WO2023051495A1 - Composés isoquinolinone et quinazolinone, et composition et utilisation de ceux-ci - Google Patents

Composés isoquinolinone et quinazolinone, et composition et utilisation de ceux-ci 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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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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    • A61K31/472—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.

Abstract

La présente invention concerne des composés isoquinolinone et quinazolinone représentés par la formule (I) ou (II), une composition pharmaceutique contenant les composés, et l'utilisation des composés et de la composition pharmaceutique de ceux-ci dans la préparation d'un médicament pour prévenir, traiter et/ou atténuer des maladies, troubles et/ou états médiés par la PI3-kinase, ou pour inhiber une activité PI3-kinase. Ces composés présentent une excellente activité inhibitrice et une excellente sélectivité vis-à-vis de la kinase pour une kinase cible, et ont de bonnes propriétés pharmacocinétiques et une plus grande biodisponibilité.
PCT/CN2022/121567 2021-09-28 2022-09-27 Composés isoquinolinone et quinazolinone, et composition et utilisation de ceux-ci WO2023051495A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160122365A1 (en) * 2014-10-03 2016-05-05 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
CN105793255A (zh) * 2013-10-04 2016-07-20 无限药品股份有限公司 杂环化合物及其用途
US20190135833A1 (en) * 2016-06-08 2019-05-09 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US20190202835A1 (en) * 2016-03-17 2019-07-04 Infinity Pharmaceuticals, Inc. Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as pi3k kinase inhibitors
WO2019228404A1 (fr) * 2018-05-31 2019-12-05 信达生物制药(苏州)有限公司 Nouveau inhibiteur de phosphoïnositide 3-kinase et procédé de préparation et d'utilisation associé
WO2021004421A1 (fr) * 2019-07-08 2021-01-14 浙江海正药业股份有限公司 Dérivé alcyne, son procédé de préparation et ses utilisations

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105793255A (zh) * 2013-10-04 2016-07-20 无限药品股份有限公司 杂环化合物及其用途
US20160122365A1 (en) * 2014-10-03 2016-05-05 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US20190202835A1 (en) * 2016-03-17 2019-07-04 Infinity Pharmaceuticals, Inc. Isotopologues of isoquinolinone and quinazolinone compounds and uses thereof as pi3k kinase inhibitors
US20190135833A1 (en) * 2016-06-08 2019-05-09 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
WO2019228404A1 (fr) * 2018-05-31 2019-12-05 信达生物制药(苏州)有限公司 Nouveau inhibiteur de phosphoïnositide 3-kinase et procédé de préparation et d'utilisation associé
WO2021004421A1 (fr) * 2019-07-08 2021-01-14 浙江海正药业股份有限公司 Dérivé alcyne, son procédé de préparation et ses utilisations

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