷脂碱基蛋白(MBP)来完成的。制备20μg/mL的MBP(Sigma#M-1891)三羟甲基氨基甲烷缓冲盐溶液(TBS；50mM Tris pH 8.0,138mM NaCl,2.7mM KCl)，包被高结合性的白384孔板(Greiner)，每孔60μL。4℃，孵育24小时。之后用100μL TBS洗板3次。激酶反应在总体积为34μL的激酶缓冲液(5mM Hepes pH 7.6,15mM NaCl,0.01％牛血清白蛋白(Sigma#I-5506),10mM MgCl 2,1mM DTT,0.02％TritonX-100)中进行。将化合物溶解在DMSO中，加入各孔中，DMSO的最终浓度为1％。每个数据测定两遍，每个化合物的测定至少进行两次试验。比如，酶的最终浓度为10nM或20nM。加入没有标记的ATP(10μM)和γ-33P标记的ATP(每孔2×106cpm，3000Ci/mmole)开始反应。反应在室温下震荡进行1个小时。384孔板用7x的PBS清洗，然后加入每孔50μL的闪烁液。用Wallac Trilux计亦可。 Kinase Activity Assay The activity of the compounds of the present invention as PI3K and mTOR kinase inhibitors can be evaluated by the following assays. General Description of Kinase Assays Kinase assays are performed by detecting myelin basic protein (MBP) incorporation of [gamma]-33P-ATP. Prepare 20 μg/mL of MBP (Sigma#M-1891) tris-buffered saline (TBS; 50 mM Tris pH 8.0, 138 mM NaCl, 2.7 mM KCl), and coat a high-binding white 384-well plate (Greiner ), 60 μL per well. Incubate at 4°C for 24 hours. The plate was then washed 3 times with 100 μL TBS. Kinase reactions were performed in a total volume of 34 μL of kinase buffer (5 mM Hepes pH 7.6, 15 mM NaCl, 0.01% bovine serum albumin (Sigma #I-5506), 10 mM MgCl 2 , 1 mM DTT, 0.02% TritonX-100). Compounds were dissolved in DMSO and added to the wells at a final concentration of 1% DMSO. Each data was measured twice, and the determination of each compound was carried out at least twice. For example, the final concentration of the enzyme is 10 nM or 20 nM. The reaction was started by adding unlabeled ATP (10 μM) and γ-33P-labeled ATP (2×10 6 cpm per well, 3000Ci/mmole). The reaction was carried out with shaking at room temperature for 1 hour. The 384-well plate was washed with 7x PBS, and then 50 μL of scintillation fluid was added to each well. A Wallac Trilux meter can also be used.
上述试验方法可以得到抑制的IC 50和/或抑制常数Ki。IC 50定义为在试验条件下，抑制50％酶活性时的化合物浓度。利用1/2log的稀释倍数做出包含10个浓度点的曲线，估算IC 50值(例如，通过以下化合物浓度做出一条典型的曲线：10μM,3μM,1μM,0.3μM,0.1μM,0.03μM,0.01μM,0.003μM,0.001μM和0μM)。 IC50 of inhibition and/or inhibition constant Ki can be obtained by the above test method. IC50 is defined as the concentration of compound that inhibits 50% of the enzyme activity under the assay conditions. Use a 1/2 log dilution to generate a curve containing 10 concentration points to estimate the IC50 value (for example, make a typical curve through the following compound concentrations: 10μM, 3μM, 1μM, 0.3μM, 0.1μM, 0.03μM, 0.01μM, 0.003μM, 0.001μM and 0μM).
PI3激酶的一般试验方案General Assay Protocol for PI3 Kinase
PI3K(p110α/p85α)(h)[非放射性试验]PI3K(p110α/p85α)(h) [non-radioactive assay]
PI3K(p110α/p85α)(h)在含有10μM磷酸酰肌醇-4,5-二磷酸和MgATP(浓度根据需求确定)的缓冲溶液中孵育。加入ATP溶液后，开始反应。室温下孵育30分钟之后，向其中加入含有EDTA和生物素磷脂酰肌醇-3,4,5-三磷酸的终止液来终止反应。最后，加入检测缓冲液，包括铕标记的抗GST单抗，GST标记的GRP1PH结构域和链亲和素-别藻蓝蛋白。孔板在时间分辨荧光模式下读数，均相时间分辨荧光(HTRF)信号由方程式HTRF＝10000×(Em665nm/Em620nm)确定。PI3K(p110α/p85α) (h) was incubated in a buffer solution containing 10 μM phosphoinositide-4,5-bisphosphate and MgATP (concentration as needed). After adding the ATP solution, the reaction was started. After incubation at room temperature for 30 minutes, a stop solution containing EDTA and biotin-phosphatidylinositol-3,4,5-triphosphate was added to stop the reaction. Finally, detection buffer including europium-labeled anti-GST mAb, GST-labeled GRP1PH domain and streptavidin-allophycocyanin was added. Plates were read in time-resolved fluorescence mode, and the homogeneous time-resolved fluorescence (HTRF) signal was determined by the equation HTRF = 10000 x (Em665nm/Em620nm).
PI3K(p110β/p85α)(h)[非放射性试验]PI3K(p110β/p85α)(h) [non-radioactive assay]
PI3K(p110β/p85α)(h)在含有10μM磷酸酰肌醇-4,5-二磷酸和MgATP(浓度根据需求确定)的缓冲溶液中 孵育。加入ATP溶液后，开始反应。室温下孵育30分钟之后，向其中加入含有EDTA和生物素磷脂酰肌醇-3,4,5-三磷酸的终止液来终止反应。最后，加入检测缓冲液，包括铕标记的抗GST单抗，GST标记的GRP1PH结构域和链亲和素-别藻蓝蛋白。孔板在时间分辨荧光模式下读数，均相时间分辨荧光(HTRF)信号由方程式HTRF＝10000×(Em665nm/Em620nm)确定。PI3K(p110β/p85α) (h) was incubated in a buffer solution containing 10 μM phosphoinositide-4,5-bisphosphate and MgATP (concentration as needed). After adding the ATP solution, the reaction was started. After incubation at room temperature for 30 minutes, a stop solution containing EDTA and biotin-phosphatidylinositol-3,4,5-triphosphate was added to stop the reaction. Finally, detection buffer including europium-labeled anti-GST mAb, GST-labeled GRP1PH domain and streptavidin-allophycocyanin was added. Plates were read in time-resolved fluorescence mode, and the homogeneous time-resolved fluorescence (HTRF) signal was determined by the equation HTRF = 10000 x (Em665nm/Em620nm).
PI3K(p110δ/p85α)(h)[非放射性试验]PI3K(p110δ/p85α)(h) [non-radioactive assay]
PI3K(p110δ/p85α)(h)在含有10μM磷酸酰肌醇-4,5-二磷酸和MgATP(浓度根据需求确定)的缓冲溶液中孵育。加入ATP溶液后，开始反应。室温下孵育30分钟之后，向其中加入含有EDTA和生物素磷脂酰肌醇-3,4,5-三磷酸的终止液来终止反应。最后，加入检测缓冲液，包括铕标记的抗GST单抗，GST标记的GRP1PH结构域和链亲和素-别藻蓝蛋白。孔板在时间分辨荧光模式下读数，均相时间分辨荧光(HTRF)信号由方程式HTRF＝10000×(Em665nm/Em620nm)决定。PI3K(p110δ/p85α) (h) was incubated in a buffer solution containing 10 μM phosphoinositide-4,5-bisphosphate and MgATP (concentration as needed). After adding the ATP solution, the reaction was started. After incubation at room temperature for 30 minutes, a stop solution containing EDTA and biotin-phosphatidylinositol-3,4,5-triphosphate was added to stop the reaction. Finally, detection buffer including europium-labeled anti-GST mAb, GST-labeled GRP1PH domain and streptavidin-allophycocyanin was added. The plate was read in time-resolved fluorescence mode, and the homogeneous time-resolved fluorescence (HTRF) signal was determined by the equation HTRF=10000×(Em665nm/Em620nm).
PI3K(p120γ)(h)[非放射性试验]PI3K(p120γ)(h) [non-radioactive test]
PI3K(p120γ)(h)在含有10μM磷酸酰肌醇-4,5-二磷酸和MgATP(浓度根据需求确定)的缓冲溶液中孵育。加入ATP溶液后，开始反应。室温下孵育30分钟之后，向其中加入含有EDTA和生物素磷脂酰肌醇-3,4,5-三磷酸的终止液来终止反应。最后，加入检测缓冲液，包括铕标记的抗GST单抗，GST标记的GRP1PH结构域和链亲和素-别藻蓝蛋白。孔板在时间分辨荧光模式下读数，均相时间分辨荧光(HTRF)信号由方程式HTRF＝10000×(Em665nm/Em620nm)确定。PI3K(p120γ) (h) was incubated in a buffer solution containing 10 μM phosphoinositide-4,5-bisphosphate and MgATP (concentration as needed). After adding the ATP solution, the reaction was started. After incubation at room temperature for 30 minutes, a stop solution containing EDTA and biotin-phosphatidylinositol-3,4,5-triphosphate was added to stop the reaction. Finally, detection buffer including europium-labeled anti-GST mAb, GST-labeled GRP1PH domain and streptavidin-allophycocyanin was added. Plates were read in time-resolved fluorescence mode, and the homogeneous time-resolved fluorescence (HTRF) signal was determined by the equation HTRF = 10000 x (Em665nm/Em620nm).
本发明中的激酶试验是由法国Eurofins公司来完成的(Eurofins Cerep SA,Le Bois L'Evêque,86600Celle L'Evescault,France)，测试结果如表1所示，其中，+：>100nM；++：50-100nM；+++：10-50nM；++++：＜10nM。Kinase test among the present invention is finished by French Eurofins company (Eurofins Cerep SA, Le Bois L'Evêque, 86600 Celle L'Evescault, France), test result is as shown in table 1, wherein, +: >100nM; ++ : 50-100nM; +++: 10-50nM; ++++: <10nM.
表1.本发明化合物的激酶抑制数据Table 1. Kinase Inhibition Data for Compounds of the Invention
Figure PCTCN2022121567-appb-000098
Figure PCTCN2022121567-appb-000098
Figure PCTCN2022121567-appb-000099
Figure PCTCN2022121567-appb-000099
试验结果表明，本发明化合物对PI3Kγ激酶很好的抑制活性，并且针对其他亚型具有高的选择性。细胞活性试验The test results show that the compound of the present invention has good inhibitory activity on PI3Kγ kinase and has high selectivity for other subtypes. Cell Viability Test
本发明化合物作为PI3K激酶抑制剂的细胞活性可以通过下述试验来进行评价的。The cellular activity of the compounds of the present invention as PI3K kinase inhibitors can be evaluated by the following tests.
细胞试验的一般性描述：General description of cell assays:
PI3K-α,γ亚型：首先化合物从储藏浓度用100％的DMSO稀释到5mM。第二步将5mM的化合物作为第一个点用100％DMSO 4倍稀释10个点。第三步用不含有血清的培养基250倍稀释，此时DMSO的浓度是0.4％。然后转50μL已经用培养基稀释好的化合物到50μL的细胞板里，此时DMSO的浓度是0.2％，化合物的最终浓度是10000nM,2500nM,625nM,156.25nM,39.06nM,9.77nM,2.44nM,0.61nM,0.15nM,0.04nM。PI3K-α,γ subtypes: First the compounds were diluted to 5 mM from stock concentration with 100% DMSO. In the second step, 5 mM compound was used as the first point and diluted 10 points by 4 times with 100% DMSO. In the third step, it is diluted 250-fold with serum-free medium, and the concentration of DMSO at this time is 0.4%. Then transfer 50 μL of the compound that has been diluted with medium to a 50 μL cell plate. At this time, the concentration of DMSO is 0.2%, and the final concentration of the compound is 10000nM, 2500nM, 625nM, 156.25nM, 39.06nM, 9.77nM, 2.44nM, 0.61nM, 0.15nM, 0.04nM.
PI3K-β，δ亚型：首先将化合物从储藏浓度用100％的DMSO稀释到1.25mM。第二步将1.25mM的化合物作为第一个点用100％DMSO 4倍稀释10个点。第三步用不含有血清的培养基35.714倍稀释，然后转2.5μL已经用培养基稀释好的化合物到30μL的细胞板里，培养箱里孵育1个小时，再加入2.5μL anti-IgM这个时候DMSO的浓度是0.2％，化合物的最终浓度是2500nM,625nM,156.25nM,39.06nM,9.77nM,2.44nM,0.61nM,0.15nM,0.04nM,0.01nM.PI3K-beta, delta isoforms: Compounds were first diluted from stock concentration to 1.25 mM in 100% DMSO. In the second step, 1.25 mM compound was used as the first point and diluted 10 points by 4 times with 100% DMSO. The third step is to dilute 35.714 times with serum-free medium, then transfer 2.5 μL of the compound that has been diluted with the medium to a 30 μL cell plate, incubate in the incubator for 1 hour, and then add 2.5 μL anti-IgM at this time The concentration of DMSO was 0.2%, and the final concentrations of the compounds were 2500nM, 625nM, 156.25nM, 39.06nM, 9.77nM, 2.44nM, 0.61nM, 0.15nM, 0.04nM, 0.01nM.
PI3K-α抑制活性检测方法PI3K-α inhibitory activity detection method
SKOV-3细胞以60000个/50μL/孔的密度种入细胞培养级别的96孔板中，细胞培养基是不加血清的RPMI-1640.在37℃，5％CO2培养箱中培养过夜。在细胞里加入50μL/孔的待测化合物在37℃，5％CO2培养箱中培养60分钟，最终DMSO浓度为0.2％，吸出培养基，每孔加入50μL 1x裂解液。室温震荡45分钟。将16μL裂解物转入384板，加入4μL Cisbio公司的Phospho-AKT(Ser473)试剂盒的预混抗体。1000rpm/min离心一分钟，在22℃孵育4小时后用Spark读数(665nm/615nm)。SKOV-3 cells were seeded into a 96-well plate of cell culture level at a density of 60,000 cells/50 μL/well, and the cell culture medium was RPMI-1640 without serum. Cultivated overnight in a 5% CO2 incubator at 37°C. Add 50 μL/well of the test compound to the cells and incubate for 60 minutes at 37°C in a 5% CO2 incubator with a final DMSO concentration of 0.2%. Aspirate the medium and add 50 μL of 1x lysis solution to each well. Shake at room temperature for 45 minutes. Transfer 16 μL of the lysate to a 384 plate, and add 4 μL of premixed antibody from Cisbio’s Phospho-AKT (Ser473) kit. Centrifuge at 1000 rpm/min for one minute, and read (665nm/615nm) with Spark after incubation at 22°C for 4 hours.
PI3K-β抑制活性检测方法PI3K-β inhibitory activity detection method
786-O细胞以30000个/50μL/孔的密度种入细胞培养级别的96孔板中，细胞培养基是不加血清的RPMI-1640.在37℃，5％CO2培养箱中培养过夜。在细胞里加入50μL/孔的待测化合物在37℃，5％CO2培养箱中培养60分钟，最终DMSO浓度为0.2％，吸出培养基，每孔加入50μL 1x裂解液。室温震荡45分钟。将16μL裂解物转入384板，加入4μL Cisbio公司的Phospho-AKT(Ser473)试剂盒的预混抗体。1000rpm/min离心一分钟，22℃孵育4小时后用Envision读数(665nm/615nm)。786-O cells were seeded into a 96-well plate of cell culture level at a density of 30,000 cells/50 μL/well, and the cell culture medium was RPMI-1640 without serum. Cultured overnight in a 5% CO2 incubator at 37°C. Add 50 μL/well of the test compound to the cells and incubate for 60 minutes at 37°C in a 5% CO2 incubator with a final DMSO concentration of 0.2%. Aspirate the medium and add 50 μL of 1x lysis solution to each well. Shake at room temperature for 45 minutes. Transfer 16 μL of the lysate to a 384 plate, and add 4 μL of premixed antibody from Cisbio’s Phospho-AKT (Ser473) kit. Centrifuge at 1000rpm/min for one minute, incubate at 22°C for 4 hours and read with Envision (665nm/615nm).
PI3K-δ抑制活性检测方法PI3K-δ inhibitory activity detection method
Raji细胞以每孔30μL，50,000个细胞种在96孔板中培养，细胞培养基是不加血清的RPMI-1640。细胞在5％CO2和37℃培养箱中孵育过夜。无血清饥饿18小时后，在细胞中加入2.5μL化合物(14X)，在培养箱中孵育60分钟。然后加入2.5μL(14X，用血清培养基稀释)的anti-human IgM(Jackson Immuno Research)，放入培养箱内刺激30分钟(终浓度为10μg/mL)。每孔加入11.5μL的4x裂解液。室温震荡45 分钟。将16μL裂解物加入转入384板，加入4μL Cisbio公司的Phospho-AKT(Ser473)试剂盒的预混抗体。1000rpm/min离心一分钟，22℃孵育4小时后用Spark读数(665nm/615nm)。Raji cells were cultured in 96-well plates at 30 μL per well, 50,000 cells, and the cell culture medium was RPMI-1640 without serum. Cells were incubated overnight in a 5% CO2 incubator at 37°C. After 18 hours of serum-free starvation, 2.5 μL of compound (14X) was added to the cells and incubated for 60 minutes in the incubator. Then 2.5 μL (14X, diluted with serum medium) of anti-human IgM (Jackson Immuno Research) was added and placed in the incubator to stimulate for 30 minutes (final concentration was 10 μg/mL). Add 11.5 µL of 4x Lysis Buffer to each well. Shake at room temperature for 45 minutes. Add 16 μL of the lysate to the 384 plate, and add 4 μL of the premixed antibody of the Phospho-AKT (Ser473) kit from Cisbio. Centrifuge at 1000rpm/min for one minute, incubate at 22°C for 4 hours and read with Spark (665nm/615nm).
PI3K-γ抑制活性检测方法PI3K-γ inhibitory activity detection method
用无血清DMEM培养基重悬RAW264.7细胞，在96孔板中每孔加入60000个/45μL的细胞悬液。细胞置于5％CO2，37℃培养箱中孵育过夜。无血清饥饿18小时后，加入50μL化合物，在培养箱中培养60min。然后加入5μL的25nM的C5a(R&D Systems，用血清培养基稀释)刺激5min。吸出培养基每孔加入50μL 1x裂解液。室温震荡45分钟。将16μL裂解物转入384板，加入4μL Cisbio公司的Phospho-AKT(Ser473)试剂盒的预混抗体。1000rpm/min离心一分钟，22℃.孵育4小时后用Spark读数(665nm/615nm)。RAW264.7 cells were resuspended in serum-free DMEM medium, and 60,000 cells/45 μL of cell suspension were added to each well of a 96-well plate. Cells were incubated overnight in a 5% CO2, 37°C incubator. After 18 hours of serum-free starvation, 50 μL of the compound was added and incubated in the incubator for 60 minutes. Then, 5 μL of 25 nM C5a (R&D Systems, diluted with serum medium) was added to stimulate for 5 min. Aspirate the medium and add 50 μL of 1x Lysis Buffer to each well. Shake at room temperature for 45 minutes. Transfer 16 μL of the lysate to a 384 plate, and add 4 μL of premixed antibody from Cisbio’s Phospho-AKT (Ser473) kit. Centrifuge at 1000rpm/min for one minute at 22°C. After incubation for 4 hours, read with Spark (665nm/615nm).
本发明中的激酶试验是由保诺生物科技(江苏)有限公司完成的，测试结果如表2所示，其中，+：>500nM；++：100-500nM；+++：50-100nM；++++：＜50nM。The kinase test in the present invention is completed by BaoDuo Biotechnology (Jiangsu) Co., Ltd., and the test results are shown in Table 2, wherein, +: >500nM; ++: 100-500nM; +++: 50-100nM; ++++: <50nM.
阳性药IPI-549的合成参照专利WO2015143012A1。其化学结构式如下所示：The synthesis of positive drug IPI-549 refers to patent WO2015143012A1. Its chemical structural formula is as follows:
Figure PCTCN2022121567-appb-000100
Figure PCTCN2022121567-appb-000100
表2本发明化合物的细胞活性数据The cell activity data of the compound of the present invention in table 2
Figure PCTCN2022121567-appb-000101
Figure PCTCN2022121567-appb-000101
试验结果表明，本发明化合物对PI3Kγ具有显著的抑制活性，并对其他PI3K亚型具有非常明显的选择性。本发明化合物相对阳性药IPI-549具有更高的选择性。The test results show that the compound of the present invention has significant inhibitory activity on PI3Kγ, and has very obvious selectivity on other PI3K subtypes. The compound of the present invention has higher selectivity than the positive drug IPI-549.
本发明化合物在人肝微粒体中代谢稳定性研究Study on the metabolic stability of the compounds of the present invention in human liver microsomes
本发明化合物作为PI3K激酶抑制剂的代谢稳定性可以通过下述试验来进行评价。The metabolic stability of the compounds of the present invention as PI3K kinase inhibitors can be evaluated by the following assay.
肝微粒体稳定性试验的一般性描述：General description of the liver microsomal stability assay:
将受试化合物与人肝微粒体进行共孵育，加入NADPH，反应启动。在0，5，15，30和60分钟分别取出30微升并转移至300微升含有内标的乙腈中终止反应。随后剧烈涡旋1分钟，再在4℃以下以4000rpm的转速离心15分钟。蛋白沉淀后，取出100微升上层清液，加入100微升蒸馏水稀释后由LC-MS/MS方法分析。 根据受试化合物在孵育体系中的清除半衰期算出体外内在清除率。维拉帕米作为对照化合物，均平行孵育5分钟。The test compound was co-incubated with human liver microsomes, and NADPH was added to start the reaction. At 0, 5, 15, 30 and 60 minutes, 30 microliters were withdrawn and transferred to 300 microliters of acetonitrile containing an internal standard to stop the reaction. This was followed by vigorous vortexing for 1 minute and centrifugation at 4000 rpm for 15 minutes below 4°C. After protein precipitation, 100 microliters of the supernatant was taken out, diluted with 100 microliters of distilled water and analyzed by LC-MS/MS method. Calculate the intrinsic clearance rate in vitro according to the elimination half-life of the test compound in the incubation system. Verapamil was used as a control compound, and both were incubated in parallel for 5 minutes.
数据分析：data analysis:
剩余百分比(％Remaining)由非零时间点样品与零时刻样品中受试化合物的峰面积之比计算出。受试化合物清除半衰期(T 1/2，min)以及体外内在清除率(C Lint,μL.min -1.mg -1)由以下方程式得出： The percent remaining (%Remaining) was calculated from the ratio of the peak area of the test compound in the non-zero time point sample to the zero time point sample. The elimination half-life (T 1/2 , min) and in vitro intrinsic clearance (C Lint , μL.min -1 .mg -1 ) of the test compound are obtained by the following equation:
Figure PCTCN2022121567-appb-000102
Figure PCTCN2022121567-appb-000102
Figure PCTCN2022121567-appb-000103
Figure PCTCN2022121567-appb-000103
Figure PCTCN2022121567-appb-000104
Figure PCTCN2022121567-appb-000104
本发明实施例化合物与IPI-549的人肝微粒体稳定性的相关参数如表3所示。Table 3 shows the parameters related to the stability of human liver microsomes of the compounds of the examples of the present invention and IPI-549.
表3本发明化合物的人肝微粒体稳定性的相关参数The relevant parameters of the human liver microsome stability of the compound of the present invention in table 3
化合物compound 半衰期(T 1/2，min) Half-life (T 1/2 , min)
IPI-549IPI-549 122.6122.6
实施例13Example 13 63.763.7
实施例16Example 16 154.7154.7
实施例21Example 21 77.277.2
实施例28Example 28 656.9656.9
实施例37Example 37 94.794.7
试验结果表明，与IPI-549相比，本发明实施例16和实施例28的半衰期明显延长，人肝微粒体稳定性显著提高。对比本发明实施例16和实施例28，当吡唑上甲基的氢被氘取代后，人肝微粒体稳定性均显著提高；同样，对比本发明实施例21和实施例37，吡唑上甲基的氢被氘取代后，人肝微粒体稳定性亦均显著提高。本发明化合物CD-1小鼠口服药代动力学研究The test results show that, compared with IPI-549, the half-life of Example 16 and Example 28 of the present invention is significantly prolonged, and the stability of human liver microsomes is significantly improved. Comparing Example 16 and Example 28 of the present invention, when the hydrogen of the methyl group on pyrazole is replaced by deuterium, the stability of human liver microsomes is significantly improved; similarly, comparing Example 21 and Example 37 of the present invention, the After the hydrogen of the methyl group was replaced by deuterium, the stability of human liver microsomes was also significantly improved. Oral pharmacokinetic study of the compound CD-1 of the present invention in mice
本发明化合物作为PI3K激酶抑制剂的药代动力学研究可以通过下述试验来进行评价。The pharmacokinetic studies of the compounds of the present invention as PI3K kinase inhibitors can be evaluated by the following tests.
药代动力学试验的一般性描述：General description of pharmacokinetic studies:
以CD-1小鼠为受试动物，采用LC-MS/MS方法测定灌胃给予本发明化合物，测定其不同时刻血浆中的药物浓度。静脉注射给药剂量及配方：2mg/kg，5％NMP/40％PEG400/55％PBS；口服剂量给药及配方：10.0mg/kg，0.5％(w/v)羟甲基纤维素和0.05％Tween 80的水溶液。称取适量待测化合物，加入到适量的0.5％(w/v)羟甲基纤维素和0.05％Tween 80的水溶液，涡旋和超声，最终配置成浓度为1mg/mL的待测溶液。静脉注射组采样时间为：给药后0.0833,0.25,0.5,1,2,4,8,24h。口服组采样时间为：0.25,0.5,1,2,4,8,24h。最后采用LC-MS/MS法测定不同的化合物静脉注射和口服给药后CD-1小鼠血浆中的待测化合物的含量。Taking CD-1 mice as test animals, LC-MS/MS method was used to determine the compound of the present invention administered by gavage, and to measure the drug concentration in plasma at different times. Dosage and formulation for intravenous injection: 2mg/kg, 5% NMP/40% PEG400/55% PBS; oral dosage and formulation: 10.0mg/kg, 0.5% (w/v) hydroxymethylcellulose and 0.05 % Tween 80 in water. Weigh an appropriate amount of the compound to be tested, add it to an appropriate amount of 0.5% (w/v) hydroxymethylcellulose and 0.05% Tween 80 in water, vortex and sonicate, and finally configure the solution to be tested with a concentration of 1 mg/mL. The sampling time of the intravenous injection group was: 0.0833, 0.25, 0.5, 1, 2, 4, 8, 24 hours after administration. The sampling time of the oral group is: 0.25, 0.5, 1, 2, 4, 8, 24h. Finally, the LC-MS/MS method was used to determine the content of the test compound in the plasma of CD-1 mice after intravenous injection and oral administration of different compounds.
表4本发明化合物的药代动力学参数The pharmacokinetic parameter of table 4 compound of the present invention
Figure PCTCN2022121567-appb-000105
Figure PCTCN2022121567-appb-000105
试验结果表明，本发明实施例16和实施例37在CD-1小鼠中的药代吸收良好，半衰期较长，生物利用度高，均具有良好的药代动力学性质。The test results show that the pharmacokinetic absorption of Example 16 and Example 37 of the present invention in CD-1 mice is good, the half-life is long, the bioavailability is high, and both have good pharmacokinetic properties.
最后，需要注意的是，还有其他方式用来实施本发明。相应地，本发明的实施例是将作为例证进行说明，但并不限于本发明所描述的内容，还可能是在本发明范围内所作的修改或在权利要求中所添加的等同内容。本发明所引用的所有出版物或专利都将作为本发明的参考文献。Finally, it should be noted that there are other ways to implement the invention. Accordingly, the embodiments of the present invention will be described as illustrations, but are not limited to the content described in the present invention, and may be modified within the scope of the present invention or equivalent content added in the claims. All publications or patents cited in the present invention shall be regarded as reference documents of the present invention.

Claims (25)

  1. 化合物，其具有式(I)所示结构：Compound, it has the structure shown in formula (I):
    Figure PCTCN2022121567-appb-100001
    Figure PCTCN2022121567-appb-100001
    或其立体异构体、互变异构体、氘代物、氮氧化物、溶剂化物、或药学上可接受的盐；Or its stereoisomers, tautomers, deuterated substances, nitrogen oxides, solvates, or pharmaceutically acceptable salts;
    其中，in,
    X是-C(R c)-、或N； X is -C(R c )-, or N;
    Z 1和Z 2各自独立地为-C(R 4d)-或N； Z 1 and Z 2 are each independently -C(R 4d )- or N;
    R a、R b和R c各自独立地为H、D、F、Cl、C 1-3烷基、C 1-6氘代烷基、C 1-3烷氧基、C 1-3卤代烷基、C 1-3羟基烷基、C 1-3氨基烷基、C 1-3氰基烷基、C 1-6氘代烷氧基、被1至5个氘取代的C 1-6卤代烷基、被1至5个氘取代的C 1-6羟基烷基、被1至5个氘取代的C 3-8环烷基、或被1至5个氘取代的C 1-9杂芳基； R a , R b and R c are each independently H, D, F, Cl, C 1-3 alkyl, C 1-6 deuterated alkyl, C 1-3 alkoxy, C 1-3 haloalkyl , C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, C 1-3 cyanoalkyl, C 1-6 deuterated alkoxy, C 1-6 haloalkyl substituted by 1 to 5 deuteriums , a C 1-6 hydroxyalkyl group substituted by 1 to 5 deuteriums, a C 3-8 cycloalkyl group substituted by 1 to 5 deuteriums, or a C 1-9 heteroaryl group substituted by 1 to 5 deuteriums;
    R 1是H、D、-C 1-6烷基-NR eR f、-C(＝O)R 7、-C(＝O)OR 7a、-C(＝O)NR 7R 7a、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 3-8环烷基、C 2-9杂环基、C 6-10芳基、或C 1-9杂芳基；其中R 1任选地被0、1、2、3或4个R 5取代； R 1 is H, D, -C 1-6 alkyl-NR e R f , -C(=O)R 7 , -C(=O)OR 7a , -C(=O)NR 7 R 7a , C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl, or C 1-9 Heteroaryl; wherein R is optionally substituted by 0, 1, 2, 3 or 4 R 5 ;
    R 2在每次出现时，分别独立地为H、D、F、Cl、Br、I、-OH、-CN、-NO 2、-NR eR f、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基、或C 1-9杂芳基；其中R 2在每次出现时，独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基和C 1-6卤代烷基的基团取代； Each occurrence of R 2 is independently H, D, F, Cl, Br, I, -OH, -CN, -NO 2 , -NR e R f , C 1-6 alkyl, C 1- 6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2-9 heterocyclyl, C 3-8 cycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein R, at each occurrence, is independently optionally 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH , -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy and C 1-6 haloalkyl;
    R 3是H、D、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8氘代环烷基、C 2-9杂环基、C 6-10芳基、或C 1-9杂芳基；其中R 3任选地被0、1、2、3、4或5个R 6取代； R 3 is H, D, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkane Base, C 3-8 deuterated cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein R 3 is optionally replaced by 0, 1, 2, 3 , 4 or 5 R 6 substitutions;
    R 4a、R 4b、R 4c和R 4d各自独立地为H、D、F、Cl、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基、或C 1-9杂芳基；其中R 4a、R 4b、R 4c和R 4d各自独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基、C 1-6氘代烷氧基、C 1-6卤代烷基和C 1-6卤代氘代烷基的基团取代； R 4a , R 4b , R 4c and R 4d are each independently H, D, F, Cl, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2-9 hetero Cyclic group, C 3-8 cycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein R 4a , R 4b , R 4c and R 4d are each independently optionally replaced by 0, 1, 2 , 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 deuterated alkyl group, C 1-6 alkoxy group, C 1-6 deuterated alkoxy group, C 1-6 haloalkyl group and C 1-6 halodeuteroalkyl group substitution;
    R 5和R 6，在每次出现时，分别独立地为H、D、氧代(＝O)、F、Cl、Br、I、-OH、-CN、-NO 2、-NR eR f、-C(＝O)R 7、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基、或C 1-9杂芳基；其中所述各-NR eR f、-C(＝O)R 7、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基和C 1-9杂芳基独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基和C 1-6卤代烷基的基团取代； R 5 and R 6 , at each occurrence, are independently H, D, oxo (=O), F, Cl, Br, I, -OH, -CN, -NO 2 , -NR e R f , -C(=O)R 7 , C 1-6 alkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1 -6 haloalkyl, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2-9 heterocyclyl, C 3-8 Cycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein each of -NR e R f , -C(=O)R 7 , C 1-6 alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2-9 heterocyclyl, C 3-8 cycloalkyl, C 6-10 aryl and C 1-9 heteroaryl are independently optional 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 alkoxy group and C 1-6 haloalkyl group substitution;
    R e、R f、R 7和R 7a，在每次出现时，分别独立地为H、D、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、 C 1-6羟基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-9杂环基、C 2-9杂环基C 1-6烷基、C 6-10芳基、C 6-10芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-9杂环基、C 2-9杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基和C 1-6卤代烷基的基团取代；和 R e , R f , R 7 and R 7a , at each occurrence, are independently H, D, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 2-9 heterocyclyl, C 2-9 heterocyclyl C 1-6 alkyl , C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each C 1 -6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-9 heterocyclyl, C 2-9 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl and C 1-9 heteroaryl C 1-6 alkyl groups are independently optionally selected from 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy and C 1-6 haloalkyl group substitution; and
    n是0、1、2、或3；n is 0, 1, 2, or 3;
    条件是：1)当R 1是吡唑基时、其中R 1任选地被0、1、2、3或4个R 5取代，则各R 2、R 4a、R 4b和R 4c中的至少一个独立地为F、Cl、-CN、C 1-6烷氧基、C 1-6氘代烷基、C 1-6氘代烷氧基、被1至5个氘取代的C 1-6卤代烷基、被1至5个氘取代的C 1-6羟基烷基、被1至5个氘取代的C 3-8环烷基、或被1至5个氘取代的C 1-9杂芳基；或者2)当R 1是H、D、-C 1-6烷基-NR eR f、-C(＝O)R 7、-C(＝O)OR 7a、-C(＝O)NR 7R 7a、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 3-8环烷基、C 2-9杂环基、C 6-10芳基、或除吡唑基以外的C 1-9杂芳基时、其中R 1任选地被0、1、2、3或4个R 5取代，则各R a、R b、R c、R 2、R 3、R 4a、R 4b、R 4c和R 4d中的至少一个独立地为D(氘)、C 1-6氘代烷基、C 1-6氘代烷氧基、被1至5个氘取代的C 1-6卤代烷基、被1至5个氘取代的C 1-6羟基烷基、被1至5个氘取代的C 3-8环烷基、或被1至5个氘取代的C 1-9杂芳基。 Provided that: 1) when R 1 is pyrazolyl, wherein R 1 is optionally substituted by 0, 1, 2, 3 or 4 R 5 , then each of R 2 , R 4a , R 4b and R 4c At least one is independently F, Cl, -CN, C 1-6 alkoxy, C 1-6 deuterated alkyl, C 1-6 deuterated alkoxy, C 1- substituted by 1 to 5 deuteriums 6 haloalkyl, C 1-6 hydroxyalkyl substituted by 1 to 5 deuterium, C 3-8 cycloalkyl substituted by 1 to 5 deuterium, or C 1-9 heteroalkyl substituted by 1 to 5 deuterium Aryl; or 2) when R 1 is H, D, -C 1-6 alkyl-NR e R f , -C(=O)R 7 , -C(=O)OR 7a , -C(=O )NR 7 R 7a , C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl When C 1-9 heteroaryl group or C 1-9 heteroaryl group other than pyrazolyl, wherein R 1 is optionally substituted by 0, 1, 2, 3 or 4 R 5 , then each R a , R b , R c , At least one of R 2 , R 3 , R 4a , R 4b , R 4c and R 4d is independently D (deuterium), C 1-6 deuterated alkyl, C 1-6 deuterated alkoxy, 1 C 1-6 haloalkyl substituted by 1 to 5 deuterium, C 1-6 hydroxyalkyl substituted by 1 to 5 deuterium, C 3-8 cycloalkyl substituted by 1 to 5 deuterium, or 1 to 5 deuterium-substituted C 1-9 heteroaryl.
  2. 根据权利要求1所述的化合物，其具有式(Ia)所示结构：The compound according to claim 1, which has a structure shown in formula (Ia):
    Figure PCTCN2022121567-appb-100002
    Figure PCTCN2022121567-appb-100002
    或其立体异构体、互变异构体、氘代物、氮氧化物、溶剂化物、或药学上可接受的盐。Or a stereoisomer, tautomer, deuterated substance, nitrogen oxide, solvate, or a pharmaceutically acceptable salt thereof.
  3. 根据权利要求1所述的化合物，其中，R 1是苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、三嗪基、噻唑基、咪唑基、噁唑基、噻二唑基、
    Figure PCTCN2022121567-appb-100003
    Figure PCTCN2022121567-appb-100004
    The compound according to claim 1 , wherein R is phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, thiazolyl, imidazolyl, oxazolyl, thiadiazolyl,
    Figure PCTCN2022121567-appb-100003
    Figure PCTCN2022121567-appb-100004
    其中Y 1是O、S、或-NH-； Wherein Y 1 is O, S, or -NH-;
    Y 6是O、或-NH-； Y 6 is O, or -NH-;
    t3和t4各自独立地为1、2、3或4；和t3 and t4 are each independently 1, 2, 3 or 4; and
    其中R 1任选地被0、1、2、3或4个R 5取代； wherein R is optionally substituted by 0, 1, 2, 3 or 4 R 5 ;
    条件是：1)当R 1为
    Figure PCTCN2022121567-appb-100005
    时、其中R 1任选地被0、1、2、3或4个R 5取代，则各R 2、R 4a、R 4b和R 4c 中的至少一个独立地为F、Cl、-CN、C 1-3烷氧基、C 1-3氘代烷基、C 1-3氘代烷氧基、被1至5个氘取代的C 1-3卤代烷基、被1至5个氘取代的C 1-3羟基烷基、被1至5个氘取代的C 3-6环烷基、或被1至5个氘取代的C 1-9杂芳基；2)当R 1为苯基、吡啶基、哒嗪基、吡嗪基、嘧啶基、三嗪基、噻唑基、咪唑基、噁唑基、噻二唑基、
    Figure PCTCN2022121567-appb-100006
    时、其中R 1任选地被0、1、2、3或4个R 5取代，则各R a、R b、R c、R 2、R 3、R 4a、R 4b、R 4c和R 4d中的至少一个独立地为D(氘)、C 1-3氘代烷基、C 1-3氘代烷氧基、被1至5个氘取代的C 1-3卤代烷基、被1至5个氘取代的C 1-3羟基烷基、被1至5个氘取代的C 3-6环烷基、或被1至5个氘取代的C 1-9杂芳基。     The conditions are: 1) When R1 is
    Figure PCTCN2022121567-appb-100005
    When, wherein R 1 is optionally substituted by 0, 1, 2, 3 or 4 R 5 , then at least one of each R 2 , R 4a , R 4b and R 4c is independently F, Cl, -CN, C 1-3 alkoxy, C 1-3 deuterated alkyl, C 1-3 deuterated alkoxy, C 1-3 haloalkyl substituted by 1 to 5 deuteriums, substituted by 1 to 5 deuteriums C 1-3 hydroxyalkyl, C 3-6 cycloalkyl substituted by 1 to 5 deuteriums, or C 1-9 heteroaryl substituted by 1 to 5 deuteriums; 2) when R 1 is phenyl, Pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, thiazolyl, imidazolyl, oxazolyl, thiadiazolyl,
    Figure PCTCN2022121567-appb-100006
    , wherein R 1 is optionally substituted by 0, 1, 2, 3 or 4 R 5 , then each of R a , R b , R c , R 2 , R 3 , R 4a , R 4b , R 4c and R At least one of 4d is independently D (deuterium), C 1-3 deuterated alkyl, C 1-3 deuterated alkoxy, C 1-3 haloalkyl substituted by 1 to 5 deuterium, 1 to 3 C 1-3 hydroxyalkyl substituted with 5 deuteriums, C 3-6 cycloalkyl substituted with 1 to 5 deuteriums, or C 1-9 heteroaryl substituted with 1 to 5 deuteriums.
  4. 根据权利要求1-3任一项所述的化合物，其中，R 4a、R 4b、R 4c和R 4d各自独立地为H、D、F、Cl、C 1-3烷基、C 1-3氘代烷基、C 1-3烷氧基、C 1-3卤代烷基、C 1-3卤代烷氧基、C 1-3羟基烷基、C 1-3氨基烷基、C 1-3氰基烷基、C 3-6杂环基、C 3-6氘代杂环基、C 3-6环烷基、C 3-6氘代环烷基、苯基、或5-6个原子组成的杂芳基；其中R 4a、R 4b、R 4c和R 4d各自独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-3烷基、C 1-3氘代烷基、C 1-3烷氧基、C 1-3氘代烷氧基、C 1-3卤代烷基和C 1-3卤代氘代烷基的基团取代。 The compound according to any one of claims 1-3, wherein R 4a , R 4b , R 4c and R 4d are each independently H, D, F, Cl, C 1-3 alkyl, C 1-3 Deuterated alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, C 1-3 cyano Alkyl, C 3-6 heterocyclyl, C 3-6 deuterated heterocyclyl, C 3-6 cycloalkyl, C 3-6 deuterated cycloalkyl, phenyl, or 5-6 atoms Heteroaryl; wherein R 4a , R 4b , R 4c and R 4d are each independently optionally 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 alkoxy, C 1-3 deuterated The group substitution of alkoxy, C 1-3 haloalkyl and C 1-3 halodeuteroalkyl.
  5. 根据权利要求1-3任一项所述的化合物，其中，R 4a、R 4b、R 4c和R 4d各自独立地为H，F，Cl，D，-CN，-OCH 3，-OCH 2CH 3，
    Figure PCTCN2022121567-appb-100007
    Figure PCTCN2022121567-appb-100008
    The compound according to any one of claims 1-3, wherein R 4a , R 4b , R 4c and R 4d are each independently H, F, Cl, D, -CN, -OCH 3 , -OCH 2 CH 3 ,
    Figure PCTCN2022121567-appb-100007
    Figure PCTCN2022121567-appb-100008
  6. 化合物，其具有式(II)所示结构：Compound, it has the structure shown in formula (II):
    Figure PCTCN2022121567-appb-100009
    Figure PCTCN2022121567-appb-100009
    或其立体异构体、互变异构体、氘代物、氮氧化物、溶剂化物、或药学上可接受的盐；Or its stereoisomers, tautomers, deuterated substances, nitrogen oxides, solvates, or pharmaceutically acceptable salts;
    其中，in,
    X是-C(R c)-、或N； X is -C(R c )-, or N;
    W是C 3-10环烷基、C 2-9杂环基、C 6-10芳基、或C 1-9杂芳基；其中W任选地被0、1、2、3或4个R 4取代； W is C 3-10 cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein W is optionally replaced by 0, 1, 2, 3 or 4 R 4 replaces;
    R a、R b和R c各自独立地为H、D、F、Cl、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、或C 1-6氰基烷基； R a , R b and R c are each independently H, D, F, Cl, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, or C 1-6 cyanoalkyl;
    R 1是-C 1-3羟基烷基-C(＝O)OR 7a，-C(＝O)OR 7a，-C(＝O)NR 7R 7a，
    Figure PCTCN2022121567-appb-100010
    Figure PCTCN2022121567-appb-100011
    R 1 is -C 1-3 hydroxyalkyl-C(=O)OR 7a , -C(=O)OR 7a , -C(=O)NR 7 R 7a ,
    Figure PCTCN2022121567-appb-100010
    Figure PCTCN2022121567-appb-100011
    其中Y 2和Y 3各自独立地为-(CH 2) t1-、-(CH 2) t1-L-、-(CH 2) t1-L-(CH 2) t2-、O、或-NH-； wherein Y 2 and Y 3 are each independently -(CH 2 ) t1 -, -(CH 2 ) t1 -L-, -(CH 2 ) t1 -L-(CH 2 ) t2 -, O, or -NH- ;
    Y 4是-(CH 2) t1-、-(CH 2) t1-L-、-(CH 2) t1-L-(CH 2) t2-、-C(＝O)-、O、S、或-NH-； Y 4 is -(CH 2 ) t1 -, -(CH 2 ) t1 -L-, -(CH 2 ) t1 -L-(CH 2 ) t2 -, -C(=O)-, O, S, or -NH-;
    Y 5是-CH-、或N； Y 5 is -CH-, or N;
    Y 6是O、或-NH-； Y 6 is O, or -NH-;
    Y 7是O、或-NH-； Y 7 is O, or -NH-;
    L是-C(＝O)-、O、S、或-NH-；L is -C(=O)-, O, S, or -NH-;
    t1、t2和t3在每次出现时，各自独立地为1、2、3或4；each occurrence of t1, t2 and t3 is independently 1, 2, 3 or 4;
    t4是1；t5是1或2；和t4 is 1; t5 is 1 or 2; and
    Figure PCTCN2022121567-appb-100012
    代表单键或双键；和
    Figure PCTCN2022121567-appb-100012
    represents a single or double bond; and
    其中R 1任选地被0、1、2、3或4个R 5取代； wherein R is optionally substituted by 0, 1, 2, 3 or 4 R 5 ;
    R 2在每次出现时，分别独立地为H、D、F、Cl、Br、I、-OH、-CN、-NO 2、-NR eR f、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基、或C 1-9杂芳基；其中R 2在每次出现时，独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基和C 1-6卤代烷基的基团取代； Each occurrence of R 2 is independently H, D, F, Cl, Br, I, -OH, -CN, -NO 2 , -NR e R f , C 1-6 alkyl, C 1- 6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2-9 heterocyclyl, C 3-8 cycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein R, at each occurrence, is independently optionally 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH , -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy and C 1-6 haloalkyl;
    R 3是H、D、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、C 3-8氘代环烷基、C 2-9杂环基、C 6-10芳基、或C 1-9杂芳基；其中R 3任选地被0、1、2、3、4或5个R 6取代； R 3 is H, D, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkane Base, C 3-8 deuterated cycloalkyl, C 2-9 heterocyclyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein R 3 is optionally replaced by 0, 1, 2, 3 , 4 or 5 R 6 substitutions;
    R 4在每次出现时，分别独立地为H、D、F、Cl、Br、I、-OH、-CN、-NO 2、-NR eR f、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基、或C 1-9杂芳基；其中R 4在每次出现时，独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基和C 1-6卤代烷基的基团取代； Each occurrence of R 4 is independently H, D, F, Cl, Br, I, -OH, -CN, -NO 2 , -NR e R f , C 1-6 alkyl, C 1- 6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl , C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2-9 heterocyclyl, C 3-8 cycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein R is , at each occurrence, independently optionally 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH , -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy and C 1-6 haloalkyl;
    R 5和R 6，在每次出现时，分别独立地为H、D、氧代(＝O)、F、Cl、Br、I、-OH、-CN、-NO 2、-NR eR f、-C(＝O)R 7、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基、或C 1-9杂芳基；其中所述各-NR eR f、-C(＝O)R 7、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基和C 1-9杂芳基独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基和C 1-6卤代烷基的基团取代； R 5 and R 6 , at each occurrence, are independently H, D, oxo (=O), F, Cl, Br, I, -OH, -CN, -NO 2 , -NR e R f , -C(=O)R 7 , C 1-6 alkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1 -6 haloalkyl, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2-9 heterocyclyl, C 3-8 Cycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein each of -NR e R f , -C(=O)R 7 , C 1-6 alkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 2-9 heterocyclyl, C 3-8 cycloalkyl, C 6-10 aryl and C 1-9 heteroaryl are independently optional 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl group, C 1-6 deuterated alkyl group, C 1-6 alkoxy group and C 1-6 haloalkyl group substitution;
    R 5a是-C(＝O)R 7、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基、或C 1-9杂芳基；其中所述各-C(＝O)R 7、C 1-6烷基、C 1-6氘代烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6卤代烷氧基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 2-9杂环基、C 3-8环烷基、C 6-10芳基和C 1-9杂芳基独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基和C 1-6卤代烷基的基团取代； R 5a is -C(=O)R 7 , C 1-6 alkyl, C 1-6 deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl , C 2-9 heterocyclyl, C 3 -8 cycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein each of -C(=O)R 7 , C 1-6 alkyl, C 1-6 deuterated alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 cyanoalkyl, C 2-9 heterocyclyl, C 3-8 cycloalkyl, C 6-10 aryl and C 1-9 heteroaryl are independently optionally replaced by O, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-6 Alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy and C 1-6 haloalkyl group substitution;
    R e、R f、R 7和R 7a，在每次出现时，分别独立地为H、D、C 1-6烷基、C 1-6氘代烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-9杂环基、C 2-9杂环基C 1-6烷基、C 6-10芳基、C 6-10芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-9杂环基、C 2-9杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6氘代烷基、C 1-6烷氧基和C 1-6卤代烷基的基团取代；和 R e , R f , R 7 and R 7a , at each occurrence, are independently H, D, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkyl, C 2-9 heterocyclyl, C 2-9 heterocyclyl C 1-6 alkyl , C 6-10 aryl, C 6-10 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each C 1 -6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-9 heterocyclyl, C 2-9 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl and C 1-9 heteroaryl C 1-6 alkyl groups are independently optionally selected from 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 alkoxy and C 1-6 haloalkyl group substitution; and
    n是0、1、2、或3。n is 0, 1, 2, or 3.
  7. 根据权利要求6所述的化合物，其中，W是The compound according to claim 6, wherein W is
    C 3-8环烷基、C 3-8杂环基、
    Figure PCTCN2022121567-appb-100013
    Figure PCTCN2022121567-appb-100014
    C 3-8 cycloalkyl, C 3-8 heterocyclyl,
    Figure PCTCN2022121567-appb-100013
    Figure PCTCN2022121567-appb-100014
    其中Z 1、Z 2和Z 3各自独立地为-CH-、或N；和 wherein Z 1 , Z 2 and Z 3 are each independently -CH-, or N; and
    其中W任选地被0、1、2、3或4个R 4取代。 wherein W is optionally substituted by 0, 1, 2, 3 or 4 R 4 .
  8. 根据权利要求6所述的化合物，其具有式(IIa)所示结构：The compound according to claim 6, which has a structure shown in formula (IIa):
    Figure PCTCN2022121567-appb-100015
    Figure PCTCN2022121567-appb-100015
    或其立体异构体、互变异构体、氘代物、氮氧化物、溶剂化物、或药学上可接受的盐；Or its stereoisomers, tautomers, deuterated substances, nitrogen oxides, solvates, or pharmaceutically acceptable salts;
    其中，m是0、1、2或3。wherein m is 0, 1, 2 or 3.
  9. 根据权利要求6-8任一项所述的化合物，其中，R 1是
    Figure PCTCN2022121567-appb-100016
    Figure PCTCN2022121567-appb-100017
    Figure PCTCN2022121567-appb-100018
    其中R 1任选地被0、1、2、3或4个R 5取代。     The compound according to any one of claims 6-8, wherein R 1 is
    Figure PCTCN2022121567-appb-100016
    Figure PCTCN2022121567-appb-100017
    Figure PCTCN2022121567-appb-100018
    wherein R 1 is optionally substituted by 0, 1, 2, 3 or 4 R 5 .
  10. 根据权利要求6-8任一项所述的化合物，其中，R 4在每次出现时，分别独立地为H、D、F、Cl、Br、I、-OH、-CN、-NO 2、-NH 2、C 1-3烷基、C 1-3氘代烷基、C 1-3烷氧基、C 1-3卤代烷基、C 1-3卤代烷氧基、C 1-3 羟基烷基、C 1-3氨基烷基、C 1-3氰基烷基、C 3-6杂环基、C 3-6环烷基、苯基、或5-6个原子组成的杂芳基；其中R 4在每次出现时，分别独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-3烷基、C 1-3氘代烷基、C 1-3烷氧基和C 1-3卤代烷基的基团取代。 The compound according to any one of claims 6-8, wherein, at each occurrence, R 4 is independently H, D, F, Cl, Br, I, -OH, -CN, -NO 2 , -NH 2 , C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 1-3 hydroxyalkyl , C 1-3 aminoalkyl, C 1-3 cyanoalkyl, C 3-6 heterocyclyl, C 3-6 cycloalkyl, phenyl, or heteroaryl consisting of 5-6 atoms; where Each occurrence of R is independently optionally 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH , -NH 2 , -CN, -NO 2 , C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 alkoxy and C 1-3 haloalkyl.
  11. 根据权利要求6-8任一项所述的化合物，其中，R 5a是-C(＝O)R 7、C 1-4烷基、C 1-4氘代烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4羟基烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 3-6杂环基、C 3-6环烷基、C 6-10芳基、或C 1-9杂芳基；其中所述各-C(＝O)R 7、C 1-4烷基、C 1-4氘代烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4卤代烷氧基、C 1-4羟基烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 3-6杂环基、C 3-6环烷基、C 6-10芳基和C 1-9杂芳基独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-4氘代烷基、C 1-4烷氧基和C 1-4卤代烷基的基团取代。 The compound according to any one of claims 6-8, wherein R 5a is -C(=O)R 7 , C 1-4 alkyl, C 1-4 deuterated alkyl, C 2-4 alkenyl , C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl , C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1- 4 cyanoalkyl, C 3-6 heterocyclyl, C 3-6 cycloalkyl, C 6-10 aryl, or C 1-9 heteroaryl; wherein each -C(=O)R 7 , C 1-4 alkyl, C 1-4 deuterated alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 Haloalkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-6 heterocyclyl , C 3-6 cycloalkyl, C 6-10 aryl and C 1-9 heteroaryl are independently optionally selected from 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH , -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-4 deuterated alkyl, C 1-4 alkoxy and C 1-4 haloalkyl.
  12. 根据权利要求1-3和6-8任一项所述的化合物，其中，R 3是环丙基、吡啶基、或苯基；其中R 3任选地被0、1、2、3、4或5个独立选自H、D、F、Cl、Br、I、-OH、-CN、-NO 2、-NR eR f、C 1-3烷基、C 1-3烷氧基、C 1-3氘代烷基和C 1-3卤代烷基的基团取代。 The compound according to any one of claims 1-3 and 6-8, wherein R is cyclopropyl, pyridyl, or phenyl; wherein R is optionally replaced by 0, 1, 2, 3 , 4 or 5 independently selected from H, D, F, Cl, Br, I, -OH, -CN, -NO 2 , -NR e R f , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 deuterated alkyl and C 1-3 haloalkyl group substitution.
  13. 根据权利要求1-3和6-8任一项所述的化合物，其中，R 5和R 6在每次出现时，分别独立地为H、D、氧代(＝O)、F、Cl、Br、I、-OH、-CN、-NO 2、-NR eR f、-C(＝O)R 7、C 1-3烷基、C 1-3氘代烷基、C 1-3烷氧基、C 1-3卤代烷基、C 1-3羟基烷基、C 3-6环烷基、苯基、或5-6个原子组成的杂芳基；其中所述各-NR eR f、-C(＝O)R 7、C 1-3烷基、C 1-3氘代烷基、C 1-3烷氧基、C 1-3卤代烷基、C 1-3羟基烷基、C 3-6环烷基、苯基和5-6个原子组成的杂芳基独立任选地被0、1、2、3、4或5个独立选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-3烷基、C 1-3氘代烷基、C 1-3烷氧基和C 1-3卤代烷基的基团取代。 The compound according to any one of claims 1-3 and 6-8, wherein R and R are each independently H, D, oxo (=O), F, Cl , Br, I, -OH, -CN, -NO 2 , -NR e R f , -C(=O)R 7 , C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 alkane Oxygen, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, phenyl, or heteroaryl consisting of 5-6 atoms; wherein each -NR e R f , -C(=O)R 7 , C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, phenyl and heteroaryl consisting of 5-6 atoms are independently and optionally 0, 1, 2, 3, 4 or 5 independently selected from H, D, oxo (=O) , F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-3 alkyl, C 1-3 deuterated alkyl, C 1-3 alkoxy and C 1- 3 haloalkyl groups are substituted.
  14. 根据权利要求1-3和6-8任一项所述的化合物，其中，R 5和R 6在每次出现时，分别独立地为H、D、氧代(＝O)、F、Cl、Br、I、-OH、-CN、-NO 2、-NR eR f、甲基、乙基、环丙基、-CD 3、-OCD 3、-CF 3、-CH 2CH 2OH、-C(＝O)CH 3、-C(＝O)CH 2CH 3、或-CH 2CH 2OCH 3。 The compound according to any one of claims 1-3 and 6-8, wherein R and R are each independently H, D, oxo (=O), F, Cl , Br, I, -OH, -CN, -NO 2 , -NR e R f , methyl, ethyl, cyclopropyl, -CD 3 , -OCD 3 , -CF 3 , -CH 2 CH 2 OH, - C(=O) CH3 , -C (= O ) CH2CH3 , or -CH2CH2OCH3 .
  15. 根据权利要求1-3和6-8任一项所述的化合物，其中，R a、R b和R c各自独立地为H、D、F、-CN、-NO 2、-NR eR f、甲基、乙基、异丙基、-CD 3、-CHD 2、-CH 2D、甲氧基、乙氧基、卤代甲基、卤代乙基、或-CH 2CH 2OH。 The compound according to any one of claims 1-3 and 6-8, wherein R a , R b and R c are each independently H, D, F, -CN, -NO 2 , -NR e R f , methyl, ethyl, isopropyl, -CD 3 , -CHD 2 , -CH 2 D, methoxy, ethoxy, halomethyl, haloethyl, or -CH 2 CH 2 OH.
  16. 根据权利要求1-3和6-8任一项所述的化合物，其中，R e、R f、R 7和R 7a，在每次出现时，分别独立地为H、D、C 1-4烷基、C 1-4氘代烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 3-6杂环基、C 3-6杂环基C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-4烷基；其中所述各C 1-4烷基、C 1-4氘代烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 3-6杂环基、C 3-6杂环基C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基和C 1-9杂芳基C 1-4烷基独立任选地被0、1、2、3、4或5个独立地选自H、D、氧代(＝O)、F、Cl、Br、I、-OH、-NH 2、-CN、-NO 2、C 1-4烷基、C 1-4氘代烷基、C 1-4烷氧基和C 1-4卤代烷基的基团取代。 The compound according to any one of claims 1-3 and 6-8, wherein R e , R f , R 7 and R 7a , at each occurrence, are independently H, D, C 1-4 Alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-4 alkyl, C 3-6 heterocyclyl, C 3-6 heterocyclyl C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-4 alkyl; wherein each C 1-4 alkyl, C 1-4 deuterated alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-4 alkyl, C 3-6 heterocyclyl, C 3-6 heterocyclyl C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, C 1-9 heteroaryl and C 1-9 heteroaryl C 1-4 alkyl are independently optionally replaced by 0, 1, 2, 3, 4 or 5 each independently selected from H, D, oxo (=O), F, Cl, Br, I, -OH, -NH 2 , -CN, -NO 2 , C 1-4 alkyl, C 1-4 deuterium Substituted alkyl group, C 1-4 alkoxy group and C 1-4 haloalkyl group substitution.
  17. 根据权利要求1所述的化合物，其为具有以下结构之一的化合物：The compound according to claim 1, which is a compound having one of the following structures:
    Figure PCTCN2022121567-appb-100019
    Figure PCTCN2022121567-appb-100019
    Figure PCTCN2022121567-appb-100020
    Figure PCTCN2022121567-appb-100020
    Figure PCTCN2022121567-appb-100021
    Figure PCTCN2022121567-appb-100021
    或其立体异构体、互变异构体、氘代物、氮氧化物、溶剂化物、或药学上可接受的盐。Or a stereoisomer, tautomer, deuterated substance, nitrogen oxide, solvate, or a pharmaceutically acceptable salt thereof.
  18. 根据权利要求6所述的化合物，其为具有以下结构之一的化合物：The compound according to claim 6, which is a compound having one of the following structures:
    Figure PCTCN2022121567-appb-100022
    Figure PCTCN2022121567-appb-100022
    Figure PCTCN2022121567-appb-100023
    Figure PCTCN2022121567-appb-100023
    Figure PCTCN2022121567-appb-100024
    Figure PCTCN2022121567-appb-100024
    或其立体异构体、互变异构体、氮氧化物、溶剂化物、或药学上可接受的盐。Or a stereoisomer, tautomer, nitrogen oxide, solvate, or a pharmaceutically acceptable salt thereof.
  19. 药物组合物，所述药物组合物包含权利要求1-18任一项所述的化合物或其立体异构体、互变异构体、氮氧化物、溶剂化物、或药学上可接受的盐，以及药学上可接受的辅料、稀释剂或载体、或其组合。A pharmaceutical composition comprising the compound of any one of claims 1-18 or its stereoisomer, tautomer, nitrogen oxide, solvate, or pharmaceutically acceptable salt, And a pharmaceutically acceptable adjuvant, diluent or carrier, or a combination thereof.
  20. 根据权利要求19所述的药物组合物，其进一步包含附加治疗剂。The pharmaceutical composition according to claim 19, further comprising an additional therapeutic agent.
  21. 使用根据权利要求1-18任一项所述的化合物或权利要求19-20任一项所述的药物组合物在制备用于预防、处理、治疗、和/或减轻PI3-激酶介导的疾病、病症、和/或病况，或抑制PI3-激酶活性的药物中的用途。Use the compound according to any one of claims 1-18 or the pharmaceutical composition according to any one of claims 19-20 in the preparation for preventing, treating, treating, and/or alleviating PI3-kinase-mediated diseases , disease, and/or condition, or use in a medicament that inhibits PI3-kinase activity.
  22. 根据权利要求21所述的用途，其中所述PI3-激酶介导的疾病、病症、和/或病况选自呼吸道疾病，病毒感染，非病毒呼吸道感染，过敏性疾病，自身免疫性疾病，炎性疾病，心血管疾病，恶性血液病，神经退行性疾病，胰腺炎，多器官衰竭，肾病，血小板聚集，癌症，精子活力，移植排斥，移植物排斥，肺损伤或疼痛。The use according to claim 21, wherein the PI3-kinase-mediated disease, disorder, and/or condition is selected from respiratory diseases, viral infections, non-viral respiratory infections, allergic diseases, autoimmune diseases, inflammatory Disease, cardiovascular disease, hematological malignancy, neurodegenerative disease, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, lung injury or pain.
  23. 根据权利要求21所述的用途，其中所述PI3-激酶介导的疾病、病症、和/或病况选自哮喘，慢性阻塞性肺病(COPD)，病毒性呼吸道感染，病毒性呼吸道疾病恶化，曲霉病，利什曼病，过敏性鼻炎，过敏性皮肤炎，风湿性关节炎，多发性硬化，炎性肠病，血栓症，动脉粥样硬化，恶性血液病，神经退行性疾病，胰腺炎，多器官衰竭，肾病，血小板聚集，癌症，精子活力，移植排斥，移植物排斥，肺损伤，与类风湿性关节炎或骨关节炎相关的疼痛，背痛，全身炎症性疼痛，肝后神经痛，糖尿病性神经病变，炎症性神经性疼痛(外伤)，三叉神经痛或中枢性疼痛。The use according to claim 21, wherein the PI3-kinase-mediated disease, disorder, and/or condition is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), viral respiratory infection, exacerbation of viral respiratory disease, Aspergillus disease, leishmaniasis, allergic rhinitis, atopic dermatitis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, thrombosis, atherosclerosis, hematological malignancies, neurodegenerative diseases, pancreatitis, Multiple organ failure, kidney disease, platelet aggregation, cancer, sperm motility, transplant rejection, graft rejection, lung injury, pain associated with rheumatoid arthritis or osteoarthritis, back pain, systemic inflammatory pain, retrohepatic neuralgia , diabetic neuropathy, inflammatory neuropathic pain (trauma), trigeminal neuralgia or central pain.
  24. 根据权利要求22或23所述的用途，其中所述癌症选自急性骨髓性白血病，脊髓发育异常综合征，骨髓增生病，慢性骨髓性白血病，T细胞急性淋巴细胞白血病，B细胞急性淋巴细胞白血病，非霍奇金淋巴瘤，B细胞淋巴瘤，实体瘤，或乳腺癌。The use according to claim 22 or 23, wherein the cancer is selected from acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative disease, chronic myelogenous leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia , non-Hodgkin's lymphoma, B-cell lymphoma, solid tumor, or breast cancer.
  25. 根据权利要求21所述的用途，其中所述PI3-激酶是PI3K-γ。The use according to claim 21, wherein the PI3-kinase is PI3K-γ.
PCT/CN2022/121567 2021-09-28 2022-09-27 Isoquinolinone and quinazolinone compounds, and composition and use thereof WO2023051495A1 (en)

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