WO2019057123A1 - 作为ido抑制剂和/或ido-hdac双重抑制剂的多环化合物 - Google Patents

作为ido抑制剂和/或ido-hdac双重抑制剂的多环化合物 Download PDF

Info

Publication number
WO2019057123A1
WO2019057123A1 PCT/CN2018/106768 CN2018106768W WO2019057123A1 WO 2019057123 A1 WO2019057123 A1 WO 2019057123A1 CN 2018106768 W CN2018106768 W CN 2018106768W WO 2019057123 A1 WO2019057123 A1 WO 2019057123A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
alkyl
cycloalkyl
membered
Prior art date
Application number
PCT/CN2018/106768
Other languages
English (en)
French (fr)
Inventor
张汉承
叶向阳
Original Assignee
杭州英创医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 杭州英创医药科技有限公司 filed Critical 杭州英创医药科技有限公司
Priority to US16/649,455 priority Critical patent/US11266640B2/en
Priority to CN201880002070.7A priority patent/CN109843872B/zh
Priority to JP2020516814A priority patent/JP2020534336A/ja
Priority to EP18857966.8A priority patent/EP3686196A4/en
Publication of WO2019057123A1 publication Critical patent/WO2019057123A1/zh

Links

Classifications

    • 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
    • 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
    • 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
    • A61K31/495—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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • 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
    • 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
    • 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
    • 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
    • C07D215/04—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • 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
    • C07D215/04—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
    • 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
    • C07D215/12—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • 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
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • This invention relates to polycyclic compounds, to processes for their preparation and to their use as IDO inhibitors.
  • Indoleamine 2,3-dioxygenase is a catalyzed cleavage of guanidine urate pathway in guanamine molecules such as tryptophan. Speed enzyme.
  • IDO plays an important role in tumor immune exemption and tumorigenesis. Under normal circumstances, IDO is expressed at a low level in the body, and most tumor cells constitute a high expression of IDO, which converts L-tryptophan to N-formyl kynurenine, which reduces the color in the cell microenvironment. The concentration of tryptophan makes the tryptophan-dependent T cell synthesis arrest in the G1 phase, and the proliferation of T cells is inhibited, thereby inhibiting the killing effect of the body's immune system on tumor tissues. At the same time, the metabolite of tryptophan under the action of IDO is cytotoxic and can directly dissolve T cells.
  • IDO inhibitors can effectively prevent the degradation of tryptophan around the tumor cells, promote the proliferation of T cells, and thereby enhance the body's ability to attack tumor cells.
  • IDO inhibitors can also be combined with chemotherapeutic drugs to reduce the resistance of tumor cells, thereby enhancing the anti-tumor activity of conventional cytotoxic therapies.
  • Simultaneous administration of IDO inhibitors can also increase the efficacy of therapeutic vaccines for cancer patients.
  • IDO is also closely associated with the pathogenesis of a variety of diseases associated with cellular immune activation. IDO has been identified as a target for major diseases such as infections, malignancies, autoimmune diseases, and AIDS associated with cellular immune activation.
  • inhibition of IDO is an important therapeutic strategy for patients with neurological diseases such as depression and Alzheimer's disease. Therefore, IDO inhibitors have broad clinical application prospects.
  • HDAC histone acetyltransferase
  • the acetylation of histones reverses the acetylation of lysine residues of HAT and restores the positive charge of lysine residues, which facilitates the dissociation of DNA and histone octamers, and the relaxation of nucleosome structures, thus making various Transcription factors and co-transcription factors bind specifically to the DNA binding site and activate transcription of the gene. Due to the overexpression of HDAC in tumor cells, the deacetylation of histones is enhanced. By restoring the positive charge of histones and increasing the gravitation between DNA and histones, the relaxed nucleosomes become very tight, which is not conducive to specific Gene expression, including some tumor suppressor genes.
  • HDAC inhibitors can regulate the expression and stability of apoptosis and differentiation-related proteins by increasing histone acetylation in specific regions of chromatin, induce tumor cell cycle arrest and apoptosis, promote tumor cell autophagy, and inhibit The formation of tumor angiogenesis promotes the immunogenicity of tumor cells.
  • HDAC inhibitors not only become a targeted therapy for tumors, but also play a role in neurological diseases, inflammation, and promotion of autoimmunity. Preclinical and clinical studies have shown that HDAC inhibitors can also effectively synergistically inhibit tumor growth when combined with other anti-tumor compounds.
  • HDAC is responsible for removing acetyl groups on histones, gene expression, and oncoproteins. Stability, cell migration, protein catabolism, and cell cycle regulation have significant effects.
  • X is a bond, NH, N(C 1-4 alkyl), O, C(O), C(S), C(O)NH, C(O)O, or C(O)NCH 3 ;
  • Y is a bond, NH, N(C 1-4 alkyl), O, C(O), C(S), or C(O)NH;
  • A is C 6-10 aryl, 5- to 15-membered heteroaryl, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl (including single a ring, a spiro ring, a cyclo ring, a bridged ring, etc.), or a 4- to 20-membered heterocyclic group (including a monocyclic ring, a spiro ring, a ring, a bridged ring, etc., preferably a 4- to 10-membered heterocyclic group);
  • B is a C 3-8 monocycloalkyl group, having one to more 4- to 8-membered monocyclic heterocyclic groups selected from N, O, S, C 7-12 polycycloalkyl, or one to a plurality of 5- to 12-membered polycyclic heterocyclic groups selected from N, O, and S;
  • polycyclic alkyl or polycyclic heterocyclic groups herein refers to saturated or partially unsaturated rings of more than one ring. Structure, including spiro, parallel, bridge, etc.; and when B is When s can only be 1, then R 3 in CR 2 R 3 is none;
  • E is a C 6-10 aryl group, a 5- to 10-membered heteroaryl group, a 1-5 ring heterocyclic group selected from N, O, S, a C 4-8 naphthenic group. And aryl, or C 4-8 cycloalkylheteroaryl, or a 5- to 10-membered heterocyclic group selected from N, O, S, and an aryl or heteroaryl base;
  • Each R 1 is independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 alkyl, hydroxy, C 1-4 alkoxy, hydroxy C 1-4 alkyl, hydroxy C 1-4 alkoxy , C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl (including monocyclic, spiro, polycyclic, bridged, etc.), 4- to 10-membered heterocyclic (including single ring) , spiro ring, ring, bridge ring, etc.), NR 10 R 11 , cyano group, C(O)R 12 , C(O)NR 10 R 11 , OC(O)NR 10 R 11 , NR 10 C(O NR 10 R 11 , NR 10 SO 2 R 12 , NR 10 SO 2 NR 10 R 11 , CO 2 R 13 , halogenated C 1-4 alkyl, C 1-4 alkoxy C 1-4 alkyl, Halogenated C 1-4 alkoxy,
  • the precondition is that the definition of R 1 above should be related to the definition of A to ensure that the formed structure is a stable chemical structure;
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo C 1-8 alkyl, C 3-8 naphthenic a group comprising 1-2 4- to 8-membered heterocyclic groups selected from N, O or S, a C 6-10 aryl group, a 5- to 10-membered heteroaryl group, a C 3-6 cycloalkyl group C 1-4 alkyl, having 1-2 4- to 8-membered heterocyclic C 1-4 alkyl groups selected from N, O or S, C 6-10 aryl C 1-4 alkyl, 5- To 10-membered heteroaryl C 1-4 alkyl, fluorine, OH, CN, CO 2 H, C(O)NH 2 , NR 10 R 11 , C 1-4 alkoxy, (CR 8 R 9 ) p -OH, (CR 8 R 9 ) p -Z-(CR 8 R 9
  • R 2 and a carbon atom attached to R 2 together with one or two carbon atoms on B form a C 3-6 cycloalkyl group or contain 1-2 3- to 6-members selected from N, O or S a heterocyclic group, such a cyclic structure is a spiro ring or a fused ring;
  • R 2 and R 3 must ensure that a stable chemical structure is formed together with other groups (including X and Y, and B and A);
  • Each R 6 is independently hydrogen, deuterium, halogen, C 1-4 alkyl, hydroxy, CN, C 1-4 alkoxy;
  • R 7 is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 8-membered heterocyclic group, C(O)C 1-4 alkyl, C(O)C 3-6 ring alkyl;
  • R 8 and R 9 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 alkyl, hydroxy, CN, C 1-4 alkoxy;
  • R 10 and R 11 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 3-8 cycloalkyl, 4- to 8-membered heterocyclic, 6-membered aryl, 5- to a 6-membered heteroaryl group, a C 1-4 alkoxy C 1-4 alkyl group, a bis(C 1-4 alkyl)amino C 1-4 alkyl group, wherein a cycloalkyl group, a heterocyclic group, an aryl group, Or a heteroaryl group is optionally substituted by from 1 to 3 R 14 , wherein R 14 is as defined above; or R 10 and R 11 together form a 4- to 8-membered ring together with the nitrogen atom to which they are attached.
  • the cyclic structure may additionally contain 0-2 heteroatoms selected from N, O, and S, provided that the cyclic structure formed is a stable structure. This cyclic structure is optionally substituted with from 1 to 3 R 14 ;
  • R 12 is C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 4- to 8-membered heterocyclic, 6-membered aryl, 5- To a 6-membered heteroaryl;
  • R 13 is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 8-membered heterocyclic group selected from N, O, S, 6-membered aryl, 5- to 6-membered heteroaryl; the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups herein may be optionally substituted by halogen, CN, hydroxy as long as the structure formed is a stable structure. ;
  • R 14 is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, 4- to 8-membered heterocyclic group selected from N, O, S, 6-membered aryl, 5- to 6-membered heteroaryl;
  • n 0, 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • o 0, 1, 2 or 3;
  • p 0, 1, 2, 3 or 4;
  • q 0, 1, 2 or 3;
  • r 0, 1, 2, 3 or 4;
  • s is 0 or 1;
  • B is a C 3-8 monocycloalkyl group or a one to more 4- to 8-membered monocyclic heterocyclic group selected from N, O, S, and R 1 , R 2 and R 3
  • A is not a group selected from the group consisting of phenyl, 5- to 6-membered heteroaryl, C 5-7 cycloalkyl;
  • R 1 , R 2 and R 3 do not contain a C(O)-NH-OH group means that R 1 , R 2 and R 3 are not C(O)-NH-OH groups, And the C(O)-NH-OH structural fragment is not included in the R 1 , R 2 and R 3 groups)
  • each of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups is optionally and independently independently substituted with from 1 to 3 each independently selected from the group consisting of Base substitution: hydrogen, hydrazine, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-4 alkyl, C 3-8 cycloalkyl, containing 1- 2 4- to 8-membered heterocyclic groups selected from N, O or S, C 6-10 aryl, 5- to 10-membered heteroaryl, OH, CN, NO 2 , OR 13 , SR 13 , N(R 7 ) 2 , C(O)R 12 , CO 2 R 13 , CONR 10 R 11 , SO 2 NR 10 R 11 ; in the substituent, the definition of each group is as described above.
  • the compound of the formula (I) in the present patent application does not include the compounds of the following published patent applications: WO2015188085, WO2016073738, WO2016073770, WO2016073774, WO2017192840, WO2017192844, WO2017192845, WO20171928.
  • X is NH, N(C 1-4 alkyl), O, C(O), C(O)O, C(O)NH, or C(O)NCH 3 ;
  • Y is NH, N(C 1-4 alkyl), O, C(O), or C(O)NH;
  • X is NH, C(O)NH, or C(O).
  • Y is C(O) or NH.
  • the prerequisite is that the structure formed by the combination of X and Y is a stable chemical structure.
  • Y-X is the following combination:
  • Y-X is the following combination:
  • R 2 is hydrogen, deuterium or fluorine
  • R 3 is C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-4 alkyl, Hydroxy, C 1-4 alkoxy, C 3-6 cycloalkyl, (CR 8 R 9 ) p -Z-(CR 8 R 9 ) r -CO 2 H, (CR 8 R 9 ) p -Z- (CR 8 R 9 ) r -C(O)NHOH.
  • R 2 and R 3 are each independently selected from the group consisting of methyl, or R 2 and R 3 together with the carbon atom to which they are attached form a cyclopropyl group.
  • B is the following structure:
  • A is a C 6-10 aryl group, a 5- to 15-membered heteroaryl group, a C 3-10 cycloalkyl group, a 4- to 15-membered heterocyclic group, or A is the following structure:
  • each R 1 is independently halogen, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, cyano, C ( O) R 12 , NR 10 SO 2 NR 10 R 11 , CO 2 R 13 , CONR 10 R 11 , halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, (CR 8 R 9 ) n -C(O)-NHOH,
  • E is a C 6 - 10 aryl group, a 5- to 10-membered heteroaryl group, and a 5- to 10-membered heterocyclic group having 1-3 members selected from N, O, and S. , or E is the following structure:
  • E is the following structure:
  • B is selected from the group consisting of:
  • the compound has the following structure:
  • T 1 and T 2 are each independently selected from CR 15 or N, wherein R 15 is H, F, or OH;
  • YX is selected from the following combinations:
  • the compound has the following structure:
  • YX is selected from the following combinations:
  • the compound has the following structure:
  • T 1 and T 2 are each independently selected from CR 15 or N, wherein R 15 is H, F, or OH, and YX is selected from the group consisting of:
  • the compound has the following structure:
  • YX is selected from the following combinations:
  • the compound has the following structure:
  • G 1 is selected from the group consisting of:
  • the G2 is selected from the group consisting of:
  • the G1 is selected from the group consisting of:
  • the G2 is selected from the group consisting of:
  • each group is a corresponding group in a particular compound of the examples.
  • the compound of formula (I) has a structure selected from the group consisting of:
  • all olefinic linkage configurations include the cis configuration and the trans configuration. Furthermore, when two substituents are simultaneously on one saturated ring (including the ring), it is possible to produce cis and trans configurations, which are also within the scope of the present invention.
  • the tumor is selected from the group consisting of lung cancer, bladder cancer, breast cancer, gastric cancer, liver cancer, salivary gland sarcoma, ovarian cancer, prostate cancer, cervical cancer, epithelial cell carcinoma, multiple myeloma, pancreatic cancer. Lymphoma, chronic myelogenous leukemia, lymphocytic leukemia, cutaneous T-cell lymphoma, etc.
  • a third aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: (i) a therapeutically effective amount of a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof; And (ii) a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises an effective component selected from the group consisting of a therapeutically effective amount of PD-1 and/or PD-L1.
  • a method for inhibiting IDO activity, and/or a method for dually inhibiting the activity of IDO-HDAC characterized in that the method comprises the step of administering an inhibitory effective amount of the inhibitory subject to the present invention.
  • the inhibition is IDO selective inhibition.
  • the inhibition is IDO-HDAC selective inhibition.
  • the inhibition of IDO activity is non-therapeutic inhibition in vitro.
  • the inhibition of IDO-HDAC activity is non-therapeutic inhibition in vitro.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: the compound I according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, and optionally Antibody PD-1 or PD-L1 or CTLA-4.
  • the pharmaceutical composition is for treating cancer.
  • the cancer is selected from the group consisting of breast cancer, lymphoma, leukemia, lung cancer, ovarian cancer, cervical cancer, testicular cancer, liver cancer, melanoma, colon cancer, rectal cancer, renal cell carcinoma , small bowel cancer and esophageal cancer, head and neck cancer, bladder cancer, prostate cancer, pancreatic cancer, or pharyngeal cancer.
  • the ⁇ in the middle represents a double key.
  • the present inventors After long-term and intensive research, the present inventors have unexpectedly discovered a class of polycyclic compounds having IDO inhibitory activity and/or dual inhibitory activity of IDO-HDAC, and thus can be used for the preparation of therapeutic and IDO and/or HDAC activities or expression levels.
  • a pharmaceutical composition of a related disease Based on the above findings, the inventors completed the present invention.
  • each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • alkyl refers to a straight (ie, unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of straight and branched chains. .
  • the alkyl group has a carbon number limitation (e.g., C 1-10 ) it means that the alkyl group has 1 to 10 carbon atoms.
  • C 1-8 alkyl refers to an alkyl group containing from 1 to 8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or Similar group.
  • alkenyl when used alone or as part of another substituent, refers to a straight or branched, carbon chain group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When the alkenyl group has a carbon number limitation (e.g., C 2-8 ), it means that the alkenyl group has 2 to 8 carbon atoms. For example, C 2-8 alkenyl refers to an alkenyl group having 2-8 carbon atoms, including ethenyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or the like. group.
  • C 2-8 alkenyl refers to an alkenyl group having 2-8 carbon atoms, including ethenyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or the like. group.
  • alkynyl when used alone or as part of another substituent, refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond.
  • the alkynyl group can be straight or branched, or a combination thereof.
  • the alkynyl group has a carbon number limitation (e.g., C 2-8 alkynyl group), it means that the alkynyl group has 2 to 8 carbon atoms.
  • C 2-8 alkynyl refers to a straight or branched alkynyl group having 2-8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, A sec-butynyl group, a tert-butynyl group, or the like.
  • cycloalkyl refers to a unit ring having a saturated or partially saturated ring, a bicyclic or polycyclic (fused ring, bridged or spiro) ring system. .
  • a certain cycloalkyl group has a carbon number limitation (e.g., C 3-10 )
  • C 3-8 cycloalkyl refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having from 3 to 8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentane.
  • Spirocycloalkyl refers to a bicyclic or polycyclic group that shares a carbon atom (called a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings have fully conjugated ⁇ electrons. system.
  • Fused cycloalkyl means an all-carbon bicyclic or polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more Key, but none of the rings have a fully conjugated ⁇ -electron system.
  • “Bridge cycloalkyl” refers to an all-carbon polycyclic group in which two rings share two carbon atoms that are not directly bonded, which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system .
  • the atoms contained in the cycloalkyl group are all carbon atoms.
  • Aryl means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a conjugated ⁇ -electron system, such as phenyl and naphthyl.
  • the aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings), but may not contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be in a conjugated pi-electron system.
  • the aryl group can be substituted or unsubstituted. The following are some examples of aryl groups, and the present invention is not limited to the aryl groups described below.
  • Heteroaryl refers to a heteroaromatic group containing one to more heteroatoms.
  • the heteroatoms referred to herein include oxygen, sulfur, and nitrogen.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring.
  • the heteroaryl group can be optionally substituted or unsubstituted.
  • the following are some examples of heteroaryl groups, and the present invention is not limited to the following heteroaryl groups. Among them, the last three heteroaryl groups are tricyclic heteroaryl groups, which are the focus of the present invention.
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more of the ring atoms are selected from nitrogen, oxygen or sulfur and the remaining ring atoms are carbon.
  • monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl.
  • Polycyclic heterocyclic group refers to a heterocyclic group including a spiro ring, a fused ring, and a bridged ring.
  • Spirocyclic heterocyclyl refers to a polycyclic heterocyclic group in which each ring of the system shares an atom (referred to as a spiro atom) with other rings in the system, wherein one or more of the ring atoms is selected from the group consisting of nitrogen and oxygen. Or sulfur, the remaining ring atoms are carbon.
  • “Fused ring heterocyclyl” refers to a polycyclic heterocyclic group in which each ring of the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none One ring has a fully conjugated pi-electron system, and wherein one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon.
  • “Bridged heterocyclyl” refers to a polycyclic heterocyclic group in which any two rings share two atoms which are not directly bonded, these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system And wherein one or more of the ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. If a heterocyclic group has both a saturated ring and an aromatic ring (for example, the saturated ring and the aromatic ring are fused together), the point attached to the parent must be on the saturated ring. Note: When the point attached to the parent is on the aromatic ring, it is called a heteroaryl group and is not called a heterocyclic group. Some examples of the heterocyclic group are as follows, and the present invention is not limited to the following heterocyclic group.
  • halogen when used alone or as part of another substituent, refers to F, Cl, Br, and I.
  • substituted when with or without “optionally” means that one or more hydrogen atoms on a particular group are replaced by a particular substituent.
  • Particular substituents are the substituents described above in the corresponding paragraphs, or the substituents which appear in the examples.
  • an optionally substituted group may have a substituent selected from a particular group at any substitutable position of the group, and the substituents may be the same or different at each position.
  • a cyclic substituent, such as a heterocyclic group may be attached to another ring, such as a cycloalkyl group, to form a spirobicyclic ring system, i.e., the two rings have a common carbon atom.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents are, for example but not limited to, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclic , aryl, heteroaryl, halogen, hydroxy, carboxy (-COOH), C 1-8 aldehyde, C 2-10 acyl, C 2-10 ester, amino.
  • a pharmaceutically acceptable salt of a compound of the invention refers to a salt that is suitable for contact with the tissue of a subject (eg, a human) without causing unpleasant side effects.
  • a pharmaceutically acceptable salt of a compound of the invention includes a salt (eg, a potassium salt, a sodium salt, a magnesium salt, a calcium salt) of a compound of the invention having an acidic group or is basic A salt of a compound of the invention (e.g., a sulfate, a hydrochloride, a phosphate, a nitrate, a carbonate).
  • the compound of the formula I of the present invention can be produced by the following method, however, the conditions of the method, such as the reactant, the solvent, the base, the amount of the compound used, the reaction temperature, the time required for the reaction, and the like are not limited to the following explanations.
  • the compounds of the present invention may also be conveniently prepared by combining various synthetic methods described in the specification or known in the art, and such combinations are readily made by those skilled in the art to which the present invention pertains.
  • each reaction is usually carried out in an inert solvent at a reaction temperature of -78 ° C to 150 ° C (preferably 20 to 120 ° C).
  • the reaction time in each step is usually from 0.5 to 48 h, preferably from 2 to 12 h.
  • Reaction Scheme A-1 describes a general synthetic method for Compound A11:
  • Reaction Scheme A-2 describes a general synthetic method for Compound A13:
  • Reaction Scheme A-3 describes another general synthetic method for Intermediate A9:
  • Reaction Scheme A-4 describes a general chiral synthesis method for Compound A20:
  • A20 here is one of the chiral enantiomers of A13.
  • the preparation of the other enantiomer can be carried out according to the above reaction formula using another chiral induction reagent (also known as Evans chiral auxiliary).
  • R 102 is usually a phenyl group or a benzyl group.
  • the compound B7 here is a racemate.
  • the two optically pure single enantiomers of B7 can be prepared by the method of Reaction Scheme A-4 as needed.
  • Reaction Scheme B-2 describes a general synthetic method for Compound B14:
  • B14 can also be obtained by directly performing a substitution reaction with the intermediates B12 and B15.
  • L is a leaving group
  • Reaction Scheme C-2 describes another general synthetic method for intermediate C4.
  • Intermediate C4 is the key raw material for the preparation of compound C6:
  • L is a leaving group
  • L is a leaving group
  • the compounds D2 and D6 herein are racemates. Their respective two optically pure, single enantiomers can be separated by chiral preparative HPLC.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention and a pharmaceutically acceptable inorganic and organic acid, wherein preferred inorganic acids include, but are not limited to, hydrochloric acid, hydrogen Bromic acid, phosphoric acid, nitric acid, sulfuric acid; preferred organic acids include, but are not limited to: formic acid, acetic acid, propionic acid, succinic acid, naphthalene disulfonic acid (1, 5), asiamic acid, oxalic acid, tartaric acid, lactic acid , salicylic acid, benzoic acid, valeric acid, diethyl acetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, Gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic
  • pharmaceutically acceptable solvate refers to a compound of the invention that forms a solvate with a pharmaceutically acceptable solvent, wherein the pharmaceutically acceptable solvent includes, but is not limited to, water , ethanol, methanol, isopropanol, tetrahydrofuran, dichloromethane.
  • pharmaceutically acceptable stereoisomer means that the chiral carbon atom to which the compound of the invention relates may be in the R configuration, in the S configuration, or a combination thereof.
  • the compound of the present invention has excellent inhibitory activity against IDO
  • the compound of the present invention and various crystal forms thereof, a pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and a compound containing the present invention are main active ingredients.
  • the pharmaceutical composition can be used to treat, prevent, and alleviate diseases associated with IDO activity or expression levels.
  • the compounds of the present invention are useful for treating (but not limited to) various diseases such as lung cancer, bladder cancer, breast cancer, gastric cancer, liver cancer, salivary gland sarcoma, ovarian cancer, prostate cancer, cervical cancer, Epithelial cell carcinoma, multiple myeloma, pancreatic cancer, lymphoma, chronic myelogenous leukemia, lymphocytic leukemia, cutaneous T-cell lymphoma, etc.; bone-related diseases such as bone dysplasia, dysplasia, dwarfism, Crouzon syndrome; T cell-mediated inflammation and autoimmune diseases such as rheumatoid arthritis, collagen II arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, juvenile diabetes, Sjogren's syndrome , thyroid disease, sarcoidosis, inflammatory bowel disease, celiac disease and so on.
  • various diseases such as lung cancer, bladder cancer, breast cancer, gastric cancer, liver cancer, salivary gland s
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 5 to 200 mg of the compound of the invention per agent.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • vegetable oil such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyol such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifier such as Tween
  • a wetting agent such as sodium lauryl sulfate
  • a coloring agent such as a flavoring agent, a stabilizer, an antioxidant, a preservative
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration. .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 5 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • IDO inhibitors and/or dual inhibitors of IDO-HDAC which inhibits the activity of IDO at very low concentrations, and the preparation and use thereof.
  • a class of pharmaceutical compositions for treating diseases associated with IDO and/or IDO-HDAC activity is provided.
  • Compound 1 can be prepared by another synthetic route, and the specific reaction formula is as follows:
  • the above route uses triethyl-2-phosphonopropyl ester in the initial step to introduce a methyl group at the position of the carboxylic acid, and after a similar reaction, the ratio of the compound 1ag to the compound 1ah is about 5:1.
  • the cis-ester 1ag is subjected to basic hydrolysis to give the acid 1ai, which is then condensed with p-chloroaniline to give the racemic compound 1.
  • the racemic compound 1 was chiralized by SFC to give compounds 1A and 1B.
  • the absolute stereo configuration of peak 1 and peak 2 has not been determined.
  • Compound 1A is prepared from compound 1q, and detailed procedures can be found in the patents WO2016073774 and WO2016073770.
  • Tetrahydrofuran (0.5 mL) and LDA in tetrahydrofuran (2.0 M, 1.22 mL, 2.44 mmol) were placed in a dry round bottom flask, cooled to -78 ° C under nitrogen and N,N-dimethyl propylene was added.
  • a solution of the base urea (118 mg, 0.92 mmol) and 1j (0.2 g, 0.61 mmol) in tetrahydrofuran (0.5 mL) was stirred at -20 ° C for one hour. Methyl iodide (0.35 g, 2.44 mmol) was then added. Stirring was continued for 1 hour at this temperature.
  • Compound 5 was prepared from Compound 1k and 4-chloroaniline according to the above preparation method of Compound 2.
  • Trifluoroacetic acid (1.46 mL, 23.10 mmol) was slowly added to a solution of compound 9c (0.65 g, 2.31 mmol) in dichloromethane (2 mL) After completion of the reaction, the mixture was evaporated. The crude material was used in the next reaction without further purification.
  • Compound 10b was prepared from compound 10a according to the procedures of patents WO2016073774 and WO2016073770.
  • Compound 10c was prepared from compound 10b (for detailed procedures, see the preparation of 1o).
  • the compound 11 is a main product obtained by hydrating the compound 1h and condensing the obtained acid 11a and 4-chloroaniline.
  • 1 H NMR 500MHz, CD 3 OD
  • 7.67–7.50 m, 3H
  • the compound 20 is obtained by subjecting the intermediate 1k to hydrolysis to obtain 20a, followed by amide condensation reaction with the compound 19a.
  • LCMS m/z 4
  • 2-Amino-5-chloropyridine (17a, 45 mg, 0.35 mmol) was dissolved in tetrahydrofuran (3 mL).
  • EtOAc EtOAc
  • the petroleum solid compound 26 (54 mg, yield 43%) was obtained.
  • the racemic compound 26 was chiralized by SFC to give the compounds 26A and 26B.
  • the absolute stereo configuration of peak 1 and peak 2 has not been determined.
  • Compound 32a was prepared according to WO 2017/024996 A1. Cyclopropylpyrazole-4-boronic acid pinacol ester (100 mg, 0.42 mmol), 5-amino-2-bromopyridine (62 mg, 0.36 mmol), Pd(dppf) 2 Cl 2 (26 mg, 0.036 mmol) and Potassium carbonate (60 mg, 0.42 mmol) was dissolved in dioxane (4 mL) and water (1 mL), and the mixture was warmed to 100 ° C under nitrogen atmosphere and stirred at this temperature for 2 hours. The reaction mixture was extracted with EtOAc EtOAc (EtOAc m. Solid compound 32a (50 mg, yield 70%).
  • Compound 38 is prepared by a multi-step synthesis reaction from compound 38b, and the specific experimental procedure is referred to the synthesis step of compound 1.
  • compound 40 and compound 41 were obtained by a multi-step reaction according to the synthesis procedure of compound 1 and compound 38, followed by preparative thin-layer chromatography, in a ratio of 1.5:1.
  • Compounds 42 and 43 were prepared according to the methods of Compounds 40 and 41.
  • LCMS m/z 466.2 [M+H] + .
  • the compound 44c (1.90 g, 5.36 mmol) was dissolved in ethyl acetate (25 mL), and 10% Pd/C (200 mg) was added and reacted for 1 hour under a hydrogen atmosphere, and the conversion of the starting material 44c was completed by thin-plate chromatography.
  • the reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated.
  • the obtained crude product was purified (jjjjjlililili
  • the compound 46a (43 mg, 0.13 mmol) was dissolved in methanol (5 mL), and then a solution of lithium hydroxide (10M, 5mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour, and all of the starting material 46a was converted by thin-plate chromatography. The reaction mixture was concentrated. EtOAc (EtOAc m.
  • Oxalyl chloromethyl ester (576 mg, 4.70 mmol) was slowly added dropwise to p-chloroaniline (300 mg, 2.35 mmol), N,N-diisopropylethylamine (909 mg, 7.05 mmol) in dichloromethane. The reaction was allowed to rise to room temperature overnight, and the reaction was complete by TLC. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate, and ethyl acetate (3 ⁇ 30 mL). -10%, ethyl acetate: petroleum ether)yield Compound 47a (418 mg,yield: 83%).
  • the compound 53b is obtained from the compound 51c in two steps, and then reacted with the compound 53c to obtain the compound 53.
  • Compound 56a can be synthesized from compound 10a with reference to the preparation of compound 1 and compound 10.
  • Compound 61a was prepared according to the synthesis method of Compound 11a, and subjected to multiple column chromatography to give pure intermediates 61b and 61c.
  • Compound 61b is subjected to catalytic hydrogenation to give two isomers 66a and 66b which can be separated by multiple column chromatography, in a ratio of 10:1.
  • the stereo configuration of compound 66a is
  • Compound 78 is a small amount of by-product isolated during the preparation of compound 77 in Example 78.
  • LCMS m/z 486.2 [M+H] + .
  • the intermediate 83b is obtained by the reaction of 83a and 82a (refer to the preparation method of the compound 77 in Example 78).
  • the compound 84e was prepared by a multi-step synthesis with reference to the synthetic route of the compound 1. Catalytic hydrogenation of compound 84e gives main product 84f and the other three isomers (small amounts). In this step, these isomers are close to the main product, and silica gel column chromatography is difficult to separate, so the mixture Continued for the next reaction (ester hydrolysis and preparation of acid chloride), and finally in the preparation of the amide, these three small isomers can be separated by thin plate chromatography.
  • Trimethylsulfoxonium iodide 48 mg, 0.51 mmol
  • sodium hydride 24 mg, 0.41 mmol
  • DMF 1 mL
  • a solution of compound 92e 120 mg, 0.34 mmol
  • DMF 1.5 mL
  • EtOAc EtOAc
  • EtOAc EtOAc
  • the preparation method of the compound 93 is similar to the preparation method of the compound 92.
  • the preparation method of Compound 100 is similar to the preparation method of Compound 99.
  • the preparation method of Compound 101 is similar to the preparation method of Compound 26.
  • the preparation method of Compound 102 is similar to the preparation method of Compound 26.
  • Compound 1k is subjected to ester hydrolysis, formation of an acid chloride, and then reacted with compound 103a to give compound 103. Specifically, reference is made to the preparation method of Compound 26. LCMS m/z 472.2 [M+H] + .
  • Compound 105 is a by-product produced in the synthesis of compound 104, and is separated by a plurality of preparative thin-wall chromatography separations in the last step reaction due to the close proximity to the product.
  • Compound 92d is subjected to ester hydrolysis, formation of an acid chloride, and then reacted with compound 17a to give compound 107 (main product) and compound 108 (by-product). Specifically, reference is made to the preparation method of Compound 26. [Note: In these reactions, a decarburization reaction occurs. Additionally, the stereo configuration of compounds 107 and 108 is tentatively specified and is not finalized. ]
  • Test method for IDO inhibition activity based on HEK293T cells 1. Test method for IDO inhibition activity based on HEK293T cells:
  • the first step cell transfection and plating. 5x106 293T cells were separately seeded into two T75 flasks and incubated overnight at 37 ° C in a 5% CO 2 incubator. 0.6 ⁇ L of a mixture containing 1.5 ⁇ g of hIDO1 plasmid and 300 ⁇ L of opti-MEM was used to prepare a mixture A; 18 ⁇ L of liposome fugene 6 and 300 ⁇ L of opti-MEM were mixed, and allowed to stand at room temperature for 5 minutes. Mixture A and Mix B were mixed, placed at room temperature for 20 minutes, added to a 293T culture flask, and the other bottle was used as a control, and incubated overnight at 37 ° C in a 5% CO 2 incubator.
  • the medium was discarded, digested with trypsin, and after digestion, the cells were neutralized with serum-containing medium, and the cells were blown to cause the cells to fall off.
  • the cell suspension was pipetted into a centrifuge tube and centrifuged at 800-1000 for 1-3 minutes. Aspirate the cell supernatant from the centrifuge tube. Add an appropriate volume of medium to the tube and gently blister to resuspend the cells. Count using a Vi-Cell XR cytometer. Adjust the cell suspension to the appropriate concentration. The cell suspension was added to a white-well 96-well plate at 80 ⁇ l/well. The second step: preparation and addition of the compound.
  • the compound was formulated into 600 ⁇ M in DMSO, and the compound was diluted in a DMSO gradient according to the following table to give 6 concentration gradient compounds.
  • the 200 ⁇ compound prepared in DMSO was formulated into a 10 ⁇ dilution solution in proportion to the corresponding cell culture medium. 10 ⁇ L of 10 ⁇ corresponding compound dilution and 10 ⁇ L of 10 ⁇ TRP were added to each well except for Min. Incubate for 16 hours in a 37 ° C incubator. The third step: detection and analysis. Cell morphology was observed under an inverted microscope.
  • 80 ⁇ L of the supernatant was added to a 3894 plate, and 10 ⁇ L of 6.1 N trichloroacetic acid was added to each well, shaken for 2 minutes, and placed in a 50-degree incubator for 30 minutes. Centrifuge, 2500 rpm for 10 minutes. 70 ⁇ L of the supernatant was transferred to a 3635 UV plate, and 70 ⁇ L of the reaction solution was added thereto, and the mixture was shaken for 2 minutes to make the reaction uniform. The data at the OD value of 480 nm was detected using EnSpire (PE). The cell culture plate 3903 was allowed to stand at room temperature for 30 minutes. 100 ⁇ L/well of the cell activity detecting reagent was added to the culture plate.
  • the activities of representative compounds are shown in Table 1.
  • the IC 50 value is represented by: A: IC 50 value ⁇ 10 nM; B: 10 nM ⁇ IC 50 value ⁇ 50 nM; C: 50 nM ⁇ IC 50 value ⁇ 100 nM; D: IC 50 value > 100 nM.
  • the first step cell plating. Prepare complete medium and mix well. Cell lines that are in good growth state are selected. Remove the cell culture flask from the incubator and check the cell name, media type and cell number on the bottle. The medium was discarded, digested with trypsin, and after digestion, the cells were neutralized with serum-containing medium, and the cells were blown to cause the cells to fall off. The cell suspension was pipetted into a centrifuge tube and centrifuged at 800-1000 for 3-5 minutes. Aspirate the cell supernatant from the centrifuge tube. Add an appropriate volume of medium to the tube and gently blister to resuspend the cells. Count using a Vi-Cell XR cytometer. Adjust the cell suspension to the appropriate concentration.
  • the cell suspension was added to a white-well 96-well plate at 80 ⁇ l/well according to the schematic below.
  • the second step preparation and addition of the compound.
  • the compound was formulated into 600 ⁇ M in DMSO, and the compound was diluted in a DMSO gradient according to the following table to give 6 concentration gradient compounds.
  • the 200 ⁇ compound prepared in DMSO was formulated into a 10 ⁇ dilution solution in proportion to the corresponding cell culture medium. After the cells were seeded for 24 hours, 10 ⁇ L of 10 ⁇ corresponding compound dilution and 10 ⁇ L of 10 ⁇ IFN ⁇ were added to each well. Incubate for 48 hours in a 37 ° C incubator.
  • the third step detection and analysis. Cell morphology was observed under an inverted microscope.
  • Compound code IDO inhibitory activity Compound code IDO inhibitory activity Compound code IDO inhibitory activity Compound code IDO inhibitory activity Compound 1 A Compound 42 A Compound 87 A Compound 1A A Compound 43 C Compound 88 A Compound 1B A Compound 44 A Compound 89 A Compound 2 B Compound 45 B Compound 90 A Compound 3 D Compound 46 C Compound 91 A Compound 4 A Compound 47 C Compound 92 A Compound 5 A Compound 48 D Compound 93 A Compound 6 B Compound 49 B Compound 94 A Compound 7 B Compound 50 B Compound 95 A Compound 8 B Compound 51 D Compound 96 A Compound 9 D Compound 52 D Compound 97 B Compound 10 D Compound 53 D Compound 98 A Compound 11 A Compound 54 D Compound 99 B Compound 12 C Compound 55 D Compound 100 D Compound 13 D Compound 56 B Compound 101 B Compound 14 D Compound 57 A Compound 102 A Compound 15 D Compound 58 B Compound 103 D Compound
  • Compound 26 A Compound 69A Compound 26A A Compound 70A Compound 26B A Compound 71B Compound 27 A Compound 72A Compound 28 D Compound 73A Compound 29 C Compound 74A Compound 30 D Compound 75B Compound 31 D Compound 76A Compound 32 D Compound 77A Compound 33 C Compound 78C Compound 34 A Compound 79D Compound 35 B Compound 80A Compound 36 A Compound 81B Compound 37 A Compound 82D Compound 38 A Compound 83D Compound 39 A Compound 84D Compound 40 A Compound 85B Compound 41 B Compound 86A

Abstract

本发明提供了一种作为IDO抑制剂和/或IDO-HDAC双重抑制剂的多环化合物，具体地，本发明提供了一种如下式(I)所示的化合物，其中，各基团的定义如说明书中所述。所述的化合物具有IDO抑制活性或IDO-HDAC双重抑制活性，可以用于预防或治疗与IDO和/或IDO-HDAC活性或表达量相关的疾病。同时本发明专利所述化合物可以和免疫抗肿瘤的抗体如PD-1和PD-L1等进行联合用药，这样的联合用药能够大大提高抗体的抗肿瘤的应答率，拓宽所要治疗的肿瘤的种类。(I)

Description

作为IDO抑制剂和/或IDO-HDAC双重抑制剂的多环化合物 技术领域
本发明涉及多环化合物，还涉及其制备方法和作为IDO抑制剂的用途。
背景技术
吲哚胺2，3-双加氧酶(Indoleamine 2，3-dioxygenase，IDO)是催化色氨酸等吲哚胺类分子中吲哚环氧化裂解，使其按犬尿酸途径分解代谢的限速酶。
IDO在肿瘤免疫豁免及肿瘤发生过程中起着重要作用。正常情况下，IDO在体内呈低水平表达，而大多数肿瘤细胞则会组成的高表达IDO，将L-色氨酸转化为N-甲酰犬尿氨酸，降低了细胞微环境中的色氨酸浓度，使得色氨酸依赖的T细胞合成停滞于Gl期，T细胞增殖受到抑制，从而抑制了机体免疫***对肿瘤组织的杀伤作用。同时，IDO作用下色氨酸的代谢产物存在细胞毒性，可对T细胞产生直接溶解作用。因此，抑制IDO的活性可以有效地阻止肿瘤细胞周围色氨酸的降解，促进T细胞的增殖，从而增强机体对肿瘤细胞的攻击能力。并且，IDO抑制剂还可以与化疗药物合用，降低肿瘤细胞的耐药性，从而增强常规细胞毒疗法的抗肿瘤活性。同时服用IDO抑制剂也可提高癌症病人的治疗性疫苗的疗效。除了在肿瘤细胞耐药性方面发挥着重要作用，IDO还与多种与细胞免疫激活相关的疾病的发病机制密切相关。IDO已被证实是与细胞免疫激活相关的感染、恶性肿瘤、自身免疫性疾病、艾滋病等重大疾病的靶标。同时，抑制IDO还是对于患有神经***疾病如抑郁症，阿尔茨海默病的病人的重要治疗策略。因此，IDO抑制剂具有广阔的临床应用前景。
HDAC是一类蛋白酶，对染色体的结构修饰和基因表达调控发挥着重要的作用。HDAC使组蛋白氨基末端的赖氨酸侧链去乙酰化，组蛋白乙酰化与组蛋白去乙酰化过程处于动态平衡，由组蛋白乙酰化转移酶(HAT)和组蛋白去乙酰化酶共同调控。组蛋白的乙酰化，逆转HAT的赖氨酸残基乙酰化作用，恢复赖氨酸残基正电荷，有利于DNA与组蛋白八聚体的解离，核小体结构松弛，从而使各种转录因子和协同转录因子能与DNA结合位点特异性结合，激活基因的转录。由于HDAC在肿瘤细胞中的过度表达，使组蛋白的去乙酰化作用增强，通过恢复组蛋白正电荷增加DNA与组蛋白之间的引力，使松弛的核小体变得十分紧密，不利于特定基因的表达，包括一些肿瘤抑制基因。HDAC抑制剂可通过提高染色质特定区域组蛋白乙酰化，从而调控细胞凋亡及分化相关蛋白的表达和稳定性，可以诱导肿瘤细胞周期阻滞和凋亡，促进肿瘤细胞自我吞噬，还可以抑制肿瘤新生血管的生成，促进肿瘤细胞的免疫原性，HDAC抑制剂不仅成为用于肿瘤的靶向治疗，而且可以在神经性疾病，炎症，促进自身免疫等方面发挥作用。临床前期和临床研究试验表明，HDAC抑制剂在和其他抗肿瘤化合物联用时也可以有效的发挥协同作用，抑制肿瘤生长，HDAC负责去除组蛋白上的乙酰基团，对基因的表达,癌蛋白的稳定性，细胞迁移，蛋白质的分解代谢，和细胞周期的调控都有明显的影响。
利用同一个小分子同时抑制IDO和HDAC，尚未见有报道。我们认为，同时抑制这两个靶点，很可能会改善肿瘤细胞的微环境，从而提高免疫力，产生更有效的抗癌作用。
综上所述，本领域尚缺乏IDO和HDAC双重抑制剂。
发明内容
本发明的目的是提供一类结构新颖的IDO抑制剂，和/或IDO-HDAC双重抑制剂，以 及它们的制备方法和应用。
本发明的第一方面，提供了一种如式(I)所示的化合物，或其光学异构体，药学上可接受的盐、前药、氘代衍生物、水合物、或溶剂合物：
Figure PCTCN2018106768-appb-000001
其中：
Figure PCTCN2018106768-appb-000002
表示单键或双键；
X为键、NH、N(C 1-4烷基)、O、C(O)、C(S)、C(O)NH、C(O)O、或C(O)NCH 3；
Y为键、NH、N(C 1-4烷基)、O、C(O)、C(S)、或C(O)NH；
前提条件是X、Y、B和s的组合所形成的结构为稳定的化学结构；
A为C 6-10芳基、5-至15-元杂芳基、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-10环烷基(包括单环、螺环、并环、桥环等)、或4-至20元杂环基(包括单环、螺环、并环、桥环等，优选为4至10元杂环基)；
B为C 3-8单环烷基、含一个到多个任选自N、O、S的4-至8-元单环杂环基、C 7-12多环烷基、或含一个到多个任选自N、O、S的5-至12-元多环杂环基；这里的多环烷基或多环杂环基是指多于一个环的饱和的或部分不饱和的环状结构，包括螺环、并环、桥环等；且当B为
Figure PCTCN2018106768-appb-000003
时，s只能为1，此时CR 2R 3中的R 3为无；
D为键、氧、C(R 6) 2、C(O)、C≡C、C＝C、CH 2O、OCH 2、S(O) 2、或NR 7，前提条件是D与B和E连接所形成的结构为稳定的化学结构，比如，当D为氧或NR 7时，D与B或E的连接位点不能为N原子；
E为C 6-10芳基、5-至10-元杂芳基、含1-3个任选自N、O、S的5-至10-元的杂环基、C 4-8环烷基并芳基、或C 4-8环烷基并杂芳基、或含1-3个任选自N、O、S的5-至10-元的杂环基并一个芳基或杂芳基；
各个R 1各自独立地选自下组：氢、氘、卤素、C 1-4烷基、羟基、C 1-4烷氧基、羟基C 1-4烷基、羟基C 1-4烷氧基、C 2-4烯基、C 2-4炔基、C 3-10环烷基(包括单环、螺环、并环、桥环等)、4-至10元杂环基(包括单环、螺环、并环、桥环等)、NR 10R 11、氰基、C(O)R 12、C(O)NR 10R 11、OC(O)NR 10R 11、NR 10C(O)NR 10R 11、NR 10SO 2R 12、NR 10SO 2NR 10R 11、CO 2R 13、卤代C 1-4烷基、C 1-4烷氧基C 1-4烷基、卤代C 1-4烷氧基、C 1-4烷氧基C 1-4烷氧基、C 1-4烷氧基卤代C 1-4烷氧基、C 1-4烷氧基C 2-4烯基、C 1-4烷氧基C 2-4炔基、S-C 1-4烷基、双(C 1-4烷基)氨基C 1-4烷氧基、(CR 8R 9) n-C(O)-NHOH、O(CR 8R 9) n-C(O)-NHOH、NR 10(CR 8R 9) n-C(O)-NHOH、
Figure PCTCN2018106768-appb-000004
或者两个R 1与其相连的碳原子共同形成C＝O、C 3-8环烷基或含有1-2个选自N、O或S的4-至8-元杂环基，其中所述的环烷基或杂环基任选地被1-2个R 14取代；或者当两个R 1连接点为毗邻的两个碳原子时，两个R 1与其相连的碳原子共同形成C 3-8环烷基 或含有1-2个选自N、O或S的4-至8-元杂环基，其中所述的环烷基或杂环基任选地被1-2个R 14取代。这里，各个R 14各自独立地选自氢、氘、卤素、C 1-4烷基、羟基、C 1-4烷氧基、CN、NR 10R 11、C 3-6环烷基、含有1-2个选自N、O或S的4-至8-元的杂环基、C 6-10芳基、5-至10-元杂芳基、或＝O。前提条件是上述R 1的定义应和A的定义联系起来，确保所形成的结构为稳定的化学结构；
R 2和R 3各自独立地选自氢、氘、C 1-8烷基、C 2-8烯基、C 2-8炔基、卤代C 1-8烷基、C 3-8环烷基、含有1-2个选自N、O或S的4-至8-元杂环基、C 6-10芳基、5-至10-元杂芳基、C 3-6环烷基C 1-4烷基、含有1-2个选自N、O或S的4-至8-元杂环基C 1-4烷基、C 6-10芳基C 1-4烷基、5-至10-元杂芳基C 1-4烷基、氟、OH、CN、CO 2H、C(O)NH 2、NR 10R 11、C 1-4烷氧基、(CR 8R 9) p-OH、(CR 8R 9) p-Z-(CR 8R 9) r-CO 2H、(CR 8R 9) p-Z-(CR 8R 9) r-C(O)NH 2、(CR 8R 9) p-Z-(CR 8R 9) r-C(O)NHR 10、(CR 8R 9) p-Z-(CR 8R 9) r-C(O)NR 10R 11、(CR 8R 9) p-Z-(CR 8R 9) r-C(O)NHOH；其中，Z为键、CH＝CH、C≡C、O、S、NR 7、C(O)、C 3-8环烷基、4-至-元杂环基、C 6-10芳基、5-至10-元杂芳基；或R 3为无；
或R 2和R 3与其相连的碳原子共同形成C＝O、C 3-8环烷基或含有1-2个选自N、O或S的4-至8-元杂环基；
或R 2及与R 2相连的碳原子与B上的一个或两个碳原子共同形成C 3-6环烷基或含有1-2个选自N、O或S的3-至6-元杂环基，这样的环状结构为螺环或稠环；
上述R 2和R 3的定义必须保证与其它基团(包括X和Y，以及B和A)共同组成稳定的化学结构；
各个R 4各自独立地为氢、氘、卤素、C 1-4烷基、羟基、CN、C 1-4烷氧基，或当两个R 4连接在同一个碳原子上，这两个R 4和被连接的碳一起组成羰基(C＝O)，或当两个R 4连接在相邻的两个碳原子上，这两个R 4和两个碳形成含氧的三元杂环结构(即环氧化合物)；
各个R 5各自独立地为氢、氘、卤素、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、含有1-2个选自N、O或S的4-至6-元杂环基、C 6芳基、5-至6-元杂芳基、卤代C 1-4烷基、羟基、CN、卤代C 1-4烷氧基、C(O)R 12、CO 2R 13、CONR 10R 11、SO 2NR 10R 11、NR 10SO 2NR 10R 11、NR 10C(O)R 12、或＝O；
各个R 6各自独立地为氢、氘、卤素、C 1-4烷基、羟基、CN、C 1-4烷氧基；
R 7为氢、C 1-4烷基、C 3-6环烷基、4-至8-元杂环基、C(O)C 1-4烷基、C(O)C 3-6环烷基；
R 8和R 9各自独立地选自如下基团：氢、氘、卤素、C 1-4烷基、羟基、CN、C 1-4烷氧基；
R 10和R 11各自独立地选自如下基团：氢、C 1-4烷基、C 3-8环烷基、4-至8-元杂环基、6-元芳基、5-至6-元杂芳基、C 1-4烷氧基C 1-4烷基、双(C 1-4烷基)氨基C 1-4烷基，其中环烷基、杂环基、芳基、或杂芳基任选地被1-3个R 14取代，这里的R 14定义如上所述；或者R 10和R 11一起与和它们连接的氮原子共同形成4-至8-元的环状结构，此环状结构可额外含有0-2个任选自N、O、S的杂原子，前提条件是所形成的环状结构为稳定的结构。此环状结构任选地被1-3个R 14取代；
R 12为C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、4-至8-元杂环基、6-元芳基、5-至6-元杂芳基；
R 13为氢、C 1-4烷基、C 3-6环烷基、含有1-2个选自N、O、S的4-至8-元的杂环基、6-元芳基、5-至6-元杂芳基；这里的烷基、环烷基、杂环基、芳基和杂芳基可以任选地被卤素、CN、羟基取代，只要所形成的结构为稳定的结构；
R 14为氢、C 1-4烷基、C 3-6环烷基、含有1-2个选自N、O、S的4-至8-元的杂环基、6-元芳基、5-至6-元杂芳基；
m为0、1、2或3；
n为0、1、2或3；
o为0、1、2或3；
p为0、1、2、3或4；
q为0、1、2或3；
r为0、1、2、3或4；
s为0或1；
例外情况是：当B为C 3-8单环烷基或含一个到多个任选自N、O、S的4-至8元单环杂环基，且R 1、R 2和R 3均不包含C(O)-NH-OH基团时，A不是选自下组的基团：苯基、5-至6-元的杂芳基、C 5-7的环烷基；
(其中，所述的R 1、R 2和R 3均不包含C(O)-NH-OH基团指R 1、R 2和R 3均不为C(O)-NH-OH基团，且R 1、R 2和R 3基团中不包括C(O)-NH-OH结构片段)
其中，各个上述的烷基、烯基、炔基、环烷基、杂环基、芳基、和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：氢、氘、卤素、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤代C 1-4烷基、C 3-8环烷基、含有1-2个选自N、O或S的4-至8-元杂环基、C 6-10芳基、5-至10-元杂芳基、OH、CN、NO 2、OR 13、SR 13、N(R 7) 2、C(O)R 12、CO 2R 13、CONR 10R 11、SO 2NR 10R 11；取代基中，各个基团的定义分别如上所述。
应该指出，本专利申请中的式(I)所要求的权利化合物里，不包含如下已经发表的专利申请书里的化合物：WO2015188085,WO2016073738,WO2016073770,WO2016073774,WO2017192840,WO2017192844,WO2017192845,WO20171928。
在另一优选例中，X为NH、N(C 1-4烷基)、O、C(O)、C(O)O、C(O)NH、或C(O)NCH 3；Y为NH、N(C 1-4烷基)、O、C(O)、或C(O)NH；
在另一优选例中，X为NH、C(O)NH、或C(O)。
在另一优选例中，Y为C(O)或NH。
前提条件是X和Y的组合所形成的结构为稳定的化学结构。
在另一优选例中，Y-X为如下组合：
Figure PCTCN2018106768-appb-000005
Figure PCTCN2018106768-appb-000006
表示与A连接的点，
Figure PCTCN2018106768-appb-000007
表示与CR 2R 3连接的点。
在另一优选例中，Y-X为如下组合：
Figure PCTCN2018106768-appb-000008
Figure PCTCN2018106768-appb-000009
表示与A连接的点，
Figure PCTCN2018106768-appb-000010
表示与CR 2R 3连接的点。其它各个基团的定义分别如上所述。
在另一优选例中，R 2为氢、氘、或氟，R 3为C 1-4烷基、C 2-4烯基、C 2-4炔基、卤代C 1-4烷基、羟基、C 1-4烷氧基、C 3-6环烷基、(CR 8R 9) p-Z-(CR 8R 9) r-CO 2H、(CR 8R 9) p-Z-(CR 8R 9) r-C(O)NHOH。
在另一优选例中，R 2和R 3各自独立地选自下组：氢、氘、氟、C 1-4烷基，或R 2和R 3与其相连的碳原子共同形成C 3-6环烷基或C＝O。
在另一优选例中，R 2和R 3各自独立地选自下组：甲基，或R 2和R 3与其相连的碳原子共同形成环丙基。
在另一优选例中，B为如下结构：
Figure PCTCN2018106768-appb-000011
Figure PCTCN2018106768-appb-000012
表示与D连接的点，
Figure PCTCN2018106768-appb-000013
表示与CR2R3连接的点。其它各个基团的定义分别如上所述。前提条件是，当B为
Figure PCTCN2018106768-appb-000014
时，s只能为1，且CR 2R 3中的R 3为无。
在另一优选例中，A为C 6-10芳基、5-至15-元杂芳基、C 3-10环烷基、4-至15元杂环基、或A为如下结构：
Figure PCTCN2018106768-appb-000015
在另一优选例中，各个R 1各自独立地为卤素、C 1-4烷基、C 1-4烷氧基、C 2-4烯基、C 2-4炔基、氰基、C(O)R 12、NR 10SO 2NR 10R 11、CO 2R 13、CONR 10R 11、卤代C 1-4烷基、卤代C 1-4烷氧基、(CR 8R 9) n-C(O)-NHOH、
Figure PCTCN2018106768-appb-000016
在另一优选例中，E为C 6- 10芳基、5-至10-元杂芳基、含1-3个任选自N、O、S的5-至10-元的杂环基，或E为如下结构：
Figure PCTCN2018106768-appb-000017
Figure PCTCN2018106768-appb-000018
在另一优选例中，E为如下结构：
Figure PCTCN2018106768-appb-000019
在另一优选例中，B选自下组：
Figure PCTCN2018106768-appb-000020
其中
Figure PCTCN2018106768-appb-000021
表示与D连接的点，
Figure PCTCN2018106768-appb-000022
表示与CR 2R 3连接的点。前提条件是，当B为
Figure PCTCN2018106768-appb-000023
时，CR 2R 3中的R 3为无。
在另一优选例中，所述的化合物具有以下结构：
Figure PCTCN2018106768-appb-000024
其中，T 1和T 2各自独立地选自CR 15或N，其中R 15为H、F、或OH；
Y-X选自如下组合：
Figure PCTCN2018106768-appb-000025
Figure PCTCN2018106768-appb-000026
表示与A连接的点，
Figure PCTCN2018106768-appb-000027
表示与CR 2R 3连接的点；
其它各个基团的定义分别如上所述。
在另一优选例中，所述的化合物具有以下结构：
Figure PCTCN2018106768-appb-000028
Y-X选自如下组合：
Figure PCTCN2018106768-appb-000029
Figure PCTCN2018106768-appb-000030
表示与A连接的点，
Figure PCTCN2018106768-appb-000031
表示与CR 2R 3连接的点。
在另一优选例中，所述的化合物具有以下结构：
Figure PCTCN2018106768-appb-000032
其中，T 1和T 2各自独立地选自CR 15或N，其中R 15为H、F、或OH,Y-X选自如下组合：
Figure PCTCN2018106768-appb-000033
Figure PCTCN2018106768-appb-000034
表示与A连接的点，
Figure PCTCN2018106768-appb-000035
表示与CR 2R 3连接的点；
其它各个基团的定义分别如上所述。
在另一优选例中，所述的化合物具有以下结构：
Figure PCTCN2018106768-appb-000036
Y-X选自如下组合：
Figure PCTCN2018106768-appb-000037
Figure PCTCN2018106768-appb-000038
表示与A连接的点，
Figure PCTCN2018106768-appb-000039
表示与CR 2R 3连接的点。
在另一优选例中，所述的化合物具有以下结构：
Figure PCTCN2018106768-appb-000040
其中，所述的G 1选自下组：
Figure PCTCN2018106768-appb-000041
所述的G2选自下组：
Figure PCTCN2018106768-appb-000042
Figure PCTCN2018106768-appb-000043
在另一优选例中，所述的G1选自下组：
Figure PCTCN2018106768-appb-000044
所述的G2选自下组：
Figure PCTCN2018106768-appb-000045
在另一优选例中，各个基团为实施例中具体化合物中的对应基团。
在另一优选例中，所述的式(I)所示的化合物具有选自下组的结构：
Figure PCTCN2018106768-appb-000046
Figure PCTCN2018106768-appb-000047
Figure PCTCN2018106768-appb-000048
Figure PCTCN2018106768-appb-000049
Figure PCTCN2018106768-appb-000050
其中,“*”表示手性中心。
上述各个化合物，如果涉及到一个或多个手性中心的，表明本发明专利所指的化合物是它们的对映异构体，非对映异构体，和/或它们的消旋物和混合物；
除非特别标明，所有烯键的构型均包括顺式构型和反式构型。此外，当两个取代基同时在一个饱和环上(包括并环)，可能产生顺式和反式构型，也在本发明包括的范围内。
本发明的第二方面，提供了一种如本发明第一方面所述的式I化合物的用途，用于：
(a)制备治疗与IDO活性或表达相关的疾病的药物；和/或
(b)制备治疗与HDAC活性或表达相关的疾病的药物；和/或
(c)制备IDO免疫抑制剂；和/或
(d)制备IDO-HDAC双重免疫/靶向抑制剂；和/或(e)体外非治疗性地抑制IDO的活性；和/或双重抑制IDO-HDAC的活性。
在另一优选例中，所述肿瘤选自下组：肺癌、膀胱癌、乳腺癌、胃癌、肝癌、唾液腺肉瘤、卵巢癌、***癌、***、上皮细胞癌、多发性骨髓瘤、胰腺癌、淋巴瘤、慢性髓性白血病、淋巴细胞性白血病、皮肤T细胞淋巴瘤等。
本发明的第三方面，提供了一种药物组合物，所述的药物组合物包括：(i)治疗有效量的如本发明第一方面所述的化合物，或其药学上可接受的盐；和(ii)药学上可接受的载体。
在另一优选例中，所述的药物组合物还包括选自下组的有效组分：治疗有效量的PD-1和/或PD-L1。
本发明的第四方面，提供了一种抑制IDO活性的方法，和/或双重抑制IDO-HDAC的活性的方法，其特征在于，所述方法包括步骤：对抑制对象施用抑制有效量的如本发明第一方面所述的式I化合物，或其药学上可接受的盐，或对抑制对象施用抑制有效量的如本发明第三方面所述的药物组合物。
在另一优选例中，所述的抑制是IDO选择性抑制。
在另一优选例中，所述的抑制是IDO-HDAC选择性抑制。
在另一优选例中，所述的IDO活性抑制是体外非治疗性的抑制。
在另一优选例中，所述的IDO-HDAC活性抑制是体外非治疗性的抑制。
本发明的第五方面，提供了一种药物组合物，其特征在于，所述的药物组合物包括：本发明第一方面所述的化合物I，或其药学上可接受的盐，和任选的抗体PD-1或PD-L1或CTLA-4。
在另一优选例中，所述的药物组合物用于治疗癌症。
在另一优选例中，所述的癌症选自下组：乳腺癌、淋巴癌、白血病、肺癌、卵巢癌、***、睾丸癌、肝癌、黑素瘤、结肠癌、直肠癌、肾细胞癌、小肠癌和食道癌、头颈癌、膀胱癌、***癌、胰腺癌、或咽癌。
本发明的第六方面，提供了一种如本发明第一方面所述化合物的制备方法，所述方法包括步骤：
Figure PCTCN2018106768-appb-000051
Figure PCTCN2018106768-appb-000052
中\表示双键。
(i)在惰性溶剂中，通过Wittig反应，然后经Pd-C催化氢化及脱保护基团，将化合物I-1转化为I-2；
(ii)在惰性溶剂中，在碱(如2,6-双叔丁基吡啶或KHMDS或LiHMDS)和Tf 2O(或PhNTf 2)的作用下将化合物I-2转变为I-3，然后再与相应的芳基或杂芳基的硼化合物反应，得到含有烯键的偶联化合物，经催化氢化得到化合物I-4；
(iii)化合物I-4经酯水解，得到的酸与I-5反应，得到化合物I-6；
(iv)在惰性溶剂中，在碱的作用下可在化合物I-6的酰胺基的α-位引入基团，得到化合物I；
Figure PCTCN2018106768-appb-000053
(v)化合物I-4经酯水解，得到的酸与Evans的手性试剂(通常R”为苯基或苄基)反应得II-1，从而达到在酰胺基的α-位引入手性基团R 3，得到化合物II-2；
(vi)化合物II-2水解后得到酸II-3，然后与I-5反应得到化合物II。
(vii)当(v)中所用的Evans的手性试剂(通常R”为苯基或苄基)为另一个构型时，上述(v)和(vi)步骤可制备得到化合物IIa。化合物IIa是化合物II的对映异构体。
Figure PCTCN2018106768-appb-000054
(viii)从化合物I-1出发，经多步反应制备α-酮酸酯III-4,然后经Wittig反应制备α,β-不饱和酯III-5。化合物III-5的双键环丙化反应得到化合物III-6。最后酯水解和酰胺化反应得到化合物III。
Figure PCTCN2018106768-appb-000055
Figure PCTCN2018106768-appb-000056
中的\表示双键。
应理解，在本发明的范围中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，意外地发现了一类具有IDO抑制活性和/或IDO-HDAC双重抑制活性的多环化合物，因此可以用于制备治疗与IDO和/或HDAC活性或表达量相关的疾病的药物组合物。基于上述发现，发明人完成了本发明。
术语
除特别说明之处，本文中提到的“或”具有与“和/或”相同的意义(指“或”以及“和”)。
除特别说明之处，本发明的所有化合物之中，各手性碳原子(手性中心)可以任选地为R构型或S构型，或R构型和S构型的混合物。
如本文所用，在单独或作为其他取代基一部分时，术语“烷基”指只含碳原子的直链(即，无支链)或支链饱和烃基，或直链和支链组合的基团。当烷基前具有碳原子数限定(如C 1-10)时，指所述的烷基含有1-10个碳原子。例如，C 1-8烷基指含有1-8个碳原子的烷基，包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“烯基”是指直链或支链，具有至少一个碳-碳双键的碳链基团。烯基可以是取代的或未取代的。当烯基前具有碳原子数限定(如C 2-8)时，指所述的烯基含有2-8个碳原子。例如，C 2-8烯基指含有2-8个碳原子烯基，包括乙烯基、丙烯基、1,2-丁烯基、2,3-丁烯基、丁二烯基、或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“炔基”是指具有至少一个碳-碳三键的脂肪族碳氢基团。所述的炔基可以是直链或支链的，或其组合。当炔基前具有碳原子数限定(如C 2-8炔基)时，指所述的炔基含有2-8个碳原子。例如，术语“C 2-8炔基”指具有2-8个碳原子的直链或支链炔基，包括乙炔基、丙炔基、异丙炔基、丁炔基、异丁炔基、仲丁炔基、叔丁炔基、或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“环烷基”指具有饱和的或部分饱和的单元环，二环或多环(稠环、桥环或螺环)环系基团。当某个环烷基前具有碳原子数限定(如C 3-10)时，指所述的环烷基含有3-10个碳原子。在一些优选实施例中，术语“C 3-8环烷基”指具有3-8个碳原子的饱和或部分饱和的单环或二环烷基，包括环丙基、环丁基、环戊基、环庚基、或类似基团。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的二环或多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。“稠环烷基”指***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳二环或多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。所述环烷基所含原子全部为碳原子。如下是环烷基的一些例子，本发明并不仅局限下述的环烷基。
Figure PCTCN2018106768-appb-000057
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义。“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环)，但不能含有杂原子如氮，氧，或硫，同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的。如下是芳基的一些例子，本发明并不仅局限下述的芳基。
Figure PCTCN2018106768-appb-000058
“杂芳基”指包含一个到多个杂原子的杂芳族基团。这里所指的杂原子包括氧、硫和氮。例如呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。如下是杂芳基的一些例子，本发明并不仅局限下述的杂芳基。其中，最后三个杂芳基是三环杂芳基，是本发明的重点。
Figure PCTCN2018106768-appb-000059
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基。多环杂环基指包括螺环、稠环和桥环的杂环基。“螺环杂环基”指***中的每个环与体系中的其他环之间共用一个原子(称螺原子)的 多环杂环基团，其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。“稠环杂环基”指***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，而且其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。“桥环杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，而且其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。如果杂环基里同时有饱和环和芳环存在(比如说饱和环和芳环稠合在一起)，连接到母体的点一定是在饱和的环上。注：当连接到母体的点在芳环上时，称为杂芳基，不称为杂环基。如下是杂环基的一些例子，本发明并不仅局限下述的杂环基。
Figure PCTCN2018106768-appb-000060
如本文所用，在单独或作为其他取代基一部分时，术语“卤素”指F、Cl、Br和I。
如本文所用，术语“取代”(在有或无“任意地”修饰时)指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个任意取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。环状取代基，例如杂环基，可以与另一个环相连，例如环烷基，从而形成螺二环系，即两个环具有一个共用碳原子。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-8环烷基、3-至12-元杂环基，芳基、杂芳基、卤素、羟基、羧基(-COOH)、C 1-8醛基、C 2-10酰基、C 2-10酯基、氨基。
为了方便以及符合常规理解，术语“任意取代”或“任选取代”只适用于能够被取代基所取代的位点，而不包括那些化学上不能实现的取代。
如本文所用，除非特别说明，术语“药学上可接受的盐”指适合与对象(例如，人)的组织接触，而不会产生不适度的副作用的盐。在一些实施例中，本发明的某一化合物的药学上可接受的盐包括具有酸性基团的本发明的化合物的盐(例如，钾盐，钠盐，镁盐，钙盐)或具有碱性基团的本发明的化合物的盐(例如，硫酸盐，盐酸盐，磷酸盐，硝酸盐，碳酸盐)。
化合物的通用合成方法
本本发明通式I所示化合物可通过如下的方法制得，然而该方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易地进行。
在本发明的制备方法中，各反应通常在惰性溶剂中，反应温度-78℃～150℃(优选 20～120℃)下进行。各步反应时间通常为0.5～48h，较佳地为2～12h。
反应式A-1描述了化合物A11的通用合成方法：
反应式A-1
Figure PCTCN2018106768-appb-000061
反应式A-2描述了化合物A13的通用合成方法：
反应式A-2
Figure PCTCN2018106768-appb-000062
反应式A-3描述了中间体A9的另外一个通用合成方法：
反应式A-3
Figure PCTCN2018106768-appb-000063
中间体A9是一个关键中间体，它可以用来制备化合物A11和A13(见反应式A-1和A-2)。应该提到的是，上述方法得到得的化合物A13是消旋体。
反应式A-4描述了化合物A20的通用手性合成方法：
反应式A-4
Figure PCTCN2018106768-appb-000064
这里的A20是A13的其中一个手性对映异构体。另一个对映异构体的制备可根据上面反应式，使用另一个手性诱导试剂(也称Evans chiral auxiliary)如
Figure PCTCN2018106768-appb-000065
来完成。这里的R 102通常为苯基或苄基。
反应式B-1描述了化合物B7的通用合成方法：
反应式B-1
Figure PCTCN2018106768-appb-000066
这里的化合物B7是消旋体。可以根据需要使用反应式A-4的方法来制备B7的两个旋光纯度高的单一的对映异构体。
反应式B-2描述了化合物B14的通用合成方法：
反应式B-2
Figure PCTCN2018106768-appb-000067
其中，L为离去基团。这里得到的化合物B14为消旋体。可以通过手性的制备HPLC分离得到B14的两个旋光纯度高的单一的对映异构体。
另外，B14也可以通过中间体B12和B15直接进行取代反应得到。
Figure PCTCN2018106768-appb-000068
反应式C-1描述了化合物C6的通用合成方法：
反应式C-1
Figure PCTCN2018106768-appb-000069
其中，L为离去基团。
反应式C-2描述了中间体C4另一个通用合成方法。中间体C4是制备化合物C6的关键原料：
反应式C-2
Figure PCTCN2018106768-appb-000070
其中，L为离去基团。
反应式D-1描述了化合物D2的通用合成方法：
反应式D-1:
Figure PCTCN2018106768-appb-000071
反应式D-2描述了化合物D6的通用合成方法：
反应式D-2
Figure PCTCN2018106768-appb-000072
其中，L为离去基团。
这里的化合物D2和D6为消旋体。可以通过手性的制备HPLC分离得到它们各自的两个旋光纯度高的单一的对映异构体。
如下化合物D7,D8,D9,和D10可根据上述所列出的反应式进行组合来制备得到：
Figure PCTCN2018106768-appb-000073
反应式E-1描述了化合物E10的通用合成方法：
反应式E-1:
Figure PCTCN2018106768-appb-000074
反应式F-1描述了化合物F7的通用合成方法：
反应式F-1:
Figure PCTCN2018106768-appb-000075
应该指出的是，上述各反应式旨在以化合物A11,A13,A20,B7,B14,C6,D2,D6,D7,D8,D9,D10,E10和F7为例子，列出它们的通式合成路线。我们的实际合成路线并不局限于上述路线。其他的相关的合成路线对于有专业知识的有机化学家和药物化学家来说，应该是显而易见的。在这里就不一一阐述。所述的化合物A11,A13,A20,B7,B14,C6,D2,D6,D7,D8,D9,D10,E10和F7都是式(I)的一部分。其它的没有列出的式(I)分子可以根据上面的反应式进行设计合成来得到。
药学上可接受的盐、溶剂合物、立体异构体、互变异构体
如本文所用，术语“药学上可接受的盐”指本发明化合物与药学上可接受的无机酸和有机酸所形成的盐，其中，优选的无机酸包括(但并不限于)：盐酸、氢溴酸、磷酸、硝酸、硫酸；优选的有机酸包括(但并不限于)：甲酸、乙酸、丙酸、丁二酸、萘二磺酸(1,5)、亚细亚酸、草酸、酒石酸、乳酸、水杨酸、苯甲酸、戊酸、二乙基乙酸、丙二酸、琥珀酸、富马酸、庚二酸、己二酸、马来酸、苹果酸、氨基磺酸、苯丙酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲磺酸、对甲苯磺酸、柠檬酸，以及氨基酸。
如本文所用，术语“药学上可接受的溶剂合物”指本发明化合物与药学上可接受的溶剂形成溶剂合物，其中，所述药学上可接受的溶剂包括(但并不限于)：水、乙醇、甲醇、异丙醇、四氢呋喃、二氯甲烷。
如本文所用，术语“药学上可接受的立体异构体”指本发明化合物所涉及手性碳原子可以为R构型，也可以为S构型，或其组合。
药物组合物和施用方法
由于本发明化合物具有优异的对IDO的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由与IDO活性或表达量相关的疾病。根据现有技术，本发明化合物可用于治疗以下疾病(但并不限于)：各种癌症，列如肺癌、膀胱癌、乳腺癌、胃癌、肝癌、唾液腺肉瘤、卵巢癌、***癌、***、上皮细胞癌、多发性骨髓瘤、胰腺癌、淋巴瘤、慢性髓性白血病、淋巴细胞性白血病、皮肤T细胞淋巴瘤等；与骨骼相关的疾病，例如骨发育不全、软骨发育不良、侏儒症、克鲁宗综合征等；T细胞调节的炎症和自身免疫疾病，例如：类风湿关节炎、胶原II关节炎、多发性硬化症、***性红斑狼疮、银屑病、青少年型糖尿病、干燥综合征、甲状腺疾病、结节病、炎性肠病、乳糜泻等等。本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2018106768-appb-000076
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药 剂量通常为1～2000mg，优选5～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括：
1.提供了一种如式I所示的化合物。
2.提供了一种结构新颖的IDO抑制剂和/或IDO-HDAC双重抑制剂及其制备和应用，所述的抑制剂在极低浓度下即可抑制IDO的活性。
3.提供了一类治疗与IDO和/或IDO-HDAC活性相关疾病的药物组合物。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1 化合物1的制备
Figure PCTCN2018106768-appb-000077
将化合物1a(10g，72.4mmol)，乙二醇(4.1mL)和对甲苯磺酸(1.4g，0.73mmol)溶于二氯甲烷(200mL)中，在50℃下搅拌过夜。对反应液进行水洗(100mL)后，收集有机相，加入无水硫酸钠干燥，过滤，滤液减压浓缩后，经硅胶柱层析纯化(乙酸乙酯/石油醚＝0-20％)得到无色油状液体1b(6.5g，收率49％)。 1H NMR(500MHz,CDCl 3)δ3.87(s,4H),2.83–2.81(m,2H),2.48–2.43(m,2H),2.22–2.12(m,4H),1.70(dd,J＝13.8,5.3Hz,2H)。
将化合物1b(6.5g，35.7mmol)溶于甲苯(50mL)中，随后加入甲氧甲酰基亚甲基三苯基膦(17.9g，53.5mmol)。该反应体系在135℃的封管中搅拌48小时。反应液用 乙酸乙酯(50mL)稀释，并用饱和食盐水(15mL)洗涤。有机相经无水硫酸钠干燥，过滤。滤液减压浓缩后，粗品经硅胶柱层析纯化(乙酸乙酯/石油醚＝0-10％)得到灰色固体化合物1c(6.8g，收率80％)。 1H NMR(500MHz,CDCl 3)δ5.77(s,1H),3.88(s,4H),3.68(s,3H),3.00(dd,J＝19.3,9.2Hz,1H),2.82–277(m,1H),2.872–2.67(m,2H),2.62–2.57(m,1H),2.40(J＝17.3,4.8Hz,1H),2.10–2.01(m,2H),1.67–1.59(m,2H)。
将化合物1c(6.8g，28.5mmol)溶于乙酸乙酯(50mL)中，随后加入10％Pd/C(0.6g)，在氢气氛围下室温搅拌过夜。将Pd/C用硅藻土过滤除去，减压浓缩后得到无色油状液体1d(6.2g，收率91％)。顺式和反式的比例大约为4.5：1。
将化合物1d(3.2g，13.3mmol)溶解在四氢呋喃(50mL)中，冰水浴下缓慢滴加HCl(1N，20mL)，缓慢升到室温并搅拌过夜。乙酸乙酯萃取(3X 30mL)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，通过硅胶柱纯化(乙酸乙酯/石油醚＝0-20％)分离得到无色油状液体1e(1.9g，收率73％)。
将化合物1e(1.9g,9.7mmol)溶于二氯甲烷(40mL)中，0℃下缓慢滴加2,6-二叔丁基-4-甲基吡啶(2.98g,14.5mmol)，搅拌1小时后，在0℃条件下缓慢滴加三氟甲磺酸酐(5.5g,19.5mmol)，缓慢升到室温并搅拌过夜。在0℃将反应液加入到饱和碳酸钠溶液(30mL)中，随后将混合溶液进行分液，水相用二氯甲烷萃取(2X 40mL)。合并的有机相用饱和食盐水(20mL)涤，将有机相用无水硫酸钠干燥，过滤，减压浓缩。粗品经硅胶柱纯化(乙酸乙酯/石油醚＝0-10％)分离得到无色油状液体化合物1f(2.1g，收率60％)。
将化合物1f(2.1g，6.4mmol)，双联频哪醇基二硼烷(1.95g,7.68mmol)，醋酸钾(1.59g,16.2mmol)，Pd(dppf) 2Cl 2(145mg，19.8mmol)，溶于1,4-二氧六环(40mL)，以及氮气保护下80℃搅拌过夜。反应液减压浓缩，加入乙酸乙酯(40mL)稀释，水洗，乙酸乙酯萃取水层(2X 40mL)，合并有机相，饱和食盐水洗涤(1X 15mL)，，用无水硫酸钠干燥，过滤，减压浓缩得到粗产物。经硅胶柱纯化(乙酸乙酯/石油醚＝0-10％)分离得到无色油状液体化合物1g(1.3g，收率66％)。
将化合物1g(620mg，2mmol)，4-溴-6-氟喹啉(570mg，2.4mmol)，碳酸钾(840mg，6.1mmol)，Pd(PPh 3) 4(240mg，0.21mmol)，溶于1,4-二氧六环(20mL)和水(5mL)，氮气保护下80℃搅拌4小时。减压浓缩，加入乙酸乙酯(20mL)，水洗，乙酸乙酯萃取(2X 40mL)，合并有机相，饱和食盐水洗，用无水硫酸钠干燥，过滤，减压浓缩。所得的粗品经过硅胶柱纯化(乙酸乙酯/石油醚＝0-25％)分离得到无色油状液体化合物1h(510mg，收率77％)。化合物1h是两个立体异构体的混合物，比例大约为1：0.7。
将化合物1h(510mg，1.57mmol)溶于乙酸乙酯(20mL),随后加入10％Pd/C(50mg)，在氢气氛围下室温搅拌2小时，将Pd/C用硅藻土过滤除去，减压，浓缩得到粗产物。经硅胶柱纯化(乙酸乙酯/石油醚＝0-20％)分离得到无色油状液体化合物1j(391.9mg，收率82％)和1k(87.1mg，收率18％)。
将化合物1j(84mg，0.255mmol)溶于甲醇(2mL)中，加入饱和氢氧化锂水溶液(1mL)，薄层层析检测原料反应完全。向反应体系中滴加盐酸(1N)，将pH调至6左右。用乙酸乙酯萃取(3X 5mL)，合并有机相，用饱和氯化钠洗涤，用无水硫酸钠干燥，过滤。滤液减压浓缩后，得到白色固体化合物1m(72mg，收率91％)。
将1m(72mg，0.228mmol)，对氯苯胺(43.8mg，0.342mmol)，HATU(105mg，0.276mmol)，N,N-二异丙基乙胺(93mg，0.72mmol)溶于N,N-二甲基甲酰胺(5mL)，氮气保护下搅拌0.5小时，加水淬灭，用乙酸乙酯萃取(3X 10mL)，合并有机相，用饱 和氯化钠洗涤，无水硫酸钠干燥，过滤。滤液减压浓缩，粗品经硅胶柱层析纯化(0-25％乙酸乙酯：石油醚)得到白色固体化合物1n(50mg，收率53％)。
将化合物1n(50mg，0.12mmol)，DMAP(38.7mg，0.18mmol)和BOC酸酐(21.67mg，0.18mmol)溶于乙腈(1mL)中，加热到50℃搅拌5分钟。反应液减压浓缩，所得的粗品经制备薄板层析分离(30％，乙酸乙酯：石油醚)得白色固体化合物1o(35mg，收率57％)。
将化合物1o(32mg,0.061mmol)溶于四氢呋喃(0.5mL)中并在氮气保护下冷却至-20℃,慢慢加入LDA(0.085mL，0.18mmol)，升温至0℃搅拌20分钟，然后冷却至-20℃，将MeI(26mg，0.18mmol)加入上述溶液，在0℃搅拌20分钟。向反应液中加入饱和NH 4Cl水溶液(5mL)，用乙酸乙酯萃取(3X 10mL)，合并有机相，用饱和食盐水洗涤(3X 10mL)，用无水硫酸钠干燥，过滤减压浓缩，所得的粗品经制备薄板层析分离(30％，乙酸乙酯：石油醚)得到淡黄色的固体化合物1p(6.0mg，收率18％)。
在0℃下向化合物1p(6mg,0.009mmol)的二氯甲烷(0.5mL)加入HCl(0.004mL，4M)的二氧六环溶液，在0℃下继续搅拌20分钟。向反应液中加入碳酸氢钠的水溶液(5mL)，用乙酸乙酯萃取(3X 4mL)，合并有机相，用饱和食盐水洗涤(3X 4mL)，用无水硫酸钠干燥，过滤减压浓缩，所得的粗品经制备薄板层析分离(50％，乙酸乙酯：石油醚)得到淡黄色的固体化合物1(3.0mg，收率61％)。 1H NMR(500MHz,CDCl 3)δ8.79(d,J＝5.0Hz,1H),8.11–8.08(m,1H),7.69–7.67(m,1H),7.50–7.44(m,3H),7.35–7.34(m,1H),7.29-7.27(m,2H),7.22(s,1H),3.73–3.71(m,1H),2.72–2.69(m,2H),2.45–2.37(m,2H),2.32–2.21(m,2H),2.20–2.16(m,2H),1.50–1.48(m,2H),1.27(d,J＝5.0Hz,3H),1.14–1.05(m,2H)。LCMS m/z 437.3[M+H] +。
化合物1可以用另一种合成路线来制备，具体反应式如下：
Figure PCTCN2018106768-appb-000078
上述路线在开始的步骤中使用了三乙基-2-膦酰基丙酯，从而在羧酸的位引入甲基，经过类似的反应，得到了化合物1ag和化合物1ah的比例大约为5：1。顺式的酯1ag经碱性水解，得酸1ai，然后与对氯苯胺缩合，得消旋的化合物1。
消旋的化合物1经SFC手性拆分得到化合物1A和1B。制备SFC条件：仪器：SFC-80 (Thar,Waters)；手性柱：CHIRALCEL OJ(30*250mm 5μm)(Daicel)；柱温：35℃；流速：45mL/分钟；检测波长：215nm；流动相A：CO 2；流动相B：甲醇。30％B恒定洗脱。峰1：8.8-10.2分钟；峰2：11.4-13.2分钟。e.e.值均大于99％。这里峰1和峰2的绝对立体构型尚未确定。
Figure PCTCN2018106768-appb-000079
峰1化合物： 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.6Hz,1H),8.11(dd,J＝9.2,5.7Hz,1H),7.69(dd,J＝10.5,2.7Hz,1H),7.50(d,J＝8.7Hz,2H),7.49–7.44(m,1H),7.36(d,J＝4.6Hz,1H),7.30(d,J＝8.8Hz,2H),7.11(s,1H),3.77–3.71(m,1H),2.74–2.70(m,2H),2.47–2.38(m,2H),2.36–2.25(m,2H),2.22–2.15(m,2H),1.54–1.48(m,2H),1.28(d,J＝6.8Hz,3H),1.16–1.02(m,2H)。LCMS m/z 437.3[M+H] +。e.e.值99.0％。
峰2化合物： 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.6Hz,1H),8.11(dd,J＝9.2,5.7Hz,1H),7.68(dd,J＝10.5,2.7Hz,1H),7.50(d,J＝8.8Hz,2H),7.50–7.45(m,1H),7.36(d,J＝4.6Hz,1H),7.29(d,J＝8.8Hz,2H),7.19(s,1H),3.77–3.70(m,1H),2.73–2.66(m,2H),2.49–2.37(m,2H),2.37–2.24(m,2H),2.21–2.18(m,2H),1.53–1.47(m,2H),1.28(d,J＝6.8Hz,3H),1.17–1.02(m,2H)。LCMS m/z 437.3[M+H] +。e.e.值99.0％。
实施例2 化合物1A的制备
Figure PCTCN2018106768-appb-000080
化合物1m(35mg，0.11mmol)在二氯亚砜中回流1小时。减压蒸馏除去剩余的二氯亚砜。粗品酰氯直接用于下一步反应。在一个干燥的圆底瓶中将(R)-4-苯基-2-恶唑烷酮(34mg，0.11mmol)溶解在四氢呋喃(1mL)中，在氮气保护下冷却至-65℃，然后将LDA(0.1mL，0.21mmol)慢慢地加入，在此温度搅拌15分钟。将粗品酰氯的四氢呋喃(2mL)溶液加入到上述反应液中，在此温度继续搅拌1小时。加入饱和的氯化铵水溶液(6mL)，用乙酸乙酯萃取(3X 5mL)。合并有机相，用饱和食盐水洗涤(3X 5mL)。有机相干燥过滤，滤液减压浓缩所的粗品经制备薄板层析分离(50％，乙酸乙酯：石油醚)得到白色固体化合物1q(15mg，收率31％)。LCMS m/z 459.2[M+H] +。
化合物1A是从化合物1q制备得到的，详细的步骤可参考专利WO2016073774和WO2016073770。
实施例3 化合物2的制备
Figure PCTCN2018106768-appb-000081
按照上述化合物1的制备方法制备，化合物2即是上述化合物1n。 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.2Hz,1H),8.10(dd,J＝9.3,6.0Hz,1H),7.68(d,J＝10.4Hz,1H),7.48(d,J＝8.4Hz,2H),7.36(d,J＝4.5Hz,1H),7.28(d,J＝8.4Hz,3H),7.15(s,1H),3.74–3.73(m,1H),3.61–3.57(m,1H),2.75–2.73(m,2H),2.57–2.50(m,1H),2.45–2.38(m,3H),2.28–2.26(m,2H),1.48–1.44(m,2H),11.13–1.12(m,2H)。LCMS m/z 423.1[M+H] +。
实施例4 化合物3的制备
Figure PCTCN2018106768-appb-000082
将四氢呋喃(0.5mL)和LDA的四氢呋喃溶液(2.0M，1.22mL，2.44mmol)，放在一个干燥的圆底烧瓶中，氮气保护下冷却至-78℃，加入N,N-二甲基丙烯基脲(118mg，0.92mmol)和1j(0.2g，0.61mmol)的四氢呋喃(0.5mL)溶液，在-20℃下搅拌1小时。然后加入碘甲烷(0.35g，2.44mmol)。在此温度下继续搅拌1小时。向反应液中加入饱和氯化铵水溶液(5mL)，用乙酸乙酯萃取(3X 5mL)，合并有机相，用饱和食盐水洗涤(3X 4mL)。无水硫酸钠干燥，过滤，减压浓缩得粗品。经制备薄板层析分离(20％乙酸乙酯：石油醚)得到淡黄色固体化合物3a(120mg，收率58％)。
将化合物3a(120mg，0.35mmol)溶在甲醇(2mL)和水(0.4mL)中，然后加入氢氧化钾(197mg，3.5mmol)，在50℃下搅拌30分钟。薄板层析显示反应完成。冷却至0℃，用HCl水溶液(3N)调节至pH＝6，然后用乙酸乙酯萃取(3X 10mL)，合并有机相，饱和食盐水洗涤(3X 5mL)，无水硫酸钠干燥，过滤，减压浓缩得淡棕色的固体化合物3b(100mg，收率87％)。
将3b(14mg，0.043mmol),HOBT(8.67mg，0.064mmol),EDCI(12.3mg，0.064mmol)和N,N-二异丙基乙胺(16.58mg，0.13mmol)溶在N,N-二甲基甲酰胺(0.5mL)中，然后加入4-氨基四氢吡喃(6.5mg，0.064mmol) ，反应在50℃搅拌2小时。减压浓缩得粗品，经制备薄板层析分离(20％，乙酸乙酯：石油醚)得到白色固体化合物3(2mg，收率5％)。 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.5Hz,1H),8.11(dd,J＝9.0,5.7Hz,1H),7.69(dd,J＝10.4,2.4Hz,1H),7.51–7.43(m,1H),7.36(d,J＝4.4Hz,1H),5.30(d,J＝8.0Hz,1H),4.08–3.91(m,3H),3.72(m,1H),3.49(t,J＝11.5Hz,2H),2.72(m,2H),2.41(m,2H),2.27–2.14(m,2H),2.08(m,1H),2.02–1.82(m,3H),1.55–1.38(m,4H),1.17(d,J＝8.4Hz,3H),1.03(m,2H)。LCMS m/z 411.2[M+H] +。
实施例5 化合物4的制备
Figure PCTCN2018106768-appb-000083
化合物4是从化合物3b和4-氯苯胺按照上述化合物3的制备方法制备得到的。 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.5Hz,1H),8.11(dd,J＝9.1,5.7Hz,1H),7.68(d,J＝10.5,1H),7.51(d,J＝8.7Hz,2H),7.48(t,J＝8.3Hz,1H),7.30(d,J＝8.7Hz,2H),7.28(s,1H),7.21(s,1H),3.59–3.57(m,1H),3.14(t,J＝12.0Hz,1H),2.19(t,J＝7.2Hz,1H),2.16–2.08(m,1H),2.07–2.03(m,1H),1.84–1.60(m,6H),1.47–1.39(m,2H),1.30(d,J＝6.7Hz,3H)。LCMS m/z 437.1[M+H] +。
实施例6 化合物5的制备
Figure PCTCN2018106768-appb-000084
化合物5是从化合物1k和4-氯苯胺按照上述化合物2的制备方法制备得到的。 1H NMR(500MHz,CDCl 3)δ8.79(d,J＝4.6Hz,1H),8.10(dd,J＝9.2,5.7Hz,1H),7.68(dd,J＝10.5,2.8Hz,1H),7.48(d,J＝8.8Hz,2H),7.47–7.44(m,1H),-7.34(m,J＝4.6Hz,1H),7.32(s,1H),7.28(d,J＝8.8Hz,2H),3.48–3.40(m,1H),2.81–2.75(m,2H),2.57–2.54(m,1H),2.41(d,J＝7.1Hz,2H),2.40-2.35(m,2H),1.78(dd,J＝12.8,5.7Hz,2H),1.46–1.37(m,4H)。LCMS m/z 423.1[M+H] +。
实施例7 化合物6的制备
Figure PCTCN2018106768-appb-000085
化合物6是从化合物3b和5-氨基-2-甲氧基吡啶按照上述化合物3的制备方法制备得到的。 1H NMR(500MHz,CDCl 3)δ8.79(d,J＝4.5Hz,1H),8.15(d,J＝2.7Hz,1H),8.10(dd,J＝9.1,5.7Hz,1H),7.96(dd,J＝8.9,2.1Hz,1H),7.68(dd,J＝10.4,2.6Hz,1H),7.49–7.44(m,1H),7.35(d,J＝4.5Hz,1H),7.28(s,1H),6.73(d,J＝8.9Hz,1H),3.91(s,3H),3.74–3.69(m,1H),2.73–2.69(m,2H),2.44–2.36(m,2H),2.33–2.17(m,4H),1.49(dd,J＝20.2,12.0Hz,2H),1.28(d,J＝6.7Hz,3H),1.17–1.02(m,2H)。LCMS m/z434.2[M+H] +。
实施例8 化合物7的制备
Figure PCTCN2018106768-appb-000086
化合物7是从化合物3b和3-氯苯胺按照上述化合物3的制备方法制备得到的。 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.5Hz,1H),8.11(dd,J＝9.2,5.7Hz,1H),7.54(dd,J＝5.8,3.3Hz,2H),7.50–7.44(m,1H),7.38(s,1H),7.36(d,J＝4.7Hz,1H),7.24(d,J＝8.1Hz,1H),7.16(s,1H),7.09(d,J＝8.0Hz,1H),3.80–3.68(m,1H),2.78–2.66(m,2H),2.46–2.16(m,6H),1.54–1.41(m,2H),1.28(d,J＝6.8Hz,3H),1.17–1.04(m,2H)。LCMS m/z 437.1[M+H] +。
实施例9 化合物8的制备
Figure PCTCN2018106768-appb-000087
化合物8是从化合物3b和4-氨基苯甲酸甲酯按照上述化合物3的制备方法制备得到的。 1H NMR(500MHz,CDCl 3)δ8.79(d,J＝4.6Hz,1H),8.10(dd,J＝9.2,5.7Hz,1H),8.01(d,J＝8.7Hz,2H),7.68(dd,J＝10.5,2.7Hz,1H),7.63(d,J＝8.7Hz,2H),7.49–7.44(m,1H),7.35(d,J＝4.6Hz,1H),7.33(s,1H),3.90(s,3H),3.77–3.69(m,1H),2.73–2.67(m,2H),2.45–2.20(m,7H),2.03–1.98(m,1H),1.29(d,J＝6.7Hz,3H),1.17–1.04(m,2H)。LCMS m/z 461.2[M+H] +。
实施例10 化合物9的制备
Figure PCTCN2018106768-appb-000088
将化合物9a(1.0g，4.44mmol)溶于甲苯(10mL)中，加入甲氧甲酰基亚甲基三苯基膦(2.23g，6.66mmol)。该反应体系在110℃的封管中搅拌18小时。反应液用乙酸乙酯(50mL)稀释，并用饱和食盐水洗涤(15mL)。有机相经无水硫酸钠干燥，过滤。滤液减压浓缩后，粗品经硅胶柱层析纯化(乙酸乙酯/石油醚＝0-15％)得到灰色固体化 合物9b(0.69g，收率55％)。
将化合物9b(0.69g，2.45mmol)溶于乙醇(5mL)，随后加入10％Pd/C(261mg)，在一个大气压的氢气氛下室温搅拌过夜。将Pd/C用硅藻土过滤除去，减压浓缩后得到无色油状液体9c(0.65g，收率94％)。
将三氟乙酸(1.46mL，23.10mmol)慢慢加入到化合物9c(0.65g，2.31mmol)的二氯甲烷(2mL)溶液中，在室温下搅拌30分钟。反应结束后，减压浓缩得到浅黄色的油状物9d(0.3g，收率71％)。粗品不进一步纯化直接用于下面反应。
将化合物9d(0.3g，1.64mmol)，4-氯-6-氟喹啉(357mg，1.96mmol)，N,N-二异丙基乙胺(0.634g，4.91mmol)溶于二甲亚砜(3mL)。反应物在氮气保护下加热至90℃搅拌18小时。反应液减压浓缩后，粗品经硅胶柱层析纯化(乙酸乙酯/石油醚＝0-50％)，得到淡黄色的油状化合物9e(0.44g，收率81％)。 1H NMR显示顺式/反式的比例约为5：1。
将氢氧化锂(36.46mg，1.5mmol)加入到化合物9e(50mg，0.15mmol)的甲醇(2mL)和水(0.4mL)溶液中，反应液在室温下搅拌，薄板层析显示反应完全。将反应液用盐酸(3N)调节pH＝6，然后用乙酸乙酯萃取(3X 5mL)。有机相用无水硫酸钠干燥，过滤，减压浓缩得到淡黄色得固体9f(45mg，收率94％)。粗品不进一步纯化直接用于下面反应。
将化合物9f(45mg，0.14mmol)，HOBT(29.4mg，0.21mmol)，EDCI(41.2mg，0.24mmol)溶于N,N-二甲基甲酰胺(1mL)中，然后加入N,N-二异丙基乙胺(55.5mg，0.43mmol)，反应物在50℃下搅拌2小时。减压浓缩后经薄板层析分离(50％，乙酸乙酯：CH 2Cl 2)得到化合物9g(25mg，收率41％)。
将化合物9g(25mg，0.059mmol)，4-二甲氨基吡啶(10.8mg，0.088mmol)，二碳酸二叔丁酯(19.3mg，0.088mmol)溶于乙腈(1mL)中，在50℃搅拌5分钟。反应物减压蒸馏。粗品经薄板层析分离得到化合物9h。
将化合物9h(15mg，0.028mmol)溶于四氢呋喃(0.5mL)，在氮气保护下冷却至-20℃，慢慢加入LDA(0.085mL，0.086mmol)。在0℃下搅拌20分钟，然后冷却至-20℃，加入碘甲烷(12mg，0.085mmol)，在此温度下继续搅拌20分钟。向反应体系加入饱和氯化铵水溶液(4mL)，用乙酸乙酯萃取(3X 5mL)。合并有机相，用饱和食盐水洗涤(3X 5mL)，然后干燥浓缩。粗品经制备薄板层析分离(50％，乙酸乙酯：二氯甲烷)得到淡黄色的固体9i(5mg，收率32％)。
将化合物9i(5mg，9.0mol)溶于二氯甲烷(0.5mL)，然后在0℃下加入盐酸的二氧六环溶液(4L，4M HCl)。搅拌20分钟后薄板层析显示反应完全。向反应体系加入饱和碳酸氢钠水溶液，并用乙酸乙酯萃取(3X 3mL)，有机相干燥过滤，滤液减压浓缩所的粗品经制备薄板层析分离(50％，乙酸乙酯：二氯甲烷)得到白色固体化合物9(0.74mg，收率18％)。 1H NMR(500MHz,CD 3OD)δ8.43(d,J＝5.6Hz,1H),7.93(dd,J＝5.5,3.5Hz,1H),7.90(d,J＝3.1Hz,1H),7.63–7.53(m,2H),7.51(dd,J＝11.8,5.4Hz,1H),7.32–7.21(m,2H),6.79(d,J＝5.6Hz,1H),3.69–3.46(m,5H),2.93–2.77(m,2H),2.45–2.10(m,4H),1.47–1.38(m,1H),1.25(d,J＝6.8Hz,3H)。LCMS m/z 437.99[M+H] +。
实施例11 化合物10的制备
Figure PCTCN2018106768-appb-000089
化合物10b是根据专利WO2016073774和WO2016073770的步骤从化合物10a制备得到的。化合物10c是从化合物10b制备得到的(详细步骤见1o的制备)。
将化合物10c(120mg，0.24mmol)溶在四氢呋喃(0.5mL)中，冷却至-20℃，慢慢加入LDA(0.42mL，0.85mmol),升温至0℃搅拌20分钟，然后冷却至-20℃，将10d(205mg，0.85mmol)加入上述溶液，在0℃搅拌20分钟。向反应液中加入饱和氯化铵水溶液(5mL)，用乙酸乙酯萃取(3X 10mL)，合并有机相，用饱和食盐水洗涤(3X 10mL)，用硫酸钠干燥，过滤减压浓缩，所得的粗品经制备薄板层析分离(30％乙酸乙酯：石油醚)得到淡黄色的固体化合物10e(76mg，率收40％)。
化合物10f是从化合物10e制备得到的(详细步骤见1的制备)。
化合物10g是从化合物10f制备得到的(详细步骤见1m的制备)。
将化合物10g(7.8mg，14.31mol)，HOBt(2.90mg，21.47mol)，EDCI(4.12mg，21.47mol)和N,N-二异丙基乙胺(5.55mg，42.39mol)溶于N,N-二甲基甲酰胺(0.5mL)，然后加入O-苄基羟胺(2.64mg，21.47mmol)，在室温下搅拌2小时。反应液减压浓缩后，粗品经制备薄板层析分离(10％，甲醇：二氯甲烷)得到无色液体化合物10h(4.1mg，收率44％)。LCMS m/z 650.2[M+H] +。
将化合物10h(4.1mg，6.31mol)溶于甲醇(0.5mL)中，加入10％Pd/C(6.71mg，63.06mol)，反应体系在一个大气压的氢气环境下搅拌10分钟。薄板层析显示反应完全。将Pd/C过滤，滤液减压浓缩，粗品经薄板层析分离(10％，甲醇：二氯甲烷)得到化合物10(0.51mg，收率14％)。LCMS m/z 560.2[M+H] +。
实施例12 化合物11的制备
Figure PCTCN2018106768-appb-000090
化合物11是从化合物1h经水解，所得的酸11a和4-氯苯胺缩合得到的主产物。 1H NMR (500MHz,CD 3OD)δ8.75(d,J＝4.6Hz,1H),8.08(dd,J＝9.3,5.5Hz,1H),7.85(dd,J＝10.3,2.8Hz,1H),7.67–7.50(m,3H),7.42(d,J＝4.6Hz,1H),7.35–7.23(m,2H),6.08(d,J＝1.6Hz,1H),3.56–3.49(m,1H),3.19–3.11(m,1H),2.96–2.87(m,1H),2.59(d,J＝16.7Hz,1H),2.47(d,J＝6.5Hz,2H),2.36(dd,J＝14.8,8.2Hz,2H),2.26(dd,J＝12.1,7.0Hz,1H),1.32–1.17(m,2H)。LCMS m/z 421.2[M+H] +。
实施例13 化合物12的制备
Figure PCTCN2018106768-appb-000091
化合物12是由中间体1m和4,4-二氟环己基胺经酰胺缩合反应得到的。 1H NMR(500MHz,CDCl 3)δ8.79(d,J＝4.6Hz,1H),8.10(dd,J＝9.2,5.7Hz,1H),7.68(dd,J＝10.4,2.7Hz,1H),7.54–7.44(m,1H),7.35(d,J＝4.5Hz,1H),5.29(d,J＝7.6Hz,1H),3.92–3.89(m,1H),3.76–3.69(m,1H),2.73–2.68(m,2H),2.45–2.38(m,3H),2.24(d,J＝7.2Hz,2H),2.21–2.16(m,2H),2.10–2.08(m,2H),2.02–1.97(m,2H),1.93–1.79(m,2H),1.54–1.46(m,4H),1.08–1.01(m,2H)。LCMS m/z 431.4[M+H] +。
实施例14 化合物13的制备
Figure PCTCN2018106768-appb-000092
化合物13是由中间体1m和化合物13a经酰胺缩合反应得到的。 1H NMR(500MHz,CDCl 3)δ8.78(d,J＝4.5Hz,1H),8.11–8.08(m,1H),7.67(d,J＝10.0Hz,1H),7.45–7.44(m,1H),7.35(d,J＝4.4Hz,1H),7.09(s,1H),7.02(d,J＝8.4Hz,1H),6.96(s,1H),6.70–6.67(m,1H),4.12(t,J＝6.9Hz,1H),4.03–4.02(m,1H),3.95–3.91(m,1H),3.85–3.84(m,1H),3.75–3.70(m,2H),3.49–3.44(m,1H),3.28–3.24(m,1H),3.18–3.17(m,1H),2.84–2.80(m,1H),2.76–2.66(m,2H),2.54–2.48(m,1H),2.41–2.38(m,4H),2.25–2.23(m,2H),1.52–1.46(m,2H),1.12–1.06(m,2H)。LCMS m/z 502.3[M+H] +。
实施例15 化合物14的制备
Figure PCTCN2018106768-appb-000093
化合物14是由中间体1m和化合物14a经酰胺缩合反应得到的。 1H NMR(500MHz,DMSO-d 6)δ12.95(s,1H),9.85(s,1H),8.80(d,J＝4.5Hz,1H),8.11(s,1H),8.07(dd,J＝9.1,5.8Hz,1H),8.00–7.97(m,2H),7.67–7.64(m,1H),7.53(d,J＝4.4Hz,1H),7.47–7.41(m,2H),3.87–3.82(m,1H),2.72–2.64(m,3H),2.42(d,J＝16.4Hz,2H),2.33–2.32(m,2H),2.12–2.09(m,2H),1.51–1.45(m,2H),1.15–1.09(m,2H)。LCMS m/z429.4[M+H] +。
实施例16 化合物15的制备
Figure PCTCN2018106768-appb-000094
化合物15是由中间体1m和化合物15a经酰胺缩合反应得到的。 1H NMR(500MHz,CDCl 3)δ8.79(d,J＝4.6Hz,1H),8.10(dd,J＝9.2,5.7Hz,1H),7.99(d,J＝1.3Hz,1H),7.91(s,1H),7.68(dd,J＝10.4,2.7Hz,1H),7.48–7.31(m,5H),4.05(s,3H),3.77–3.69(m,1H),2.74–2.70(m,2H),2.58–2.55(m,1H),2.47(d,J＝7.2Hz,2H),2.44–2.39(m,2H)2.31–2.26(m,2H),1.54–1.48(m,2H),1.16–1.10(m,2H)。LCMS m/z 443.4[M+H] +。
实施例17 化合物16的制备
Figure PCTCN2018106768-appb-000095
化合物16是由中间体1m和化合物16a经酰胺缩合反应得到的。 1H NMR(500MHz,DMSO-d 6)δ10.11(s,1H),8.80(d,J＝4.5Hz,1H),8.07(dd,J＝9.2,5.8Hz,1H),7.98(dd,J＝10.9,2.7Hz,1H),7.78(d,J＝1.9Hz,1H),7.67–7.63(m,1H),7.53(d,J＝4.5Hz,1H),7.33–7.32(m,1H),7.24(dd,J＝8.8,2.0Hz,1H),3.87–3.80(m,1H),2.66–2.64(m,2H),2.39–2.31(m,5H),2.10–2.07(m,2H),1.50–1.44(m,2H),1.10–1.06(m,2H)。LCMS m/z 469.3[M+H] +。
实施例18 化合物17的制备
Figure PCTCN2018106768-appb-000096
化合物17是由中间体1m和化合物17a经酰胺缩合反应得到的。 1H NMR(500MHz,CDCl 3)δ8.81(d,J＝4.6Hz,1H),8.22–8.21(m,2H),8.12(dd,J＝9.2,5.7Hz,1H),7.89(s,1H),7.70–7.66(m,2H),7.49–7.45(m,1H),7.38(d,J＝4.5Hz,1H),3.77–3.70(m,1H),2.76–2.71(m,2H),2.57–2.51(m,1H),2.49(d,J＝7.2Hz,2H),2.45–2.40(m,2H),2.29–2.24(m,2H),1.59–1.49(m,2H),1.16–1.09(m,2H)。LCMS m/z 424.22[M+H] +。
实施例19 化合物18的制备
Figure PCTCN2018106768-appb-000097
化合物18是由中间体1m和化合物18a经酰胺缩合反应得到的。 1H NMR(500MHz, CDCl 3)δ8.81(s,1H),8.36(d,J＝2.2Hz,1H),8.22–8.18(m,2H),7.71(dd,J＝10.1,2.2Hz,1H),7.53–7.49(m,1H),7.43(s,1H),7.30(d,J＝8.7Hz,1H),3.80–3.73(m,1H),2.78–2.73(m,2H),2.55–2.50(m,1H),2.49(d,J＝6.9Hz,2H),2.44(dt,J＝12.4,6.2Hz,2H),2.30–2.25(m,2H),1.53(dd,J＝20.0,12.1Hz,2H),1.13(dd,J＝19.3,11.4Hz,2H)。LCMS m/z 424.21[M+H] +。
实施例20 化合物19的制备
Figure PCTCN2018106768-appb-000098
化合物19是由中间体1m和化合物19a经酰胺缩合反应得到的。 1H NMR(500MHz,CDCl 3)δ8.79(d,J＝4.5Hz,1H),8.11(dd,J＝9.2,5.7Hz,1H),7.68(dd,J＝10.4,2.6Hz,1H),7.51(d,J＝8.4Hz,2H),7.49–7.44(m,3H),7.36(d,J＝4.7Hz,2H),3.76–3.49(m,1H),3.04(s,1H),2.77–2.67(m,2H),2.56–2.52(m,1H),2.45(d,J＝7.1Hz,2H),2.43–2.37(m,2H),2.28–2.23(m,2H),1.53–1.48(m,2H),1.13–1.07(m,2H)。LCMS m/z413.29[M+H] +。
实施例21 化合物20的制备
Figure PCTCN2018106768-appb-000099
化合物20是由中间体1k经水解得到20a，再与化合物19a经酰胺缩合反应得到的。 1H NMR(500MHz,CDCl 3)δ8.79(d,J＝4.5Hz,1H),8.11(dd,J＝9.2,5.7Hz,1H),7.69(dd,J＝10.5,2.7Hz,1H),7.52(d,J＝8.5Hz,2H),7.48–7.45(m,3H),7.35(d,J＝4.6Hz,1H),7.33(s,1H),3.48–3.41(m,1H),3.05(s,1H),2.82–2.74(m,2H),2.62–2.52(m,1H),2.43(d,J＝7.1Hz,2H),2.41–2.35(m,2H),1.79(dd,J＝12.8,5.7Hz,2H),1.47–1.37(m,4H)。LCMS m/z 413.30[M+H] +。
实施例22 化合物21的制备
Figure PCTCN2018106768-appb-000100
将化合物20a(150mg，0.479mmol)溶解在氯化亚砜(5mL)中，将反应加热到50℃搅拌30分钟。减压浓缩得到白色固体化合物21a(150mg，收率94.3％)。粗品不经纯化，直接用于下一步反应。
将2-氨基-5-氯吡啶(17a,15mg，0.117mmol)溶解在四氢呋喃(1.0mL)中，冰水浴下缓慢加入60％的NaH(4.7mg,0.117mmol)，缓慢升到室温并搅拌1小时，将化合物20b(38.71mg，0.117mmol)的四氢呋喃(1mL)溶液缓慢加入到反应液中，升温到60℃搅拌6小时。将反应液缓慢加入到饱和碳酸氢钠溶液中，用乙酸乙酯萃取(3X 2mL)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，通过柱层析纯化(乙酸乙酯/石油醚 ＝0-5％)分离得到白色固体化合物21(9.87mg，收率20％)。 1H NMR(500MHz,CDCl 3)δ8.81(d,J＝4.6Hz,1H),8.24–8.19(m,3H),7.96(s,1H),7.72(dd,J＝10.3,1.7Hz,1H),7.68(dd,J＝8.9,2.4Hz,1H),7.52–7.48(m,1H),7.41(s,1H),3.51–3.44(m,1H),2.84–2.76(m,2H),2.61–2.52(m,1H),2.47(d,J＝7.1Hz,2H),2.42–2.36(m,2H),1.80(dd,J＝12.8,5.7Hz,2H),1.44(dt,J＝19.9,12.8Hz,4H)。LCMS m/z 424.20[M+H] +。
实施例23 化合物22的制备
Figure PCTCN2018106768-appb-000101
化合物22是由中间体20a和化合物18a经酰胺缩合反应得到的。 1H NMR(500MHz,CDCl 3)δ8.79(d,J＝4.5Hz,1H),8.36(d,J＝2.7Hz,1H),8.19(dd,J＝8.6,2.5Hz,1H),8.12(dd,J＝9.1,5.7Hz,1H),7.69(dd,J＝10.4,2.6Hz,1H),7.48(dd,J＝8.6,2.0Hz,1H),7.40(s,1H),7.36(d,J＝4.5Hz,1H),7.30(d,J＝8.7Hz,1H),3.49–3.42(m,1H),2.84–2.73(m,2H),2.62–2.50(m,1H),2.46(d,J＝7.0Hz,2H),2.42–2.38(m,2H),1.79(dd,J＝12.7,5.7Hz,2H),1.49–1.35(m,4H)。LCMS m/z 424.26[M+H] +。
实施例24 化合物23的制备
Figure PCTCN2018106768-appb-000102
化合物23是由中间体20a和化合物23a经酰胺缩合反应得到的。 1H NMR(500MHz,CDCl 3)δ8.78(d,J＝4.3Hz,1H),8.14(s,1H),7.70–7.68(m,3H),7.63–7.57(m,2H),7.51–7.43(m,1H),7.37(d,J＝4.0Hz,1H),7.32(s,1H),3.50–3.41(m,1H),2.83–2.74(m,2H),2.60–2.52(m,1H),2.45(d,J＝7.1Hz,2H),2.42–2.35(m,2H),1.79(dd,J＝12.8,5.7Hz,2H),1.46–1.38(m,4H)。LCMS m/z 414.24[M+H] +。
实施例25 化合物24的制备
Figure PCTCN2018106768-appb-000103
化合物24是由中间体20a和化合物24a经酰胺缩合反应得到的。 1H NMR(500MHz,CDCl 3)δ8.78(d,J＝4.6Hz,1H),8.49(d,J＝2.4Hz,1H),8.24(dd,J＝8.5,2.2Hz,1H),8.16(s,1H),7.69(dd,J＝10.4,2.7Hz,1H),7.50–7.44(m,2H),7.38(d,J＝4.3Hz,1H),7.30(s,1H),3.50–3.41(m,1H),3.11(s,1H),2.78(dd,J＝12.9,7.2Hz,2H),2.60-2.52(m,1H),2.46(d,J＝7.0Hz,2H),2.42–2.35(m,2H),1.79(dd,J＝12.8,5.7Hz,2H),1.46–1.38(m,4H)。LCMS m/z 207.78[1/2M+H] +。
实施例26 化合物25的制备
Figure PCTCN2018106768-appb-000104
化合物25是由中间体20a和化合物25a经酰胺缩合反应得到的。 1H NMR(500MHz,CDCl 3)δ8.72(d,J＝4.6Hz,1H),8.31(d,J＝1.6Hz,1H),8.14(d,J＝8.7Hz,1H),8.06(dd,J＝8.7,5.8Hz,1H),7.85(s,1H),7.72(dd,J＝8.6,2.1Hz,1H),7.62(dd,J＝10.4,2.7Hz,1H),7.45–7.37(m,1H),7.30(d,J＝4.5Hz,1H),3.42-3.35(m,1H),3.09(s,1H),2.76–2.67(m,2H),2.53–2.46(m,1H),2.40(d,J＝7.1Hz,2H),2.32(dd,J＝11.8,6.5Hz,2H),1.72(dd,J＝12.8,5.7Hz,2H),1.41–1.29(m,4H)。LCMS m/z 414.28[M+H] +。
实施例27 化合物26的制备
Figure PCTCN2018106768-appb-000105
将化合物1ai(300mg，0.92mmol)溶解在氯化亚砜(10mL)中，将反应加热到50℃搅拌30分钟。减压浓缩得到白色固体化合物1aj(300mg，收率95％)。粗品不经纯化，直接用于下一步反应。
将2-氨基-5-氯吡啶(17a,45mg，0.35mmol)溶解在四氢呋喃(3mL)中，冰水浴下缓慢加入60％的NaH(14mg,0.35mmol)，缓慢升到室温并搅拌1小时，将化合物1aj(100mg，0.29mmol)的四氢呋喃(2mL)溶液缓慢加入到反应液中，升温到60℃搅拌6小时。将反应液缓慢加入到饱和碳酸氢钠溶液中，用乙酸乙酯萃取(3X 5mL)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，通过柱层析纯化(乙酸乙酯/石油醚＝0-5％)分离得到白色固体化合物26(54mg，收率43％)。 1H NMR(500MHz,CD 3OD)δ8.72(d,J＝4.7Hz,1H),8.26(d,J＝2.6Hz,1H),8.13(d,J＝8.9Hz,1H),8.05(dd,J＝9.2,5.6Hz,1H),7.88(dd,J＝10.6,2.7Hz,1H),7.77(dd,J＝8.9,2.5Hz,1H),7.59–7.54(m,2H),3.94–3.83(m,1H),2.77–2.71(m,2H),2.49–2.37(m,3H),2.31–2.24(m,2H),2.06–2.02(m,1H),,1.60–1.51(m,2H),1.22(d,J＝6.8Hz,3H),1.18–1.09(m,2H)。LCMS m/z438.26[M+H] +。
Figure PCTCN2018106768-appb-000106
消旋化合物26经SFC手性拆分得到化合物26A和26B。制备SFC条件：仪器：SFC-80(Thar,Waters)；手性柱：CHIRALPAK AS-3(30*250mm 5μm)(Daicel)；柱温：35℃；流速：45mL/分钟；检测波长：215nm；流动相A：CO 2；流动相B：甲醇。20％B恒定洗脱。峰1：15-17.5分钟；峰2：20-23分钟。这里峰1和峰2的绝对立体构型尚未确定。
峰1化合物： 1H NMR(500MHz,CD 3OD)δ8.74(d,J＝4.7Hz,1H),8.27(d,J＝2.6Hz,1H),8.15(d,J＝8.9Hz,1H),8.06(dd,J＝9.2,5.6Hz,1H),7.89(dd,J＝10.6,2.7Hz,1H),7.78(dd,J＝8.9,2.6Hz,1H),7.61–7.57(m,1H),7.55(d,J＝4.8Hz,1H),3.91–3.84(m,1H),2.82–2.64(m,2H),2.53–2.36(m,3H),2.33–2.20(m,2H),2.13–2.01(m,1H),1.62–1.48(m, 2H),1.23(d,J＝6.8Hz,3H),1.17–1.08(m,1H)。LCMS m/z 438.1[M+H] +。e.e.值99.8％。
峰2化合物： 1H NMR(500MHz,CD 3OD)δ8.75(d,J＝4.7Hz,1H),8.29(d,J＝2.6Hz,1H),8.16(d,J＝8.9Hz,1H),8.07(dd,J＝9.2,5.6Hz,1H),7.91(dd,J＝10.6,2.8Hz,1H),7.79(dd,J＝8.9,2.6Hz,1H),7.62–7.58(m,1H),7.57(d,J＝4.9Hz,1H),3.93–3.86(m,1H),2.83–2.70(m,2H),2.55–2.38(m,3H),2.33–2.21(m,2H),2.12–2.04(m,1H),1.62–1.54(m,2H),1.25(d,J＝6.8Hz,3H),1.16–1.09(m,1H)。LCMS m/z 438.1[M+H] +。e.e.值99.0％。
实施例28 化合物27的制备
Figure PCTCN2018106768-appb-000107
化合物27是由中间体1aj和化合物18a经酰胺缩合反应得到的。 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.5Hz,1H),8.36(d,J＝2.7Hz,1H),8.21(d,J＝8.7Hz,1H),8.10(dd,J＝9.2,5.7Hz,1H),7.68(dd,J＝10.4,2.6Hz,1H),7.49–7.45(m,1H),7.35–7.34(m,1H),7.31–7.29(m,1H),7.22(s,1H),3.78–3.69(m,1H),2.76–2.67(m,2H),2.45–2.40(m,2H),2.30–2.22(m,3H),2.17–2.15(m,1H),1.51–1.50(m,2H),1.28(d,J＝9.0Hz,3H),1.14–1.06(m,2H)。LCMS m/z 438.28[M+H] +。
实施例29 化合物28的制备
Figure PCTCN2018106768-appb-000108
化合物28是由中间体1aj和化合物28a经酰胺缩合反应得到的。 1H NMR(500MHz,CD 3OD)δ8.76(d,J＝4.7Hz,1H),8.08(dd,J＝9.3,5.5Hz,1H),8.03–8.01(m,1H),7.92(dd,J＝10.6,2.7Hz,1H),7.62–7.27(m,3H),6.57(d,J＝9.8Hz,1H),3.93–3.88(m,1H),2.85–2.74(m,2H),2.47–2.43(m,2H),2.36–2.25(m,3H),2.11–2.07(m,1H),1.62–1.55(m,2H),1.24(d,J＝6.7Hz,3H),1.21–1.12(m,2H)。LCMS m/z 420.30[M+H] +。
实施例30 化合物29的制备
Figure PCTCN2018106768-appb-000109
化合物29是由中间体1aj和化合物29a经酰胺缩合反应得到的。 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.6Hz,1H),8.65(s,1H),8.55(d,J＝9.3Hz,1H),8.10(dd,J＝9.2,5.7Hz,1H),7.67(dd,J＝10.4,2.7Hz,1H),7.52(d,J＝9.4Hz,1H),7.48–7.44(m,1H),7.36(d,J＝4.5Hz,1H),3.75–3.71(m,1H),2.72–2.70(m,2H),2.44–2.38(m,2H),2.35–2.20(m,3H),2.16–2.13(m,1H),1.52–1.50(m,2H),1.30(d,J＝8.9Hz,3H),1.18–1.19(m,2H)。LCMS m/z 439.26[M+H] +。
实施例31 化合物30的制备
Figure PCTCN2018106768-appb-000110
将化合物30a(300mg，2.14mmol)和4-二甲氨基吡啶(314mg，2.57mmol)溶解在乙腈(2mL)中，室温下加入二碳酸二叔丁酯(561mg，2.57mmol)。将反应升到50℃并在此温度搅拌30分钟。将反应液减压浓缩，通过柱层析纯化(乙酸乙酯/石油醚＝0-20％)分离得到黄色固体化合物30b(120mg，收率24％)。
将化合物30b(120mg，0.5mmol)溶解在甲醇(2mL)中，将10％Pd/C(10mg，0.1mmol)加入到溶液中，并在氢气氛围下室温搅拌3小时。将反应液过滤，减压浓缩，通过薄层硅胶板纯化(20％，乙酸乙酯：石油醚)分离得到黄色色固体化合物30c(87mg，收率83％)。
将化合物1aj(20mg，0.062mmol)，化合物30c(16mg，0.073mmol)，4-二甲氨基吡啶(8mg，0.0062mmol)溶解于吡啶(2mL)中，在100℃下搅拌18小时。减压浓缩后，粗品经制备薄板层析纯化(50％，乙酸乙酯：石油醚)得到白色固体化合物30d(2mg，收率6％)。
将化合物30d(4mg，0.0039mmol)溶解在二氯甲烷(0.5mL)中，冰水浴下缓慢滴加盐酸-二氧六环溶液(0.5mL，4N)，缓慢升到室温并搅拌1小时。将反应液用饱和碳酸氢钠溶液调节pH＝7，用乙酸乙酯萃取(3X 5mL)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，经制备薄板层析纯化(50％，乙酸乙酯：石油醚)分离得到白色固体化合物30(0.99mg，收率61％)。 1H NMR(500MHz,CDCl 3)δ8.81(s,1H),8.79(d,J＝4.6Hz,1H),8.10(dd,J＝9.2,5.7Hz,1H),7.68(dd,J＝10.4,2.7Hz,1H),7.48–7.44(m,2H),7.35(d,J＝4.6Hz,1H),7.25(s,2H),3.78–3.69(m,1H),2.74–2.68(m,2H),2.46–2.14(m,6H),1.50–1.46(m,2H),1.28(d,J＝7.1Hz,3H),1.16–1.05(m,2H)。LCMS m/z420.32[M+H] +。
实施例32 化合物31的制备
Figure PCTCN2018106768-appb-000111
中间体1aj和化合物31a反应得到化合物31b，经酸性条件去保护得化合物31。 1H NMR(500MHz,CDCl 3)δ13.12(s,1H),8.80(s,1H),8.77(d,J＝4.5Hz,1H),8.09(dd,J＝9.2,5.7Hz,1H),7.66(dd,J＝10.4,2.5Hz,1H),7.47–7.43(m,1H),7.31(d,J＝4.5Hz,1H),3.73–3.68(m,1H),2.99–2.93(m,1H),2.73–2.63(m,2H),2.44–2.39(m,2H),2.34–2.28(m,2H),2.10–2.05(m,1H),1.58–1.42(m,2H),1.35(d,J＝6.8Hz,3H),1.27–1.22(m,2H)。LCMS m/z 411.30[M+H] +。
实施例33 化合物32的制备
Figure PCTCN2018106768-appb-000112
化合物32a是根据WO2017/024996A1制备的。将环丙基吡唑-4-硼酸频哪醇酯(100mg，0.42mmol)，5-氨基-2-溴吡啶(62mg，0.36mmol)，Pd(dppf) 2Cl 2(26mg,0.036mmol)和碳酸钾(60mg,0.42mmol)溶于二氧六环(4mL)和水(1mL)中，将反应液在氮气保护下加热到100℃并在此温度搅拌2小时。反应液用乙酸乙酯萃取(3X 10mL)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，通过柱层析纯化(乙酸乙酯/石油醚＝0-30％)分离得到黄色固体化合物32a(50mg，收率70％)。
中间体1aj和化合物32a反应得到化合物32。 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.4Hz,1H),8.54(s,1H),8.31(s,1H),8.14–8.11(m,1H),8.05(s,1H),7.92(s,1H),7.68(dd,J＝10.4,1.9Hz,1H),7.48–7.46(m,2H),7.37(d,J＝4.6Hz,1H),3.75–3.71(m,1H),3.65–3.64(m,1H),2.75–2.69(m,2H),2.44–2.40(m,2H),2.36–2.16(m,4H),1.53–1.49(m,2H),1.30(d,J＝6.1Hz,3H),1.22–1.17(m,3H),1.13–1.05(m,3H)。LCMS m/z510.31[M+H] +。
实施例34 化合物33的制备
Figure PCTCN2018106768-appb-000113
中间体1aj和化合物33a反应得到化合物33。 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.5Hz,1H),8.13(dd,J＝9.1,5.7Hz,1H),7.89(dd,J＝5.7,2.2Hz,1H),7.69(dd,J＝10.3,2.5Hz,1H),7.50–7.37(m,3H),7.17(s,1H),7.09–7.06(m,1H),3.78–3.71(m,1H),2.74–2.71(m,2H),2.48–2.16(m,6H),1.54–1.48(m,2H),1.28(d,J＝6.7Hz,3H),1.17–1.04(m,2H)。LCMS m/z 501.15[M+H] +。
实施例35 化合物34的制备
Figure PCTCN2018106768-appb-000114
中间体1aj和化合物34a反应得到化合物34。 1H NMR(500MHz,CD 3OD)δ8.72(d,J＝4.7Hz,1H),8.05(dd,J＝9.2,5.6Hz,1H),7.89(dd,J＝10.6,2.7Hz,1H),7.59–7.53(m,4H),7.40–7.39(m,2H),3.90–3.83(m,1H),3.40(s,1H),2.77–2.69(m,2H),2.45–2.34(m,3H),2.29–2.22(m,2H),2.09–2.06(m,1H),1.59–1.50(m,2H),1.21(d,J＝6.7Hz,3H),1.16–1.08(m,2H)。LCMS m/z 427.32[M+H] +。
实施例36 化合物35的制备
Figure PCTCN2018106768-appb-000115
中间体1aj和化合物35a反应得到化合物35。 1H NMR(500MHz,CDCl 3)δ11.0(s,1H),8.83(s,1H),8.42–8.29(m,2H),8.21(dd,J＝8.8,5.7Hz,1H),7.08(s,1H),7.71(dd,J＝10.3,2.6Hz,1H),7.53–7.43(m,2H),3.76–3.73(m,1H),3.68–3.64(m,1H),3.11–3.08(m,1H),3.71(t,J＝7.6Hz,3H),2.43–2.14(m,7H),1.27(d,J＝6.5Hz,3H)。LCMS m/z 438.25[M+H] +。
实施例37 化合物36的制备
Figure PCTCN2018106768-appb-000116
中间体1aj和化合物23a反应得到化合物36。 1H NMR(500MHz,CD 3OD)δ8.72(d,J＝4.7Hz,1H),8.04(d,J＝5.5Hz,1H),7.89(dd,J＝10.6,2.7Hz,1H),7.79–7.78(m,2H),7.67–7.65(m,2H),7.59–7.53(m,2H),3.91–3.84(m,1H),2.79–2.69(m,2H),2.43–2.38(m,3H),2.31–2.22(m,2H),2.09–2.00(m,1H),1.59–1.50(m,2H),1.23(d,J＝6.8Hz,3H),1.19–1.06(m,2H)。LCMS m/z 428.3[M+H] +。
实施例38 化合物37的制备
Figure PCTCN2018106768-appb-000117
中间体1aj和化合物24a反应得到化合物37。 1H NMR(500MHz,CD 3OD)δ8.73(d,J＝4.5Hz,1H),8.70(d,J＝2.2Hz,1H),8.15(dd,J＝8.6,2.5Hz,1H),8.05(dd,J＝9.2,5.6Hz,1H),7.89(dd,J＝10.6,2.7Hz,1H),7.59–7.52(m,3H),3.91–3.84(m,1H),3.68(s,1H),2.80–2.72(m,2H),2.45–2.39(m,3H),2.28–2.25(m,2H),2.09–2.06(m,1H),1.60–1.51(m,2H),1.23(d,J＝7.2Hz,3H),1.20–1.09(m,2H)。LCMS m/z 428.26[M+H] +。
实施例39 化合物38的制备
Figure PCTCN2018106768-appb-000118
Figure PCTCN2018106768-appb-000119
将化合物1b(200mg，1.1mmol)溶于无水四氢呋喃(3mL)，在-78℃下向反应体系中滴加LDA(235mg，2.2mmol)，在该温度下搅拌1小时后，加入N-苯基双(三氟甲烷磺酰)亚胺38a(588mg，1.65mmol)，缓慢升至室温并搅拌1小时，加入饱和氯化铵溶液(2mL)淬灭，乙酸乙酯萃取(3X 10mL)，合并有机相，加入无水硫酸钠干燥，过滤，滤液减压浓缩后，经硅胶柱层析纯化(乙酸乙酯/石油醚＝0-20％)得到无色油状液体38b(200mg，收率57％)。
从化合物38b经多步合成反应制备化合物38，具体实验步骤参照化合物1的合成步骤。
化合物38d： 1H NMR(500MHz,CD 3OD)δ8.82(d,J＝4.5Hz,1H),8.13(dd,J＝9.2,5.6Hz,1H),7.96(dd,J＝10.5,2.8Hz,1H),7.51–7.50(m,1H),7.25(d,J＝4.4Hz,1H),5.93(dd,J＝3.8,1.9Hz,1H),4.06–3.94(m,4H),3.61–3.54(m,1H),3.18–3.16(m,1H),3.17–3.14(m,1H),3.11–3.02(m,1H),2.70–2.63(m,1H),2.25–2.14(m,2H),1.95–1.88(m,1H),1.86–1.79(m,1H)。
化合物38e： 1H NMR(500MHz,CD 3OD)δ8.79(d,J＝4.5Hz,1H),8.10(dd,J＝9.2,5.6Hz,1H),7.71(dd,J＝10.5,2.7Hz,1H),7.47-7.45(m,1H),7.40(d,J＝4.6Hz,1H),4.00–3.87(m,4H),3.62–3.50(m,1H),2.83–2.72(m,2H),2.38–2.31(m,2H),2.07(dd,J＝13.5,9.0Hz,2H),1.80–1.68(m,4H)。化合物38e的立体构型是根据二维核磁共振实验(COSY和NOESY)确定的，喹啉和并环上两个桥头氢处于反式的位置。
化合物38： 1H NMR(500MHz,CD 3OD)δ8.61–8.56(m,1H),7.97–7.93(m,1H),7.82–7.79(m,1H),7.49–7.43(m,3H),7.41–7.32(m,1H),7.21–7.19(m,2H),3.61–3.59(m,1H),3.31(s,1H),3.22–3.21(m,2H),2.87–2.83(m,1H),2.59–2.52(m,1H),2.45–2.41(m,1H),2.25(d,J＝4.6Hz,1H),2.15–2.11(m,1H),1.48–1.34(m,2H),1.25(d,J＝6.8Hz,3H)。LCMS m/z 435.26[M+H] +。
实施例40 化合物39的制备
Figure PCTCN2018106768-appb-000120
化合物39是从化合物38h和化合物27a反应来制备的。 1H NMR(500MHz,CD 3OD)δ8.72(dd,J＝13.5,4.7Hz,1H),8.60(t,J＝2.7Hz,1H),8.13(dd,J＝8.7,2.7Hz,1H),8.09–8.06(m,1H),7.93(dd,J＝10.6,2.6Hz,1H),7.62–7.58(m,1H),7.53(d,J＝4.7Hz, 1H),7.45(dd,J＝15.9,6.7Hz,1H),5.65(s,1H),3.77–3.70(m,1H),3.46–3.38(m,3H),3.01–2.95(m,1H),2.67(dd,J＝16.1,8.8Hz,1H),2.56(dt,J＝20.7,7.5Hz,1H),2.40–2.36(m,1H),2.28–2.23(m,1H),1.60–1.48(m,2H),1.39(d,J＝6.7Hz,3H)。LCMS m/z436.2[M+H] +。
实施例41和42化合物40和化合物41的制备
Figure PCTCN2018106768-appb-000121
从化合物40a出发，根据化合物1和化合物38的合成步骤，经多步反应,然后用制备薄板层析纯化得到化合物40和化合物41，比例为1.5：1。化合物40： 1H NMR(500MHz,CDCl 3)δ8.79(d,J＝4.5Hz,1H),8.12–8.09(m,1H),7.65(dd,J＝10.4,2.7Hz,1H),7.50(d,J＝8.8Hz,2H),7.49–7.44(m,1H),7.33(d,J＝4.5Hz,1H),7.30–7.27(m,3H),3.61–3.53(m,1H),2.36–2.23(m,1H),2.10–2.06(m,1H),2.05–2.00(m,1H),1.97–1.77(m,7H),1.26(d,J＝6.7Hz,3H),1.19(s,3H),1.16(s,3H)。LCMS m/z 465.3[M+H] +。化合物41： 1H NMR(500MHz,CDCl 3)δ8.70(d,J＝4.3Hz,1H),8.05–8.02(m,1H),7.58–7.56(m,1H),7.43–7.38(m,3H),7.31(s,1H),7.27(d,J＝4.3Hz,1H),7.20(d,J＝8.5Hz,2H),3.90–3.82(m,1H),2.42–2.37(m,1H),2.12–1.99(m,3H),1.92–1.78(m,4H),1.58–1.53(m,1H),1.50–1.45(m,1H),1.18–1.15(m,3H),1.09(s,3H),1.07(s,3H)。LCMS m/z 465.25[M+H] +。
实施例43和44化合物42和化合物43的制备
Figure PCTCN2018106768-appb-000122
化合物42和43是根据化合物40和41的方法制备得到的。化合物42： 1H NMR(500MHz,CD 3OD)δ8.64(d,J＝4.7Hz,1H),8.48(d,J＝2.7Hz,1H),8.01(dd,J＝8.7,2.8Hz,1H),7.97(dd,J＝9.2,5.6Hz,1H),7.72(dd,J＝10.4,2.7Hz,1H),7.51–7.45(m,2H),7.31(d,J＝8.7Hz,1H),3.37–3.60(m,1H),2.23–2.18(m,2H),1.97–1.65(m,8H),1.14(s,3H),1.12(d,J＝6.8Hz,3H),1.11(s,3H)。LCMS m/z 466.2[M+H] +。
化合物43： 1H NMR(500MHz,CD 3OD)δ8.73(d,J＝4.7Hz,1H),8.58(d,J＝2.7Hz,1H),8.11–8.07(m,2H),7.85(dd,J＝10.5,2.8Hz,1H),7.63–7.57(m,2H),7.41(d,J＝8.7Hz,1H),4.10–4.07(m,1H),2.52–2.36(m,2H),2.23–2.13(m,2H),2.07–2.05(m,1H),1.95–1.91(m,1H),1.80–1.64(m,4H),1.23(s,3H),1.22(d,J＝6.8Hz,3H),1.20(s,3H)。LCMS m/z 466.2[M+H] +。
实施例45 化合物44的制备
Figure PCTCN2018106768-appb-000123
在氮气保护下将LDA(2.0M，16mL)在-65℃下缓慢滴加到化合物9a(3.6g，15.98mmol)的四氢呋喃(20mL)溶液中，该温度下搅拌1小时，然后将N-苯基双(三氟甲烷磺酰)亚胺(8.56g，23.97mmol)溶于四氢呋喃(10mL)中缓慢滴加到上述反应液中，反应升至室温，薄板层析跟踪反应至原料9a转化完全。冰浴下加入饱和氯化铵溶液(15mL)，然后加入水(15mL)，乙酸乙酯萃取(3X 30mL)。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤后减压浓缩，粗品经硅胶柱层析纯化(0-10％，乙酸乙酯：石油醚)得淡黄色油状液体化合物44a(4.31g，收率75％)。 1H NMR(500MHz,CDCl 3)δ5.61–5.52(m,1H),3.77–3.63(m,1H),3.55–3.48(m,1H),3.44–3.32(m,2H),3.23–3.08(m,1H),2.90(dd,J＝25.7,9.5Hz,2H),2.39(d,J＝15.7Hz,1H),1.45(s,9H)。
在氮气保护下将化合物44a(4.31g，12.06mmol)，联硼酸频那醇酯(3.06g，12.6mmol)，醋酸钾(3.55g，36.18mmol)，Pd(pddf) 2Cl 2(984mg，1.21mmol)加入到二氧六环(25mL)中，加热至80℃反应过夜，薄板层析检测原料44a全部转化。反应液加水，乙酸乙酯萃取(3X 30mL)。合并有机相，用饱和食盐水洗涤，干燥过滤，减压浓缩。粗品经硅胶柱层析纯化(0-10％，乙酸乙酯：石油醚)得灰色油状液体化合物44b(3.13g，收率77％)。 1H NMR(500MHz,DMSO-d 6)δ6.23–6.16(m,1H),3.43(d,J＝10.8Hz,1H),2.80–2.70(m,2H),2.16(d,J＝16.5Hz,1H),1.31(s,9H),1.24(d,J＝2.2Hz,1H),1.14(s,12H),1.12–1.08(m,3H)。
在氮气保护下化合物44b(3.13g，9.34mmol)，4-氯-6-氟喹啉(1.70g，9.34mmol)，碳酸钾(3.87g，28.01mmol)，Pd(PPh 3) 4(1.08g，0.93mmol)加入到二氧六环(36mL)和水(9mL)中，然后加热至80℃反应5小时，薄板层析检测原料44b全部转化。反应液冷却至室温后，加水，用乙酸乙酯萃取(3X 30mL)。合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤后减压浓缩。粗品经硅胶柱层析纯化(0-20％，乙酸乙酯：石油醚)得淡黄色油状液体化合物44c(2.12g，收率64％)。 1H NMR(500MHz,DMSO-d 6)δ8.81(dd,J＝4.5, 1.8Hz,1H),8.15–8.09(m,1H),7.71(d,J＝10.3Hz,1H),7.49(m,1H),7.24(d,J＝4.5Hz,1H),6.01–5.96(m,1H),3.80–3.76(m,1H),3.66–3.64(m,4H),3.19–3.08(m,2H),2.66–2.63(m,1H),1.49(s,9H)。
化合物44c(1.90g，5.36mmol)溶于乙酸乙酯(25mL)中，加入10％Pd/C(200mg)，在氢气氛围中反应1小时，薄板层析检测原料44c转化完全。反应液冷却至室温，过滤，滤液减压浓缩。所得粗品经硅胶柱层析纯化(0-20％，乙酸乙酯：石油醚)得灰白色固体化合物44d(1.67g，收率87％)。
将盐酸的二氧六环溶液(2M，10mL)缓慢滴加到化合物44d(1.67g，4.69mmol)的二氯甲烷(10mL)溶液中，然后常温下搅拌反应1小时。薄板层析检测原料44d全部转化。反应液减压浓缩得白色固体化合物44e(1.71g，收率100％)。粗品不经纯化直接用于下一步。
化合物44e(156mg，0.61mmol)，2-溴丙酸乙酯(193mg，1.22mmol)，碳酸钾(252mg，1.83mmol)溶于乙腈(8mL)中，然后加热至80℃反应过夜，薄板层析检测原料44e全部转化。反应液减压浓缩，加水，并用乙酸乙酯萃取(3X 10mL)。合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，减压浓缩。经硅胶柱层析纯化(0-20％，乙酸乙酯：石油醚)得无色油状液体化合物44f(142mg，收率78％)。 1H NMR(500MHz,CDCl 3)δ8.82(d,J＝4.5Hz,1H),8.12(dd,J＝9.2,5.7Hz,1H),7.72(dd,J＝10.5,2.7Hz,1H),7.50–7.40(m,2H),4.24–4.18(m,2H),3.58–3.50(m,1H),3.30-3.27(m,1H),2.83–2.59(m,6H),2.41(m,2H),1.70(d,J＝7.1Hz,2H),1.38(d,J＝6.5Hz,3H),1.31(t,J＝7.1Hz,3H)。
将化合物44f(142mg，0.40mmol)溶于甲醇(5mL)中，然后滴加氢氧化锂(10M，5mL)溶液，常温下搅拌1小时，薄板层析检测原料44f全部转化。反应液浓缩，用稀盐酸(3N)调节pH至5-6，乙酸乙酯萃取3次，合并有机相，无水硫酸钠干燥，过滤后减压浓缩得白色固体粗品44g(98mg，收率75％)。
化合物44g(15mg，0.05mmol)，HATU(28mg，0.08mmol)，N,N-二异丙基乙基胺(20mg，0.15mmol)，对氯苯胺(10mg，0.08mmol)溶于N,N-二甲基甲酰胺(1mL)中，常温搅拌过夜，LCMS检测反应完全。反应液浓缩除去溶剂，加水，乙酸乙酯萃取(3X 5mL)，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩。所得粗品经制备薄板层析纯化(50％，乙酸乙酯：石油醚)得白色固体化合物44(6.2mg，收率16％)。 1H NMR(500MHz,CDCl 3)δ9.13(s,1H),8.86(d,J＝4.4Hz,1H),8.15(dd,J＝9.0,5.8Hz,1H),7.72(d,J＝10.3Hz,1H),7.51(dd,J＝11.6,5.5Hz,1H),7.48–7.39(m,3H),7.26(d,J＝1.8Hz,1H),3.64–3.53(m,1H),3.14(q,J＝6.6Hz,1H),2.86(s,2H),2.79(d,J＝9.2Hz,2H),2.62–2.48(m,4H),1.60(d,J＝8.6Hz,2H),1.40(d,J＝6.9Hz,3H)。LCMS m/z 438.23[M+H] +。
实施例46 化合物45的制备
Figure PCTCN2018106768-appb-000124
化合物45的合成参照化合物44的合成方法。LCMS m/z 220.2[1/2M+H] +。
实施例47 化合物46的制备
Figure PCTCN2018106768-appb-000125
化合物44e(60mg，0.21mmol)，溴乙酸甲酯(38mg，0.25mmol)，碳酸钾(85mg，0.63mmol)溶于乙腈(5mL)中，然后加热至50℃反应过夜，薄板层析检测原料44e全部转化。反应液减压浓缩，加水，乙酸乙酯萃取(3X 10mL)，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩得粗品，通过硅胶快速柱色谱法纯化(10-50％，乙酸乙酯：石油醚)得化合物淡黄色油状液体46a(43mg，收率64％)。
化合物46a(43mg，0.13mmol)溶于甲醇(5mL)中，然后滴加氢氧化锂(10M，5mL)溶液，常温下搅拌1小时，薄板层析检测原料46a全部转化。反应液浓缩，用稀盐酸(3N)调节pH至5-6，然后用乙酸乙酯萃取(3X 10mL)，无水硫酸钠干燥，浓缩得白色固体化合物46b(21mg，收率51％)。
化合物46b(21mg，0.07mmol)，对氯苯胺(17mg，0.14mmol)，HATU(32mg，0.08mmol)，N,N-二异丙基乙基胺(27mg，0.21mmol)溶于N,N-二甲基甲酰胺(2mL)中，常温搅拌过夜，LCMS检测反应完全。反应液浓缩除去溶剂，加水，乙酸乙酯萃取(3X 5mL)，合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩。所得粗品经制备薄板层析纯化(50％，乙酸乙酯：石油醚)得白色固体化合物46(9.10mg，收率32％)。 1H NMR(500MHz,CDCl 3)δ9.14(s,1H),8.79(d,J＝4.5Hz,1H),8.08(dd,J＝9.2,5.7Hz,1H),7.63(dd,J＝10.4,2.8Hz,1H),7.46–7.41(m,3H),7.38–7.34(m,1H),7.20(d,J＝8.8Hz,2H),3.52(m,1H),3.27(s,2H),2.85–2.66(m,4H),2.62–2.43(m,4H),1.63–1.59(m,2H)。LCMS m/z 424.11[M+H] +。
实施例48 化合物47的制备
Figure PCTCN2018106768-appb-000126
草酰氯甲酯(576mg，4.70mmol)在冰浴下缓慢滴加到对氯苯胺(300mg，2.35mmol)，N,N-二异丙基乙基胺(909mg，7.05mmol)的二氯甲烷中，升至室温反应过夜，TLC检测反应完全。反应液倒入饱和碳酸氢钠溶液中，乙酸乙酯萃取(3X 30mL)，合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩得粗品，通过硅胶快速柱色谱法纯化(0-10％，乙酸乙酯：石油醚)得淡黄色油状液体化合物47a(418mg，收率83％)。
化合物47a(418mg，1.96mmol)溶于甲醇(5mL)中，然后滴加氢氧化锂(10M，5mL) 水溶液，常温下搅拌1小时，薄板层析检测原料47a全部转化。反应液浓缩，用稀盐酸(3N)调节pH至5-6，然后乙酸乙酯萃取(3X 10mL)，无水硫酸钠干燥，浓缩得白色固体化合物47b(327mg，收率84％)。
化合物44e(10mg，0.03mmol)，47b(10mg，0.05mmol)，HATU(14mg，0.04mmol)，N,N-二异丙基乙基胺(12mg，0.09mmol)溶于N,N-二甲基甲酰胺(1mL)中，常温搅拌过夜，LCMS检测反应完全。反应液浓缩除去溶剂，加水，乙酸乙酯萃取(3X 5mL)。合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤后减压浓缩。所得粗品经制备薄板层析纯化(50％，乙酸乙酯：石油醚)得白色固体化合物47(6.10mg，收率41)％。 1H NMR(500MHz,CDCl 3)δ9.46(s,1H),8.80(d,J＝4.5Hz,1H),8.14(dd,J＝9.2,5.6Hz,1H),7.65(dd,J＝10.3,2.7Hz,1H),7.60–7.54(m,2H),7.48(m,1H),7.35(d,J＝4.6Hz,1H),7.32(d,J＝2.2Hz,1H),7.31(d,J＝2.1Hz,1H),4.32–4.19(m,2H),3.84–3.75(m,2H),3.07–3.05(m,1H),2.94–2.90(m,1H),2.55–2.52(m,2H),1.75–1.70(m,1H),1.70–1.64(m,2H)。LCMS m/z 438.23[M+H] +。
实施例49 化合物48的制备
Figure PCTCN2018106768-appb-000127
化合物48a(24mg，0.15mmol)溶于二氯甲烷(1mL)中，在冰浴冷却下缓慢滴加到化合物44e(30mg，0.10mmol)，N,N-二异丙基乙基胺(39mg，0.30mmol)的二氯甲烷(2mL)溶液中。滴加完后在常温搅拌过夜，LCMS检测反应完全。反应液加水，用乙酸乙酯萃取(3X 10mL)，合并的有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤后减压浓缩。所得的粗品经制备薄板层析纯化(50％，乙酸乙酯：石油醚)得白色固体化合物48(16.5mg，收率39％)。 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.6Hz,1H),8.13(dd,J＝9.3,5.7Hz,1H),7.65(dd,J＝10.4,2.8Hz,1H),7.50-7.46(m,1H),7.39–7.34(m,3H),7.24–7.21(m,2H),6.22(s,1H),3.76(m,1H),3.69(dd,J＝10.3,7.5Hz,2H),3.51–3.46(m,2H),3.04–2.94(m,2H),2.60–2.48(m,2H),1.73-1.70(m,2H)。LCMS m/z 410.25[M+H] +。
实施例50 化合物49的制备
Figure PCTCN2018106768-appb-000128
将化合物11(180mg,0.427mmol)溶于氯仿(4mL)中，在0℃下，加入间氯过氧苯甲酸。反应液在0℃下搅拌0.5小时，缓慢升至室温，薄板层析跟踪至原料完全消失，加入饱和亚硫酸钠淬灭反应。用二氯甲烷(3×10mL)萃取，接着分别用饱和碳酸钠，饱和食盐水洗有机相，无水硫酸钠干燥，过滤，减压浓缩。粗品经硅胶柱层析纯化(乙酸乙酯/石油醚＝0-100％)得到淡黄色固体化合物49(85mg，收率45％)。 1H NMR(500MHz,CD 3OD)δ8.76(dd,J＝9.5,5.3Hz,1H),8.57(d,J＝6.3Hz,1H),7.98–7.96(m,1H),7.76–7.72(m,1H),7.56(d,J＝8.7Hz,2H),7.45(d,J＝6.3Hz,1H),7.29(d,J＝8.7Hz,2H), 6.15(s,1H),3.52(d,J＝7.7Hz,1H),3.15(dd,J＝16.2,8.7Hz,1H),2.95–2.88(m,1H),2.60(d,J＝16.2Hz,1H),2.47–2.45(m,2H),2.37–2.34(m,2H),2.27–2.23(m,1H),1.34–1.33(m,2H)。LCMS m/z 437.3[M+H] +。
实施例51 化合物50的制备
Figure PCTCN2018106768-appb-000129
将化合物49(10mg，0.023mmol)溶于乙酸乙酯(3mL)，加入10％Pd/C(3mg)，氢气氛下0℃搅拌1小时，薄板层析跟踪至原料基本反应完全。将Pd/C用硅藻土过滤除去，减压浓缩。粗品经硅胶柱层析纯化(二氯甲烷/甲醇＝0-10％)得到白色固体化合物50(3mg，收率30％)。 1H NMR(500MHz,CDCl 3)δ8.86–8.83(m,1H),8.43(d,J＝6.3Hz,1H),7.69(dd,J＝9.9,2.5Hz,1H),7.53–7.47(m,3H),7.34(s,1H),7.28(d,J＝8.8Hz,2H),7.25(s,1H),3.67–3.60(m,1H),2.73–2.69(m,2H),2.54–2.50(m,1H),2.43–2.39(m,3H),2.32–2.20(m,2H),1.49–1.43(m 2H),1.10–1.07(m,2H)。LCMS m/z 439.23[M+H] +。
实施例52 化合物51的制备
Figure PCTCN2018106768-appb-000130
将化合物1d(1.20g，5.0mmol)溶于甲醇(10mL)中，滴加氢氧化钠(0.80g，20.0mmol)水溶液(2mL)，室温搅拌过夜，TLC检测反应完全。减压浓缩除去甲醇，加入水(10mL)，冰浴条件下缓慢滴加盐酸(0.5N)调pH＝5，再用乙酸乙酯萃取(3X 10mL)，合并有机相，干燥浓缩得到粗品51a(1.04g，92％)。
将化合物51a(600mg，2.65mmol)溶于N,N-二甲基甲酰胺(15mL)中，加入HATU(1.20g，3.18mmol)，N,N-二异丙基乙基胺(1.03g，7.95mmol)，再加入对氯苯胺(0.51g，3.98mmol)，氮气保护室温搅拌1小时。向反应体系中加水(10mL)淬灭，乙酸乙酯萃取(3X 20mL)，合并有机相，卤水洗涤，干燥浓缩得到粗品。柱层析分离(乙酸乙酯/石油醚＝0–20％)，得到混合物51b(1.02g，114％)。 1H NMR(500MHz,CDCl 3)δ7.46(d,J＝7.6Hz,2H),7.31(s,1H),7.27–7.25(m,2H),3.91–3.87(m,4H),2.54(d,J＝3.6Hz,2H),2.38(d,J＝7.2Hz,2H),2.29–2.24(m,1H),2.15–2.11(m,2H),1.98–1.96(m,2H),1.59(dd,J＝13.3,2.8Hz,2H),1.13(dd,J＝20.1,11.5Hz,2H)。
将化合物51b(1.02g，3.04mmol)溶于四氢呋喃(20mL)中，冰浴条件下缓慢滴加盐 酸(12.5mL，1N)，室温下搅拌1.0小时。减压浓缩，用乙酸乙酯萃取水层(3X 20mL)，合并有机相，经饱和食盐水洗涤，干燥浓缩。粗品经硅胶柱层析分离(乙酸乙酯/石油醚＝0–33％)，得到化合物51c(560mg)和化合物51d(120mg)。51c： 1H NMR(500MHz,CDCl 3)δ7.58(s,1H),7.47(d,J＝8.6Hz,2H),7.27(d,J＝7.8Hz,2H),2.74–2.71(m,2H),2.54–2.50(m,2H),2.40(d,J＝7.1Hz,2H),2.35–2.28(m,2H),2.05(d,J＝7.2Hz,1H),2.01(d,J＝6.8Hz,1H),1.08–1.02(m,1H)。51d： 1H NMR(500MHz,CDCl 3)δ7.46(d,J＝8.8Hz,2H),7.28(d,J＝8.9Hz,2H),7.15(s,1H),2.90–2.85(m,1H),2.60–2.40(m,3H),2.39(d,J＝7.3Hz,2H),2.09–2.06(m,2H),1.80–1.65(m,4H),0.89–0.84(m,1H)。
将化合物51c(140mg，0.48mmol)溶于四氢呋喃(10mL)中，加入硼氢化钠(90mg，2.40mmol)冰浴条件下搅拌2.0小时。用饱和氯化铵水溶液淬灭，乙酸乙酯萃取(2X 10mL)，合并有机相，用卤水洗涤，干燥浓缩得到化合物51e(100mg，71％)。
化合物51e(90mg，0.31mmol)溶于二氯甲烷(5mL)中，加入三乙胺(78mg，0.78mmol)，冰浴条件下缓慢滴加甲磺酰氯(53mg，0.46mmol)。室温反应2.0小时。反应液用饱和碳酸氢钠溶液洗涤，二氯甲烷萃取(2X 10mL)，合并有机相用，饱和食盐水洗涤，干燥后减压浓缩。所得的粗品经硅胶柱层析纯化(乙酸乙酯/石油醚＝0–1/3)，得化合物51f(103mg，产率88％)。
将4-羟基喹啉(20mg，0.068mmol)溶于无水四氢呋喃(5mL)中，在0℃条件下加入适量氢化钠(8.3mg，0.21mmol，60％)，室温搅拌反应0.5小时，加入化合物51f(20mg，0.068mmol)，升温至60□C反应1小时。将反应液倒入饱和氯化铵溶液(10mL)中淬灭，用乙酸乙酯萃取(3X 10mL)，合并有机相，用饱和食盐水洗涤，干燥过滤后，减压浓缩。所得粗品经制备薄板层析纯化(乙酸乙酯/石油醚＝1/3)得到化合物51(4.10mg，产率14％)。 1H NMR(500MHz,CDCl 3)δ8.71(d,J＝5.2Hz,1H),8.17(d,J＝8.3Hz,1H),8.01(d,J＝8.3Hz,1H),7.68(t,J＝7.1Hz,1H),7.49(d,J＝5.7Hz,4H),7.28(s,1H),6.71(d,J＝5.2Hz,1H),5.11–5.09(m,1H),2.81–2.73(m,2H),2.38–2.34(m,1H),2.26–2.23(m,2H),2.22–2.18(m,2H),2.12–2.00(m,2H),1.89–1.82(m,2H),1.02–0.96(m,2H),0.91–0.84(m,1H)。LCMS m/z 421.11[M+H] +。
实施例53 化合物52的制备
Figure PCTCN2018106768-appb-000131
称取51f(5mg，0.013mmol)，加入1,2,3,4-四氢喹啉(0.5mL)，无溶剂条件下室温搅拌3.0小时。粗品经硅胶柱层析纯化(乙酸乙酯/石油醚＝0–1/5)得到化合物52(2.67mg，产率49％)。 1H NMR(500MHz,CDCl 3)δ7.47(d,J＝8.7Hz,2H),7.28(d,J＝8.7Hz,2H),7.09–7.05(m,2H),6.94(d,J＝7.3Hz,1H),6.68(d,J＝8.0Hz,1H),6.55(t,J＝7.3Hz,1H),4.17–4.13(m,1H),3.18(t,J＝5.8Hz,2H),2.72(t,J＝6.3Hz,2H),2.54(d,J＝6.2Hz,2H),2.42(d,J＝6.5Hz,2H),2.31–2.20(m,3H),1.90–1.88(m,2H),1.74–1.68(m,2H),1.62–1.59(m,2H),0.89–0.84(m,2H)。LCMS m/z 409.33[M+H] +。
实施例54 化合物53的制备
Figure PCTCN2018106768-appb-000132
按照化合物44c的合成方法，由化合物51c经两步得到化合物53b，再与化合物53c反应得到化合物53。 1H NMR(500MHz,CDCl 3)δ8.41(d,J＝3.3Hz,1H),8.34(d,J＝4.9Hz,1H),7.46(d,J＝8.5Hz,2H),7.28(d,J＝8.8Hz,2H),7.18–7.16(m,1H),7.08(s,1H),6.52(s,1H),3.40(d,J＝7.4Hz,1H),2.98–2.94(m,1H),2.81–2.78(m,1H),2.52(d,J＝17.5Hz,1H),2.35–2.33(m,2H),2.26–2.22(m,1H),1.14–1.12(m,2H),1.04–1.02(m,1H),0.88–0.85(m,1H)。LCMS m/z 371.25[M+H] +。
实施例55 化合物54的制备
Figure PCTCN2018106768-appb-000133
与制备化合物53的方法相同，以化合物51d经多步反应得到化合物54。 1H NMR(500MHz,CDCl 3)δ8.40(s,1H),8.33(d,J＝5.0Hz,1H),7.45(d,J＝8.1Hz,2H),7.28(d,J＝6.2Hz,2H),7.15–7.13(m,2H),6.40(s,1H),3.52–3.48(m,1H),3.13–3.08(m,1H),2.67(d,J＝14.3Hz,1H),2.50(d,J＝16.5Hz,1H),2.34–2.31(m,2H),1.95–1.89(m,2H),1.80–1.77(m,1H),1.51–1.47(m,2H),1.14–1.13(m,1H),0.89–0.87(m,1H)。LCMS m/z 371.24[M+H] +。
实施例56 化合物55的制备
Figure PCTCN2018106768-appb-000134
化合物55是从化合物53b和化合物55a制备的，详细的合成步骤参见化合物53的合成。 1H NMR(500MHz,CDCl 3)δ7.85(d,J＝8.2Hz,1H),7.40(t,J＝4.3Hz,2H),7.35–7.29(m,2H),7.22(d,J＝2.0Hz,2H),7.13–7.10(m,1H),7.02(s,1H),6.31(s,1H),3.98(s,3H),3.41–3.36(m,1H),3.09(dd,J＝16.2,8.8Hz,1H),2.78–2.71(m,1H),2.36–2.24(m,5H),2.20–2.16(m,1H),2.00–1.96(m,1H)。LCMS m/z 406.3[M+H] +。
实施例57 化合物56的制备
Figure PCTCN2018106768-appb-000135
参照化合物1和化合物10的制备，从化合物10a可以合成化合物56a。 1H NMR(500MHz,CDCl 3)δ8.73(d,J＝4.6Hz,1H),8.06(dd,J＝9.2,5.8Hz,1H),7.63(dd,J＝10.4,2.6Hz,1H),7.45–7.38(m,1H),7.18(d,J＝4.5Hz,1H),5.68(s,1H),4.03(dd,J＝15.2,4.7Hz,1H),3.65(s,3H),3.39(t,J＝12.0Hz,1H),2.47–2.38(m,2H),2.13(dd,J＝9.3,6.0Hz,3H),1.74–1.59(m,2H)。
三甲基碘化亚砜(18mg，0.08mmol)的二甲基亚砜溶液在0□C滴加到氢化钠(4mg，0.9mmol)中，室温反应1小时，然后降至0□C滴加化合物56a(20mg，0.06mmol)的二甲基亚砜溶液。滴加完毕升至室温，搅拌过夜。薄板层析检测反应完全。反应液加水，乙酸乙酯萃取(3X 10mL)。合并的有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤后减压浓缩。所得的粗品经制备薄板层析纯化(50％，乙酸乙酯：石油醚)得无色油状液体化合物56b(8mg，收率38％)。
化合物56b(8mg，0.03mmol)溶于甲醇(3mL)中，然后滴加氢氧化锂(10M，5mL)溶液，常温下搅拌1小时，薄板层析检测原料56b全部转化。反应液浓缩，用稀盐酸(3N)调节pH至5-6，然后乙酸乙酯萃取(3X 10mL)，无水硫酸钠干燥，过滤后浓缩，得白色固体粗品56c(7mg，收率92％)。
化合物56c(7mg，0.02mmol)，对氯苯胺(5mg，0.04mmol)，HOBT(5mg，0.04mmol)，EDCI(7mg，0.04mmol)，N,N-二甲基乙基胺(10mg，0.08mmol)溶于N,N-二甲基甲酰胺(1mL)中，常温搅拌过夜，LCMS检测反应完全。反应液浓缩除去溶剂，加水，乙酸乙酯萃取3次。合并的有机相用饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤后减压浓缩，所得的粗品经制备薄板层析纯化(50％，乙酸乙酯：石油醚)得白色固体化合物56(3.56mg，收率37％)。 1H NMR(500MHz,CDCl 3)δ8.71(d,J＝4.1Hz,1H),8.06(dd,J＝8.7,5.8Hz,1H),7.60(dd,J＝10.4,2.0Hz,1H),7.44(d,J＝8.8Hz,2H),7.43–7.36(m,2H),7.23(d,J＝8.7Hz,2H),3.23–3.15(m,1H),2.15–2.07(m,2H),1.98(d,J＝12.7Hz,1H),1.93–1.82(m,2H),1.42(d,J＝3.4Hz,1H),1.43–1.31(m,3H),1.05(d,J＝13.5Hz,1H),0.95(dd,J＝7.5,4.4Hz,1H)。LCMS m/z 409.2[M+H] +。
实施例58 化合物57的制备
Figure PCTCN2018106768-appb-000136
参照化合物1和化合物10的制备，从化合物38f可以合成化合物57b,然后合成消旋化合物57。 1H NMR(500MHz,CDCl 3)δ8.78(d,J＝4.3Hz,1H),8.13(dd,J＝9.1,5.7Hz,1H),7.71(dd,J＝10.4,2.6Hz,1H),7.49(dd,J＝8.6,2.1Hz,1H),7.47–7.44(m,2H),7.36–7.34(m,2H),7.28(d,J＝8.7Hz,2H),5.72–5.65(m,1H),3.63–3.56(m,1H),3.45(dd,J＝15.9,7.9Hz,1H),3.21(q,J＝15.6Hz,2H),3.00–2.94(m,1H),2.73(dd,J＝16.8,8.8Hz,1H),2.59–2.54(m,1H),2.42(dt,J＝11.7,5.7Hz,1H),2.23(d,J＝16.7Hz,1H),1.60–1.55(m,1H),1.53–1.46(m,1H)。LCMS m/z 421.3[M+H] +。
实施例59 化合物58的制备
Figure PCTCN2018106768-appb-000137
将乙酸乙酯(132mg，1.49mmol)溶于四氢呋喃(1mL)中，在-78℃，氮气保护下，缓慢滴加LDA(0.75mL，1.49mmol)，反应液在-78℃C下搅拌1小时。在-78□C下将化合物38f(80mg，0.3mmol)的四氢呋喃(1mL)溶液滴加到上述反应液中，缓慢升温至室温后搅拌1小时，向反应液中加入饱和氯化铵水溶液(1mL)，加入乙酸乙酯(5mL)，分别用水以及饱和食盐水洗上述反应液，有机相用无水硫酸钠干燥，过滤，减压浓缩，得到淡黄色油状液体58a。
参照化合物1h的制备方法来制备化合物58。 1H NMR(500MHz,CDCl 3)δ8.77(d,J＝4.0Hz,1H),8.59(s,1H),8.10(dd,J＝9.1,5.7Hz,1H),7.49(d,J＝8.7Hz,2H),7.47–7.44(m,1H),7.41(d,J＝4.4Hz,1H),7.27(d,J＝8.7Hz,2H),3.60–3.53(m,1H),2.79–2.78(m,2H),2.65(s,2H),2.39(dd,J＝11.5,5.9Hz,2H),1.99–1.91(m,4H),1.87(d,J＝11.6Hz,2H)。LCMS m/z 439.19[M+H] +。
实施例60 化合物59的制备
Figure PCTCN2018106768-appb-000138
将化合物58(13mg，0.03mmol)溶于二氯甲烷(1.5mL)中，在0℃和氮气保护下，加入二乙氨基三氟化硫(14mg，0.088mmol)，逐渐升温到室温，薄板层析检测至反应完全。减压除去二氯甲烷。粗品经制备薄板层析纯化(50％，乙酸乙酯：石油醚)得白色固体化合物59。 1H NMR(500MHz,CD 3OD)δ8.74(d,J＝4.7Hz,1H),8.06(dd,J＝9.2,5.6Hz,1H),7.92(dd,J＝10.6,2.7Hz,1H),7.62–7.51(m,4H),7.33–7.26(m,2H),3.96–3.88(m,1H),3.06–2.94(m,2H),2.85(d,J＝19.9Hz,2H),2.53–2.44(m,2H),2.41–2.31(m,2H),1.85(dd,J＝14.1,7.8Hz,1H),1.77(dd,J＝14.1,7.8Hz,1H),1.63–1.57(m,2H)。LCMS m/z 441.22[M+H] +。
实施例61 化合物60的制备
Figure PCTCN2018106768-appb-000139
化合物3a在低温LDA作用下与碘甲烷反应得到中间体60a，按照化合物3的合成方法制备化合物60。LCMS m/z 451.16[M+H] +。
实施例62 化合物61的制备
Figure PCTCN2018106768-appb-000140
化合物61a是根据化合物11a的合成方法制备的，经过多次柱层析，得到纯的中间体61b和61c。化合物61b: 1H NMR(500MHz,CDCl 3)δ8.78(d,J＝4.5Hz,1H),8.09(dd,J＝9.2,5.6Hz,1H),7.74(dd,J＝10.4,2.8Hz,1H),7.55–7.39(m,1H),7.22(d,J＝4.5Hz,1H),5.98(d,J＝1.8Hz,1H),4.14(q,J＝7.1Hz,2H),3.52–3.34(m,1H),3.09–3.03(m,1H),2.89–2.81(m,1H),2.52(dd,J＝16.5,1.7Hz,1H),2.43–2.36(m,2H),2.34–2.25(m,2H),2.25–2.17(m,2H),1.26(t,J＝7.1Hz,3H),1.19–1.06(m,2H)。化合物61c: 1H NMR(500MHz,CDCl 3)δ8.79(d,J＝4.5Hz,1H),8.11(dd,J＝9.2,5.6Hz,1H),7.77–7.65(m,1H),7.53–7.38(m,1H),7.24(d,J＝4.5Hz,1H),5.87(d,J＝2.0Hz,1H),4.15(q,J＝7.1Hz,2H),3.56(t,J＝8.4Hz,1H),3.25–3.10(m,1H),3.10–2.94(m,1H),2.59–2.49(m,1H),2.48–2.40(m,1H),2.40–2.33(m,2H),1.90(dd,J＝12.6,5.8Hz,1H),1.79(dd,J＝12.6,5.8Hz,1H),1.63–1.53(m,1H),1.52–1.43(m,1H),1.27(t,J＝7.1Hz,3H)。
化合物61b经酯水解得酸，然后进一步转化为酰氯61d。化合物61d和17a反应得化合物61。详见化合物26的制备方法。 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.5Hz,1H),8.23(d,J＝7.2Hz,1H),8.21(s,1H),8.12(dd,J＝9.1,5.6Hz,1H),7.87(s,1H),7.76(dd,J＝10.3,2.8Hz,1H),7.67(dd,J＝8.8,2.6Hz,1H),7.52–7.44(m,1H),6.01(d,J＝1.6Hz,1H),3.49(d,J＝6.8Hz,1H),3.18–2.97(m,1H),2.89(t,J＝9.2Hz,1H),2.55(d,J＝16.6Hz,1H),2.51(d,J＝6.5Hz,2H),2.42–2.36(m,2H),2.32–2.28(m,1H),1.28–1.13(m,2H)。LCMS m/z 424.14[M+H] +。
实施例63 化合物62的制备
Figure PCTCN2018106768-appb-000141
化合物61d和2-氯-5-氨基吡啶18a反应制备得到消旋化合物62。参考化合物11的制备方法。 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.5Hz,1H),8.36(d,J＝2.8Hz,1H),8.20(dd,J＝8.6,2.7Hz,1H),8.11(dd,J＝9.2,5.6Hz,1H),7.76(dd,J＝10.4,2.8Hz,1H),7.54–7.40(m,1H),7.31(d,J＝8.7Hz,1H),7.24(d,J＝4.5Hz,2H),6.01(d,J＝1.6Hz,1H),3.54–3.42(m,1H),3.16–3.03(m,1H),2.93–2.87(m,1H),2.55(d,J＝16.8Hz,1H),2.50(d,J＝5.5Hz,2H),2.44–2.34(m,2H),2.33–2.27(m,1H),1.27–1.12(m,2H)。LCMS m/z 424.12[M+H] +。
实施例64 化合物63的制备
Figure PCTCN2018106768-appb-000142
与化合物61制备方法相同，化合物61d和化合物25a反应制备得到化合物63。 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.5Hz,1H),8.38(d,J＝2.0Hz,1H),8.22(d,J＝8.8Hz,1H),8.15–8.07(m,1H),7.89(s,1H),7.83–7.72(m,2H),7.51–7.48(m,1H),6.08–5.97(m,1H),3.53–3.47(m,1H),3.17(s,1H),3.13–3.05(m,1H),2.93–2.85(m,1H),2.56(d,J＝17.7Hz,1H),2.51(d,J＝6.6Hz,2H),2.44–2.36(m,2H),2.33–2.28(m,1H),1.25–1.17(m,2H)。LCMS m/z 412.20[M+H] +。
实施例65 化合物64的制备
Figure PCTCN2018106768-appb-000143
化合物61d和化合物24a反应制备得到化合物64。 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.5Hz,1H),8.50(d,J＝2.5Hz,1H),8.25(d,J＝8.5Hz,1H),8.11(dd,J＝9.2,5.6Hz,1H),7.76(dd,J＝10.4,2.8Hz,1H),7.51–7.44(m,2H),7.24(d,J＝4.5Hz,1H),6.01(d,J＝1.7Hz,1H),3.53–3.47(m,1H),3.12(s,1H),3.11–3.05(m,1H),2.94–2.83(m,1H),2.55(d,J＝16.5Hz,1H),2.51(d,J＝6.0Hz,2H),2.47–2.36(m,2H),2.35–2.26(m,1H),1.23–1.14(m,2H)。LCMS m/z 206.74[1/2M+H] +。
实施例66 化合物65的制备
Figure PCTCN2018106768-appb-000144
化合物61c经酯水解得酸，然后进一步转化为酰氯65a。化合物65a和化合物25a 反应制备得到化合物65。参照化合物26的合成。 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.5Hz,1H),8.39(d,J＝1.9Hz,1H),8.22(d,J＝8.7Hz,1H),8.11(dd,J＝9.2,5.6Hz,1H),7.90(s,1H),7.80(dd,J＝8.6,2.1Hz,1H),7.76(dd,J＝10.4,2.8Hz,1H),7.51–7.45(m,1H),7.24–7.23(m,1H),5.90(d,J＝2.0Hz,1H),3.65–3.60(m,1H),3.24–3.19(m,1H),3.17(s,1H),3.11–3.06(m,1H),2.61–2.55(m,2H),2.50–2.46(m,2H),1.98(dd,J＝12.5,5.7Hz,1H),1.88(dd,J＝12.5,5.3Hz,1H),1.63(dd,J＝22.0,9.3Hz,2H)。LCMS m/z 412.22[M+H] +。
实施例67 化合物66的制备
Figure PCTCN2018106768-appb-000145
化合物61b经催化氢化，得两个异构体66a和66b,经多次柱层析分离可将这两个异构体分开，它们的比例为10：1。化合物66a: 1H NMR(500MHz,CDCl 3)δ8.78(d,J＝4.6Hz,1H),8.09(dd,J＝9.2,5.7Hz,1H),7.67(dd,J＝10.5,2.8Hz,1H),7.47–7.43(m,1H),7.35(d,J＝4.6Hz,1H),4.13(q,J＝7.1Hz,2H),3.74–3.67(m,1H),2.77–2.60(m,2H),2.49–2.33(m,5H),2.21–2.16(m,2H),1.59–1.43(m,2H),1.26(t,J＝7.1Hz,3H),1.09–1.03(m,2H)。化合物66a的立体构型由NOESY确定。
化合物66a经酯水解得酸，然后进一步转化为酰氯66c。化合物66c和24a反应制备得到化合物66。 1H NMR(500MHz,CD 3OD)δ8.74(d,J＝4.7Hz,1H),8.69(d,J＝2.2Hz,1H),8.15(dd,J＝8.6,2.5Hz,1H),8.06(dd,J＝9.2,5.6Hz,1H),7.90(dd,J＝10.6,2.7Hz,1H),7.61–7.58(m,1H),7.57(d,J＝4.5Hz,1H),7.54(d,J＝8.6Hz,1H),3.92–3.85(m,1H),3.69(s,1H),2.85–2.73(m,2H),2.58–2.46(m,3H),2.47–2.39(m,2H),2.26–2.18(m,2H),1.61–1.54(m,2H),1.19(dd,J＝19.3,11.5Hz,2H)。LCMS m/z 414.29[M+H] +。
实施例68 化合物67的制备
Figure PCTCN2018106768-appb-000146
化合物66c和化合物25a反应制备得到化合物67。 1H NMR(500MHz,CD 3OD)δ8.76(d,J＝4.7Hz,1H),8.38(s,1H),8.13(d,J＝8.6Hz,1H),8.07(dd,J＝9.2,5.5Hz,1H),7.93(dd,J＝10.5,2.7Hz,1H),7.82(dd,J＝8.6,2.2Hz,1H),7.63–7.57(m,2H),3.93–3.86(m,1H),3.64(s,1H),2.87–2.71(m,2H),2.57–2.48(m,3H),2.47–2.38(m,2H), 2.22(dd,J＝12.2,6.4Hz,2H),1.61–1.55(m,2H),1.19(dd,J＝19.5,11.7Hz,1H)。LCMS m/z 414.19[M+H] +。
实施例69 化合物68的制备
Figure PCTCN2018106768-appb-000147
将化合物38g(30mg，0.085mmol)溶于甲苯(1mL)中，加入三氟乙酸(194mg，1.70mmol)，在封管中升温至120℃，搅拌反应5小时。用饱和碳酸氢钠溶液调pH＝7，乙酸乙酯萃取(3X 5mL)，合并有机相，无水硫酸钠干燥，减压浓缩得到粗品化合物68a(25mg，91％)。该中间体不纯化，直接用于下一步反应。
将化合物68a与4-氯苯胺反应，参考化合物38的制备方法，得到化合物68。 1H NMR(500MHz,CD 3OD)δ8.73(d,J＝4.7Hz,1H),8.06(dd,J＝9.3,5.5Hz,1H),7.89(dd,J＝10.6,2.7Hz,1H),7.64–7.55(m,3H),7.54(d,J＝4.6Hz,1H),7.33–7.28(m,2H),3.87–3.74(m,1H),2.89–2.77(m,3H),2.66(dd,J＝17.3,8.3Hz,1H),2.53–2.36(m,4H),1.95(s,3H),1.57–1.46(m,2H)。LCMS m/z 435.26[M+H] +。
实施例70 化合物69的制备
Figure PCTCN2018106768-appb-000148
与化合物61制备方法相同，化合物61d和化合物69a反应制备得到消旋化合物69。LCMS m/z 413.4[M+H] +。
实施例71 化合物70的制备
Figure PCTCN2018106768-appb-000149
与化合物21制备方法相同，化合物21a和化合物69a反应制备得到化合物70。LCMS m/z 415.4[M+H] +。
实施例72 化合物71的制备
Figure PCTCN2018106768-appb-000150
与化合物26制备方法相同，化合物21a和化合物71a反应制备得到化合物71。 1H NMR(500MHz,CDCl 3)δ8.72(d,J＝4.5Hz,1H),8.53(d,J＝2.4Hz,1H),8.37(dd,J＝8.6,2.5Hz,1H),8.03(dd,J＝9.2,5.7Hz,1H),7.64–7.59(m,2H),7.46(s,1H),7.42–7.37(m,1H),7.28(d,J＝4.5Hz,1H),3.43–3.35(m,1H),2.72(dd,J＝12.9,7.2Hz,2H),2.56–2.47(m,1H),2.44(d,J＝7.0Hz,2H),2.36–2.28(m,2H),1.72(dd,J＝12.7,5.6Hz,2H),1.41–1.30(m,4H)。LCMS m/z 415.2[M+H] +。
实施例73 化合物72的制备
Figure PCTCN2018106768-appb-000151
与化合物26制备方法相同，化合物1aj和化合物71a反应制备得到化合物72。 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.6Hz,1H),8.61(d,J＝2.5Hz,1H),8.47(dd,J＝8.6,2.6Hz,1H),8.10(dd,J＝9.2,5.7Hz,1H),7.68(d,J＝8.8Hz,1H),7.66(s,1H),7.62(s,1H),7.49–7.46(m,1H),7.34(d,J＝4.6Hz,1H),3.77–3.70(m,1H),2.72(d,J＝3.5Hz,2H),2.46–2.39(m,2H),2.34–2.19(m,3H),2.17–2.13(m,1H),1.52–1.46(m,2H),1.30(d,J＝6.4Hz,3H),1.17–1.01(m,2H)。LCMS m/z 429.2[M+H] +。
实施例74 化合物73的制备
Figure PCTCN2018106768-appb-000152
与化合物26制备方法相同，化合物1aj和化合物69a反应制备得到化合物73。 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.5Hz,1H),8.55(d,J＝2.1Hz,1H),8.39(d,J＝8.8Hz,1H),8.17–8.09(m,1H),8.00(s,1H),7.95(dd,J＝8.8,2.2Hz,1H),7.68(dd,J＝10.4,2.5Hz,1H),7.51–7.41(m,1H),7.37(d,J＝4.3Hz,1H),3.77–3.70(m,1H),2.83–2.55(m,2H),2.45–2.39(m,2H),2.35–2.22(m,3H),2.20–2.10(m,1H),1.51–1.48(m,2H),1.30(d,J＝6.1Hz,3H),1.21–1.00(m,2H)。LCMS m/z 429.23[M+H] +。
实施例75 化合物74的制备
Figure PCTCN2018106768-appb-000153
在实施例1中化合物1的合成过程中，中间体1af经Pd-C催化氢化反应得到混合物1ag和1ah。该混合物里的两个异构体很难分开，所以实际操作中通常将混合物水解得酸74a,经酰氯74b,再和化合物25a反应制备得到化合物74(合成方法同化合物26的合成)。主产物化合物74： 1H NMR(500MHz,CDCl 3)δ8.73(d,J＝4.5Hz,1H),8.32(d,J＝1.7Hz,1H),8.16(d,J＝8.6Hz,1H),8.03(dd,J＝9.2,5.7Hz,1H),7.80(s,1H),7.72(dd,J＝8.7,2.2Hz,1H),7.60(dd,J＝10.4,2.7Hz,1H),7.42–7.36(m,1H),7.29(d,J＝4.5Hz,1H),3.69–3.62(m,1H),3.09(s,1H),2.68–2.60(m,2H),2.37–2.31(m,2H),2.21–2.17(m,3H),2.13–2.06(m,1H),1.47–1.41(m,2H),1.22(d,J＝6.5Hz,3H),1.11–0.98(m,2H)。LCMS m/z 428.2[M+H] +。
实施例76 化合物75的制备
Figure PCTCN2018106768-appb-000154
化合物75是在实施例75中化合物74的制备过程中的少量的副产物。 1H NMR(500MHz,CDCl 3)δ8.72(d,J＝4.5Hz,1H),8.32(d,J＝2.1Hz,1H),8.17(d,J＝8.6Hz,1H),8.03(dd,J＝9.4,5.7Hz,1H),7.84(s,1H),7.72(dd,J＝8.6,2.1Hz,1H),7.61(dd,J＝10.5,2.7Hz,1H),7.41–7.36(m,1H),7.29(d,J＝4.6Hz,1H),3.41–3.32(m,1H),3.09(s,1H),2.74–2.66(m,2H),2.37–2.30(m,1H),2.30–2.18(m,2H),2.15–2.01(m,1H),1.70(dd,J＝12.5,5.3Hz,1H),1.63(dd,J＝12.7,5.7Hz,1H),1.41–1.35(m,2H),1.17(d,J＝6.9Hz,3H),1.12–1.01(m,2H)。LCMS m/z 428.3[M+H] +。
实施例77 化合物76的制备
Figure PCTCN2018106768-appb-000155
化合物76是根据实施例75中化合物74的制备方法，用中间体74b和76a反应得到含有两个异构体的混合物。 1H NMR(500MHz,CDCl 3)δ8.73(d,J＝4.6Hz,1H),8.39(d,J＝2.1Hz,1H),8.03(d,J＝8.7Hz,2H),7.89(dd,J＝8.8,2.2Hz,1H),7.72(s,1H),7.60(dd,J＝10.5,2.7Hz,1H),7.42–7.37(m,1H),7.29(d,J＝4.5Hz,1H),3.69–3.63(m,1H),2.63(t,J＝6.9Hz,2H),2.40–2.14(m,5H),2.13–2.04(m,1H),1.37–1.32(m,2H),1.21 (d,J＝6.5Hz,3H),1.11–0.99(m,2H)。LCMS m/z 530.1[M+H] +。
实施例78 化合物77的制备
Figure PCTCN2018106768-appb-000156
将76(20mg,0.04mmol)，77a(10mg,0.12mmol)，(Ph 3P) 2PdCl 2(5mg),Ph 3P(2mg)，Et 3N(38mg，0.40mmol)和CuI(1mg)溶解在四氢呋喃(2mL)中，升到60℃并搅拌4小时。将反应液缓慢加入到水中，用乙酸乙酯萃取(3X 5mL)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩。粗品经制备薄板层析纯化(甲醇/二氯甲烷＝5％)分离得到白色固体化合物77。化合物77为主产物。 1H NMR(500MHz,CDCl 3)δ8.73(d,J＝4.6Hz,1H),8.24(d,J＝1.5Hz,1H),8.14(d,J＝8.7Hz,1H),8.03(dd,J＝9.2,5.7Hz,1H),7.85(s,1H),7.65(dd,J＝8.6,2.1Hz,1H),7.43–7.35(m,2H),7.29(d,J＝4.6Hz,1H),3.69–3.62(m,1H),2.66–2.60(m,2H),2.40–2.27(m,2H),2.21–2.16(m,3H),2.13–2.04(m,1H),1.56(s,6H),1.48–1.39(m,2H),1.20(d,J＝7.3Hz,3H),1.12–1.05(m,1H),1.01(dd,J＝19.6,11.4Hz,1H)。LCMS m/z 243.8[M/2+H] +。
实施例79 化合物78的制备
化合物78是在实施例78中化合物77的制备过程中分离得到的少量的副产物。LCMS m/z 486.2[M+H] +。
实施例80 化合物79的制备
Figure PCTCN2018106768-appb-000157
参照化合物77的制备(实施例78)，化合物76和79a反应，经分离纯化得主产物化合物79。LCMS m/z 468.3[M+H] +。
实施例81 化合物80的制备
Figure PCTCN2018106768-appb-000158
参照化合物76的制备(实施例77)，化合物74b和80a反应，经分离纯化得主产物化合物80。 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.6Hz,1H),8.62(d,J＝2.3Hz,1H),8.49(d,J＝8.6Hz,1H),8.10(dd,J＝9.2,5.7Hz,1H),7.78–7.60(m,2H),7.50–7.45(m,1H),7.44(s,1H),7.35(d,J＝4.5Hz,1H),3.77–3.70(m,1H),2.75–2.69(m,2H),2.45–2.40(m,2H),2.36–2.24(m,3H),2.20–2.12(m,1H),1.51–1.47(m,2H),1.31(d,J＝6.5Hz,3H),1.19–1.03(m,2H)。LCMS m/z 472.2[M+H] +。
实施例82 化合物81的制备
Figure PCTCN2018106768-appb-000159
参照化合物76的制备(实施例77)，化合物74b和81a反应，经分离纯化得主产物化合物81。 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.6Hz,1H),8.53(s,1H),8.39(d,J＝8.8Hz,1H),8.10(dd,J＝9.1,5.7Hz,1H),8.01(s,1H),7.92(d,J＝2.3Hz,1H),7.67(dd,J＝10.4,2.7Hz,1H),7.49–7.42(m,1H),7.36(d,J＝4.6Hz,1H),3.76–3.69(m,1H),2.74–2.68(m,2H),2.45–2.38(m,2H),2.32–2.20(m,3H),2.20–2.11(m,1H),1.52–1.48(m,2H),1.30(d,J＝6.3Hz,3H),1.20–1.02(m,2H)。LCMS m/z 472.2[M+H] +。
实施例83 化合物82的制备
Figure PCTCN2018106768-appb-000160
参照化合物77的制备(实施例78)，化合物76和82a反应，经分离纯化得主产物化合物82。 1H NMR(500MHz,CDCl 3)δ8.73(d,J＝4.5Hz,1H),8.21(d,J＝1.8Hz,1H),8.11(d,J＝8.6Hz,1H),8.03(dd,J＝9.2,5.7Hz,1H),7.83(s,1H),7.65–7.57(m,2H),7.39(ddd,J＝9.2,8.0,2.8Hz,1H),7.29(d,J＝4.6Hz,1H),3.65(dq,J＝18.0,5.9Hz,1H),2.68–2.55(m,2H),2.33(ddd,J＝18.7,12.2,5.8Hz,2H),2.24–2.13(m,3H),2.12–2.05(m,1H),1.99(s,3H),1.43(dt,J＝12.2,10.0Hz,2H),1.21(d,J＝6.6Hz,3H),1.10–1.04(m,1H),1.02–0.95(m,1H)。LCMS m/z 442.2[M+H] +。
实施例84 化合物83的制备
Figure PCTCN2018106768-appb-000161
中间体83b是由83a和82a反应得到的(参照实施例78中化合物77的制备方法)。
化合物74b和83b反应，经纯化得到主产物化合物83(参照化合物76的制备)。 1H NMR(500MHz,CDCl 3)δ8.73(d,J＝4.5Hz,1H),8.40(d,J＝2.4Hz,1H),8.13(dd,J＝8.6,2.6Hz,1H),8.03(dd,J＝9.2,5.7Hz,1H),7.61(dd,J＝10.4,2.7Hz,1H),7.43–7.35(m,2H),7.30–7.25(m,2H),3.66(ddd,J＝17.9,11.9,5.9Hz,1H),2.63(d,J＝7.3Hz,2H),2.38–2.31(m,2H),2.26–2.15(m,3H),2.12–2.07(m,1H),1.98(s,3H),1.42(dd,J＝19.2,12.0Hz,2H),1.20(d,J＝7.1Hz,3H),1.07(dd,J＝11.6,8.1Hz,1H),1.01–0.94(m,1H)。 LCMS m/z 442.2[M+H] +。
实施例85 化合物84的制备
Figure PCTCN2018106768-appb-000162
将化合物1ab(3.0g,11.18mmol)和TMEDA(2.6g,22.36mmol)溶于四氢呋喃(20mL)中并在氮气保护下冷却至-78℃,缓慢滴加LDA(11.18mL，22.36mmol)，于-78℃下搅拌1小时后，将碘甲烷(3.17g，22.36mmol)缓慢滴加至上述溶液，在-78℃搅拌30分钟(析出大量白色固体)。向反应液中加入饱和NH 4Cl水溶液(20mL)，用乙酸乙酯萃取(3x 30mL)。合并的有机相用饱和食盐水洗涤(3x 20mL)，用无水硫酸钠干燥，过滤减压浓缩，所得的粗品经硅胶柱纯化(乙酸乙酯/石油醚＝0-10％)分离得到无色油状液体化合物84a(1.9g,收率60％)。
从化合物84a出发，参照化合物1的合成路线，经多步合成，制备了化合物84e。化合物84e经催化氢化反应，得到了主产物84f及其它三个异构体(少量)，在这一步反应中，这些异构体和主产物靠得近，硅胶柱层析比较难分开，所以混合物继续用于下一步反应(酯水解和酰氯的制备)，最后在酰胺的制备中，这三个少量的异构体可以用薄板层析分开。 1H NMR(500MHz,CD 3OD)δ8.72(d,J＝4.7Hz,1H),8.29(d,J＝2.6Hz,1H),8.10(d,J＝8.9Hz,1H),8.04(dd,J＝9.2,5.6Hz,1H),7.88(dd,J＝10.6,2.8Hz,1H),7.79(dd,J＝8.9,2.6Hz,1H),7.59–7.54(m,2H),3.90–3.83(m,1H),2.76–2.73(m,2H),2.51–2.45(m,1H),2.44–2.38(m,2H),2.00–1.95(m,2H),1.58–1.50(m,2H),1.28(s,6H),1.35–1.26(m,2H)。LCMS m/z 452.2[M+H] +。
实施例86 化合物85的制备
Figure PCTCN2018106768-appb-000163
与化合物26制备方法相同，化合物84j和化合物18a反应制备得到化合物85。 1H NMR(500MHz,CD 3OD)δ8.72(d,J＝4.7Hz,1H),8.58(d,J＝2.7Hz,1H),8.09–8.03 (m,2H),7.88(dd,J＝10.6,2.7Hz,1H),7.59–7.54(m,2H),7.41(d,J＝8.7Hz,1H),3.31–3.29(m,1H),2.79–2.69(m,2H),2.50–2.45(m,1H),2.44–2.38(m,2H),2.03–1.95(m,2H),1.58–1.51(m,2H),1.28(s,6H),1.32–1.23(m,2H)。LCMS m/z 452.2[M+H] +。
实施例87 化合物86的制备
Figure PCTCN2018106768-appb-000164
与化合物26制备方法相同，化合物84j和化合物25a反应制备得到化合物86。 1H NMR(500MHz,CD 3OD)δ8.72(d,J＝4.7Hz,1H),8.39(d,J＝1.6Hz,1H),8.10(d,J＝8.7Hz,1H),8.05(dd,J＝9.2,5.6Hz,1H),7.88(dd,J＝10.6,2.8Hz,1H),7.84(dd,J＝8.7,2.3Hz,1H),7.61–7.52(m,2H),3.90–3.83(m,1H),3.65(s,1H),2.75–2.73(m,2H),2.51–2.45(m,1H),2.44–2.38(m,2H),2.00–1.95(m,2H),1.58–1.51(m,2H),1.28(s,6H),1.32–1.25(m,2H)。LCMS m/z 442.3[M+H] +。
实施例88 化合物87的制备
Figure PCTCN2018106768-appb-000165
与化合物26制备方法相同，化合物84j和化合物24a反应制备得到化合物87。 1H NMR(500MHz,CD 3OD)δ8.73–8.72(m,2H),8.12(dd,J＝8.6,2.5Hz,1H),8.05(dd,J＝9.2,5.6Hz,1H),7.88(dd,J＝10.6,2.8Hz,1H),7.59–7.53(m,3H),3.90–3.83(m,1H),3.69(s,1H),2.74–2.73(m,2H),2.51–2.46(m,1H),2.44–2.38(m,2H),2.00–1.95(m,2H),1.58–1.51(m,2H),1.28(s,6H),1.32–1.25(m,2H)。LCMS m/z 442.2[M+H] +。
实施例89 化合物88的制备
Figure PCTCN2018106768-appb-000166
与化合物26制备方法相同，化合物84j和化合物69a反应制备得到化合物88。 1H NMR(500MHz,CDCl 3)δ8.81(d,J＝4.6Hz,1H),8.62(d,J＝2.5Hz,1H),8.45(dd,J＝8.6,2.6Hz,1H),8.12(dd,J＝9.2,5.7Hz,1H),7.70–7.67(m,2H),7.52(s,1H),7.50–7.46(m,1H),7.37(d,J＝4.6Hz,1H),3.77–3.70(m,1H),2.73–2.66(m,2H),2.45–2.36(m,3H),2.04–2.01(m,2H),1.53–1.48(m,2H),1.35(s,6H),1.29–1.20(m,2H)。LCMS m/z 443.2[M+H] +。
实施例90 化合物89的制备
Figure PCTCN2018106768-appb-000167
与化合物26制备方法相同，化合物84j和化合物71a反应制备得到化合物89。 1H NMR(500MHz,CDCl 3)δ8.73(d,J＝4.6Hz,1H),8.49(d,J＝1.5Hz,1H),8.33(d,J＝8.8Hz,1H),8.10(s,1H),8.06(s,1H),7.88(dd,J＝8.8,2.2Hz,1H),7.61(dd,J＝10.4,2.5Hz,1H),7.43–7.40(m,1H),7.31(s,1H),3.69–3.64(m,1H),2.65–2.58(m,2H),2.37–2.28(m,3H),1.97–1.91(m,2H),1.48–1.40(m,2H),1.26(s,6H),1.18–1.13(m,2H)。LCMS m/z 443.3[M+H] +。
实施例91 化合物90的制备
Figure PCTCN2018106768-appb-000168
与化合物26制备方法相同，化合物84j和化合物90a反应制备得到化合物90。 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.5Hz,1H),8.30(d,J＝1.8Hz,1H),8.20(d,J＝8.7Hz,1H),8.12(dd,J＝9.1,5.7Hz,1H),8.00(s,1H),7.71–7.67(m,2H),7.49–7.45(m,1H),7.37(d,J＝4.5Hz,1H),3.76–3.69(m,1H),2.75–2.65(m,2H),2.43–2.35(m,3H),2.07(s,3H),2.04–1.99(m,2H),1.54–1.47(m,2H),1.32(s,6H),1.26–1.20(m,2H)。LCMS m/z 456.2[M+H] +。
实施例92 化合物91的制备
Figure PCTCN2018106768-appb-000169
与化合物26制备方法相同，化合物84j和化合物83b反应制备得到化合物91。 1H NMR(500MHz,CDCl 3)δ8.81(d,J＝4.6Hz,1H),8.46(d,J＝2.5Hz,1H),8.19(dd,J＝8.6,2.6Hz,1H),8.14(s,1H),7.69(dd,J＝10.4,2.7Hz,1H),7.50–7.47(m,1H),7.39–7.35(m,3H),3.77–3.70(m,1H),2.75–2.65(m,2H),2.44–2.36(m,3H),2.08(s,3H),2.05–2.00(m,2H),1.55–1.48(m,2H),1.33(s,6H),1.26–1.20(m,2H)。LCMS m/z 456.2[M+H] +。
实施例93 化合物92的制备
Figure PCTCN2018106768-appb-000170
化合物92a(2.37g,6.68mmol)溶于四氢呋喃(15mL)中，在氮气保护下冷却至-78℃。在搅拌下，向上述溶液中加入六甲基二硅基氨基锂(3.34mL,6.68mmol)，反应30分钟。然后向上述混合物中滴加化合物38f(1.5g,5.57mmol)的四氢呋喃(5mL)溶液，反应2 小时后，加入饱和氯化铵水溶液(30mL)。水相用乙酸乙酯萃取(3x 10mL)，合并的有机相用饱和食盐水洗涤，然后干燥(无水硫酸钠)，过滤。滤液减压浓缩后，经硅胶柱层析纯化(乙酸乙酯/石油醚＝0-10％)得到无色油状液体92b(1.9g，收率73％)。
在0℃下，向化合物92b(1.9g,4.05mmol)的乙腈(10mL)溶液中依次加入CsF(3.07g,20.23mmol)和冰醋酸(2.43g,40.45mmol)。加毕，在0℃下搅拌30分钟。然后慢慢升至室温反应至原料消失。反应混合液用饱和碳酸氢钠水溶液调节至pH为7，分离出有机相，水相用乙酸乙酯萃取(3x 10mL)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤后，滤液减压浓缩后，经硅胶柱层析纯化(乙酸乙酯/石油醚＝0-20％)得到白色固体92c(280mg)和无色油状液体92d(450mg)。
在-78□C和氮气保护下，向甲基三苯基溴化磷(503mg,1.41mmol)的四氢呋喃(3mL)溶液加入六甲基二硅基氨基钾(1N的四氢呋喃溶液，1.41mL,1.41mmol)。在-78□C下搅拌1小时后，向该反应体系加入化合物92d(250mg,0.7mmol)的四氢呋喃(2mL)溶液，缓慢将反应体系的温度升高到室温并在室温下搅拌1小时。向反应体系中加入饱和氯化铵溶液(1mL)淬灭，接着加入乙酸乙酯(10mL)稀释。分出有机相，水相用乙酸乙酯萃取(3x 10mL)，合并的有机相依次用水和饱和食盐水洗涤1次。有机相经干燥(无水硫酸钠)，过滤，减压浓缩后得到粗品。粗品经硅胶柱层析纯化(乙酸乙酯/石油醚＝0-100％)得到无色油状液体化合物92e(120mg,收率48％)。
将三甲基碘化亚砜(48mg,0.51mmol)和氢化钠(24mg,0.41mmol)置于反应瓶中，在0℃下加入DMF(1mL)并搅拌十分钟。然后升温至60℃下，向上述反应体系中加入化合物92e(120mg,0.34mmol)的DMF(1.5mL)溶液。加毕反应体系在此温度下搅拌过夜。加入饱和氯化铵(1mL)淬灭反应，并用乙酸乙酯(10mL)稀释。混合物用饱和氯化钠水溶液洗涤1次。有机相经干燥(无水硫酸钠)，过滤，减压浓缩后得到粗品。粗品经硅胶柱层析纯化(乙酸乙酯)得到白色固体化合物92f(35mg,收率37％)。
根据化合物26的合成步骤和方法，从化合物92f出发，经酰氯制备化合物92。 1H NMR(500MHz,CD 3OD)δ8.73(d,J＝4.7Hz,1H),8.27(d,J＝2.5Hz,1H),8.09(d,J＝8.9Hz,1H),8.05(dd,J＝9.2,5.6Hz,1H),7.89(dd,J＝10.6,2.8Hz,1H),7.77(dd,J＝8.9,2.6Hz,1H),7.61(d,J＝4.7Hz,1H),7.59–7.55(m,1H),3.61–3.54(m,1H),2.87–2.77(m,3H),2.41–2.36(m,2H),1.63(dd,J＝12.8,5.8Hz,2H),1.53(dd,J＝21.3,12.2Hz,2H),1.42–1.36(m,2H),1.05(q,J＝4.6Hz,2H),0.86(dd,J＝6.7,4.8Hz,2H)。LCMS m/z450.1[M+H] +。
实施例94 化合物93的制备
Figure PCTCN2018106768-appb-000171
化合物93的制备方法和化合物92的制备方法类似。 1H NMR(500MHz,CDCl 3)δ8.80(d,J＝4.5Hz,1H),8.50(d,J＝2.3Hz,1H),8.21(dd,J＝8.6,2.6Hz,1H),8.15(dd,J＝9.2,5.7Hz,1H),7.70(dd,J＝10.4,2.7Hz,1H),7.59(s,1H),7.51–7.47(m,1H),7.46(d,J＝8.6Hz,1H),7.40(d,J＝4.4Hz,1H),3.48–3.43(m,1H),3.12(s,1H),2.80–2.74(m,2H),2.73–2.67(m,1H),2.46–2.41(m,2H),1.66(dd,J＝12.9,5.8Hz,2H),1.47–1.38(m,4H),1.12(q,J＝4.8Hz,2H),0.87(q,J＝4.9Hz,2H)。LCMS m/z 440.2[M+H] +。
实施例95 化合物94的制备
Figure PCTCN2018106768-appb-000172
化合物94的制备方法和化合物92的制备方法类似。 1H NMR(500MHz,CDCl 3)δ8.82(d,J＝4.5Hz,1H),8.54(d,J＝1.6Hz,1H),8.36(dd,J＝8.8,0.5Hz,1H),8.21(s,1H),8.14(dd,J＝9.2,5.7Hz,1H),7.93(dd,J＝8.8,2.2Hz,1H),7.70(dd,J＝10.4,2.7Hz,1H),7.52–7.46(m,1H),7.40(d,J＝4.5Hz,1H),3.51–3.44(m,1H),2.83–2.70(m,3H),2.48–2.43(m,2H),1.68(dd,J＝12.9,5.9Hz,2H),1.49–1.36(m,4H),1.17(q,J＝4.7Hz,2H),0.92(q,J＝4.9Hz,2H)。LCMS m/z 441.2[M+H] +。
实施例96 化合物95的制备
Figure PCTCN2018106768-appb-000173
化合物95a是从化合物92c根据化合物92e的方法制备的。化合物95a的立体构型是由NOESY确定的。 1H NMR(500MHz,CDCl 3)δ8.65(d,J＝4.4Hz,1H),7.96(dd,J＝9.2,5.7Hz,1H),7.55(dd,J＝10.5,2.7Hz,1H),7.36–7.28(m,1H),7.23(d,J＝4.6Hz,1H),6.00(s,1H),5.44(d,J＝1.1Hz,1H),4.08(q,J＝7.1Hz,2H),3.65–3.51(m,1H),2.97–2.89(m,1H),2.70–2.53(m,2H),2.33–2.23(m,2H),2.19–2.07(m,2H),1.45–1.36(m,2H),1.17(t,J＝5.7Hz,3H),1.16–1.12(m,2H)。
从化合物95a制备化合物95，可参照化合物92的制备方法。 1H NMR(500MHz,CDCl 3)δ8.73(d,J＝4.5Hz,1H),8.15(dd,J＝6.8,6.1Hz,2H),8.04(dd,J＝9.1,5.6Hz,2H),7.64–7.57(m,2H),7.44–7.37(m,1H),7.29(d,J＝4.6Hz,1H),3.74–3.61(m,1H),2.76–2.59(m,3H),2.41–2.30(m,2H),2.14–2.02(m,2H),1.49–1.37(m,2H),1.10(q,J＝4.5Hz,2H),1.03–0.96(m,2H),0.80(dd,J＝6.7,4.6Hz,2H)。LCMS m/z 450.1[M+H] +。
实施例97 化合物96的制备
Figure PCTCN2018106768-appb-000174
化合物96的制备方法和化合物92的制备方法类似。 1H NMR(500MHz,CDCl 3)δ8.73(d,J＝4.6Hz,1H),8.33(d,J＝1.7Hz,1H),8.14(d,J＝8.6Hz,1H),8.08(s,1H),8.05(dd,J＝8.5,6.1Hz,1H),7.72(dd,J＝8.7,2.2Hz,1H),7.61(dd,J＝10.4,2.7Hz,1H),7.45–7.37(m,1H),7.30(d,J＝4.4Hz,1H),3.71–3.64(m,1H),3.10(s,1H),2.76–2.59(m,3H),2.40–2.30(m,2H),2.16–2.03(m,2H),1.43(dd,J＝12.2,4.2Hz,2H),1.11(q,J＝4.5Hz,2H),1.01–0.96(m,2H),0.80(dd,J＝6.8,4.6Hz,2H)。LCMS m/z 440.1[M+H] +。
实施例98 化合物97的制备
Figure PCTCN2018106768-appb-000175
化合物97的制备方法和化合物92的制备方法类似。 1H NMR(500MHz,CDCl 3)δ8.74(d,J＝4.7Hz,1H),8.42(d,J＝2.5Hz,1H),8.16(dd,J＝8.5,2.7Hz,1H),8.05(d,J＝6.2Hz,1H),7.62–7.60(m,2H),7.43–7.39(m,1H),7.30(d,J＝5.7Hz,1H),3.71–3.66(m,1H),3.06(s,1H),2.72–2.61(m,3H),2.38(dd,J＝12.8,6.6Hz,2H),2.31–2.22(m,2H),2.11–2.03(m,2H),1.09(dd,J＝6.6,4.4Hz,2H),1.03–1.01(m,2H),0.83–0.80(m,2H)。LCMS m/z 220.1[M/2+H] +。
实施例99 化合物98的制备
Figure PCTCN2018106768-appb-000176
化合物98的制备方法和化合物92的制备方法类似。 1H NMR(500MHz,CDCl 3)δ8.73(d,J＝4.5Hz,1H),8.51–8.46(m,1H),8.30(d,J＝8.8Hz,1H),8.23(s,1H),8.04(dd,J＝9.2,5.7Hz,1H),7.87(dd,J＝8.8,2.2Hz,1H),7.61(dd,J＝10.4,2.7Hz,1H),7.43–7.38(m,1H),7.29(d,J＝4.6Hz,1H),3.71–3.64(m,1H),2.75–2.61(m,3H),2.41–2.32(m,2H),2.13–2.03(m,2H),1.46–1.39(m,2H),1.13(dd,J＝6.8,4.5Hz,2H),1.04–0.96(m,2H),0.85(dd,J＝6.9,4.6Hz,2H)。LCMS m/z 441.3[M+H] +。
实施例100 化合物99的制备
Figure PCTCN2018106768-appb-000177
将化合物99a(100mg,0.65mmol)溶解在氯化亚砜(5mL)中，将反应加热到50℃搅拌30分钟。减压浓缩得到无色油状物99b(112mg，收率100％)。粗品不经纯化，直接用于下一步反应。
将2-氨基-5-氯吡啶(101mg，0.78mmol)溶解在四氢呋喃(2mL)中，冰水浴下缓慢加入60％的NaH(52mg,1.31mmol)，缓慢升到室温并搅拌1小时，将其缓慢加入到化合物99b(112mg，0.65mmol)的四氢呋喃(1mL)溶液中。加毕混合物升温到60℃搅拌3小时。将反应液缓慢加入到饱和碳酸氢钠溶液中，用乙酸乙酯萃取(3X 10mL)。合并的有机相经干燥(无水硫酸钠)，过滤，减压浓缩。粗品经硅胶柱层析纯化(乙酸乙 酯/石油醚＝0-20％)得到淡黄色固体化合物99c(82mg，收率47.63％)。
44e(20mg,0.07mmol)，99c(22mg,0.08mmol)，碳酸钾(29mg,0.21mmol)溶于乙腈(3mL)中，然后加热至80℃反应过夜。反应液加水，用乙酸乙酯萃取(3x 10mL)，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，过制备薄板层析纯化(乙酸乙酯/石油醚＝100％)分离得到白色固体化合物99(2mg)。 1H NMR(500MHz,CDCl 3)δ9.77(s,1H),8.82(d,J＝4.6Hz,1H),8.19(d,J＝2.3Hz,1H),8.15(d,J＝8.8Hz,1H),8.07(dd,J＝9.1,5.7Hz,1H),7.65(dd,J＝10.4,2.5Hz,1H),7.63–7.58(m,2H),7.44–7.38(m,1H),3.50(ddd,J＝17.9,12.1,5.7Hz,1H),3.14(q,J＝7.0Hz,1H),2.72(dd,J＝19.8,10.4Hz,4H),2.49–2.39(m,4H),1.69(dd,J＝20.6,12.2Hz,2H),1.33(d,J＝7.0Hz,3H)。LCMS m/z 439.2[M+H] +。
实施例101 化合物100的制备
Figure PCTCN2018106768-appb-000178
化合物100的制备方法和化合物99的制备方法类似。 1H NMR(500MHz,CDCl 3)δ10.12(s,1H),8.83(d,J＝4.6Hz,1H),8.17(dd,J＝22.0,5.7Hz,2H),8.07(dd,J＝9.7,6.0Hz,1H),7.74(d,J＝3.1Hz,1H),7.66(dd,J＝10.6,2.5Hz,1H),7.60(dd,J＝8.8,2.4Hz,1H),7.43(dd,J＝7.9,1.2Hz,1H),3.57–3.44(m,1H),2.72(dd,J＝12.0,6.9Hz,2H),2.60(d,J＝9.1Hz,2H),2.50(dd,J＝9.1,6.2Hz,2H),2.45–2.39(m,2H),1.75–1.67(m,2H),1.28(s,6H)。LCMS m/z 453.2[M+H] +。
实施例102 化合物101的制备
Figure PCTCN2018106768-appb-000179
化合物101的制备方法和化合物26的制备方法类似。 1H NMR(500MHz,CDCl 3)δ8.73(d,J＝4.5Hz,1H),8.53(d,J＝2.4Hz,1H),8.37(dd,J＝8.6,2.5Hz,1H),8.05(dd,J＝9.2,5.7Hz,1H),7.68(dd,J＝10.3,2.7Hz,1H),7.61(d,J＝8.6Hz,1H),7.42(dd,J＝8.6,2.3Hz,1H),7.40–7.37(m,1H),7.17(d,J＝4.4Hz,1H),5.94(d,J＝1.5Hz,1H),3.44(d,J＝7.0Hz,1H),3.03(dd,J＝16.5,8.7Hz,1H),2.85(dd,J＝17.0,8.2Hz,1H),2.49(d,J＝7.3Hz,3H),2.40–2.30(m,2H),2.24(dd,J＝12.6,6.2Hz,1H),1.15–1.07(m,2H)。LCMS m/z 413.2[M+H] +。
实施例103 化合物102的制备
Figure PCTCN2018106768-appb-000180
化合物102的制备方法和化合物26的制备方法类似。 1H NMR(500MHz,CDCl 3)δ8.81(d,J＝4.6Hz,1H),8.60(d,J＝2.5Hz,1H),8.45(dd,J＝8.6,2.6Hz,1H),8.11(dd,J＝9.2,5.7Hz,1H),7.70–7.68(m,2H),7.50–7.48(m,1H),7.47–7.46(m,1H),7.37(d,J＝4.6Hz,1H),3.76(ddd,J＝18.0,11.9,5.8Hz,1H),2.79–2.73(m,2H),2.54(d,J＝1.6Hz,2H),2.48–2.42(m,2H),2.31–2.26(m,2H),1.54–1.49(m,3H),1.13(dd,J＝18.7,11.2Hz,2H)。Ms m/z 415.20[M+H] +。
实施例104 化合物103的制备
Figure PCTCN2018106768-appb-000181
化合物1k经酯水解，酰氯的形成，然后与化合物103a反应，制备得到化合物103。具体参照化合物26的制备方法。LCMS m/z 472.2[M+H] +。
实施例105 化合物104和化合物105的制备
Figure PCTCN2018106768-appb-000182
在0℃和搅拌条件下向化合物92d(40mg,0.11mmol)的二氯甲烷(2mL)溶液加入二乙胺基三氟化硫(91mg,0.56mmol)。该反应体系缓慢升至室温并搅拌过夜。接着向反应液中加入饱和碳酸氢钠溶液，加入二氯甲烷(5mL)，将反应液用水洗，收集有机相，加入无水硫酸钠干燥，过滤，滤液减压浓缩后得到粗品。粗品经硅胶柱层析纯化(乙酸乙酯/石油醚＝0-30％)得到无色油状液体104e(28mg,收率66％)。化合物104a经酯水解，酰氯的形成，然后与化合物17a反应，制备得到化合物104。化合物105是在合成化合物104时产生的副产物，由于和产物靠的很近，在最后一步反应中经多次制备性薄板层析分离才分开。其中的一个分离条件为(丙酮/石油醚＝0-100％)。至于化合物105是在哪一步产生的，如何产生的，未进行仔细研究。化合物104： 1H NMR(500MHz,CDCl 3)δ8.81(d,J＝4.4Hz,1H),8.62(s,1H),8.31(d,J＝2.4Hz,1H),8.23(d,J＝8.9Hz,1H),8.15(dd,J＝8.9,5.7Hz,1H),7.75(dd,J＝8.8,2.5Hz,1H),7.69(dd,J＝10.3,2.4Hz,1H),7.51–7.47(m,1H),7.37(d,J＝4.4Hz,1H),3.49(ddd,J＝17.7,12.0,5.4Hz,1H),3.02–2.92(m,1H),2.89–2.83(m,2H),2.50–2.37(m,2H),1.86(td,J＝12.5,8.0Hz,2H),1.76(dd,J＝12.9,6.3Hz,2H),1.46–1.39(m,2H)。LCMS m/z 460.07[M+H] +。化合物105：LCMS m/z 440.07[M+H] +。
实施例106 化合物106的制备
Figure PCTCN2018106768-appb-000183
将化合物38f(50mg,0.185mmol)溶于THF/MeOH(1：1，2mL)中，室温下加入硼氢化钠(11mg,0.278mmol)并搅拌1小时。加入饱和氯化铵水溶液(0.5mL)淬灭，并用乙酸乙酯(5mL)稀释。反应液用水洗涤1次，分类的有机相，经干燥(无水硫酸钠)，过滤，减压浓缩后得到粗品化合物106a和106b(核磁谱显示106a和106b的比例约为3：1)。粗品直接用于下一步反应。
将化合物106a和106b的混合物(13mg,0.048mmol)溶于THF(2mL)中，接着在室温下加入二甲氨基吡啶(12mg,0.096mmol)，搅拌几分钟后加入对氯苯基异氰酸酯(11mg,0.072mmol)。该反应体系在60□C下搅拌3小时，加入乙酸乙酯稀释(5mL)，将反应液用水洗，收集有机相，加入无水硫酸钠干燥，过滤，滤液减压浓缩后得到粗品，粗品经制备薄板层析纯化(乙酸乙酯：石油醚＝0-100％)得到白色固体化合物106(4mg,收率20％)。 1H NMR(500MHz,CD 3OD)δ8.69(s,1H),8.05(dd,J＝9.2,5.6Hz,1H),7.90(dd,J＝10.6,2.7Hz,1H),7.57(ddd,J＝9.2,8.2,2.8Hz,2H),7.41(d,J＝8.5Hz,2H),7.26–7.23(m,2H),5.21–5.18(m,1H),3.77–3.70(m,1H),2.90–2.81(m,2H),2.44–2.41(m,2H),2.22–2.17(m,2H),1.86(d,J＝14.1Hz,2H),1.78(d,J＝8.4Hz,2H)。LCMS m/z425.1[M+H] +。[注：在此条件下，少量的异构体106b并没有和对氯苯基异氰酸酯反应。另外，化合物106a,106b,和106c的立体构型是暂时指定的，并非最后确定。]
实施例107 化合物107和化合物108的制备
Figure PCTCN2018106768-appb-000184
化合物92d经酯水解，酰氯的形成，然后与化合物17a反应，制备得到化合物107(主产物)和化合物108(副产物)。具体参照化合物26的制备方法。[注：在这几步反应中，有脱碳基反应发生。另外，化合物107和108的立体构型是暂时指定的，并非最后确定。]
化合物107： 1H NMR(500MHz,CDCl 3)δ8.82(d,J＝4.5Hz,1H),8.30(s,1H),8.24(d,J＝8.9Hz,1H),8.22(d,J＝2.4Hz,1H),8.14(dd,J＝9.2,5.7Hz,1H),7.68(ddd,J＝8.7,5.8,2.7Hz,2H),7.48(ddd,J＝9.2,8.0,2.8Hz,1H),7.32(d,J＝4.6Hz,1H),3.53–3.45(m,1H),2.99–2.85(m,3H),2.51–2.42(m,2H),2.07(td,J＝12.8,8.0Hz,2H),1.88(dd,J＝13.0,6.2Hz,2H),1.37(td,J＝12.4,9.1Hz,2H)。LCMS m/z 410.2[M+H] +。
化合物108： 1H NMR(500MHz,CD 3OD)δ8.75(d,J＝4.7Hz,1H),8.25(d,J＝2.6Hz,1H),8.15(d,J＝8.9Hz,1H),8.06(dd,J＝9.2,5.6Hz,1H),7.90(dd,J＝10.6,2.8Hz,1H),7.76(dd,J＝8.9,2.6Hz,1H),7.59(t,J＝3.8Hz,1H),7.58–7.55(m,1H),3.92(dq,J＝ 18.1,6.0Hz,1H),3.11(ddd,J＝10.9,6.9,3.9Hz,1H),2.87–2.82(m,2H),2.45–2.40(m,2H),2.27(dt,J＝13.0,7.7Hz,2H),1.78(td,J＝12.8,7.8Hz,2H),1.70(td,J＝12.3,8.2Hz,2H).LCMS m/z 410.2[M+H] +。
实施例108
1.基于HEK293T细胞的IDO抑制活性测试方法：
第一步：细胞转染及铺板。将5x106的293T细胞分别种到2个T75的培养瓶里置于37℃,5％CO 2的培养箱内孵育过夜。将0.6μL含有1.5μg hIDO1质粒与300μL的opti-MEM制成混和液A；18μL的脂质体fugene6与300μL的opti-MEM制成混和液B，并在室温下放置5分钟。混和液A与混液B混匀，在室温下放置20分钟后，加到种有293T的培养瓶里，另外一瓶作为对照，置于37℃，5％CO 2的培养箱内孵育过夜。弃去培养基，用胰酶消化，消化完后，用含血清的培养基中和，吹打细胞，使细胞脱落。用移液管将细胞悬液移入离心管中，800-1000的转速离心1-3分钟。吸弃离心管中的细胞上清液。向离心管中加适当体积的培养基，轻柔吹打使细胞重悬均匀。使用Vi-Cell XR细胞计数仪计数。将细胞悬液调至合适浓度。将细胞悬液加入底透壁白的96孔板中，80微升/孔。第二步：化合物的准备和添加。用DMSO将化合物配制成600μM，以DMSO将化合物按照下列表格的倍数梯度稀释，得到6个浓度梯度的化合物。将DMSO配制的200×化合物按比例用对应的细胞培养液配成10×稀释液。每孔中加入10μL 10×相应化合物稀释液和10μL 10×TRP，Min除外。在37℃培养箱中孵育16小时。第三步：检测及分析。在倒置显微镜下观察细胞形态。取80μL上清加到3894板中，每孔加10μL 6.1N trichloroacetic acid，振荡2分钟，放入50度恒温箱中反应30分钟。离心，2500转10分钟。取上清70μL转到3635UV板中，加入70μL反应液，振荡2分钟，使其反应均匀。使用EnSpire(PE)检测OD值为480nm时的数据。将细胞培养板3903放置室温中平衡30分钟。将细胞活性检测试剂100μL/孔加入培养板中。在振板机上混匀2分钟，诱导细胞溶解。将96孔板在室温中放置10分钟，使其发光信号稳定。粘贴白色的底膜于培养板底部,使用Flexstation3测板.(相关设置为：发光，整合时间500ms)。记录分析所得的实验结果。
代表性化合物的活性如表1所示。IC 50值通过以下方式表示：A:IC 50值≤10nM；B:10nM＜IC 50值≤50nM；C:50nM＜IC 50值≤100nM；D:IC 50值>100nM。
表1HEK293T细胞IDO抑制活性(IC 50)
化合物1 A
化合物1A A
化合物1B A
化合物2 B
化合物4 B
化合物5 A
化合物6 B
化合物7 B
化合物9 D
化合物10 D
化合物11 B
化合物12 D
化合物22 B
化合物26 B
化合物27 B
化合物34 A
化合物38 A
化合物40 B
化合物42 B
化合物45 B
化合物50 B
化合物51 D
化合物57 B
化合物67 A
化合物68 A
化合物72 A
化合物73 A
化合物74 B
化合物79 B
化合物84 A
化合物85 A
化合物86 A
化合物87 A
化合物88 A
化合物90 A
化合物92 A
化合物93 A
化合物94 B
化合物95 A
化合物96 A
2.基于Hela细胞的IDO抑制活性测试方法
第一步：细胞铺板。配制完全培养基，充分混匀。选择生长状态良好的细胞株。将细胞培养瓶从培养箱中取出，核对瓶上标记的细胞名称，培养基类型及细胞代数。弃去培养基，用胰酶消化，消化完后，用含血清的培养基中和，吹打细胞，使细胞脱落。用移液管将细胞悬液移入离心管中，800-1000的转速离心3-5分钟。吸弃离心管中的细胞上清液。向离心管中加适当体积的培养基，轻柔吹打使细胞重悬均匀。使用Vi-Cell XR细胞计数仪计数。将细胞悬液调至合适浓度。依照下面的示意图将细胞悬液加入底透壁白的96孔板中，80微升/孔。第二步：化合物的准备和添加。用DMSO将化合物配制成600μM，以DMSO将化合物按照下列表格的倍数梯度稀释，得到6个浓度梯度的化合物。将DMSO配制的200×化合物按比例用对应的细胞培养液配成10×稀释液。细胞种板24小时后，每孔中加入10μL 10×相 应化合物稀释液和10μL 10×IFNγ。在37℃培养箱中孵育48小时。第三步：检测及分析。在倒置显微镜下观察细胞形态。取80μL上清加到3894板中，每孔加10μL 6.1N三氯乙酸，振荡2分钟，放入50度恒温箱中反应30分钟。离心，2500转10分钟。
取上清70μL转到3635UV板中，加入70μL反应液，振荡2分钟，使其反应均匀。使用EnSpire(PE)检测OD值为480nm时的数据。将细胞培养板3903放置室温中平衡30分钟。将细胞活性检测试剂100μL/孔加入培养板中。在振板机上混匀2分钟，诱导细胞溶解。将96孔板在室温中放置10分钟，使其发光信号稳定。粘贴白色的底膜于培养板底部，使用Flexstation3测板.(相关设置为：发光，整合时间500ms)。记录分析所得的实验结果。
代表性化合物的活性如表2所示。IC 50值通过以下方式表示：
A:IC 50值≤5nM；B:5nM＜IC 50值≤25nM；C:25nM＜IC 50值≤100nM；D:IC 50值>100nM。
表2Hela细胞IDO抑制活性(IC 50)
化合物代码 IDO抑制活性 化合物代码 IDO抑制活性 化合物代码 IDO抑制活性
化合物1 A 化合物42 A 化合物87 A
化合物1A A 化合物43 C 化合物88 A
化合物1B A 化合物44 A 化合物89 A
化合物2 B 化合物45 B 化合物90 A
化合物3 D 化合物46 C 化合物91 A
化合物4 A 化合物47 C 化合物92 A
化合物5 A 化合物48 D 化合物93 A
化合物6 B 化合物49 B 化合物94 A
化合物7 B 化合物50 B 化合物95 A
化合物8 B 化合物51 D 化合物96 A
化合物9 D 化合物52 D 化合物97 B
化合物10 D 化合物53 D 化合物98 A
化合物11 A 化合物54 D 化合物99 B
化合物12 C 化合物55 D 化合物100 D
化合物13 D 化合物56 B 化合物101 B
化合物14 D 化合物57 A 化合物102 A
化合物15 D 化合物58 B 化合物103 D
化合物16 D 化合物59 B 化合物104 C
化合物17 B 化合物60 A 化合物105 D
化合物18 A 化合物61 B 化合物106 D
化合物19 A 化合物62 A 化合物107 D
化合物20 A 化合物63 A 化合物108 B
化合物21 B 化合物64 A    
化合物22 B 化合物65 B    
化合物23 A 化合物66 A    
化合物24 A 化合物67 A    
化合物25 A 化合物68 A    
化合物26 A 化合物69A    
化合物26A A 化合物70A    
化合物26B A 化合物71B    
化合物27 A 化合物72A    
化合物28 D 化合物73A    
化合物29 C 化合物74A    
化合物30 D 化合物75B    
化合物31 D 化合物76A    
化合物32 D 化合物77A    
化合物33 C 化合物78C    
化合物34 A 化合物79D    
化合物35 B 化合物80A    
化合物36 A 化合物81B    
化合物37 A 化合物82D    
化合物38 A 化合物83D    
化合物39 A 化合物84D    
化合物40 A 化合物85B    
化合物41 B 化合物86A    
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (26)

  1. 一种如式(I)所示的化合物，或其光学异构体，药学上可接受的盐、前药、氘代衍生物、水合物、或溶剂合物：
    Figure PCTCN2018106768-appb-100001
    其中：
    Figure PCTCN2018106768-appb-100002
    表示单键或双键；
    X为键、NH、N(C 1-4烷基)、O、C(O)、C(S)、C(O)NH、C(O)O、或C(O)NCH 3；
    Y为键、NH、N(C 1-4烷基)、O、C(O)、C(S)、或C(O)NH；
    前提条件是X、Y、B和s的组合所形成的结构为稳定的化学结构；
    A为C 6-10芳基、5-至15-元杂芳基、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 3-10环烷基、或4-至20元杂环基；
    B为C 3-8单环烷基、含一个到多个任选自N、O、S的4-至8-元单环杂环基、C 7-12多环烷基、或含一个到多个任选自N、O、S的5-至12-元多环杂环基、这里的多环烷基或多环杂环基是指多于一个环的饱和的或部分不饱和的环状结构，包括螺环、并环、桥环；且当B为
    Figure PCTCN2018106768-appb-100003
    时，s只能为1，此时CR 2R 3中的R 3为无；
    D为键、氧、C(R 6) 2、C(O)、C≡C、C＝C、CH 2O、OCH 2、S(O) 2、或NR 7，前提条件是D与B和E连接所形成的结构为稳定的化学结构，比如，当D为氧或NR 7时，D与B或E的连接位点不能为N原子；
    E为C 6-10芳基、5-至10-元杂芳基、含1-3个任选自N、O、S的5-至10-元的杂环基、C 4-8环烷基并芳基、或C 4-8环烷基并杂芳基、或含1-3个任选自N、O、S的5-至10-元的杂环基并一个芳基或杂芳基；
    各个R 1各自独立地选自下组：氢、氘、卤素、C 1-4烷基、羟基、C 1-4烷氧基、羟基C 1-4烷基、羟基C 1-4烷氧基、C 2-4烯基、C 2-4炔基、C 3-10环烷基、4-至10元杂环基、NR 10R 11、氰基、C(O)R 12、C(O)NR 10R 11、OC(O)NR 10R 11、NR 10C(O)NR 10R 11、NR 10SO 2R 12、NR 10SO 2NR 10R 11、CO 2R 13、卤代C 1-4烷基、C 1-4烷氧基C 1-4烷基、卤代C 1-4烷氧基、C 1-4烷氧基C 1-4烷氧基、C 1-4烷氧基卤代C 1-4烷氧基、C 1-4烷氧基C 2-4烯基、C 1-4烷氧基C 2-4炔基、S-C 1-4烷基、双(C 1-4烷基)氨基C 1-4烷氧基、(CR 8R 9) n-C(O)-NHOH、O(CR 8R 9) n-C(O)-NHOH、NR 10(CR 8R 9) n-C(O)-NHOH、
    Figure PCTCN2018106768-appb-100004
    或者两个R 1与其相连的碳原子共同形成C＝O、C 3-8环烷基或含有1-2个选自N、O或S的4-至8-元杂环基，其中所述的环烷基或杂环基任选地被1-2个R 14取代；或者当两个R 1连接点为毗邻的两个碳原子时，两个R 1与其相连的碳原子共同形成C 3-8环烷基或含有1-2个选自N、O或S的4-至8-元杂环基，其中所述的环烷基或杂环基任选地被 1-2个R 14取代；这里，各个R 14各自独立地选自氢、氘、卤素、C 1-4烷基、羟基、C 1-4烷氧基、CN、NR 10R 11、C 3-6环烷基、含有1-2个选自N、O或S的4-至8-元的杂环基、C 6-10芳基、5-至10-元杂芳基、或＝O；前提条件是上述R 1的定义应和A的定义联系起来，确保所形成的结构为稳定的化学结构；
    R 2和R 3各自独立地选自氢、氘、C 1-8烷基、C 2-8烯基、C 2-8炔基、卤代C 1-8烷基、C 3-8环烷基、含有1-2个选自N、O或S的4-至8-元杂环基、C 6-10芳基、5-至10-元杂芳基、C 3-6环烷基C 1-4烷基、含有1-2个选自N、O或S的4-至8-元杂环基C 1-4烷基、C 6-10芳基C 1-4烷基、5-至10-元杂芳基C 1-4烷基、氟、OH、CN、CO 2H、C(O)NH 2、NR 10R 11、C 1-4烷氧基、(CR 8R 9) p-OH、(CR 8R 9) p-Z-(CR 8R 9) r-CO 2H、(CR 8R 9) p-Z-(CR 8R 9) r-C(O)NH 2、(CR 8R 9) p-Z-(CR 8R 9) r-C(O)NHR 10、(CR 8R 9) p-Z-(CR 8R 9) r-C(O)NR 10R 11、(CR 8R 9) p-Z-(CR 8R 9) r-C(O)NHOH；其中，Z为键、CH＝CH、C≡C、O、S、NR 7、C(O)、C 3-8环烷基、4-至-元杂环基、C 6-10芳基、5-至10-元杂芳基；或R 3为无；
    或R 2和R 3与其相连的碳原子共同形成C＝O、C 3-8环烷基或含有1-2个选自N、O或S的4-至8-元杂环基；
    或R 2及与R 2相连的碳原子与B上的一个或两个碳原子共同形成C 3-6环烷基或含有1-2个选自N、O或S的3-至6-元杂环基，这样的环状结构为螺环或稠环；
    上述R 2和R 3的定义必须保证与其它基团(包括X和Y，以及B和A)共同组成稳定的化学结构；
    各个R 4各自独立地为氢、氘、卤素、C 1-4烷基、羟基、CN、C 1-4烷氧基，或当两个R 4连接在同一个碳原子上，这两个R 4和被连接的碳一起组成羰基(C＝O)，或当两个R 4连接在相邻的两个碳原子上，这两个R 4和两个碳形成含氧的三元杂环结构；
    各个R 5各自独立地为氢、氘、卤素、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、含有1-2个选自N、O或S的4-至6-元杂环基、C 6芳基、5-至6-元杂芳基、卤代C 1-4烷基、羟基、CN、卤代C 1-4烷氧基、C(O)R 12、CO 2R 13、CONR 10R 11、SO 2NR 10R 11、NR 10SO 2NR 10R 11、NR 10C(O)R 12、或＝O；
    各个R 6各自独立地为氢、氘、卤素、C 1-4烷基、羟基、CN、C 1-4烷氧基；
    R 7为氢、C 1-4烷基、C 3-6环烷基、4-至8-元杂环基、C(O)C 1-4烷基、C(O)C 3-6环烷基；
    R 8和R 9各自独立地选自如下基团：氢、氘、卤素、C 1-4烷基、羟基、CN、C 1-4烷氧基；
    R 10和R 11各自独立地选自如下基团：氢、C 1-4烷基、C 3-8环烷基、4-至8-元杂环基、6-元芳基、5-至6-元杂芳基、C 1-4烷氧基C 1-4烷基、双(C 1-4烷基)氨基C 1-4烷基，其中环烷基、杂环基、芳基、或杂芳基任选地被1-3个R 14取代，这里的R 14定义如上所述；或者R 10和R 11一起与和它们连接的氮原子共同形成4-至8-元的环状结构，此环状结构可额外含有0-2个任选自N、O、S的杂原子，前提条件是所形成的环状结构为稳定的结构；此环状结构任选地被1-3个R 14取代；
    R 12为C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、4-至8-元杂环基、6-元芳基、5-至6-元杂芳基；
    R 13为氢、C 1-4烷基、C 3-6环烷基、含有1-2个选自N、O、S的4-至8-元的杂环基、6-元芳基、5-至6-元杂芳基；这里的烷基、环烷基、杂环基、芳基和杂芳基可以任选地被卤素、CN、羟基取代，只要所形成的结构为稳定的结构；
    R 14为氢、C 1-4烷基、C 3-6环烷基、含有1-2个选自N、O、S的4-至8-元的杂环基、6-元芳基、5-至6-元杂芳基；
    m为0、1、2或3；
    n为0、1、2或3；
    o为0、1、2或3；
    p为0、1、2、3或4；
    q为0、1、2或3；
    r为0、1、2、3或4；
    s为0或1；
    例外情况是：当B为C 3-8单环烷基或含一个到多个任选自N、O、S的4-至8元单环杂环基，且R 1、R 2和R 3均不包含C(O)-NH-OH基团时，A不是选自下组的基团：苯基、5-至6-元的杂芳基、C 5-7的环烷基；
    (其中，所述的R 1、R 2和R 3均不包含C(O)-NH-OH基团指R 1、R 2和R 3均不为C(O)-NH-OH基团，且R 1、R 2和R 3中不包括C(O)-NH-OH结构片段)
    其中，各个上述的烷基、烯基、炔基、环烷基、杂环基、芳基、和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：氢、氘、卤素、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤代C 1-4烷基、C 3-8环烷基、含有1-2个选自N、O或S的4-至8-元杂环基、C 6-10芳基、5-至10-元杂芳基、OH、CN、NO 2、OR 13、SR 13、N(R 7) 2、C(O)R 12、CO 2R 13、CONR 10R 11、SO 2NR 10R 11；取代基中，各个基团的定义分别如上所述。
  2. 如权利要求1所述的化合物，其特征在于，
    X为NH、N(C 1-4烷基)、O、C(O)、C(O)O、C(O)NH、或C(O)NCH 3；
    Y为NH、N(C 1-4烷基)、O、C(O)、或C(O)NH。
  3. 如权利要求2所述的化合物，其特征在于，Y-X为如下组合：
    Figure PCTCN2018106768-appb-100005
    Figure PCTCN2018106768-appb-100006
    表示与A连接的点，
    Figure PCTCN2018106768-appb-100007
    表示与CR 2R 3连接的点。
  4. 如权利要求3所述的化合物，其特征在于，Y-X为如下组合：
    Figure PCTCN2018106768-appb-100008
    Figure PCTCN2018106768-appb-100009
    表示与A连接的点，
    Figure PCTCN2018106768-appb-100010
    表示与CR 2R 3连接的点。
  5. 如权利要求1所述的化合物，其特征在于，R 2为氢、氘、或氟，R 3为C 1-4烷基、C 2-4烯基、C 2-4炔基、卤代C 1-4烷基、羟基、C 1-4烷氧基、C 3-6环烷基、(CR 8R 9) p-Z-(CR 8R 9) r-CO 2H、(CR 8R 9) p-Z-(CR 8R 9) r-C(O)NHOH。
  6. 如权利要求5所述的化合物，其特征在于，R 2和R 3各自独立地选自下组：氢、氘、氟、C 1-4烷基，或R 2和R 3与其相连的碳原子共同形成C 3-6环烷基或C＝O。
  7. 如权利要求6所述的化合物，其特征在于，R 2和R 3各自独立地选自下组：甲基，或R 2和R 3与其相连的碳原子共同形成环丙基。
  8. 如权利要求1所述的化合物，其特征在于，B为如下结构：
    Figure PCTCN2018106768-appb-100011
    Figure PCTCN2018106768-appb-100012
    表示与D连接的点，
    Figure PCTCN2018106768-appb-100013
    表示与CR 2R 3连接的点；其它各个基团的定义分别如上所述；前提条件是，当B为
    Figure PCTCN2018106768-appb-100014
    时，s只能为1，且CR 2R 3中的R 3为无。
  9. 如权利要求1所述的化合物，其特征在于，A为C 6-10芳基、5-至15-元杂芳基、C 3-10环烷基、4-至15元杂环基、或A为如下结构：
    Figure PCTCN2018106768-appb-100015
  10. 如权利要求1所述的化合物，其特征在于，各个R 1各自独立地为卤素、C 1-4烷基、C 1-4烷氧基、C 2-4烯基、C 2-4炔基、氰基、C(O)R 12、NR 10SO 2NR 10R 11、CO 2R 13、CONR 10R 11、卤代C 1-4烷基、卤代C 1-4烷氧基、(CR 8R 9) n-C(O)-NHOH、
    Figure PCTCN2018106768-appb-100016
  11. 如权利要求1所述的化合物，其特征在于，E为C 6-10芳基、5-至10-元杂芳基、含1-3个任选自N、O、S的5-至10-元的杂环基，或E为如下结构：
    Figure PCTCN2018106768-appb-100017
    Figure PCTCN2018106768-appb-100018
  12. 如权利要求11所述的化合物，其特征在于，E为如下结构：
    Figure PCTCN2018106768-appb-100019
  13. 如权利要求1所述的化合物，其特征在于，B选自下组：
    Figure PCTCN2018106768-appb-100020
    其中
    Figure PCTCN2018106768-appb-100021
    表示与D连接的点，
    Figure PCTCN2018106768-appb-100022
    表示与CR 2R 3连接的点；前提条件是，当B为
    Figure PCTCN2018106768-appb-100023
    时，CR 2R 3中的R 3为无。
  14. 如权利要求1所述的化合物，其特征在于，所述的化合物具有以下结构：
    Figure PCTCN2018106768-appb-100024
    其中，T 1和T 2各自独立地选自CR 15或N，其中R 15为H、F、或OH；
    Y-X选自如下组合：
    Figure PCTCN2018106768-appb-100025
    Figure PCTCN2018106768-appb-100026
    表示与A连接的点，
    Figure PCTCN2018106768-appb-100027
    表示与CR 2R 3连接的点。
  15. 如权利要求14所述的化合物，其特征在于，所述的化合物具有以下结构：
    Figure PCTCN2018106768-appb-100028
    Y-X选自如下组合：
    Figure PCTCN2018106768-appb-100029
    Figure PCTCN2018106768-appb-100030
    表示与A连接的点，
    Figure PCTCN2018106768-appb-100031
    表示与CR 2R 3连接的点。
  16. 如权利要求1所述的化合物，其特征在于，所述的化合物具有以下结构：
    Figure PCTCN2018106768-appb-100032
    其中，T 1和T 2各自独立地选自CR 15或N，其中R 15为H、F、或OH,
    Y-X选自如下组合：
    Figure PCTCN2018106768-appb-100033
    Figure PCTCN2018106768-appb-100034
    表示与A连接的点，
    Figure PCTCN2018106768-appb-100035
    表示与CR 2R 3连接的点。
  17. 如权利要求16所述的化合物，其特征在于，所述的化合物具有以下结构：
    Figure PCTCN2018106768-appb-100036
    Y-X选自如下组合：
    Figure PCTCN2018106768-appb-100037
    Figure PCTCN2018106768-appb-100038
    表示与A连接的点，
    Figure PCTCN2018106768-appb-100039
    表示与CR 2R 3连接的点。
  18. 如权利要求1所述的化合物，其特征在于，所述的化合物具有以下结构：
    Figure PCTCN2018106768-appb-100040
    其中，所述的G 1选自下组：
    Figure PCTCN2018106768-appb-100041
    所述的G2选自下组：
    Figure PCTCN2018106768-appb-100042
    Figure PCTCN2018106768-appb-100043
  19. 如权利要求1所述的化合物，其特征在于，
    所述的G1选自下组：
    Figure PCTCN2018106768-appb-100044
    所述的G2选自下组：
    Figure PCTCN2018106768-appb-100045
  20. 如权利要求1所述的式(I)所示的化合物，其特征在于，具有选自下组的结构：
    Figure PCTCN2018106768-appb-100046
    Figure PCTCN2018106768-appb-100047
    Figure PCTCN2018106768-appb-100048
    Figure PCTCN2018106768-appb-100049
    Figure PCTCN2018106768-appb-100050
    其中,“*”表示手性中心。
  21. 一种如权利要求1所述的式I化合物的用途，其特征在于，用于：
    (a)制备治疗与IDO活性或表达相关的疾病的药物；和/或
    (b)制备治疗与HDAC活性或表达相关的疾病的药物；和/或
    (c)制备IDO免疫抑制剂；和/或
    (d)制备IDO-HDAC双重免疫/靶向抑制剂；和/或(e)体外非治疗性地抑制IDO的活性；和/或双重抑制IDO-HDAC的活性。
  22. 一种药物组合物，其特征在于，所述的药物组合物包括：(i)治疗有效量的权利要求1所述的化合物，或其药学上可接受的盐；和(ii)药学上可接受的载体。
  23. 如权利要求22所述的药物组合物，其特征在于，所述的药物组合物还包括选自下组的第二治疗剂：抗体PD-1、PD-L1、CTLA-4。
  24. 如权利要求22所述的药物组合物，其特征在于，所述的药物组合物用于治疗癌症；优选地，所述的癌症选自下组：乳腺癌、淋巴癌、白血病、肺癌、卵巢癌、***、睾丸癌、肝癌、黑素瘤、结肠癌、直肠癌、肾细胞癌、小肠癌和食道癌、头颈癌、膀胱癌、***癌、胰腺癌、或咽癌。
  25. 一种抑制IDO活性的方法，和/或双重抑制IDO-HDAC的活性的方法，其特征在于，所述方法包括步骤：对抑制对象施用抑制有效量的如权利要求1所述的式I化合物或其药学上可接受的盐，或对抑制对象施用抑制有效量的如权利要求20所述的药物组合物。
  26. 一种如权利要求1所述化合物的制备方法，其特征在于，所述方法包括步骤：
    Figure PCTCN2018106768-appb-100051
    Figure PCTCN2018106768-appb-100052
    中\表示双键；
    (viii)在惰性溶剂中，通过Wittig反应，然后经Pd-C催化氢化及脱保护基团，将化合物I-1转化为I-2；
    (ix)在惰性溶剂中，在碱(如2,6-双叔丁基吡啶或KHMDS或LiHMDS)和Tf 2O(或PhNTf 2)的作用下将化合物I-2转变为I-3，然后再与相应的芳基或杂芳基的硼化合物反应，得到含有烯键的偶联化合物，经催化氢化得到化合物I-4；
    (x)化合物I-4经酯水解，得到的酸与I-5反应，得到化合物I-6；
    (xi)在惰性溶剂中，在碱的作用下可在化合物I-6的酰胺基的α-位引入基团，得到化合物I；
    Figure PCTCN2018106768-appb-100053
    (xii)化合物I-4经酯水解，得到的酸与Evans的手性试剂(通常R”为苯基或苄基)反应得II-1，从而达到在酰胺基的α-位引入手性基团R 3，得到化合物II-2；
    (xiii)化合物II-2水解后得到酸II-3，然后与I-5反应得到化合物II；
    (xiv)当(v)中所用的Evans的手性试剂为另一个构型时，上述(v)和(vi)步骤可制备得到化合物IIa，化合物IIa是化合物II的对映异构体；
    Figure PCTCN2018106768-appb-100054
    (viii)从化合物I-1出发，经多步反应制备α-酮酸酯III-4,然后经Wittig反应制备α,β-不饱和酯III-5，化合物III-5的双键环丙化反应得到化合物III-6，最后酯水解和酰胺化反应得到化合物III；
    Figure PCTCN2018106768-appb-100055
    Figure PCTCN2018106768-appb-100056
    中的\表示双键。
PCT/CN2018/106768 2017-09-20 2018-09-20 作为ido抑制剂和/或ido-hdac双重抑制剂的多环化合物 WO2019057123A1 (zh)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US16/649,455 US11266640B2 (en) 2017-09-20 2018-09-20 Polycyclic compound acting as IDO inhibitor and/or IDO-HDAC dual inhibitor
CN201880002070.7A CN109843872B (zh) 2017-09-20 2018-09-20 作为ido抑制剂和/或ido-hdac双重抑制剂的多环化合物
JP2020516814A JP2020534336A (ja) 2017-09-20 2018-09-20 Ｉｄｏ阻害剤および／またはｉｄｏ−ｈｄａｃ二重阻害剤としての多環式化合物
EP18857966.8A EP3686196A4 (en) 2017-09-20 2018-09-20 POLYCYCLIC CONNECTION AS IDO INHIBITOR AND / OR IDO HDAC DOUBLE INHIBITOR

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN201710854520.2 2017-09-20
CN201710854520 2017-09-20
CN201711397888 2017-12-21
CN201711397888.7 2017-12-21
CN201810119324 2018-02-06
CN201810119324.5 2018-02-06

Publications (1)

Publication Number Publication Date
WO2019057123A1 true WO2019057123A1 (zh) 2019-03-28

Family

ID=65810056

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/106768 WO2019057123A1 (zh) 2017-09-20 2018-09-20 作为ido抑制剂和/或ido-hdac双重抑制剂的多环化合物

Country Status (5)

Country Link
US (1) US11266640B2 (zh)
EP (1) EP3686196A4 (zh)
JP (1) JP2020534336A (zh)
CN (1) CN109843872B (zh)
WO (1) WO2019057123A1 (zh)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019196780A1 (zh) * 2018-04-09 2019-10-17 信达生物制药(苏州)有限公司 一种新型吲哚胺2，3-双加氧酶抑制剂及其制备方法和用途
WO2020063618A1 (zh) * 2018-09-27 2020-04-02 深圳微芯生物科技股份有限公司 具有吲哚胺-2,3-双加氧酶抑制活性的喹啉衍生物
US10766884B2 (en) 2018-04-26 2020-09-08 Pfizer Inc. Cyclin dependent kinase inhibitors
CN111909107A (zh) * 2019-05-10 2020-11-10 中国药科大学 Ido/hdac双重抑制剂及其药物组合物和应用
US11008572B2 (en) 2017-08-04 2021-05-18 Skyhawk Therapeutics, Inc. Methods and compositions for modulating splicing
JP2021513549A (ja) * 2018-02-13 2021-05-27 上海 インスティテュート オブ オーガニック ケミストリー、チャイニーズ アカデミー オブ サイエンシーズＳｈａｎｇｈａｉ Ｉｎｓｔｉｔｕｔｅ Ｏｆ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ， Ｃｈｉｎｅｓｅ Ａｃａｄｅｍｙ Ｏｆ Ｓｃｉｅｎｃｅｓ インドール−２、３−ジオキシゲナーゼ阻害剤としてのスピロ化合物
US11845744B2 (en) 2019-02-05 2023-12-19 Skyhawk Therapeutics, Inc. Methods and compositions for modulating splicing
US11964971B2 (en) 2019-02-06 2024-04-23 Skyhawk Therapeutics, Inc. Methods and compositions for modulating splicing

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019078968A2 (en) * 2017-10-18 2019-04-25 Angex Pharmaceutical, Inc. CYCLIC COMPOUNDS AS IMMUNOMODULATORS
CA3159783A1 (en) * 2019-11-12 2021-05-20 Nammi Therapeutics, Inc. Formulated and/or co-formulated liposome compositions containing ido antagonist prodrugs useful in treating of cancer and methods thereof

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090192141A1 (en) * 2004-04-29 2009-07-30 Abbott Laboratories Methods of use of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
WO2015188085A1 (en) 2014-06-06 2015-12-10 Flexus Biosciences, Inc. Immunoregulatory agents
WO2016073774A2 (en) 2014-11-05 2016-05-12 Flexus Biosciences, Inc. Immunoregulatory agents
WO2016073738A2 (en) 2014-11-05 2016-05-12 Flexus Biosciences, Inc. Immunoregulatory agents
WO2016073770A1 (en) 2014-11-05 2016-05-12 Flexus Biosciences, Inc. Immunoregulatory agents
WO2017001928A1 (en) 2015-07-02 2017-01-05 buildpulse, Inc. Advanced identification and classification of sensors and other points in a building automation system
WO2017024996A1 (zh) 2015-08-07 2017-02-16 江苏恒瑞医药股份有限公司 羟基脒类衍生物、其制备方法及其在医药上的应用
CN106916164A (zh) * 2017-03-06 2017-07-04 中国药科大学 噻唑并嘧啶酮类ido1抑制剂及其医药用途
WO2017192844A1 (en) 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2017192845A1 (en) 2016-05-04 2017-11-09 Motif BioSciences Inc. Systems and methods for treating bacterial infection
WO2017192840A1 (en) 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use

Family Cites Families (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1265660A (zh) * 1997-08-15 2000-09-06 辉瑞产品公司 2－(4－芳基或杂芳基－哌嗪－1－基甲基)－1h－吲哚衍生物
MY137020A (en) * 2000-04-27 2008-12-31 Abbott Lab Diazabicyclic central nervous system active agents
EP1177792A3 (en) * 2000-07-27 2002-10-23 Pfizer Products Inc. Dopamine D4 Ligands for the treatment of novelty-seeking disorders
WO2003070244A1 (en) * 2002-02-22 2003-08-28 Abbott Laboratories Antagonist of melanin concentrating hormone and their uses
US7435830B2 (en) * 2004-03-03 2008-10-14 Chemocentryx, Inc. Bicyclic and bridged nitrogen heterocycles
AU2005277203A1 (en) * 2004-08-20 2006-03-02 Entremed, Inc. Compositions and methods comprising proteinase activated receptor antagonists
GB0510204D0 (en) * 2005-05-19 2005-06-22 Chroma Therapeutics Ltd Enzyme inhibitors
TW200932236A (en) * 2007-10-31 2009-08-01 Janssen Pharmaceutica Nv Aryl-substituted bridged diamines as modulators of leukotriene A4 hydrolase
FR2924343A1 (fr) * 2007-12-04 2009-06-05 Palumed Sa Nouvelles utilisations therapeutiques de molecules duales contenant un derive peroxydique.
FR2945533B1 (fr) * 2009-05-12 2011-05-27 Sanofi Aventis Derives de cyclopenta°c!pyrrolyl-alkylcarbamates d'heterocycles a 5 chainons, leur preparation et leur application en therapeutique
AU2012264651A1 (en) * 2011-06-02 2013-12-12 Intervet International B.V. Imidazole derivatives
SI2796460T1 (sl) * 2011-12-21 2018-10-30 Jiangsu Hengrui Medicine Co. Ltd Pirolni šestčlenski derivat heteroarilnega obroča, postopek priprave zanj in medicinske uporabe le-tega
TW201444836A (zh) * 2013-03-14 2014-12-01 Abbvie Inc 吡咯并［２，３－ｂ］吡啶ｃｄｋ９激酶抑制劑
US9637450B2 (en) * 2013-03-14 2017-05-02 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
AR101528A1 (es) * 2013-03-14 2016-12-28 Abbvie Inc Inhibidores de cdk9 quinasa de pirrolo[2,3-b]piridina
CA2934989C (en) * 2014-02-03 2017-08-08 Cadila Healthcare Limited Novel heterocyclic compounds
WO2016115463A1 (en) * 2015-01-15 2016-07-21 Whitehead Institute For Biomedical Research Inhibitors of phosphoglycerate dehydrogenase (phgdh) and uses thereof
PL3319959T3 (pl) * 2015-07-06 2022-02-14 Alkermes, Inc. Hetero-haloinhibitory deacetylazy histonowej
CN106478607B (zh) * 2015-08-28 2019-05-24 广东东阳光药业有限公司 取代的杂芳基化合物及其组合物和用途
JP2018527362A (ja) * 2015-09-11 2018-09-20 サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． 置換されたヘテロアリール化合物および使用方法
CA3007699A1 (en) * 2015-12-10 2017-06-15 Bayer Pharma Aktiengesellschaft Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same
CN110540521A (zh) * 2018-05-28 2019-12-06 北京诺诚健华医药科技有限公司 八氢戊搭烯类化合物、其制备方法及其在医药学上的应用

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090192141A1 (en) * 2004-04-29 2009-07-30 Abbott Laboratories Methods of use of inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
WO2015188085A1 (en) 2014-06-06 2015-12-10 Flexus Biosciences, Inc. Immunoregulatory agents
WO2016073774A2 (en) 2014-11-05 2016-05-12 Flexus Biosciences, Inc. Immunoregulatory agents
WO2016073738A2 (en) 2014-11-05 2016-05-12 Flexus Biosciences, Inc. Immunoregulatory agents
WO2016073770A1 (en) 2014-11-05 2016-05-12 Flexus Biosciences, Inc. Immunoregulatory agents
WO2017001928A1 (en) 2015-07-02 2017-01-05 buildpulse, Inc. Advanced identification and classification of sensors and other points in a building automation system
WO2017024996A1 (zh) 2015-08-07 2017-02-16 江苏恒瑞医药股份有限公司 羟基脒类衍生物、其制备方法及其在医药上的应用
WO2017192844A1 (en) 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2017192845A1 (en) 2016-05-04 2017-11-09 Motif BioSciences Inc. Systems and methods for treating bacterial infection
WO2017192840A1 (en) 2016-05-04 2017-11-09 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
CN106916164A (zh) * 2017-03-06 2017-07-04 中国药科大学 噻唑并嘧啶酮类ido1抑制剂及其医药用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
See also references of EP3686196A4
TOPCZEWSKI, J.J. ET AL.: "Palladium-Catalysed Transannular C-H Functionalization of Alicyclic Amines", NATURE, vol. 531, no. 7593, 10 March 2016 (2016-03-10), pages 220 - 224, XP055584145 *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11021708B2 (en) 2017-08-04 2021-06-01 Skyhawk Therapeutics, Inc. Methods and compositions for modulating splicing
US11603531B1 (en) 2017-08-04 2023-03-14 Skyhawk Therapeutics, Inc. Methods and compositions for modulating splicing
US11434489B1 (en) 2017-08-04 2022-09-06 Skyhawk Therapeutics, Inc. Methods and compositions for modulating splicing
US11326165B1 (en) 2017-08-04 2022-05-10 Skyhawk Therapeutics, Inc. Methods and compositions for modulating splicing
US11162101B2 (en) 2017-08-04 2021-11-02 Skyhawk Therapeutics, Inc. Methods and compositions for modulating splicing
US11008572B2 (en) 2017-08-04 2021-05-18 Skyhawk Therapeutics, Inc. Methods and compositions for modulating splicing
US11091475B2 (en) 2017-08-04 2021-08-17 Skyhawk Therapeutics, Inc. Methods and compositions for modulating splicing
JP7106659B2 (ja) 2018-02-13 2022-07-26 上海 インスティテュート オブ オーガニック ケミストリー、チャイニーズ アカデミー オブ サイエンシーズ インドール－２、３－ジオキシゲナーゼ阻害剤としてのスピロ化合物
JP2021513549A (ja) * 2018-02-13 2021-05-27 上海 インスティテュート オブ オーガニック ケミストリー、チャイニーズ アカデミー オブ サイエンシーズＳｈａｎｇｈａｉ Ｉｎｓｔｉｔｕｔｅ Ｏｆ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ， Ｃｈｉｎｅｓｅ Ａｃａｄｅｍｙ Ｏｆ Ｓｃｉｅｎｃｅｓ インドール−２、３−ジオキシゲナーゼ阻害剤としてのスピロ化合物
WO2019196780A1 (zh) * 2018-04-09 2019-10-17 信达生物制药(苏州)有限公司 一种新型吲哚胺2，3-双加氧酶抑制剂及其制备方法和用途
US11220494B2 (en) 2018-04-26 2022-01-11 Pfizer Inc. Cyclin dependent kinase inhibitors
US10766884B2 (en) 2018-04-26 2020-09-08 Pfizer Inc. Cyclin dependent kinase inhibitors
CN110950842A (zh) * 2018-09-27 2020-04-03 深圳微芯生物科技股份有限公司 具有吲哚胺-2,3-双加氧酶抑制活性的喹啉衍生物
WO2020063618A1 (zh) * 2018-09-27 2020-04-02 深圳微芯生物科技股份有限公司 具有吲哚胺-2,3-双加氧酶抑制活性的喹啉衍生物
CN110950842B (zh) * 2018-09-27 2023-06-20 深圳微芯生物科技股份有限公司 具有吲哚胺-2,3-双加氧酶抑制活性的喹啉衍生物
US11845744B2 (en) 2019-02-05 2023-12-19 Skyhawk Therapeutics, Inc. Methods and compositions for modulating splicing
US11964971B2 (en) 2019-02-06 2024-04-23 Skyhawk Therapeutics, Inc. Methods and compositions for modulating splicing
CN111909107A (zh) * 2019-05-10 2020-11-10 中国药科大学 Ido/hdac双重抑制剂及其药物组合物和应用
CN111909107B (zh) * 2019-05-10 2023-02-03 药康众拓(江苏)医药科技有限公司 Ido/hdac双重抑制剂及其药物组合物和应用

Also Published As

Publication number Publication date
JP2020534336A (ja) 2020-11-26
CN109843872B (zh) 2022-08-30
EP3686196A4 (en) 2021-03-31
CN109843872A (zh) 2019-06-04
EP3686196A1 (en) 2020-07-29
US11266640B2 (en) 2022-03-08
US20200276180A1 (en) 2020-09-03

Similar Documents

Publication Publication Date Title
WO2019057123A1 (zh) 作为ido抑制剂和/或ido-hdac双重抑制剂的多环化合物
CN113286794B (zh) Kras突变蛋白抑制剂
CN113767103B (zh) 新型螺环类K-Ras G12C抑制剂
AU2016311426B2 (en) Compounds and compositions useful for treating disorders related to NTRK
WO2021129824A1 (zh) 新型K-Ras G12C抑制剂
WO2022105855A1 (en) Kras g12d inhibitors
WO2019158019A1 (zh) 嘧啶并环化合物及其制备方法和应用
WO2020259432A1 (zh) Kras-g12c抑制剂
WO2022214102A1 (zh) 作为kras g12d抑制剂的杂环化合物
WO2018171633A1 (zh) 吡唑[3,4-d]嘧啶-3-酮的大环衍生物、其药物组合物及应用
CA2567404C (en) Cyclopenta[b]benzofuran derivatives and the utilization thereof
TW202229285A (zh) Kras g12d抑制劑
CN110099909B (zh) 作为Syk抑制剂和/或Syk-HDAC双重抑制剂的杂环化合物
WO2020061375A1 (en) Antibacterial compounds
WO2018209049A1 (en) Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
WO2023174175A1 (zh) Kif18a抑制剂
WO2022268230A1 (zh) 作为kif18a抑制剂的化合物
CN112300153A (zh) 一种杂环化合物、药物组合物和用途
TW201208687A (en) Condensed ring pyridine compound
WO2023280182A1 (zh) 作为kat6抑制剂的化合物
WO2022122044A1 (zh) 作为gls1抑制剂的杂环化合物
WO2021228216A1 (zh) 可用作RORγ调节剂的联芳基类化合物
WO2021245473A1 (en) Tlr 9 inhibitors
WO2019144781A1 (zh) 五氟硫烷基取代的酰胺类化合物、其制备方法及其在医药学上的应用
WO2019149128A1 (zh) 作为抗肿瘤药物的5-氯-2,4-嘧啶衍生物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18857966

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2020516814

Country of ref document: JP

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2018857966

Country of ref document: EP

Effective date: 20200420