WO2020043122A1 - Dérivés de quinazoline servant d'inhibiteur de kinase rip2 - Google Patents

Dérivés de quinazoline servant d'inhibiteur de kinase rip2 Download PDF

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WO2020043122A1
WO2020043122A1 PCT/CN2019/102999 CN2019102999W WO2020043122A1 WO 2020043122 A1 WO2020043122 A1 WO 2020043122A1 CN 2019102999 W CN2019102999 W CN 2019102999W WO 2020043122 A1 WO2020043122 A1 WO 2020043122A1
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compound
pharmaceutically acceptable
acceptable salt
optical isomer
alkyl
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Chinese (zh)
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牟剑锋
吴松亮
贺海鹰
杨亚讯
张红进
张臣
龚珍
黎健
陈曙辉
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南京明德新药研发有限公司
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Priority to CN201980056903.2A priority Critical patent/CN112638905A/zh
Publication of WO2020043122A1 publication Critical patent/WO2020043122A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings

Definitions

  • the present invention relates to a class of quinazoline derivatives, in particular to a compound represented by formula (I) and a pharmaceutically acceptable salt thereof, and its application in preparing a RIP2 kinase inhibitor.
  • NOD 1/2 nucleotide binding protein 1/2 containing oligomeric domains
  • NOD 1/2 can activate downstream RIP2 kinases, which in turn activates NF-kB and MAPK signaling pathways, thereby promoting the production of multiple cytokines.
  • Excessive activation of RIP2 kinase is observed in both patients with IBD and Blau syndrome: 1) In patients with Blau syndrome, mutations in the NOD2 gene can cause excessive activation of this signaling pathway characterized by increased levels of RIP2 phosphorylation; 2) From the pediatric CD and UC patients' small intestine biopsy tissues, it has been found that the activation of RIP2 kinase and the increase of phosphorylation levels are extensive.
  • RIP2 kinase In patients with UC and CD, RIP2 kinase is also in an overphosphorylated state. The above evidence shows that by inhibiting RIP2 kinase and inhibiting the NOD / RIP2 signaling pathway, it can be used for the treatment of various inflammatory diseases.
  • GSK reported a series of amine quinazoline compounds (WO 2013025958), which have very good activity of inhibiting RIP2 kinase, representative compound X (see Example 21 in WO2013025958).
  • 2 mg / kg of Compound X can significantly reduce the MDP-induced comprehensive cytokine levels (TNF ⁇ , IL-6, IL-8, and IL-1 ⁇ ) in whole blood.
  • the positive drug prednisolone is comparable.
  • the present invention provides a compound represented by formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof,
  • n 0, 1, 2 or 3;
  • L is selected from a single bond, -O-, -N (R 5 )-, and
  • Ring A is selected from a 5- to 10-membered heteroaryl group
  • R 1 is independently selected from H, halogen, OH, NH 2 and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2 or 3 R a ;
  • R 2 is selected from the group consisting of halogen, OH, NH 2 , C 1-6 alkyl, and 3 to 6-membered heterocycloalkyl, and the C 1-6 alkyl and 3 to 6-membered heterocycloalkyl are optionally Or 3 R b substitutions;
  • R 3 is selected from C 1-6 alkyl, which C 1-6 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R 4 is selected from C 1-6 alkyl, which C 1-6 alkyl is optionally substituted with 1, 2 or 3 Rd ;
  • R 3 and R 4 are linked together with a phosphorus atom connected to them to form a 5- to 6-membered heterocycloalkyl or 5- to 8-membered heterocycloalkenyl, 5- to 8-membered heterocycloalkenyl is optionally substituted with 1, 2 or 3 R c ;
  • R 5 is independently selected from H and C 1-3 alkyl, wherein C 1-3 alkyl is optionally substituted with 1, 2 or 3 R e ;
  • R a, R b, R c , R d and R e are each independently selected from F, Cl, Br, I, OH, NH 2, Me , and
  • the present invention provides a compound represented by formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof,
  • n 0, 1, 2 or 3;
  • L is selected from a single bond, -O-, -N (R 5 )-, and
  • Ring A is selected from a 5- to 10-membered heteroaryl group
  • R 1 is selected from H, halogen, OH, NH 2 and C 1-3 alkyl, said C 1-3 alkyl optionally substituted with 1, 2 or 3 R a;
  • R 2 is selected from the group consisting of halogen, OH, NH 2 , C 1-6 alkyl, and 3 to 6-membered heterocycloalkyl, and the C 1-6 alkyl and 3 to 6-membered heterocycloalkyl are optionally Or 3 R b substitutions;
  • R 3 is selected from C 1-3 alkyl, which C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c ;
  • R 4 is selected from C 1-3 alkyl, which C 1-3 alkyl is optionally substituted with 1, 2 or 3 Rd ;
  • R 3 and R 4 are linked together with a phosphorus atom connected to them to form a 5- to 6-membered heterocycloalkyl group together;
  • R 5 is selected from H and C 1-3 alkyl, said C 1-3 alkyl being optionally substituted with 1, 2 or 3 R e ;
  • R a, R b, R c , R d and R e are each independently selected from F, Cl, Br, I, OH, NH 2, Me , and
  • R 1 is selected from H, F, Cl, Br, I, OH, NH 2 , and Me, and Me is optionally substituted by 1, 2 or 3 R a . Defined by invention.
  • R 1 is selected from H, F, Cl, Br, I, OH, NH 2 and Me, and other variables are as defined in the present invention.
  • the ring A is selected from pyrazolyl and benzo [d] thiazolyl, and other variables are as defined in the present invention.
  • R 2 is selected from F, Cl, Br, I, OH, NH 2, C 1-3 alkyl, and 3 to 6-membered heterocycloalkyl, C 1-3 alkyl and
  • the 3- to 6-membered heterocycloalkyl group is optionally substituted with 1, 2 or 3 Rb , and other variables are as defined in the present invention.
  • R 2 is selected from F, Cl, Br, I, OH, NH 2, C 1-3 alkyl, and 4-6 membered heterocycloalkyl, C 1-3 alkyl and the
  • the 4- to 6-membered heterocycloalkyl group is optionally substituted with 1, 2 or 3 Rb , and other variables are as defined in the present invention.
  • the R 2 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , Me, Mentioned Me, It is optionally substituted by 1, 2 or 3 Rb , other variables are as defined in the present invention.
  • the R 2 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , Me, Mentioned Me, It is optionally substituted by 1, 2 or 3 Rb , other variables are as defined in the present invention.
  • the R 2 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , Me, Et, CF 3 ⁇
  • Other variables are as defined in the present invention.
  • the R 2 is selected from the group consisting of F, Cl, Br, I, OH, NH 2 , Me, Other variables are as defined in the present invention.
  • the R 3 is selected from C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted with 1, 2 or 3 R c , and other variables are as defined in the present invention.
  • R 3 is selected from Me, the Me is optionally substituted by 1, 2 or 3 R c , and other variables are as defined in the present invention.
  • the R 3 is selected from Me, In some aspects of the present invention, the above R 3 is selected from Me, and other variables are as defined in the present invention.
  • the above R 4 is selected from C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted with 1, 2 or 3 Rd , and other variables are as defined in the present invention.
  • R 4 is selected from Me, and the Me is optionally substituted with 1, 2 or 3 Rd , and other variables are as defined in the present invention.
  • the R 4 is selected from Me, Other variables are as defined in the present invention.
  • R 4 is selected from Me, and other variables are as defined in the present invention.
  • R 5 is selected from H and Me, Me said optionally substituted with 1, 2, or 3 R e, the other variables are as defined in the present invention.
  • R 5 is selected from H and Me, and other variables are defined in the present invention.
  • the L is selected from a single bond, -O-, -N (Me)-, Other variables are as defined in the present invention.
  • the aforementioned compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • R 1 , R 2 , R 3 , R 4 , and L are as defined above.
  • the invention provides a compound of the formula, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
  • the present invention provides the use of the aforementioned compound or a pharmaceutically acceptable salt thereof in the preparation of a RIP2 kinase inhibitor.
  • the invention provides the application of the above composition in the preparation of a RIP2 kinase inhibitor.
  • the compound of the present invention shows a good effect of inhibiting RIP2 kinase in a kinase test, and can be used for treating various inflammatory diseases such as IBD.
  • the introduction of the phosphine group is expected to reduce the fat solubility of the compound, increase the solubility of the compound, improve the binding of plasma proteins, and thereby increase the drugability of the molecule.
  • the compound of the present invention can significantly improve single or partial indexes of rat pharmacokinetics, and the compound of the present invention has better plasma exposure and oral bioavailability.
  • the compound 1 of the present invention has a highly specific kinase selectivity. In addition to having a high inhibitory effect on RIPK2, the inhibitory activity on most other kinases is weak. Relative to compound X, the inhibitory activity of compound 1 on six kinases, such as Abl (h); Arg (h); Flt4 (h); KDR (h); LOK (h); Ret (h), was significantly reduced, which may show It has lower off-target activity and better safety than Compound X. In a TNBS-induced mouse colitis model, Compound 1 exhibited a potency comparable to Compound X, which could significantly reduce the histological score of colitis. Compound 1 had no significant inhibitory effect on hERG channels.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and / or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit / risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, prepared from a compound having a specific substituent and a relatively non-toxic acid or base found in the present invention.
  • base addition salts can be obtained by contacting a sufficient amount of a base with a neutral form of such compounds in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc .; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by a conventional chemical method. Generally, such salts are prepared by reacting these compounds in the form of a free acid or base with a stoichiometric appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • This invention contemplates all such compounds, including cis and trans isomers, (-)-and (+)-enantiomers, (R)-and (S) -enantiomers, diastereomers Isomers, (D) -isomers, (L) -isomers, and racemic and other mixtures thereof, such as enantiomeric or diastereomeric enriched mixtures, all of which belong to the present Within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and their mixtures are included in the scope of the present invention.
  • substituted refers to the replacement of any one or more hydrogen atoms on a specific atom with a substituent, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • O oxygen
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable such as R
  • its definition in each case is independent.
  • the group may be optionally substituted with at most two R, and R in each case has independent options.
  • combinations of substituents and / or variants are only permitted if such combinations result in stable compounds.
  • substituents When a substituent is vacant, it means that the substituent does not exist.
  • X in A-X indicates that the structure is actually A.
  • substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be passed through any of the pyridine rings. The carbon atom is attached to a substituted group.
  • the intermediate linking group L is -MW-.
  • -MW- can be connected to ring A and ring B in the same direction as the reading order from left to right. You can also connect ring A and ring B in the opposite direction from the reading order from left to right.
  • the number of atoms on a ring is generally defined as the number of rings, for example, a "5-7 member ring” refers to a “ring” arranged around 5-7 atoms.
  • C 1-6 alkyl is used to indicate a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
  • the C 1-6 alkyl includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl, etc .; it may Is monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • C 1-6 alkyl examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and the like.
  • C 1-3 alkyl is used to indicate a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, and the like; it may be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine).
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 2-8 alkenyl is used to indicate a straight or branched hydrocarbon group consisting of 2 to 8 carbon atoms containing at least one carbon-carbon double bond, a carbon-carbon double bond It can be located anywhere on this group.
  • the C 2-8 alkenyl includes C 2-6 , C 2-4 , C 2-3 , C 4 , C 3, and C 2 alkenyl, and the like; it may be monovalent, divalent, or polyvalent.
  • Examples of C 2-8 alkenyl include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, and the like.
  • the term "3- to 6-membered heterocycloalkyl" itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 ring atoms of which Are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S (O) p , p Is 1 or 2). It includes single ring and double ring systems, where the double ring system includes a spiro ring, a parallel ring and a bridge ring.
  • the heteroatom may occupy the position of attachment of the heterocycloalkyl group to the rest of the molecule.
  • the 3-6 membered heterocycloalkyl includes 4-6 members, 5-6 members, 4 members, 5 members, 6 members, and the like.
  • 3- to 6-membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuryl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazyl, isoxazolidinyl, isothiazolyl,
  • the term "4- to 6-membered heterocycloalkyl" itself or in combination with other terms means a saturated cyclic group consisting of 4 to 6 ring atoms, which has 1, 2, 3 or 4 ring atoms Are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S (O) p , p Is 1 or 2). It includes single ring and double ring systems, where the double ring system includes a spiro ring, a parallel ring and a bridge ring.
  • a heteroatom may occupy a connection position between the heterocycloalkyl group and the rest of the molecule.
  • the 4- to 6-membered heterocycloalkyl includes 5- to 6, 4-, 5-, and 6-membered heterocycloalkyl.
  • 4- to 6-membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuryl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazyl, isoxazolidinyl, isothiazolyl,
  • the term "5- to 6-membered heterocycloalkyl" itself or in combination with other terms means a saturated cyclic group consisting of 5 to 6 ring atoms, which has 1, 2, 3 or 4 ring atoms Are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S (O) p , p Is 1 or 2). It includes single ring and double ring systems, where the double ring system includes a spiro ring, a parallel ring and a bridge ring.
  • a heteroatom may occupy a connection position between the heterocycloalkyl group and the rest of the molecule.
  • the 5- to 6-membered heterocycloalkyl includes 5- and 6-membered heterocycloalkyl.
  • Examples of 5- to 6-membered heterocycloalkyl include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.) , Tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1 -Piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithiaalkyl, isoxazolidinyl, isothiazolyl Alkyl, 1,2-oxazinyl, 1,2-thiazinyl
  • the term "5- to 8-membered heterocycloalkenyl" itself or in combination with other terms respectively means a partially unsaturated cyclic group consisting of 5 to 8 ring atoms containing at least one carbon-carbon double bond 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally Oxidation (ie NO and S (O) p , p is 1 or 2).
  • the 5-8 membered heterocycloalkenyl includes 5-7 members, 5-6 members, 4-5 members, 4 members, 5 members, 6 members, and the like. Examples of 5-8 membered heterocyclenyl include, but are not limited to
  • 5-10 membered heteroaryl ring and “5-10 membered heteroaryl group” in the present invention are used interchangeably, and the term “5-10 membered heteroaryl group” means from 5 to 10 rings
  • a cyclic group consisting of atoms with a conjugated ⁇ -electron system.
  • One, two, three or four ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic system, where each ring is aromatic.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S (O) p , p is 1 or 2).
  • 5- to 10-membered heteroaryl groups can be attached to the rest of the molecule through heteroatoms or carbon atoms.
  • the 5-10 membered heteroaryl group includes 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl, and the like.
  • Examples of the 5- to 10-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyryl) Oxazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, etc.), thiazolyl (
  • C n-n + m or C n -C n + m includes any specific case of n to n + m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , and also include any range from n to n + m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.
  • n yuan to n + m means that the number of atoms on the ring is n to n + m.
  • a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, and a 9-membered ring.
  • 3-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring Ring, 5-7 member ring, 6-7 member ring, 6-8 member ring, and 6-10 member ring, etc.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those familiar to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • aq stands for water
  • HATU O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate
  • EDC stands for N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride
  • m-CPBA stands for 3-chloroperoxybenzoic acid
  • eq stands for equivalent, equivalent
  • CDI stands for Carbonyl diimidazole
  • DCM stands for dichloromethane
  • PE stands for petroleum ether
  • DIAD diisopropyl azodicarboxylate
  • DMF stands for N, N-dimethylformamide
  • DMSO stands for dimethyl sulfoxide
  • EtOAc stands for ethyl acetate EtOH for ethanol; MeOH for methanol
  • CBz benzyl
  • Figure 1 Experimental results of TNBS-induced mouse acute colitis model.
  • Step 1 Synthesis of compound BB-1-2.
  • Step 2 Synthesis of compound BB-1-3.
  • Step 3 Synthesis of compound BB-1-4.
  • Step 4 Synthesis of compound BB-1-5.
  • Step 5 Synthesis of compound BB-1.
  • BB-1-5 8 g, 24.96 mmol, 1 eq
  • the reaction solution was concentrated under reduced pressure to obtain a crude product.
  • the crude product was purified by beating with 50 mL of acetonitrile and filtered to obtain compound BB-1.
  • Step 1 Synthesis of compound BB-2.
  • n-propylmagnesium chloride tetrahydrofuran (1M, 6.52mL, 3eq) was added dropwise to BB-2-1 (0.3g, 2.17mmol, 280.37 ⁇ L, 1eq) and stirred at 20 ° C for 2 hours.
  • An aqueous solution (1.1 mL) of potassium carbonate (900.71 mg, 6.52 mmol, 3 eq) was slowly added to the reaction system at 0 ° C and stirred at 20 ° C for 0.2 hours.
  • the reaction solution was filtered, and the filter cake was washed with ethanol (10 mL) x 2 and concentrated.
  • the concentrated crude product was dissolved with diethyl ether (10 mL), filtered, and the filtrate was concentrated to give compound BB-2.
  • Step 1 Synthesis of compound BB-3.
  • Step 1 Synthesis of compound BB-4.
  • BB-1 (424mg, 976.39umol, 1eq) was dissolved in DMF (20mL), the system was replaced with nitrogen three times, and dimethylphosphine oxide (110.24mg, 1.41mmol, 1.45eq) and Benzylacetone) dipalladium (70.38mg, 76.86 ⁇ mol, 0.08eq), 4,5-bis (diphenylphosphine) -9,9-dimethyloxanthene (83.10mg, 143.62 ⁇ mol, 0.16eq) and Triethylamine (250.16 mg, 2.47 mmol, 344.10 ⁇ L, 2.53 eq). The reaction solution was stirred at 90 ° C for 3 hours.
  • reaction solution was directly concentrated to obtain a crude product.
  • Ethyl acetate (30 mL) was added to the crude product, and the mixture was stirred at 20 ° C. for 1 hour and then filtered, and the filter cake was washed with ethyl acetate (6 mL ⁇ 2) to obtain compound 1.
  • Step 1 Synthesis of Compound 2-1.
  • Step 1 Synthesis of Compound 5-1.
  • Step 1 Synthesis of compound 6-2.
  • Step 2 Synthesis of compound 6-3.
  • Step 4 Synthesis of compound 6 and compound 6A.
  • Triethylamine (29.48mg, 291.30 ⁇ mol, 40.55 ⁇ L, 2.53eq), tris (dibenzylideneacetone) dipalladium (1.05mg, 1.15 ⁇ mol, 0.01eq), and 4,5-bis (diphenylphosphine)
  • BB-2 22.40 mg, 166.95 ⁇ mol, 15.31 ⁇ L, 1.45 eq
  • BB- 1 0.05 g, 115.14 ⁇ mol, 1 eq
  • the substrate compound 10-2 (0.3 g, 687.34 ⁇ mol, 1 eq) was dissolved in toluene (20 mL), and the air was replaced with nitrogen. Then the Grubbs first-generation catalyst (56.56 mg, 68.73 ⁇ mol, 0.1 eq) was added to the reaction system, and the reaction was refluxed at 110 ° C. for 12 hours. Product signal detected by LCMS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the crude product was separated and purified by preparative HPLC (neutral system) to obtain compound 10.
  • the substrate 2-bromopropane (249.06 mg, 2.03 mmol, 190.12 ⁇ L, 5 eq) and compound 2-1 (0.15 g, 405.01 ⁇ mol, 1 eq) were dissolved in DMF (14 mL), and potassium carbonate (167.93 mg, 1.22 mmol, 3eq) was added to the reaction system, and stirred at 25 ° C for 12 hours.
  • potassium carbonate 167.93 mg, 1.22 mmol, 3eq
  • the purpose of this test is to detect the compounds' inhibitory activity against RIPK2 kinase in vitro.
  • the enzyme used in this test is human-derived RIPK2 kinase, and Eurofins Pharma Discovery Service provides activity detection methods.
  • the results of the test compounds' inhibitory activity on RIPK2 kinase are shown in Table 1.
  • RIPK2 (h) was treated with a buffer solution (20 mM tris (hydroxymethyl) aminomethane hydrochloride pH 8.5, 0.2 mM EDTA, 0.1% 7-mercaptoethanol, 0.01% Brij-35, 5% glycerol, and 1 mg / mL bovine serum Protein), and then added to the reaction system.
  • a buffer solution (20 mM tris (hydroxymethyl) aminomethane hydrochloride pH 8.5, 0.2 mM EDTA, 0.1% 7-mercaptoethanol, 0.01% Brij-35, 5% glycerol, and 1 mg / mL bovine serum Protein
  • the reaction was
  • the scintillation luminescence counter measures the intensity of the emitted photons and compares the number of times per minute (cpm) of the enzyme sample with the cpm of the internal control sample. The level of the photon intensity reflects the strength of the RIPK2 kinase activity.
  • the compound of the present invention has a good inhibitory effect on RIPK2 kinase.
  • the whatman stopper is pressed near the liquid surface, so that the filter membrane in the stopper is in uniform contact with the liquid surface.
  • the whatman vial was placed in a shaker and shaken at room temperature for 24 hours, and the speed was set to 600 r / min.
  • the supernatant was taken out, and a precise amount of 10 ⁇ l was taken out and diluted 100 times.
  • the obtained diluent and stock solution were simultaneously entered into a high-performance liquid chromatography for detection and analysis, and the results were calculated by the external standard method based on the peak area and the dilution factor.
  • This project used 6 female SD rats, 3 rats were administered intravenously at a dose of 1 mg / kg, collected 0 h (before administration) and 0.0833, 0.25, 0.5, 1, 2, 4 after administration
  • Plasma samples at 8, 24 h, and 3 other rats were administered orally by gavage at a dose of 2 mg / kg, collected 0 h (before administration) and 0.5, 1, 2, 3, 4, 8, after administration,
  • the plasma samples were collected for 24 hours, and then the collected samples were analyzed by LC / MS / MS and data were collected.
  • the collected analysis data was calculated using Phoenix WinNonlin 6.2.1 software.
  • AUC 0-last represents the area under the plasma concentration-time curve from the zero time point to the last detectable concentration time point; C max represents the peak concentration; T max represents the peak time; T 1/2 represents the half-life; CL represents the clearance Rate; T last represents the last quantifiable time point; po represents oral; iv represents intravenous injection.
  • the compound of the present invention can significantly improve single or partial indicators of pharmacokinetics in rats, and the compound of the present invention has better plasma exposure and oral bioavailability.
  • MDP as a broad bacterial product, can be used to construct a mouse peritonitis model. Its pathogenesis is mainly the combination of MDP and its ligand NOD, and through the RIPK2 signal transduction, the downstream NF-kB inflammatory signal transduction pathway is activated, thereby initiating the release of target genes and inflammatory factors related to the natural immune response.
  • RIPK2 as a key kinase that initiates the transmission of activation signals from NOD proteins to NF-kB, plays a key role in the occurrence and development of various diseases, such as chronic periodontitis, Crohn's disease, and allergic asthma.
  • the MDP powder was dissolved in a quantity of pyrogen-free water to prepare an MDP solution with a final concentration of 0.625 mg / ml, and stored in a separate device at -20 ° C.
  • mice C57BL / 6 mice were randomly assigned to different groups, and the prepared MDP solution was intraperitoneally injected with 0.2 ml / head (including 125 micrograms of MDP). MDP was not given to mice in the normal group.
  • mice The experimental animals were randomly divided into 5 groups of 3 mice each.
  • the first group was normal mice without any treatment; the second group was given a vehicle; the third group was given prednisolone acetate injection (Prednisolone), and the prednisolone was used as a positive control drug at a dose of 3mg / kg ;
  • the fourth group was administered Compound 1 at a dose of 10 mg / kg; the fifth group was administered Compound X.
  • the prednisolone group was administered orally 30 minutes before MDP injection; the other groups were administered orally 15 minutes before MDP injection. Animals were administered orally with a volume of 10 ml / kg.
  • mice were anesthetized with isoflurane, blood was collected from the iliac vein of the eye, and the whole blood was allowed to stand at room temperature for 1 hour.
  • the serum was collected by centrifugation at 8000 g for 10 min.
  • the serum samples were stored at -80 ° C for testing. Thaw once.
  • the method is sandwich enzyme-linked immunosorbent assay (ELISA).
  • ELISA sandwich enzyme-linked immunosorbent assay
  • the mouse IL-6 ELISA kit was used to detect the serum IL-6 content in the mouse.
  • the purpose of this test is to detect the inhibitory activity of Compound 1 against various kinases in vitro.
  • Kinases used in this test include 279 kinases, and activity detection methods provided by Eurofins Pharma Discovery Service.
  • the test was performed using the 33 P radiolabeled kinase activity test with a concentration of Compound 1 of 1 ⁇ M and an ATP concentration of 10 ⁇ M.
  • Table 1 shows the results of Compound 1 inhibiting the target kinase by 30% or more.
  • the IC 50 of Compound X and Compound 1 was measured for 6 of these kinases, and the results are shown in Table 6.
  • the compound 1 of the present invention has highly specific kinase selectivity. In addition to having a high inhibitory effect on RIPK2, the inhibitory activity on most other kinases is weak. Relative to compound X, the inhibitory activity of compound 1 on six kinases, such as Abl (h); Arg (h); Flt4 (h); KDR (h); LOK (h); Ret (h), was significantly reduced, which may show It has lower off-target activity and better safety than Compound X.
  • CHO-hERG cells were cultured in a 175cm2 culture flask. After the cell density grew to 60 to 80%, the culture solution was removed, washed with 7mL of PBS (Phosphate Buffered Saline, phosphate buffered saline), and then added with 3mL of Detachin . After the digestion is completed, add 7 mL of culture solution to neutralize, then centrifuge, remove the supernatant, and resuspend by adding 5 mL of culture solution to ensure that the cell density is 2 ⁇ 5 ⁇ 106 / mL. Prepare extracellular fluid and cells according to Table 7. ⁇ ⁇ Internal fluid.
  • the single-cell high-impedance sealing and the whole-cell pattern formation process are all completed automatically by Qpatch instrument. Using the whole-cell recording mode, this voltage is applied every 15 seconds. After recording for 2 minutes, extracellular fluid is recorded for 5 minutes, and then the administration process is started. The compound concentration starts from the lowest test concentration, and each test concentration is given for 2.5 minutes. After all the concentrations are given continuously, the positive control compound is given 3 ⁇ M Cisapride. Test at least 3 cells at each concentration (n ⁇ 3). The experimental data was analyzed by GraphPad Prism 5.0 software. The inhibitory effect of Cisapride on hERG channels was set as a positive control. The experimental results are shown in Table 8.
  • Trinitrobenzenesulfonic acid (TNBS) -induced colitis model is one of the most commonly used mouse models for studying IBD.
  • the mixture of TNBS and ethanol was injected into the colon of animals to induce inflammation.
  • ethanol is used to destroy the intestinal mucosal barrier, so that TNBS can enter the intestinal wall, and interact with intestinal bacteria and the body's own proteins to form antigens and induce immune sensitization reactions.
  • mice Eight-week-old male BALB / c mice were selected and randomly assigned. According to the design protocol, the test compound (or control substance) was given to the animals in each group on the first day to the fourth day, and TNBS was given to the animals in each group on the second day. On the fifth day, animal colon tissue was collected, fixed with 10% formalin solution, and stored in 70% ethanol solution for tissue sectioning. Tissue section scores are divided into 4 items, each with 0 to 4 points, and the sum of the four items is taken as an index to evaluate the level of colitis (0 to 16 points). The four scores were: inflammation, edema, goblet cell loss, and epidermal damage.
  • the scoring criteria were: no change compared with the sham operation group, 0 points; 1 point for minor changes; 2 to 3 points for moderate changes, and 4 points for severe changes.
  • Statistical methods used one-way analysis of variance (One-way ANOVA, SPSS Version 22.0) and Dunnett's test (Dunnett's test). The experimental method was provided by Eurofins Pharma Discovery Service.
  • CONCLUSION In a mouse colitis model induced by TNBS, Compound 1 exhibits a drug effect comparable to Compound X, which can significantly reduce the histological score of colitis.

Abstract

L'invention concerne des dérivés de quinazoline, et plus particulièrement des composés représentés par la formule (I) et des sels pharmaceutiquement acceptables de ceux-ci, ainsi que des utilisations dans la préparation d'inhibiteurs de kinase RIP2.
PCT/CN2019/102999 2018-08-28 2019-08-28 Dérivés de quinazoline servant d'inhibiteur de kinase rip2 WO2020043122A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004058267A1 (fr) * 2002-12-23 2004-07-15 Ariad Pharmaceuticals, Inc. Heterocycles et leurs utilisations
WO2013025958A1 (fr) * 2011-08-18 2013-02-21 Glaxo Group Limited Amino-quinazolines en tant qu'inhibiteurs de kinase
WO2014043446A1 (fr) * 2012-09-13 2014-03-20 Glaxosmithkline Llc Promédicaments d'un inhibiteur de kinase amino-quinazoline
WO2014128622A1 (fr) * 2013-02-21 2014-08-28 Glaxosmithkline Intellectual Property Development Limited Quinazolines en tant qu'inhibiteurs de kinase
WO2016172134A2 (fr) * 2015-04-22 2016-10-27 Glaxosmithkline Intellectual Property Development Limited Nouveaux composés
WO2017046036A1 (fr) * 2015-09-14 2017-03-23 Glaxosmithkline Intellectual Property Development Limited Composés pour la modulation de l'activité de la kinase rip2
WO2017182418A1 (fr) * 2016-04-20 2017-10-26 Glaxosmithkline Intellectual Property Development Limited Conjugués comprenant des inhibiteurs de ripk2

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004058267A1 (fr) * 2002-12-23 2004-07-15 Ariad Pharmaceuticals, Inc. Heterocycles et leurs utilisations
WO2013025958A1 (fr) * 2011-08-18 2013-02-21 Glaxo Group Limited Amino-quinazolines en tant qu'inhibiteurs de kinase
WO2014043446A1 (fr) * 2012-09-13 2014-03-20 Glaxosmithkline Llc Promédicaments d'un inhibiteur de kinase amino-quinazoline
WO2014128622A1 (fr) * 2013-02-21 2014-08-28 Glaxosmithkline Intellectual Property Development Limited Quinazolines en tant qu'inhibiteurs de kinase
WO2016172134A2 (fr) * 2015-04-22 2016-10-27 Glaxosmithkline Intellectual Property Development Limited Nouveaux composés
WO2017046036A1 (fr) * 2015-09-14 2017-03-23 Glaxosmithkline Intellectual Property Development Limited Composés pour la modulation de l'activité de la kinase rip2
WO2017182418A1 (fr) * 2016-04-20 2017-10-26 Glaxosmithkline Intellectual Property Development Limited Conjugués comprenant des inhibiteurs de ripk2

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