WO2019228170A1 - Composé d'octahydropentène, son procédé de préparation, et son utilisation pharmaceutique - Google Patents

Composé d'octahydropentène, son procédé de préparation, et son utilisation pharmaceutique Download PDF

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WO2019228170A1
WO2019228170A1 PCT/CN2019/086302 CN2019086302W WO2019228170A1 WO 2019228170 A1 WO2019228170 A1 WO 2019228170A1 CN 2019086302 W CN2019086302 W CN 2019086302W WO 2019228170 A1 WO2019228170 A1 WO 2019228170A1
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cancer
compound
alkyl
pharmaceutically acceptable
ring
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Chinese (zh)
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陈向阳
庞育成
高英祥
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北京诺诚健华医药科技有限公司
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Publication of WO2019228170A1 publication Critical patent/WO2019228170A1/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
    • A61K31/33—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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • 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
    • 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
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to a novel octahydropentadiene-containing compound or a pharmaceutically acceptable salt thereof which regulates or inhibits the activity of indoleamine 2,3-dioxygenase (IDO), or contains the compound or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition of a salt, a method for preparing the compound or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof are prepared. Use in a medicament for the treatment and / or prevention of IDO-mediated related disorders, particularly tumors, and methods of using the same.
  • Indoleamine 2,3-dioxygenase is a heme-containing monomeric protein that is widely distributed in tissues other than the liver. It catalyzes the oxidative degradation of tryptophan to kynurenine, which is canine urine. The rate-limiting enzyme of the amino acid metabolic pathway. Tryptophan is an essential amino acid for T cell proliferation and is also a precursor substance for the synthesis of neurotransmitters. If the tryptophan concentration in the cell microenvironment is reduced and the kynurenine level is increased, T cells will stagnate in the middle stage of G1, which will affect the proliferation, differentiation and activity of T cells.
  • IDO is expressed at a low level in normal cells, but it is overexpressed in many tumor tissues, leading to abnormal tryptophan metabolism in the tumor and the formation of regulatory T cells, which in turn mediates the local T cell immune tolerance in tumors. Played an important role in the process of occurrence, development and transfer. If IDO activity is inhibited, tryptophan metabolism around tumor cells is effectively prevented, which can promote the growth of T cells, thereby enhancing the body's immune system's ability to fight tumors. Therefore, the research and development of IDO inhibitors has become the forefront of research on tumor immunotherapy drugs.
  • IDO inhibitors can also be combined with other anti-tumor small molecule drugs and immune checkpoint inhibitors, such as CTLA-4, PD-1 and PD-L1 antibodies, to enhance the anti-tumor efficacy of the drug.
  • immune checkpoint inhibitors such as CTLA-4, PD-1 and PD-L1 antibodies.
  • the combined immunotherapy of small molecule IDO inhibitors and immune checkpoint inhibitors is in clinical trials, such as indoximod / ipilimumab, epacadostat / pembrolizumab, epacadostat / nivolumab, indoximod / MEDI-4736, etc.
  • IDO In addition to cancer, IDO is also associated with many other diseases, such as immunosuppression, chronic infections, viral infections, autoimmune diseases or conditions (such as rheumatoid arthritis), neurological or neuropsychiatric diseases or conditions (such as depression), and the like. Therefore, IDO inhibitors have great therapeutic value.
  • IDO inhibitor drugs are still in clinical trials.
  • INCY-024360 epacadostat
  • Incyte Indoximod of NewLink Genetics
  • BMS-986205 BMS-986205 of Bristol-Myers Squibb.
  • IDO inhibitors have attracted the attention of many biopharmaceutical companies due to the prospects shown by them in the treatment of various tumors and other diseases individually and in combination with immunotherapy.
  • a series of patent applications for IDO inhibitors have been published, including WO2006122150A1 , WO2011056652A1, WO2013069765A1, WO2014186035A1, WO2015002918A1, WO2016073738A2, WO2016073770A1, WO2016181348A1, WO2016161960A1, WO2017079669A1, etc., but there is still a need to develop new compounds that have better drugability and higher response rates in immunotherapy.
  • the present invention has designed compounds having a structure represented by the general formula (I), and found that compounds having such a structure exhibit excellent effects and effects of inhibiting IDO activity.
  • the present invention provides a compound represented by the general formula (I) as an IDO inhibitor:
  • Ring D is an optionally substituted benzene ring or a 5-6 membered heteroaryl ring
  • R 1 and R 2 are each independently selected from H or optionally substituted C 1-4 alkyl, C 3-6 cycloalkyl, or 4-7 membered heterocyclyl; or, R 1 and R 2 and the attached carbon The atoms together form a 3-7 membered ring optionally containing heteroatoms selected from O, N and S;
  • R 3 and R 4 are each independently selected from H or C 1-4 alkyl
  • A is N or CR 5 ;
  • B is N or CR 6 ;
  • L is a bond, -O- or -CR 7 R 8- ;
  • C is optionally substituted 4-7 membered heterocyclic group, 6-10 membered aryl group or 5-10 membered heteroaryl group;
  • R 5 and R 6 are each independently selected from H, halogen, OH, or optionally substituted C 1-4 alkyl or -OC 1-4 alkyl;
  • R 7 and R 8 are each independently selected from H or optionally substituted C 1-4 alkyl.
  • An embodiment of the present invention relates to a compound represented by the above-mentioned general formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof, and a mixture thereof, wherein:
  • Ring D is an optionally substituted benzene ring or a 6-membered heteroaryl ring
  • R 1 and R 2 are each independently selected from H or optionally substituted C 1-4 alkyl
  • R 3 and R 4 are each independently selected from H or CH 3 ;
  • A is N or CH
  • B is N or CH
  • L is a bond or -O-
  • C is a 4-7 membered heterocyclic group, a 6-10 membered aryl group, or a 5-10 membered heteroaryl group optionally substituted with halogen, cyano, C 1-4 alkyl, or halogenated C 1-4 alkyl.
  • Another embodiment of the present invention relates to the compound according to any one of the above embodiments, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof, and a mixture thereof, the compound having the general formula (II) Compound shown:
  • Ring D is an optionally substituted benzene ring or a pyridine ring
  • R 1 and R 2 are each independently selected from H or C 1-4 alkyl
  • A is N or CH
  • C is a 5-10 membered heteroaryl group optionally substituted with halogen, cyano, C 1-4 alkyl, or halo C 1-4 alkyl.
  • Another embodiment of the present invention relates to a compound or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer thereof, or a mixture thereof according to any one of the above embodiments, wherein ring D is optionally halogen, Cyano, -SF 5 , C 1-4 alkyl, halo C 1-4 alkyl, -OC 1-4 alkyl or -O-halo C 1-4 alkyl substituted benzene ring or pyridine ring.
  • Another embodiment of this invention is directed to a compound according to any one of the preceding embodiments, wherein C is a quinolinyl group optionally substituted with halogen, cyano, C 1-4 alkyl or halo C 1-4 alkyl Pyridyl, especially fluoroquinolinyl.
  • Another embodiment of this invention is directed to a compound according to any one of the above embodiments, wherein R 1 is C 1-4 alkyl and R 2 is H, especially R 1 is methyl and R 2 is H.
  • Another embodiment of this invention is directed to a compound according to any one of the above embodiments, which is a compound of the following general formulae (IIIa)-(IIIc):
  • Another embodiment of this invention is directed to a compound according to any one of the above embodiments, which is a compound of the following general formula (IV):
  • Another embodiment of the present invention relates to a compound represented by the above-mentioned general formula (IV), wherein R 1 is a methyl group.
  • One embodiment of the present invention relates to a compound represented by the above general formula (I), wherein the compound is selected from:
  • the compound of the present invention has a significant inhibitory effect on the activity of IDO in Hela cells, and preferably has an IC 50 of less than 200 nM, and more preferably an IC 50 of less than 50 nM.
  • the compounds of the invention are therefore useful in the treatment or prevention of IDO-mediated related diseases, including but not limited to cancer, immunosuppression, chronic infection, viral infection, autoimmune disease or disorder (e.g. rheumatoid arthritis), neurological or neuropsychiatric Diseases or conditions (e.g. depression) and the like.
  • IDO-mediated related diseases including but not limited to cancer, immunosuppression, chronic infection, viral infection, autoimmune disease or disorder (e.g. rheumatoid arthritis), neurological or neuropsychiatric Diseases or conditions (e.g. depression) and the like.
  • the compounds of the present invention are used to treat or prevent IDO-related tumors, including, but not limited to, prostate cancer, colon cancer, rectal cancer, glandular cancer, cervical cancer, gastric cancer, endometrial cancer, brain cancer, liver cancer, bladder cancer, ovary Cancer, testicular cancer, head and neck cancer, skin cancer (including melanoma and basal cancer), mesothelioma, lymphoma, leukemia, esophageal cancer, breast cancer, muscle cancer, connective tissue cancer, lung cancer (including small cell lung cancer and (Non-small cell cancer), adrenal cancer, thyroid cancer, kidney cancer, bone cancer, glioblastoma, mesothelioma, sarcoma (including Kaposi's sarcoma), choriocarcinoma, skin basal cell carcinoma, or testicular seminoma Tumor and so on.
  • IDO-related tumors including, but not limited to, prostate cancer, colon cancer, rectal cancer, glandular cancer, cervical cancer, gastric cancer
  • the present invention provides a method for treating or preventing an IDO-mediated disease (such as the tumor), which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable Salts, prodrugs, stable isotope derivatives, isomers and mixtures thereof, or pharmaceutical compositions comprising said compounds.
  • Another aspect of the present invention relates to a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, a prodrug, a stable isotope derivative, an isomer, and a mixture thereof, which is used as a medicine or for medical use.
  • Treat or prevent IDO-mediated diseases such as cancer, immunosuppression, chronic infections, viral infections, autoimmune diseases or conditions (such as rheumatoid arthritis), neurological or neuropsychiatric diseases or conditions (such as depression), and the like.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the invention or a pharmaceutically acceptable salt thereof, a prodrug, a stable isotope derivative, an isomer and a mixture thereof, and a pharmaceutically acceptable carrier And excipients.
  • Another aspect of the present invention relates to a compound represented by the general formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture thereof, or a pharmaceutical composition in the preparation of a medicament.
  • the medicament is used to treat or prevent IDO-mediated diseases such as tumors and immunosuppression.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, a prodrug, a stable isotope derivative, an isomer, and a mixture thereof And at least one additional drug, wherein the at least one additional drug is a chemotherapeutic agent, an immune and / or inflammation modulator (such as an immune checkpoint inhibitor), a neuro-related disease modulator, or an anti-infective agent.
  • the medicament may be any pharmaceutical dosage form, including but not limited to tablets, capsules, solutions, lyophilized preparations, injections.
  • the pharmaceutical preparation of the present invention may be administered in the form of a dosage unit containing a predetermined amount of an active ingredient per dosage unit.
  • a dosage unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, and particularly preferably 5 mg to 300 mg of a compound of the present invention depending on the condition to be treated, the method of administration and the age, weight and condition of the patient.
  • Preferred dosage unit formulations are those containing the daily or divided dose or active fraction thereof as indicated above.
  • this type of pharmaceutical preparation can be prepared using methods known in the pharmaceutical art.
  • the pharmaceutical formulations of the present invention may be suitable for administration by any desired suitable method, such as by oral (including oral or sublingual), rectal, nasal, topical (including oral, sublingual or transdermal), vaginal or parenteral (Including subcutaneous, intramuscular, intravenous or intradermal) methods.
  • suitable methods such as by oral (including oral or sublingual), rectal, nasal, topical (including oral, sublingual or transdermal), vaginal or parenteral (Including subcutaneous, intramuscular, intravenous or intradermal) methods.
  • Such formulations can be prepared using all methods known in the pharmaceutical art, for example, by combining the active ingredient with one or more excipients or one or more adjuvants.
  • C xy means the range of the number of carbon atoms, where x and y are integers, for example, C 3-8 cycloalkyl represents a cycloalkyl group having 3-8 carbon atoms, that is, having 3 , 4, 5, 6, 7, or 8 carbon atom cycloalkyl. It should also be understood that “ C3-8 " also includes any sub-ranges thereof, such as C3-7 , C3-6 , C4-7 , C4-6 , C5-6, and the like.
  • Alkyl refers to a saturated straight or branched chain hydrocarbon group containing 1 to 20 carbon atoms, such as 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl Methyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl and 2-ethylbutyl.
  • Cycloalkyl refers to a saturated cyclic hydrocarbon substituent having 3 to 14 carbon ring atoms.
  • a cycloalkyl group can be a single carbocyclic ring and typically contains 3 to 8, 3 to 7, or 3 to 6 carbon ring atoms.
  • Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl can optionally be bi or tricyclic fused together, such as decahydronaphthyl. The cycloalkyl group may be optionally substituted.
  • Heterocyclyl or heterocyclic refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic group, which includes 3 to 20 ring atoms, and may be 3 to 14, 3 to 12, 3 to 10, for example Three, eight, three to six, or five to six ring atoms, one or more of which are selected from nitrogen, oxygen, or S (O) m (where m is an integer from 0 to 2), but does not include The ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, and nitrogen Heterocycloalkyl.
  • Polycyclic heterocyclyls include fused, bridged, or spiro polycyclic heterocyclyls, such as octahydrocyclopentadieno [c] pyrrole, octahydropyrrolo [1,2-a] pyrazine, 3,8-bis Azabicyclo [3.2.1] octane, 5-azaspiro [2.4] heptane, 2-oxa-7-azaspiro [3.5] nonane, etc.
  • the heterocyclyl or heterocyclic ring may be optionally substituted.
  • Aryl or aromatic ring refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 members, such as phenyl and naphthyl, and most preferably phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include:
  • the aryl or aromatic ring may be optionally substituted.
  • Heteroaryl or heteroaryl ring refers to a heteroaromatic system containing 5 to 14 ring atoms, wherein 1 to 4 ring atoms are selected from heteroatoms including oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 members. More preferably heteroaryl is 5- or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, tetrazolyl, Oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:
  • heteroaryl or heteroaryl ring may be optionally substituted.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Cyano refers to -CN.
  • an heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not exist, and the expression includes a case where the heterocyclic group is substituted with an alkyl group and a case where the heterocyclic group is not substituted with an alkyl group .
  • Optionally substituted refers to one or more hydrogen atoms in a group, preferably 5 and more preferably 1 to 3 hydrogen atoms, independently of one another, with a corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort.
  • an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.
  • the substituents include, but are not limited to, halogen, cyano, nitro, oxo, -SF 5 , C 1-4 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5 -6 membered heteroaryl, -OR ', -NR'R ", -C (O) R', -C (O) OR ', -C (O) NR'R", -C (O) N ( R ′) OR ′′, -OC (O) R ′, -OC (O) NR′R ′′, -N (R ′) C (O) OR ′′, -N (R ′) C (O) R ′′, -N (R ′) C (O) OR ′′, -N (R ′) C (O) R ′′, -N (R ′ ′′) C (O) NR′R ′′, -N (R ′) S (O
  • R ′, R ′′, and R ′ ′′ are each independently selected from H, C 1-4 alkyl, C 3-7 cycloalkyl, optionally containing heteroatoms selected from N, O, and S, 4- 7-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl, wherein the alkane Group, cycloalkyl, heterocyclyl, phenyl or heteroaryl is optionally selected from one or more of halogen, cyano, C 1-4 alkyl, halo C 1-4 alkyl, -OC 1- 4 alkyl and other substituents; R ′ and R ′′ on the same nitrogen atom are optionally combined with the nitrogen atom to which they are attached to form a 4- atom optionally containing another heteroatom selected from O, S and N 7-membered heterocyclic ring.
  • “Isomer” refers to a compound that has the same molecular formula but differs in the form or order in which its atoms are bound or the arrangement of their atoms in space. Isomers whose atomic arrangement is different are called “stereoisomers”. Stereoisomers include optical isomers, geometric isomers, and conformers.
  • the compounds of the invention may exist as optical isomers. Depending on the configuration of the substituents around the chiral carbon atom, these optical isomers are in the "R" or "S” configuration. Optical isomers include enantiomers and diastereomers. Methods for preparing and separating optical isomers are known in the art.
  • the compounds of the invention may also exist as geometric isomers.
  • the present invention contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclic groups.
  • the substituents around the carbon-carbon double bond or carbon-nitrogen bond are designated as the Z or E configuration, and the substituents around the cycloalkyl or heterocyclic ring are designated as the cis or trans configuration.
  • the compounds of the invention may also exhibit tautomerism, such as keto-enol tautomerism.
  • the present invention includes any tautomeric or stereoisomeric form and mixtures thereof, and is not limited to any one of the tautomeric or stereoisomeric forms used in the nomenclature or chemical structural formula of the compound.
  • isotopes include all isotopes of the atoms present in the compounds of the invention. Isotopes include those atoms that have the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl.
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples, using appropriate isotopically-labeled reagents instead of non-isotopically-labeled reagents. Such compounds have a variety of potential uses, such as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds have the potential to beneficially alter biological, pharmacological or pharmacokinetic properties.
  • Prodrug means that a compound of the invention can be administered in the form of a prodrug.
  • Prodrugs refer to derivatives of biologically active compounds of the present invention that are transformed under physiological conditions in vivo, such as by oxidation, reduction, hydrolysis, etc. (they are each performed with or without the participation of an enzyme).
  • prodrugs are compounds in which an amino group in a compound of the invention is acylated, alkylated, or phosphorylated, such as eicosanoylamino, alanylamino, pivaloyloxymethylamino, or Where the hydroxyl group is acylated, alkylated, phosphorylated, or converted to a borate such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaroyloxy, alanyloxy Group, or where the carboxyl group is esterified or amidated, or where the thiol group forms a disulfide bridge with a carrier molecule, such as a peptide, that selectively delivers the drug to the target and / or to the cytosol of the cell.
  • a carrier molecule such as a peptide
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt” refers to a salt made from a pharmaceutically acceptable base or acid, including an inorganic base or acid and an organic base or acid. Where the compounds of the invention contain one or more acidic or basic groups, the invention also includes their corresponding pharmaceutically acceptable salts.
  • the compounds of the invention containing acidic groups can exist in the form of salts and can be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium, potassium, calcium, magnesium, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine, or amino acids.
  • the compounds of the invention containing basic groups may exist in the form of salts and may be used according to the invention in the form of their addition salts with inorganic or organic acids.
  • suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propylene Acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, Adipic acid and other acids known to those skilled in the art.
  • the invention includes, in addition to the salt forms mentioned, internal salts or internal ammonium salts.
  • Each salt can be obtained by conventional methods known to those skilled in the art, such as by contacting these with organic or inorganic acids or bases in a solvent or dispersant or by anion exchange or cation exchange with other salts.
  • “Pharmaceutical composition” refers to a compound containing one or more of the compounds described herein, or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, isomer and mixture thereof, and other components such as a pharmaceutically acceptable carrier And excipient composition.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.
  • tumor includes benign and malignant tumors (eg, cancer).
  • terapéuticaally effective amount means an amount that includes a compound of the invention that is effective to inhibit the function of IDO and / or treat or prevent the disease.
  • the present invention also provides a method for preparing the compound.
  • the preparation of the compound of the general formula (I) of the present invention can be accomplished by the following exemplary methods and examples, but these methods and examples should not be considered as limiting the scope of the present invention in any way.
  • the compounds of the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or a method known in the art and a method of the present invention can be used in combination.
  • the products obtained in each step are obtained using separation techniques known in the art, including, but not limited to, extraction, filtration, distillation, crystallization, chromatographic separation, and the like.
  • the starting materials and chemical reagents required for the synthesis can be routinely synthesized or purchased according to the literature (available from SciFinder).
  • the octahydropentadiene compound of the general formula (I) of the present invention can be synthesized according to the route described in Method A: firstly, the intermediate acid A2 is changed into an acid chloride or activated with an amide condensing agent, and then the (hetero) arylamine A1 Coupling gave the target amide compound A3.
  • the achiral intermediate acid A2 is synthesized according to the conventional method; the chiral intermediate acid A2 can be synthesized according to the route described in Method B: one ketone in B1 is protected with ethylene glycol, and the other ketone is reacted with trifluoro under basic conditions Methanesulfonic anhydride reacts to form alkenyl trifluoromethanesulfonate B2; B2 and borate or CB (OR) 2 are obtained by Suzuki coupling reaction to obtain B3, which is reduced to hydrogenation and deprotected to form B4; B4 undergoes Wittig reaction Monoene is formed (the ester is hydrolyzed to acid in the reaction, otherwise alkali is added to promote ester hydrolysis), and then hydrogenated to obtain acid B5; B5 first forms acid anhydride with acid chloride (such as pivaloyl chloride) under base catalysis, and is then used as a chiral auxiliary (Lithium salt of ((R) -4-benzylox
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR measurement was performed using a Bruker ASCEND-400 nuclear magnetic analyzer.
  • the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDC1 3 ), and deuterated methanol (CD 3 OD).
  • DMSO-d 6 dimethyl sulfoxide
  • CDC1 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS methylsilyl
  • the chemical shift is given in units of 10 -6 (ppm).
  • the MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, model: 6120).
  • ESI Agilent SQD
  • the thin-layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate.
  • the thin-layer chromatography (TLC) silica gel plate uses a size of 0.15 to 0.2mm.
  • the thin-layer chromatography separation and purification product uses a size of 0.4 to 0.5mm silica gel plate. .
  • the known starting materials of the present invention can be synthesized by or in accordance with methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Beijing Coupling chemicals and other companies.
  • reaction is performed in an argon atmosphere or a nitrogen atmosphere.
  • An argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the hydrogen atmosphere means that a reaction balloon is connected to a hydrogen balloon with a volume of about 1 L.
  • the hydrogenation reaction is usually evacuated and charged with hydrogen, and the operation is repeated 3 times.
  • reaction temperature is room temperature, and the temperature range is 20 ° C-30 ° C.
  • the reaction progress in the examples was monitored using an Agilent LC / MS instrument (1260/6120).
  • the reaction progress can also be monitored by thin-layer chromatography (TLC).
  • the systems used as the eluent are A: dichloromethane and methanol; B: petroleum ether and ethyl acetate.
  • the volume ratio of the solvent depends on the polarity of the compound. Adjust differently.
  • the eluent system for column chromatography and the eluent system for thin-layer chromatography used to purify compounds include A: dichloromethane and methanol systems; B: petroleum ether and ethyl acetate systems. It can be adjusted by different polarities. It can also be adjusted by adding a small amount of triethylamine and acidic or alkaline reagents, or using other solvent systems.
  • the purified compounds also used Waters' mass spectrometry-oriented automatic preparation system (mass detector: SQD2).
  • acetonitrile / water containing 0.1% trifluoroacetic acid or formic acid
  • acetonitrile / water containing 0.05% ammonia
  • a reverse phase high pressure column (XBridge-C18, 19 ⁇ 150 mm, 5 ⁇ m) was eluted with a gradient at a flow rate of 20 mL / min.
  • reaction mixture (3aR, 6aS) -3,3a, 4,6a-tetrahydro-1H-spiro [pentaene-2,2 '-[1,3] dioxolane] -5-yltrifluoromethyl Sulfonate 1c (9.55g, 30.4mmol), (2-methylpyridin-4-yl) boronic acid (5g, 36.5mmol), [1,1'-bis (diphenylphosphine) ferrocene] dichloro Palladium dichloromethane complex (1.24g, 1.52mmol), sodium carbonate (6.44g, 60.8mmol), N, N-dimethylformamide (100mL) and water (10mL) heated to 110 ° C under nitrogen , And stirred overnight.
  • Methyl iodide (170 mg, 1.2 mmol) was added, and stirring was continued at -70 ° C for 3 hours. The reaction was quenched with a saturated ammonium chloride solution (10 mL), warmed to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (30 mL ⁇ 3). The organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure.
  • reaction mixture (3aR, 6aS) -3,3a, 4,6a-tetrahydro-1H-spiro [pentaene-2,2 '-[1,3] dioxolane] -5-yltrifluoromethyl Sulfonate 1c (66 g, 210 mmol), (6-fluoroquinolin-4-yl) boronic acid (47 g, 250 mmol), sodium carbonate (56 g, 525 mmol), [1,1'-bis (diphenylphosphine) di Ferrocene] palladium dichloride dichloromethane complex (8.5 g, 10.5 mmol), dioxane (1.2 L) and water (250 mL) were heated to 90 ° C.
  • Example 7-12 were synthesized with reference to the operation method of Example 5, but in the operation, different aromatic amines were used instead of 5-chloropyridin-2-amine 5a.
  • the characterization data are shown in the following table:
  • N-phenylbis (trifluoromethanesulfonyl) imide (12.7 g, 35.6 mmol) was added in portions, and the reaction solution was warmed to room temperature and stirred for 2 hours. It was quenched with a saturated ammonium chloride solution and extracted with ethyl acetate (100 mL ⁇ 2).
  • the experimental principle is summarized as follows: without any induction conditions, the expression of IDO in Hela cells is low, but a certain concentration of IFN- ⁇ can induce Hela cells to express IDO and catalyze tryptophan to produce N-formyl kynurenine, which It can be hydrolyzed by trichloroacetic acid to generate kynurenine, and then develop a color reaction with Ehrlich reagent to detect the activity of IDO.
  • the absorbance (OD490) at 490nm is directly proportional to the activity of IDO.
  • the compound was dissolved in DMSO (Sigma, Cat. No. D5879) and diluted to 5 mM, and then serially diluted 3 times with DMSO to a minimum concentration of 2.29 ⁇ M, and each concentration point was treated with FBS-free DMEM medium (ThermoFisher, Cat. 11995073) diluted 50-fold. If the compound is very low IC 50 values, the concentration of the starting compound can be reduced.
  • Hela cells ATCC, article number CCL-2
  • DMEM complete medium containing 10% FBS GBICO, article number 10099-141
  • penicillin mixed solution ThermoFisher, article number 15140122.
  • the cells were digested with 0.25% trypsin (containing EDTA) (ThermoFisher, Cat. No. 25200056) and blown and planted in 96-well plates (Corning, Cat. No. 3599). 30,000 cells (80 ⁇ L DMEM medium), and then cultured in a 96-well plate in a 37 ° C, 5% CO 2 incubator overnight (18-20 hours).
  • trypsin containing EDTA
  • 30,000 cells 80 ⁇ L DMEM medium
  • Y is the inhibition percentage
  • Bottom is the bottom plateau value of the S-shaped curve
  • Top is the top plateau value of the S-shaped curve
  • X is the logarithmic value of the concentration of the test compound
  • slope factor is the slope coefficient of the curve.
  • Compound number IC 50 Compound number IC 50 1 A 2 A 3 A 4 A 5 A 6 A 7 A 8 A 9 B 10 B 11 A 12 A
  • the compound of the embodiment of the present invention has a significant inhibitory effect on the activity of IDO in the cells, respectively, preferably the IC 50 is less than 200 nM, and more preferably the IC 50 is less than 50 nM.

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Abstract

L'invention concerne un composé d'octahydropentène destiné à réguler ou à inhiber l'activité de l'indoléamine 2,3-dioxygénase (IDO), son procédé de préparation et son utilisation pharmaceutique. Plus particulièrement, la présente invention concerne un composé de formule (I) et des sels pharmaceutiquement acceptables de celui-ci; une composition pharmaceutique comprenant le composé ou les sels pharmaceutiquement acceptables de celui-ci; une méthode de traitement et/ou de prévention de maladies associées à l'IDO, en particulier des tumeurs, à l'aide du composé ou des sels pharmaceutiquement acceptables de celui-ci; et un procédé de préparation du composé ou des sels pharmaceutiquement acceptables de celui-ci. L'invention concerne également l'utilisation du composé ou de ses sels pharmaceutiquement acceptables ou d'une composition pharmaceutique contenant le composé ou des sels pharmaceutiquement acceptables de celui-ci dans la préparation de médicaments pour le traitement et/ou la prévention de maladies associées à l'IDO, en particulier des tumeurs. La définition de chaque substituant dans la formule (I) est identique à celle donnée dans la description.
PCT/CN2019/086302 2018-05-28 2019-05-10 Composé d'octahydropentène, son procédé de préparation, et son utilisation pharmaceutique WO2019228170A1 (fr)

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US11266640B2 (en) * 2017-09-20 2022-03-08 Hangzhou Innogate Pharma Co., Ltd. Polycyclic compound acting as IDO inhibitor and/or IDO-HDAC dual inhibitor

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JP7455133B2 (ja) * 2018-09-27 2024-03-25 シェンチェン チップスクリーン バイオサイエンシズ カンパニー、リミテッド インドールアミン－２，３－ジオキシゲナーゼ阻害活性を有するキノロン誘導体

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* Cited by examiner, † Cited by third party
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