WO2015081813A1 - Composé présentant une activité d'inhibition d'alk et sa préparation et son utilisation - Google Patents

Composé présentant une activité d'inhibition d'alk et sa préparation et son utilisation Download PDF

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WO2015081813A1
WO2015081813A1 PCT/CN2014/092492 CN2014092492W WO2015081813A1 WO 2015081813 A1 WO2015081813 A1 WO 2015081813A1 CN 2014092492 W CN2014092492 W CN 2014092492W WO 2015081813 A1 WO2015081813 A1 WO 2015081813A1
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group
compound
alkyl
halogen
substituted
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PCT/CN2014/092492
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Chinese (zh)
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仝朝龙
孙兴义
盛锡军
张秀春
喻红平
徐耀昌
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上海翰森生物医药科技有限公司
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Priority to CN201480055111.0A priority Critical patent/CN105612151B/zh
Publication of WO2015081813A1 publication Critical patent/WO2015081813A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D417/14—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 containing three or more hetero rings

Definitions

  • the invention belongs to the technical field of medicinal chemistry, and particularly relates to a compound having ALK inhibitory activity and preparation and use thereof.
  • Anaplastic lymphoma kinase is a receptor tyrosine protein kinase that was first discovered in a subtype of anaplastic large cell lymphoma (ALCL), hence the name anaplastic lymphoma kinase (anaplastic). Lymphoma kinase, ALK) (Morris, SW et al, Science, 1994, 263, 1281-1284; Shiota, M. et al, Oncogene, 1994, 9, 1567-1574).
  • the ALK protein contains 1620 amino acids with a molecular weight of 177 kilodaltons (kDa) and the 254 amino acid kinase domain consists of amino acid residues 1123 to 1376, which was previously a short transmembrane region composed of amino acids.
  • Expression patterns in mice suggest that it plays a role in the development of the central and peripheral nervous systems; ALK is found in Drosophila to promote intestinal muscle tissue formation in the form of ligand binding, mammalian ligands have not been determined; detection in human retina To the ALK protein. There was no significant abnormality in the life cycle and life activities of ALK knockout mice (Webb, TR et al., Expert Rev. Anti-cancer Ther., 2009, 9, 331-356), indicating that ALK inhibition will not cause serious damage to the body. hurt.
  • ALK gene rearrangements in non-small cell lung cancer In 2007, two independent research groups identified ALK gene rearrangements in non-small cell lung cancer.
  • EML4-ALK is the only driving mutation in non-small cell lung cancer, and that inhibition of EML4-ALK activity in vivo leads to a reduction in lung cancer burden (Soda, M., Choi, YL, Enomoto, M., et al., Nature, 2007: 448).
  • EML4-ALK fusion occurs in approximately 3-5% of non-small cell lung cancers, differing between the study population and the ALK assay used, and is the only driver mutation in non-small cell lung cancer.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • Ring A is selected from a 5-10 membered cycloalkyl group, a 5-10 membered heterocyclic group, a 5-10 membered aryl group or a 5-10 membered heteroaryl group;
  • R 1 is selected from C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 3-6 cycloalkyl or 4-tolyl;
  • R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 3-8 ring Alkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkoxy, C 3-8 cycloalkoxy, -S(O)pR 9 , -C(O)R 9 , -C( O) OR 9 , -NR 10 R 11 or -C(O)NR 11 ;
  • R 6 , R 7 and R 8 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3 -8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, C 1-6 alkoxy, C 3-8 cycloalkoxy, -S(O ) pR 9 , -C(O)R 9 , -C(O)OR 9 , -NR 10 R 11 or -C(O)NR 11 ,
  • the C 1-8 alkyl group, the C 3-8 cycloalkyl group, the 3-8 membered heterocyclic group, the C 5-10 aryl group or the 5-10 membered heteroaryl group are each independently optionally further one or more One selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic ring , C 5-10 aryl, 5-10 membered heteroaryl, C 1-6 alkoxy, C 3-8 cycloalkoxy, -S(O)pR 9 , -C(O)R 9 , Substituted by a substituent of -C(O)OR 9 , -NR 10 R 11 or -C(O)NR 11 ;
  • R 9 , R 10 and R 11 are selected from the group consisting of hydrogen and C l-4 alkyl;
  • n 0, 1, 2, 3, 4;
  • L is 0, 1, 2, 3, 4, 5;
  • p 0, 1, or 2.
  • the structure formed by ring A together with its substituent is selected from the following structures:
  • the structure formed by ring A together with its substituent is selected from the following structures:
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , m, n, L, p are as defined for the compound of formula (I).
  • R 2 and R 5 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halogen-substituted C 1-6 alkyl; and R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, and hydroxyl.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (II):
  • R 3 is selected from the group consisting of hydrogen, hydroxy, cyano, nitro, C 3-8 cycloalkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkoxy, C 3-8 cycloalkoxy, -S(O)pR 9 , -C(O)R 9 , -C(O)OR 9 , -NR 10 R 11 or -C(O)NR 11 ;
  • R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , m, n, L, p are as defined for the compound of formula (I).
  • R 3 is selected from halogen-substituted C 1-6 alkoxy;
  • R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , m, n, L, p are as defined for the compound of formula (I).
  • a process for the preparation of a compound of the formula (I) which comprises the steps of: condensing a compound of the formula (III) with a compound of the formula (IV) to give a compound of the formula (I), or a formula (III)
  • the compound is condensed with the formula (IV) and then converted to the corresponding compound of the formula (I) according to a different definition of the substituent or a deprotecting group, the synthesis route of which is as follows:
  • a further aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the foregoing, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • a further aspect of the invention provides a method of modulating the catalytic activity of a protein kinase comprising contacting the protein kinase with a compound of the foregoing, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the foregoing, selected from the group consisting of a metaplastic lymphocyte Tumor kinase.
  • a further aspect of the present invention provides the use of the aforementioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, for the preparation of a medicament for treating cancer, wherein the cancer is preferably non-small cell lung cancer.
  • C 1-8 alkyl group means a linear alkyl group having 1 to 8 carbon atoms and a branched alkyl group, and the alkyl group means a saturated aliphatic hydrocarbon group.
  • the alkyl group means a saturated aliphatic hydrocarbon group.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano.
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and "C 3-8 cycloalkyl” refers to a cycloalkyl group of 3 to 8 carbon atoms, "5-10 membered ring.”
  • Alkyl means a cycloalkyl group of 5 to 10 carbon atoms, for example:
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene Alkenyl, cyclooctyl and the like.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • “Spirocycloalkyl” refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • the spirocycloalkyl group is divided into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group according to the number of shared spiro atoms between the ring and the ring.
  • Non-limiting examples of spirocycloalkyl groups include:
  • fused cycloalkyl refers to an all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but None of the rings have a fully conjugated ⁇ -electron system. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups, and non-limiting examples of fused cycloalkyl groups include:
  • Bridge cycloalkyl refers to an all-carbon polycyclic group in which two rings share two carbon atoms that are not directly bonded, which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system . Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydrogen Naphthyl, benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8 alkane.
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O)p (where p is an integer 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • the "5-10 membered heterocyclic group” means a ring group containing 5 to 10 ring atoms
  • the "3-8 membered heterocyclic group” means a ring group containing 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged heterocyclic groups.
  • “Spiroheterocyclyl” refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O)p (where p is an integer) The heteroatoms of 0, 1, 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • the spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspiroheterocyclic group depending on the number of common spiro atoms between the ring and the ring.
  • Non-limiting examples of spirocycloalkyl groups include:
  • fused heterocyclyl refers to a polycyclic heterocyclic group in which each ring of the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none
  • the ring has a fully conjugated pi-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(O)p (where p is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon.
  • p is an integer from 0 to 2
  • fused heterocyclic groups include:
  • Bridge heterocyclyl refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly bonded, and these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, One or more of the ring atoms are selected from the group consisting of nitrogen, oxygen or S(O)p (where p is an integer 0, 1, 2) heteroatom, and the remaining ring atoms are carbon. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups.
  • Non-limiting examples of bridged cycloalkyl groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples comprising:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8 alkane.
  • Aryl means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a polycyclic ring of a conjugated ⁇ -electron system (ie, having a ring adjacent to a carbon atom) a group
  • C 5-10 aryl means an all-carbon aryl group having 5 to 10 carbons
  • 5-10 membered aryl group means an all-carbon aryl group having 5 to 10 carbons, such as phenyl and Naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8 alkyl, C. 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, C 1-6 Alkoxy, C 3-8 cycloalkoxy, -S(O)pR 9 , -C(O)R 9 , -C(O)OR 9 , -NR 10 R 11 or -C(O)NR 11 Substituted by a substituent.
  • the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8 alkyl, C. 2-8 alkenyl, C 2-8 alkynyl, C
  • Heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms including nitrogen, oxygen and a hetero atom of S(O)p (where p is an integer 0, 1, 2), 5-
  • a 7-membered heteroaryl group means a heteroaromatic system having 5 to 7 ring atoms
  • a 5-10 membered heteroaryl group means a heteroaromatic system having 5 to 10 ring atoms, such as furyl, thienyl, pyridyl, Pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples comprising:
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8 alkane.
  • Alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, and a C 2-8 alkenyl group means a straight or branched olefin containing from 2 to 8 carbons base.
  • alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • a C 2-8 alkenyl group means a straight or branched olefin containing from 2 to 8 carbons base.
  • vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like are examples of the alkenyl group.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8 alkyl, C. 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, C 1-6 Alkoxy, C 3-8 cycloalkoxy, -S(O)pR 9 , -C(O)R 9 , -C(O)OR 9 , -NR 10 R 11 or -C(O)NR 11 Substituted by a substituent.
  • the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8 alkyl, C. 2-8 alkenyl, C 2-8 alkynyl,
  • Alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond
  • C2-8 alkynyl refers to a straight or branched alkynyl group containing from 2 to 8 carbons.
  • ethynyl 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8 alkyl, C.
  • Alkoxy means -O-(alkyl) wherein alkyl is as defined above.
  • the C 1-6 alkoxy group means an alkyloxy group having 1 to 6 carbons, and the non-limiting examples include a methoxy group, an ethoxy group, a propoxy group, a butoxy group and the like.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, C 1-6 alkoxy, C 3-8 cycloalkoxy, -S(O)pR 9 , -C(O)R 9 , -C(O)OR 9 , -NR 10 R 11 or -C( O) substituted with a substituent of NR 11 ;
  • Cycloalkoxy refers to -O-(unsubstituted cycloalkyl) wherein cycloalkyl is as defined above.
  • the C 3-8 cycloalkoxy group means a cycloalkyloxy group having 3-8 carbons, and the non-limiting examples include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group and the like.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8 alkane.
  • Halogen-substituted C 1-6 alkyl means a hydrogen 1-6 alkylalkyl group optionally substituted by fluorine, chlorine, bromine or iodine, such as difluoromethyl or dichloromethyl, on the alkyl group.
  • Base dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.
  • the hydrogen on the "halogen-substituted C1-6 alkoxy"alkyl group is optionally a 1-6 carboalkoxy group substituted with a fluorine, chlorine, bromine or iodine atom.
  • a fluorine chlorine, bromine or iodine atom.
  • Halogen means fluoro, chloro, bromo or iodo.
  • Hydrophilicity refers to an -OH group.
  • Niro refers to a -NO 2 group.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers and excipient.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • reaction solvent was stirred, water and dichloromethane were added, and the aqueous layer and organic layer were separated, and the aqueous phase was extracted three times with dichloromethane.
  • the organic phases were combined and dried over anhydrous sodium sulfate.
  • the solvent was distilled off, and the product was separated and purified by column chromatography.
  • Second step Preparation of tert-butyl 4-(4-amino-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylate
  • the third step preparation of 2-isopropyl decyl-3-nitropyridine
  • the fourth step preparation of 2-isopropylsulfone-3-nitropyridine
  • Step 6 Preparation of 2,5-dichloro-N-(2-(isopropylsulfonyl)pyridin-3-yl)pyrimidine-4-amine
  • Step 7 4-(4-((5-Chloro-4-((2-(isopropylsulfonyl)pyridin-3-yl)amino)pyrimidin-2-yl)amino)-5-isopropyloxy
  • Step 8 5-Chloro-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-(2-(isopropylsulfonyl)pyridin-3-yl Preparation of pyrimidine-2,4-diamine
  • the third step preparation of 2-chloro-5-(difluoromethoxy)-N-(2-(isopropylsulfonyl)phenyl)pyrimidine-4-amine
  • the fifth step 5-difluoromethoxy-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-[2-(propane-2-sulfonyl)- Preparation of phenyl]-pyrimidine-2,4-diamine
  • EtOAc (EtOAc m.) 1- ⁇ 4-[4-Amino-2-methyl-5-(propan-2-yloxy)phenyl]piperidin-1-yl ⁇ -ethanone (62.5 mg, 215 ⁇ mol) was added thereto, p-toluene The sulfonic acid (46.3 mg, 269 ⁇ mol) was heated to 150 ° C overnight and the reaction was monitored by LCMS. The reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc m.
  • the third step preparation of 2-(propan-2-ylsulfonyl)thiophen-3-amine
  • the fifth step 1-(4- ⁇ 4-[(5-chloro-4- ⁇ [2-(propan-2-ylsulfonyl)thiophen-3-yl]amino ⁇ pyrimidin-2-yl)amino]- Preparation of 2-methyl-5-(propane-2-oxy)phenyl ⁇ piperidin-1-yl)ethanone
  • Step 6 5-Chloro-N-2-[5-methyl-4-(piperidin-4-acetyl)-2-(propan-2-oxy)phenyl]-N-4-[2 Preparation of -(propan-2-ylsulfonyl)thiophen-3-yl]pyrimidine-2,4-diamine
  • Step 7 5-Chloro-N-2-[5-methyl-4-(piperidin-4-yl)-2-(propan-2-oxy)phenyl]-N-4-[2- Preparation of (propan-2-ylsulfonyl)thiophen-3-yl]pyrimidine-2,4-diamine
  • the following in vitro assays can be used to determine the proliferation inhibitory activity of the compounds of the invention against the human lymphoma cell Karpas 299, which is highly expressed by the ALK gene fusion.
  • the in vitro cell assay described below can determine the proliferation inhibitory activity of the test compound against human lymphoma cell Karpas 299, and its activity can be expressed by the IC 50 value.
  • the general protocol for such an experiment is as follows: First, human lymphoma cell Karpas 299 is selected and seeded on a 96-well culture plate at a suitable cell concentration (for example, 100 ⁇ L of medium in 6000 cells/well), followed by addition to each well. A series of gradient test concentrations (generally 6 to 10 concentrations) of the test compound solution diluted in the medium were continuously cultured for 72 hours. After 72 hours, available Luminescent Cell Viability Assay kit (purchased from Promega). The method measures the activity of a compound to inhibit cell proliferation.
  • the IC 50 value can be calculated by measuring the inhibition of cell proliferation by a test compound at a range of different concentrations.
  • biochemical activity of the compounds of the present invention was determined by the above test, and the measured IC 50 values are shown in the following table.
  • the following in vitro assays may be used to assay the compounds of the present invention to produce and ALK kinase kinase inhibitory activity ALKL1196M variation, which activity can be expressed by IC 50 values.
  • the half-inhibitory concentration IC 50 of the compound (the concentration of the compound required to inhibit a certain concentration of the enzyme activity to 50%) is determined by mixing a certain amount of the kinase with a specific substrate and a different concentration of the test compound. of.
  • the ALK kinase used in this experiment is a human recombinant protein in a reaction system containing 50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 2 M DTT (1000 ⁇ ) buffer solution and 30 ⁇ M ATP with polypeptide substrate and different concentrations.
  • the test compounds were co-reacted (25 ° C, 45 min), followed by FAM-labeled antibodies to label the substrate, and finally the ALK kinase activity was quantified by Mobility shift technology based on microfluidic chip technology.
  • biochemical activity of the compounds of the present invention was determined by the above test, and the measured IC 50 values are shown in the following table.

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Abstract

La présente invention porte sur un composé présentant une activité d'inhibition d'ALK et sur une préparation et une utilisation de ce dernier. En particulier, la présente invention porte sur un composé tel que représenté par la formule (I) ou un sel pharmaceutiquement acceptable de ce dernier, sur un procédé de préparation de ce dernier et sur une utilisation de ce dernier. Le composé présente une activité d'inhibition d'ALK et peut être utilisé pour le traitement de cancers ALK positifs et donc présente de larges perspectives en médication.
PCT/CN2014/092492 2013-12-03 2014-11-28 Composé présentant une activité d'inhibition d'alk et sa préparation et son utilisation WO2015081813A1 (fr)

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WO2018044767A3 (fr) * 2016-08-29 2018-04-12 The Regents Of The University Of Michigan Aminopyrimidines utilisées comme inhibiteurs d'alk
WO2018146472A1 (fr) 2017-02-07 2018-08-16 Oblique Therapeutics Ab Pyridines à substitution hydrocarbylsulfonyle et leur utilisation dans le traitement du cancer
JP2018532759A (ja) * 2015-11-05 2018-11-08 湖北生物医薬産業技術研究院有限公司Ｈｕｂｅｉ Ｂｉｏ−Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｉｎｄｕｓｔｒｉａｌ Ｔｅｃｈｎｏｌｏｇｉｃａｌ Ｉｎｓｔｉｔｕｔｅ Ｉｎｃ． ピリミジン誘導体及びその使用
CN109963844A (zh) * 2017-09-03 2019-07-02 上海美志医药科技有限公司 一类抑制并降解酪氨酸蛋白激酶alk的化合物
CN110563656A (zh) * 2018-06-06 2019-12-13 四川大学 嘧啶类小分子化合物及在制备抗分枝杆菌药物中的用途
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US11028067B2 (en) 2017-02-07 2021-06-08 Oblique Therapeutics Ab Heteroarylsulfonyl-substituted pyridines and their use in the treatment of cancer
US11168069B2 (en) 2017-02-07 2021-11-09 Oblique Therapeutics Ab Heterocyclylsulfonyl-substituted pyridines and their use in the treatment of cancer
US11208384B2 (en) 2017-02-07 2021-12-28 Oblique Therapeutics Ab Sulfinylpyridines and their use in the treatment of cancer
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EP3150592A4 (fr) * 2014-05-30 2018-01-24 Beijing Pearl Biotechnology Limited Liability Company Inhibiteur de la kinase alk, son procédé de préparation et son utilisation
US10899710B2 (en) 2015-08-07 2021-01-26 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Pyridines and their use in the treatment of cancer
US10695347B2 (en) 2015-11-05 2020-06-30 Hubei Bio-Pharmaceutical Industrial Technological Institute, Inc. Pyrimidine derivative and use thereof
JP2018532759A (ja) * 2015-11-05 2018-11-08 湖北生物医薬産業技術研究院有限公司Ｈｕｂｅｉ Ｂｉｏ−Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｉｎｄｕｓｔｒｉａｌ Ｔｅｃｈｎｏｌｏｇｉｃａｌ Ｉｎｓｔｉｔｕｔｅ Ｉｎｃ． ピリミジン誘導体及びその使用
KR20190039760A (ko) * 2016-08-29 2019-04-15 더 리젠츠 오브 더 유니버시티 오브 미시건 Alk 억제제로서의 아미노피리미딘
CN109715620A (zh) * 2016-08-29 2019-05-03 密歇根大学董事会 作为alk抑制剂的氨基嘧啶
KR102530871B1 (ko) * 2016-08-29 2023-05-09 더 리젠츠 오브 더 유니버시티 오브 미시건 Alk 억제제로서의 아미노피리미딘
JP2019528307A (ja) * 2016-08-29 2019-10-10 ザ・リージェンツ・オブ・ザ・ユニバーシティ・オブ・ミシガンＴｈｅ Ｒｅｇｅｎｔｓ Ｏｆ Ｔｈｅ Ｕｎｉｖｅｒｓｉｔｙ Ｏｆ Ｍｉｃｈｉｇａｎ Ａｌｋ阻害剤としてのアミノピリミジン類
CN115043821A (zh) * 2016-08-29 2022-09-13 密歇根大学董事会 作为alk抑制剂的氨基嘧啶
EP4001273A3 (fr) * 2016-08-29 2022-08-24 The Regents Of The University Of Michigan Aminopyrimidines en tant qu'inhibiteurs d'alk
CN109715620B (zh) * 2016-08-29 2022-05-06 密歇根大学董事会 作为alk抑制剂的氨基嘧啶
US10709705B2 (en) 2016-08-29 2020-07-14 The Regents Of The University Of Michigan Aminopyrimidines as ALK inhibitors
AU2021203098B2 (en) * 2016-08-29 2023-05-25 The Regents Of The University Of Michigan Aminopyrimidines as ALK inhibitors
AU2017319135B2 (en) * 2016-08-29 2021-03-18 The Regents Of The University Of Michigan Aminopyrimidines as ALK inhibitors
WO2018044767A3 (fr) * 2016-08-29 2018-04-12 The Regents Of The University Of Michigan Aminopyrimidines utilisées comme inhibiteurs d'alk
US11110090B2 (en) 2016-08-29 2021-09-07 The Regents Of The University Of Michigan Aminopyrimidines as ALK inhibitors
JP7094566B2 (ja) 2016-08-29 2022-07-04 ザ・リージェンツ・オブ・ザ・ユニバーシティ・オブ・ミシガン Ａｌｋ阻害剤としてのアミノピリミジン類
US11028067B2 (en) 2017-02-07 2021-06-08 Oblique Therapeutics Ab Heteroarylsulfonyl-substituted pyridines and their use in the treatment of cancer
US11208384B2 (en) 2017-02-07 2021-12-28 Oblique Therapeutics Ab Sulfinylpyridines and their use in the treatment of cancer
US11168069B2 (en) 2017-02-07 2021-11-09 Oblique Therapeutics Ab Heterocyclylsulfonyl-substituted pyridines and their use in the treatment of cancer
US11161815B2 (en) 2017-02-07 2021-11-02 Oblique Therapeutics Ab Hydrocarbylsulfonyl-substituted pyridines and their use in the treatment of cancer
WO2018146472A1 (fr) 2017-02-07 2018-08-16 Oblique Therapeutics Ab Pyridines à substitution hydrocarbylsulfonyle et leur utilisation dans le traitement du cancer
CN109963844B (zh) * 2017-09-03 2022-08-12 上海美志医药科技有限公司 一类抑制并降解酪氨酸蛋白激酶alk的化合物
CN109963844A (zh) * 2017-09-03 2019-07-02 上海美志医药科技有限公司 一类抑制并降解酪氨酸蛋白激酶alk的化合物
CN110563656A (zh) * 2018-06-06 2019-12-13 四川大学 嘧啶类小分子化合物及在制备抗分枝杆菌药物中的用途
WO2020024825A1 (fr) * 2018-07-31 2020-02-06 Ascentage Pharma (Suzhou) Co., Ltd. Méthode de traitement du cancer à l'aide d'une combinaison d'inhibiteur de fak/alk/ros1 et d'inhibiteur d'egfr
US11478477B2 (en) 2018-07-31 2022-10-25 Ascentage Pharma (Suzhou) Co., Ltd. Method for treating cancer by combination of FAK/ALK/ROS1 inhibitor and EGFR inhibitor
US11529350B2 (en) 2019-07-03 2022-12-20 Sumitomo Pharma Oncology, Inc. Tyrosine kinase non-receptor 1 (TNK1) inhibitors and uses thereof

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