WO2019134661A1 - Isoindolinone et son dérivé en tant qu'inhibiteur de csf-1r - Google Patents

Isoindolinone et son dérivé en tant qu'inhibiteur de csf-1r Download PDF

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WO2019134661A1
WO2019134661A1 PCT/CN2019/070227 CN2019070227W WO2019134661A1 WO 2019134661 A1 WO2019134661 A1 WO 2019134661A1 CN 2019070227 W CN2019070227 W CN 2019070227W WO 2019134661 A1 WO2019134661 A1 WO 2019134661A1
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compound
synthesis
mmol
group
μmol
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PCT/CN2019/070227
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Chinese (zh)
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钱文远
杨纯道
徐光海
李婕
黎健
陈曙辉
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南京明德新药研发股份有限公司
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—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 three or more hetero rings

Definitions

  • the present invention relates to a class of isoindolinone derivatives and their use in the preparation of a medicament for the treatment of a disease associated with a novel colony stimulating factor 1 receptor (CSF-1R) inhibitor. Specifically, it relates to a compound of the formula (I), and a pharmaceutically acceptable salt thereof or a stereoisomer thereof.
  • CSF-1R colony stimulating factor 1 receptor
  • Colony stimulating factor 1 (CSF-1, also known as macrophage colony stimulating factor, M-CSF) is an important growth factor that controls bone marrow progenitor cells, monocytes, macrophages, and giants. The growth of osteoclasts and dendritic cells differentiated by phagocytes must be combined with its unique cell surface receptor CSF-1R to exert its biological effects.
  • CSF-1R is encoded by the proto-oncogene c-FMS, also known as c-FMS, a receptor tyrosine kinase that binds CSF-1 and CSF-1R in the extracellular domain and induces dimerization of CSF-1R. Furthermore, the CSF-1R kinase domain is autophosphorylated in the cell.
  • CSF-1R acts as a docking site for several cytoplasmic signaling molecules, which ultimately triggers a series of signal cascades. For example, phosphorylation of the 697th tyrosine residue of CSF-1R activates the MAPK signaling pathway, and phosphorylation of its 721th tyrosine residue initiates the PI3K and PLC ⁇ signaling pathways.
  • CSF-1 tumor-associated macrophage
  • TAM tumor-associated macrophage
  • CSF-1 can also be secreted by cells. Their addition promotes the formation of complex micro-environment of tumors. This micro-environment can help tumor cells to develop immune tolerance to autoimmune functions, thereby promoting the proliferation, invasion and metastasis of tumor cells in vivo. .
  • CSF-1R By inhibiting CSF-1R, it may be beneficial to treat diseases caused by osteoclasts, dendritic cells, and macrophage lesions, such as autoimmune/infectious diseases, cancer, and bone-related diseases.
  • CSF-1R inhibitors can be used in a variety of ways in the field of disease treatment. It can be used alone or in combination with a variety of anti-cancer therapies, such as anti-angiogenesis, adoptive transfer of T cells, Radiotherapy, chemotherapy, and immunological checkpoint therapy. Many of the drugs on the market have inhibitory activities against CSF-1R, such as imatinib, dasatinib and sunitinib, but selective CSF-1R inhibitors are not yet marketed.
  • PLX-3397 a dual inhibitor of CSF-1R and c-Kit, is currently in clinical phase III for the treatment of multiple cancers such as giant cell tumor of the tendon sheath (TGCT).
  • Array's ARRY-382 and Novartis' BLZ-945 are more selective CSF-1R inhibitors and are currently in clinical phase II.
  • Patent No. WO2016179412 discloses a reference 1, mainly related to the targets c-kit, c-fms and Flt3, for the treatment of giant cell tumor of tendon sheath;
  • Patent No. US2005026976 discloses a reference 2, the main target is KDR, for treating tumors cancer.
  • the present invention provides a compound of the formula (I): and a pharmaceutically acceptable salt thereof or a stereoisomer thereof:
  • T is selected from N or CH;
  • R 1 is selected from H, F, Cl, Br, I, OH or CN, or is selected from the group consisting of 1, 2 or 3 R substituted: C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkenyl, C 1-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-O- or 3- to 7-membered heterocycloalkyl-O-;
  • R 2 is independently selected from H, F, Cl, Br, I, OH, NH 2 or CN, respectively, or independently selected from C 1-3 alkyl optionally substituted by 1, 2 or 3 R;
  • R 3 is independently selected from H, F, Cl, Br, I, OH, NH 2 or CN, respectively, or independently selected from C 1 1-6 alkyl optionally substituted by 1, 2 or 3 R, C 1-6 heteroalkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-O-, 3-7 -membered heterocycloalkyl-O- or 3-7-membered heterocycloalkyl-C 1 -3 alkyl-;
  • Ring A is selected from C 4-8 cycloalkyl, phenyl or 5- to 10-membered heteroaryl;
  • n 0, 1 or 2;
  • n 1, 2 or 3;
  • R is independently selected from H, F, Cl, Br, I, OH, NH 2 or CN, or from a group optionally substituted by 1, 2 or 3 R': C 1-6 alkyl or C 1- 6 heteroalkyl;
  • R' is independently selected from the group consisting of F, Cl, Br, I, OH, NH 2 , CN or -CH 3 ;
  • the hetero atom or hetero atom in the C 1-6 heteroalkyl group, the 5-10 membered heteroaryl group, the 3 to 7 membered heterocycloalkyl group is independently selected from N, —O—, —S—, —NH. -;
  • the number of the above heteroatoms or heteroatoms is independently selected from 1, 2, 3 or 4.
  • the above R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from: C 1-3 alkane optionally substituted by 1, 2 or 3 R'
  • the group, C 1-3 alkoxy group and C 1-3 alkylamino group, other variables are as defined in the present invention.
  • said R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from: -CH 3 , optionally substituted by 1, 2 or 3 R', CH 2 CH 3 , Other variables are as defined by the present invention.
  • the above R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 3 , Other variables are as defined by the present invention.
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, or selected from the group consisting of 1, 2 or 3 R: C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkynyl, cyclopropane, cyclopropyl-O-, oxetanyl-O-, other variables are as defined in the present invention.
  • said R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, or selected from the group consisting of: 1, 2 or 3 R: -CH 3 , -CH 2 CH 3 , -CH 2 CH 3 CH 3 , Other variables are as defined by the present invention.
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 3 CH 3 , Other variables are as defined by the present invention.
  • R 2 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from, optionally substituted by 1, 2 or 3 R. :-CH 3 or -CH 2 CH 3 , other variables are as defined in the present invention.
  • R 2 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, -CH 3 , respectively, and other variables are as defined herein.
  • said R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from, optionally substituted by 1, 2 or 3 R :C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, cyclopropyl, cyclobutane, cyclopentyl, acetonyl, tetrahydrofuranyl, tetrahydropyranyl , piperazinyl, piperidinyl, morpholinyl, -CH 2 -piperazinyl, -CH 2 -piperidinyl, -O-cyclopropane, -O-cyclobutane, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, imidazol-2-one, oxazolidin-2-one or pyrrolidin-2-one, other variables are as defined herein.
  • said R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from, optionally substituted by 1, 2 or 3 R :-CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -OCH 3 , -OCH 2 CH 3 , -NH(CH 3 ), -N(CH 3 ) 2 , Other variables are as defined by the present invention.
  • the above R 3 are independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -C(CH 3 ) 3 , -OCH 3 , -OCH 2 CH 3 , -NH(CH 3 ), -N(CH 3 ) 2 ,
  • Other variables are as defined by the present invention.
  • the above ring A is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, pyrazolyl, benzo[b]thiophene, 2,3 -dihydro-[1,4]dioxan[2,3-b]pyridine, benzo[d]thiazolyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, others Variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the present invention provides a compound represented by the formula (I), and a pharmaceutically acceptable salt thereof or a stereoisomer thereof
  • T is selected from N or CH;
  • R 1 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, or selected from C 1 1-6 alkyl, C 1-6 alkoxy optionally substituted by 1, 2 or 3 R a group, a C 1-6 alkenyl group, a C 1-6 alkynyl group, a C 3-7 cycloalkyl group, a C 3-7 cycloalkyl-O-, a 3 to 7 membered heterocycloalkyl-O-;
  • R 2 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from: C 1-3 alkyl optionally substituted by 1, 2 or 3 R;
  • R 3 is each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from C 1 1-6 alkyl optionally substituted by 1, 2 or 3 R, C 1-6 heteroalkyl, C 3-7 cycloalkyl, 3-7 -membered heterocycloalkyl-C 1-3 alkyl-;
  • Ring A is selected from: C 5-8 cycloalkyl, phenyl or 5- to 6-membered heteroaryl;
  • n is selected from: 0, 1 or 2;
  • n is selected from: 1, 2 or 3;
  • R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, or selected from the group consisting of 1, 2 or 3 R's substituted: C 1-6 alkyl, C 1-6 hetero alkyl;
  • R' is selected from the group consisting of: F, Cl, Br, I, OH, NH 2 , CN, Me;
  • hetero of the C 1-6 heteroalkyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl is selected from the group consisting of N, -O-, -S-, -NH-;
  • the number of the above heteroatoms or heteroatoms is independently selected from 1, 2, 3 or 4.
  • the above R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from: C 1-3 alkane optionally substituted by 1, 2 or 3 R'
  • the group, C 1-3 alkoxy group and C 1-3 alkylamino group, other variables are as defined in the present invention.
  • R is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, or selected from the group consisting of 1, 2 or 3 R' substitutions: Me, Et, Other variables are as defined by the present invention.
  • the above R is selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, Me, CH 2 F, CHF 2 , CF 3 , Et, Other variables are as defined by the present invention.
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, or selected from: C 1-3 alkyl optionally substituted by 1, 2 or 3 R', C 1-3 alkoxy, C 1-3 alkynyl, cyclopropane, cyclopropyl-O-, oxetanyl-O-, other variables are as defined in the present invention.
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, or selected from the group consisting of 1, 2 or 3 R' substitutions: Me, Et, Pr, Other variables are as defined by the present invention.
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, OH, CN, Me, Et, Pr, Other variables are as defined by the present invention.
  • R 2 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from, optionally substituted by 1, 2 or 3 R. : Me, Et, other variables as defined by the present invention.
  • R 2 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, Me, respectively, and other variables are as defined herein.
  • said R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from, optionally substituted by 1, 2 or 3 R : C 1-3 alkyl, C 1-3 heteroalkyl, cyclopentyl, piperazinyl-CH 2 -, piperidinyl-CH 2 -, other variables are as defined in the invention.
  • said R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, or independently selected from, optionally substituted by 1, 2 or 3 R :Me, Other variables are as defined by the present invention.
  • R 3 are independently selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, Me, Other variables are as defined by the present invention.
  • the above ring A is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, cyclopentyl, cyclohexyl, cyclooctyl, and other variables such as The invention is defined.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • the structural unit Selected from Other variables are as defined by the present invention.
  • f is selected from: 1, 2, 3 or 4;
  • l selected from: 0 or 1;
  • n, m, T, R 1 to R 3 are as defined in the present invention.
  • the above compound, an isomer thereof or a pharmaceutically acceptable salt thereof is
  • f is selected from: 1, 2, 3 or 4;
  • l selected from: 0 or 1;
  • R 1 to R 3 are as defined in the present invention.
  • the present invention also provides the following compound, an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound, an isomer thereof or a pharmaceutically acceptable salt thereof or the above composition for the preparation of a medicament for treating a novel colony stimulating factor-1 receptor inhibitor.
  • the above-described drug associated with the novel colony stimulating factor-1 receptor inhibitor is a drug for treating tumor and autoimmune diseases.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, 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 me
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of one another.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate a single bond due to a double bond or a ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirrored relationship.
  • wedge-shaped dashed keys Represents the absolute configuration of a solid center with straight solid keys
  • straight dashed keys Indicates the relative configuration of the stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid key And straight dashed keys
  • tautomer or “tautomeric form” mean that the different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted into each other. If tautomers are possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • prototropic tautomers include interconversions by proton transfer, such as keto-enol isomerization and imine-enes. Amine isomerization.
  • the valence tautomer includes the mutual transformation of some of the bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms "enriched in one isomer”, “isomer enriched”, “enriched in one enantiomer” or “enantiomeric enriched” refer to one of the isomers or pairs
  • the content of the oligo is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, 99.7% or more, 99.8% or more, or greater than or equal to 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the two isomers or the relative percentages of the two enantiomers. For example, if one of the isomers or enantiomers is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomeric excess (ee value) is 80%. .
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C).
  • hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
  • the bond composed of barium and carbon is stronger than the bond composed of common hydrogen and carbon.
  • deuterated drugs have reduced side effects and increased drug stability. Enhance the efficacy and prolong the biological half-life of the drug. Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Oxygen substitution does not occur on the aromatic group.
  • 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 eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • a substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A.
  • the substituent can be attached to more than one atom on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit. It is indicated that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene.
  • substituents When the listed substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings. A carbon atom is attached to the substituted group.
  • the medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
  • the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from 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 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
  • C 1-12 is selected from C 1
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • alkenyl refers to an alkyl group having one or more carbon-carbon double bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkenyl group include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a butadienyl group, a pentadienyl group, a hexadienyl group and the like.
  • alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and the like.
  • a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
  • a cycloalkenyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more unsaturated carbon-carbon double bonds at any position of the ring, and may be monosubstituted or polysubstituted, It can be one price, two price or multiple price.
  • Examples of such cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.
  • a cycloalkynyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more carbon-carbon triple bonds at any position of the ring, which may be monosubstituted or polysubstituted, and may be one Price, price or price.
  • cycloalkenylalkyl or “cycloalkenylalkyl” refers to a cycloalkenyl substituted alkyl.
  • cycloalkynyl or “cycloalkynylalkyl” refers to a cycloalkynyl substituted alkyl.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl or heteroaryl groups include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isomerism Azyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indolyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1 -naphthyl, 2-naphthyl, 4-biphenylyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl
  • aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • 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 set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium 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 Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • the compounds of the present invention have significant CSF-1R kinase inhibition with a significant increase in permeability and metabolic stability.
  • Compound 2-B was prepared in the same manner as Compound II-B in Intermediate II except that the corresponding material was used.
  • N-Bromosuccinimide 800.73 mg, 4.50 mmol, 1.10 eq was added to a solution of 3-A (500.00 mg, 4.09 mmol) in acetonitrile (10.00 mL), and stirred at 25 ° C for 2 hours. Filtration gave a solid which gave compound 5-B without purification.
  • N-bromosuccinimide (106.07 mg, 595.99 ⁇ mol) was added to a solution of 6-E (170.00 mg, 95.99 ⁇ mol) in acetonitrile (10.00 mL), and stirred under an atmosphere of 25 ° C for 0.5 hour. Concentration gave the crude product which was purified by preparative EtOAc (EtOAc:EtOAc
  • Compound 8-B was prepared in the same manner as in the compound 5-C of Example 5 except that the corresponding material was used.
  • Aqueous ammonia (3.64 g, 103.85 mmol, 4.00 mL) was added to a solution of Compound 11-B (170.00 mg, 521.54 ⁇ mol) in acetonitrile (2.00 mL) at 20 ° C. After the addition, the reaction mixture was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give Compound 11-C.
  • Compound 21-G was prepared in the same manner as in the preparation of Compound I in Intermediate I, except that the corresponding materials were used.
  • Compound 22-B was prepared in the same manner as in the preparation of compound 21-B in Example 21 except that the corresponding materials were used.
  • 24-F (120.00 mg, 268.26 ⁇ mol) was dissolved in dioxane (10 mL) and water (1 mL), and Compound II-B (92.86 mg, 268.26 ⁇ mol), 2-dicyclohexylphosphonium-2 was added thereto.
  • ',4',6'-triisopropylbiphenyl 51.15 mg, 107.30 ⁇ mol
  • potassium phosphate 17.3 mg, 804.78 ⁇ mol
  • Compound 25-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding materials were used.
  • Compound 25 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
  • Compound 26-A was prepared in the same manner as in the preparation of compound 22-B in Example 22 except that the corresponding material was used.
  • Acetone dipalladium (74.61 mg, 81.48 ⁇ mol), and the mixture was stirred at 90 ° C for 12 hours under nitrogen atmosphere, and then water (10 mL) was added and extracted with dichloromethane (40 mL), and brine (10 mL) The organic layer was dried over sodium sulfate, filtered and evaporated to dryness.
  • 28-E (130 mg, 230.29 ⁇ mol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (770.00 mg, 6.75 mmol) was added thereto, and the reaction was stirred at 24 ° C for 30 minutes, then saturated carbonate was added to the mixture.
  • the sodium hydrogen hydride solution was adjusted to pH 8 and then diluted with water (20 mL), dichloromethane (50 mL), and brine (50 mL).
  • the petroleum ether/ethyl acetate 6/1) (6 mL) was washed and worked up to afford 28.
  • Compound 31-E was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
  • Compound 31 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
  • Compound 33 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
  • Compound 34-A was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
  • Compound 34 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
  • Compound 35-A was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
  • Compound 35 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
  • Compound 36-B was prepared in the same manner as in the preparation of compound 5-C in Example 5 except that the corresponding material was used.
  • Compound 36-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
  • Compound 36 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
  • Compound 42 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
  • Compound 44-A was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
  • Compound 44 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
  • Compound 45-B was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
  • Compound 45 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
  • Compound 47-A was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
  • Compound 47 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
  • Compound 48-B was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
  • Compound 48 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
  • 2,5-Dibromopyridine 500 mg, 2.11 mmol was dissolved in toluene (10 mL), n-butyllithium (162.24 mg, 2.53 mmol, 2.5 M) was added dropwise at -70 ° C, and the reaction was at -70 ° C. After stirring for 1 hour, a solution of 49-A (167.31 mg, 2.32 mmol) dissolved in toluene (1 mL) was added dropwise.
  • Compound 49-C was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
  • Compound 49 was prepared in the same manner as in the preparation of compound 32 in Example 32 except that the corresponding material was used.
  • Compound 50-D was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
  • Compound 50 was prepared in the same manner as Compound 9 in Example 9, except that the corresponding materials were used.
  • Compound 51-E was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
  • Compound 51 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
  • Compound 52-B was prepared in the same manner as in the preparation of compound 5C in Example 5 except that the corresponding material was used.
  • Compound 52-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
  • Compound 52 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
  • Compound 53-C was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
  • Compound 53 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
  • Compound 54-D was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
  • Compound 54 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding material was used.
  • Compound 56-C was prepared in the same manner as in the preparation of compound 32-A in Example 32 except that the corresponding material was used.
  • Compound 56-D was prepared in the same manner as in the preparation of compound 9-A in Example 9 except that the corresponding material was used.
  • Compound 56 was prepared in the same manner as in the preparation of compound 9 in Example 9 except that the corresponding materials were used.
  • Step 1 Synthesis of Compound 57-B

Abstract

La présente invention concerne un type de dérivés d'isoindolinone et leur utilisation dans la préparation d'un médicament pour le traitement de maladies associées à un nouvel inhibiteur du récepteur du facteur 1 de stimulation des colonies (CSF-1R). En particulier, la présente invention concerne un composé de formule (I) et un sel pharmaceutiquement acceptable de celui-ci ou un stéréoisomère de celui-ci.
PCT/CN2019/070227 2018-01-03 2019-01-03 Isoindolinone et son dérivé en tant qu'inhibiteur de csf-1r WO2019134661A1 (fr)

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WO2023125896A1 (fr) * 2021-12-31 2023-07-06 海思科医药集团股份有限公司 Intermédiaire agoniste de glp -1, son procédé de préparation et son utilisation en médecine

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WO2013052394A1 (fr) * 2011-10-05 2013-04-11 Merck Sharp & Dohme Corp. Inhibiteurs de tyrosine kinase de la rate (syk) contenant un 2-pyridyl carboxamide
CN104583199A (zh) * 2012-06-26 2015-04-29 色品疗法有限公司 用作csf-1r激酶抑制剂的2-氨基吡嗪衍生物
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US7129260B2 (en) * 2003-06-02 2006-10-31 Abbott Laboratories Isoindolinone kinase inhibitors
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WO2013052394A1 (fr) * 2011-10-05 2013-04-11 Merck Sharp & Dohme Corp. Inhibiteurs de tyrosine kinase de la rate (syk) contenant un 2-pyridyl carboxamide
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EP3738961A4 (fr) * 2018-01-03 2021-06-30 Medshine Discovery Inc. Composé hétérocyclique en tant qu'inhibiteur de csf -1 r et son utilisation
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WO2023125896A1 (fr) * 2021-12-31 2023-07-06 海思科医药集团股份有限公司 Intermédiaire agoniste de glp -1, son procédé de préparation et son utilisation en médecine

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