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WO2019042470A1 - AGENT DE BLOCAGE DE CD47/SIRPα ET APPLICATION ASSOCIÉE - Google Patents

AGENT DE BLOCAGE DE CD47/SIRPα ET APPLICATION ASSOCIÉE Download PDF

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WO2019042470A1
WO2019042470A1 PCT/CN2018/103974 CN2018103974W WO2019042470A1 WO 2019042470 A1 WO2019042470 A1 WO 2019042470A1 CN 2018103974 W CN2018103974 W CN 2018103974W WO 2019042470 A1 WO2019042470 A1 WO 2019042470A1
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optionally substituted
group
cancer
alkyl
hydrogen
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Chinese (zh)
Inventor
李洪林
朱丽丽
徐玉芳
赵振江
全丽娜
王婉琦
温迪莎
李文杰
王艳玲
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East China University of Science and Technology
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East China University of Science and Technology
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    • 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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
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    • C07D498/06—Peri-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the field of medicinal chemistry; in particular, the present invention relates to compounds which block the interaction of SIRP ⁇ protein with CD47 and uses thereof.
  • SIRP ⁇ Signal regulatory protein ⁇
  • SIRP ⁇ is a widely expressed glycoprotein molecule, also known as a protein tyrosine phosphatase substrate containing the SHP-2 domain, and belongs to the transmembrane protein of the immunoglobulin superfamily.
  • SIRP ⁇ contains an Immune-receptor tyrosin-based inhibitory motif (ITIM). When cells are stimulated by growth factors, SIRP ⁇ can inhibit the growth factor activity by phosphorylation of ITIM. SIRP ⁇ can be widely expressed on the surface of myeloid cells such as macrophages and dendritic cells.
  • CD47 also known as Integrin-associated protein (IAP), belongs to the membrane protein of the immunoglobulin superfamily and is highly expressed on various tumor cell membranes. SIRP ⁇ is an important surface receptor of CD47. The CD47-SIRP ⁇ signal produced by the combination of the two has a negative regulatory effect in the immune system and is of great significance in the process of macrophage phagocytosis.
  • SIRP ⁇ When SIRP ⁇ binds to CD47, it leads to aggregation of receptor molecules leading to tyrosine phosphorylation and activation and inhibition of macrophage synaptophysin accumulation, in which SIRP ⁇ with phosphorylated ITIM can recruit and activate tyrosine
  • the phosphorylases SHP-1 and SHP-2 which transmit an inhibitory signal, thereby inhibiting the phagocytosis of macrophages, ultimately leading to immune escape of tumor cells. Therefore, blocking the binding of SIRP ⁇ to CD47 can restore the related functions of macrophages, and finally achieve the effect of treating tumors.
  • the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt, prodrug, or solvate thereof, for the manufacture of a medicament for blocking the interaction of a SIRP ⁇ protein with CD47,
  • Y is selected from N or C, wherein when Y is N, R 3 is absent;
  • R 1 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, halogen, optionally substituted C 1 -C 10 alkoxy, optionally substituted C 6 -C 10 aryl, optionally substituted Benzyl, nitro, CN;
  • R 2 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl or cycloalkyl, halogen, C 1 -C 10 alkoxy, optionally substituted C 6 -C 10 aryl, NR a R b , Wherein R a and R b are independently selected from the group consisting of: hydrogen, optionally substituted C 1 -C 6 alkyl;
  • R 1 and R 2 may be joined to form Wherein n is an integer from 1 to 3;
  • R 3 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 10 alkoxy, optionally substituted alkylthio;
  • R 4 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted benzyl ;
  • R 3 and R 4 form an optionally substituted six-membered ring, or an optionally substituted oxygen-containing or sulfur-containing six-membered heterocyclic ring;
  • R 5 is selected from the group consisting of: hydrogen, optionally substituted C 1 -C 10 alkyl, halogen;
  • R 6 is selected from the group consisting of: H, R c —COOH, R c —COOR d , R c —CONR 8 R 9 , optionally substituted hydroxy C 1 -C 3 alkyl;
  • R c is absent or optionally substituted -(CH 2 ) m -, m is an integer selected from 1 to 3;
  • R d is an optionally substituted C 1 -C 3 alkyl group;
  • R 8 and R 9 Independently selected from: H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 6 -C 10 aryl;
  • R 7 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, halogen, amino.
  • the compound is as shown in Formula II,
  • R 1 is selected from the group consisting of: hydrogen, optionally substituted C 1 -C 10 alkyl, halogen, optionally substituted C 6 -C 10 aryl;
  • R 2 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, An optionally substituted C 6 -C 10 aryl group, NR a R b , wherein R a and R b are as defined above;
  • R 3 is selected from the group consisting of: hydrogen, halogen, optionally substituted C 1 -C 10 alkoxy;
  • R 4 is selected from the group consisting of: an optionally substituted cyclopropyl, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted phenyl group, an optionally substituted benzyl group;
  • R 3 and R 4 form an optionally substituted six-membered ring
  • R 7 is selected from the group consisting of hydrogen and amino groups
  • Y is selected from: C or N, wherein when Y is N, R 3 is absent.
  • the compound is as shown in Formula III,
  • R 1 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, halogen;
  • R 2 is selected from the group consisting of hydrogen
  • R 7 is selected from the group consisting of hydrogen and amino groups
  • R 10 is selected from the group consisting of: hydrogen, optionally substituted C 1 -C 10 alkyl;
  • Z is selected from: C, O, S;
  • R 6 is as described above.
  • R 6 is R c -COOH or R c -COOR d ; wherein R c is absent or optionally substituted -(CH 2 ) m -, m is an integer selected from 1 to 3 R d is an optionally substituted C 1 -C 3 alkyl group; more preferably, R 6 is -COOH.
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the medicament is for inhibiting a tumor, or preventing or treating an infection caused by a bacterium, a virus or a fungus, or treating an inflammatory disease.
  • the tumor includes, but is not limited to, melanoma, lung cancer (preferably non-small cell lung cancer), kidney cancer, ovarian cancer, prostate cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, skin cancer , head and neck cancer, uterine cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophagus Cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid carcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, pediatric Solid tumor, lymphocytic lymphoma, bladder cancer, renal or ureteral cancer, renal pelvic cancer, central nervous system
  • lung cancer
  • the viruses include, but are not limited to, hepatitis viruses (types A, B, and C), herpes viruses, influenza viruses, adenoviruses, coronaviruses, measles viruses, dengue viruses, polioviruses, rabies viruses;
  • the bacteria include, but are not limited to, Chlamydia, Rickettsia, Mycobacterium, Staphylococcus, Pneumococci, Vibrio cholerae, Clostridium tetanus;
  • the fungus includes, but is not limited to, Candida, Aspergillus, dermatitis;
  • the inflammatory diseases include, but are not limited to, ankylosing spondylitis, autoimmune hemolytic anemia, arthritis, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, pernicious anemia, polymyositis.
  • the present invention provides a compound of the formula: or a pharmaceutically acceptable salt, prodrug or solvate thereof,
  • R 1 is selected from the group consisting of hydrogen, halogen (preferably F or Cl), optionally substituted C 1 -C 10 alkyl (preferably C 1 -C 6 alkyl, more preferably C 1 -C 3 alkyl), nitro, Optionally substituted C 6 -C 10 aryl (preferably phenyl), cyano;
  • R 2 is selected from the group consisting of: an optionally substituted substituted phenyl, butyl, morpholinyl, piperidinyl, piperazinyl, NR a R b ; R a and R b are independently selected from: hydrogen, optionally substituted C 1 -C 6 alkyl;
  • R 4 is selected from the group consisting of: an optionally substituted C 3 -C 8 cycloalkyl group (preferably an optionally substituted cyclohexyl group), an optionally substituted C 1 -C 6 alkyl group (for example, an optionally substituted butyl group), (CH 2 ) o - optionally substituted phenyl (preferable ), optionally replaced o is an integer selected from 0-2
  • R 6 is selected from the group consisting of: COOH, C(O)-OC 1 -C 4 alkyl (preferably COOCH 3 or COOCH 2 CH 3 ), CONR 8 R 9 , CONHC 6 H 5 , CH 2 OH;
  • R 8 and R 9 are independently selected from: H, optionally substituted C 1 -C 10 alkyl (preferably optionally substituted C 1 -C 6 alkyl), optionally substituted C 6 -C 10 aryl (preferably Optionally substituted phenyl).
  • the invention provides a compound selected from the group consisting of:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the second or third aspect of the present invention, or a pharmaceutically acceptable salt, prodrug, solvate thereof, and optionally A pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition is for inhibiting tumors, or preventing or treating infections caused by bacteria, viruses or fungi or treating inflammatory diseases.
  • the tumor includes, but is not limited to, melanoma, lung cancer (preferably non-small cell lung cancer), kidney cancer, ovarian cancer, prostate cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, skin cancer , head and neck cancer, uterine cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophagus Cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid carcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, pediatric Solid tumor, lymphocytic lymphoma, bladder cancer, renal or ureteral cancer, renal pelvic cancer, central nervous system
  • lung cancer
  • the viruses include, but are not limited to, hepatitis viruses (types A, B, and C), herpes viruses, influenza viruses, adenoviruses, coronaviruses, measles viruses, dengue viruses, polioviruses, rabies viruses;
  • the bacteria include, but are not limited to, Chlamydia, Rickettsia, Mycobacterium, Staphylococcus, Pneumococci, Vibrio cholerae, Clostridium tetanus;
  • the fungus includes, but is not limited to, Candida, Aspergillus, dermatitis;
  • the inflammatory diseases include, but are not limited to, ankylosing spondylitis, autoimmune hemolytic anemia, arthritis, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, pernicious anemia, polymyositis.
  • the present invention provides a method of blocking binding of SIRP ⁇ to CD47, comprising blocking SIRP ⁇ by using the compound of the first, second or third aspect of the invention or the pharmaceutical composition of the fourth aspect The step of CD47 binding.
  • Figure 1 shows a SPR diagram of Compound 8 of the present invention and human SIRP ⁇ protein
  • Figure 2 shows a SPR diagram of Compound 9 of the present invention and human SIRP ⁇ protein
  • Figure 3 shows a SPR diagram of Compound 11 of the present invention and human SIRP ⁇ protein
  • Figure 4 shows a SPR diagram of Compound 13 of the present invention and human SIRP ⁇ protein
  • Figure 5 shows a SPR diagram of Compound 14 of the present invention and human SIRP ⁇ protein
  • Figure 6 shows a SPR diagram of Compound 15 of the present invention and human SIRP ⁇ protein
  • Figure 7 shows a SPR map of Compound 16 of the present invention and human SIRP ⁇ protein
  • Figure 8 shows a SPR diagram of Compound 17 of the present invention and human SIRP ⁇ protein
  • Figure 9 shows a SPR diagram of Compound 18 of the present invention and human SIRP ⁇ protein
  • Figure 10 shows a SPR diagram of Compound 19 of the present invention and human SIRP ⁇ protein
  • Figure 11 shows a SPR diagram of Compound 20 of the present invention and human SIRP ⁇ protein
  • Figure 12 shows a SPR diagram of Compound 23 of the present invention and human SIRP ⁇ protein
  • Figure 13 shows a SPR map of Compound 24 of the present invention and human SIRP ⁇ protein
  • Figure 14 shows a SPR diagram of Compound 25 of the present invention and human SIRP ⁇ protein
  • Figure 15 shows a SPR diagram of the compound D2 of the present invention and a human SIRP ⁇ protein
  • Figure 16 shows an SPR diagram of the compound D3 of the present invention and a human SIRP ⁇ protein
  • Figure 17 shows a SPR diagram of the compound D4 of the present invention and a human SIRP ⁇ protein
  • Figure 18 shows an SPR diagram of the compound D7 of the present invention and a human SIRP ⁇ protein
  • Figure 19 shows an SPR diagram of the compound D8 of the present invention and a human SIRP ⁇ protein
  • Figure 20 shows an SPR diagram of the compound D9 of the present invention and a human SIRP ⁇ protein
  • Figure 21 shows a SPR diagram of the compound D11 of the present invention and a human SIRP ⁇ protein
  • Figure 22 shows a SPR diagram of the compound D15 of the present invention and a human SIRP ⁇ protein
  • Figure 23 shows a SPR diagram of the compound D17 of the present invention and a human SIRP ⁇ protein
  • Figure 24 shows the SPR map of the compound D21 of the present invention and the human SIRP ⁇ protein.
  • SIRP ⁇ protein refers to Signal Regulatory Protein ⁇ (SIRP ⁇ ), which is a broad class of glycoprotein molecules.
  • CD47 also known as integrin-related protein, is also a membrane protein belonging to the immunoglobulin superfamily. SIRP ⁇ is an important surface receptor for CD47, and the signals produced by the combination of the two have a negative regulatory effect in the immune system.
  • alkyl refers to a saturated branched or straight chain alkyl group having a carbon chain length of from 1 to 10 carbon atoms, preferably an alkyl group of from 1 to 6 carbon atoms, more preferably from 1 to 3 carbon atoms. Alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, heptyl, and the like.
  • cycloalkyl refers to a saturated cyclic alkyl group having a carbon chain length of from 3 to 10 carbon atoms, preferably a cycloalkyl group having a cycloalkyl group of from 3 to 6 carbon atoms; for example but not limited to ) cyclopropyl.
  • an alkyl or cycloalkyl group can be substituted, for example by a halogen.
  • a halogen-substituted C 1 -C 3 alkyl group is preferred.
  • alkoxy refers to an oxy group substituted with an alkyl group.
  • Preferred alkoxy groups are alkoxy groups of 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and the like.
  • the alkoxy group can be substituted, for example by a halogen.
  • a halogen-substituted C 1 -C 3 alkoxy group is preferred.
  • heterocyclyl includes, but is not limited to, a 5- or 6-membered heterocyclic group containing from 1 to 3 heteroatoms selected from O, S or N, including but not limited to furyl, thienyl, pyrrolyl, Pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, piperidinyl, morpholinyl, isodecyl and the like.
  • a heterocyclic group can be substituted, for example, by a halogen.
  • amino refers to a group of the formula "NR a R b ", wherein R a and R b may be independently selected from H or an optionally substituted C 1 -C 6 alkyl group, for example, C 1 -C 6 haloalkyl. In specific embodiments herein the “amino” may be -NH 2.
  • halogen refers to fluoro, chloro, bromo and iodo. In a preferred embodiment, the halogen is chlorine or fluorine.
  • Carboxy or “carboxylic acid group” refers to a group of the formula “R c -COOH” wherein R c is optionally substituted C 1 -C 3 alkyl. In a specific embodiment, “carboxy” or “carboxylic acid group” means "-COOH”.
  • ester group or “carboxylate group” refers to a group of the formula “R c -COOR d ", wherein R c is as defined above; R d is optionally substituted C 1 -C 3 alkyl.
  • substituents which may be substituted for other groups include, but are not limited to, hydroxyl, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy , phenyl, amino, nitro.
  • the present invention provides a compound having a common parent core which is capable of binding SIRP ⁇ , thereby blocking the interaction of SIRP ⁇ with CD47. These compounds are low in toxicity and safe.
  • the invention provides a compound of Formula I, or a pharmaceutically acceptable salt, prodrug, solvate thereof,
  • Y is selected from N or C, wherein when Y is N, R 3 is absent;
  • R 1 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, halogen, optionally substituted C 1 -C 10 alkoxy, optionally substituted C 6 -C 10 aryl, optionally substituted Benzyl, nitro, CN;
  • R 2 is selected from the group consisting of hydrogen, C 1 -C 10 alkyl or cycloalkyl, halogen, C 1 -C 10 alkoxy, optionally substituted C 6 -C 10 aryl, NR a R b , Wherein R a and R b are independently selected from the group consisting of: hydrogen, optionally substituted C 1 -C 6 alkyl;
  • R 1 and R 2 may be joined to form Wherein n is an integer from 1 to 3;
  • R 3 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 10 alkoxy, optionally substituted alkylthio;
  • R 4 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted benzyl ;
  • R 3 and R 4 form an optionally substituted six-membered ring, or an optionally substituted oxygen-containing or sulfur-containing six-membered heterocyclic ring;
  • R 5 is selected from the group consisting of: hydrogen, optionally substituted C 1 -C 10 alkyl, halogen;
  • R 6 is selected from the group consisting of: H, R c —COOH, R c —COOR d , R c —CONR 8 R 9 , optionally substituted hydroxy C 1 -C 3 alkyl;
  • R c is absent or optionally substituted -(CH 2 ) m -, m is an integer selected from 1 to 3;
  • R d is an optionally substituted C 1 -C 3 alkyl group;
  • R 8 and R 9 Independently selected from: H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 6 -C 10 aryl;
  • R 7 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, halogen, amino.
  • the compound of the invention is as shown in Formula II,
  • R 1 is selected from the group consisting of: hydrogen, optionally substituted C 1 -C 10 alkyl, halogen, optionally substituted C 6 -C 10 aryl;
  • R 2 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, An optionally substituted C 6 -C 10 aryl group, NR a R b , wherein R a and R b are as defined above;
  • R 3 is selected from the group consisting of: hydrogen, halogen, optionally substituted C 1 -C 10 alkoxy;
  • R 4 is selected from the group consisting of: an optionally substituted cyclopropyl, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted phenyl group, an optionally substituted benzyl group;
  • R 3 and R 4 form an optionally substituted six-membered ring
  • R 7 is selected from the group consisting of hydrogen and amino groups
  • Y is selected from: C or N, wherein when Y is N, R 3 is absent.
  • R 3 and R 4 may form a ring to form a compound of the following formula III.
  • R 1 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, halogen;
  • R 2 is selected from the group consisting of hydrogen
  • R 7 is selected from the group consisting of hydrogen and amino groups
  • R 10 is selected from the group consisting of: hydrogen, optionally substituted C 1 -C 10 alkyl;
  • Z is selected from: C, O, S;
  • R 6 is as defined above.
  • the compound of the invention is a compound of formula IV, or a pharmaceutically acceptable salt, prodrug, solvate thereof,
  • R 1 is selected from the group consisting of hydrogen, halogen (preferably F or Cl), optionally substituted C 1 -C 10 alkyl (preferably C 1 -C 6 alkyl, more preferably C 1 -C 3 alkyl), nitro, Optionally substituted C 6 -C 10 aryl (preferably phenyl), cyano;
  • R 2 is selected from the group consisting of: an optionally substituted substituted phenyl, butyl, morpholinyl, piperidinyl, piperazinyl, NR a R b ; R a and R b are independently selected from: hydrogen, optionally substituted C 1 -C 6 alkyl;
  • R 4 is selected from the group consisting of: an optionally substituted C 3 -C 8 cycloalkyl group (preferably an optionally substituted cyclohexyl group), an optionally substituted C 1 -C 6 alkyl group (for example, an optionally substituted butyl group), (CH 2 ) o - optionally substituted phenyl (preferable ), optionally replaced o is an integer selected from 0-2;
  • R 6 is selected from the group consisting of: COOH, C(O)-OC 1 -C 4 alkyl (preferably COOCH 3 or COOCH 2 CH 3 ), CONR 8 R 9 , CONHC 6 H 5 , CH 2 OH;
  • R 8 and R 9 are independently selected from: H, optionally substituted C 1 -C 10 alkyl (preferably optionally substituted C 1 -C 6 alkyl), optionally substituted C 6 -C 10 aryl (preferably Optionally substituted phenyl).
  • the formula of the present invention also includes a compound in which a specific substituent in the compound specifically disclosed by the present invention is selected from other substituents in the formula; It will also be understood by those skilled in the art that such compounds are capable of obtaining and capable of having the same or similar activities as the compounds specifically disclosed in the Examples. Thus, in particular embodiments, all of the substituents in the formula of the invention may each be a corresponding group in any of the compounds specifically disclosed herein.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • Examples of pharmaceutically acceptable salts of the compounds of the invention include, but are not limited to, inorganic and organic acid salts such as the hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate salts. , fumarate, mandelate and oxalate; and inorganic and formed with bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methylglucamine Organic base salt. While each person's needs vary, one skilled in the art can determine the preferred dosage for every 10 active ingredients in the pharmaceutical compositions of the present invention.
  • inorganic and organic acid salts such as the hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate salts. , fumarate, mandelate and oxalate
  • bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methylglucamine Organic base
  • a unit oral dose can include from about 0.01 to 50 mg, preferably from about 0.1 to 10 mg, of a compound of the invention.
  • the unit dose may be administered one or more times per day in one or more tablets, each tablet containing from about 0.1 to 50 mg, conveniently from about 0.25 to 10 mg of the compound of the invention or a solvate thereof.
  • the pharmaceutical composition of the present invention can be formulated into a form suitable for various administration routes, including but not limited to being formulated for parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial A form of administration, intranasal or topical, for the treatment of tumors and other diseases.
  • the amount administered is an amount effective to ameliorate or eliminate one or more conditions.
  • an effective amount is an amount sufficient to ameliorate or in some way alleviate the symptoms associated with the disease.
  • Such doses can be administered as a single dose or can be administered according to an effective therapeutic regimen.
  • the amount administered may cure the disease, but administration is usually to improve the symptoms of the disease.
  • the dosage of the drug will be determined by the age of the patient, the health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.
  • the pharmaceutical preparation of the present invention can be administered to any mammal as long as they can obtain the therapeutic effect of the compound of the present invention. Important among these mammals is humans.
  • the compounds of the invention or pharmaceutical compositions thereof are useful for treating diseases mediated by the interaction of SIRP ⁇ with CD47.
  • the disease mediated by the interaction of SIRP ⁇ and CD47 is various cancers.
  • the cancer includes, but is not limited to, melanoma, lung cancer (preferably non-small cell lung cancer), kidney cancer, ovarian cancer, prostate cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, Rectal cancer, anal cancer, gastric cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system Cancer, thyroid cancer, parathyroid carcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, acute myeloid leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, pediatric solid tumor, lymphocytic lymph Tumor, bladder cancer, kidney or ureteral cancer, renal pelvic cancer, central nervous system (CNS) tumor,
  • the pharmaceutical or pharmaceutical preparation of the invention can be produced in a known manner. For example, it is manufactured by a conventional mixing, granulating, tableting, dissolving, or freeze drying process. In the manufacture of oral formulations, the mixture can be selectively milled by combining the solid adjuvant with the active compound. If necessary or necessary, after adding an appropriate amount of auxiliary agent, the mixture of particles is processed to obtain a tablet or tablet core.
  • Suitable excipients are, in particular, fillers, such as sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate; and binders, such as starch pastes, including corn starch.
  • a disintegrating agent such as the above-mentioned starch, and carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added.
  • Adjuvants are especially flow regulators and lubricants, for example, silica, talc, stearates such as calcium magnesium stearate, stearic acid or polyethylene glycol.
  • the tablet core can be provided with a suitable coating that is resistant to gastric juice.
  • a concentrated sugar solution can be applied.
  • This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, a lacquer solution and a suitable organic solvent or solvent mixture.
  • a suitable cellulose solution such as cellulose acetate phthalic acid or hydroxypropyl methylcellulose phthalic acid can be used.
  • a dye or pigment can be added to the coating of the tablet or tablet core. For example, a combination for identifying or for characterizing the dosage of an active ingredient.
  • the pharmaceutical compositions of the present invention are in a dosage form suitable for oral administration, including, but not limited to, tablets, solutions, suspensions, capsules, granules, powders.
  • the invention further provides a method of treating a disease mediated by the interaction of SIRP ⁇ with CD47, the method comprising administering to a subject in need thereof a compound or pharmaceutical composition of the invention.
  • Methods of administration include, but are not limited to, various methods of administration well known in the art, which can be determined based on the actual circumstances of the patient. These methods include, but are not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, nasal or topical routes of administration.
  • the invention also encompasses the use of a compound of the invention in the manufacture of a medicament for the prophylaxis or treatment of a disease mediated by the interaction of SIRP ⁇ with CD47.
  • the present inventors have for the first time discovered that a series of compounds can bind to SIRP ⁇ , thereby blocking the interaction of SIRP ⁇ with CD47;
  • the compound of the present invention is a highly effective and low-toxic SIRP ⁇ blocker, and thus has important academic value and practical significance.
  • the product of the previous step (65 mg, 0.18 mmol) and anhydrous piperazine (62 mg, 0.72 mmol) were added to a 25 mL reaction flask, dissolved in pyridine, and slowly refluxed under stirring. After reacting for 8 hours, the pyridine was distilled off under reduced pressure to obtain The crude product was heated to reflux with 1 mL of ethanol, and after 30 minutes, it was cooled to room temperature, and the solid was precipitated, suction filtered, washed with a small amount of ethanol, and dried. 20 mg of a pale yellow solid was obtained in a yield of 27%. The yield was low, and the product was also obtained by esterification with the purchased bulk drug, with a yield of 66.3%.
  • the ethyl ester product (100 mg, 0.26 mmol) was placed in a 25 mL reaction flask, 5% NaOH solution was added, and refluxed at 100 ° C. After 4 hours, the reaction was completed, pH was adjusted to 2 to 3, solids were precipitated, suction filtered, washed with water, and dried. Dry to give a pale yellow solid (yield: 55 mg).
  • the ethyl ester product (0.315 mg, 0.87 mmol), cesium fluoride (0.143 mg, 0.87 mmol), phenylboronic acid (0.184 mg, 1.13 mmol) was placed in a 50 mL three-necked flask, dissolved in toluene, and deoxygenated for 15 minutes. The amount of palladium catalyst was deoxygenated for 15 minutes, and heated under reflux with argon.
  • the ethyl ester product (500 mg, 1.37 mmol) was placed in a 100 mL reaction flask, and a 5% NaOH solution was added thereto, and refluxed at 100 ° C. After 4 hours, the reaction was completed, pH was adjusted to 2 to 3, solids were precipitated, suction filtered, washed with water, and dried. Dry to give 296 mg of a white solid (yield: 64.14%).
  • the acetate (80 mg, 0.19 mmol) of the above-mentioned drug substance was dissolved in methanol, and a methanol solution containing NaBH 4 (29 mg, 0.76 mmol) was added dropwise thereto, and the mixture was stirred for 1 hour, and a catalytic amount of p-toluenesulfonic acid was added thereto, followed by heating to reflux.
  • the binding constant of the compound of the present invention to SIRP ⁇ was determined by surface plasmon resonance.
  • the following compounds 1-24 used in this example were purchased from Aladdin Corporation.
  • the surface plasmon resonance (SPR) experiment was performed using a Biacore T200 to determine the binding constant between the compound of the present invention and the human SIRP ⁇ protein.
  • the specific experimental steps are as follows: First, the purchased SIRP ⁇ protein (Beijing Yiqiao Shenzhou Biotechnology Co., Ltd.) was diluted to 50 ⁇ g/ml with sodium acetate pH 4.5, and the protein was coupled to the CM7 chip using an amino coupling kit to 10 ⁇ l. The flow rate of /min is combined for 600 s and the final coupling amount is approximately 15000 RU.
  • the CM7 chip was equilibrated to a steady state with a buffer (1.05 x PBS, 0.05% P20).
  • the compound was then diluted with running buffer (1.05 x PBS, 0.05% P20, 1% DMSO) to a range of different concentrations, with running buffer flowing through the surface of the chip at a flow rate of 30 ⁇ L/min, a binding time of 90 s, and a dissociation time of 120 s.
  • running buffer (1.05 x PBS, 0.05% P20, 1% DMSO)
  • This example investigates the binding affinities of the 13 compounds of the invention to the SIRP ⁇ protein.
  • Biacore T200 CM5 sensor chip, maintenance chip, Biacore maintenance kit type 2, dimethyl sulfoxide (DMSO), filter head (0.22 ⁇ M), 10X HBS, amino coupling kit.
  • DMSO dimethyl sulfoxide
  • the protein is coupled to the surface of the CM5 chip, and when the analyte flows through the surface with the solution, binding to the coupled protein produces a response signal, the response signal and the amount of analyte bound to the sensor chip. In direct proportion.
  • the K D value was obtained by steady state fitting.

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Abstract

La présente invention concerne un composé en tant qu'agent de blocage de l'interaction CD47/SIRPα. En particulier, la présente invention concerne un composé représenté par la formule I suivante, une composition pharmaceutique comprenant le composé de formule I, et des utilisations du composé dans le traitement d'une maladie induite par l'interaction CD47/SIRPα, ainsi que dans la préparation d'un médicament destiné au traitement d'une maladie induite par l'interaction CD47/SIRPα.
PCT/CN2018/103974 2017-09-04 2018-09-04 AGENT DE BLOCAGE DE CD47/SIRPα ET APPLICATION ASSOCIÉE Ceased WO2019042470A1 (fr)

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