WO2021057696A1 - Heteroaryl compound and application thereof - Google Patents

Heteroaryl compound and application thereof Download PDF

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WO2021057696A1
WO2021057696A1 PCT/CN2020/116696 CN2020116696W WO2021057696A1 WO 2021057696 A1 WO2021057696 A1 WO 2021057696A1 CN 2020116696 W CN2020116696 W CN 2020116696W WO 2021057696 A1 WO2021057696 A1 WO 2021057696A1
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independently
substituted
alkyl
butyl
group
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PCT/CN2020/116696
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French (fr)
Chinese (zh)
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杨磊
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隆泰申医药科技(南京)有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • 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
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/495—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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61K31/695—Silicon compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage

Definitions

  • the invention relates to a heteroaryl compound and its application.
  • Chronic lymphocytic leukemia originates from B lymphocytes.
  • B lymphocytes have different activation and maturation stages. They are derived from antigen-experienced B cells with different immunoglobulin chain variable (IgVH) gene mutations (Chiorazzi Net al., N. Engl. J. Med., 2005, 352, 804-15).
  • IgVH immunoglobulin chain variable
  • ROR1 is a member of the RTK family of orphan receptors related to muscle-specific kinase (MUSK) and Trk neurotrophin receptors (Glass DJ, et al., Cell, 1996, 85, 513-23; Masiakowski Petal., J. Biol. Chem., 1992, 267, 26181-90; Valenzuela DM et al., Neuron, 1995, 15, 573-84).
  • MUSK muscle-specific kinase
  • Trk neurotrophin receptors Glass DJ, et al., Cell, 1996, 85, 513-23; Masiakowski Petal., J. Biol. Chem., 1992, 267, 26181-90; Valenzuela DM et al., Neuron, 1995, 15, 573-84.
  • ROR receptors are cell surface receptors involved in signal transduction, cell-cell interaction, regulation of cell proliferation, differentiation, cell metabolism and survival (Masiakowski P et al., Biol. Chem., 1992, 267, 26181-90; Yoda A et al., J. Recept. Signal Iransduct. Res., 2003, 23, 1-15). They are evolutionarily highly conservative among different species such as humans, mice, fruit flies and C. elegans, and exhibit important biological functions.
  • the human ROR1 gene has a 2814bp coding region, has a predicted 937 amino acid sequence and a protein size of 105kDa, including Ig-like domains, Kringle domains, tyrosine kinase domains and proline-rich domains (Yoda A et al. al., J. Recept. Signal Transduct. Res., 2003, 23, 1-15).
  • ROR1 is located on the chromosome region Ip31.3 (http://ensembl.org), which is a region where chromosomal aberrations are not common in hematological malignancies.
  • ROR1 is expressed at the gene level in the heart, lung and kidney, but less expressed in placenta, pancreas and skeletal muscle (Reddy UR et al., Oncogene, 1996, 13, 1555-9). Importantly, there is almost no ROR1 protein expression in normal adult tissues and organs. ROR1 was originally cloned from a neuronal cell line (Masiakowski Petal., J. Biol. Chem., 1992, 267, 26181-90), and the shorter form that lacks the entire extracellular domain but contains the transmembrane domain will be removed from the fetus. Separated from the fetal brain library.
  • t-Ror1 The truncated ROR1 (t-Ror1) gene (Reddy UR et al., Oncogene) has been reported in the fetal and adult central nervous system, human leukemia, lymphoma cell lines, and a variety of human cancers derived from neuroectoderm. , 1996, 13, 1555-9). Shorter transcripts of exons 1-7 containing a short portion of intrinsic factor 7 are also described, with a predicted length of 393 amino acids and a molecular weight of 44kDa (Ensembl ID: ENSG0000185483).
  • CLL chronic lymphocytic leukemia
  • AML stem cells may potentially explain the resistance to many cytotoxic drugs.
  • the anti-ROR1 chimera (UC99961) inhibited ROR1+AML stem cells but not ROR-AML cells in a dose-dependent manner and was not a colony form of normal CD34+ stem cells.
  • the results show that targeting ROR may represent the eradication of AML and potentially other difficult-to-treat cancers, such as an important part of stem cell-driven malignant tumor stem cells (Balaian L et al., Blood, ASH Annual Meeting, 2012, Abstract 2560).
  • ALL acute lymphoblastic leukemia
  • pre-BCR pre-B cell receptor
  • ROR1 Human breast cancer cells, but not normal breast epithelial cells, also express ROR1. Hormone receptor-negative tumor patients and patients with low cell differentiation (ie patients with poor prognosis) have higher ROR1 expression intensity. The silence of ROR1 impaired the growth of human breast cancer cells in vitro and in immunodeficient mice. The results support the concept that ROR1 has biological and clinical significance in breast cancer and may be a potential target of therapy (Zang, S., et al., Plos one, 7(3): e31127, 2012).
  • ROR1 In human lung cancer cells, ROR1 is overexpressed, and ROR1 kinase activity maintains a favorable pro-survival balance between proliferative P13K/AKT and apoptotic p38 signaling. This is partly due to excessive ROR1 kinase-dependent src kinase activity and low kinase-independent activity. Maintain EGFR/ERBB3 phosphorylation and PI3K activation. ROR1 knockdown effectively inhibits the growth of lung cancer cells in vitro and in vivo, regardless of EGFR status, including those cells that are resistant to the EGFR tyrosine kinase inhibitor gefitinib.
  • ROR1 expression is associated with high-level histology and activation of AKT and CREB.
  • Silencing ROR1 using shRNA induces apoptosis of pancreatic and ovarian cancer cells and down-regulation of ROR1 protein and activated AKT and CREB (Zhan S., et al., American Journal of Pathology, 181:1903-1910, 2012).
  • melanoma cells express ROR1, and ROR1 siRNA induces down-regulation of mRNA and protein levels of ROR1 before apoptosis.
  • ROR1 targeting melanoma cells by a ROR1-directed monoclonal antibody induced significant apoptosis without the need for immune cells or complement.
  • the degree of apoptosis induced by antibodies varies from cell to cell (Hodjat-Farsangi M., et al., Plos One, 8, e61167, 2013).
  • CLL chronic lymphocytic leukemia
  • Antibody inhibitors of ROR1 have been described in the literature: for example, PCT Int.Appl.WO2011079902, and small molecule inhibitors of tyrosine kinase-like orphan receptor 1 (ROR1) have also been reported in the literature, such as PCT Int.Appl.WO2018011138, WO2016124553 .
  • the compounds provided in WO2018011138 and WO2016124553 only disclose that they have a certain inhibitory activity on peripheral blood mononuclear cells (PBMC) of patients with chronic lymphocytic leukemia (CLL).
  • PBMC peripheral blood mononuclear cells
  • CLL chronic lymphocytic leukemia
  • the technical problem to be solved by the present invention is to provide a heteroaryl compound, an intermediate, a preparation method and application thereof in view of the defect of insufficient ROR1 inhibitors in the prior art.
  • the heteroaryl compounds of the present invention can be used as inhibitors of tyrosine kinase-like orphan receptor 1 (ROR1) in mammals; they are used for the treatment of diseases, such as the regulation of human kinase activity, including various hyperproliferations.
  • sexual diseases such as hematological tumors such as chronic lymphocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia or mantle cell lymphoma, and solid tumors such as lung, ovarian, breast or pancreatic tumors, and other metabolic complications related to obesity Diseases, autoimmune diseases and inflammatory disorders.
  • hematological tumors such as chronic lymphocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia or mantle cell lymphoma
  • solid tumors such as lung, ovarian, breast or pancreatic tumors, and other metabolic complications related to obesity Diseases, autoimmune diseases and inflammatory disorders.
  • the present invention solves the above technical problems through the following technical solutions.
  • the present invention provides a heteroaryl compound as shown in formula I, its tautomer, stereoisomer or pharmaceutically acceptable salt;
  • X and Y are independently
  • R 4 is independently H, F, Cl, Br, I, or a C 1 -C 4 alkyl group that is unsubstituted or substituted with one or more R 4a ; when the substitutions are multiple, they are the same or different;
  • R 2 is independently C 1 -C 6 alkyl
  • n 0, 1, 2, 3 or 4;
  • W is independently a linkage, -O-(C 1 -C 3 alkylene)-, -S-(C 1 -C 3 alkylene)- or -N(R W1 )-(C 1 -C 3 Alkylene)-;
  • R W1 is independently H or C 1 -C 4 alkyl
  • R 3a , R 3a' , R 3b and R 3b' are independently H or C 1 -C 6 alkyl
  • R 1 is independently
  • R 5 and R 5' are independently H or C 1 -C 6 alkyl
  • o, p1 and q1 are independently 1, 2 or 3; p2 and q2 are independently 1 or 2;
  • L 1 is independently -SO 2 -or C 1 -C 3 alkylene
  • L 2 is independently C 1 -C 3 alkylene
  • R a and R b are independently unsubstituted or substituted with one or more substituents
  • R a1 is C l -C 6 alkyl
  • R a2 is C 3 ⁇ C 6 cycloalkyl group
  • R a3 is C 2 ⁇ C 9 heterocycloalkyl
  • R a4 is C 6 ⁇ C 10 aryl group, or an unsubstituted or substituted by one or more
  • R a5 in the C 2 ⁇ C 9 heterocycloalkyl group, the heteroatom is selected from one or more of N, O or S, and the number of heteroatoms is 1.
  • the heteroatom is selected from one or more of N, O or S, and the number of heteroatoms is 1 to 4
  • R a1 , R a2 , R a3 , R a4 and R a5 are independently H, F, Cl, Br, I, unsubstituted or substituted by one or more R 1a-1 C 1 -C 6 alkyl, unsubstituted C 1 -C 6 alkyl-O- substituted or substituted with one or more R 1a-2, N(R b2 )SO 2 -R b2' or -N(R b3 R b3' ); when there are multiple substitutions, they are the same or different;
  • R c is independently
  • R b1 , R b1 ' , R b1 " , R b2' , R c2 , R c2 ' , R c2" , R c3' and R c4 are independently C 1 -C 6 alkyl groups;
  • R b2 , R b3 , R b3' and R c3 are independently H or C 1 -C 6 alkyl;
  • R c1 independently is H, F, Cl, Br, I, unsubstituted or substituted with one or more R c1-1 is C l -C 6 alkyl, or unsubstituted or substituted by one or more R c1-2 Substituted C 1 -C 6 alkyl-O-; when there are multiple substitutions, they are the same or different;
  • R 4a , R 1a-1 , R 1a-2 , R c1-1 and R c1-2 are independently F, Cl, Br or I;
  • a carbon atom with "*" means an achiral carbon atom or a chiral carbon atom. When it is a chiral carbon atom, it is in the S configuration, R configuration or a mixture thereof.
  • the C 1 -C 4 alkyl group in the C 1 -C 4 alkyl group that is unsubstituted or substituted with one or more R 4a is independently methyl, ethyl, or normal Propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
  • R 4a , R 1a-1 , R 1a-2 , R c1-1 and R c1-2 are independently F or Cl.
  • R 2 is independently C 1 -C 6 alkyl group in the C 1 -C 6 alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) independently
  • the ground is a C 1 -C 4 alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), preferably methyl.
  • n is 0 or 1, such as 0.
  • W may be located in the ring Ortho, meta or para; preferably meta or para; more preferably para.
  • W is independently -O-(C 1 -C 3 alkylene)-, -S-(C 1 -C 3 alkylene)- or -N(R W1 )- (C 1 -C 3 alkylene)-in C 1 -C 3 alkylene is independently methylene (-CH 2 -), ethylene (e.g. -CH 2 CH 2 -or -CH (CH 3 )-), isopropylidene (for example -CH(CH 3 )CH 2 -or -C(CH 3 ) 2 -); preferably -(CH 2 )- or -(CH 2 ) 2 -.
  • R W1 is independently a C 1 -C 4 alkyl group in a C 1 -C 4 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, (Isobutyl, sec-butyl or tert-butyl) is preferably methyl.
  • R 3a , R 3a' , R 3b and R 3b' are independently a C 1 -C 6 alkyl group in a C 1 -C 6 alkyl group (e.g., methyl, ethyl, propyl Group, butyl, pentyl or hexyl) are independently C 1 to C 4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) Group), preferably methyl.
  • a C 1 -C 6 alkyl group in a C 1 -C 6 alkyl group e.g., methyl, ethyl, propyl Group, butyl, pentyl or hexyl
  • C 1 to C 4 alkyl e.g. methyl, ethyl, n-propyl, isopropyl, n-but
  • R 5 and R 5' are independently a C 1 -C 6 alkyl group in a C 1 -C 6 alkyl group (e.g., methyl, ethyl, propyl, butyl, pentyl Or hexyl) independently C 1 ⁇ C 4 alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), preferably methyl.
  • a C 1 -C 6 alkyl group in a C 1 -C 6 alkyl group e.g., methyl, ethyl, propyl, butyl, pentyl Or hexyl
  • C 1 ⁇ C 4 alkyl for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-
  • o is 1 or 2.
  • p is 1 or 2.
  • q is 1 or 2.
  • L 1 and L 2 are independently a C 1 -C 3 alkylene group in a C 1 -C 3 alkylene group and independently are methylene (-CH 2 -), ethylene Group (for example -CH 2 CH 2 -or -CH(CH 3 )-), isopropylidene (for example -CH(CH 3 )CH 2 -or -C(CH 3 ) 2 -); preferably- (CH 2 )-or-(CH 2 ) 2 -.
  • the unsubstituted or substituted with one or more R a1 is C l -C 6 alkyl group in the C l -C 6 alkyl (e.g. methyl, ethyl, propyl , Butyl, pentyl or hexyl) independently C 1 ⁇ C 4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl ), preferably methyl.
  • C l -C 6 alkyl e.g. methyl, ethyl, propyl , Butyl, pentyl or hexyl
  • C 1 ⁇ C 4 alkyl e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-buty
  • the C 3 ⁇ C 6 cycloalkyl group in the C 3 ⁇ C 6 cycloalkyl group that is unsubstituted or substituted with one or more Ra2 is independently a cyclopropyl group, a ring group Butyl, cyclopentyl or cyclohexyl, for example cyclopropyl.
  • the C 2 ⁇ C 9 heterocycloalkyl group in the C 2 ⁇ C 9 heterocycloalkyl group substituted with one or more Ra3 is independently C 3 ⁇ C 6 heterocycloalkyl, wherein the heteroatom is N, and the number of heteroatoms is 1 or 2; for example, piperazinyl (also for example ).
  • the C 6 -C 10 aryl group in the C 6 -C 10 aryl group substituted with one or more Ra4 is independently phenyl or naphthyl.
  • the C 2 ⁇ C 9 heteroaryl group in the C 2 ⁇ C 9 heteroaryl group that is unsubstituted or substituted with one or more Ra5 is independently a pyridyl group (for example, ), benzofuranyl (also for example ) Or indazolyl (also for example ).
  • R a1 , R a2 , R a3 , R a4 and R a5 are independently unsubstituted or substituted with one or more R 1a-1 C 1 -C 6 alkyl, unsubstituted by one or more R 1a-2 substituted C l -C 6 alkyl Lane -O- C 1 -C 6 alkyl (e.g.
  • methyl ethyl, propyl, butyl, pentyl or hexyl
  • It is independently a C 1 -C 4 alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), preferably methyl.
  • R b1 , R b1 ' , R b1 " , R b2' , R c2 , R c2 ' , R c2" , R c3' , R c4 , R b2 , R b3 , R b3 ' And R c3 are independently C 1 -C 6 alkyl in C 1 -C 6 alkyl (for example, methyl, ethyl, propyl, butyl, pentyl or hexyl) are independently C 1 ⁇ C 4
  • the alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) is preferably methyl.
  • R c1 is independently a C 1 -C 6 alkyl group that is unsubstituted or substituted by one or more R c1-1 , or is unsubstituted or substituted by one or more R c1-2 the C l -C 6 alkyl Lane -O- C 1 -C 6 alkyl (e.g.
  • methyl, ethyl, propyl, butyl, pentyl or hexyl group is independently C 1 ⁇ C 4 alkyl group ( For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), preferably methyl.
  • the C 1 -C 4 alkyl substituted by one or more R 4a may be trifluoromethyl or difluoromethyl.
  • R 4 is independently H or Cl.
  • W is independently -O-(C 1 -C 3 alkylene)-; preferably -O-(CH 2 )-.
  • -WR 3 is independently
  • L 1 is independently -SO 2 -.
  • L 1 is independently a C 1 -C 3 alkylene group; preferably a methylene group.
  • L 2 is a C 1 -C 3 alkylene group; preferably a methylene group.
  • the C 6 ⁇ C 10 aryl group that is unsubstituted or substituted with one or more R a4 is selected from:
  • the C 2 -C 9 heteroaryl group that is unsubstituted or substituted with one or more Ra5 is selected from:
  • R 1 is
  • R 1 is independently Preferably
  • R 1 is independently Preferably
  • R 1 is Where R c is independently Preferably Preferably
  • R 1 is Where R c is independently Preferably Preferably
  • R 1 is Where R c is independently Preferably Preferably
  • R 1 is Where R c is independently Preferably Preferably
  • R a is independently unsubstituted or substituted with one or more R a4 is C 6 ⁇ C 10 aryl group.
  • R b is independently unsubstituted or substituted with one or more R a1 is C l -C 6 alkyl, unsubstituted or substituted with one or more R a2 is C 3 ⁇ C 6 cycloalkyl, or unsubstituted or C 6 -C 10 aryl substituted with one or more Ra4.
  • X and Y are independently Or, Y is independently X is independently That is Said Can be (Or tautomerism: )or (Or tautomerism: ); said Can be (E.g )or
  • heteroaryl compound represented by formula I is represented by formula Ia:
  • R 1 is R c is independently
  • R 2 , R 3 , R 4a , R a , R b , R 5 , R 5 ' , L 1 , L 2 , R c2 , R c2' , R c2 " , R c3 , R c3 ' , R c4 , W , O, p1, q1, p2, q2, and n are all defined as described above.
  • heteroaryl compound represented by formula I is represented by formula Ib:
  • the carbon atom with "*" when it is a chiral carbon, it may be in the R or S configuration, more preferably in the R configuration.
  • heteroaryl compound represented by formula I its tautomers, stereoisomers or pharmaceutically acceptable salts
  • heteroaryl compounds represented by formula I The heteroaryl compounds shown are selected from the following structures:
  • heteroaryl compounds represented by formula I their tautomers, stereoisomers or pharmaceutically acceptable salts.
  • the groups and their substituents are selected to provide stable heteroaryl compounds as shown in formula I, their stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs, including But it is not limited to the compounds described in the examples of the present invention.
  • the heteroaryl compound represented by formula I, its tautomers, stereoisomers or pharmaceutically acceptable salts of the present invention can be synthesized by methods similar to those known in the chemical field, and the steps And conditions can refer to the steps and conditions of similar reactions in the art, especially the synthesis according to the instructions herein.
  • the starting materials are usually from commercial sources, such as Aldrich or can be easily prepared using methods known to those skilled in the art (obtained via SciFinder, Reaxys online databases).
  • the heteroaryl compound represented by formula I can also be prepared by the formula I
  • the heteroaryl compounds shown in I, their tautomers, stereoisomers, or pharmaceutically acceptable salts can be modified peripherally by conventional methods in the art to obtain other described compounds as shown in Formula I Heteroaryl compounds, tautomers, stereoisomers or pharmaceutically acceptable salts thereof.
  • the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the definition of the substituents is as shown in Formula I.
  • the following reaction schemes and examples are used to further illustrate the content of the present invention.
  • the method for preparing the heteroaryl compound shown in formula I includes the following steps: in an organic solvent, in the presence of a reducing agent, the compound shown in formula 1 is combined with the compound shown in formula 2. The compound shown is subjected to the condensation reaction shown below to obtain the heteroaryl compound shown in formula I;
  • X, Y, R 1 , R 2 , n, W and R 3 are as defined above.
  • the conditions and operations of the condensation reaction can be conventional conditions and operations in this type of reaction in the art, for example, refer to the conditions and operations of the reaction in Yang, D, et al., Synthesis, 2005, 47-56.
  • the organic solvent may be ethanol;
  • the reducing agent may be sodium thiosulfate;
  • the temperature of the condensation reaction may be 70 ⁇ 5°C.
  • the preparation method may further include the following steps.
  • the compound represented by formula 3 and the compound represented by formula 4 are subjected to the substitution reaction shown below to obtain the compound represented by formula 1 Compound is enough;
  • the conditions and operations of the substitution reaction can be conventional conditions and operations in this type of reaction in the art.
  • the organic solvent may be isopropanol; the temperature of the substitution reaction may be 70 ⁇ 5°C.
  • the necessary raw materials or reagents for preparing the compound of Formula I can be obtained commercially, or prepared by synthetic methods known in the art.
  • the pharmaceutically acceptable salt can be prepared by adding the corresponding acid in a suitable organic solvent of the organic base and processing according to a conventional method.
  • salt formation examples include: salt formation with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and salts formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, Ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid , Mucofuroic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid or trimethyl acetic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
  • the heteroaryl compounds shown in formula I may have one or more chiral carbon atoms, so they can be separated to obtain optically pure isomers, such as pure enantiomers, racemates, or mixed isoforms. Construct.
  • the pure single isomer can be obtained by separation methods in the art, such as chiral crystallization into a salt, or chiral preparation column separation.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the heteroaryl compound represented by formula I, its tautomers, stereoisomers or pharmaceutically acceptable salts, and, at least one Kind of medicinal excipients.
  • the pharmaceutical composition may further include one or more additional active ingredients.
  • this pharmaceutical composition may contain one or more additional heteroaryl compounds as shown in Formula I, tautomers, stereoisomers or pharmaceutically acceptable salts thereof.
  • the pharmaceutical composition may, for example, contain a heteroaryl compound other than the heteroaryl compound shown in formula I, its tautomers, stereoisomers or pharmaceutically acceptable One or more active ingredients other than salt.
  • the components in the pharmaceutical composition can be used simultaneously or separately (for example, used sequentially); when the components in the pharmaceutical composition are used at the same time, the components in the pharmaceutical composition can be uniformly mixed (That is, a mixture of components).
  • Each component in the pharmaceutical composition can be prepared into a single pharmaceutical composition and used at the same time, or each component can be prepared into a single independent pharmaceutical composition (for example, in the form of a set). These single independent pharmaceuticals
  • the compositions can be used simultaneously or separately (e.g., used sequentially).
  • the amount of the heteroaryl compound represented by formula I, its tautomer, stereoisomer or pharmaceutically acceptable salt can be a therapeutically effective amount.
  • the heteroaryl compound represented by formula I in the pharmaceutical composition, the heteroaryl compound represented by formula I, its tautomers, stereoisomers or pharmaceutically acceptable salts, and, the other
  • the active ingredients can be administered simultaneously or separately (e.g., sequential administration).
  • the present invention also provides the heteroaryl compound as shown in formula I, its tautomer, stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition as described above for preparing kinase (Such as tyrosine kinase-like orphan receptor 1 (ROR1)) inhibitors.
  • kinase Such as tyrosine kinase-like orphan receptor 1 (ROR1)
  • the present invention also provides the heteroaryl compound as shown in formula I, its tautomer, stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition as described above for preparing medicine In the application.
  • the present invention also provides the heteroaryl compound as shown in formula I, its tautomer, stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition as described above in preparation Application in the prevention and/or treatment of tumor drugs;
  • the drugs can prevent and/or treat tumors by regulating the activity of ROR1;
  • the tumors can be malignant tumor proliferation disorders (also known as malignant proliferative disorders), examples include but Not limited to blood cancers, such as chronic lymphocytic leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia or cell lymphoma, and solid tumors, such as lung cancer, ovarian cancer, breast cancer or pancreatic cancer.
  • the cells of the tumor may be human chronic myeloid leukemia cells K562 (also known as human chronic lymphocytic leukemia cells K562), human acute lymphoblastic leukemia Jurkat cells, human promyelocytic leukemia cells HL-60, human lung adenocarcinoma cells A549, Human lung adenocarcinoma cells H1299, human triple-negative breast cancer cells MDA-MB-231, human triple-negative breast cancer cells MDA-MB-468, human ovarian cancer cells A2780, human ovarian cancer cells OVCAR-3, human ovarian cancer cells SK -OV-3, human umbilical vein endothelial cell HUVEC, human breast cancer resistant strain MDA-MB-231/Adr, human lung cancer taxol resistant strain A549/Taxol, human ovarian cancer taxol resistant strain A2780/Taxol and One or more of the human leukocyte vincristine-resistant strains HL60/VCR.
  • the tumor can also be prostate cancer.
  • the cells of the tumor are human mantle cell line lymphoma cell line Z138, human diffuse large B lymphoma cell WSU-DLCL2, human diffuse large B lymphoma cell DOHH-2, and human prostate cancer cell line PC -3.
  • the present invention also provides a method for the prevention and/or treatment of diseases (such as malignant hyperplasia disorders, disorders of malignant hyperplasia, etc.) related to the regulation or disorder of tyrosine kinase-like orphan receptor 1 activity in mammals (such as for humans).
  • diseases such as malignant hyperplasia disorders, disorders of malignant hyperplasia, etc.
  • tyrosine kinase-like orphan receptor 1 activity in mammals (such as for humans).
  • Obesity-related metabolic complications, autoimmune diseases or inflammations by feeding an effective amount of the heteroaryl compound as shown in formula I to mammals (especially humans) in need of such treatment, Its tautomers, stereoisomers or pharmaceutically acceptable salts or pharmaceutical compositions as described above.
  • the present invention also provides a method for preventing and/or treating cancer, which comprises administering to a subject an effective dose of the heteroaryl compound represented by formula I, its tautomer, Stereoisomers or pharmaceutically acceptable salts, or pharmaceutical compositions as described above.
  • the present invention also provides a therapeutic agent, which comprises the heteroaryl compound as shown in formula I, its tautomer, stereoisomer or pharmaceutically acceptable salt, or as described above Pharmaceutical composition.
  • the compounds of the present invention can be administered locally or systemically, for example, for enteral administration, such as rectal or oral administration, or for parenteral administration to mammals (especially humans).
  • enteral administration such as rectal or oral administration
  • parenteral administration to mammals (especially humans).
  • the compounds of the present invention can also be administered parenterally, for example, by inhalation, injection or infusion, such as by intravenous, intraarterial, intraosseous, intramuscular, intracerebral, extraventricular, intrasynovial, intrasternal, sheath Intra, intralesional, intracranial, intratumoral, intradermal and subcutaneous injection or infusion.
  • the effective amount of the compound, pharmaceutical composition or drug of the present invention depends on the type of mammal, weight, age, individual condition, individual pharmacokinetic parameters, disease to be treated, and mode of administration.
  • the effective amount of the compound, pharmaceutical composition or drug of the present invention can be easily determined by routine experimentation, and the most effective and convenient route of administration and the most appropriate formulation can also be determined by routine experimentation.
  • the pharmaceutical excipients can be those that are widely used in the field of pharmaceutical production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to enable the subject to dissolve the active ingredient at a desired rate after receiving the administration, or to promote the subject’s activity after the administration of the composition The ingredients are effectively absorbed.
  • the pharmaceutical excipients may be inert fillers or provide certain functions, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition.
  • the pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesion Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents and sweetening agents.
  • excipients binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesion Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents and sweetening agents.
  • Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum proteins, and buffer substances such as phosphate, glycine, sorbic acid, and sorbic acid.
  • Potassium acid a mixture of partial glycerides of saturated plant fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium base cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl ole
  • composition of the present invention can be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or freeze-drying processes.
  • the pharmaceutical dosage form of the compound of the present invention can be provided in the form of an immediate release, controlled release, sustained release or target drug release system.
  • commonly used dosage forms include solutions and suspensions, (micro)emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovules, implants, amorphous Or crystalline powder, aerosol and freeze-dried formulations.
  • special devices may be required to administer or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks (Specialflask).
  • Pharmaceutical dosage forms often consist of drugs, excipients, and container/sealing systems.
  • One or more excipients also known as inactive ingredients
  • Pharmaceutical excipients exist in this field and include those listed in various pharmacopoeias.
  • the pharmaceutical dosage form of the compound of the present invention can be manufactured by any method well known in the art, for example, by conventional mixing, sieving, dissolving, melting, granulating, making sugar-coated pills, tableting, suspending, squeezing, spray drying, Grinding, emulsification, (nano/micron) encapsulation, encapsulation or freeze-drying process.
  • the composition of the present invention may include one or more physiologically acceptable inactive ingredients, which can facilitate the processing of active molecules into preparations for medical use.
  • the pharmaceutical composition of the present invention can be administered locally or systemically, for example, for enteral administration, such as rectal or oral administration, or for parenteral administration to mammals (especially humans), and includes The compound, its stereoisomer or its pharmaceutically acceptable salt as a therapeutically effective amount of the active ingredient, together with a pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable excipient such as a pharmaceutically acceptable carrier.
  • the therapeutically effective amount of the active ingredient is defined in the context and depends on the type of mammal, weight, age, individual condition, individual pharmacokinetic parameters, disease to be treated, and mode of administration.
  • enteral administration such as oral drugs
  • the compounds of the present invention can be formulated into a wide variety of dosage forms.
  • the pharmaceutical composition and dosage form may contain one or more compounds of the present invention, stereoisomers thereof, or one or more pharmaceutically acceptable salts thereof as active ingredients.
  • the pharmaceutically acceptable carrier can be solid or liquid. Solid form preparations include powders, tablets, pills, lozenges, capsules, cachets, suppositories, and dispersible granules.
  • the solid carrier can also be one or more substances that act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. In powders, the carrier is usually a finely divided solid, which is a mixture with the finely divided active component.
  • the active ingredient is usually mixed with a carrier having the necessary binding capacity in a suitable ratio and compacted according to the desired shape and size.
  • Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, methyl cellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter, etc. .
  • the formulation of the active compound may include an encapsulating material as a carrier to provide a capsule in which the active component with or without a carrier is surrounded by a carrier combined with it.
  • liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations intended to be converted into liquid form preparations shortly before use.
  • Emulsions can be prepared in a solution, such as an aqueous solution of propylene glycol, or can contain emulsifiers, such as lecithin, sorbitan monooleate, or gum arabic.
  • Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, fragrances, stabilizers, and thickeners.
  • Aqueous suspensions can be prepared by dispersing finely divided active ingredients in water with binders such as natural or synthetic gums, resins, methyl cellulose, carboxymethyl cellulose and other commonly used suspending agents.
  • Solid form preparations include solutions, suspensions and emulsions.
  • active ingredients they may also contain colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, and solubilizers. Wait.
  • Exemplary combinations for rectal administration include suppositories, which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glycerides or polyethylene glycols, which are solid at normal temperature, but in the rectal cavity Melt and/or dissolve to release the drug.
  • suitable non-irritating excipients such as cocoa butter, synthetic glycerides or polyethylene glycols, which are solid at normal temperature, but in the rectal cavity Melt and/or dissolve to release the drug.
  • the compounds of the present invention can also be administered parenterally, for example, by inhalation, injection or infusion, such as by intravenous, intraarterial, intraosseous, intramuscular, intracerebral, extraventricular, intrasynovial, intrasternal, sheath Intra, intralesional, intracranial, intratumoral, intradermal and subcutaneous injection or infusion.
  • the pharmaceutical composition of the present invention may be in the form of a sterile injectable or infusible injectable preparation, for example, as a sterile aqueous or oily suspension.
  • the suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents (for example Tween 80) and suspending agents.
  • the sterile injectable or infusible preparation may also be a sterile injectable or infusible solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
  • the pharmaceutical composition may be a solution in 1,3-butanediol.
  • sterile non-volatile oils are often used as solvents or suspending media. Any bland, non-volatile oil can be used for this purpose, including synthetic mono- or di-glycerides. Fatty acids such as oleic acid and its glyceride derivatives can be used to prepare injections, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in its polyoxyethylated form. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants.
  • Suitable stabilizers include antioxidants, such as sodium bisulfate, sodium sulfite or ascorbic acid, citric acid and its salts and sodium EDTA alone or in combination.
  • Suitable stabilizers may also contain preservatives such as benzalkonium chloride, p-hydroxybenzoic acid or propyl p-hydroxybenzoate and chlorobutanol.
  • suitable pharmaceutical preparation chamber particles, aerosols, powders, mists or small droplets for example, have an average size of about 10 microns or less in diameter.
  • a composition for inhalation in the form of a solution can be prepared in saline, using benzyl alcohol or other suitable preservatives, absorption enhancers for increasing bioavailability, fluorocarbons and/or other enhancements known in the art. Solvent or dispersant.
  • the pharmaceutical composition of the present invention can also be administered topically to the skin or mucous membranes.
  • the pharmaceutical composition may be, for example, a lotion, gel, paste, tincture, transdermal patch, gel for transmucosal delivery.
  • the pharmaceutical composition can be formulated with a suitable ointment containing the active ingredient suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water.
  • the pharmaceutical composition can be formulated as a suitable lotion or emulsion containing the active compound suspended or in a solvent in a carrier.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.
  • composition of the present invention can also be topically applied to the lower intestinal tract through rectal suppository formulations or suitable enema formulations.
  • suitable pharmaceutical excipients such as carriers
  • methods for preparing pharmaceutical dosage forms are described in standard reference textbooks in the field of pharmaceutical preparations (Remington's Pharmaceutical Sciences, Mack Publishing Company)
  • the pharmaceutical composition may contain from about 1% to about 95%, preferably from about 20% to about 90% of the heteroaryl compound represented by formula I, its tautomers, stereoisomers or pharmaceuticals. Above acceptable salt, and at least one pharmaceutically acceptable excipient.
  • the compounds of the present invention will be administered in a therapeutically effective amount by any accepted mode of administration for agents of similar utility.
  • a suitable daily dose is usually 1 to 1000 mg, such as 1-500 mg per day, or 1-50 mg per day, depending on many factors, such as the severity of the disease being treated, the age and relative health of the patient, the effectiveness of the compound used, and the The route and form of medicine and the indications for the administration.
  • Those of ordinary skill in the technical field of treating these diseases will be able to determine the effective therapeutic amount of the compound of the present invention for a given disease without undue experimentation, relying on personal knowledge and the disclosure of this application.
  • the compounds of the present invention can be administered as pharmaceutical preparations, including preparations suitable for enteral or parenteral administration.
  • the preferred mode of administration is generally oral, and a convenient daily dosage regimen can be adjusted according to the patient's condition.
  • the composition can be formulated in an aqueous solution, if necessary, using physiologically compatible buffers, including, for example, phosphate, histidine or citrate used to adjust the pH of the formulation, and such as chlorine Tonicity agent for sodium or dextrose.
  • physiologically compatible buffers including, for example, phosphate, histidine or citrate used to adjust the pH of the formulation, and such as chlorine Tonicity agent for sodium or dextrose.
  • semi-solid, liquid formulations or patches may be preferred, and may contain penetration enhancers; such penetration agents are generally known in the art.
  • the compounds can be formulated into liquid or solid dosage forms and used as immediate release or controlled release/sustained release formulations.
  • Suitable dosage forms for oral ingestion by individuals include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, ointments, suspensions and emulsions.
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, for example containing conventional suppository bases such as cocoa butter or other glycerides.
  • Solid oral dosage forms can be obtained using excipients, which include fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, anti-adherents, and cation exchange Resins, humectants, antioxidants, preservatives, coloring agents and flavoring agents.
  • excipients include fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, anti-adherents, and cation exchange Resins, humectants, antioxidants, preservatives, coloring agents and flavoring agents.
  • excipients can be of synthetic or natural origin.
  • excipients examples include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium lauryl sulfate/sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinylpyrrolidone, silicic acid Salt, silicon dioxide, sodium benzoate, sorbitol, starch, stearic acid or its salt, sugar (i.e. dextrose, sucrose, lactose, etc.), talc, tragacanth mucilage, vegetable oil (hydrogenated ) And wax. Ethanol and water can be used as granulation aids.
  • the tablet it is necessary to coat the tablet with, for example, a taste-masking film, a gastric acid resistant film, or a delayed release film.
  • a taste-masking film e.g., a gastric acid resistant film, or a delayed release film.
  • natural and synthetic polymers are combined with colorants, sugar and organic solvents or water to coat tablets to produce dragees.
  • the capsule is superior to the tablet, the drug powder, suspension or solution can be delivered in a compatible hard-shell or soft-shell capsule form.
  • the compounds of the present invention can be administered topically, for example via skin patches, semi-solid or liquid formulations, such as gels, (micro)emulsions, ointments, solutions, (nano/micron) suspensions or foams .
  • the skin and underlying tissue penetration of the drug can be adjusted in the following ways: for example, the use of penetration enhancers; the use of appropriate selection and combination of lipophilic, hydrophilic and amphiphilic excipients, including water, organic solvents, waxes, oils, Synthetic and natural polymers, surfactants, emulsifiers; by adjusting pH; and using complexing agents.
  • Other techniques such as iontophoresi can also be used to modulate the skin penetration of the compounds of the invention. For example, where local administration with minimal systemic exposure is required, transdermal or local administration will be preferred.
  • the compounds used according to the invention are conveniently administered in the form of solutions, suspensions, emulsions or semi-solid aerosols from a pressurized pack or nebulizer, usually with the aid of a propellant,
  • a propellant for example, halocarbons derived from methane and ethane, carbon dioxide or any other suitable gas.
  • hydrocarbons such as butane, isobutene, and pentane are suitable.
  • the appropriate dosage unit can be determined by providing a valve to deliver the meter.
  • Capsules and cartridges with, for example, gelatin can be formulated for use in inhalers or insufflators. These usually contain a powder mixture of the compound and a suitable powder base such as lactose or starch.
  • compositions formulated for parenteral administration by injection are generally sterile and can be provided in unit dosage forms, such as ampoules, syringes, injection pens, or multi-dose containers, the latter usually containing a preservative.
  • the composition can take the form of a suspension, solution or emulsion in an oily or aqueous carrier, and can contain formulation reagents, such as buffers, tonicity agents, viscosity enhancers, surfactants, suspending and dispersing agents, and antioxidants. , Biocompatible polymers, chelating agents and preservatives.
  • the carrier may contain water, synthetic or vegetable oils, and/or organic co-solvents.
  • parenteral preparations will be reconstituted or diluted before administration.
  • Depot formulations that provide controlled or sustained release of the compounds of the present invention may include injectable suspensions of nano/micro-sized particles or nano/micro-sized or non-micronized crystals.
  • Other well-known matrices in the art, polymers such as poly(lactic acid), poly(glycolic acid) or copolymers thereof, can be used as a controlled release/sustained release matrix.
  • Other depot-type drug delivery systems can be provided in the form of implants and pumps that require incisions.
  • Suitable carriers for the compounds of the present invention for intravenous injection are well known in the art and include water-based solutions containing alkalis (such as sodium hydroxide) for the formation of ionic compounds; sucrose or sodium chloride as tonicity agents; for example Buffer containing phosphate or histidine. Co-solvents such as polyethylene glycol can be added. These water-based systems can effectively dissolve the compounds of the present invention and produce low toxicity after systemic administration. Without destroying the solubility and toxicity characteristics, the ratio of the components of the solution system can be greatly changed. In addition, the characteristics of the components can be changed.
  • alkalis such as sodium hydroxide
  • sucrose or sodium chloride as tonicity agents
  • Buffer containing phosphate or histidine Buffer containing phosphate or histidine.
  • Co-solvents such as polyethylene glycol can be added.
  • low-toxicity surfactants such as polysorbate or poloxamer
  • polyethylene glycol or other co-solvents can also be used
  • biological phases such as polyvinylpyrrolidone can be added.
  • Capacitive polymers, and other sugars and polyols can be used to replace dextrose.
  • the therapeutically effective dose can be estimated first using various methods well known in the art.
  • the initial dose for animal studies can be based on the effective concentration established in the cell culture assay.
  • the dosage range suitable for a human individual can be determined, for example, using data obtained from animal studies and cell culture assays.
  • the compound of the present invention can be prepared as a medicament for oral administration.
  • the effective amount or therapeutically effective amount or dose of an agent refers to the amount of an agent or compound that causes improvement in symptoms or prolonged survival of an individual.
  • Toxicity and therapeutic efficacy of the molecule can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by measuring the LD 50 (the dose lethal to 50% so that the population) and 50 (50% of the population of a therapeutically effective ED dose).
  • the dose ratio of toxicity and therapeutic effects is the therapeutic index and can be expressed as LD 50 / ED 50.
  • a drug showing a high therapeutic index is preferred.
  • the effective amount or therapeutically effective amount is the amount of a compound or pharmaceutical composition that will trigger a biological or medical response in a tissue, system, animal, or human being explored by researchers, veterinarians, doctors, or other clinicians. Dosages preferably fall within a range of circulating concentrations that include the ED 50 of minimal toxicity or no toxicity. The dosage can vary within this range, depending on the dosage form used and/or the route of administration used. The correct formulation, route of administration, dosage, and interval between administrations should be selected according to methods known in the art, taking into account the particularity of individual conditions.
  • the dose and interval can be individually adjusted to provide a plasma level of the active part sufficient to obtain the desired effect; that is, the minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC of each compound will be different, but can be estimated, for example, from invitro data and animal experiments.
  • the dose necessary to obtain MEC will depend on individual characteristics and route of administration. In the case of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
  • the amount of the medicament or composition administered can be determined by various factors, including the sex, age and weight of the individual to be treated, the severity of the pain, the method of administration, and the judgment of the prescribing physician.
  • the composition of the present invention can be provided by a packaging or dispensing device containing one or more unit dosage forms (containing the active ingredient).
  • the packaging or device may comprise metal or plastic foil (such as foam packaging) or glass and rubber stoppers, such as in vials.
  • the packaging or dispensing device may be accompanied by instructions for medicines. It is also possible to prepare a composition containing the compound of the present invention formulated in a compatible pharmaceutical carrier, place it in an appropriate container, and label it for the treatment of a specified condition.
  • “Pharmaceutically acceptable” refers to a situation that can be used to prepare a drug combination, which is generally safe and non-toxic, and is not biologically or otherwise undesirable, and includes those for veterinary and human drug use Acceptable situation.
  • excipient refers to a pharmaceutically acceptable chemical substance, such as an agent known to a person of ordinary skill in the pharmaceutical field to assist in the administration of medicine. It is a compound that can be used to prepare pharmaceutical components, is generally safe, non-toxic, and undesirable in biology or other aspects, and includes excipients acceptable for veterinary and human pharmaceuticals. Common excipients include binders, surfactants, diluents, disintegrants and lubricants.
  • the term "effective treatment amount” refers to the amount of the compound used that is sufficient to achieve such treatment of the disease state when administered to a subject to treat the disease state.
  • the “effective treatment amount” will vary according to the compound, the disease state to be treated, the severity of the disease to be treated, the age and relative health of the subject, the route and method of administration, and the judgment of the attending medical treatment or veterinarian, etc.
  • treatment or “treatment” is to obtain beneficial or desired results, including clinical results.
  • beneficial or desired clinical results include, but are not limited to, reduction or improvement of one or more symptoms or conditions, reduction of disease degree, stabilization of disease state (if not worsening), prevention of disease transmission, delay or slowing of disease progression, disease state Improvement or alleviation, and partial or full improvement, whether it is detectable or undetectable.
  • the term can also refer to prolonged survival compared to the expected survival without treatment.
  • mammal refers to humans or any mammals, such as primates, farm animals, pet animals, or laboratory animals. Examples of these animals are monkeys, cows, sheep, horses, pigs, dogs, cats, rabbits, mice and rats. Mammals are preferred to humans.
  • malignant hyperproliferative disorder refers to any malignant growth or tumor caused by abnormal and uncontrolled cell division, which may spread to other parts of the body through the lymphatic system or blood circulatory system, including solid tumors and blood sources Sex tumors.
  • Exemplary cancers include adrenal cortical cancer, AIDS-related cancer, AIDS-related lymphoma, anal cancer, anorectal cancer, appendix cancer, childhood cerebellar astrocytoma, basal cell carcinoma, biliary tract cancer, extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma , Urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain tumor, brainstem glioma, cerebellar astrocytoma, cerebral astrocytoma, malignant glioma, ependymoma, Neuroblastoma, visual pathway and hypothalamic glioma, breast cancer, bronchi
  • Granuloma fungoides Sezary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal tumors, gastrointestinal tract Stromal tumor, germ cell carcinoma, ovarian germ cell tumor, gestational trophoblastoma glioma, head and neck cancer, liver cancer, Hodgkin’s lymphoma, throat cancer, Kaposi’s sarcoma, kidney cancer, acute lymphoblastic leukemia, Acute myelogenous leukemia, hairy cell leukemia, lip and oral cavity cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, non-Hodgkin lymphoma, primary central nervous system lymphoma, Waldenstrom macroglobulinemia Disease, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic squamous neck cancer, tongue cancer, multiple
  • autoimmune disorder refers to any disorder caused by an inappropriate immune response to substances and tissues normally present in the body. This response may be limited to certain organs or involve specific tissues in different places.
  • exemplary autoimmune disorders are acute encephalomyelitis (ADEM), Addison's disease, agammaglobulinemia, alopecia areata, amyotrophic lateral sclerosis, ankylosing spondylitis, antiphospholipid syndrome, antisynthetic enzyme syndrome , Atopic allergy.
  • ADAM acute encephalomyelitis
  • Addison's disease agammaglobulinemia
  • alopecia areata
  • amyotrophic lateral sclerosis ankylosing spondylitis
  • antiphospholipid syndrome antisynthetic enzyme syndrome
  • Atopic allergy Atopic allergy.
  • Atopic dermatitis autoimmune aplastic anemia, autoimmune cardiomyopathy, autoimmune bowel disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphocyte proliferation syndrome, autoimmune peripheral neuropathy , Autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune luteal dermatitis, autoimmune thrombocytopenic purpura, autoimmune urticaria, autoimmune uveitis, Balo disease/Balo concentric sclerosis, Behcet's disease, Berger's disease, Bickerstaff's encephalitis, Blau syndrome, bullous pemphigoid, Castleman's disease, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multipathic osteomyelitis, chronic obstructive Pulmonary disease, Churg-Strauss syndrome, epileptic pemphigoid, Cogan syndrome, cold agglutinin disease, complement component
  • inflammatory disorder refers to a case state related to inflammation, usually caused by leukocyte infiltration.
  • Inflammatory disorders may be acute or chronic.
  • Exemplary inflammatory disorders include inflammatory skin diseases, including but not limited to psoriasis and atopic dermatitis, systemic scleroderma and sclerosis, and reactions related to inflammatory bowel disease (IBD) (such as Crohn’s disease and ulcers) Colitis); ischemic reperfusion disorders, including surgical tissue reperfusion injury, myocardial ischemic conditions such as myocardial infarction, cardiac arrest, reperfusion after cardiac surgery, and coarctation after percutaneous transluminal coronary angioplasty , Stroke and abdominal aortic aneurysm, cerebral edema secondary to stroke, cranial trauma, hypovolemic shock, asphyxia, adult respiratory distress syndrome, acute lung injury, Behcet’s disease, dermatomyositis, polymyositis, Multiple sclerosis, dermatitis, men
  • Immunopathological reaction to tissue or organ transplantation including pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, hypersensitivity pneumonia, idiopathic lung Fibrosis (IPF) and cystic fibrosis, etc.
  • metabolic syndrome generally refers to metabolic complications caused by obesity, commonly referred to as metabolic syndrome, which is characterized by plasma lipid imbalance (atherogenic dyslipidemia), elevated Blood pressure, elevated plasma glucose, and prethrombotic state.
  • plasma lipid imbalance atherogenic dyslipidemia
  • elevated Blood pressure elevated Blood pressure
  • elevated plasma glucose elevated plasma glucose
  • prethrombotic state prethrombotic state.
  • the clinical consequences of this metabolic syndrome are, for example, coronary heart disease and stroke, type II diabetes and complications, fatty liver and cholesterol gallstones.
  • C 1 -C 6 alkyl refers to alkyl groups having a total of 5 or 6 carbon atoms as defined below.
  • the total number of carbon atoms in the simplified notation does not include the carbons that may be present in the substituents of the group.
  • the numerical range defined in the substituents such as 0 to 4, 1-4, 1 to 3, etc., indicates an integer within the range, for example, 1-6 is 1, 2, 3, 4, 5, 6.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, including deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable .
  • substituted means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Further, when the group is substituted by one or more of the substituents, the substituents are independent of each other, that is, the one or more substituents may be different from each other or the same of. Unless otherwise indicated, a substituent group can be substituted at each substitutable position of the substituted group. When more than one position in the given structural formula can be substituted by one or more substituents selected from specific groups, then the substituents can be substituted at each position with the same or different ones.
  • C 1 ⁇ C 6 alkyl or “C 1 - 6 alkyl” refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl group; "C 1 - 4 alkyl” refers specifically disclosed independently methyl, ethyl, C 3 alkyl (i.e. propyl, including n-propyl and isopropyl), C 4 alkyl (i.e. butyl, comprising N-butyl, isobutyl, sec-butyl and tert-butyl).
  • halogen is selected from F, Cl, Br or I, especially F or Cl.
  • alkyl (general formula C n H 2n+1 ) means to include Branched and straight chain saturated aliphatic hydrocarbon groups with the number of carbon atoms; for example, C 1 -C 16 alkyl groups.
  • C 1 -C 6 alkyl it includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms in a linear or branched structure.
  • propyl is C 3 alkyl (including isomers, such as n-propyl or isopropyl); butyl is C 4 alkyl (including isomers, such as n-butyl, sec-butyl) , Isobutyl or tert-butyl); pentyl is C 5 alkyl (including isomers, such as n-pentyl, 1-methyl-butyl, 1-ethyl-propyl, 2-methyl -1-butyl, 3-methyl-1-butyl, isopentyl, tert-pentyl or neopentyl); hexyl is C 6 alkyl (including isomers, such as n-hexyl, 1-ethyl 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl , 1,3-dimethylbutyl, 2-ethyl
  • heptyl is C 7 alkyl (including isomers, such as n-heptyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl Group, 2-ethylpentyl, 3-ethylpentyl).
  • Octyl is C 8 alkyl (including isomers, such as n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2 -Dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethyl Pentyl, 2-methyl-3-ethylpentyl).
  • isomers such as n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2 -Dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-e
  • Nonyl is C 9 alkyl (including isomers, such as n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl base).
  • Quinyl is a C10 alkyl group (including isomers such as n-quinyl, 3,3-diethylhexyl, and 2,2-diethylhexyl).
  • the "alkyl” is preferably a linear or branched alkyl group containing 1 to 6 carbon atoms.
  • the "alkyl” refers to a C 1 -C 6 alkyl group.
  • the "alkyl” refers to a C 1 -C 4 alkyl group.
  • cycloalkyl means a saturated monocyclic, polycyclic or bridged carbocyclic substitution consisting of only carbon atoms and hydrogen atoms Group, and it can be connected to the rest of the molecule through a single bond via any suitable carbon atom; when it is a polycyclic ring, it can be a fused ring connection or a spiro ring connection (that is, the two geminal hydrogens on the carbon atom are alkylene Group substitution) bridged ring system or spiro ring system.
  • the cycloalkyl substituent can be attached to the central molecule via any suitable carbon atom.
  • a ring having 3-16 carbon atoms can be represented as a C 3 -C 16 cycloalkyl group.
  • the C 3 to C 6 cycloalkyl group includes cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopentyl (C 5 ), and cyclohexyl (C 6 ).
  • examples of C 3 ⁇ C 10 cycloalkyl groups include the above-mentioned C 3 ⁇ C 6 cycloalkyl groups together with cycloheptyl (C 7 ), cyclooctyl (C 8 ), cyclononyl ( C 9 ) and cyclodecyl (C 10 ).
  • heterocycloalkyl means 2-6 carbon atoms (preferably 2-5 carbon atoms) and 1-4 selected from nitrogen, A stable 3- to 7-membered saturated cyclic group composed of oxygen and sulfur heteroatoms.
  • Exemplary 3-membered heterocyclyl groups include, but are not limited to, aziridinyl, oxiranyl, and thiolanyl, or stereoisomers thereof; exemplary 4-membered heterocyclic groups Including, but not limited to, azetidinyl, propylene oxide, thietane, or isomers and stereoisomers thereof; exemplary 5-membered heterocyclyl groups include but not Limited to tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, dioxolane, oxygen Heterothiofuranyl, dithiofuranyl, or its isomers and stereoisomers.
  • Exemplary 6-membered heterocyclyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, cyclopentanyl sulfide, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl , Piperazinyl, triazinyl, or its isomers and stereoisomers;
  • exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxepane Group, thiepanyl, and diazacycloheptyl, or its isomers and stereoisomers.
  • heterocycloalkyl is C 3 ⁇ C 5 heterocycloalkyl, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, or 3. A.
  • aryl refers to a monocyclic or polycyclic group having 6-14 ring atoms and zero heteroatoms provided in the aromatic ring system (E.g., bicyclic or tricyclic) groups of 4n+2 aromatic ring systems (e.g., having 6, 10, or 14 shared p electrons in a cyclic array) ("C 6 -C 14 aryl ").
  • aromatic ring system E.g., bicyclic or tricyclic
  • 4n+2 aromatic ring systems e.g., having 6, 10, or 14 shared p electrons in a cyclic array
  • Examples of the aforementioned aryl unit include phenyl, naphthyl, phenanthryl, or anthracenyl.
  • heteroaryl refers to having carbon atoms and 1-3 heteroatoms provided in the aromatic ring system (where each heteroatom is independent 4n+2 aromatic ring system (for example, having 6 or 10 shared p-electrons in a cyclic array) of 4--16 membered monocyclic or bicyclic 4n+2 aromatic ring system (" 4-16 membered heteroaryl").
  • the point of attachment can be a carbon or nitrogen atom, as long as the valence allows.
  • the heteroaryl group is one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 5-10 membered heteroaryl groups. In some embodiments, the heteroaryl group is one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 4-6 membered heteroaryl groups, preferably It is a 5-6 membered heteroaryl group.
  • Exemplary 5-membered heteroaryl groups include, but are not limited to: pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazole Group, oxadiazolyl, thiadiazolyl, furazanyl, oxtriazolyl or tetrazolyl.
  • Exemplary 6-membered heteroaryl groups include, but are not limited to: pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, or tetrazinyl.
  • part refers to specific fragments or functional groups in a molecule.
  • the chemical moiety is generally considered to be a chemical entity embedded or attached to a molecule.
  • substituents When the listed substituents do not indicate through which atom they are connected to the compounds included in the general formula of the chemical structure but are not specifically mentioned, such substituents may be bonded through any of its atoms. Combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • linking substituents are described.
  • the Markush variables listed for the group should be understood as the linking group.
  • the Markush group definition of the variable lists “alkyl” or “aryl” it should be understood that the “alkyl” or “aryl” respectively represents the attached Alkylene group or arylene group.
  • alkyl group when an alkyl group is clearly expressed as a linking group, the alkyl group represents a linked alkylene group, for example, the group "halo-C 1 ⁇ C 6 alkane
  • the C 1 -C 6 alkyl group in "radical” should be understood as a C 1 -C 6 alkylene group.
  • alkylene refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated linear or branched hydrocarbon group.
  • alkylene groups include methylene (-CH 2 -), ethylene ⁇ including -CH 2 CH 2 -or -CH(CH 3 )- ⁇ , isopropylene ⁇ including -CH(CH 3 )CH 2 -or -C(CH 3 ) 2 - ⁇ and so on.
  • the present invention adopts traditional methods of mass spectrometry and elemental analysis, and the steps and conditions can refer to the conventional operating steps and conditions in the art.
  • the present invention adopts standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention is that the heteroaryl compound as shown in formula I, its tautomers, stereoisomers or pharmaceutically acceptable salts provided by the present invention have good tumor suppressive activity, Especially for human chronic lymphocytic leukemia, lung adenocarcinoma, breast cancer, ovarian cancer, breast cancer or pancreatic cancer; and have good inhibitory activity on drug-resistant breast cancer, lung cancer, ovarian cancer or leukemia.
  • ACN Acetonitrile
  • DCE 1,2-Dichloroethane
  • DCM Dichloromethane
  • DIPEA N,N-Diisopropylethylamine
  • DMF N,N-Dimethylformamide
  • DMSO Dimethyl Sulfoxide
  • EtOAc ethyl acetate
  • EtOH ethanol
  • ESI electrospray mass spectrometry
  • HPLC high performance liquid chromatography
  • iPrOH isopropanol
  • MeOH methanol
  • MS mass spectrometry
  • NCS N-chlorosuccinimide
  • NMR nuclear magnetic resonance
  • TFA trifluoroacetic acid
  • MTBE methyl tert-butyl ether
  • eq. equivalent weight.
  • 1 H NMR data reports include solvent information, reported in the following forms: chemical shift ( ⁇ ppm), multiplicity, coupling constant, and integral. Expression of multiplicity: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak. All 1 H NMR are collected in Bruker spectrometer at frequencies of 400MHz, The solvent is deuterated chloroform or deuterated thionyl chloride. Mass spectrometry was collected from Waters ACQUITY UPLC/Xevo G2 QTOF SYSTEM. Liquid chromatography was collected from Agilent 1290 Infinity LC System.
  • the above crude product was dissolved in dichloromethane (100ml), and then hydrochloric acid/isopropanol solution (5N, 10ml) was added. The mixture was stirred at room temperature for 2 hours, then concentrated, the residue was slurried with methyl tert-butyl ether, and then filtered to obtain the hydrochloride of the target product.
  • 4,5-Dichloropyridin-2-amine (5g, 31mmol) was divided into small portions and concentrated sulfuric acid (30ml) was added to maintain the internal temperature below 30°C.
  • the solid was dissolved in ethyl acetate, then washed with sodium hydroxide aqueous solution (0.5N), saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and dried to obtain the target compound I-3 (4,5-dichloro-3 -Nitropyridine-2-amine 3.5g (70%)).
  • NCS (1.3g, 1.5eq) was added to a solution of 3-fluoro-2-nitroaniline (1g, 6.4mmol, 1eq) in acetonitrile (10ml), and the reaction solution was stirred at 50°C for 5 hours.
  • the reaction solution was concentrated, then separated and purified with a silica gel column, eluted with ethyl acetate/n-heptane (1:4), concentrated and dried to obtain a brown solid 4-chloro-3-fluoro-2-nitroaniline I-25 (0.2 g, 17%), and 6-chloro-3-fluoro-2-nitroaniline I-26 (0.28g, 23%).
  • General method E related compound N-(4-((4-((2-amino-5-chloro-3-nitropyridin-4-yl)amino)piperidin-1-yl)methylene)phenyl )-N-methylmethylsulfonamide (I-40, 1eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1, 1eq).
  • General method E related compound 6-chloro-N 1 -(1-((1-methyl-1hydro-indol-5-yl)methylene)piperidin-4-yl)-2-nitrobenzene 1,3-diamine (I-53, 1eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1, 1eq). Purification by silica gel column, eluent: EtOAc/MeOH/TEA (100:1:1).
  • RPMI-1640 (batch number: 1970736), DMEM (batch number: 2027913) and L-15 medium (batch number: AD18274267) were purchased from Gibco; CCK8 cell viability detection kit (batch number: EG20190416) ) Provided by Nanjing Enjing Biotechnology Co., Ltd.
  • CCK8 method to detect the effect of the test substance on the proliferation activity of each cell in vitro Take logarithmic growth phase cells for experiment. The cells were digested and counted to prepare a cell suspension of 1 ⁇ 10 5 cells/mL, seeded in a 96-well plate (100 ⁇ L/well), and placed in a 37°C, 5% CO 2 incubator for 24 hours; each well Add the test substance with the corresponding concentration, and set up a negative control group and a blank group at the same time, each group has 3 duplicate holes; after the plate is placed in an incubator for 72 hours, the cell morphology of each group is observed under a microscope, and 10 ⁇ L of CCK8 solution is added to each well. Continue to incubate for 4 hours in the cell incubator, measure the absorbance at 450 nm, and calculate the proliferation inhibition rate.
  • Table 1 lists the results of in vitro activities of some compounds on the listed tumor cells.
  • Table 1 Summary of the in vitro proliferation activity IC 50 ( ⁇ M) of 8 test substances on each tumor cell.
  • RPMI-1640, DMEM and MEM medium were purchased from Gibco;
  • the CCK8 cell viability test kit was provided by Nanjing Enjing Biotechnology Co., Ltd., batch number: EG20190416.
  • the CCK8 method detects the effect of the test substance on the proliferation activity of each cell in vitro:
  • the cells were digested and counted to prepare a cell suspension of 1 ⁇ 10 5 cells/mL, seeded in a 96-well plate (100 ⁇ L/well), and placed in a 37°C, 5% CO 2 incubator for 24 hours; each well Add the test substance with the corresponding concentration, and set up a negative control group and a blank group at the same time, each group has 3 duplicate holes; after the plate is placed in an incubator for 72 hours, the cell morphology of each group is observed under a microscope, and 10 ⁇ L of CCK8 solution is added to each well. Continue to incubate for 2-4 hours in the cell incubator, measure the absorbance at 450nm, and calculate the proliferation inhibition rate.
  • Table 2 Summary of the IC 50 of the in vitro proliferation activity of the test substances on each tumor cell (unit: ⁇ M).
  • control compound H1 used in the experiment is the compound in the examples of WO2016124553.
  • tumor inhibition rate (%) (model group tumor weight-given) Tumor weight in drug group/tumor weight in model group*100%), the results are shown in Table 3.
  • the two compounds have a significant inhibitory effect on the growth of human prostate cancer PC-3 xenograft tumors in nude mice.
  • the order of anti-tumor activity against PC-3 xenograft tumors from strong to weak is: compound 12>compound H1.
  • Test drugs Compound H5, Compound 12, Compound 23.
  • Solvent 5% DMSO, 25% polyethylene glycol (PEG400), 70% normal saline.
  • Source, strain, strain ICR mice, provided by Nantong University (Experimental animal production license: SCXK ( ⁇ )2016-0010); Laboratory animal use license: SYXK ( ⁇ )2017-0035.
  • Age 4-6 weeks at the time of purchase, 6-8 weeks at the start of dosing
  • the experimental animals were half male and half male and randomly divided into three groups, namely compound H5 (4500 mg/kg), compound 12 (4500 mg/kg), and compound 23 (4500 mg/kg). There are 10 animals in each group, half male and half male. The animals in each group were given a single intragastric administration, and the administration volume was 0.2ml/10g body weight. Observe the state of the animals after the administration, record the number of deaths, and continue to observe the surviving animals.
  • the median lethal dose (LD50) of compound H5 is about 4500 mg/kg; the median lethal dose (LD50) of compound 12 and compound 23 is greater than 4500 mg/kg.

Abstract

Disclosed are a heteroaryl compound and an application thereof. The present invention provides the heteroaryl compound represented by formula I, and a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof. The invention has good tumor suppression activity, particularly for human chronic lymphocytic leukemia, lung adenocarcinoma, breast cancer, ovarian cancer, breast cancer, or pancreatic cancer; and it has good inhibitory activity against drug-resistant breast cancer, lung cancer, ovarian cancer, and leukemia.

Description

一种杂芳基类化合物及其应用A kind of heteroaryl compound and its application
本申请要求申请日为2019/9/27的中国专利申请2019109231023的优先权。本申请引用上述中国专利申请的全文。This application claims the priority of the Chinese patent application 2019109231023 with the filing date of 2019/9/27. This application quotes the full text of the aforementioned Chinese patent application.
技术领域Technical field
本发明涉及一种杂芳基类化合物及其应用。The invention relates to a heteroaryl compound and its application.
背景技术Background technique
慢性淋巴细胞性白血病(CLL)起源于B淋巴细胞，B淋巴细胞在活化和成熟阶段不同，其来源于具有不同免疫球蛋白链可变(IgVH)基因突变的经历过抗原的B细胞(Chiorazzi Net al.,N.Engl.J.Med.,2005,352,804-15)。与具有未突变基因的患者相比具有突变IgHV基因的患者具有更好的预后效果(Damle RN et al.,Blood 1999,94,1840-7；Hamblin TJ et al.,Blood,1999,94,1848-54)。全球基因表达谱研究表明，在突变和未突变的白血病B细胞中部分区别但总体重叠的表达谱，表明了共同的表型(Klein U et.al.,J.Exp.Med.,2001,194,1625-38；Rosenwald A et al.,J.Exp.Med.,2001,194,1639-47)。Chronic lymphocytic leukemia (CLL) originates from B lymphocytes. B lymphocytes have different activation and maturation stages. They are derived from antigen-experienced B cells with different immunoglobulin chain variable (IgVH) gene mutations (Chiorazzi Net al., N. Engl. J. Med., 2005, 352, 804-15). Compared with patients with unmutated genes, patients with mutated IgHV genes have a better prognostic effect (Damle RN et al., Blood 1999, 94, 1840-7; Hamblin TJ et al., Blood, 1999, 94, 1848 -54). Global gene expression profile studies have shown that the partially different but overall overlapping expression profiles in mutated and unmutated leukemia B cells indicate a common phenotype (Klein U et.al., J. Exp. Med., 2001, 194 ,1625-38; Rosenwald A et al.,J.Exp.Med.,2001,194,1639-47).
基因表达谱研究表明CLL细胞中孤儿受体激酶酪氨酸激酶(RTK)ROR1的43.8倍的增加(Klein U et.al.,J.Exp.Med.,2001,194,1625-38)。ROR1是与肌肉特异性激酶(MUSK)和Trk神经营养因子(Trk neurotrophin)受体相关的孤儿受体的RTK家族成员(Glass DJ,etal.,Cell,1996,85,513-23；Masiakowski Pet al.,J.Biol.Chem.,1992,267,26181-90；Valenzuela DM et al.,Neuron,1995,15,573-84)。ROR受体是参与信号转导、细胞-细胞相互作用、调节细胞增殖、分化、细胞代谢和存活的细胞表面受体(Masiakowski P et al.,Biol.Chem.,1992,267,26181-90；Yoda A et al.,J.Recept.Signal Iransduct.Res.,2003,23,1-15)。它们在不同物种如人、小鼠、果蝇和秀丽隐杆线虫(C.elegans)之间在进化上具有高度保守性，表现出重要的生物学功能。Gene expression profile studies have shown a 43.8-fold increase of orphan receptor kinase tyrosine kinase (RTK) ROR1 in CLL cells (Klein U et. al., J. Exp. Med., 2001, 194, 1625-38). ROR1 is a member of the RTK family of orphan receptors related to muscle-specific kinase (MUSK) and Trk neurotrophin receptors (Glass DJ, et al., Cell, 1996, 85, 513-23; Masiakowski Petal., J. Biol. Chem., 1992, 267, 26181-90; Valenzuela DM et al., Neuron, 1995, 15, 573-84). ROR receptors are cell surface receptors involved in signal transduction, cell-cell interaction, regulation of cell proliferation, differentiation, cell metabolism and survival (Masiakowski P et al., Biol. Chem., 1992, 267, 26181-90; Yoda A et al., J. Recept. Signal Iransduct. Res., 2003, 23, 1-15). They are evolutionarily highly conservative among different species such as humans, mice, fruit flies and C. elegans, and exhibit important biological functions.
人体ROR1基因具有2814bp的编码区，具有预测的937个氨基酸序列和105kDa的蛋白质大小，包括Ig样结构域、Kringle结构域、酪氨酸激酶结构域和富含脯氨酸结构域(Yoda A et al.,J.Recept.Signal Transduct.Res.,2003,23,1-15)。ROR1位于染色体区Ip31.3上(http://ensembl.org)，该染色体区是在血液恶性肿瘤中染色体畸变不常见的区域。人体在ROR1在心脏、肺和肾脏中以基因水平表达，但在胎盘、胰腺和骨骼肌中表达较少(Reddy UR et al.,Oncogene,1996,13,1555-9)。重要的是，正常成年人组织和器官中几乎完全没有 ROR1蛋白表达。ROR1最初从神经细胞系克隆(Masiakowski Pet al.,J.Biol.Chem.,1992,267,26181-90)，且随后将缺少整个细胞外结构域但包含跨膜结构域的较短形式从胎脑库(fetal brain library)中分离。已经报道了在胎儿和成年人中枢神经***、人类白血病、淋巴瘤细胞系和源自神经外胚层的多种人类癌症中的截短的ROR1(t-Ror1)基因(Reddy UR et al.,Oncogene,1996,13,1555-9)。还描述了包含内因子7的短部分的外显子1-7的较短转录物，预测长度为393个氨基酸，分子量为44kDa(Ensembl ID:ENSG0000185483)。The human ROR1 gene has a 2814bp coding region, has a predicted 937 amino acid sequence and a protein size of 105kDa, including Ig-like domains, Kringle domains, tyrosine kinase domains and proline-rich domains (Yoda A et al. al., J. Recept. Signal Transduct. Res., 2003, 23, 1-15). ROR1 is located on the chromosome region Ip31.3 (http://ensembl.org), which is a region where chromosomal aberrations are not common in hematological malignancies. In humans, ROR1 is expressed at the gene level in the heart, lung and kidney, but less expressed in placenta, pancreas and skeletal muscle (Reddy UR et al., Oncogene, 1996, 13, 1555-9). Importantly, there is almost no ROR1 protein expression in normal adult tissues and organs. ROR1 was originally cloned from a neuronal cell line (Masiakowski Petal., J. Biol. Chem., 1992, 267, 26181-90), and the shorter form that lacks the entire extracellular domain but contains the transmembrane domain will be removed from the fetus. Separated from the fetal brain library. The truncated ROR1 (t-Ror1) gene (Reddy UR et al., Oncogene) has been reported in the fetal and adult central nervous system, human leukemia, lymphoma cell lines, and a variety of human cancers derived from neuroectoderm. , 1996, 13, 1555-9). Shorter transcripts of exons 1-7 containing a short portion of intrinsic factor 7 are also described, with a predicted length of 393 amino acids and a molecular weight of 44kDa (Ensembl ID: ENSG0000185483).
慢性淋巴细胞性白血病(CLL)患者的基因谱和蛋白质表达研究已显示ROR1的表达增加，而来自健康供体的成熟白细胞不表达该蛋白(DaneshManesh,AH et al.,Int.,J.Cancer,2008,123,1190-5)。在CLL细胞中用siRNA使ROR1沉默导致凋亡，而来自正常供体的B细胞的siRNA处理没有导致凋亡(Choudhury,A et al.,Brit.J.Haematol.,2010,151,327-35)。Studies on the gene profile and protein expression of patients with chronic lymphocytic leukemia (CLL) have shown increased expression of ROR1, while mature white blood cells from healthy donors do not express this protein (Danesh Manesh, AH et al., Int., J. Cancer, 2008,123,1190-5). Silencing ROR1 with siRNA in CLL cells resulted in apoptosis, while siRNA treatment of B cells from normal donors did not cause apoptosis (Choudhury, A et al., Brit. J. Haematol., 2010, 151, 327-35).
急性骨髓性白血病(AML)干细胞(CD34+)可能潜在地解释了对许多细胞毒性药物的耐性。在外体测定中，对抗ROR1的嵌合体(UC99961)以剂量依赖性方式抑制ROR1+AML干细胞而不是ROR-AML细胞且不是正常CD34+干细胞的集落形式。结果表明，靶向ROR可能代表根除AML以及潜在的其它难治疗性癌症，如干细胞驱动的恶性肿瘤干细胞的重要组成部分(Balaian L et al.,Blood,ASH Annual Meeting,2012,Abstract 2560)。在急性淋巴母细胞性白血病(ALL)中，ROR1以与导致AKR、ERK和MEK的激酶的前B细胞受体(pre-BCR)信号转导平衡的方式上调调节。siRNA转染诱导ALL细胞的生长受损和凋亡(Biocca V.et al.,Cancer Cell,22,656-667,2012)。Acute myeloid leukemia (AML) stem cells (CD34+) may potentially explain the resistance to many cytotoxic drugs. In the exosomal assay, the anti-ROR1 chimera (UC99961) inhibited ROR1+AML stem cells but not ROR-AML cells in a dose-dependent manner and was not a colony form of normal CD34+ stem cells. The results show that targeting ROR may represent the eradication of AML and potentially other difficult-to-treat cancers, such as an important part of stem cell-driven malignant tumor stem cells (Balaian L et al., Blood, ASH Annual Meeting, 2012, Abstract 2560). In acute lymphoblastic leukemia (ALL), ROR1 is up-regulated in a balanced manner with pre-B cell receptor (pre-BCR) signal transduction of kinases that cause AKR, ERK, and MEK. siRNA transfection induces impaired growth and apoptosis of ALL cells (Biocca V. et al., Cancer Cell, 22, 656-667, 2012).
人乳腺癌细胞，但不是正常乳腺上皮细胞，也表达了ROR1。激素受体阴性肿瘤患者以及细胞分化程度低的患者(即预后差的患者)的ROR1表达强度较高。ROR1的沉默损害了人体乳腺癌细胞在体外生长和在免疫缺陷小鼠中的生长。结果支持了这样一个概念，ROR1在乳腺癌中具有生物学和临床学意义，可能是疗法的潜在靶点(Zang,S.,et al.,Plos one,7(3):e31127,2012)。Human breast cancer cells, but not normal breast epithelial cells, also express ROR1. Hormone receptor-negative tumor patients and patients with low cell differentiation (ie patients with poor prognosis) have higher ROR1 expression intensity. The silence of ROR1 impaired the growth of human breast cancer cells in vitro and in immunodeficient mice. The results support the concept that ROR1 has biological and clinical significance in breast cancer and may be a potential target of therapy (Zang, S., et al., Plos one, 7(3): e31127, 2012).
在人体肺癌细胞中，ROR1过度表达，ROR1激酶活性在增殖P13K/AKT和凋亡性p38信号传导之间维持有利的促存活平衡，这部分是过度ROR1激酶依赖性src激酶活性以及激酶非依赖低维持EGFR/ERBB3磷酸化和PI3K激活。ROR1敲低在体外和体内有效抑制肺癌细胞的生长，不管EGFR状态如何，包括对EGFR酪氨酸激酶抑制剂吉非替尼具有抗性的那些细胞。这些数据也表面ROR1在肺癌中的重要生物学作用和用于靶向疗法的结构(Yamaguchi et al.,Cancer Cell,21,348-361,2012)。意外的是，CLL细胞表现出ERBB2的过度表达和src/PI3K、AKT/mTOR/CREB脱磷酸化(自身未公布的观测结果)。In human lung cancer cells, ROR1 is overexpressed, and ROR1 kinase activity maintains a favorable pro-survival balance between proliferative P13K/AKT and apoptotic p38 signaling. This is partly due to excessive ROR1 kinase-dependent src kinase activity and low kinase-independent activity. Maintain EGFR/ERBB3 phosphorylation and PI3K activation. ROR1 knockdown effectively inhibits the growth of lung cancer cells in vitro and in vivo, regardless of EGFR status, including those cells that are resistant to the EGFR tyrosine kinase inhibitor gefitinib. These data also indicate the important biological role of ROR1 in lung cancer and the structure for targeted therapy (Yamaguchi et al., Cancer Cell, 21, 348-361, 2012). Surprisingly, CLL cells showed overexpression of ERBB2 and dephosphorylation of src/PI3K, AKT/mTOR/CREB (self-unpublished observations).
在另一项研究中，许多实体肿瘤组织(肺、卵巢、胰腺)表达ROR1，但正常的细胞对应物不表达。ROR1表达与高级组织学和AKT和CREB的激活相关。使用shRNA使ROR1沉默诱导胰腺和卵巢癌细胞的凋亡和ROR1蛋白以及活化的AKT和CREB的下调(Zhan S.,et al.,American Jouranl of Pathology,181:1903-1910,2012)。In another study, many solid tumor tissues (lung, ovary, pancreas) expressed ROR1, but normal cell counterparts did not. ROR1 expression is associated with high-level histology and activation of AKT and CREB. Silencing ROR1 using shRNA induces apoptosis of pancreatic and ovarian cancer cells and down-regulation of ROR1 protein and activated AKT and CREB (Zhan S., et al., American Journal of Pathology, 181:1903-1910, 2012).
已经表明黑素瘤细胞表达ROR1，在凋亡之前ROR1siRNA诱导mRNA和蛋白质水平的ROR1下调。通过ROR1定向单克隆抗体靶向黑素瘤细胞的ROR1诱导了显著凋亡，不需要免疫细胞或补体。有抗体诱导的凋亡程度在细胞之间变化(Hodjat-Farsangi M.,et al.,Plos One,8,e61167,2013)。此外，最近研究表明，ROR1在3T3-L1细胞中的脂肪形成和葡萄糖体内平衡中起重要作用(Sanchez-Solana B.,Laborda J.,Baladron V.,Molecular Endocrinology 26:110-127,2012)。因此，调控WNT途径(如通过调节ROR1)来改变脂肪细胞的组成可能构成对抗肥胖相关代谢并发症的有吸引力的药物开发目标(Christodoulidies C.,Lagthu C.,Sethi J.K.,Vidal-Puig A.,Trends Endocrinol.Metab.,2009,Jan:20(1):16-24)。It has been shown that melanoma cells express ROR1, and ROR1 siRNA induces down-regulation of mRNA and protein levels of ROR1 before apoptosis. ROR1 targeting melanoma cells by a ROR1-directed monoclonal antibody induced significant apoptosis without the need for immune cells or complement. The degree of apoptosis induced by antibodies varies from cell to cell (Hodjat-Farsangi M., et al., Plos One, 8, e61167, 2013). In addition, recent studies have shown that ROR1 plays an important role in fat formation and glucose homeostasis in 3T3-L1 cells (Sanchez-Solana B., Laborda J., Baladron V., Molecular Endocrinology 26:110-127, 2012). Therefore, regulating the WNT pathway (such as by regulating ROR1) to change the composition of adipocytes may constitute an attractive drug development target to combat obesity-related metabolic complications (Christodoulidies C., Lagthu C., Sethi JK, Vidal-Puig A. , Trends Endocrinol. Metab., 2009, Jan:20(1):16-24).
上述数据用于说明调节ROR1活性以治疗失调和疾病的有效性，所述失调和疾病不仅包括慢性淋巴细胞性白血病(CLL)，还包括其它血液恶性肿瘤以及实体肿瘤和肥胖相关的代谢并发症。The above data is used to illustrate the effectiveness of regulating ROR1 activity to treat disorders and diseases, which include not only chronic lymphocytic leukemia (CLL), but also other hematological malignancies, solid tumors and obesity-related metabolic complications.
ROR1的抗体抑制剂已经在文献中描述：例如PCT Int.Appl.WO2011079902,酪氨酸激酶样孤儿受体1(ROR1)小分子抑制剂也有报道于文献中，例如PCT Int.Appl.WO2018011138，WO2016124553。但是，该WO2018011138，WO2016124553中提供的化合物仅公开了其对于慢性淋巴细胞性白血病(CLL)患者的周边血单核细胞(PBMC)具有一定的抑制活性。但是经研究发现，其对于其它癌细胞的抑制作用研究不足，药代性质，毒理特点还有改进的空间。Antibody inhibitors of ROR1 have been described in the literature: for example, PCT Int.Appl.WO2011079902, and small molecule inhibitors of tyrosine kinase-like orphan receptor 1 (ROR1) have also been reported in the literature, such as PCT Int.Appl.WO2018011138, WO2016124553 . However, the compounds provided in WO2018011138 and WO2016124553 only disclose that they have a certain inhibitory activity on peripheral blood mononuclear cells (PBMC) of patients with chronic lymphocytic leukemia (CLL). However, studies have found that its inhibitory effect on other cancer cells is insufficient, and there is room for improvement in its pharmacokinetic properties and toxicological characteristics.
发明内容Summary of the invention
本发明所要解决的技术问题是针对现有技术中ROR1抑制剂不足的缺陷，而提供了一种杂芳基类化合物、中间体、其制备方法及应用。本发明的杂芳基类化合物，可以用作哺乳动物中酪氨酸激酶样孤儿受体1(ROR1)抑制剂；其用于治疗，如人体激酶活性的调节有益的病症，包括各种过度增生性疾病，如血液肿瘤如慢性淋巴细胞性白血病，急性骨髓性白血病，急性淋巴母细胞白血病或套细胞淋巴瘤，以及实体肿瘤如肺、卵巢、乳腺或胰腺肿瘤，其它还包括肥胖相关的代谢并发症、自身免疫疾病和炎性病症。The technical problem to be solved by the present invention is to provide a heteroaryl compound, an intermediate, a preparation method and application thereof in view of the defect of insufficient ROR1 inhibitors in the prior art. The heteroaryl compounds of the present invention can be used as inhibitors of tyrosine kinase-like orphan receptor 1 (ROR1) in mammals; they are used for the treatment of diseases, such as the regulation of human kinase activity, including various hyperproliferations. Sexual diseases, such as hematological tumors such as chronic lymphocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia or mantle cell lymphoma, and solid tumors such as lung, ovarian, breast or pancreatic tumors, and other metabolic complications related to obesity Diseases, autoimmune diseases and inflammatory disorders.
本发明是通过下述技术方案来解决上述技术问题的。The present invention solves the above technical problems through the following technical solutions.
本发明提供了一种如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐；The present invention provides a heteroaryl compound as shown in formula I, its tautomer, stereoisomer or pharmaceutically acceptable salt;
Figure PCTCN2020116696-appb-000001
Figure PCTCN2020116696-appb-000001
其中，
Figure PCTCN2020116696-appb-000002
表示咪唑环中的不饱和键； among them,
Figure PCTCN2020116696-appb-000002
Represents the unsaturated bond in the imidazole ring;
X和Y独立地为
Figure PCTCN2020116696-appb-000003
X and Y are independently
Figure PCTCN2020116696-appb-000003
R 4独立地为H、F、Cl、Br、I、或未取代或被一个或多个R 4a取代的C 1-C 4烷基；当所述的取代为多个时，相同或不同； R 4 is independently H, F, Cl, Br, I, or a C 1 -C 4 alkyl group that is unsubstituted or substituted with one or more R 4a ; when the substitutions are multiple, they are the same or different;
R 2独立地为C 1-C 6烷基； R 2 is independently C 1 -C 6 alkyl;
n为0、1、2、3或4；n is 0, 1, 2, 3 or 4;
W独立地为连接键、-O-(C 1-C 3亚烷基)-、-S-(C 1-C 3亚烷基)-或-N(R W1)-(C 1-C 3亚烷基)-； W is independently a linkage, -O-(C 1 -C 3 alkylene)-, -S-(C 1 -C 3 alkylene)- or -N(R W1 )-(C 1 -C 3 Alkylene)-;
R W1独立地为H或C 1-C 4烷基； R W1 is independently H or C 1 -C 4 alkyl;
R 3独立地为-C(＝O)-NR 3aR 3a’或-NR 3b-C(＝O)-R 3b’； R 3 is independently -C(=O)-NR 3a R 3a' or -NR 3b -C(=O)-R 3b' ;
R 3a、R 3a’、R 3b和R 3b’独立地为H或C 1-C 6烷基； R 3a , R 3a' , R 3b and R 3b' are independently H or C 1 -C 6 alkyl;
R 1独立地为
Figure PCTCN2020116696-appb-000004
R 1 is independently
Figure PCTCN2020116696-appb-000004
R 5和R 5’独立地为H或C 1-C 6烷基； R 5 and R 5'are independently H or C 1 -C 6 alkyl;
o、p1和q1独立地为1、2或3；p2和q2独立地为1或2；o, p1 and q1 are independently 1, 2 or 3; p2 and q2 are independently 1 or 2;
L 1独立地为-SO 2-或C 1-C 3亚烷基； L 1 is independently -SO 2 -or C 1 -C 3 alkylene;
L 2独立地为C 1-C 3亚烷基； L 2 is independently C 1 -C 3 alkylene;
R a和R b独立地为未取代或被一个或多个R a1取代的C l-C 6烷基、未取代或被一个或多个R a2取代的C 3～C 6环烷基、未取代或被一个或多个R a3取代的C 2～C 9杂环烷基、未取代或被一个或多个R a4取代的C 6～C 10芳基、或、未取代或被一个或多个R a5取代的C 2～C 9杂芳基；所述的C 2～C 9杂环烷基中，杂原子选自N、O或S中的一种或多种，杂原子数为1～3个；所述的C 2～C 9杂芳基中，杂原子选自N、O或S中的一种或多种，杂原子数为1～4个；当所述的取代为多个时，相同或不同； R a and R b are independently unsubstituted or substituted with one or more substituents R a1 is C l -C 6 alkyl, unsubstituted or substituted with one or more R a2 is C 3 ~ C 6 cycloalkyl group, is not unsubstituted or substituted with one or more R a3 is C 2 ~ C 9 heterocycloalkyl, unsubstituted or substituted with one or more R a4 is C 6 ~ C 10 aryl group, or an unsubstituted or substituted by one or more A C 2 ～C 9 heteroaryl group substituted by R a5 ; in the C 2 ～C 9 heterocycloalkyl group, the heteroatom is selected from one or more of N, O or S, and the number of heteroatoms is 1. ～3; In the C 2 ～C 9 heteroaryl group, the heteroatom is selected from one or more of N, O or S, and the number of heteroatoms is 1 to 4; when the substitution is more When, same or different;
R a1、R a2、R a3、R a4和R a5独立地为H、F、Cl、Br、I、未取代或被一个或多个R 1a-1取代的C l-C 6烷基、未取代或被一个或多个R 1a-2取代的C l-C 6烷基-O-、
Figure PCTCN2020116696-appb-000005
N(R b2)SO 2-R b2’或-N(R b3R b3’)；当所述的取代为多个时，相同或不同； R a1 , R a2 , R a3 , R a4 and R a5 are independently H, F, Cl, Br, I, unsubstituted or substituted by one or more R 1a-1 C 1 -C 6 alkyl, unsubstituted C 1 -C 6 alkyl-O- substituted or substituted with one or more R 1a-2,
Figure PCTCN2020116696-appb-000005
N(R b2 )SO 2 -R b2' or -N(R b3 R b3' ); when there are multiple substitutions, they are the same or different;
R c独立地为
Figure PCTCN2020116696-appb-000006
R c is independently
Figure PCTCN2020116696-appb-000006
R b1、R b1’、R b1”、R b2’、R c2、R c2’、R c2”、R c3’和R c4独立地为C l-C 6烷基；R b2、R b3、R b3’和R c3独立地为H或C l-C 6烷基； R b1 , R b1 ' , R b1 " , R b2' , R c2 , R c2 ' , R c2" , R c3' and R c4 are independently C 1 -C 6 alkyl groups; R b2 , R b3 , R b3' and R c3 are independently H or C 1 -C 6 alkyl;
R c1独立地为H、F、Cl、Br、I、未取代或被一个或多个R c1-1取代的C l-C 6烷基、或未取代或被一个或多个R c1-2取代的C l-C 6烷基-O-；当所述的取代为多个时，相同或不同； R c1 independently is H, F, Cl, Br, I, unsubstituted or substituted with one or more R c1-1 is C l -C 6 alkyl, or unsubstituted or substituted by one or more R c1-2 Substituted C 1 -C 6 alkyl-O-; when there are multiple substitutions, they are the same or different;
R 4a、R 1a-1、R 1a-2、R c1-1和R c1-2独立地为F、Cl、Br或I； R 4a , R 1a-1 , R 1a-2 , R c1-1 and R c1-2 are independently F, Cl, Br or I;
带“*”碳原子表示为非手性碳原子或手性碳原子，当为手性碳原子时，为S构型、R构型或它们的混合物。A carbon atom with "*" means an achiral carbon atom or a chiral carbon atom. When it is a chiral carbon atom, it is in the S configuration, R configuration or a mixture thereof.
本发明中，所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐中某些取代基的定义可如下所述，未提及的取代基的定义均如上任一方案所述。In the present invention, the definitions of certain substituents in the heteroaryl compound represented by formula I, its tautomers, stereoisomers or pharmaceutically acceptable salts may be as follows. The definitions of the mentioned substituents are as described in any of the above schemes.
本领域技术人员可以理解，
Figure PCTCN2020116696-appb-000007
包含互变异构体：
Figure PCTCN2020116696-appb-000008
Those skilled in the art can understand,
Figure PCTCN2020116696-appb-000007
Contains tautomers:
Figure PCTCN2020116696-appb-000008
在本发明的某一方案中，所述的未取代或被一个或多个R 4a取代的C 1-C 4烷基里的C 1-C 4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基。 In a certain aspect of the present invention, the C 1 -C 4 alkyl group in the C 1 -C 4 alkyl group that is unsubstituted or substituted with one or more R 4a is independently methyl, ethyl, or normal Propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
在本发明的某一方案中，R 4a、R 1a-1、R 1a-2、R c1-1和R c1-2独立地为F或Cl。 In a certain aspect of the present invention, R 4a , R 1a-1 , R 1a-2 , R c1-1 and R c1-2 are independently F or Cl.
在本发明的某一方案中，R 2独立地为C 1-C 6烷基里的C 1-C 6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)，较佳地为甲基。 In one embodiment of the present invention, R 2 is independently C 1 -C 6 alkyl group in the C 1 -C 6 alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) independently The ground is a C 1 -C 4 alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), preferably methyl.
在本发明的某一方案中，n为0或1，例如0。In a certain aspect of the present invention, n is 0 or 1, such as 0.
在本发明的某一方案中，W可位于环
Figure PCTCN2020116696-appb-000009
的邻位、间位或对位；较佳地为间位或对位；更佳地为对位。 In a certain aspect of the present invention, W may be located in the ring
Figure PCTCN2020116696-appb-000009
Ortho, meta or para; preferably meta or para; more preferably para.
在本发明的某一方案中，W独立地为-O-(C 1-C 3亚烷基)-、-S-(C 1-C 3亚烷基)-或-N(R W1)-(C 1-C 3亚烷基)-里的C 1-C 3亚烷基独立地为亚甲基(-CH 2-)，亚乙基(例如-CH 2CH 2-或-CH(CH 3)-)，亚异丙基(例如-CH(CH 3)CH 2-或-C(CH 3) 2-)；较佳地为-(CH 2)-或者-(CH 2) 2-。 In a certain aspect of the present invention, W is independently -O-(C 1 -C 3 alkylene)-, -S-(C 1 -C 3 alkylene)- or -N(R W1 )- (C 1 -C 3 alkylene)-in C 1 -C 3 alkylene is independently methylene (-CH 2 -), ethylene (e.g. -CH 2 CH 2 -or -CH (CH 3 )-), isopropylidene (for example -CH(CH 3 )CH 2 -or -C(CH 3 ) 2 -); preferably -(CH 2 )- or -(CH 2 ) 2 -.
在本发明的某一方案中，R W1独立地为C 1-C 4烷基里的C 1-C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)较佳地为甲基。 In a certain aspect of the present invention, R W1 is independently a C 1 -C 4 alkyl group in a C 1 -C 4 alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, (Isobutyl, sec-butyl or tert-butyl) is preferably methyl.
在本发明的某一方案中，R 3a、R 3a’、R 3b和R 3b’独立地为C 1-C 6烷基里的C 1-C 6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)，较佳地为甲基。 In a certain aspect of the present invention, R 3a , R 3a' , R 3b and R 3b' are independently a C 1 -C 6 alkyl group in a C 1 -C 6 alkyl group (e.g., methyl, ethyl, propyl Group, butyl, pentyl or hexyl) are independently C 1 to C 4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) Group), preferably methyl.
在本发明的某一方案中，R 5和R 5’独立地为C 1-C 6烷基里的C 1-C 6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)，较佳地为甲基。 In a certain embodiment of the present invention, R 5 and R 5'are independently a C 1 -C 6 alkyl group in a C 1 -C 6 alkyl group (e.g., methyl, ethyl, propyl, butyl, pentyl Or hexyl) independently C 1 ～C 4 alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), preferably methyl.
在本发明的某一方案中，o为1或2。In a certain aspect of the present invention, o is 1 or 2.
在本发明的某一方案中，p为1或2。In a certain aspect of the present invention, p is 1 or 2.
在本发明的某一方案中，q为1或2。In a certain aspect of the present invention, q is 1 or 2.
在本发明的某一方案中，L 1和L 2独立地为C 1-C 3亚烷基里的C 1-C 3亚烷基独立地为亚甲基(-CH 2-)，亚乙基(例如-CH 2CH 2-或-CH(CH 3)-)，亚异丙基(例如-CH(CH 3)CH 2-或-C(CH 3) 2-)；较佳地为-(CH 2)-或者-(CH 2) 2-。 In a certain aspect of the present invention, L 1 and L 2 are independently a C 1 -C 3 alkylene group in a C 1 -C 3 alkylene group and independently are methylene (-CH 2 -), ethylene Group (for example -CH 2 CH 2 -or -CH(CH 3 )-), isopropylidene (for example -CH(CH 3 )CH 2 -or -C(CH 3 ) 2 -); preferably- (CH 2 )-or-(CH 2 ) 2 -.
在本发明的某一方案中，所述的未取代或被一个或多个R a1取代的C l-C 6烷基里的C l-C 6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)，较佳地为甲基。 In one embodiment of the present invention, the unsubstituted or substituted with one or more R a1 is C l -C 6 alkyl group in the C l -C 6 alkyl (e.g. methyl, ethyl, propyl , Butyl, pentyl or hexyl) independently C 1 ～C 4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl ), preferably methyl.
在本发明的某一方案中，所述的未取代或被一个或多个R a2取代的C 3～C 6环烷基里的C 3～C 6环烷基独立地为环丙基、环丁基、环戊基或环己基，例如环丙基。 In a certain aspect of the present invention, the C 3 ～C 6 cycloalkyl group in the C 3 ～C 6 cycloalkyl group that is unsubstituted or substituted with one or more Ra2 is independently a cyclopropyl group, a ring group Butyl, cyclopentyl or cyclohexyl, for example cyclopropyl.
在本发明的某一方案中，所述的未取代或被一个或多个R a3取代的C 2～C 9杂环烷基里的C 2～C 9杂环烷基独立地为C 3～C 6杂环烷基，其中的杂原子为N，杂原子数为1或2个；例如，哌嗪基(又例如
Figure PCTCN2020116696-appb-000010
)。 In a certain aspect of the present invention, the C 2 ～C 9 heterocycloalkyl group in the C 2 ～C 9 heterocycloalkyl group substituted with one or more Ra3 is independently C 3 ～ C 6 heterocycloalkyl, wherein the heteroatom is N, and the number of heteroatoms is 1 or 2; for example, piperazinyl (also for example
Figure PCTCN2020116696-appb-000010
).
在本发明的某一方案中，所述的未取代或被一个或多个R a4取代的C 6～C 10芳基里的C 6～C 10芳基独立地为苯基或萘基。 In a certain aspect of the present invention, the C 6 -C 10 aryl group in the C 6 -C 10 aryl group substituted with one or more Ra4 is independently phenyl or naphthyl.
在本发明的某一方案中，所述的未取代或被一个或多个R a5取代的C 2～C 9杂芳基里的C 2～C 9杂芳基独立地为吡啶基(又例如
Figure PCTCN2020116696-appb-000011
)，苯并呋喃基(又例如
Figure PCTCN2020116696-appb-000012
)或吲唑基(又例如
Figure PCTCN2020116696-appb-000013
)。 In a certain aspect of the present invention, the C 2 ～C 9 heteroaryl group in the C 2 ～C 9 heteroaryl group that is unsubstituted or substituted with one or more Ra5 is independently a pyridyl group (for example,
Figure PCTCN2020116696-appb-000011
), benzofuranyl (also for example
Figure PCTCN2020116696-appb-000012
) Or indazolyl (also for example
Figure PCTCN2020116696-appb-000013
).
在本发明的某一方案中，R a1、R a2、R a3、R a4和R a5独立地为未取代或被一个或多个R 1a-1取代的C l-C 6烷基、未取代或被一个或多个R 1a-2取代的C l-C 6烷基-O-里的C 1-C 6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)，较佳地为甲基。 In a certain aspect of the present invention, R a1 , R a2 , R a3 , R a4 and R a5 are independently unsubstituted or substituted with one or more R 1a-1 C 1 -C 6 alkyl, unsubstituted by one or more R 1a-2 substituted C l -C 6 alkyl Lane -O- C 1 -C 6 alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) It is independently a C 1 -C 4 alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), preferably methyl.
在本发明的某一方案中，R b1、R b1’、R b1”、R b2’、R c2、R c2’、R c2”、R c3’、R c4、R b2、R b3、R b3’和R c3独立地为C l-C 6烷基里的C 1-C 6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)，较佳地为甲基。 In a certain aspect of the present invention, R b1 , R b1 ' , R b1 " , R b2' , R c2 , R c2 ' , R c2" , R c3' , R c4 , R b2 , R b3 , R b3 ' And R c3 are independently C 1 -C 6 alkyl in C 1 -C 6 alkyl (for example, methyl, ethyl, propyl, butyl, pentyl or hexyl) are independently C 1 ～C 4 The alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl) is preferably methyl.
在本发明的某一方案中，R c1独立地为未取代或被一个或多个R c1-1取代的C l-C 6烷基、或未取代或被一个或多个R c1-2取代的C l-C 6烷基-O-里的C 1-C 6烷基(例如甲基、乙基、丙基、丁基、戊基或己基)独立地为C 1～C 4烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)，较佳地为甲基。 In a certain embodiment of the present invention, R c1 is independently a C 1 -C 6 alkyl group that is unsubstituted or substituted by one or more R c1-1 , or is unsubstituted or substituted by one or more R c1-2 the C l -C 6 alkyl Lane -O- C 1 -C 6 alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl group) is independently C 1 ~ C 4 alkyl group ( For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl), preferably methyl.
在本发明的某一方案中，所述的被一个或多个R 4a取代的C 1-C 4烷基可为三氟甲基或二氟甲基。 In a certain aspect of the present invention, the C 1 -C 4 alkyl substituted by one or more R 4a may be trifluoromethyl or difluoromethyl.
在本发明的某一方案中，R 4独立地为H或Cl。 In a certain aspect of the invention, R 4 is independently H or Cl.
在本发明的某一方案中，W独立地为-O-(C 1-C 3亚烷基)-；较佳地为-O-(CH 2)-。 In a certain aspect of the present invention, W is independently -O-(C 1 -C 3 alkylene)-; preferably -O-(CH 2 )-.
在本发明的某一方案中，R 3独立地为-C(＝O)-NR 3aR 3a’；较佳地为-C(＝O)-NHCH 3。 In a certain aspect of the present invention, R 3 is independently -C(=O)-NR 3a R 3a' ; preferably -C(=O)-NHCH 3 .
在本发明的某一方案中，-W-R 3独立地为
Figure PCTCN2020116696-appb-000014
In a certain aspect of the present invention, -WR 3 is independently
Figure PCTCN2020116696-appb-000014
在本发明的某一方案中，
Figure PCTCN2020116696-appb-000015
独立地为
Figure PCTCN2020116696-appb-000016
In a certain aspect of the present invention,
Figure PCTCN2020116696-appb-000015
Independently
Figure PCTCN2020116696-appb-000016
在本发明的某一方案中，
Figure PCTCN2020116696-appb-000017
独立地为哌啶基，例如
Figure PCTCN2020116696-appb-000018
(又例如
Figure PCTCN2020116696-appb-000019
)。 In a certain aspect of the present invention,
Figure PCTCN2020116696-appb-000017
Independently piperidinyl, for example
Figure PCTCN2020116696-appb-000018
(Another example
Figure PCTCN2020116696-appb-000019
).
在本发明的某一方案中，L 1独立地为-SO 2-。 In a certain aspect of the present invention, L 1 is independently -SO 2 -.
在本发明的某一方案中，L 1独立地为C 1-C 3亚烷基；较佳地为亚甲基。 In a certain aspect of the present invention, L 1 is independently a C 1 -C 3 alkylene group; preferably a methylene group.
在本发明的某一方案中，L 2为C 1-C 3亚烷基；较佳地为亚甲基。 In a certain aspect of the present invention, L 2 is a C 1 -C 3 alkylene group; preferably a methylene group.
在本发明的某一方案中，
Figure PCTCN2020116696-appb-000020
独立地为
Figure PCTCN2020116696-appb-000021
In a certain aspect of the present invention,
Figure PCTCN2020116696-appb-000020
Independently
Figure PCTCN2020116696-appb-000021
在本发明的某一方案中，
Figure PCTCN2020116696-appb-000022
为
Figure PCTCN2020116696-appb-000023
In a certain aspect of the present invention,
Figure PCTCN2020116696-appb-000022
for
Figure PCTCN2020116696-appb-000023
在本发明的某一方案中，-N(R b2)SO 2-R b2’和
Figure PCTCN2020116696-appb-000024
独立地为-N(CH 3)SO 2-CH 3。 In a certain aspect of the present invention, -N(R b2 )SO 2 -R b2' and
Figure PCTCN2020116696-appb-000024
Independently -N(CH 3 )SO 2 -CH 3 .
在本发明的某一方案中，
Figure PCTCN2020116696-appb-000025
为
Figure PCTCN2020116696-appb-000026
In a certain aspect of the present invention,
Figure PCTCN2020116696-appb-000025
for
Figure PCTCN2020116696-appb-000026
在本发明的某一方案中，
Figure PCTCN2020116696-appb-000027
为
Figure PCTCN2020116696-appb-000028
In a certain aspect of the present invention,
Figure PCTCN2020116696-appb-000027
for
Figure PCTCN2020116696-appb-000028
在本发明的某一方案中，所述的未取代或被一个或多个R a4取代的C 6～C 10芳基选自：
Figure PCTCN2020116696-appb-000029
Figure PCTCN2020116696-appb-000030
较佳地为
Figure PCTCN2020116696-appb-000031
In a certain aspect of the present invention, the C 6 ～C 10 aryl group that is unsubstituted or substituted with one or more R a4 is selected from:
Figure PCTCN2020116696-appb-000029
Figure PCTCN2020116696-appb-000030
Preferably
Figure PCTCN2020116696-appb-000031
在本发明的某一方案中，所述的未取代或被一个或多个R a5取代的C 2～C 9杂芳基选自：
Figure PCTCN2020116696-appb-000032
较佳地为
Figure PCTCN2020116696-appb-000033
In a certain aspect of the present invention, the C 2 -C 9 heteroaryl group that is unsubstituted or substituted with one or more Ra5 is selected from:
Figure PCTCN2020116696-appb-000032
Preferably
Figure PCTCN2020116696-appb-000033
在本发明的某一方案中，R 1为
Figure PCTCN2020116696-appb-000034
Figure PCTCN2020116696-appb-000035
Figure PCTCN2020116696-appb-000036
In a certain aspect of the present invention, R 1 is
Figure PCTCN2020116696-appb-000034
Figure PCTCN2020116696-appb-000035
Figure PCTCN2020116696-appb-000036
在本发明的某一方案中，R 1独立地为
Figure PCTCN2020116696-appb-000037
较佳地为
Figure PCTCN2020116696-appb-000038
In a certain aspect of the present invention, R 1 is independently
Figure PCTCN2020116696-appb-000037
Preferably
Figure PCTCN2020116696-appb-000038
在本发明的某一方案中，R 1独立地为
Figure PCTCN2020116696-appb-000039
较佳地为
Figure PCTCN2020116696-appb-000040
In a certain aspect of the present invention, R 1 is independently
Figure PCTCN2020116696-appb-000039
Preferably
Figure PCTCN2020116696-appb-000040
在本发明的某一方案中，R 1为
Figure PCTCN2020116696-appb-000041
其中，R c独立地为
Figure PCTCN2020116696-appb-000042
较佳地为
Figure PCTCN2020116696-appb-000043
Figure PCTCN2020116696-appb-000044
较佳地为
Figure PCTCN2020116696-appb-000045
In a certain aspect of the present invention, R 1 is
Figure PCTCN2020116696-appb-000041
Where R c is independently
Figure PCTCN2020116696-appb-000042
Preferably
Figure PCTCN2020116696-appb-000043
Figure PCTCN2020116696-appb-000044
Preferably
Figure PCTCN2020116696-appb-000045
在本发明的某一方案中，R 1为
Figure PCTCN2020116696-appb-000046
其中，R c独立地为
Figure PCTCN2020116696-appb-000047
较佳地为
Figure PCTCN2020116696-appb-000048
较佳地为
Figure PCTCN2020116696-appb-000049
In a certain aspect of the present invention, R 1 is
Figure PCTCN2020116696-appb-000046
Where R c is independently
Figure PCTCN2020116696-appb-000047
Preferably
Figure PCTCN2020116696-appb-000048
Preferably
Figure PCTCN2020116696-appb-000049
在本发明的某一方案中，R 1为
Figure PCTCN2020116696-appb-000050
其中，R c独立地为
Figure PCTCN2020116696-appb-000051
较佳地为
Figure PCTCN2020116696-appb-000052
较佳地为
Figure PCTCN2020116696-appb-000053
In a certain aspect of the present invention, R 1 is
Figure PCTCN2020116696-appb-000050
Where R c is independently
Figure PCTCN2020116696-appb-000051
Preferably
Figure PCTCN2020116696-appb-000052
Preferably
Figure PCTCN2020116696-appb-000053
在本发明的某一方案中，R 1为
Figure PCTCN2020116696-appb-000054
其中，R c独立地为
Figure PCTCN2020116696-appb-000055
较佳地为
Figure PCTCN2020116696-appb-000056
较佳地为
Figure PCTCN2020116696-appb-000057
In a certain aspect of the present invention, R 1 is
Figure PCTCN2020116696-appb-000054
Where R c is independently
Figure PCTCN2020116696-appb-000055
Preferably
Figure PCTCN2020116696-appb-000056
Preferably
Figure PCTCN2020116696-appb-000057
在本发明的某一方案中，R a独立地为未取代或被一个或多个R a4取代的C 6～C 10芳基。 In one embodiment of the invention, R a is independently unsubstituted or substituted with one or more R a4 is C 6 ~ C 10 aryl group.
在本发明的某一方案中，R b独立地为未取代或被一个或多个R a1取代的C l-C 6烷基、未取代或被一个或多个R a2取代的C 3～C 6环烷基、或未取代或被一个或多个R a4取代的C 6～C 10芳基。 In one embodiment of the present invention, R b is independently unsubstituted or substituted with one or more R a1 is C l -C 6 alkyl, unsubstituted or substituted with one or more R a2 is C 3 ~ C 6 cycloalkyl, or unsubstituted or C 6 -C 10 aryl substituted with one or more Ra4.
在本发明的某一方案中，
Figure PCTCN2020116696-appb-000058
为
Figure PCTCN2020116696-appb-000059
本领域技术人员可以理解，当化合物价允许时，
Figure PCTCN2020116696-appb-000060
可以互变异构的形式存在；例如，
Figure PCTCN2020116696-appb-000061
可以为互变异构：
Figure PCTCN2020116696-appb-000062
可为互变异构：
Figure PCTCN2020116696-appb-000063
In a certain aspect of the present invention,
Figure PCTCN2020116696-appb-000058
for
Figure PCTCN2020116696-appb-000059
Those skilled in the art can understand that when the compound price allows,
Figure PCTCN2020116696-appb-000060
Can exist in tautomeric forms; for example,
Figure PCTCN2020116696-appb-000061
Can be tautomerism:
Figure PCTCN2020116696-appb-000062
Can be tautomerism:
Figure PCTCN2020116696-appb-000063
在本发明的某一方案中，
Figure PCTCN2020116696-appb-000064
为
Figure PCTCN2020116696-appb-000065
较佳地为
Figure PCTCN2020116696-appb-000066
(或 互变异构：
Figure PCTCN2020116696-appb-000067
)。 In a certain aspect of the present invention,
Figure PCTCN2020116696-appb-000064
for
Figure PCTCN2020116696-appb-000065
Preferably
Figure PCTCN2020116696-appb-000066
(Or tautomerism:
Figure PCTCN2020116696-appb-000067
).
在本发明的某一方案中，
Figure PCTCN2020116696-appb-000068
不为
Figure PCTCN2020116696-appb-000069
In a certain aspect of the present invention,
Figure PCTCN2020116696-appb-000068
Not for
Figure PCTCN2020116696-appb-000069
在本发明的某一方案中，
Figure PCTCN2020116696-appb-000070
为
Figure PCTCN2020116696-appb-000071
Figure PCTCN2020116696-appb-000072
In a certain aspect of the present invention,
Figure PCTCN2020116696-appb-000070
for
Figure PCTCN2020116696-appb-000071
Figure PCTCN2020116696-appb-000072
在本发明的某一方案中，X和Y独立地为
Figure PCTCN2020116696-appb-000073
或者，Y独立地为
Figure PCTCN2020116696-appb-000074
X独立地为
Figure PCTCN2020116696-appb-000075
即为
Figure PCTCN2020116696-appb-000076
所述的
Figure PCTCN2020116696-appb-000077
可为
Figure PCTCN2020116696-appb-000078
(或互变异构：
Figure PCTCN2020116696-appb-000079
)或
Figure PCTCN2020116696-appb-000080
(或互变异构：
Figure PCTCN2020116696-appb-000081
)；所述的
Figure PCTCN2020116696-appb-000082
可为
Figure PCTCN2020116696-appb-000083
(例如
Figure PCTCN2020116696-appb-000084
Figure PCTCN2020116696-appb-000085
)或
Figure PCTCN2020116696-appb-000086
In a certain aspect of the present invention, X and Y are independently
Figure PCTCN2020116696-appb-000073
Or, Y is independently
Figure PCTCN2020116696-appb-000074
X is independently
Figure PCTCN2020116696-appb-000075
That is
Figure PCTCN2020116696-appb-000076
Said
Figure PCTCN2020116696-appb-000077
Can be
Figure PCTCN2020116696-appb-000078
(Or tautomerism:
Figure PCTCN2020116696-appb-000079
)or
Figure PCTCN2020116696-appb-000080
(Or tautomerism:
Figure PCTCN2020116696-appb-000081
); said
Figure PCTCN2020116696-appb-000082
Can be
Figure PCTCN2020116696-appb-000083
(E.g
Figure PCTCN2020116696-appb-000084
Figure PCTCN2020116696-appb-000085
)or
Figure PCTCN2020116696-appb-000086
所述的
Figure PCTCN2020116696-appb-000087
较佳地为
Figure PCTCN2020116696-appb-000088
(或互变异构：
Figure PCTCN2020116696-appb-000089
)或
Figure PCTCN2020116696-appb-000090
(或互变异构：
Figure PCTCN2020116696-appb-000091
)；所述的
Figure PCTCN2020116696-appb-000092
较佳地为
Figure PCTCN2020116696-appb-000093
(或互变异构：
Figure PCTCN2020116696-appb-000094
)、
Figure PCTCN2020116696-appb-000095
(或互变异构：
Figure PCTCN2020116696-appb-000096
)或
Figure PCTCN2020116696-appb-000097
(或互变异构：
Figure PCTCN2020116696-appb-000098
)。 Said
Figure PCTCN2020116696-appb-000087
Preferably
Figure PCTCN2020116696-appb-000088
(Or tautomerism:
Figure PCTCN2020116696-appb-000089
)or
Figure PCTCN2020116696-appb-000090
(Or tautomerism:
Figure PCTCN2020116696-appb-000091
); said
Figure PCTCN2020116696-appb-000092
Preferably
Figure PCTCN2020116696-appb-000093
(Or tautomerism:
Figure PCTCN2020116696-appb-000094
),
Figure PCTCN2020116696-appb-000095
(Or tautomerism:
Figure PCTCN2020116696-appb-000096
)or
Figure PCTCN2020116696-appb-000097
(Or tautomerism:
Figure PCTCN2020116696-appb-000098
).
在本发明的某一方案中，所述的如式I所示的杂芳基类化合物为如式Ia所示：In a certain aspect of the present invention, the heteroaryl compound represented by formula I is represented by formula Ia:
Figure PCTCN2020116696-appb-000099
Figure PCTCN2020116696-appb-000099
其中，R 1为
Figure PCTCN2020116696-appb-000100
R c独立地为
Figure PCTCN2020116696-appb-000101
Where R 1 is
Figure PCTCN2020116696-appb-000100
R c is independently
Figure PCTCN2020116696-appb-000101
R 2、R 3、R 4a、R a、R b、R 5、R 5’、L 1、L 2、R c2、R c2’、R c2”、R c3、R c3’、R c4、W、o、p1、q1、p2、q2和n的定义均如上所述。 R 2 , R 3 , R 4a , R a , R b , R 5 , R 5 ' , L 1 , L 2 , R c2 , R c2' , R c2 " , R c3 , R c3 ' , R c4 , W , O, p1, q1, p2, q2, and n are all defined as described above.
在本发明的某一方案中，所述的如式I所示的杂芳基类化合物为如式Ib所示：In a certain aspect of the present invention, the heteroaryl compound represented by formula I is represented by formula Ib:
Figure PCTCN2020116696-appb-000102
Figure PCTCN2020116696-appb-000102
其中，X和Y独立地为
Figure PCTCN2020116696-appb-000103
或者，Y独立地为
Figure PCTCN2020116696-appb-000104
X独立地为
Figure PCTCN2020116696-appb-000105
Figure PCTCN2020116696-appb-000106
R 1、R 2、R 3、R 4、W和n的定义均如上所述。 Where X and Y are independently
Figure PCTCN2020116696-appb-000103
Or, Y is independently
Figure PCTCN2020116696-appb-000104
X is independently
Figure PCTCN2020116696-appb-000105
Figure PCTCN2020116696-appb-000106
The definitions of R 1 , R 2 , R 3 , R 4 , W and n are as described above.
在本发明的某一方案中，当带“*”碳原子为手性碳时，可为构型R或S构型，更佳地为R构型。In a certain aspect of the present invention, when the carbon atom with "*" is a chiral carbon, it may be in the R or S configuration, more preferably in the R configuration.
在本发明的某一方案中，所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐中，所述的如式I所示的杂芳基类化合物选自如下结构：In a certain aspect of the present invention, in the heteroaryl compound represented by formula I, its tautomers, stereoisomers or pharmaceutically acceptable salts, the heteroaryl compounds represented by formula I The heteroaryl compounds shown are selected from the following structures:
Figure PCTCN2020116696-appb-000107
Figure PCTCN2020116696-appb-000107
Figure PCTCN2020116696-appb-000108
Figure PCTCN2020116696-appb-000108
由此，在本说明书通篇中，本领域技术人员可对所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐中所述基团及其取代基进行选择，以提供稳定的如式I所示的杂芳基类化合物、其立体异构体、互变异构体、药学上可接受的盐或前药，包括但不限于本发明的实施例中所述的化合物。Therefore, throughout this specification, those skilled in the art can understand the heteroaryl compounds represented by formula I, their tautomers, stereoisomers or pharmaceutically acceptable salts. The groups and their substituents are selected to provide stable heteroaryl compounds as shown in formula I, their stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs, including But it is not limited to the compounds described in the examples of the present invention.
本发明所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐可通过包括与化学领域公知方法相似的方法合成，其步骤和条件可参考本领域类似反应的步骤和条件，特别是根据本文说明进行合成。起始原料通常是来自商业来源，例如Aldrich或可使用本领域技术人员公知的方法(通过SciFinder、Reaxys联机数据库得到)容易地制备。The heteroaryl compound represented by formula I, its tautomers, stereoisomers or pharmaceutically acceptable salts of the present invention can be synthesized by methods similar to those known in the chemical field, and the steps And conditions can refer to the steps and conditions of similar reactions in the art, especially the synthesis according to the instructions herein. The starting materials are usually from commercial sources, such as Aldrich or can be easily prepared using methods known to those skilled in the art (obtained via SciFinder, Reaxys online databases).
本发明中，所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐，也可以通过已制备得到的所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐，采用本领域常规方法，经外周修饰进而得到其他所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐。In the present invention, the heteroaryl compound represented by formula I, its tautomers, stereoisomers or pharmaceutically acceptable salts can also be prepared by the formula I The heteroaryl compounds shown in I, their tautomers, stereoisomers, or pharmaceutically acceptable salts can be modified peripherally by conventional methods in the art to obtain other described compounds as shown in Formula I Heteroaryl compounds, tautomers, stereoisomers or pharmaceutically acceptable salts thereof.
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式I所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the definition of the substituents is as shown in Formula I. The following reaction schemes and examples are used to further illustrate the content of the present invention.
本发明中，所述的如式I所示的杂芳基类化合物的制备方法，其包括如下步骤：在有机溶剂中，在还原剂存在下，将如式1所示的化合物与如式2所示的化合物进行如下所示的缩合反应，得到所述的如式I所示的杂芳基类化合物即可；In the present invention, the method for preparing the heteroaryl compound shown in formula I includes the following steps: in an organic solvent, in the presence of a reducing agent, the compound shown in formula 1 is combined with the compound shown in formula 2. The compound shown is subjected to the condensation reaction shown below to obtain the heteroaryl compound shown in formula I;
Figure PCTCN2020116696-appb-000109
Figure PCTCN2020116696-appb-000109
其中，X、Y、R 1、R 2、n、W和R 3的定义如上所述。 Wherein, X, Y, R 1 , R 2 , n, W and R 3 are as defined above.
所述的缩合反应的条件和操作可为本领域该类反应中常规的条件和操作，例如参考Yang,D,et al.,Synthesis,2005,47-56中的反应的条件和操作。其中，所述的有机溶剂可 为乙醇；所述的还原剂可为硫代硫酸钠；所述的缩合反应的温度可为70±5℃。The conditions and operations of the condensation reaction can be conventional conditions and operations in this type of reaction in the art, for example, refer to the conditions and operations of the reaction in Yang, D, et al., Synthesis, 2005, 47-56. Wherein, the organic solvent may be ethanol; the reducing agent may be sodium thiosulfate; the temperature of the condensation reaction may be 70±5°C.
所述的制备方法还可包括如下步骤，在有益溶剂中，将如式3所示的化合物与如式4所示的化合物进行如下所示的取代反应，得到所述的如式1所示的化合物即可；The preparation method may further include the following steps. In a beneficial solvent, the compound represented by formula 3 and the compound represented by formula 4 are subjected to the substitution reaction shown below to obtain the compound represented by formula 1 Compound is enough;
Figure PCTCN2020116696-appb-000110
Figure PCTCN2020116696-appb-000110
其中，X、Y和R 1的定义如上所述。 Wherein, the definitions of X, Y and R 1 are as described above.
所述的取代反应的条件和操作可为本领域该类反应中常规的条件和操作。其中，所述的有机溶剂可为异丙醇；所述的取代反应的温度可为70±5℃。The conditions and operations of the substitution reaction can be conventional conditions and operations in this type of reaction in the art. Wherein, the organic solvent may be isopropanol; the temperature of the substitution reaction may be 70±5°C.
用于制备如式I中化合物的必要原料或试剂可以商购获得，或者通过本领域已知的合成方法制备。The necessary raw materials or reagents for preparing the compound of Formula I can be obtained commercially, or prepared by synthetic methods known in the art.
药学上可接受的盐可以通过在有机碱的合适的有机溶剂中加入相应的酸，根据常规方法处理来制备药学上可接受的盐。The pharmaceutically acceptable salt can be prepared by adding the corresponding acid in a suitable organic solvent of the organic base and processing according to a conventional method.
成盐实例包括：与无机酸成盐，如盐酸、氢溴酸、硫酸、硝酸、磷酸；和有机酸所形成的盐，如醋酸、苯磺酸、苯甲酸、樟脑磺酸、柃檬酸、乙磺酸、富马酸、葡庚糖酸、谷氨酸、乙醇酸、羟基萘甲酸、2-羟基乙磺酸、乳酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、黏糠酸、2-萘磺酸、丙酸、水杨酸、琥铂酸、酒石酸、对甲苯磺酸或三甲基乙酸。Examples of salt formation include: salt formation with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and salts formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, Ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid , Mucofuroic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid or trimethyl acetic acid.
如式I所示的杂芳基类化合物可能具有一个或多个手性碳原子，因此可以分离得到光学纯度异构体，例如纯的对映异构体，或者外消旋体，或者混合异构体。可以通过本领域的分离方法来获得纯的单一异构体，如手性结晶成盐，或者手性制备柱分离得到。The heteroaryl compounds shown in formula I may have one or more chiral carbon atoms, so they can be separated to obtain optically pure isomers, such as pure enantiomers, racemates, or mixed isoforms. Construct. The pure single isomer can be obtained by separation methods in the art, such as chiral crystallization into a salt, or chiral preparation column separation.
各种合成步骤可以交替或顺次的进行以得到最终的目标产物。Various synthesis steps can be performed alternately or sequentially to obtain the final target product.
本发明提供了一种药物组合物，其包含所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐，和，至少一种药用辅料。所述的药物组合物进一步可包括一种或多种另外的活性成分。举例来说，这种药物组合物可以包含一种或多种另外的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐。作为另外一种选择或除此之外，所述药物组合物还可以例如包含除如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐以外的一种或多种活性成分。The present invention provides a pharmaceutical composition comprising the heteroaryl compound represented by formula I, its tautomers, stereoisomers or pharmaceutically acceptable salts, and, at least one Kind of medicinal excipients. The pharmaceutical composition may further include one or more additional active ingredients. For example, this pharmaceutical composition may contain one or more additional heteroaryl compounds as shown in Formula I, tautomers, stereoisomers or pharmaceutically acceptable salts thereof. Alternatively or in addition, the pharmaceutical composition may, for example, contain a heteroaryl compound other than the heteroaryl compound shown in formula I, its tautomers, stereoisomers or pharmaceutically acceptable One or more active ingredients other than salt.
所述药物组合物中的各组分可同时使用或分开使用(例如顺序使用)；当所述药物组合中的各组分同时使用时，所述药物组合物中的各组分可均匀混合(即各组分的混合物)。The components in the pharmaceutical composition can be used simultaneously or separately (for example, used sequentially); when the components in the pharmaceutical composition are used at the same time, the components in the pharmaceutical composition can be uniformly mixed ( That is, a mixture of components).
所述药物组合物中的各组分可以制备成一个单一的药物组合物同时使用，也可以将 各组分分别制成单个独立的药物组合物(例如以套装的形式)，这些单个独立的药物组合物可同时使用或分开使用(例如顺序使用)。Each component in the pharmaceutical composition can be prepared into a single pharmaceutical composition and used at the same time, or each component can be prepared into a single independent pharmaceutical composition (for example, in the form of a set). These single independent pharmaceuticals The compositions can be used simultaneously or separately (e.g., used sequentially).
在所述的药物组合物中，所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐的用量可为治疗有效量。In the pharmaceutical composition, the amount of the heteroaryl compound represented by formula I, its tautomer, stereoisomer or pharmaceutically acceptable salt can be a therapeutically effective amount.
在所述的药物组合物中，所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐，和，所述的另外的活性成分可以同时或者分开施用(例如顺序施用)。In the pharmaceutical composition, the heteroaryl compound represented by formula I, its tautomers, stereoisomers or pharmaceutically acceptable salts, and, the other The active ingredients can be administered simultaneously or separately (e.g., sequential administration).
本发明还提供了所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐、或者如上所述的药物组合物在制备激酶(例如酪氨酸激酶样孤儿受体1(ROR1))抑制剂中的应用。The present invention also provides the heteroaryl compound as shown in formula I, its tautomer, stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition as described above for preparing kinase (Such as tyrosine kinase-like orphan receptor 1 (ROR1)) inhibitors.
本发明还提供了所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐、或者如上所述的药物组合物在制备药物中的应用。The present invention also provides the heteroaryl compound as shown in formula I, its tautomer, stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition as described above for preparing medicine In the application.
本发明还提供了所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐、或者如上所述的药物组合物在制备用于预防和/或***药物中的应用；所述的药物可通过调节ROR1活性预防和/或***；所述的肿瘤可为恶性肿瘤增生失调(又称恶性增生型失调)，例子包括但不限于，血癌，如慢性淋巴细胞性白血病，急性骨髓性白血病，急性淋巴母细胞性白血病或者细胞淋巴瘤，以及实体肿瘤，例如，肺癌，卵巢癌，乳腺癌或者胰腺癌。所述的肿瘤的细胞可为人慢性髓系白血病细胞K562(又称人慢性淋巴白血病细胞K562)、人急性淋巴细胞白血病Jurkat细胞、人原髓细胞白血病细胞HL-60、人肺腺癌细胞A549、人肺腺癌细胞H1299、人三阴性乳腺癌MDA-MB-231细胞、人三阴性乳腺癌MDA-MB-468细胞、人卵巢癌细胞A2780、人卵巢癌细胞OVCAR-3、人卵巢癌细胞SK-OV-3、人脐静脉内皮细胞HUVEC、人乳腺癌阿霉素耐药株MDA-MB-231/Adr、人肺癌紫杉醇耐药株A549/Taxol、人卵巢癌紫杉醇耐药株A2780/Taxol和人白细胞长春新碱耐药株HL60/VCR中的一种或多种。The present invention also provides the heteroaryl compound as shown in formula I, its tautomer, stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition as described above in preparation Application in the prevention and/or treatment of tumor drugs; the drugs can prevent and/or treat tumors by regulating the activity of ROR1; the tumors can be malignant tumor proliferation disorders (also known as malignant proliferative disorders), examples include but Not limited to blood cancers, such as chronic lymphocytic leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia or cell lymphoma, and solid tumors, such as lung cancer, ovarian cancer, breast cancer or pancreatic cancer. The cells of the tumor may be human chronic myeloid leukemia cells K562 (also known as human chronic lymphocytic leukemia cells K562), human acute lymphoblastic leukemia Jurkat cells, human promyelocytic leukemia cells HL-60, human lung adenocarcinoma cells A549, Human lung adenocarcinoma cells H1299, human triple-negative breast cancer cells MDA-MB-231, human triple-negative breast cancer cells MDA-MB-468, human ovarian cancer cells A2780, human ovarian cancer cells OVCAR-3, human ovarian cancer cells SK -OV-3, human umbilical vein endothelial cell HUVEC, human breast cancer resistant strain MDA-MB-231/Adr, human lung cancer taxol resistant strain A549/Taxol, human ovarian cancer taxol resistant strain A2780/Taxol and One or more of the human leukocyte vincristine-resistant strains HL60/VCR.
在某一方案中，所述的肿瘤还可为***癌。In a certain scheme, the tumor can also be prostate cancer.
在某一方案中，所述的肿瘤的细胞为人套细胞系淋巴瘤细胞株Z138、人弥漫大B淋巴瘤细胞WSU-DLCL2、人弥漫大B淋巴瘤细胞DOHH-2、人***癌细胞株PC-3、人***癌细胞株DU145、人套细胞淋巴瘤细胞株Jeko-1和人胰腺癌细胞株BXPC-3中的一种或多种。In a certain scheme, the cells of the tumor are human mantle cell line lymphoma cell line Z138, human diffuse large B lymphoma cell WSU-DLCL2, human diffuse large B lymphoma cell DOHH-2, and human prostate cancer cell line PC -3. One or more of human prostate cancer cell line DU145, human mantle cell lymphoma cell line Jeko-1, and human pancreatic cancer cell line BXPC-3.
本发明还提供了一种用于预防和/或治疗哺乳动物(如用于人)中，与酪氨酸激酶样孤儿受体1的活性调节或混乱状况有关的疾病(如恶性增生型失调，肥胖相关代谢并发 症，自身免疫性疾病或炎症)的方法，通过对需要此种治疗的哺乳动物(尤其是人类)喂服有效量的所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐或者如上所述的药物组合物。The present invention also provides a method for the prevention and/or treatment of diseases (such as malignant hyperplasia disorders, disorders of malignant hyperplasia, etc.) related to the regulation or disorder of tyrosine kinase-like orphan receptor 1 activity in mammals (such as for humans). Obesity-related metabolic complications, autoimmune diseases or inflammations), by feeding an effective amount of the heteroaryl compound as shown in formula I to mammals (especially humans) in need of such treatment, Its tautomers, stereoisomers or pharmaceutically acceptable salts or pharmaceutical compositions as described above.
本发明还提供了一种用于预防和/或治疗癌症的方法，其包括给受试者施用有效剂量的所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐、或者如上所述的药物组合物。The present invention also provides a method for preventing and/or treating cancer, which comprises administering to a subject an effective dose of the heteroaryl compound represented by formula I, its tautomer, Stereoisomers or pharmaceutically acceptable salts, or pharmaceutical compositions as described above.
本发明还提供了一种治疗剂，其包括所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐、或者如上所述的药物组合物。The present invention also provides a therapeutic agent, which comprises the heteroaryl compound as shown in formula I, its tautomer, stereoisomer or pharmaceutically acceptable salt, or as described above Pharmaceutical composition.
本发明的化合物可以用局部或全身给药，例如，用于肠内给药，比如直肠或口服用药，或用于肠胃外给药至哺乳动物(尤其指人)。本发明的化合物也可在肠胃外给药，例如，通过吸入式、注射或输液、如通过静脉内、动脉内、骨内、肌内、大脑内、脑室外、滑膜内、胸骨内、鞘内、病灶内、颅内、肿瘤内、皮内和皮下注射或输入。The compounds of the present invention can be administered locally or systemically, for example, for enteral administration, such as rectal or oral administration, or for parenteral administration to mammals (especially humans). The compounds of the present invention can also be administered parenterally, for example, by inhalation, injection or infusion, such as by intravenous, intraarterial, intraosseous, intramuscular, intracerebral, extraventricular, intrasynovial, intrasternal, sheath Intra, intralesional, intracranial, intratumoral, intradermal and subcutaneous injection or infusion.
本发明所述化合物、药物组合物或药物的有效量取决于哺乳动物的种类、体重、年龄、个体状况、个体药代动力学参数、待治疗的疾病和给药方式。The effective amount of the compound, pharmaceutical composition or drug of the present invention depends on the type of mammal, weight, age, individual condition, individual pharmacokinetic parameters, disease to be treated, and mode of administration.
本发明所述化合物、药物组合物或药物的有效量可通过常规实验容易的测定，最有效和方便的给药途径以及最适当的制剂也可通过常规实验测定。The effective amount of the compound, pharmaceutical composition or drug of the present invention can be easily determined by routine experimentation, and the most effective and convenient route of administration and the most appropriate formulation can also be determined by routine experimentation.
所述的药用辅料可为药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种：粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。The pharmaceutical excipients can be those that are widely used in the field of pharmaceutical production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method to enable the subject to dissolve the active ingredient at a desired rate after receiving the administration, or to promote the subject’s activity after the administration of the composition The ingredients are effectively absorbed. The pharmaceutical excipients may be inert fillers or provide certain functions, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesion Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents and sweetening agents.
可作为药学上可接受辅料的物质包括，但并不限于，离子交换剂，铝，硬脂酸铝，卵磷脂，血清蛋白，如人血清蛋白，缓冲物质如磷酸盐，甘氨酸，山梨酸，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶体硅，三硅酸镁，聚乙烯吡咯烷酮，聚丙烯酸脂，蜡，聚乙烯-聚氧丙烯-阻断聚合体，羊毛脂，糖，如乳糖，葡萄糖和蔗糖；淀粉如玉米淀粉和土豆淀粉；纤维素和它的衍生物如羧甲基纤维素钠，乙基纤维素和乙酸纤维素；树胶粉；麦芽；明胶；滑石粉；辅料如可可豆脂和栓剂蜡状物；油如花生油，棉子油，红花油，麻油，橄 榄油，玉米油和豆油；二醇类化合物，如丙二醇和聚乙二醇；酯类如乙基油酸酯和乙基月桂酸酯；琼脂；缓冲剂如氢氧化镁和氢氧化铝；海藻酸；无热原的水；等渗盐；林格(氏)溶液；乙醇，磷酸缓冲溶液，和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁，着色剂，释放剂，包衣衣料，甜味剂，调味剂和香料，防腐剂和抗氧化剂。Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum proteins, and buffer substances such as phosphate, glycine, sorbic acid, and sorbic acid. Potassium acid, a mixture of partial glycerides of saturated plant fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium base cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed Acid; pyrogen-free water; isotonic salt; Ringer's solution; ethanol, phosphate buffer solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, Coating materials, sweeteners, flavors and spices, preservatives and antioxidants.
本发明的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如，常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。The pharmaceutical composition of the present invention can be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or freeze-drying processes.
本发明的化合物的医药剂型可以以速释、控释、缓释或靶药物释放***形式提供。例如，常用剂型包括溶液和悬浮液、(微)乳液、软膏、凝胶和贴片、脂质体、片剂、糖衣药丸、软壳或硬壳胶囊、栓剂、胚珠、植入物、非晶形或结晶粉末、气溶胶和冻干制剂。视所用的给药途径而定，可能需要特殊装置来施用或给予药物，例如注射器和针、吸入器、泵、注射笔、涂药器或专用瓶(Specialflask)。药物剂型常常由药物、赋形剂和容器/密封***组成。可将一种或多种赋形剂(又称为非活性成分)添加到本发明的化合物中来改善或促进药物的制造、稳定性、给药和安全性，并且可提供获得所需药物释放曲线的方法。因此，添加到药物中的赋形剂类型可视各种因素而定，例如药物的物理和化学特性、给药途径和制备步骤。在该领域中存在药用赋形剂并且包括各种药典中所列的那些。(参见美国药典(U.S.Pharmacopeia,USP)、日本药典(Japanese Pharmacopoeia,JP)、欧洲药典(European Pharmacopoeia,EP)和英国药典(British pharmacopoeia,BP)；美国食品与药品管理局(the U.S.Food and Drug Administration,www.fda.gov)药物评价与研究中心(Centerfor Drug Evaluation and Research,CEDR)出版物，例如《非活性组分指南》(Inactive Ingredient Guide,1996)；Ash和Ash编写的《药物添加剂手册》(Hand book of Pharmaceutical Additives,2002,联合信息资源公司(Synapse Information Resources,Inc.,Endicott NY；etc.)。The pharmaceutical dosage form of the compound of the present invention can be provided in the form of an immediate release, controlled release, sustained release or target drug release system. For example, commonly used dosage forms include solutions and suspensions, (micro)emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovules, implants, amorphous Or crystalline powder, aerosol and freeze-dried formulations. Depending on the route of administration used, special devices may be required to administer or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks (Specialflask). Pharmaceutical dosage forms often consist of drugs, excipients, and container/sealing systems. One or more excipients (also known as inactive ingredients) can be added to the compounds of the present invention to improve or promote the manufacture, stability, administration and safety of the drug, and can provide the desired drug release Curve method. Therefore, the type of excipients added to the drug may depend on various factors, such as the physical and chemical properties of the drug, the route of administration, and the preparation steps. Pharmaceutical excipients exist in this field and include those listed in various pharmacopoeias. (See US Pharmacopoeia (USPharmacopeia, USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP) and British Pharmacopoeia (BP); US Food and Drug Administration (the US Food and Drug) Administration, www.fda.gov) Center for Drug Evaluation and Research (CEDR) publications, such as "Inactive Ingredient Guide" (Inactive Ingredient Guide, 1996); "Drug Additives Manual" compiled by Ash and Ash "(Handbook of Pharmaceutical Additives, 2002, Synapse Information Resources, Inc., Endicott NY; etc.).
本发明化合物的药物剂型可通过本领域中熟知的任一种方法来制造，例如通过常规混合、筛分、溶解、熔化、造粒、制造糖衣药丸、压片、悬浮、挤压、喷雾干燥、研磨、乳化、(纳米/微米级)囊封、包理或冻干工艺。如上文所述，本发明的组合物可包括一种或一种以上生理学上可接受的非活性成分，这些非活性成分会促进活性分子被加工成用于医药用途的制剂。The pharmaceutical dosage form of the compound of the present invention can be manufactured by any method well known in the art, for example, by conventional mixing, sieving, dissolving, melting, granulating, making sugar-coated pills, tableting, suspending, squeezing, spray drying, Grinding, emulsification, (nano/micron) encapsulation, encapsulation or freeze-drying process. As described above, the composition of the present invention may include one or more physiologically acceptable inactive ingredients, which can facilitate the processing of active molecules into preparations for medical use.
本发明的药物组合物可以用局部或全身给药，例如，用于肠内给药，比如直肠或口服用药，或用于肠胃外给药至哺乳动物(尤其指人)，并且包括根据本发明的化合物、其立体异构体或其药学上可接受的盐作为活性成分的治疗有效量，连同药学上可接受的赋形剂，如药学上可接受的载体。活性成份的治疗有效量如上下文所定义，并且取决于哺乳动物的种类、体重、年龄、个体状况、个体药代动力学参数、待治疗的疾病和给药方式 对于肠内给药，如口服药，本发明化合物可以配制成广泛的多种剂型。The pharmaceutical composition of the present invention can be administered locally or systemically, for example, for enteral administration, such as rectal or oral administration, or for parenteral administration to mammals (especially humans), and includes The compound, its stereoisomer or its pharmaceutically acceptable salt as a therapeutically effective amount of the active ingredient, together with a pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier. The therapeutically effective amount of the active ingredient is defined in the context and depends on the type of mammal, weight, age, individual condition, individual pharmacokinetic parameters, disease to be treated, and mode of administration. For enteral administration, such as oral drugs The compounds of the present invention can be formulated into a wide variety of dosage forms.
所述药物组合物和剂型可以包含一种或多种本发明的化合物、其立体异构体或其一种或多种药学上可接受的盐作为活性组分。药学上可接受的载体可以是固体或液体。固体的形式的制剂包括粉剂、片剂、丸剂、锭剂、胶囊剂、扁嚢剂、栓剂和可分散的颗粒剂。固体载体可以还是作为稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、防腐剂、片剂崩解剂或者包封材料的一种或多种物质。在粉剂中，载体通常是细碎的固体，其是与细碎的活性组分的混合物。在片剂中，活性组分通常与具有必要粘合能力的载体以合适的比例混合并按照所需的形状和尺寸压实。合适的载体包括但不限于碳酸镁、硬脂酸镁、滑石、糖、乳糖、果胶、糊精，淀粉、明胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡，可可脂等。活性化合物的制剂可以包括作为载体的包封材料，提供胶囊，其中有或没有载体的活性组分被与其结合的载体包围。The pharmaceutical composition and dosage form may contain one or more compounds of the present invention, stereoisomers thereof, or one or more pharmaceutically acceptable salts thereof as active ingredients. The pharmaceutically acceptable carrier can be solid or liquid. Solid form preparations include powders, tablets, pills, lozenges, capsules, cachets, suppositories, and dispersible granules. The solid carrier can also be one or more substances that act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. In powders, the carrier is usually a finely divided solid, which is a mixture with the finely divided active component. In tablets, the active ingredient is usually mixed with a carrier having the necessary binding capacity in a suitable ratio and compacted according to the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, methyl cellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter, etc. . The formulation of the active compound may include an encapsulating material as a carrier to provide a capsule in which the active component with or without a carrier is surrounded by a carrier combined with it.
适于口服给药的其它形式包括液体形式制剂，包括乳液、糖浆剂、酏剂、水溶液、水性悬浊液、或意图在使用前不久转化成液体形式制剂的固体形式制剂。乳液可以在溶液中制备，例如丙二醇水溶液中，或者可以含有乳化剂，如卵磷脂、脱水山梨糖醇单油酸酯或***胶。水溶液可以通过将活性组分溶解在水中并加入合适的着色剂、香料、稳定剂和增稠剂来制备。水性混悬液可以通过将细小颗粒的活性成分用粘合剂如天然或合成胶、树脂、甲基纤维素、羧甲基纤维素和其它常用的悬浮剂分散在水中制备。固体形式的制剂包括溶液剂、混悬剂和乳液，除了活性组分外，还可以含有着色剂、香料、稳定剂、缓冲剂、人造和天然甜味剂、分散剂、增稠剂、增溶剂等。Other forms suitable for oral administration include liquid form preparations, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations intended to be converted into liquid form preparations shortly before use. Emulsions can be prepared in a solution, such as an aqueous solution of propylene glycol, or can contain emulsifiers, such as lecithin, sorbitan monooleate, or gum arabic. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, fragrances, stabilizers, and thickeners. Aqueous suspensions can be prepared by dispersing finely divided active ingredients in water with binders such as natural or synthetic gums, resins, methyl cellulose, carboxymethyl cellulose and other commonly used suspending agents. Solid form preparations include solutions, suspensions and emulsions. In addition to the active ingredients, they may also contain colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, and solubilizers. Wait.
用于直肠给药的示例性组合包括栓剂，其可以包含例如适合的非刺激性赋形剂，例如可可脂、合成甘油酯或聚乙二醇，其在常温下是固体，但是在直肠腔中融化和/或溶解以释放药物。Exemplary combinations for rectal administration include suppositories, which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glycerides or polyethylene glycols, which are solid at normal temperature, but in the rectal cavity Melt and/or dissolve to release the drug.
本发明的化合物也可在肠胃外给药，例如，通过吸入式、注射或输液、如通过静脉内、动脉内、骨内、肌内、大脑内、脑室外、滑膜内、胸骨内、鞘内、病灶内、颅内、肿瘤内、皮内和皮下注射或输入。The compounds of the present invention can also be administered parenterally, for example, by inhalation, injection or infusion, such as by intravenous, intraarterial, intraosseous, intramuscular, intracerebral, extraventricular, intrasynovial, intrasternal, sheath Intra, intralesional, intracranial, intratumoral, intradermal and subcutaneous injection or infusion.
因此，对于肠胃外给药，本发明的药物组合物可以是无菌可注射或可输注射剂制剂的形式，例如，作为无菌水性或油性混悬液。该混悬液可以根据本领域已知的技术使用合适的分散剂或润湿剂(例如吐温80)和悬浮剂来配制。无菌可注射或可输注制剂也可以是无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射或可输注溶液或混悬液。例如，药物组合物可以是1,3-丁二醇中的溶液。可以用于本发明药物组合物中的可接受的媒介和溶剂的其它实例包括但不限于甘露醇、水、林格溶液和等渗氯化钠溶液。此外，无菌非 挥发性油通常用作溶剂或悬浮介质。为此目的可以使用任何温和的非挥发性油，包括合成的甘油单酯或甘油二酯。脂肪酸如油酸及其甘油脂衍生物可用于制备注射剂，同样还有天然的药学上可接受的油，例如橄榄油或蓖麻油，特别是其聚氧乙基化形式。这些油溶液或混悬液也可含有长链醇稀释剂或分散剂。用于肠胃外使用的溶液也可以包括合适的稳定剂，如果需要，可以包含缓冲物质。合适的稳定剂包括抗氧化剂，例如单独或组合的硫酸氢钠，亚硫酸钠或抗坏血酸、柃檬酸以及其盐和EDTA钠盐。肠胃外溶液也可以包含防腐剂，如苯扎氯铵、对羟基苯甲酸或对羟基苯甲酸丙酯和氯丁醇。Therefore, for parenteral administration, the pharmaceutical composition of the present invention may be in the form of a sterile injectable or infusible injectable preparation, for example, as a sterile aqueous or oily suspension. The suspension can be formulated according to techniques known in the art using suitable dispersing or wetting agents (for example Tween 80) and suspending agents. The sterile injectable or infusible preparation may also be a sterile injectable or infusible solution or suspension in a non-toxic parenterally acceptable diluent or solvent. For example, the pharmaceutical composition may be a solution in 1,3-butanediol. Other examples of acceptable vehicles and solvents that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils are often used as solvents or suspending media. Any bland, non-volatile oil can be used for this purpose, including synthetic mono- or di-glycerides. Fatty acids such as oleic acid and its glyceride derivatives can be used to prepare injections, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in its polyoxyethylated form. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants. Solutions for parenteral use may also include suitable stabilizers and, if necessary, buffer substances. Suitable stabilizers include antioxidants, such as sodium bisulfate, sodium sulfite or ascorbic acid, citric acid and its salts and sodium EDTA alone or in combination. Parenteral solutions may also contain preservatives such as benzalkonium chloride, p-hydroxybenzoic acid or propyl p-hydroxybenzoate and chlorobutanol.
对于吸入或鼻腔给药，合适的药物制剂室颗粒、气溶胶、粉末、雾或小滴液，例如平均尺寸为直径约10微米或更小。例如，可以在盐水中制备溶液形式的用于吸入的组合物，使用苄醇或其它适合的防腐剂，用于提高生物利用度的吸收促进剂，氟碳和/或本领域已知的其它增溶剂或分散剂。For inhalation or nasal administration, suitable pharmaceutical preparation chamber particles, aerosols, powders, mists or small droplets, for example, have an average size of about 10 microns or less in diameter. For example, a composition for inhalation in the form of a solution can be prepared in saline, using benzyl alcohol or other suitable preservatives, absorption enhancers for increasing bioavailability, fluorocarbons and/or other enhancements known in the art. Solvent or dispersant.
本发明的药物组合物也可以局部给药至皮肤或粘膜。对于局部应用，药物组合物可以是例如为洗剂、凝胶、糊剂、酊剂、透皮贴剂、用于经粘膜递送的凝胶。The pharmaceutical composition of the present invention can also be administered topically to the skin or mucous membranes. For topical application, the pharmaceutical composition may be, for example, a lotion, gel, paste, tincture, transdermal patch, gel for transmucosal delivery.
所述药物组合物可以用包含悬浮或溶解在载体中的活性成分的合适的软膏制剂。用于局部给予本发明化合物的载体包括但不限于矿物油、液体石油、白色石油、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。或者，药物组合物可以配制成包含悬浮或溶剂在载体中的活性化合物的合适的洗剂或乳剂。合适的载体包括但不限于矿物油、脱水山梨糖醇单硬脂酸酯、聚山梨醇酯60、鲸蜡醇、2-辛基十二烷醇、苄醇和水。本发明的药物组合物也可以通过直肠栓剂制剂或合适的灌肠制剂中局部施用于下肠道。合适的药物赋形剂(如载体)和制备药物剂型的方法描述于药物制剂领域的标准参考教科书中(Remington's Pharmaceutical Sciences,Mack Publishing Company)The pharmaceutical composition can be formulated with a suitable ointment containing the active ingredient suspended or dissolved in a carrier. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water. Alternatively, the pharmaceutical composition can be formulated as a suitable lotion or emulsion containing the active compound suspended or in a solvent in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The pharmaceutical composition of the present invention can also be topically applied to the lower intestinal tract through rectal suppository formulations or suitable enema formulations. Suitable pharmaceutical excipients (such as carriers) and methods for preparing pharmaceutical dosage forms are described in standard reference textbooks in the field of pharmaceutical preparations (Remington's Pharmaceutical Sciences, Mack Publishing Company)
药物组合物可以包含约1％至约95％，优选约20％至约90％的所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐，以及至少一种药学上可接受的赋形剂。The pharmaceutical composition may contain from about 1% to about 95%, preferably from about 20% to about 90% of the heteroaryl compound represented by formula I, its tautomers, stereoisomers or pharmaceuticals. Above acceptable salt, and at least one pharmaceutically acceptable excipient.
通常，本发明的化合物将以治疗有效量通过用于类似效用的药剂的任何接受的给药方式给予。合适的日剂量通常为1至1000毫克，例如每天1-500毫克，或每天1-50毫克，取决于许多因素，例如治疗疾病的严重程度、患者年龄和相对健康状况、使用化合物的效力、给药途径和形式以及给药所针对的适应症等。治疗这些疾病的技术领域的普通技术人员将能够在没有过度实验，依赖个人知识和本申请的公开情况下，确定对于给定疾病本发明化合物的有效治疗量。本发明的化合物可以作为药物制剂给予，包括适合于肠内或肠胃外给药的制剂。优选的给药方式一般是口服，使用方便的日剂量方案，其可 根据患者病情程度进行调整。Generally, the compounds of the present invention will be administered in a therapeutically effective amount by any accepted mode of administration for agents of similar utility. A suitable daily dose is usually 1 to 1000 mg, such as 1-500 mg per day, or 1-50 mg per day, depending on many factors, such as the severity of the disease being treated, the age and relative health of the patient, the effectiveness of the compound used, and the The route and form of medicine and the indications for the administration. Those of ordinary skill in the technical field of treating these diseases will be able to determine the effective therapeutic amount of the compound of the present invention for a given disease without undue experimentation, relying on personal knowledge and the disclosure of this application. The compounds of the present invention can be administered as pharmaceutical preparations, including preparations suitable for enteral or parenteral administration. The preferred mode of administration is generally oral, and a convenient daily dosage regimen can be adjusted according to the patient's condition.
适当的制剂视所需的给药途径而定。例如，对于静脉注射来说，组合物可配制于水溶液中，必要时使用生理上相容的缓冲剂，包括例如用于调整制剂pH值的磷酸盐、组氨酸或柠檬酸盐，以及诸如氯化钠或右旋糖的张度剂。对于经粘膜或鼻给药来说，可首选半固体、液体制剂或者贴片、可能含有渗透增强剂；所述渗透剂通常为本领域所已知。对于口服给药来说，化合物可配制成液体或固体剂型并作为速释或控释/缓释制剂。用于个体口服摄取的合适剂型包括片剂、药丸、糖衣药丸、硬壳和软壳胶囊、液体、凝胶、糖浆、膏剂、悬浮液和乳液。化合物也可以被配制在直肠组合物中，诸如栓剂或保留灌肠剂，例如含有常规的栓剂基质如可可脂或其它甘油酯。The appropriate formulation depends on the desired route of administration. For example, for intravenous injection, the composition can be formulated in an aqueous solution, if necessary, using physiologically compatible buffers, including, for example, phosphate, histidine or citrate used to adjust the pH of the formulation, and such as chlorine Tonicity agent for sodium or dextrose. For transmucosal or nasal administration, semi-solid, liquid formulations or patches may be preferred, and may contain penetration enhancers; such penetration agents are generally known in the art. For oral administration, the compounds can be formulated into liquid or solid dosage forms and used as immediate release or controlled release/sustained release formulations. Suitable dosage forms for oral ingestion by individuals include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, ointments, suspensions and emulsions. The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, for example containing conventional suppository bases such as cocoa butter or other glycerides.
固体口服剂型可使用赋形剂获得，所述赋形剂包括填充剂、崩解剂、粘合剂(干和湿)、溶解延缓剂、润滑剂、助流剂、抗粘剂、阳离子***换树脂、湿润剂、抗氧化剂、防腐剂、着色剂和调味剂。这些赋形剂可为合成或天然来源。所述赋形剂的实例包括纤维素衍生物、柠檬酸、磷酸二钙、明胶、碳酸镁、月桂基硫酸镁/月桂基硫酸钠、甘露糖醇、聚乙二醇、聚乙烯吡咯烷酮、硅酸盐、二氧化硅、苯甲酸钠、山梨糖醇、淀粉、硬脂酸或其盐、糖(即右旋糖、蔗糖、乳糖等)、滑石、西黄蓍胶浆(tragacanth mucilage)、植物油(氢化)和蜡。乙醇和水可用作造粒助剂。在某些情况下，需要用例如掩味膜、抗胃酸膜或延缓释放膜来涂覆片剂。常常将天然和合成的聚合物与着色剂、糖和有机溶剂或水组合用于涂覆片剂，从而产生糖衣药丸。当胶囊优于片剂时，可以用兼容的硬壳或软壳胶囊形式递送其药物粉末、悬浮液或溶液。Solid oral dosage forms can be obtained using excipients, which include fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, anti-adherents, and cation exchange Resins, humectants, antioxidants, preservatives, coloring agents and flavoring agents. These excipients can be of synthetic or natural origin. Examples of the excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium lauryl sulfate/sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinylpyrrolidone, silicic acid Salt, silicon dioxide, sodium benzoate, sorbitol, starch, stearic acid or its salt, sugar (i.e. dextrose, sucrose, lactose, etc.), talc, tragacanth mucilage, vegetable oil (hydrogenated ) And wax. Ethanol and water can be used as granulation aids. In some cases, it is necessary to coat the tablet with, for example, a taste-masking film, a gastric acid resistant film, or a delayed release film. Often natural and synthetic polymers are combined with colorants, sugar and organic solvents or water to coat tablets to produce dragees. When the capsule is superior to the tablet, the drug powder, suspension or solution can be delivered in a compatible hard-shell or soft-shell capsule form.
在一些实施方案中，本发明的化合物可局部给药，例如通过皮肤贴片、半固体或液体制剂，如凝胶、(微)乳液、软膏、溶液、(纳米/微米级)悬浮液或泡沫。药物的皮肤和下层组织渗透可通过以下方式来调节：例如使用渗透增强剂；使用亲脂性、亲水性和两亲性赋形剂的适当选择和组合，包括水、有机溶剂、蜡、油、合成和天然的聚合物、表面活性剂、乳化剂；通过调整pH值；和使用络合剂。例如离子电渗疗法(iontophoresi)的其它技术也可以用于调节本发明的化合物的皮肤渗透。例如在需要以最小全身性暴露局部给药的情形下，将首选透皮或局部给药。In some embodiments, the compounds of the present invention can be administered topically, for example via skin patches, semi-solid or liquid formulations, such as gels, (micro)emulsions, ointments, solutions, (nano/micron) suspensions or foams . The skin and underlying tissue penetration of the drug can be adjusted in the following ways: for example, the use of penetration enhancers; the use of appropriate selection and combination of lipophilic, hydrophilic and amphiphilic excipients, including water, organic solvents, waxes, oils, Synthetic and natural polymers, surfactants, emulsifiers; by adjusting pH; and using complexing agents. Other techniques such as iontophoresi can also be used to modulate the skin penetration of the compounds of the invention. For example, where local administration with minimal systemic exposure is required, transdermal or local administration will be preferred.
对于通过吸入给药或鼻给药来说，根据本发明使用的化合物以溶液、悬浮液、乳液或半固体气溶胶的形式从加压包或喷雾器中方便地给药，通常借助于推进剂，例如衍生自甲烷和乙烷的卤化碳、二氧化碳或任何其它合适的气体。对于局部气溶胶来说，如丁烷、异丁烯和戊烷等烃是适用的。在加压气溶胶的情况下，适当的剂量单位可通过提供阀门传递计量来测定。可配制用于吸入器或吹入器中的具有例如明胶的胶囊和药筒。这 些通常含有化合物与合适粉末基质(如乳糖或淀粉)的粉末混合物。For administration by inhalation or nasal administration, the compounds used according to the invention are conveniently administered in the form of solutions, suspensions, emulsions or semi-solid aerosols from a pressurized pack or nebulizer, usually with the aid of a propellant, For example, halocarbons derived from methane and ethane, carbon dioxide or any other suitable gas. For local aerosols, hydrocarbons such as butane, isobutene, and pentane are suitable. In the case of pressurized aerosols, the appropriate dosage unit can be determined by providing a valve to deliver the meter. Capsules and cartridges with, for example, gelatin can be formulated for use in inhalers or insufflators. These usually contain a powder mixture of the compound and a suitable powder base such as lactose or starch.
用于通过注射非经肠给药而配制的组合物通常是无菌的并且可以用单位剂型提供，例如安瓿瓶、注射器、注射笔、或多剂量容器，后者通常含有防腐剂。组合物可采用在油性或水性载体中的悬浮液、溶液或乳液等形式，并且可含有配制试剂，例如缓冲剂、张度剂、粘度增强剂、表面活性剂、悬浮剂和分散剂、抗氧化剂、生物相容性聚合物、鳌合剂和防腐剂。视注射部位而定，所述载体可含有水、合成或植物油和/或有机共溶剂。在某些情况下，例如对于冻干产物或浓缩物，会在给药之前将非经肠制剂重组或加以稀释。提供本发明的化合物的控释或缓释的贮库制剂(depot formulation)可包括纳米/微米级微粒或者纳米/微米级或非微细化晶体的可注射悬浮液。本领域其它熟知的基质，聚(乳酸)、聚(乙醇酸)或其共聚物等聚合物可被用作控释/缓释基质。可以以需要切口的植入物和泵的形式提供其它的贮库型(depot)给药***。Compositions formulated for parenteral administration by injection are generally sterile and can be provided in unit dosage forms, such as ampoules, syringes, injection pens, or multi-dose containers, the latter usually containing a preservative. The composition can take the form of a suspension, solution or emulsion in an oily or aqueous carrier, and can contain formulation reagents, such as buffers, tonicity agents, viscosity enhancers, surfactants, suspending and dispersing agents, and antioxidants. , Biocompatible polymers, chelating agents and preservatives. Depending on the injection site, the carrier may contain water, synthetic or vegetable oils, and/or organic co-solvents. In some cases, such as lyophilized products or concentrates, parenteral preparations will be reconstituted or diluted before administration. Depot formulations that provide controlled or sustained release of the compounds of the present invention may include injectable suspensions of nano/micro-sized particles or nano/micro-sized or non-micronized crystals. Other well-known matrices in the art, polymers such as poly(lactic acid), poly(glycolic acid) or copolymers thereof, can be used as a controlled release/sustained release matrix. Other depot-type drug delivery systems can be provided in the form of implants and pumps that require incisions.
用于静脉注射的本发明化合物的合适的载体为本领域所熟知并且包括含有碱(如氢氧化钠)的水基溶液，用于形成离子化合物；作为张度剂的蔗糖或氯化钠；例如含有磷酸盐或组氨酸的缓冲剂。可添加如聚乙二醇的共溶剂。这些水基体系能有效溶解本发明的化合物并且在全身性给药后产生低毒性。在不破坏溶解性和毒性特征的情况下，可大大改变溶液体系的组分的比例。此外，可改变组分的特性。举例来说，可使用诸如聚山梨醇酯或泊洛沙姆(poloxamer)的低毒性表面活性剂，也可使用聚乙二醇或其它共溶剂，可添加诸如聚乙烯毗略烷酮的生物相容性聚合物，并且可用其它糖和多元醇来替代右旋糖。Suitable carriers for the compounds of the present invention for intravenous injection are well known in the art and include water-based solutions containing alkalis (such as sodium hydroxide) for the formation of ionic compounds; sucrose or sodium chloride as tonicity agents; for example Buffer containing phosphate or histidine. Co-solvents such as polyethylene glycol can be added. These water-based systems can effectively dissolve the compounds of the present invention and produce low toxicity after systemic administration. Without destroying the solubility and toxicity characteristics, the ratio of the components of the solution system can be greatly changed. In addition, the characteristics of the components can be changed. For example, low-toxicity surfactants such as polysorbate or poloxamer can be used, polyethylene glycol or other co-solvents can also be used, and biological phases such as polyvinylpyrrolidone can be added. Capacitive polymers, and other sugars and polyols can be used to replace dextrose.
治疗有效剂量可首先使用本领域中熟知的各种方法来估算。用于动物研究的初始剂量可基于细胞培养测定中所确立的有效浓度。适合于人个体的剂量范围例如可使用从动物研究和细胞培养测定所获得的数据来确定。在某些实施方案中，可以将本发明的化合物制备为用于口服的药剂。The therapeutically effective dose can be estimated first using various methods well known in the art. The initial dose for animal studies can be based on the effective concentration established in the cell culture assay. The dosage range suitable for a human individual can be determined, for example, using data obtained from animal studies and cell culture assays. In certain embodiments, the compound of the present invention can be prepared as a medicament for oral administration.
药剂(例如本发明的化合物)的有效量或治疗有效量或剂量指的是引起个体症状改善或存活延长的药剂或化合物的量。所述分子的毒性和治疗功效可在细胞培养物或实验动物中通过标准医药程序来测定，例如通过测LD 50(使群体50％致死的剂量)和ED 50(对群体的50％治疗有效的剂量)。毒性作用与治疗作用的剂量比是治疗指数，可表示为LD 50/ED 50。优选显示高治疗指数的药剂。 The effective amount or therapeutically effective amount or dose of an agent (for example, a compound of the present invention) refers to the amount of an agent or compound that causes improvement in symptoms or prolonged survival of an individual. Toxicity and therapeutic efficacy of the molecule can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by measuring the LD 50 (the dose lethal to 50% so that the population) and 50 (50% of the population of a therapeutically effective ED dose). The dose ratio of toxicity and therapeutic effects is the therapeutic index and can be expressed as LD 50 / ED 50. A drug showing a high therapeutic index is preferred.
有效量或治疗有效量是将会引发研究人员、兽医、医生或其它临床医生所探求的组织、***、动物或人类的生物或医学反应的化合物或医药组合物的量。剂量优选在包括极小毒性或无毒性的ED 50的循环浓度的范围内。剂量可在这个范围内变化，视所用的剂型和/或所用的给药途径而定。应根据本领域中已知的方法，考虑个体状况的特殊性来选 择正确的制剂、给药途径、剂量和给药间隔时间。 The effective amount or therapeutically effective amount is the amount of a compound or pharmaceutical composition that will trigger a biological or medical response in a tissue, system, animal, or human being explored by researchers, veterinarians, doctors, or other clinicians. Dosages preferably fall within a range of circulating concentrations that include the ED 50 of minimal toxicity or no toxicity. The dosage can vary within this range, depending on the dosage form used and/or the route of administration used. The correct formulation, route of administration, dosage, and interval between administrations should be selected according to methods known in the art, taking into account the particularity of individual conditions.
剂量和间隔时间可个别地加以调整以提供足以获得所需效果的活性部分的血浆水平；即最小有效浓度(minimal effective concentration，MEC)。各化合物的MEC将有所不同，但可以例如从体外(invitro)数据和动物实验估算。获得MEC所必需的剂量将视个体特征和给药途径而定。在局部给药或选择性摄取的情况下，药物的有效局部浓度可能与血浆浓度无关。The dose and interval can be individually adjusted to provide a plasma level of the active part sufficient to obtain the desired effect; that is, the minimal effective concentration (MEC). The MEC of each compound will be different, but can be estimated, for example, from invitro data and animal experiments. The dose necessary to obtain MEC will depend on individual characteristics and route of administration. In the case of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
所施予的药剂或组合物的量可视各种因素而定，包括所治疗个体的性别、年龄和体重、病痛的严重性、给药方式和处方医师的判断。The amount of the medicament or composition administered can be determined by various factors, including the sex, age and weight of the individual to be treated, the severity of the pain, the method of administration, and the judgment of the prescribing physician.
在需要时，本发明的组合物可以用含有一个或一个以上单位剂型(含有活性成分)的包装或分配装置提供。举例来说，所述包装或装置可包含金属或塑料箔(如发泡包装)或玻璃和橡皮塞，如在小瓶中。所述包装或分配装置可附有用药说明书。也可以制备包含在相容性医药载体中配制的本发明化合物的组合物，将其置于适当容器中，并且加上用于治疗指定病状的标签。When necessary, the composition of the present invention can be provided by a packaging or dispensing device containing one or more unit dosage forms (containing the active ingredient). For example, the packaging or device may comprise metal or plastic foil (such as foam packaging) or glass and rubber stoppers, such as in vials. The packaging or dispensing device may be accompanied by instructions for medicines. It is also possible to prepare a composition containing the compound of the present invention formulated in a compatible pharmaceutical carrier, place it in an appropriate container, and label it for the treatment of a specified condition.
“药学上可接受的”是指可用于制备药物组合的情形，通常是安全的和无毒的，且非生物学以及其它方面所不期望，并且包括对于兽用和用于人的药物用途的可接受的情形。"Pharmaceutically acceptable" refers to a situation that can be used to prepare a drug combination, which is generally safe and non-toxic, and is not biologically or otherwise undesirable, and includes those for veterinary and human drug use Acceptable situation.
术语“赋形剂”是指药学上可接受的化学物质，例如药学领域的普通技术人员已知的用于帮助给予药用的试剂。它是可以用于制备药物组分的化合物，通常是安全的、无毒的，且是生物学或者其它方面所不可期望的，其包括对于兽用和人用药物可接受的赋形剂。通常的赋形剂包括粘合剂、表面活性剂、稀释剂、崩解剂和润滑剂。The term "excipient" refers to a pharmaceutically acceptable chemical substance, such as an agent known to a person of ordinary skill in the pharmaceutical field to assist in the administration of medicine. It is a compound that can be used to prepare pharmaceutical components, is generally safe, non-toxic, and undesirable in biology or other aspects, and includes excipients acceptable for veterinary and human pharmaceuticals. Common excipients include binders, surfactants, diluents, disintegrants and lubricants.
术语“有效治理量”是指当给予受试者来治疗疾病状态时足以实现疾病状态的这种治理的所用化合物的量。“有效治理量”将根据化合物、所治疗的疾病状态、所治疗疾病的严重程度、受试者的年龄和相对健康、给药途径和方式、主治医疗或兽医的判断等而变化。The term "effective treatment amount" refers to the amount of the compound used that is sufficient to achieve such treatment of the disease state when administered to a subject to treat the disease state. The "effective treatment amount" will vary according to the compound, the disease state to be treated, the severity of the disease to be treated, the age and relative health of the subject, the route and method of administration, and the judgment of the attending medical treatment or veterinarian, etc.
本专利所用“治理”或“治理中”是获得有益或期望结果，包括临床结果。有益或期望的临床结果包括但不限于一个或多个症状或病症的减轻或改善、疾病程度的减少、疾病状态的稳定化(如不恶化)，预防疾病传播、延迟或减缓疾病进展、疾病状态的改善或缓解，以及部分或全部好转，无论是可检测或不可检测的情形。相比对应没有治疗的预期生存期，该术语也可指延长生存期。As used in this patent, "treatment" or "treatment" is to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, reduction or improvement of one or more symptoms or conditions, reduction of disease degree, stabilization of disease state (if not worsening), prevention of disease transmission, delay or slowing of disease progression, disease state Improvement or alleviation, and partial or full improvement, whether it is detectable or undetectable. The term can also refer to prolonged survival compared to the expected survival without treatment.
术语哺乳动物是指人或任何哺乳动物，如灵长类动物、农场动物、宠物动物或者实验动物。这些动物的实例有猴、母牛、羊、马、猪、狗、猫、兔、小鼠和大鼠等。哺乳动物优选于人。The term mammal refers to humans or any mammals, such as primates, farm animals, pet animals, or laboratory animals. Examples of these animals are monkeys, cows, sheep, horses, pigs, dogs, cats, rabbits, mice and rats. Mammals are preferred to humans.
术语“恶性过度增殖性失调”是指由异常和不受控制的细胞***而引起的任何恶性生 长或肿瘤，其可能通过淋巴***或血液循环***扩散到身体的其它部分，包括实体肿瘤和血源性肿瘤。示例性癌症包括肾上腺皮质癌、AIDS相关癌症、AIDS相关淋巴瘤、***癌、***直肠癌、阑尾癌、儿童小脑星形细胞瘤、基底细胞癌、胆道癌、肝外胆管癌、肝内胆管癌、泌尿膀胱癌、骨和关节癌、骨肉瘤和恶性纤维组织细胞瘤、脑肿瘤、脑干胶质瘤、小脑星形细胞瘤、大脑星形细胞瘤、恶性胶质瘤、室管膜瘤、成神经细胞瘤、视觉通路和下丘脑神经胶质瘤、乳腺癌、支气管腺瘤/类癌、神经***癌症、神经***淋巴瘤、中枢神经***癌症、中枢神经***淋巴瘤、子***、儿童期癌症、慢性淋巴细胞性白血病、慢性骨髓性白血病、慢性骨髓增殖性失调、结肠癌、结直肠癌、皮肤T细胞淋巴瘤、淋巴样肿瘤、The term "malignant hyperproliferative disorder" refers to any malignant growth or tumor caused by abnormal and uncontrolled cell division, which may spread to other parts of the body through the lymphatic system or blood circulatory system, including solid tumors and blood sources Sex tumors. Exemplary cancers include adrenal cortical cancer, AIDS-related cancer, AIDS-related lymphoma, anal cancer, anorectal cancer, appendix cancer, childhood cerebellar astrocytoma, basal cell carcinoma, biliary tract cancer, extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma , Urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain tumor, brainstem glioma, cerebellar astrocytoma, cerebral astrocytoma, malignant glioma, ependymoma, Neuroblastoma, visual pathway and hypothalamic glioma, breast cancer, bronchial adenoma/carcinoid, nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, children Stage cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, skin T-cell lymphoma, lymphoid tumors,
蕈样肉芽肿，Sezary综合征、子宫内膜癌、食道癌、颅外生殖细胞瘤、性腺外生殖细胞瘤、眼癌、视网膜母细胞瘤、胆囊癌、胃癌、胃肠类肿瘤、胃肠道间质瘤、生殖细胞癌、卵巢生殖细胞瘤、妊娠滋养细胞瘤胶质瘤、头颈癌，肝癌、霍奇金淋巴瘤、咽喉癌、卡波西肉瘤、肾癌、急性淋巴母细胞性白血病、急性骨髓性白血病、毛细胞白血病、唇和口腔癌、肺癌、非小细胞肺癌、小细胞肺癌、非霍奇金淋巴瘤、原发性中枢神经***淋巴瘤、瓦尔登斯特伦巨球蛋白血症、眼内黑素瘤、Merkel细胞癌、恶性间皮瘤、转移性鳞状颈癌、舌癌、多发性内分泌肿瘤综合症、骨髓增生异常综合症、骨髓增生异常/骨髓增殖疾病、鼻咽癌、成神经细胞瘤、口咽癌、卵巢癌、卵巢上皮癌、卵巢低恶性潜在肿瘤、胰腺癌、胰岛细胞胰腺癌、鼻旁窦和鼻腔癌、甲状腺癌、***癌、嗜铬细胞瘤、松果体母细胞瘤和幕上原始神经外胚层肿瘤、垂体瘤、浆细胞肿瘤、多发性骨髓瘤、胸膜肺母细胞瘤、***癌、横纹肌肉瘤、唾液腺癌、尤文氏肿瘤肉瘤家族，软组织肉瘤、子宫癌、子宫肉瘤、皮肤癌(非黑素瘤)、皮肤癌(黑素瘤)、小肠癌、鳞状细胞癌、睾丸癌、咽喉癌、胸腺瘤、胸腺癌和胸腺瘤、甲状腺癌、肾盂和输尿管和其它泌尿器官的移行细胞癌、妊娠滋养细胞肿瘤、尿道癌、外阴癌和威尔姆氏肿瘤。Granuloma fungoides, Sezary syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal tumors, gastrointestinal tract Stromal tumor, germ cell carcinoma, ovarian germ cell tumor, gestational trophoblastoma glioma, head and neck cancer, liver cancer, Hodgkin’s lymphoma, throat cancer, Kaposi’s sarcoma, kidney cancer, acute lymphoblastic leukemia, Acute myelogenous leukemia, hairy cell leukemia, lip and oral cavity cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, non-Hodgkin lymphoma, primary central nervous system lymphoma, Waldenstrom macroglobulinemia Disease, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic squamous neck cancer, tongue cancer, multiple endocrine tumor syndrome, myelodysplastic syndrome, myelodysplastic/myeloproliferative disease, nasopharyngeal Cancer, neuroblastoma, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, ovarian low-malignant potential tumors, pancreatic cancer, islet cell pancreatic cancer, paranasal sinus and nasal cancer, thyroid cancer, penile cancer, pheochromocytoma, Pineal blastoma and supratentorial primitive neuroectodermal tumor, pituitary tumor, plasma cell tumor, multiple myeloma, pleuropulmonary blastoma, prostate cancer, rhabdomyosarcoma, salivary gland cancer, Ewing’s tumor sarcoma family, soft tissue sarcoma , Uterine cancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), small intestine cancer, squamous cell carcinoma, testicular cancer, throat cancer, thymoma, thymic cancer and thymoma, thyroid cancer, Transitional cell carcinoma of the renal pelvis and ureter and other urinary organs, gestational trophoblastic tumors, urethral cancer, vulvar cancer and Wilm’s tumors.
术语“自身免疫失调”是指对身体中通常存在的物质和组织不适当的免疫反应引起的任何失调。这种反应可能限于某些器官或涉及不同地方的特点组织。示例性自身免疫失调是急性脑脊髓炎(ADEM)、艾迪生病、无丙种球蛋白血症、斑秃、肌萎缩性侧索硬化、强直性脊柱炎、抗磷脂性综合症、抗合成酶综合症、特应性***反应。特应性皮炎、自身免疫再生性障碍贫血、自身免疫心肌病、自身免疫肠病、自身免疫溶血性贫血、自身免疫肝炎、自身免疫内耳疾病、自身免疫淋巴细胞增殖综合症、自身免疫神经周围病、自身免疫胰腺炎、自身免疫多内分泌综合症、自身免疫黄体性皮炎、自身免疫血小板减少性紫癜、自身免疫荨麻疹、自身免疫葡萄膜炎、Balo疾病/Balo同心硬化，Behcet’s病、Berger’s 病、Bickerstaff’s脑炎、Blau综合症、大疱性类天疱疮、Castleman’s病、乳糜病、查加斯病、慢性炎性脱髓鞘性多发性神经病、慢性复发性多病性骨髓炎、慢性阻塞性肺病、Churg-Strauss综合症，癫痕性类天疱疮、柯根综合症、冷凝集素病、补体成分2缺乏症、接触性皮炎、颅动脉炎、CREST综合症、克罗恩病(两种特发性肠病IBD之一)，Cusshing’s综合症、皮肤白细胞破碎性脉管炎、Dego’s病、Dercum’s病、疱疹样皮炎、皮肌炎、1型糖尿病、弥漫性皮肤***性硬化症、Dressler’s综合症、药物诱导的狼疮，盘状红斑狼疮、湿疹、子宫内膜异位症、附着点炎相关性关节炎、嗜曙红细胞筋膜炎、嗜曙红细胞性胃肠炎、获得性大疱性表皮松解症、结节性红斑、胎儿成红细胞增多病、原发性混合型冷球形蛋白血症、伊万氏综合症、进行性肌肉骨化症、纤维化肺泡炎(或特发性肺纤维化)、胃炎、胃肠类天疱疮、肾小球肾炎、古德帕斯特综合症、格雷夫斯病、格林-巴利综合症、Hashimoto’s脑病、Hashimoto’s甲状腺炎、Henoch-Schonlein紫癜、妊娠疱疹(又称妊娠类天疱疮)、化脓性汗腺炎、Hughes-Stovin综合症、低丙球蛋白血症、特发性炎性脱髓鞘病、特发性肺纤维化、特发性血小板减少性紫癜、IgA肾病、包涵体肌炎、慢性炎脱性髓鞘多神经病、间质性膀胱炎、青少年特发性关节炎(又称青少年类风湿关节炎)、Kawasaki’s病、Lambert-Eaton肌无力综合症、白细胞破碎性脉管炎、扁平苔藓、硬化性苔藓、线性IgA病、类狼疮肝炎(又称自身免疫肝炎)、红斑狼疮、Majeed综合症、Meniere’s病、显微镜多血管炎、混合性***病、硬斑病、急性苔藓痘疮糠疹，多发性硬化、重症肌无力、肌炎、多发性睡病、视神经脊髓炎、神经肌强直、眼癫痕性类天疱疮、斜视眼肌阵挛综合症、Ord氏甲状腺炎、回纹型风湿症、PANDAS(与链球菌有关的儿科自身免疫神经精神失调)、副肿瘤性小脑变性、阵发性睡眠性血红蛋白尿、Parry Romberg综合症、Parsonage-Turner综合症、扁平不睫状体炎、寻常性天疱疮、恶性贫血、静脉周围性脑脊髓炎、POEMS综合症、结节性多动脉炎、风湿性多肌痛、多肌炎、原发性胆汁性肝硬化、原发性硬化性胆管炎、进行性炎性神经病、牛皮癣、牛皮癣性关节炎、坏疽性脓皮病、纯红细胞发育不良、拉斯穆森脑炎、雷诺现象、复发性多软骨炎、赖特综合症、不宁腿综合症、腹膜后纤维化、类风湿关节炎、风湿热、结节病、精神***症、施密特综合症(APS的另一种形式)、施奈茨勒综合症、巩膜炎、硬皮病、血清病、Sjogren综合症、脊柱关节炎、僵人综合症、亚急性细菌性心内膜炎、Susac’s综合症、Sweet’s综合症、交感性眼炎、***性红斑狼疮、Takayasu’s动脉炎、巨细胞动脉炎、血小板减少症、Tolosa-Hunt综合症、横贯性脊髓炎、溃疡性结肠炎(两种特发性肠病IBD之一)、与混合型***疾病不同的未分化***疾病、未分化的脊柱关节病、荨麻疹性脉管炎、脉管炎、白癜风和魏格纳肉芽肿病。The term "autoimmune disorder" refers to any disorder caused by an inappropriate immune response to substances and tissues normally present in the body. This response may be limited to certain organs or involve specific tissues in different places. Exemplary autoimmune disorders are acute encephalomyelitis (ADEM), Addison's disease, agammaglobulinemia, alopecia areata, amyotrophic lateral sclerosis, ankylosing spondylitis, antiphospholipid syndrome, antisynthetic enzyme syndrome , Atopic allergy. Atopic dermatitis, autoimmune aplastic anemia, autoimmune cardiomyopathy, autoimmune bowel disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphocyte proliferation syndrome, autoimmune peripheral neuropathy , Autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune luteal dermatitis, autoimmune thrombocytopenic purpura, autoimmune urticaria, autoimmune uveitis, Balo disease/Balo concentric sclerosis, Behcet's disease, Berger's disease, Bickerstaff's encephalitis, Blau syndrome, bullous pemphigoid, Castleman's disease, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multipathic osteomyelitis, chronic obstructive Pulmonary disease, Churg-Strauss syndrome, epileptic pemphigoid, Cogan syndrome, cold agglutinin disease, complement component 2 deficiency, contact dermatitis, cranial arteritis, CREST syndrome, Crohn's disease (two IBD), Cusshing's syndrome, skin leukocyte destructive vasculitis, Dego's disease, Dercum's disease, herpetiform dermatitis, dermatomyositis, type 1 diabetes, diffuse skin systemic sclerosis, Dressler's Syndrome, drug-induced lupus, discoid lupus erythematosus, eczema, endometriosis, enthesitis-related arthritis, eosinophilic fasciitis, eosinophilic gastroenteritis, acquired bullous Epidermolysis, erythema nodosa, fetal polycythemia, primary mixed cryoglobulinemia, Evan's syndrome, progressive muscular ossification, fibrotic alveolitis (or idiopathic pulmonary Fibrosis), gastritis, gastrointestinal pemphigoid, glomerulonephritis, Goodpast syndrome, Graves disease, Guillain-Barre syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, Henoch-Schonlein purpura, Herpes pregnancy (also known as pemphigoid gestationis), hidradenitis suppurativa, Hughes-Stovin syndrome, hypogammaglobulinemia, idiopathic inflammatory demyelinating disease, idiopathic pulmonary fibrosis, idiopathic Thrombocytopenic purpura, IgA nephropathy, inclusion body myositis, chronic inflammatory demyelinating polyneuropathy, interstitial cystitis, juvenile idiopathic arthritis (also known as juvenile rheumatoid arthritis), Kawasaki's disease, Lambert-Eaton Myasthenia syndrome, leukocytic fragmentation vasculitis, lichen planus, lichen sclerosus, linear IgA disease, lupus-like hepatitis (also known as autoimmune hepatitis), lupus erythematosus, Majeed syndrome, Meniere's disease, microscopic polyangiitis, mixed Connective tissue disease, morphea, acute lichenpox and pityriasis, multiple sclerosis, myasthenia gravis, myositis, polysomnia, optic neuromyelitis, neuromuscular rigidity, eye epileptic pemphigoid, strabismus Ocular myoclonus syndrome, Ord's thyroiditis, reticular rheumatism, PANDAS (and Streptococcus-related pediatric autoimmune neuropsychiatric disorders), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry Romberg syndrome, Parsonage-Turner syndrome, flat noncyclitis, pemphigus vulgaris, Pernicious anemia, perivenous encephalomyelitis, POEMS syndrome, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, primary biliary cirrhosis, primary sclerosing cholangitis, progressive inflammation Neuropathy, psoriasis, psoriatic arthritis, pyoderma gangrenosum, pure red blood cell dysplasia, Rasmussen encephalitis, Raynaud's phenomenon, relapsing polychondritis, Wright syndrome, restless legs syndrome, retroperitoneum Fibrosis, rheumatoid arthritis, rheumatic fever, sarcoidosis, schizophrenia, Schmidt syndrome (another form of APS), Schneitzler syndrome, scleritis, scleroderma, serum sickness, Sjogren syndrome, spondyloarthritis, stiff man syndrome, subacute bacterial endocarditis, Susac's syndrome, Sweet's syndrome, sympathetic ophthalmia, systemic lupus erythematosus, Takayasu's arteritis, giant cell arteritis, platelet Decrease, Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis (one of the two idiopathic bowel diseases IBD), undifferentiated connective tissue disease different from mixed connective tissue disease, undifferentiated spinal joints Disease, urticaria vasculitis, vasculitis, vitiligo and Wegener’s granulomatosis.
术语“炎性失调”是指于炎症相关的病例状态，通常由白细胞浸润引起。炎性失调可能是急性或慢性的。示例性的炎症失调包括炎性皮肤疾病，包括但不限于牛皮癣和特应性皮炎，***性硬皮病和硬化症，与炎性肠病(IBD)相关的反应(如克罗恩病和溃疡性结肠炎)；缺血性再灌注失调，包括手术组织再灌注损伤，心肌缺血病症如心肌梗塞、心动停止、心脏手术后的再灌注和经皮腔内冠状动脉血管成型术后的缩窄、中风和腹部主动脉瘤，继发于中风的脑水肿，颅外伤，低血容性休克，窒息，成人呼吸窘迫综合症、急性肺损伤、***、皮肌炎、多肌炎、多发性硬化症、皮炎、脑膜炎、脑炎、葡萄膜炎、骨关节炎、狼疮性肾炎、自身免疫疾病如类风湿性关节炎、Sjogren’s综合症、脉管炎、涉及白细胞渗出的疾病、中枢神经***炎症性失调、继发于白血病或外伤的多器官损伤综合症、酒精性肝炎、细菌性肺炎、抗原-抗体复合物介导的疾病包括肾小球炎、败血症、结节病。对组织或器官移植的免疫病理性反应，肺的炎症，包括胸膜炎、肺泡炎、脉管炎、肺炎、慢性支气管炎、支气管扩张、弥漫性全细支气管炎、超敏性肺炎、特发性肺纤维化(IPF)和囊性纤维化等。The term "inflammatory disorder" refers to a case state related to inflammation, usually caused by leukocyte infiltration. Inflammatory disorders may be acute or chronic. Exemplary inflammatory disorders include inflammatory skin diseases, including but not limited to psoriasis and atopic dermatitis, systemic scleroderma and sclerosis, and reactions related to inflammatory bowel disease (IBD) (such as Crohn’s disease and ulcers) Colitis); ischemic reperfusion disorders, including surgical tissue reperfusion injury, myocardial ischemic conditions such as myocardial infarction, cardiac arrest, reperfusion after cardiac surgery, and coarctation after percutaneous transluminal coronary angioplasty , Stroke and abdominal aortic aneurysm, cerebral edema secondary to stroke, cranial trauma, hypovolemic shock, asphyxia, adult respiratory distress syndrome, acute lung injury, Behcet’s disease, dermatomyositis, polymyositis, Multiple sclerosis, dermatitis, meningitis, encephalitis, uveitis, osteoarthritis, lupus nephritis, autoimmune diseases such as rheumatoid arthritis, Sjogren's syndrome, vasculitis, diseases involving the exudation of white blood cells, Central nervous system inflammatory disorders, multiple organ injury syndrome secondary to leukemia or trauma, alcoholic hepatitis, bacterial pneumonia, and antigen-antibody complex-mediated diseases include glomerulitis, sepsis, and sarcoidosis. Immunopathological reaction to tissue or organ transplantation, inflammation of the lungs, including pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, hypersensitivity pneumonia, idiopathic lung Fibrosis (IPF) and cystic fibrosis, etc.
术语“于肥胖相关的代谢并发症”通常是指由于肥胖引起的代谢并发症，通常称为代谢综合症，该综合症的特征在于血浆脂质失调(致动脉粥样化血脂异常)，升高的血压、升高的血浆葡萄糖和血栓形成前状态。该代谢综合症的临床后果是例如冠心病和中风、II型糖尿病以及并发症、脂肪肝和胆固醇性胆结石。The term "obesity-related metabolic complications" generally refers to metabolic complications caused by obesity, commonly referred to as metabolic syndrome, which is characterized by plasma lipid imbalance (atherogenic dyslipidemia), elevated Blood pressure, elevated plasma glucose, and prethrombotic state. The clinical consequences of this metabolic syndrome are, for example, coronary heart disease and stroke, type II diabetes and complications, fatty liver and cholesterol gallstones.
非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。Unless otherwise stated, the following definitions used in this article shall apply. For the purpose of the present invention, the chemical elements are consistent with the CAS version of the Periodic Table of Elements, and "Handbook of Chemistry and Physics", 75th Edition, 1994. In addition, the general principles of organic chemistry can refer to the description in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007 , The entire contents of which are incorporated herein by reference.
在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural parts and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left.
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C 1-C 6烷基是指具有总共1、2、3、4、5或6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。 Certain chemical groups defined herein are preceded by simplified symbols to indicate the total number of carbon atoms present in the group. For example, C 1 -C 6 alkyl refers to alkyl groups having a total of 5 or 6 carbon atoms as defined below. The total number of carbon atoms in the simplified notation does not include the carbons that may be present in the substituents of the group.
在本文中，取代基中定义的数值范围如0至4、1-4、1至3等表明该范围内的整数，如1-6为1、2、3、4、5、6。In this context, the numerical range defined in the substituents, such as 0 to 4, 1-4, 1 to 3, etc., indicates an integer within the range, for example, 1-6 is 1, 2, 3, 4, 5, 6.
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则 以下术语具有如下所示的含义。In addition to the foregoing, when used in the specification and claims of this application, unless otherwise specified, the following terms have the following meanings.
术语“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。The term "including" is an open-ended expression, that is, includes the content specified in the present invention, but does not exclude other aspects.
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by substituents, including deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable .
一般而言，术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。进一步地，当该基团被1个以上所述取代基取代时，所述取代基之间是相互独立，即，所述的1个以上的取代基可以是互不相同的，也可以是相同的。除非其他方面表明，一个取代基团可以在被取代基团的各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。Generally speaking, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Further, when the group is substituted by one or more of the substituents, the substituents are independent of each other, that is, the one or more substituents may be different from each other or the same of. Unless otherwise indicated, a substituent group can be substituted at each substitutable position of the substituted group. When more than one position in the given structural formula can be substituted by one or more substituents selected from specific groups, then the substituents can be substituted at each position with the same or different ones.
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1～C 6烷基”或“C 1- 6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基；“C 1- 4烷基”特指独立公开的甲基、乙基、C 3烷基(即丙基，包括正丙基和异丙基)、C 4烷基(即丁基，包括正丁基、异丁基、仲丁基和叔丁基)。 In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the group type or scope. In particular, the present invention includes each independent sub-combination of each member of these group types and ranges. For example, the term "C 1 ~ C 6 alkyl" or "C 1 - 6 alkyl" refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl group; "C 1 - 4 alkyl" refers specifically disclosed independently methyl, ethyl, C 3 alkyl (i.e. propyl, including n-propyl and isopropyl), C 4 alkyl (i.e. butyl, comprising N-butyl, isobutyl, sec-butyl and tert-butyl).
术语“卤素”选自于F，Cl，Br或I，尤其指F或Cl。The term "halogen" is selected from F, Cl, Br or I, especially F or Cl.
在本申请中，作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中)，术语“烷基”(通式C nH 2n+1)意指包括具有指定碳原子数目的支链和直链的饱和脂族烃基；例如，C 1-C 16的烷基。如在“C 1～C 6烷基”中定义为包括在直链或者支链结构中具有1、2、3、4、5、或者6个碳原子的基团。其中，丙基为C 3烷基(包括同分异构体，例如正丙基或异丙基)；丁基为C 4烷基(包括同分异构体，例如正丁基、仲丁基、异丁基或叔丁基)；戊基为C 5烷基(包括同分异构体，例如正戊基、1-甲基-丁基、1-乙基-丙基、2-甲基-1-丁基、3-甲基-1-丁基、异戊基、叔戊基或新戊基)；己基为C 6烷基(包括同分异构体，例如正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基)。此外，庚基为C 7烷基(包括同分异构体，例如正庚基、2，4-二甲基戊基、2，2-二甲基戊基、3，3-二甲基戊基、2-乙基戊基、3-乙基戊基)。辛基为C 8烷基(包括同分异构体，例如正辛基、2，3-二甲基己基、2，4-二甲基己基、2，5-二甲基己基、2，2-二甲基己基、3，3-二甲基己基、4，4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基)。壬基为C 9烷基(包括同分异构体，例 如正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2，2-二乙基戊基)。奎基为C 10烷基(包括同分异构体，例如正奎基、3，3-二乙基己基、2，2-二乙基己基)。在某一实施方案中，所述的“烷基”优选含有1至6个碳原子的直链或支链的烷基。在某一实施方案中，所述的“烷基”是指C 1-C 6烷基。在某一实施方案中，所述的“烷基”是指C 1-C 4烷基。 In this application, as a group or part of another group (for example, used in halogen-substituted alkyl groups and the like), the term "alkyl" (general formula C n H 2n+1 ) means to include Branched and straight chain saturated aliphatic hydrocarbon groups with the number of carbon atoms; for example, C 1 -C 16 alkyl groups. As defined in "C 1 -C 6 alkyl", it includes groups having 1, 2, 3, 4, 5, or 6 carbon atoms in a linear or branched structure. Among them, propyl is C 3 alkyl (including isomers, such as n-propyl or isopropyl); butyl is C 4 alkyl (including isomers, such as n-butyl, sec-butyl) , Isobutyl or tert-butyl); pentyl is C 5 alkyl (including isomers, such as n-pentyl, 1-methyl-butyl, 1-ethyl-propyl, 2-methyl -1-butyl, 3-methyl-1-butyl, isopentyl, tert-pentyl or neopentyl); hexyl is C 6 alkyl (including isomers, such as n-hexyl, 1-ethyl 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl , 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl). In addition, heptyl is C 7 alkyl (including isomers, such as n-heptyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl Group, 2-ethylpentyl, 3-ethylpentyl). Octyl is C 8 alkyl (including isomers, such as n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2 -Dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethyl Pentyl, 2-methyl-3-ethylpentyl). Nonyl is C 9 alkyl (including isomers, such as n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl base). Quinyl is a C10 alkyl group (including isomers such as n-quinyl, 3,3-diethylhexyl, and 2,2-diethylhexyl). In a certain embodiment, the "alkyl" is preferably a linear or branched alkyl group containing 1 to 6 carbon atoms. In a certain embodiment, the "alkyl" refers to a C 1 -C 6 alkyl group. In a certain embodiment, the "alkyl" refers to a C 1 -C 4 alkyl group.
在本申请中，作为基团或是其它基团的一部分，除非另有规定，术语“环烷基”意指仅由碳原子和氢原子组成的饱和的单环、多环或者桥接碳环取代基，且其可经由任何适宜的碳原子通过单键与分子的其余部分连接；当为多环时，可为并环连接或螺环连接(即，碳原子上的两个偕氢被亚烷基取代)的桥环体系或螺环体系。环烷基取代基可以经任何适宜的碳原子连接在中心分子上。在一些实施例中，具有3-16个碳原子的环可以表示为C 3-C 16环烷基。在一些实施例中，C 3～C 6的环烷基包括环丙基(C 3)、环丁基(C 4)、环戊基(C 5)及环己基(C 6)。在一些实施例中，C 3～C 10的环烷基的实例包括上述C 3～C 6环烷基基团连同环庚基(C 7)、环辛基(C 8)、环壬基(C 9)及环癸基(C 10)。 In this application, as a group or part of another group, unless otherwise specified, the term "cycloalkyl" means a saturated monocyclic, polycyclic or bridged carbocyclic substitution consisting of only carbon atoms and hydrogen atoms Group, and it can be connected to the rest of the molecule through a single bond via any suitable carbon atom; when it is a polycyclic ring, it can be a fused ring connection or a spiro ring connection (that is, the two geminal hydrogens on the carbon atom are alkylene Group substitution) bridged ring system or spiro ring system. The cycloalkyl substituent can be attached to the central molecule via any suitable carbon atom. In some embodiments, a ring having 3-16 carbon atoms can be represented as a C 3 -C 16 cycloalkyl group. In some embodiments, the C 3 to C 6 cycloalkyl group includes cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopentyl (C 5 ), and cyclohexyl (C 6 ). In some embodiments, examples of C 3 ～C 10 cycloalkyl groups include the above-mentioned C 3 ～C 6 cycloalkyl groups together with cycloheptyl (C 7 ), cyclooctyl (C 8 ), cyclononyl ( C 9 ) and cyclodecyl (C 10 ).
在本申请中，作为基团或是其它基团的一部分，术语“杂环烷基”意指由2-6个碳原子(优选2-5个碳原子)以及1-4个选自氮、氧和硫的杂原子组成的稳定的3元至7元饱和环状基团。示例性3-元杂环基基团包括但不限于，氮杂环丙基、环氧乙烷基以及硫杂环丙烷基，或者其立体异构体；示例性4-元杂环基基团包括但不限于，氮杂环丁烷基，环氧丙烷基，硫杂环丁烷基，或者其同分异构体和立体异构体；示例性5-元杂环基基团包括但不限于，四氢呋喃基，四氢噻吩基，吡咯烷基，噻唑烷基，异噻唑烷基，噁唑烷基，异噁唑烷基，咪唑烷基，吡唑烷基，二氧戊环基，氧杂硫呋喃基，二硫呋喃基，或者其同分异构体和立体异构体。示例性6-元杂环基基团包括但不限于，哌啶基，四氢吡喃基，硫化环戊烷基，吗啉基，硫代吗啉基，二噻烷基，二噁烷基，哌嗪基，三嗪烷基，或者其同分异构体和立体异构体；示例性7-元杂环基基团包括但不限于，氮杂环庚烷基，氧杂环庚烷基，硫杂环庚烷基，以及二氮杂环庚基，或者其同分异构体和立体异构体。在某一方案中，“杂环烷基”为C 3～C 5杂环烷基，其中杂原子选自N、O和S中的一种或多种，杂原子数为1、2或3个。 In this application, as a group or part of other groups, the term "heterocycloalkyl" means 2-6 carbon atoms (preferably 2-5 carbon atoms) and 1-4 selected from nitrogen, A stable 3- to 7-membered saturated cyclic group composed of oxygen and sulfur heteroatoms. Exemplary 3-membered heterocyclyl groups include, but are not limited to, aziridinyl, oxiranyl, and thiolanyl, or stereoisomers thereof; exemplary 4-membered heterocyclic groups Including, but not limited to, azetidinyl, propylene oxide, thietane, or isomers and stereoisomers thereof; exemplary 5-membered heterocyclyl groups include but not Limited to tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, imidazolidinyl, pyrazolidinyl, dioxolane, oxygen Heterothiofuranyl, dithiofuranyl, or its isomers and stereoisomers. Exemplary 6-membered heterocyclyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, cyclopentanyl sulfide, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl , Piperazinyl, triazinyl, or its isomers and stereoisomers; exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxepane Group, thiepanyl, and diazacycloheptyl, or its isomers and stereoisomers. In a certain embodiment, "heterocycloalkyl" is C 3 ～C 5 heterocycloalkyl, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, or 3. A.
在本申请中，作为基团或是其它基团的一部分，术语“芳基”是指具有6-14个环原子以及提供在芳香族环***中的零个杂原子单环的或多环的(例如，二环的或三环的)4n+2芳香族环***(例如，在循环阵列中具有6，10，或14个共享的p电子)的基团(“C 6-C 14芳基”)。上述芳基单元的实例包括苯基、萘基、菲基、或者蒽基。 In this application, as a group or part of another group, the term "aryl" refers to a monocyclic or polycyclic group having 6-14 ring atoms and zero heteroatoms provided in the aromatic ring system (E.g., bicyclic or tricyclic) groups of 4n+2 aromatic ring systems (e.g., having 6, 10, or 14 shared p electrons in a cyclic array) ("C 6 -C 14 aryl "). Examples of the aforementioned aryl unit include phenyl, naphthyl, phenanthryl, or anthracenyl.
在本申请中，作为基团或是其它基团的一部分，术语“杂芳基”是指具有碳原子以及提供在该芳香族环***中的1-3个杂原子(其中每个杂原子独立地选自氮、氧以及硫)的4- 16元单环的或二环的4n+2芳香族环***(例如，在循环阵列中具有6或10个共享的p电子)的基团(“4-16元杂芳基”)。在包含一个或多个氮原子的杂芳基基团中，连接点可以是碳或氮原子，只要化合价允许。In this application, as a group or part of other groups, the term "heteroaryl" refers to having carbon atoms and 1-3 heteroatoms provided in the aromatic ring system (where each heteroatom is independent 4n+2 aromatic ring system (for example, having 6 or 10 shared p-electrons in a cyclic array) of 4--16 membered monocyclic or bicyclic 4n+2 aromatic ring system (" 4-16 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as long as the valence allows.
在一些实施例中，所述的杂芳基为杂原子选自N、O和S中的一种或多种，杂原子数为1-4个的5-10元杂芳基。在一些实施例中，所述的杂芳基为杂原子选自N、O和S中的一种或多种，杂原子数为1～3个的4-6元杂芳基，较佳地为5-6元杂芳基。In some embodiments, the heteroaryl group is one or more heteroatoms selected from N, O, and S, and the number of heteroatoms is 5-10 membered heteroaryl groups. In some embodiments, the heteroaryl group is one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 4-6 membered heteroaryl groups, preferably It is a 5-6 membered heteroaryl group.
示例性5-元杂芳基基团包括但不限于：吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、三氮唑基、噁二唑基、噻二唑基、呋咱基、噁***基或四唑基。示例性6-元杂芳基基团包括但不限于：吡啶基、吡嗪基、哒嗪基、嘧啶基、三嗪基或四嗪基。Exemplary 5-membered heteroaryl groups include, but are not limited to: pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazole Group, oxadiazolyl, thiadiazolyl, furazanyl, oxtriazolyl or tetrazolyl. Exemplary 6-membered heteroaryl groups include, but are not limited to: pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, or tetrazinyl.
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。The terms "part", "structural part", "chemical moiety", "group", and "chemical group" as used herein refer to specific fragments or functional groups in a molecule. The chemical moiety is generally considered to be a chemical entity embedded or attached to a molecule.
当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时，这种取代基可以通过其任何原子相键合。取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When the listed substituents do not indicate through which atom they are connected to the compounds included in the general formula of the chemical structure but are not specifically mentioned, such substituents may be bonded through any of its atoms. Combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
当所列举的基团中没有明确指明其具有取代基时，这种基团仅指未被取代。例如当“C 1～C 4烷基”前没有“取代或未取代的”的限定时，仅指“C 1～C 4烷基”本身或“未取代的C 1～C 4烷基”。 When the listed group does not clearly indicate that it has a substituent, such a group only refers to unsubstituted. For example, when there is no limitation of "substituted or unsubstituted" before "C 1 -C 4 alkyl", only "C 1 -C 4 alkyl" itself or "unsubstituted C 1 -C 4 alkyl" is meant.
在本发明的各部分，描述了连接取代基。当该结构清楚地需要连接基团时，针对该基团所列举的马库什变量应理解为连接基团。例如，如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”，则应该理解，该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。In each part of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for the group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition of the variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represents the attached Alkylene group or arylene group.
在一些具体的结构中，当烷基基团清楚地表示为连接基团时，则该烷基基团代表连接的亚烷基基团，例如，基团“卤代-C 1～C 6烷基”中的C 1-C 6烷基应当理解为C 1～C 6亚烷基。 In some specific structures, when an alkyl group is clearly expressed as a linking group, the alkyl group represents a linked alkylene group, for example, the group "halo-C 1 ～C 6 alkane The C 1 -C 6 alkyl group in "radical" should be understood as a C 1 -C 6 alkylene group.
术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团。亚烷基基团的实例包括亚甲基(-CH 2-)，亚乙基{包括-CH 2CH 2-或-CH(CH 3)-}，亚异丙基{包括-CH(CH 3)CH 2-或-C(CH 3) 2-}等等。 The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated linear or branched hydrocarbon group. Examples of alkylene groups include methylene (-CH 2 -), ethylene {including -CH 2 CH 2 -or -CH(CH 3 )-}, isopropylene {including -CH(CH 3 )CH 2 -or -C(CH 3 ) 2 -} and so on.
除非另有规定，本文使用的所有技术术语和科学术语具有要求保护主题所属领域的标准含义。倘若对于某术语存在多个定义，则以本文定义为准。Unless otherwise specified, all technical and scientific terms used herein have standard meanings in the field of the claimed subject matter. If there are multiple definitions for a term, the definition herein shall prevail.
应该理解，在本发明中使用的单数形式，如“一种”，包括复数指代，除非另有规定。 此外，术语“包括”是开放性限定并非封闭式，即包括本发明所指明的内容，但并不排除其他方面的内容。It should be understood that the singular form used in the present invention, such as "a", includes plural designations, unless otherwise specified. In addition, the term "including" is open-ended and not closed-ended, that is, includes the content specified in the present invention, but does not exclude other aspects of content.
除非另有说明，本发明采用质谱、元素分析的传统方法，各步骤和条件可参照本领域常规的操作步骤和条件。Unless otherwise specified, the present invention adopts traditional methods of mass spectrometry and elemental analysis, and the steps and conditions can refer to the conventional operating steps and conditions in the art.
除非另有指明，本发明采用分析化学、有机合成化学和光学的标准命名及标准实验室步骤和技术。在某些情况下，标准技术被用于化学合成、化学分析、发光器件性能检测。Unless otherwise specified, the present invention adopts standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“…独立地为”应做广义理解，是指所描述的各个个体之间是相互独立的，可以独立地为相同或不同的具体基团。更详细地，描述方式“…独立地为”既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响；也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。In addition, it should be noted that, unless explicitly pointed out in other ways, the description "...independently" used in the present invention should be understood in a broad sense, which means that the described individuals are independent of each other and can be independent. Ground is the same or different specific groups. In more detail, the description "...independently is" can mean that in different groups, the specific options expressed between the same symbols do not affect each other; it can also mean that in the same group, the same symbols are different. The specific options expressed in each do not affect each other.
本领域技术人员可以理解，根据本领域中使用的惯例，本申请描述基团的结构式中所使用的
Figure PCTCN2020116696-appb-000111
是指，相应的基团通过该位点与化合物中的其它片段、基团进行连接。 Those skilled in the art can understand that according to the conventions used in the art, the structural formula of the group described in this application is used
Figure PCTCN2020116696-appb-000111
It means that the corresponding group is connected to other fragments and groups in the compound through this site.
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
本发明的积极进步效果在于：本发明提供的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐具有较好的肿瘤抑制活性，特别是对人慢性淋巴细胞白血病、肺腺癌、乳腺癌、卵巢癌、乳腺癌或者胰腺癌；且对耐药的乳腺癌、肺癌、卵巢癌或白血病都有较好的抑制活性。The positive and progressive effect of the present invention is that the heteroaryl compound as shown in formula I, its tautomers, stereoisomers or pharmaceutically acceptable salts provided by the present invention have good tumor suppressive activity, Especially for human chronic lymphocytic leukemia, lung adenocarcinoma, breast cancer, ovarian cancer, breast cancer or pancreatic cancer; and have good inhibitory activity on drug-resistant breast cancer, lung cancer, ovarian cancer or leukemia.
具体实施方式detailed description
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The present invention will be further described by way of examples below, but the present invention is not limited to the scope of the described examples. The experimental methods without specific conditions in the following examples are selected in accordance with conventional methods and conditions, or in accordance with the product specification.
所有化合物，试剂以及溶剂都从商业购买，使用均没有进一步纯化除非特别说明。All compounds, reagents and solvents were purchased commercially, and were used without further purification unless otherwise specified.
缩写解释：Abbreviation explanation:
ACN：乙腈；DCE：1,2-二氯乙烷；DCM：二氯甲烷；DIPEA：N,N-二异丙基乙胺；DMF：N,N-二甲基甲酰胺；DMSO：二甲亚砜；EtOAc：乙酸乙酯；EtOH：乙醇；ESI： 电喷雾质谱；HPLC：高效液相色谱；iPrOH：异丙醇；MeOH：甲醇；MS：质谱；NCS：N-氯代琥珀酰亚胺；NMR：核磁共振；TFA：三氟乙酸；MTBE：甲基叔丁基醚；eq.：等当量。ACN: Acetonitrile; DCE: 1,2-Dichloroethane; DCM: Dichloromethane; DIPEA: N,N-Diisopropylethylamine; DMF: N,N-Dimethylformamide; DMSO: Dimethyl Sulfoxide; EtOAc: ethyl acetate; EtOH: ethanol; ESI: electrospray mass spectrometry; HPLC: high performance liquid chromatography; iPrOH: isopropanol; MeOH: methanol; MS: mass spectrometry; NCS: N-chlorosuccinimide ; NMR: nuclear magnetic resonance; TFA: trifluoroacetic acid; MTBE: methyl tert-butyl ether; eq.: equivalent weight.
1H NMR数据报道均包括溶剂信息，以以下形式报道：化学位移(δppm)，多重性，耦合常数和积分。多重性的表述：s,单峰；d,双重峰；t,三重峰；q,四重峰；m,多重峰；br,宽峰.所有 1H NMR均采集于Bruker spectrometer at frequencies of 400MHz,溶剂为氘代氯仿或者氘代二氯亚砜.质谱采集于Waters ACQUITY UPLC/Xevo G2 QTOF SYSTEM.液相色谱采集于Agilent 1290 Infinity LC System. 1 H NMR data reports include solvent information, reported in the following forms: chemical shift (δ ppm), multiplicity, coupling constant, and integral. Expression of multiplicity: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak. All 1 H NMR are collected in Bruker spectrometer at frequencies of 400MHz, The solvent is deuterated chloroform or deuterated thionyl chloride. Mass spectrometry was collected from Waters ACQUITY UPLC/Xevo G2 QTOF SYSTEM. Liquid chromatography was collected from Agilent 1290 Infinity LC System.
中间体1:2-(4-甲酰基苯氧基)-氮-甲基乙酰胺Intermediate 1: 2-(4-Formylphenoxy)-nitrogen-methylacetamide
Figure PCTCN2020116696-appb-000112
Figure PCTCN2020116696-appb-000112
通用方法A:于碳酸钾(20.6g,2eq)和2-氯-氮-甲基乙酰胺(8g,1eq)的乙腈(100ml)悬浊液中加入4-甲醛苯酚(9.8g,1.1eq)，混合液在60℃下搅拌12小时。反应液然后冷却到室温，之后浓缩除去绝大部分溶剂。残渣加入二氯甲烷(100ml)，然后过滤，将滤液浓缩，然后用硅胶柱分离纯化，洗脱液(乙酸乙酯：正庚烷＝3:2)，得到白色固体化合物2-(4-甲酰基苯氧基)-氮-甲基乙酰胺(I-1,12g,83％)。General method A: Add 4-formaldehyde phenol (9.8g, 1.1eq) to a suspension of potassium carbonate (20.6g, 2eq) and 2-chloro-nitrogen-methylacetamide (8g, 1eq) in acetonitrile (100ml) , The mixture was stirred at 60°C for 12 hours. The reaction solution was then cooled to room temperature, and then concentrated to remove most of the solvent. The residue was added with dichloromethane (100ml), then filtered, the filtrate was concentrated, and then separated and purified with a silica gel column. The eluent (ethyl acetate:n-heptane=3:2) gave a white solid compound 2-(4-methyl). Acylphenoxy)-nitrogen-methylacetamide (I-1, 12g, 83%).
1H NMR(400MHz,DMSO-d 6)δ9.88(s,1H),8.12(q,J＝4.7Hz,1H),7.95–7.82(m,2H),7.21–7.09(m,2H),4.61(s,2H),2.67(d,J＝4.6Hz,3H).MS:ESI( +):[M+H] +:194.1。 1 H NMR (400MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.12 (q, J = 4.7 Hz, 1H), 7.95-7.82 (m, 2H), 7.21-7.09 (m, 2H), 4.61 (s, 2H), 2.67 (d, J = 4.6 Hz, 3H). MS: ESI ( + ): [M+H] + : 194.1.
中间体2:1-(4-甲氧基苄基)哌啶-4-胺Intermediate 2: 1-(4-methoxybenzyl)piperidin-4-amine
Figure PCTCN2020116696-appb-000113
Figure PCTCN2020116696-appb-000113
通用方法B:于500ml的封管中加入4-甲氧基苯甲醛(6g,1eq)和4-(叔丁氧羰基-氨基)哌啶(10g,1eq)，然后加入二氯乙烷(100ml)溶液，最后缓慢加入NaBH(OAc) 3(17g,1.5eq)，反应液在室温下搅拌12小时。反应完全后，用饱和碳酸氢钠溶液(100ml)淬灭反应，混合液继续搅拌10分钟，然后用二氯甲烷(150ml)稀释。将有机相分离，依次用饱和碳酸氢钠水溶液，饱和食盐水洗涤，最后用无水硫酸钠干燥，过滤，浓缩得到黄色油状粗品。 General method B: Add 4-methoxybenzaldehyde (6g, 1eq) and 4-(tert-butoxycarbonyl-amino)piperidine (10g, 1eq) to a 500ml sealed tube, then add dichloroethane (100ml ) Solution, and finally NaBH(OAc) 3 (17g, 1.5eq) was slowly added, and the reaction solution was stirred at room temperature for 12 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate solution (100ml), the mixture was stirred for 10 minutes, and then diluted with dichloromethane (150ml). The organic phase was separated, washed with saturated aqueous sodium bicarbonate solution and saturated brine in turn, and finally dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude yellow oily product.
上述粗品溶于二氯甲烷(100ml)，然后加入盐酸/异丙醇溶液(5N,10ml)。混合液在室温下搅拌2小时，然后浓缩，残渣用甲基叔丁基醚打浆，然后过滤得到目标产物的盐 酸盐。将盐酸盐溶于水，用10％碳酸钠水溶液中和，调至pH＝8，水相用二氯甲烷萃取，二氯甲烷溶液浓缩得到油状目标产物I-2(1-(4-甲氧基苄基)哌啶-4-胺(8g,83％))。The above crude product was dissolved in dichloromethane (100ml), and then hydrochloric acid/isopropanol solution (5N, 10ml) was added. The mixture was stirred at room temperature for 2 hours, then concentrated, the residue was slurried with methyl tert-butyl ether, and then filtered to obtain the hydrochloride of the target product. The hydrochloride was dissolved in water, neutralized with a 10% sodium carbonate aqueous solution, adjusted to pH=8, the aqueous phase was extracted with dichloromethane, and the dichloromethane solution was concentrated to obtain the oily target product I-2(1-(4-methyl (Oxybenzyl)piperidin-4-amine (8g, 83%)).
1H NMR(400MHz,DMSO-d 6)δ7.22–7.13(m,2H),6.90–6.82(m,2H),3.72(s,3H),3.35(s,2H),2.75(ddt,J＝11.4,6.9,3.9Hz,3H),1.90(td,J＝11.8,2.4Hz,2H),1.80–1.66(m,2H),1.37(qd,J＝11.8,3.8Hz,2H)；MS:ESI(+)[M+H] +:221.2. 1 H NMR(400MHz,DMSO-d 6 )δ7.22-7.13(m,2H), 6.90-6.82(m,2H), 3.72(s,3H), 3.35(s,2H), 2.75(ddt,J = 11.4, 6.9, 3.9 Hz, 3H), 1.90 (td, J = 11.8, 2.4 Hz, 2H), 1.80-1.66 (m, 2H), 1.37 (qd, J = 11.8, 3.8 Hz, 2H); MS: ESI(+)[M+H] + :221.2.
中间体3:4,5-二氯-3-硝基吡啶-2-胺Intermediate 3: 4,5-Dichloro-3-nitropyridin-2-amine
Figure PCTCN2020116696-appb-000114
Figure PCTCN2020116696-appb-000114
4,5-二氯吡啶-2-胺(5g,31mmol)分成小量多次的加入浓硫酸(30ml)维持内部温度小于30℃。反应液用冰浴冷却到5℃，然后缓慢滴加发烟硝酸(3g)，反应液在冰浴中搅拌3小时。然后将反应液倒入冰水混合物(200ml)，继续搅拌10分钟至冰完全融化，过滤，滤饼用冰水(100ml)打浆，过滤，水洗至中性(pH＝7)。滤饼溶于乙酸乙酯，然后有机相用饱和食盐水洗涤，用无水硫酸钠干燥，过滤，浓缩干燥得5g固体。4,5-Dichloropyridin-2-amine (5g, 31mmol) was divided into small portions and concentrated sulfuric acid (30ml) was added to maintain the internal temperature below 30°C. The reaction solution was cooled to 5°C with an ice bath, and then fuming nitric acid (3g) was slowly added dropwise, and the reaction solution was stirred in the ice bath for 3 hours. Then the reaction solution was poured into an ice-water mixture (200ml), stirring was continued for 10 minutes until the ice was completely melted, filtered, the filter cake was slurried with ice water (100ml), filtered, and washed with water to neutral (pH=7). The filter cake was dissolved in ethyl acetate, and then the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and dried to obtain 5 g of solid.
上述固体于室温下溶于浓硫酸(50ml)，然后升温至40℃并继续搅拌2.5小时。然后冷却到室温，倒入冰水混合物(200g)并持续搅拌，至冰完全融化，黄色悬浊液过滤，用冰水洗涤至中性(pH＝7)。固体溶于乙酸乙酯，然后依次用氢氧化钠水溶液(0.5N)，饱和食盐水洗涤，用无水硫酸钠干燥，过滤，浓缩干燥得目标化合物I-3(4,5-二氯-3-硝基吡啶-2-胺3.5g(70％)).The above solid was dissolved in concentrated sulfuric acid (50ml) at room temperature, then the temperature was raised to 40°C and stirring was continued for 2.5 hours. Then it was cooled to room temperature, poured into an ice-water mixture (200 g) and continued stirring until the ice was completely melted, the yellow suspension was filtered, and washed with ice water until it was neutral (pH=7). The solid was dissolved in ethyl acetate, then washed with sodium hydroxide aqueous solution (0.5N), saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and dried to obtain the target compound I-3 (4,5-dichloro-3 -Nitropyridine-2-amine 3.5g (70%)).
1H NMR(400MHz,DMSO-d 6)δ8.39(s,1H),7.40(s,2H).MS:ESI(+):[M+H] +:208.0。 1 H NMR (400MHz, DMSO-d 6 ) δ 8.39 (s, 1H), 7.40 (s, 2H). MS: ESI (+): [M+H] + : 208.0.
中间体4:5-氯-N 4-(1-(4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺 Intermediate 4: 5-Chloro-N 4 -(1-(4-methoxybenzyl)piperidin-4-yl)-3-nitropyridine-2,4-diamine
Figure PCTCN2020116696-appb-000115
Figure PCTCN2020116696-appb-000115
通用方法C:于1-(4-甲氧基苄基)哌啶-4-胺(I-2,5g,1eq)和4,5-二氯-3-硝基吡啶-2-胺(I-3,4.8g,1eq)的异丙醇(30ml)悬浊液中加入DIPEA(13ml,3eq),混合液在70℃下搅拌12h.然后冷却到室温，悬浊液过滤，然后用少量异丙醇冲洗，拉干滤饼溶剂，真空干燥得到黄色目标化合物5-氯-N 4-(1-(4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-4, 5.8g,65％)。 General method C: in 1-(4-methoxybenzyl) piperidin-4-amine (I-2,5g, 1eq) and 4,5-dichloro-3-nitropyridin-2-amine (I -3,4.8g, 1eq) isopropanol (30ml) suspension was added DIPEA (13ml, 3eq), the mixture was stirred at 70 ℃ for 12h. Then cooled to room temperature, the suspension was filtered, and then a small amount of isopropyl alcohol Rinse with propanol, pull dry the filter cake solvent, and dry in vacuo to obtain the yellow target compound 5-chloro-N 4 -(1-(4-methoxybenzyl)piperidin-4-yl)-3-nitropyridine-2 ,4-Diamine (I-4, 5.8g, 65%).
1H NMR(400MHz,DMSO-d 6)δ8.45(s,2H),7.56–7.48(m,2H),7.03–6.98(m,2H),4.17(d,J＝4.8Hz,2H),3.78(s,3H),3.22(s,1H),2.96(q,J＝11.7Hz,2H),2.14–2.07(m,2H),1.97(q,J＝14.8,13.6Hz,2H).MS:ESI(+):[M+H] +:392.2。 1 H NMR(400MHz,DMSO-d 6 )δ8.45(s,2H), 7.56–7.48(m,2H), 7.03–6.98(m,2H), 4.17(d,J=4.8Hz,2H), 3.78 (s, 3H), 3.22 (s, 1H), 2.96 (q, J = 11.7 Hz, 2H), 2.14-2.07 (m, 2H), 1.97 (q, J = 14.8, 13.6 Hz, 2H). MS :ESI(+):[M+H] + :392.2.
中间体9:1-((6-甲氧基吡啶-3-基)亚甲基)哌啶-4-胺Intermediate 9: 1-((6-methoxypyridin-3-yl)methylene)piperidin-4-amine
Figure PCTCN2020116696-appb-000116
Figure PCTCN2020116696-appb-000116
通用方法B:相关化合物6-甲氧基尼古丁甲醛(1eq)，4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq)。General Method B: Related compounds 6-methoxynicotine formaldehyde (1eq), 4-(tert-butoxycarbonyl-amino)piperidine (1eq) and sodium triacetylborohydride (1.5eq).
1H NMR(400MHz,DMSO-d 6)δ8.01(d,J＝2.4Hz,1H),7.59(dd,J＝8.5,2.4Hz,1H),6.77(d,J＝8.4Hz,1H),3.83(s,3H),3.37(s,2H),2.76–2.57(m,3H),1.92(td,J＝11.7,2.5Hz,2H),1.77–1.63(m,2H),1.37–1.22(m,2H).MS:ESI(+):[M+H] +:222.2。 1 H NMR(400MHz,DMSO-d 6 )δ8.01(d,J=2.4Hz,1H), 7.59(dd,J=8.5,2.4Hz,1H), 6.77(d,J=8.4Hz,1H) ,3.83(s,3H),3.37(s,2H),2.76-2.57(m,3H),1.92(td,J=11.7,2.5Hz,2H),1.77-1.63(m,2H),1.37-1.22 (m,2H).MS:ESI(+):[M+H] + :222.2.
中间体10:1-((5-甲氧基吡啶-2-基)亚甲基)哌啶-4-胺Intermediate 10: 1-((5-methoxypyridin-2-yl)methylene)piperidin-4-amine
Figure PCTCN2020116696-appb-000117
Figure PCTCN2020116696-appb-000117
通用方法B:相关化合物5-甲氧基尼古丁甲醛(1eq)，4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq).General method B: Related compounds 5-methoxynicotine formaldehyde (1eq), 4-(tert-butoxycarbonyl-amino)piperidine (1eq) and sodium triacetylborohydride (1.5eq).
1H NMR(400MHz,DMSO-d 6)δ8.38(d,J＝3.0Hz,1H),7.77(d,J＝8.6Hz,1H),7.58(dd,J＝8.7,3.0Hz,1H),4.35(s,2H),3.52–3.39(m,2H),3.30(s,1H),3.13(t,J＝11.8Hz,2H),2.22-1.93(m,4H)；MS:ESI(+):[M+H] +:222.1。 1 H NMR(400MHz,DMSO-d 6 )δ8.38(d,J=3.0Hz,1H), 7.77(d,J=8.6Hz,1H), 7.58(dd,J=8.7,3.0Hz,1H) ,4.35(s,2H),3.52–3.39(m,2H),3.30(s,1H),3.13(t,J=11.8Hz,2H),2.22-1.93(m,4H); MS: ESI(+ ):[M+H] + :222.1.
中间体11:1-(4-(三甲基硅烷基)苄基)哌啶-4-胺Intermediate 11: 1-(4-(Trimethylsilyl)benzyl)piperidin-4-amine
Figure PCTCN2020116696-appb-000118
Figure PCTCN2020116696-appb-000118
通用方法B:相关化合物4-(三甲基硅烷基)苯甲醛(1eq)，4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq)。General Method B: Related compounds 4-(trimethylsilyl)benzaldehyde (1eq), 4-(tert-butoxycarbonyl-amino)piperidine (1eq) and sodium triacetylborohydride (1.5eq).
1H NMR(400MHz,DMSO-d 6)δ7.60(s,4H),4.22(d,J＝5.1Hz,2H),3.23(s,1H),3.00(q,J＝11.7Hz,2H),2.03(dt,J＝37.2,14.1Hz,5H),0.26(s,9H).MS:ESI(+):[M+H] +:263.2。 1 H NMR(400MHz,DMSO-d 6 )δ7.60(s,4H), 4.22(d,J=5.1Hz,2H), 3.23(s,1H), 3.00(q,J=11.7Hz,2H) , 2.03 (dt, J = 37.2, 14.1 Hz, 5H), 0.26 (s, 9H). MS: ESI (+): [M+H] + : 263.2.
中间体12:1-(2,5-二氟-4-甲氧基苄基)哌啶-4-胺Intermediate 12: 1-(2,5-difluoro-4-methoxybenzyl)piperidin-4-amine
Figure PCTCN2020116696-appb-000119
Figure PCTCN2020116696-appb-000119
通用方法B:相关化合物2,5-二氟-4-甲氧基苯甲醛(1eq)，4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq)。General method B: Related compounds 2,5-difluoro-4-methoxybenzaldehyde (1eq), 4-(tert-butoxycarbonyl-amino)piperidine (1eq) and sodium triacetylborohydride (1.5eq) .
1H NMR(400MHz,DMSO-d 6)δ7.75(dd,J＝11.8,6.9Hz,1H),7.25(dd,J＝11.3,7.3Hz,1H),4.20(d,J＝3.6Hz,2H),3.88(s,4H),3.26(s,2H),3.06(q,J＝12.4,11.7Hz,2H),2.23–1.91(m,5H).MS:ESI(+):[M+H] +:257.2。 1 H NMR(400MHz,DMSO-d 6 )δ7.75(dd,J=11.8,6.9Hz,1H), 7.25(dd,J=11.3,7.3Hz,1H), 4.20(d,J=3.6Hz, 2H), 3.88(s, 4H), 3.26(s, 2H), 3.06(q,J=12.4,11.7Hz,2H),2.23-1.91(m,5H).MS:ESI(+):[M+ H] + : 257.2.
中间体13:1-(2-氟-4-甲氧基苄基)哌啶-4-胺Intermediate 13: 1-(2-Fluoro-4-methoxybenzyl)piperidin-4-amine
Figure PCTCN2020116696-appb-000120
Figure PCTCN2020116696-appb-000120
通用方法B:相关化合物2-氟-4-甲氧基苯甲醛(1eq)，4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq)。General Method B: Related compounds 2-fluoro-4-methoxybenzaldehyde (1eq), 4-(tert-butoxycarbonyl-amino)piperidine (1eq) and sodium triacetylborohydride (1.5eq).
1H NMR(400MHz,DMSO-d 6)δ8.51(d,J＝5.0Hz,2H),7.59(dd,J＝12.2,2.0Hz,1H),7.38(dt,J＝8.6,1.4Hz,1H),7.23(t,J＝8.7Hz,1H),4.19(d,J＝4.7Hz,2H),3.86(s,3H),3.22(s,1H),2.99(q,J＝11.7Hz,2H),2.22–1.90(m,5H).MS:ESI(+):[M+H] +:239.2。 1 H NMR(400MHz,DMSO-d 6 )δ8.51(d,J=5.0Hz,2H), 7.59(dd,J=12.2,2.0Hz,1H), 7.38(dt,J=8.6,1.4Hz, 1H), 7.23 (t, J = 8.7Hz, 1H), 4.19 (d, J = 4.7Hz, 2H), 3.86 (s, 3H), 3.22 (s, 1H), 2.99 (q, J = 11.7Hz, 2H),2.22–1.90(m,5H).MS:ESI(+):[M+H] + :239.2.
中间体14:1-(2,5-二氟苄基)哌啶-4-胺Intermediate 14: 1-(2,5-difluorobenzyl)piperidin-4-amine
Figure PCTCN2020116696-appb-000121
Figure PCTCN2020116696-appb-000121
通用方法B:相关化合物2,5-二氟苯甲醛(1eq)，4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq)。General Method B: Related compounds 2,5-difluorobenzaldehyde (1eq), 4-(tert-butoxycarbonyl-amino)piperidine (1eq) and sodium triacetylborohydride (1.5eq).
1H NMR(400MHz,DMSO-d 6)δ8.50(d,J＝5.1Hz,2H),7.79(dd,J＝8.8,5.4Hz,1H),7.40(td,J＝6.3,1.8Hz,2H),4.28(d,J＝4.2Hz,2H),3.27(s,1H),3.11(q,J＝11.6Hz,2H),2.16–1.98(m,4H).MS:ESI(+):[M+H] +:227.2。 1 H NMR(400MHz,DMSO-d 6 )δ8.50(d,J=5.1Hz,2H), 7.79(dd,J=8.8,5.4Hz,1H), 7.40(td,J=6.3,1.8Hz, 2H), 4.28(d,J=4.2Hz,2H), 3.27(s,1H), 3.11(q,J=11.6Hz,2H), 2.16–1.98(m,4H).MS:ESI(+): [M+H] + :227.2.
中间体15:1-(3-氟-4-甲氧基苄基)哌啶-4-胺Intermediate 15: 1-(3-Fluoro-4-methoxybenzyl)piperidin-4-amine
Figure PCTCN2020116696-appb-000122
Figure PCTCN2020116696-appb-000122
通用方法B:相关化合物3-氟-4-甲氧基苯甲醛(1eq)，4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq).General Method B: Related compounds 3-fluoro-4-methoxybenzaldehyde (1eq), 4-(tert-butoxycarbonyl-amino)piperidine (1eq) and sodium triacetylborohydride (1.5eq).
1H NMR(400MHz,DMSO-d 6)δ8.13(d,J＝1.0Hz,1H),7.97(s,1H),7.73(d,J＝8.5Hz,1H),7.65(dd,J＝8.7,1.5Hz,1H),4.35(d,J＝4.9Hz,2H),4.07(s,3H),3.21(d,J＝13.1Hz,1H),3.00(q,J＝11.2Hz,2H),2.10(d,J＝14.5Hz,2H),1.99(td,J＝14.0,13.3,6.8Hz,2H).MS:ESI(+):[M+H] +:239.2。 1 H NMR(400MHz,DMSO-d 6 )δ8.13(d,J=1.0Hz,1H), 7.97(s,1H), 7.73(d,J=8.5Hz,1H), 7.65(dd,J= 8.7, 1.5 Hz, 1H), 4.35 (d, J = 4.9 Hz, 2H), 4.07 (s, 3H), 3.21 (d, J = 13.1 Hz, 1H), 3.00 (q, J = 11.2 Hz, 2H) , 2.10 (d, J=14.5 Hz, 2H), 1.99 (td, J=14.0, 13.3, 6.8 Hz, 2H). MS: ESI (+): [M+H] + : 239.2.
中间体16:1-(3,5-二氟-4-甲氧基苄基)哌啶-4-胺Intermediate 16: 1-(3,5-difluoro-4-methoxybenzyl)piperidin-4-amine
Figure PCTCN2020116696-appb-000123
Figure PCTCN2020116696-appb-000123
通用方法B:相关化合物3,5-二氟-4-甲氧基苯甲醛(1eq)，4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq)。General Method B: Related compounds 3,5-difluoro-4-methoxybenzaldehyde (1eq), 4-(tert-butoxycarbonyl-amino)piperidine (1eq) and sodium triacetylborohydride (1.5eq) .
1H NMR(400MHz,DMSO-d 6)δ8.49–8.43(m,2H),7.51(d,J＝8.8Hz,2H),4.22(d,J＝4.6Hz,2H),3.96(s,3H),3.37(d,J＝12.3Hz,2H),3.22(d,J＝13.6Hz,2H),3.08–2.90(m,2H),2.19–1.96(m,4H).MS:ESI(+):[M+H] +:257.2。 1 H NMR(400MHz,DMSO-d 6 )δ8.49–8.43(m,2H), 7.51(d,J=8.8Hz,2H), 4.22(d,J=4.6Hz,2H), 3.96(s, 3H), 3.37(d,J=12.3Hz,2H),3.22(d,J=13.6Hz,2H),3.08–2.90(m,2H),2.19–1.96(m,4H).MS:ESI(+ ):[M+H] + :257.2.
中间体17:1-(2,4-二氟苄基)哌啶-4-胺Intermediate 17: 1-(2,4-difluorobenzyl)piperidin-4-amine
Figure PCTCN2020116696-appb-000124
Figure PCTCN2020116696-appb-000124
通用方法B:相关化合物2,4-二氟苯甲醛(1eq)，4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq)。General method B: Related compounds 2,4-difluorobenzaldehyde (1eq), 4-(tert-butoxycarbonyl-amino)piperidine (1eq) and sodium triacetylborohydride (1.5eq).
1H NMR(400MHz,DMSO-d 6)δ8.48(d,J＝5.4Hz,2H),7.88(td,J＝8.6,6.5Hz,1H),7.40(td,J＝9.8,2.6Hz,1H),7.23(td,J＝8.5,2.6Hz,1H),4.27(d,J＝3.8Hz,2H),3.42(d,J＝12.3Hz,2H),3.27(d,J＝13.4Hz,1H),3.13–3.01(m,2H),2.12(d,J＝13.3Hz,2H),2.00(qd,J＝13.3,4.0Hz,2H).MS:ESI(+):[M+H] +:227.2。 1 H NMR(400MHz,DMSO-d 6 )δ8.48(d,J=5.4Hz,2H), 7.88(td,J=8.6,6.5Hz,1H), 7.40(td,J=9.8,2.6Hz, 1H), 7.23 (td, J = 8.5, 2.6 Hz, 1H), 4.27 (d, J = 3.8 Hz, 2H), 3.42 (d, J = 12.3 Hz, 2H), 3.27 (d, J = 13.4 Hz, 1H),3.13-3.01(m,2H),2.12(d,J=13.3Hz,2H),2.00(qd,J=13.3,4.0Hz,2H).MS:ESI(+):[M+H] + : 227.2.
中间体18:1-((4-甲氧基苯基)磺酰基)哌啶-4-胺Intermediate 18: 1-((4-methoxyphenyl)sulfonyl)piperidin-4-amine
Figure PCTCN2020116696-appb-000125
Figure PCTCN2020116696-appb-000125
于4-(叔丁氧羰基-氨基)哌啶(1eq)的二氯甲烷溶液中加入4-甲氧基苯磺酰氯(1eq),然后加入三乙胺(2eq),混合液在室温下搅拌20小时，然后用水淬灭反应，分离有机相。有机相中加入盐酸异丙醇溶液(4eq)并在室温下搅拌3小时，然后加入碳酸钠水溶液(10％w/w)，并搅拌20分钟，至pH～8。分离有机相，然后用无水硫酸钠干燥，过滤，浓缩得到白色目标化合物。Add 4-methoxybenzenesulfonyl chloride (1eq) to the dichloromethane solution of 4-(tert-butoxycarbonyl-amino)piperidine (1eq), then add triethylamine (2eq), and the mixture is stirred at room temperature After 20 hours, the reaction was quenched with water and the organic phase was separated. The organic phase was added with isopropanol hydrochloride solution (4eq) and stirred at room temperature for 3 hours, and then sodium carbonate aqueous solution (10% w/w) was added and stirred for 20 minutes to pH-8. The organic phase was separated, then dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the white target compound.
1H NMR(400MHz,DMSO-d 6)δ7.68–7.64(m,2H),7.17–7.13(m,2H),3.86(s,3H),3.41(dd,J＝10.8,4.6Hz,3H),2.42–2.31(m,2H),1.79–1.66(m,2H),1.40(q,J＝10.4,9.8Hz,1H),1.24(tdd,J＝13.4,10.1,3.9Hz,2H).MS:ESI(+):[M+H] +:271.2。 1 H NMR(400MHz,DMSO-d 6 )δ7.68–7.64(m,2H), 7.17–7.13(m,2H), 3.86(s,3H), 3.41(dd,J=10.8,4.6Hz,3H ), 2.42–2.31 (m, 2H), 1.79–1.66 (m, 2H), 1.40 (q, J = 10.4, 9.8 Hz, 1H), 1.24 (tdd, J = 13.4, 10.1, 3.9 Hz, 2H). MS: ESI(+): [M+H] + : 271.2.
中间体19:1-(环丙基磺酰基)哌啶-4-胺Intermediate 19: 1-(cyclopropylsulfonyl)piperidin-4-amine
Figure PCTCN2020116696-appb-000126
Figure PCTCN2020116696-appb-000126
参照I-18合成:相关化合物：环丙基磺酰氯,4-(叔丁氧羰基-氨基)哌啶和三乙胺。Refer to I-18 Synthesis: Related compounds: cyclopropylsulfonyl chloride, 4-(tert-butoxycarbonyl-amino)piperidine and triethylamine.
1H NMR(400MHz,DMSO-d 6)δ8.39(d,J＝5.1Hz,2H),3.63(dt,J＝13.3,3.7Hz,2H),3.17(ddp,J＝16.1,10.6,6.1,5.1Hz,1H),2.91(td,J＝12.3,2.5Hz,2H),2.57(tt,J＝7.9,4.8Hz,1H),2.06–1.95(m,2H),1.61(qd,J＝12.0,4.2Hz,2H),1.04–0.95(m,2H),0.95–0.88(m,2H).MS:ESI(+):[M+H] +:205.1。 1 H NMR (400MHz, DMSO-d 6 ) δ 8.39 (d, J = 5.1 Hz, 2H), 3.63 (dt, J = 13.3, 3.7 Hz, 2H), 3.17 (ddp, J = 16.1, 10.6, 6.1 ,5.1Hz,1H),2.91(td,J=12.3,2.5Hz,2H), 2.57(tt,J=7.9,4.8Hz,1H),2.06–1.95(m,2H),1.61(qd,J= 12.0, 4.2 Hz, 2H), 1.04–0.95 (m, 2H), 0.95–0.88 (m, 2H). MS: ESI(+): [M+H] + : 205.1.
中间体20:1-((1-甲基-1氢-吲哚氮唑-5-基)亚甲基)哌啶-4-胺Intermediate 20: 1-((1-methyl-1hydro-indoleazol-5-yl)methylene)piperidin-4-amine
Figure PCTCN2020116696-appb-000127
Figure PCTCN2020116696-appb-000127
通用方法B:相关化合物1-甲基-1氢-吲哚氮唑-5-甲醛(1eq)，4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq).General Method B: Related compounds 1-methyl-1hydro-indoleazole-5-carbaldehyde (1eq), 4-(tert-butoxycarbonyl-amino)piperidine (1eq) and sodium triacetylborohydride (1.5 eq).
1H NMR(400MHz,DMSO-d 6)δ8.41(s,2H),8.13(d,J＝1.0Hz,1H),7.97(s,1H),7.73(d,J＝8.5Hz,1H),7.65(dd,J＝8.7,1.5Hz,1H),4.35(d,J＝4.9Hz,2H),4.07(s,3H),3.21(d,J＝13.1Hz,1H),3.00(q,J＝11.2Hz,2H),2.10(d,J＝14.5Hz,2H),1.99(td,J＝14.0,13.3,6.8Hz,2H).MS:ESI(+):[M+H] +:245.2 1 H NMR(400MHz,DMSO-d 6 )δ8.41(s,2H),8.13(d,J=1.0Hz,1H),7.97(s,1H),7.73(d,J=8.5Hz,1H) ,7.65(dd,J=8.7,1.5Hz,1H), 4.35(d,J=4.9Hz,2H),4.07(s,3H),3.21(d,J=13.1Hz,1H), 3.00(q, J＝11.2Hz,2H), 2.10(d,J＝14.5Hz,2H),1.99(td,J＝14.0,13.3,6.8Hz,2H).MS:ESI(+):[M+H] + : 245.2
中间体21:1-(苯并呋喃-5-基亚甲基)哌啶-4-胺Intermediate 21: 1-(benzofuran-5-ylmethylene)piperidin-4-amine
Figure PCTCN2020116696-appb-000128
Figure PCTCN2020116696-appb-000128
通用方法B:相关化合物苯并呋喃-5-甲醛(1eq)，4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq).General Method B: Related compounds benzofuran-5-carbaldehyde (1eq), 4-(tert-butoxycarbonyl-amino)piperidine (1eq) and sodium triacetylborohydride (1.5eq).
1H NMR(400MHz,DMSO-d 6)δ8.08(d,J＝2.2Hz,1H),7.91(d,J＝1.8Hz,1H),7.69(d,J＝8.4Hz,1H),7.57(dd,J＝8.5,1.8Hz,1H),7.04(dd,J＝2.2,0.9Hz,1H),4.34(d,J＝4.9Hz,2H),3.40(s,1H),3.23(s,2H),3.02(q,J＝11.6Hz,2H),2.11(d,J＝13.9Hz,2H),2.00(tt,J＝13.1,6.7Hz,2H).MS:ESI(+):[M+H] +:231.2。 1 H NMR(400MHz,DMSO-d 6 )δ8.08(d,J=2.2Hz,1H), 7.91(d,J=1.8Hz,1H), 7.69(d,J=8.4Hz,1H), 7.57 (dd,J=8.5,1.8Hz,1H), 7.04(dd,J=2.2,0.9Hz,1H), 4.34(d,J=4.9Hz,2H), 3.40(s,1H), 3.23(s, 2H),3.02(q,J=11.6Hz,2H),2.11(d,J=13.9Hz,2H),2.00(tt,J=13.1,6.7Hz,2H).MS:ESI(+):[M +H] + : 231.2.
中间体22:N-(4-((4-氨哌啶-1-基)亚甲基)苯基)-N-甲基甲基磺酰胺Intermediate 22: N-(4-((4-aminopiperidin-1-yl)methylene)phenyl)-N-methylmethylsulfonamide
Figure PCTCN2020116696-appb-000129
Figure PCTCN2020116696-appb-000129
通用方法B:相关化合物N-(4-甲酰基苯基)-N-甲基甲基磺酰胺(1eq)，4-(叔丁氧羰基-氨基)哌啶(1eq)和三乙酰基硼氢化钠(1.5eq).General method B: Related compounds N-(4-formylphenyl)-N-methylmethylsulfonamide (1eq), 4-(tert-butoxycarbonyl-amino)piperidine (1eq) and triacetyl borohydride Sodium (1.5eq).
1H NMR(400MHz,DMSO-d 6)δ8.44(d,J＝5.3Hz,2H),7.67(dd,J＝9.1,2.6Hz,2H),7.50-7.46(m,2H),4.24(d,J＝5.0Hz,2H),3.35(s,1H),3.26(s,5H),2.98(s,5H),2.16-2.09(m,2H),2.07-1.93(m,2H).MS:ESI(+):[M+H] +:298.2。 1 H NMR (400MHz, DMSO-d 6 ) δ8.44 (d, J = 5.3 Hz, 2H), 7.67 (dd, J = 9.1, 2.6 Hz, 2H), 7.50-7.46 (m, 2H), 4.24 ( d, J=5.0Hz, 2H), 3.35(s, 1H), 3.26(s, 5H), 2.98(s, 5H), 2.16-2.09(m, 2H), 2.07-1.93(m, 2H).MS :ESI(+):[M+H] + :298.2.
中间体23:N 1-(4-甲氧基苄基)-N1-亚甲基乙烷-1,2-二胺 Intermediate 23: N 1 -(4-methoxybenzyl)-N1-methyleneethane-1,2-diamine
Figure PCTCN2020116696-appb-000130
Figure PCTCN2020116696-appb-000130
通用方法B:相关化合物4-甲氧基苯甲醛(1eq)，叔丁氧羰基(2-(甲基胺)乙基)(1eq)和三乙酰基硼氢化钠(1.5eq).General Method B: Related compounds 4-methoxybenzaldehyde (1eq), tert-butoxycarbonyl (2-(methylamine)ethyl) (1eq) and sodium triacetylborohydride (1.5eq).
1H NMR(400MHz,DMSO-d 6)δ8.56–8.50(m,2H),7.64–7.51(m,2H),7.04–6.96(m,2H),4.32(d,J＝37.7Hz,2H),3.78(s,3H),3.38(s,4H),2.67(s,3H).MS:ESI(+):[M+H] +:195.2。 1 H NMR(400MHz,DMSO-d 6 )δ8.56–8.50(m,2H), 7.64–7.51(m,2H), 7.04–6.96(m,2H), 4.32(d,J=37.7Hz,2H ), 3.78(s, 3H), 3.38(s, 4H), 2.67(s, 3H). MS: ESI(+): [M+H] + : 195.2.
中间体24:1-(甲基磺酰基)哌啶-4-胺Intermediate 24: 1-(methylsulfonyl)piperidin-4-amine
Figure PCTCN2020116696-appb-000131
Figure PCTCN2020116696-appb-000131
参照I-18合成:相关化合物：4-(叔丁氧羰基-氨基)哌啶(1eq)，甲基磺酰氯(1eq)和三乙胺(2eq)。Refer to I-18 synthesis: Related compounds: 4-(tert-butoxycarbonyl-amino)piperidine (1eq), methylsulfonyl chloride (1eq) and triethylamine (2eq).
1H NMR(400MHz,Chloroform-d)δ4.47(s,1H),3.75(d,J＝12.0Hz,2H),3.57(s,1H),2.78(s,5H),2.12–1.99(m,2H),1.56–1.46(m,2H).MS:ESI(+):[M+H] +:179.1。 1 H NMR (400MHz, Chloroform-d) δ 4.47 (s, 1H), 3.75 (d, J = 12.0 Hz, 2H), 3.57 (s, 1H), 2.78 (s, 5H), 2.12-1.99 (m ,2H),1.56–1.46(m,2H).MS:ESI(+):[M+H] + :179.1.
中间体25:4-氯-3-氟-2-硝基苯胺Intermediate 25: 4-chloro-3-fluoro-2-nitroaniline
Figure PCTCN2020116696-appb-000132
Figure PCTCN2020116696-appb-000132
于3-氟-2-硝基苯胺(1g,6.4mmol,1eq)的乙腈(10ml)溶液中加入NCS(1.3g,1.5eq),反应液在50℃下搅拌5小时。反应液浓缩，然后用硅胶柱分离纯化，用乙酸乙酯/正庚 烷(1:4)洗脱，浓缩干燥得到棕色固体4-氯-3-氟-2-硝基苯胺I-25(0.2g,17％),以及6-氯-3-氟-2-硝基苯胺I-26(0.28g,23％).NCS (1.3g, 1.5eq) was added to a solution of 3-fluoro-2-nitroaniline (1g, 6.4mmol, 1eq) in acetonitrile (10ml), and the reaction solution was stirred at 50°C for 5 hours. The reaction solution was concentrated, then separated and purified with a silica gel column, eluted with ethyl acetate/n-heptane (1:4), concentrated and dried to obtain a brown solid 4-chloro-3-fluoro-2-nitroaniline I-25 (0.2 g, 17%), and 6-chloro-3-fluoro-2-nitroaniline I-26 (0.28g, 23%).
1H NMR(400MHz,DMSO-d 6)δ7.65(dd,J＝8.8,5.4Hz,1H),6.84(s,2H),6.70(dd,J＝11.0,8.8Hz,1H)；MS:ESI(+)[M+1] +191.0。 1 H NMR (400MHz, DMSO-d 6 ) δ 7.65 (dd, J = 8.8, 5.4 Hz, 1H), 6.84 (s, 2H), 6.70 (dd, J = 11.0, 8.8 Hz, 1H); MS: ESI(+)[M+1] + 191.0.
中间体26:6-氯-3-氟-2-硝基苯胺Intermediate 26: 6-chloro-3-fluoro-2-nitroaniline
Figure PCTCN2020116696-appb-000133
Figure PCTCN2020116696-appb-000133
参照化合物I-25.Refer to compound I-25.
1H NMR(400MHz,Chloroform-d)δ7.30(dd,J＝9.2,7.2Hz,1H),6.56(dd,J＝9.2,2.1Hz,1H)；MS:ESI(+)[M+1] +191.0。 1 H NMR(400MHz,Chloroform-d)δ7.30(dd,J＝9.2,7.2Hz,1H), 6.56(dd,J＝9.2,2.1Hz,1H); MS: ESI(+)[M+1 ] + 191.0.
中间体27:5-氯-N 4-(1-((6-甲氧基吡啶-3-基)亚甲基)哌啶-4-基)-3-硝基吡啶-2,4-二胺 Intermediate 27: 5-Chloro-N 4 -(1-((6-methoxypyridin-3-yl)methylene)piperidin-4-yl)-3-nitropyridine-2,4-di amine
Figure PCTCN2020116696-appb-000134
Figure PCTCN2020116696-appb-000134
通用方法C:相关化合物1-((6-甲氧基吡啶-3-基)亚甲基)哌啶-4-胺(I-9,1eq),4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。General method C: Related compound 1-((6-methoxypyridin-3-yl)methylene)piperidin-4-amine (I-9,1eq), 4,5-dichloro-3-nitro Pyridin-2-amine (I-3, 1 eq) and diisopropylethylamine (3 eq).
1H NMR(400MHz,Chloroform-d)δ8.81(d,J＝8.0Hz,1H),8.02(d,J＝2.4Hz,1H),7.81(s,1H),7.56(dd,J＝8.5,2.4Hz,1H),6.72(dd,J＝8.6,0.7Hz,1H),4.42–4.28(m,1H),3.93(s,3H),3.43(s,2H),2.77(d,J＝11.5Hz,2H),2.18(t,J＝11.0Hz,2H),2.04(dt,J＝12.9,4.0Hz,2H),1.61(dtd,J＝13.4,10.0,3.6Hz,3H)；MS:ESI(+)[M+1] +394.0。 1 H NMR(400MHz,Chloroform-d)δ8.81(d,J=8.0Hz,1H), 8.02(d,J=2.4Hz,1H), 7.81(s,1H), 7.56(dd,J=8.5 ,2.4Hz,1H),6.72(dd,J=8.6,0.7Hz,1H),4.42–4.28(m,1H),3.93(s,3H),3.43(s,2H),2.77(d,J= 11.5Hz, 2H), 2.18 (t, J = 11.0 Hz, 2H), 2.04 (dt, J = 12.9, 4.0 Hz, 2H), 1.61 (dtd, J = 13.4, 10.0, 3.6 Hz, 3H); MS: ESI(+)[M+1] + 394.0.
中间体28:5-氯-N 4-(1-((5-甲氧基吡啶-2-基)亚甲基)哌啶-4-基)-3-硝基吡啶-2,4-二胺 Intermediate 28: 5-Chloro-N 4 -(1-((5-methoxypyridin-2-yl)methylene)piperidin-4-yl)-3-nitropyridine-2,4-di amine
Figure PCTCN2020116696-appb-000135
Figure PCTCN2020116696-appb-000135
通用方法C:相关化合物1-((5-甲氧基吡啶-2-基)亚甲基)哌啶-4-胺(I-10,1eq)，4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。General method C: Related compound 1-((5-methoxypyridin-2-yl)methylene)piperidin-4-amine (I-10,1eq), 4,5-dichloro-3-nitro Pyridin-2-amine (I-3, 1 eq) and diisopropylethylamine (3 eq).
1H NMR(400MHz,DMSO-d 6)δ8.19(dd,J＝2.7,1.0Hz,1H),7.88(s,1H),7.77(d,J＝8.3Hz,1H),7.58(s,2H),7.35–7.34(m,1H),3.81(s,4H),3.52(s,2H),2.70(d,J＝12.4Hz,2H),2.12(t,J＝11.0Hz,2H),1.88(d,J＝12.3Hz,2H),1.55(q,J＝9.5Hz,2H)；MS:ESI(+)[M+1] +393.0。 1 H NMR(400MHz,DMSO-d 6 )δ8.19(dd,J=2.7,1.0Hz,1H),7.88(s,1H),7.77(d,J=8.3Hz,1H),7.58(s, 2H), 7.35–7.34 (m, 1H), 3.81 (s, 4H), 3.52 (s, 2H), 2.70 (d, J = 12.4 Hz, 2H), 2.12 (t, J = 11.0 Hz, 2H), 1.88 (d, J = 12.3 Hz, 2H), 1.55 (q, J = 9.5 Hz, 2H); MS: ESI (+) [M+1] + 393.0.
中间体29:5-氯-3-硝基-N 4-(1-(4-(三甲基硅烷基)苄基)哌啶-4-基)吡啶-2,4-二胺 Intermediate 29: 5-chloro-3-nitro-N 4 -(1-(4-(trimethylsilyl)benzyl)piperidin-4-yl)pyridine-2,4-diamine
Figure PCTCN2020116696-appb-000136
Figure PCTCN2020116696-appb-000136
通用方法C:相关化合物1-(4-(三甲基硅烷基)苄基)哌啶-4-胺(I-11,1eq),4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。General method C: Related compound 1-(4-(trimethylsilyl)benzyl)piperidin-4-amine (I-11, 1eq), 4,5-dichloro-3-nitropyridine-2- Amine (I-3, 1eq) and diisopropylethylamine (3eq).
1H NMR(400MHz,DMSO-d 6)δ7.87(s,1H),7.81–7.72(m,1H),7.57(s,2H),7.49–7.42(m,2H),7.27(d,J＝7.7Hz,2H),3.91–3.72(m,1H),3.44(s,2H),2.68(d,J＝11.1Hz,2H),2.06(t,J＝11.1Hz,2H),1.87(d,J＝12.3Hz,2H),1.63–1.47(m,2H),0.23(s,9H)；MS:ESI(+)[M+1] +434.0。 1 H NMR(400MHz,DMSO-d 6 )δ7.87(s,1H),7.81-7.72(m,1H),7.57(s,2H),7.49-7.42(m,2H),7.27(d,J =7.7Hz, 2H), 3.91–3.72(m, 1H), 3.44(s, 2H), 2.68(d, J = 11.1Hz, 2H), 2.06(t, J = 11.1Hz, 2H), 1.87(d , J=12.3Hz, 2H), 1.63-1.47 (m, 2H), 0.23 (s, 9H); MS: ESI(+)[M+1] + 434.0.
中间体30:5-氯-N 4-(1-(2,5-二氟-4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺 Intermediate 30: 5-chloro-N 4 -(1-(2,5-difluoro-4-methoxybenzyl)piperidin-4-yl)-3-nitropyridine-2,4-diamine
Figure PCTCN2020116696-appb-000137
Figure PCTCN2020116696-appb-000137
通用方法C:相关化合物1-(2,5-二氟-4-甲氧基苄基)哌啶-4-胺(I-12,1eq)，4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。General method C: Related compound 1-(2,5-difluoro-4-methoxybenzyl)piperidin-4-amine (I-12,1eq), 4,5-dichloro-3-nitropyridine -2-amine (I-3, 1eq) and diisopropylethylamine (3eq).
1H NMR(400MHz,DMSO-d 6)δ7.88(s,1H),7.75(d,J＝8.3Hz,1H),7.58(s,2H),7.21(dd,J＝11.8,6.9Hz,1H),7.08(dd,J＝11.3,7.3Hz,1H),3.84(s,4H),3.44(d,J＝1.5Hz,2H),2.69(d,J＝11.4Hz,2H),2.09(t,J＝10.9Hz,2H),1.88(d,J＝12.2Hz,2H),1.55(q,J＝9.8Hz,2H).MS:ESI(+)[M+1] +428.0。 1 H NMR(400MHz,DMSO-d 6 )δ7.88(s,1H), 7.75(d,J=8.3Hz,1H), 7.58(s,2H), 7.21(dd,J=11.8,6.9Hz, 1H), 7.08 (dd, J = 11.3, 7.3 Hz, 1H), 3.84 (s, 4H), 3.44 (d, J = 1.5 Hz, 2H), 2.69 (d, J = 11.4 Hz, 2H), 2.09 ( t, J = 10.9 Hz, 2H), 1.88 (d, J = 12.2 Hz, 2H), 1.55 (q, J = 9.8 Hz, 2H). MS: ESI(+)[M+1] + 428.0.
中间体31:5-氯-N 4-(1-(2-氟-4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺 Intermediate 31: 5-chloro-N 4 -(1-(2-fluoro-4-methoxybenzyl)piperidin-4-yl)-3-nitropyridine-2,4-diamine
Figure PCTCN2020116696-appb-000138
Figure PCTCN2020116696-appb-000138
通用方法C:相关化合物1-(2-氟-4-甲氧基苯基)哌啶-4-胺(I-13,1eq)，4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。General method C: Related compound 1-(2-fluoro-4-methoxyphenyl)piperidin-4-amine (I-13,1eq), 4,5-dichloro-3-nitropyridine-2- Amine (I-3, 1eq) and diisopropylethylamine (3eq).
1H NMR(400MHz,DMSO-d 6)δ7.88(s,1H),7.77(d,J＝8.4Hz,1H),7.58(s,2H),7.14–7.01(m,3H),3.82(s,4H),2.67(d,J＝10.9Hz,2H),2.05(t,J＝10.9Hz,2H),1.88(d,J＝12.2Hz,2H),1.56(t,J＝9.9Hz,2H)；MS:ESI(+)[M+1] +410.0。 1 H NMR(400MHz,DMSO-d 6 )δ7.88(s,1H), 7.77(d,J=8.4Hz,1H), 7.58(s,2H), 7.14-7.01(m,3H), 3.82( s, 4H), 2.67 (d, J = 10.9 Hz, 2H), 2.05 (t, J = 10.9 Hz, 2H), 1.88 (d, J = 12.2 Hz, 2H), 1.56 (t, J = 9.9 Hz, 2H); MS: ESI(+)[M+1] + 410.0.
中间体32:5-氯-N 4-(1-(2,5-二氟苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺 Intermediate 32: 5-Chloro-N 4 -(1-(2,5-difluorobenzyl)piperidin-4-yl)-3-nitropyridine-2,4-diamine
Figure PCTCN2020116696-appb-000139
Figure PCTCN2020116696-appb-000139
通用方法C:相关化合物1-(2,5-二氟苄基)哌啶-4-胺(I-14,1eq)，4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。General method C: Related compound 1-(2,5-difluorobenzyl)piperidin-4-amine (I-14,1eq), 4,5-dichloro-3-nitropyridin-2-amine (I -3,1eq) and diisopropylethylamine (3eq).
1H NMR(400MHz,DMSO-d 6)δ7.88(s,1H),7.75(d,J＝8.4Hz,1H),7.57(s,2H),7.23(dq,J＝9.1,4.3Hz,2H),7.15(td,J＝8.8,8.2,4.2Hz,1H),3.83(s,1H),3.52(s,2H),2.71(d,J＝11.0Hz,2H),2.14(t,J＝11.0Hz,2H),1.89(d,J＝12.4Hz,2H),1.59(dd,J＝12.3,8.9Hz,2H).MS:ESI(+)[M+1] +398.0。 1 H NMR(400MHz,DMSO-d 6 )δ7.88(s,1H), 7.75(d,J=8.4Hz,1H), 7.57(s,2H), 7.23(dq,J=9.1,4.3Hz, 2H), 7.15 (td, J = 8.8, 8.2, 4.2 Hz, 1H), 3.83 (s, 1H), 3.52 (s, 2H), 2.71 (d, J = 11.0 Hz, 2H), 2.14 (t, J = 11.0 Hz, 2H), 1.89 (d, J = 12.4 Hz, 2H), 1.59 (dd, J = 12.3, 8.9 Hz, 2H). MS: ESI(+) [M+1] + 398.0.
中间体33:5-氯-N 4-(1-(3-氟-4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺 Intermediate 33: 5-chloro-N 4 -(1-(3-fluoro-4-methoxybenzyl)piperidin-4-yl)-3-nitropyridine-2,4-diamine
Figure PCTCN2020116696-appb-000140
Figure PCTCN2020116696-appb-000140
通用方法C:相关化合物1-(3-氟-4-甲氧基苯基)哌啶-4-胺(I-15,1eq)，4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。General method C: Related compound 1-(3-fluoro-4-methoxyphenyl)piperidin-4-amine (I-15,1eq), 4,5-dichloro-3-nitropyridine-2- Amine (I-3, 1eq) and diisopropylethylamine (3eq).
1H NMR(400MHz,DMSO-d 6)δ7.88(s,1H),7.77(d,J＝8.4Hz,1H),7.58(s,2H),7.15–7.01(m,3H),3.82(s,4H),3.39(s,2H),2.67(d,J＝11.2Hz,2H),2.05(t,J＝10.5Hz,2H),1.88(d,J＝12.3Hz,2H),1.63–1.47(m,2H)；MS:ESI(+)[M+1] +410.0。 1 H NMR(400MHz,DMSO-d 6 )δ7.88(s,1H),7.77(d,J=8.4Hz,1H),7.58(s,2H),7.15-7.01(m,3H),3.82( s, 4H), 3.39 (s, 2H), 2.67 (d, J = 11.2 Hz, 2H), 2.05 (t, J = 10.5 Hz, 2H), 1.88 (d, J = 12.3 Hz, 2H), 1.63- 1.47(m, 2H); MS: ESI(+)[M+1] + 410.0.
中间体34:5-氯-N 4-(1-(3,5-二氟-4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺 Intermediate 34: 5-chloro-N 4 -(1-(3,5-difluoro-4-methoxybenzyl)piperidin-4-yl)-3-nitropyridine-2,4-diamine
Figure PCTCN2020116696-appb-000141
Figure PCTCN2020116696-appb-000141
通用方法C:相关化合物1-(3,5-二氟-4-甲氧基苄基)哌啶-4-胺(I-16,1eq)，4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。General method C: Related compound 1-(3,5-difluoro-4-methoxybenzyl)piperidin-4-amine (I-16,1eq), 4,5-dichloro-3-nitropyridine -2-amine (I-3, 1eq) and diisopropylethylamine (3eq).
1H NMR(400MHz,Chloroform-d)δ8.81(d,J＝8.0Hz,1H),7.81(s,1H),6.91–6.84(m,2H),6.78(s,2H),4.44–4.28(m,1H),3.98(d,J＝1.0Hz,3H),2.76(d,J＝11.7Hz,2H),2.19(t,J＝11.1Hz,2H),2.11–1.97(m,2H),1.68–1.61(m,2H).MS:ESI(+)[M+1] +428.0。 1 H NMR (400MHz, Chloroform-d) δ 8.81 (d, J = 8.0Hz, 1H), 7.81 (s, 1H), 6.91-6.84 (m, 2H), 6.78 (s, 2H), 4.44-4.28 (m, 1H), 3.98 (d, J = 1.0 Hz, 3H), 2.76 (d, J = 11.7 Hz, 2H), 2.19 (t, J = 11.1 Hz, 2H), 2.11-1.97 (m, 2H) ,1.68–1.61(m,2H).MS:ESI(+)[M+1] + 428.0.
中间体35:5-氯-N 4-(1-(2,4-二氟苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺 Intermediate 35: 5-chloro-N 4 -(1-(2,4-difluorobenzyl)piperidin-4-yl)-3-nitropyridine-2,4-diamine
Figure PCTCN2020116696-appb-000142
Figure PCTCN2020116696-appb-000142
通用方法C:相关化合物1-(2,4-二氟苄基)哌啶-4-胺(I-17,1eq)，4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。General method C: Related compound 1-(2,4-difluorobenzyl)piperidin-4-amine (I-17,1eq), 4,5-dichloro-3-nitropyridin-2-amine (I -3,1eq) and diisopropylethylamine (3eq).
1H NMR(400MHz,DMSO-d 6)δ7.88(s,1H),7.75(d,J＝8.3Hz,1H),7.57(s,2H),7.43(td,J＝8.6,6.8Hz,1H),7.24–7.14(m,1H),7.09–7.02(m,1H),3.87–3.76(m,1H),3.49(s,2H),2.69(d,J＝11.7Hz,2H),2.11(t,J＝11.1Hz,2H),1.88(d,J＝12.3Hz,2H),1.61–1.47(m,2H).MS:ESI(+)[M+1] +398.0。 1 H NMR(400MHz,DMSO-d 6 )δ7.88(s,1H),7.75(d,J=8.3Hz,1H),7.57(s,2H),7.43(td,J=8.6,6.8Hz, 1H), 7.24–7.14(m,1H), 7.09–7.02(m,1H), 3.87–3.76(m,1H), 3.49(s,2H), 2.69(d,J=11.7Hz,2H), 2.11 (t, J = 11.1 Hz, 2H), 1.88 (d, J = 12.3 Hz, 2H), 1.61-1.47 (m, 2H). MS: ESI(+)[M+1] + 398.0.
中间体36:5-氯-N 4-(1-((4-甲氧基苄基)磺酰基)哌啶-4-基)-3-硝基吡啶-2,4-二胺 Intermediate 36: 5-Chloro-N 4 -(1-((4-methoxybenzyl)sulfonyl)piperidin-4-yl)-3-nitropyridine-2,4-diamine
Figure PCTCN2020116696-appb-000143
Figure PCTCN2020116696-appb-000143
通用方法C:相关化合物1-((4-甲氧基苯基)磺酰基)哌啶-4-胺(I-18,1eq)，4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。General method C: Related compound 1-((4-methoxyphenyl)sulfonyl)piperidin-4-amine (I-18,1eq), 4,5-dichloro-3-nitropyridine-2- Amine (I-3, 1eq) and diisopropylethylamine (3eq).
1H NMR(400MHz,DMSO-d 6)δ7.86(s,1H),7.69–7.65(m,2H),7.57(d,J＝8.5Hz, 1H),7.53(s,2H),7.19–7.13(m,2H),4.36(d,J＝4.2Hz,1H),3.86(s,3H),3.46(d,J＝11.9Hz,2H),2.44–2.34(m,2H),1.96(d,J＝13.0Hz,2H),1.71–1.55(m,2H).MS:ESI(+)[M+1] +442.0。 1 H NMR(400MHz,DMSO-d 6 )δ7.86(s,1H), 7.69–7.65(m,2H), 7.57(d,J=8.5Hz, 1H), 7.53(s,2H), 7.19– 7.13 (m, 2H), 4.36 (d, J = 4.2 Hz, 1H), 3.86 (s, 3H), 3.46 (d, J = 11.9 Hz, 2H), 2.44-2.34 (m, 2H), 1.96 (d ,J=13.0Hz,2H),1.71-1.55(m,2H).MS:ESI(+)[M+1] + 442.0.
中间体37:5-氯-N 4-(1-(环丙基磺酰基)哌啶-4-基)-3-硝基吡啶-2,4-二胺 Intermediate 37: 5-Chloro-N 4 -(1-(cyclopropylsulfonyl)piperidin-4-yl)-3-nitropyridine-2,4-diamine
Figure PCTCN2020116696-appb-000144
Figure PCTCN2020116696-appb-000144
通用方法C:相关化合物1-(环丙基磺酰基)哌啶-4-胺(I-19,1eq)，4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。General method C: Related compound 1-(cyclopropylsulfonyl)piperidin-4-amine (I-19, 1eq), 4,5-dichloro-3-nitropyridin-2-amine (I-3, 1eq) and diisopropylethylamine (3eq).
1H NMR(400MHz,DMSO-d 6)δ7.91(s,1H),7.65(d,J＝8.5Hz,1H),7.55(s,2H),3.97–3.82(m,1H),3.55(d,J＝12.6Hz,2H),3.01–2.90(m,2H),2.64–2.54(m,1H),1.99(dd,J＝13.3,3.7Hz,2H),1.69–1.56(m,2H),1.02–0.96(m,2H),0.95–0.90(m,2H).MS:ESI(+)[M+1] +376.0。 1 H NMR(400MHz,DMSO-d 6 )δ7.91(s,1H), 7.65(d,J=8.5Hz,1H), 7.55(s,2H), 3.97–3.82(m,1H), 3.55( d, J = 12.6Hz, 2H), 3.01–2.90 (m, 2H), 2.64–2.54 (m, 1H), 1.99 (dd, J = 13.3, 3.7 Hz, 2H), 1.69–1.56 (m, 2H) ,1.02–0.96(m,2H),0.95–0.90(m,2H). MS: ESI(+)[M+1] + 376.0.
中间体38:5-氯-N 4-(1-((1-甲基-1氢-吲哚氮唑-5-基)亚甲基)哌啶-4-基)-3-硝基吡啶-2,4-二胺 Intermediate 38: 5-chloro-N 4 -(1-((1-methyl-1hydro-indoleazol-5-yl)methylene)piperidin-4-yl)-3-nitropyridine -2,4-diamine
Figure PCTCN2020116696-appb-000145
Figure PCTCN2020116696-appb-000145
通用方法C:相关化合物1-((1-甲基-1氢-吲哚氮唑-5-基)亚甲基)哌啶-4-胺(I-20,1eq)，4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。General method C: Related compound 1-((1-methyl-1hydro-indoleazol-5-yl)methylene)piperidin-4-amine (I-20,1eq), 4,5-di Chloro-3-nitropyridin-2-amine (I-3, 1 eq) and diisopropylethylamine (3 eq).
1H NMR(400MHz,Chloroform-d)δ8.82(d,J＝7.9Hz,1H),7.93(d,J＝0.9Hz,1H),7.80(s,1H),7.61(s,1H),7.42–7.32(m,2H),6.79(s,2H),4.44–4.27(m,1H),4.07(s,3H),3.61(s,2H),2.81(d,J＝11.8Hz,2H),2.28–2.13(m,2H),2.10–1.98(m,2H),1.67–1.59(m,2H).MS:ESI(+)[M+1] +416.0。 1 H NMR (400MHz, Chloroform-d) δ 8.82 (d, J = 7.9 Hz, 1H), 7.93 (d, J = 0.9 Hz, 1H), 7.80 (s, 1H), 7.61 (s, 1H), 7.42–7.32(m,2H),6.79(s,2H),4.44–4.27(m,1H),4.07(s,3H),3.61(s,2H),2.81(d,J=11.8Hz,2H) ,2.28–2.13(m,2H),2.10–1.98(m,2H),1.67–1.59(m,2H).MS:ESI(+)[M+1] + 416.0.
中间体39:N 4-(1-(苯并呋喃-5-基亚甲基)哌啶-4-基)-5-氯-3-硝基吡啶-2,4-二胺 Intermediate 39: N 4 -(1-(benzofuran-5-ylmethylene)piperidin-4-yl)-5-chloro-3-nitropyridine-2,4-diamine
Figure PCTCN2020116696-appb-000146
Figure PCTCN2020116696-appb-000146
通用方法C:相关化合物1-(苯并呋喃-5-基亚甲基)哌啶-4-胺(I-21,1eq)，4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。General method C: Related compound 1-(benzofuran-5-ylmethylene)piperidin-4-amine (I-21,1eq), 4,5-dichloro-3-nitropyridin-2-amine (I-3, 1eq) and diisopropylethylamine (3eq).
1H NMR(400MHz,DMSO-d 6)δ7.96(d,J＝2.2Hz,1H),7.88(s,1H),7.78(d,J＝8.3Hz,1H),7.59(s,2H),7.56–7.50(m,2H),7.24(dd,J＝8.4,1.7Hz,1H),6.92(dd,J＝2.2,1.0Hz,1H),3.91–3.77(m,1H),3.54(s,2H),2.71(d,J＝11.5Hz,2H),2.09(t,J＝10.9Hz,2H),1.88(d,J＝11.9Hz,2H),1.63–1.48(m,2H).MS:ESI(+)[M+1] +402.0。 1 H NMR (400MHz, DMSO-d 6 ) δ 7.96 (d, J = 2.2 Hz, 1H), 7.88 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.59 (s, 2H) ,7.56–7.50(m,2H),7.24(dd,J=8.4,1.7Hz,1H), 6.92(dd,J=2.2,1.0Hz,1H),3.91–3.77(m,1H),3.54(s ,2H),2.71(d,J=11.5Hz,2H),2.09(t,J=10.9Hz,2H),1.88(d,J=11.9Hz,2H),1.63-1.48(m,2H).MS :ESI(+)[M+1] + 402.0.
中间体40:N-(4-((4-((2-氨-5-氯-3-硝基吡啶-4-基)氨)哌啶-1-基)亚甲基)苯基)-N-甲基甲基磺酰胺Intermediate 40: N-(4-((4-((2-Amino-5-chloro-3-nitropyridin-4-yl)amino)piperidin-1-yl)methylene)phenyl)- N-methyl methyl sulfonamide
Figure PCTCN2020116696-appb-000147
Figure PCTCN2020116696-appb-000147
通用方法C:相关化合物N-(4-((4-氨哌啶-1-基)亚甲基)苯基)-N-甲基甲基磺酰胺(I-22,1eq)，4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。General method C: Related compound N-(4-((4-aminopiperidin-1-yl)methylene)phenyl)-N-methyl methylsulfonamide (I-22, 1eq), 4,5 -Dichloro-3-nitropyridin-2-amine (I-3, 1 eq) and diisopropylethylamine (3 eq).
1H NMR(400MHz,Chloroform-d)δ8.82(d,J＝8.0Hz,1H),7.81(s,1H),7.33(s,4H),6.79(s,2H),4.49–4.23(m,1H),3.50(s,2H),3.32(s,3H),2.85(s,3H),2.78(d,J＝11.0Hz,2H),2.20(t,J＝11.0Hz,2H),2.09–1.99(m,2H),1.63(dtd,J＝13.3,10.0,3.6Hz,3H).MS:ESI(+)[M+1] +469.0。 1 H NMR (400MHz, Chloroform-d) δ 8.82 (d, J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.33 (s, 4H), 6.79 (s, 2H), 4.49-4.23 (m ,1H),3.50(s,2H),3.32(s,3H),2.85(s,3H),2.78(d,J=11.0Hz,2H),2.20(t,J=11.0Hz,2H),2.09 -1.99 (m, 2H), 1.63 (dtd, J=13.3, 10.0, 3.6 Hz, 3H). MS: ESI(+)[M+1] + 469.0.
中间体41:5-氯-N 4-(2-((4-甲氧基苄基)(亚甲基)氨)乙基)-3-硝基吡啶-2,4-二胺 Intermediate 41: 5-Chloro-N 4 -(2-((4-methoxybenzyl)(methylene)amino)ethyl)-3-nitropyridine-2,4-diamine
Figure PCTCN2020116696-appb-000148
Figure PCTCN2020116696-appb-000148
通用方法C:相关化合物N 1-(4-甲氧基苄基)-N 1-亚甲基乙烷-1,2-二胺(I-23,1eq)，4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。 General method C: Related compound N 1 -(4-methoxybenzyl)-N 1 -methyleneethane-1,2-diamine (I-23,1eq), 4,5-dichloro-3 -Nitropyridine-2-amine (I-3, 1 eq) and diisopropylethylamine (3 eq).
1H NMR(400MHz,DMSO-d 6)δ7.85(s,1H),7.72(s,1H),7.35(s,2H),7.26(d,J＝8.1Hz,2H),6.88(d,J＝8.5Hz,2H),3.74(s,3H),3.65–3.45(m,4H),3.12(qd,J＝7.3,3.3Hz,2H).MS:ESI(+)[M+1] +366.1。 1 H NMR(400MHz,DMSO-d 6 )δ7.85(s,1H),7.72(s,1H),7.35(s,2H), 7.26(d,J=8.1Hz,2H), 6.88(d, J=8.5Hz,2H),3.74(s,3H),3.65–3.45(m,4H),3.12(qd,J=7.3,3.3Hz,2H).MS:ESI(+)[M+1] + 366.1.
中间体42:5-氯-N 4-(1-(甲基磺酰基)哌啶--4-基)-3-硝基吡啶-2,4-二胺 Intermediate 42: 5-Chloro-N 4 -(1-(methylsulfonyl)piperidin-4-yl)-3-nitropyridine-2,4-diamine
Figure PCTCN2020116696-appb-000149
Figure PCTCN2020116696-appb-000149
通用方法C:相关化合物1-(甲基磺酰基)哌啶-4-胺(I-24,1eq)，4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。General method C: Related compound 1-(methylsulfonyl)piperidin-4-amine (I-24,1eq), 4,5-dichloro-3-nitropyridin-2-amine (I-3,1eq ) And diisopropylethylamine (3eq).
1H NMR(400MHz,DMSO-d 6)δ6.90(d,J＝7.9Hz,1H),3.46(dt,J＝12.5,3.9Hz,2H),3.38(d,J＝7.9Hz,1H),2.84(s,3H),2.79(td,J＝11.8,2.8Hz,2H),1.89–1.73(m,2H),1.49–1.40(m,2H).MS:ESI(+):[M+H] +:350.1。 1 H NMR (400MHz, DMSO-d 6 ) δ 6.90 (d, J = 7.9 Hz, 1H), 3.46 (dt, J = 12.5, 3.9 Hz, 2H), 3.38 (d, J = 7.9 Hz, 1H) ,2.84(s,3H),2.79(td,J=11.8,2.8Hz,2H),1.89–1.73(m,2H),1.49–1.40(m,2H).MS:ESI(+):[M+ H] + : 350.1.
中间体43:(R)-5-氯-N 4-(1-甲基哌啶-3-基)-3-硝基吡啶-2,4-二胺 Intermediate 43: (R)-5-chloro-N 4 -(1-methylpiperidin-3-yl)-3-nitropyridine-2,4-diamine
Figure PCTCN2020116696-appb-000150
Figure PCTCN2020116696-appb-000150
通用方法C:相关化合物(R)-1-甲基哌啶-3-胺(1eq)，4,5-二氯-3-硝基吡啶-2-胺(I-3,1eq)和二异丙基乙胺(3eq)。General method C: Related compounds (R)-1-methylpiperidin-3-amine (1eq), 4,5-dichloro-3-nitropyridin-2-amine (I-3,1eq) and diiso Propylethylamine (3eq).
1H NMR(400MHz,DMSO-d 6)δ7.88(s,1H),7.58(s,2H),4.16(s,1H),2.48–2.31(m,3H),2.19(s,3H),2.10(s,1H),1.58–1.42(m,4H).MS:ESI(+)[M+1] +286.2。 1 H NMR (400MHz, DMSO-d 6 ) δ 7.88 (s, 1H), 7.58 (s, 2H), 4.16 (s, 1H), 2.48-2.31 (m, 3H), 2.19 (s, 3H), 2.10(s,1H),1.58–1.42(m,4H). MS: ESI(+)[M+1] + 286.2.
中间体44:N 2-(1-(4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺 Intermediate 44: N 2 -(1-(4-methoxybenzyl)piperidin-4-yl)-3-nitropyridine-2,4-diamine
Figure PCTCN2020116696-appb-000151
Figure PCTCN2020116696-appb-000151
通用方法C:相关化合物2-氯-3-硝基吡啶-4-胺(1eq)，1-(4-甲氧基苄基)哌啶-4-胺(I-2,1eq)和二异丙基乙胺(3eq)。General method C: Related compounds 2-chloro-3-nitropyridin-4-amine (1eq), 1-(4-methoxybenzyl)piperidin-4-amine (I-2,1eq) and diiso Propylethylamine (3eq).
1H NMR(400MHz,Chloroform-d)δ7.74(d,J＝5.7Hz,1H),7.26–7.20(m,2H),6.88–6.84(m,2H),5.87(d,J＝5.7Hz,1H),4.27–4.11(m,1H),3.80(s,3H),3.46(s,2H),2.79(d,J ＝12.3Hz,2H),2.22(t,J＝10.8Hz,2H),2.04(dd,J＝12.8,3.8Hz,2H),1.62(dtd,J＝13.7,10.2,3.7Hz,2H).MS:ESI(+):[M+H] +:358.2。 1 H NMR(400MHz,Chloroform-d)δ7.74(d,J=5.7Hz,1H), 7.26–7.20(m,2H), 6.88–6.84(m,2H), 5.87(d,J=5.7Hz) ,1H), 4.27–4.11(m,1H), 3.80(s,3H), 3.46(s,2H), 2.79(d,J = 12.3Hz, 2H), 2.22(t,J = 10.8Hz, 2H) , 2.04 (dd, J=12.8, 3.8 Hz, 2H), 1.62 (dtd, J=13.7, 10.2, 3.7 Hz, 2H). MS: ESI (+): [M+H] + : 358.2.
中间体45:N 2-(1-(4-甲氧基苄基)哌啶-4-基)-5-硝基吡啶-2,4-二胺 Intermediate 45: N 2 -(1-(4-methoxybenzyl)piperidin-4-yl)-5-nitropyridine-2,4-diamine
Figure PCTCN2020116696-appb-000152
Figure PCTCN2020116696-appb-000152
通用方法C:相关化合物2-氯-5-硝基吡啶-4-胺(1eq)，1-(4-甲氧基苄基)哌啶-4-胺(I-2,1eq)和二异丙基乙胺(3eq)。General method C: Related compounds 2-chloro-5-nitropyridin-4-amine (1eq), 1-(4-methoxybenzyl)piperidin-4-amine (I-2,1eq) and diiso Propylethylamine (3eq).
1H NMR(400MHz,DMSO-d 6)δ8.79(s,1H),7.39(s,2H),7.26–7.24(m,2H),3.79(d,J＝1.5Hz,4H),3.44(s,2H),2.83(d,J＝11.4Hz,2H),2.06–2.00(m,2H),1.86(d,J＝12.9Hz,2H),1.53–1.44(m,2H).MS:ESI(+):[M+H] +:358.2。 1 H NMR (400MHz, DMSO-d 6 ) δ8.79 (s, 1H), 7.39 (s, 2H), 7.26-7.24 (m, 2H), 3.79 (d, J = 1.5Hz, 4H), 3.44 ( s,2H),2.83(d,J=11.4Hz,2H),2.06–2.00(m,2H),1.86(d,J=12.9Hz,2H),1.53–1.44(m,2H).MS:ESI (+):[M+H] + :358.2.
中间体46:N 4-(1-(4-甲氧基苄基)哌啶-4-基)-5-硝基嘧啶-4,6-二胺 Intermediate 46: N 4 -(1-(4-methoxybenzyl)piperidin-4-yl)-5-nitropyrimidine-4,6-diamine
Figure PCTCN2020116696-appb-000153
Figure PCTCN2020116696-appb-000153
于4,6-二氯-5-硝基嘧啶(0.5g)的四氢呋喃(10mL)溶液中加入1-(4-甲氧基苄基)哌啶-4-胺(I-2,1eq),升温至55℃并继续搅拌12小时。反应然后冷却至室温，于此反应液中加入氨甲醇溶液并继续搅拌12小时。然后悬浊液过滤干燥得到目标化合物N 4-(1-(4-甲氧基苄基)哌啶-4-基)-5-硝基嘧啶-4,6-二胺(I-46)。 To a solution of 4,6-dichloro-5-nitropyrimidine (0.5g) in tetrahydrofuran (10mL) was added 1-(4-methoxybenzyl)piperidin-4-amine (I-2, 1eq), The temperature was raised to 55°C and stirring was continued for 12 hours. The reaction was then cooled to room temperature, and ammonia methanol solution was added to the reaction solution and stirring was continued for 12 hours. Then the suspension was filtered and dried to obtain the target compound N 4 -(1-(4-methoxybenzyl)piperidin-4-yl)-5-nitropyrimidine-4,6-diamine (I-46).
1H NMR(400MHz,DMSO-d 6)δ9.04(d,J＝7.6Hz,1H),8.59(d,J＝13.8Hz,2H),7.98(s,1H),7.21(d,J＝8.2Hz,3H),6.88(d,J＝8.5Hz,2H),4.14(dp,J＝14.6,6.2,5.2Hz,1H),3.74(s,3H),3.40(s,2H),2.71(d,J＝11.5Hz,2H),2.10(t,J＝11.1Hz,2H),1.87(dd,J＝12.8,4.2Hz,2H),1.70–1.51(m,2H).MS:ESI(+):[M+H] +:359.2。 1 H NMR (400MHz, DMSO-d 6 ) δ9.04 (d, J = 7.6 Hz, 1H), 8.59 (d, J = 13.8 Hz, 2H), 7.98 (s, 1H), 7.21 (d, J = 8.2Hz, 3H), 6.88 (d, J = 8.5 Hz, 2H), 4.14 (dp, J = 14.6, 6.2, 5.2 Hz, 1H), 3.74 (s, 3H), 3.40 (s, 2H), 2.71 ( d,J=11.5Hz,2H),2.10(t,J=11.1Hz,2H),1.87(dd,J=12.8,4.2Hz,2H),1.70–1.51(m,2H).MS:ESI(+ ):[M+H] + :359.2.
中间体47:N 1-(1-(4-甲氧基苄基)哌啶-4-基)-2-硝基苯基-1,3-二胺 Intermediate 47: N 1 -(1-(4-methoxybenzyl)piperidin-4-yl)-2-nitrophenyl-1,3-diamine
Figure PCTCN2020116696-appb-000154
Figure PCTCN2020116696-appb-000154
通用方法D:于1-(4-甲氧基苄基)哌啶-4-胺(I-2,0.1g,1eq)和3-氟-2-硝基苯胺(71mg,1eq)的DMF(2ml)溶液中加入碳酸钾(0.1g,1.5eq),反应液升温至100℃并搅拌2小时。然后冷却至室温，深棕色反应液倒入二氯甲烷/水混合液中，摇匀，静置分相， 有机相分离，浓缩。经硅胶柱分离纯化，洗脱液乙酸乙酯/正庚烷1:2,得到棕色固体I-47。General method D: DMF(4-methoxybenzyl)piperidin-4-amine (I-2, 0.1g, 1eq) and 3-fluoro-2-nitroaniline (71mg, 1eq) ( Potassium carbonate (0.1g, 1.5eq) was added to the 2ml) solution, and the reaction solution was heated to 100°C and stirred for 2 hours. Then it was cooled to room temperature, the dark brown reaction liquid was poured into the dichloromethane/water mixture, shaken well, stood still for phase separation, the organic phase was separated and concentrated. Separation and purification by silica gel column, eluent ethyl acetate/n-heptane 1:2, to obtain brown solid I-47.
1H NMR(400MHz,Chloroform-d)δ7.25–7.21(m,2H),7.04(t,J＝8.2Hz,1H),6.89–6.83(m,2H),6.01–5.95(m,1H),5.90(dd,J＝8.1,1.3Hz,1H),3.81(s,3H),3.47(s,3H),2.78(d,J＝11.0Hz,2H),2.21(t,J＝11.0Hz,2H),2.13–1.94(m,2H),1.72–1.52(m,4H).MS:ESI(+):[M+H] +:357.3。 1 H NMR(400MHz,Chloroform-d)δ7.25-7.21(m,2H), 7.04(t,J=8.2Hz,1H), 6.89-6.83(m,2H), 6.01-5.95(m,1H) ,5.90(dd,J＝8.1,1.3Hz,1H),3.81(s,3H),3.47(s,3H),2.78(d,J＝11.0Hz,2H),2.21(t,J＝11.0Hz, 2H), 2.13–1.94 (m, 2H), 1.72–1.52 (m, 4H). MS: ESI(+): [M+H] + : 357.3.
中间体48:6-氯-N 1-(1-(4-甲氧基苄基)哌啶-4-基)-2-硝基苯基-1,3-二胺 Intermediate 48: 6-Chloro-N 1 -(1-(4-methoxybenzyl)piperidin-4-yl)-2-nitrophenyl-1,3-diamine
Figure PCTCN2020116696-appb-000155
Figure PCTCN2020116696-appb-000155
通用方法D:相关化合物1-(4-甲氧基苄基)哌啶-4-胺(I-2,1eq)，4-氯-3-氟-2-硝基苯胺(I-25,1eq)和碳酸钾。General method D: Related compound 1-(4-methoxybenzyl)piperidin-4-amine (I-2,1eq), 4-chloro-3-fluoro-2-nitroaniline (I-25,1eq ) And potassium carbonate.
1H NMR(400MHz,Chloroform-d)δ7.23(d,J＝8.6Hz,2H),7.19(d,J＝9.1Hz,1H),6.90–6.83(m,2H),5.97(d,J＝9.2Hz,1H),3.81(s,3H),3.47(s,3H),2.78(d,J＝10.0Hz,2H),2.30–2.12(m,2H),2.03(d,J＝12.5Hz,2H),1.67(d,J＝13.0Hz,2H).MS:ESI(+):[M+H] +:391.3。 1 H NMR(400MHz, Chloroform-d)δ7.23(d,J=8.6Hz,2H), 7.19(d,J=9.1Hz,1H), 6.90-6.83(m,2H), 5.97(d,J ＝9.2Hz,1H),3.81(s,3H),3.47(s,3H),2.78(d,J＝10.0Hz,2H), 2.30–2.12(m,2H),2.03(d,J＝12.5Hz , 2H), 1.67 (d, J = 13.0 Hz, 2H). MS: ESI (+): [M+H] + : 391.3.
中间体49:4-氯-N 1-(1-(4-甲氧基苄基)哌啶-4-基)-2-硝基苯基-1,3-二胺 Intermediate 49: 4-Chloro-N 1 -(1-(4-methoxybenzyl)piperidin-4-yl)-2-nitrophenyl-1,3-diamine
Figure PCTCN2020116696-appb-000156
Figure PCTCN2020116696-appb-000156
通用方法D:1-(4-甲氧基苄基)哌啶-4-胺(I-2,1eq)，6-氯-3-氟-2-硝基苯氨(I-26,1eq)和碳酸钾。General method D: 1-(4-methoxybenzyl)piperidin-4-amine (I-2,1eq), 6-chloro-3-fluoro-2-nitroaniline (I-26,1eq) And potassium carbonate.
1H NMR(400MHz,Chloroform-d)δ7.22–7.17(m,2H),7.15(d,J＝8.8Hz,1H),6.86–6.82(m,2H),6.18(d,J＝8.8Hz,1H),3.80(s,3H),3.59–3.47(m,1H),3.42(s,2H),2.75(d,J＝11.6Hz,2H),2.06(t,J＝11.3Hz,2H),1.96–1.80(m,2H),1.54–1.38(m,2H).MS:ESI(+):[M+H] +:391.3。 1 H NMR(400MHz, Chloroform-d) δ7.22–7.17(m,2H), 7.15(d,J=8.8Hz,1H), 6.86–6.82(m,2H), 6.18(d,J=8.8Hz ,1H),3.80(s,3H),3.59–3.47(m,1H),3.42(s,2H),2.75(d,J=11.6Hz,2H),2.06(t,J=11.3Hz,2H) ,1.96–1.80(m,2H),1.54–1.38(m,2H).MS:ESI(+):[M+H] + :391.3.
中间体51:6-氯-2-硝基-N 1-(1-(4-(三甲基硅烷基)苄基)哌啶-4-基)苯基-1,3-二胺 Intermediate 51: 6-Chloro-2-nitro-N 1 -(1-(4-(trimethylsilyl)benzyl)piperidin-4-yl)phenyl-1,3-diamine
Figure PCTCN2020116696-appb-000157
Figure PCTCN2020116696-appb-000157
通用方法C:相关化合物1-(4-(三甲基硅烷基)苄基)哌啶-4-胺(I-11,1eq)，4-氯-3-氟-2-硝基苯胺(I-25,1eq),硅胶柱分离,洗脱液乙酸乙酯/正庚烷/三乙胺1:8。General method C: Related compound 1-(4-(trimethylsilyl)benzyl)piperidin-4-amine (I-11, 1eq), 4-chloro-3-fluoro-2-nitroaniline (I -25,1eq), silica gel column separation, eluent ethyl acetate/n-heptane/triethylamine 1:8.
1H NMR(400MHz,Chloroform-d)δ8.49(d,J＝7.2Hz,1H),7.51–7.44(m,2H),7.31(d,J＝7.6Hz,2H),7.19(d,J＝9.2Hz,1H),6.74(s,2H),5.97(d,J＝9.2Hz,1H),3.52(s,3H),2.81(d,J＝9.4Hz,2H),2.24(t,J＝10.5Hz,2H),2.11–1.98(m,2H),1.66(d,J＝29.2Hz,2H),0.26(s,9H)；MS:ESI(+)[M+1] +433.2。 1 H NMR (400MHz, Chloroform-d) δ8.49 (d, J = 7.2Hz, 1H), 7.51-7.44 (m, 2H), 7.31 (d, J = 7.6 Hz, 2H), 7.19 (d, J ＝9.2Hz,1H),6.74(s,2H),5.97(d,J＝9.2Hz,1H),3.52(s,3H),2.81(d,J＝9.4Hz,2H),2.24(t,J = 10.5 Hz, 2H), 2.11-1.98 (m, 2H), 1.66 (d, J = 29.2 Hz, 2H), 0.26 (s, 9H); MS: ESI (+) [M+1] + 433.2.
中间体52:6-氯-N 1-(1-(2,5-二氟苄基)哌啶-4-基)-2-硝基苯基-1,3-二胺 Intermediate 52: 6-chloro-N 1 -(1-(2,5-difluorobenzyl)piperidin-4-yl)-2-nitrophenyl-1,3-diamine
Figure PCTCN2020116696-appb-000158
Figure PCTCN2020116696-appb-000158
通用方法D:相关化合物1-(2,5-二氟苯基)哌啶-4-胺(I-14,1eq)，4-氯-3-氟-2-硝基苯胺(I-25,1eq),硅胶柱分离,洗脱液乙酸乙酯/正庚烷1:8。General method D: Related compound 1-(2,5-difluorophenyl)piperidin-4-amine (I-14,1eq), 4-chloro-3-fluoro-2-nitroaniline (I-25, 1eq), silica gel column separation, eluent ethyl acetate/n-heptane 1:8.
1H NMR(400MHz,Chloroform-d)δ8.48(d,J＝7.2Hz,1H),7.20(d,J＝9.2Hz,1H),7.17–7.09(m,1H),7.04–6.87(m,2H),6.74(s,2H),5.97(d,J＝9.2Hz,1H),3.57(s,2H),3.47(s,1H),2.83(d,J＝11.8Hz,2H),2.31(t,J＝11.0Hz,2H),2.06(d,J＝12.9Hz,2H),1.75–1.61(m,2H)；MS:ESI(+)[M+1] +397.2。 1 H NMR(400MHz,Chloroform-d)δ8.48(d,J=7.2Hz,1H), 7.20(d,J=9.2Hz,1H), 7.17-7.09(m,1H), 7.04-6.87(m , 2H), 6.74 (s, 2H), 5.97 (d, J = 9.2 Hz, 1H), 3.57 (s, 2H), 3.47 (s, 1H), 2.83 (d, J = 11.8 Hz, 2H), 2.31 (t, J=11.0 Hz, 2H), 2.06 (d, J=12.9 Hz, 2H), 1.75-1.61 (m, 2H); MS: ESI(+)[M+1] + 397.2.
中间体53:6-氯-N 1-(1-((1-甲基-1氢-吲哚氮唑-5-基)亚甲基)哌啶-4-基)-2-硝基苯基-1,3-二胺 Intermediate 53: 6-Chloro-N 1 -(1-((1-methyl-1hydro-indoleazol-5-yl)methylene)piperidin-4-yl)-2-nitrobenzene Base-1,3-diamine
Figure PCTCN2020116696-appb-000159
Figure PCTCN2020116696-appb-000159
通用方法D:相关化合物1-((1-甲基-1氢-吲哚氮唑-5-基)亚甲基)哌啶-4-胺(I-20,1eq)，4-氯-3-氟-2-硝基苯胺(I-25,1eq),硅胶柱分离,洗脱液乙酸乙酯/正庚烷1:2。General method D: Related compound 1-((1-methyl-1hydro-indoleazol-5-yl)methylene)piperidin-4-amine (I-20, 1eq), 4-chloro-3 -Fluoro-2-nitroaniline (I-25, 1eq), separated on silica gel column, eluent ethyl acetate/n-heptane 1:2.
1H NMR(400MHz,Chloroform-d)δ8.49(d,J＝7.2Hz,1H),7.94(d,J＝0.9Hz,1H),7.62(s,1H),7.41(dd,J＝8.6,1.5Hz,1H),7.36(d,J＝8.7Hz,1H),7.19(d,J＝9.1Hz,1H),5.97(d,J＝9.2Hz,1H),4.07(s,3H),3.63(s,2H),3.48(s,1H),2.81(d,J＝11.7Hz,2H),2.25(t,J＝11.6Hz,2H),2.04(d,J＝13.3Hz,2H),1.72–1.61(m,2H)；MS:ESI(+)[M+1] +415.2。 1 H NMR(400MHz,Chloroform-d)δ8.49(d,J=7.2Hz,1H),7.94(d,J=0.9Hz,1H),7.62(s,1H),7.41(dd,J=8.6 ,1.5Hz,1H),7.36(d,J=8.7Hz,1H),7.19(d,J=9.1Hz,1H),5.97(d,J=9.2Hz,1H),4.07(s,3H), 3.63 (s, 2H), 3.48 (s, 1H), 2.81 (d, J = 11.7 Hz, 2H), 2.25 (t, J = 11.6 Hz, 2H), 2.04 (d, J = 13.3 Hz, 2H), 1.72–1.61(m,2H); MS: ESI(+)[M+1] + 415.2.
中间体54:N-(4-((4-((3-氨-6-氯-2-硝基苯基)氨)哌啶-1-基)亚甲基)苯基)-N-甲基甲基磺酰胺Intermediate 54: N-(4-((4-((3-Amino-6-chloro-2-nitrophenyl)amino)piperidin-1-yl)methylene)phenyl)-N-methyl Methyl sulfonamide
Figure PCTCN2020116696-appb-000160
Figure PCTCN2020116696-appb-000160
通用方法D:N-(4-((4-氨哌啶-1-基)亚甲基)苯基)-N-甲基甲基磺酰胺(I-22,1eq)和4-氯-3-氟-2-硝基苯胺(I-25,1eq),硅胶柱分离,洗脱液乙酸乙酯/正庚烷1:1；General method D: N-(4-((4-aminopiperidin-1-yl)methylene)phenyl)-N-methylmethylsulfonamide (I-22, 1eq) and 4-chloro-3 -Fluoro-2-nitroaniline (I-25, 1eq), separated on silica gel column, eluent ethyl acetate/n-heptane 1:1;
1H NMR(400MHz,Chloroform-d)δ8.49(d,J＝7.1Hz,1H),7.39–7.29(m,4H),7.20(d,J＝9.1Hz,1H),6.75(s,2H),5.98(d,J＝9.4Hz,1H),3.52(s,3H),3.33(s,3H),2.85(s,3H),2.78(d,J＝11.5Hz,2H),2.25(t,J＝11.2Hz,2H),2.04(d,J＝13.1Hz,2H),1.66(d,J＝29.1Hz,2H)；MS:ESI(+)[M+1] +468.2。 1 H NMR (400MHz, Chloroform-d) δ8.49 (d, J = 7.1Hz, 1H), 7.39-7.29 (m, 4H), 7.20 (d, J = 9.1Hz, 1H), 6.75 (s, 2H ), 5.98 (d, J = 9.4 Hz, 1H), 3.52 (s, 3H), 3.33 (s, 3H), 2.85 (s, 3H), 2.78 (d, J = 11.5 Hz, 2H), 2.25 (t , J = 11.2 Hz, 2H), 2.04 (d, J = 13.1 Hz, 2H), 1.66 (d, J = 29.1 Hz, 2H); MS: ESI(+) [M+1] + 468.2.
通用方法E:芳香胺(1eq),醛(1eq)和新配制的1M Na 2S 2O 4(3eq)水溶液在乙醇溶液中于封管中在70℃搅拌12小时。然后冷却至室温，反应液倒入5％的氨水中继续搅拌30分钟，悬浊液过滤，滤饼用水洗，真空拉干，滤饼置于乙腈悬浊液中于70℃下搅拌30分钟,然后冷却至室温，过滤，滤饼干燥得到目标化合物。 General method E: Aromatic amine (1eq), aldehyde (1eq) and a freshly prepared 1M Na 2 S 2 O 4 (3eq) aqueous solution were stirred in a sealed tube at 70°C for 12 hours in an ethanol solution. Then cool to room temperature, pour the reaction solution into 5% ammonia water and continue to stir for 30 minutes, the suspension is filtered, the filter cake is washed with water, dried under vacuum, the filter cake is placed in the acetonitrile suspension and stirred at 70°C for 30 minutes. Then it is cooled to room temperature, filtered and the filter cake is dried to obtain the target compound.
Figure PCTCN2020116696-appb-000161
Figure PCTCN2020116696-appb-000161
实施例1Example 1
化合物1:2-(4-(6-氯-7-((1-((6-甲氧基吡啶-3-基)亚甲基)哌啶-4-基)胺)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺Compound 1: 2-(4-(6-Chloro-7-((1-((6-methoxypyridin-3-yl)methylene)piperidin-4-yl)amine)-3hydro-imidazole [4,5-b]pyridin-2-yl)phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000162
Figure PCTCN2020116696-appb-000162
通用方法E:相关化合物5-氯-N 4-(1-((6-甲氧基吡啶-3-基)亚甲基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-27,50mg,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,25mg,1eq)。 General method E: Related compound 5-chloro-N 4 -(1-((6-methoxypyridin-3-yl)methylene)piperidin-4-yl)-3-nitropyridine-2,4 -Diamine (I-27, 50 mg, 1 eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1, 25 mg, 1 eq).
1H NMR(400MHz,DMSO-d 6)δ13.15(s,1H),8.17–8.02(m,4H),7.92(s,1H),7.66(dd,J＝8.5,2.4Hz,1H),7.17–7.07(m,2H),6.81(d,J＝8.4Hz,1H),5.81(d,J＝8.8Hz,1H),5.04 –4.85(m,1H),4.57(s,2H),3.84(s,3H),3.47(s,2H),2.86(d,J＝11.1Hz,2H),2.68(d,J＝4.6Hz,3H),2.15(t,J＝11.5Hz,2H),1.98(d,J＝8.7Hz,3H),1.67(q,J＝10.7,9.9Hz,2H).MS:ESI(+)[M+1] +536.0。 1 H NMR(400MHz,DMSO-d 6 )δ13.15(s,1H), 8.17-8.02(m,4H),7.92(s,1H), 7.66(dd,J=8.5,2.4Hz,1H), 7.17–7.07 (m, 2H), 6.81 (d, J = 8.4 Hz, 1H), 5.81 (d, J = 8.8 Hz, 1H), 5.04 -4.85 (m, 1H), 4.57 (s, 2H), 3.84 (s, 3H), 3.47 (s, 2H), 2.86 (d, J = 11.1 Hz, 2H), 2.68 (d, J = 4.6 Hz, 3H), 2.15 (t, J = 11.5 Hz, 2H), 1.98 (d, J = 8.7 Hz, 3H), 1.67 (q, J = 10.7, 9.9 Hz, 2H). MS: ESI(+)[M+1] + 536.0.
实施例2Example 2
化合物2:2-(4-(6-氯-7-((1-((5-甲氧基吡啶-2-基)亚甲基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺Compound 2: 2-(4-(6-Chloro-7-((1-((5-methoxypyridin-2-yl)methylene)piperidin-4-yl)amino)-3hydro-imidazole [4,5-b]pyridin-2-yl)phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000163
Figure PCTCN2020116696-appb-000163
通用方法E:相关化合物5-氯-N 4-(1-((5-甲氧基吡啶-2-基)亚甲基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-28,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。 General method E: Related compound 5-chloro-N 4 -(1-((5-methoxypyridin-2-yl)methylene)piperidin-4-yl)-3-nitropyridine-2,4 -Diamine (I-28, 1eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1, 1eq).
1H NMR(400MHz,DMSO-d 6)δ13.15(s,1H),8.24(s,1H),8.08(d,J＝8.6Hz,3H),7.92(s,1H),7.48–7.31(m,2H),7.21–7.06(m,2H),5.84(d,J＝8.6Hz,1H),4.98(s,1H),4.57(s,2H),3.83(s,3H),3.65(s,2H),2.94(s,2H),2.68(d,J＝4.6Hz,3H),2.31(d,J＝20.6Hz,2H),2.02(d,J＝11.6Hz,2H),1.72(d,J＝12.2Hz,2H)；MS:ESI(+)[M+1] +536.0。 1 H NMR (400MHz, DMSO-d 6 ) δ 13.15 (s, 1H), 8.24 (s, 1H), 8.08 (d, J = 8.6 Hz, 3H), 7.92 (s, 1H), 7.48-7.31 ( m, 2H), 7.21–7.06 (m, 2H), 5.84 (d, J = 8.6 Hz, 1H), 4.98 (s, 1H), 4.57 (s, 2H), 3.83 (s, 3H), 3.65 (s , 2H), 2.94 (s, 2H), 2.68 (d, J = 4.6 Hz, 3H), 2.31 (d, J = 20.6 Hz, 2H), 2.02 (d, J = 11.6 Hz, 2H), 1.72 (d , J=12.2Hz, 2H); MS: ESI(+)[M+1] + 536.0.
实施例3Example 3
化合物3:2-(4-(6-氯-7-((1-(4-(三甲基硅烷基)苄基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺Compound 3: 2-(4-(6-Chloro-7-((1-(4-(trimethylsilyl)benzyl)piperidin-4-yl)amino)-3hydro-imidazole [4,5 -b)pyridin-2-yl)phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000164
Figure PCTCN2020116696-appb-000164
通用方法E:相关化合物5-氯-3-硝基-N 4-(1-(4-(三甲基硅烷基)苄基)哌啶-4-基)吡啶-2,4-二胺(I-29,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。 General method E: Related compound 5-chloro-3-nitro-N 4 -(1-(4-(trimethylsilyl)benzyl)piperidin-4-yl)pyridine-2,4-diamine ( I-29, 1 eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1, 1 eq).
1H NMR(400MHz,DMSO-d 6)δ7.95–7.77(m,3H),7.67(s,1H),7.25(d,J＝7.5Hz,2H),7.09(d,J＝7.6Hz,2H),6.95–6.80(m,2H),5.53(d,J＝8.8Hz,1H),4.73(d,J＝10.9Hz,1H),4.32(s,2H),3.27(s,3H),2.63(d,J＝11.0Hz,2H),2.44(d,J＝4.6Hz,3H),1.91(t,J＝11.4Hz,2H),1.75(d,J＝11.3Hz,2H),1.44(td,J＝12.8,9.3Hz,2H)；MS:ESI(+)[M+1] +576.9。 1 H NMR(400MHz,DMSO-d 6 )δ7.95–7.77(m,3H), 7.67(s,1H), 7.25(d,J=7.5Hz,2H), 7.09(d,J=7.6Hz, 2H), 6.95-6.80 (m, 2H), 5.53 (d, J = 8.8 Hz, 1H), 4.73 (d, J = 10.9 Hz, 1H), 4.32 (s, 2H), 3.27 (s, 3H), 2.63 (d, J = 11.0 Hz, 2H), 2.44 (d, J = 4.6 Hz, 3H), 1.91 (t, J = 11.4 Hz, 2H), 1.75 (d, J = 11.3 Hz, 2H), 1.44 ( td, J=12.8, 9.3 Hz, 2H); MS: ESI(+)[M+1] + 576.9.
实施例4Example 4
化合物4:2-(4-(6-氯-7-((1-(二氟-4-甲氧基苄基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺Compound 4: 2-(4-(6-chloro-7-((1-(difluoro-4-methoxybenzyl)piperidin-4-yl)amino)-3hydro-imidazole [4,5- b)Pyridin-2-yl)phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000165
Figure PCTCN2020116696-appb-000165
通用方法E:相关化合物5-氯-N 4-(1-(2,5-二氟-4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-30,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。 General method E: Related compound 5-chloro-N 4 -(1-(2,5-difluoro-4-methoxybenzyl)piperidin-4-yl)-3-nitropyridine-2,4- Diamine (I-30, 1 eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1, 1 eq).
1H NMR(400MHz,DMSO-d 6)δ13.14(s,1H),8.07(d,J＝8.8Hz,3H),7.92(s,1H),7.26(dd,J＝11.8,6.8Hz,1H),7.19–7.02(m,3H),5.81(d,J＝8.9Hz,1H),4.95(d,J＝9.6Hz,1H),4.57(s,2H),3.85(s,3H),3.50(s,2H),2.87(d,J＝11.2Hz,2H),2.68(d,J＝4.6Hz,3H),2.19(t,J＝11.4Hz,2H),1.98(d,J＝10.9Hz,2H),1.68(q,J＝11.8,11.3Hz,2H)；MS:ESI(+)[M+1] +571.0。 1 H NMR (400MHz, DMSO-d 6 ) δ 13.14 (s, 1H), 8.07 (d, J = 8.8 Hz, 3H), 7.92 (s, 1H), 7.26 (dd, J = 11.8, 6.8 Hz, 1H), 7.19–7.02 (m, 3H), 5.81 (d, J = 8.9 Hz, 1H), 4.95 (d, J = 9.6 Hz, 1H), 4.57 (s, 2H), 3.85 (s, 3H), 3.50 (s, 2H), 2.87 (d, J = 11.2 Hz, 2H), 2.68 (d, J = 4.6 Hz, 3H), 2.19 (t, J = 11.4 Hz, 2H), 1.98 (d, J = 10.9 Hz, 2H), 1.68 (q, J=11.8, 11.3 Hz, 2H); MS: ESI(+)[M+1] + 571.0.
实施例5Example 5
化合物5:2-(4-(6-氯-7-((1-(2-氟-4-甲氧基苄基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺Compound 5: 2-(4-(6-chloro-7-((1-(2-fluoro-4-methoxybenzyl)piperidin-4-yl)amino)-3hydro-imidazole [4,5 -b)pyridin-2-yl)phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000166
Figure PCTCN2020116696-appb-000166
通用方法E:相关化合物5-氯-N 4-(1-(2-氟-4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-31,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。 General method E: Related compound 5-chloro-N 4 -(1-(2-fluoro-4-methoxybenzyl)piperidin-4-yl)-3-nitropyridine-2,4-diamine ( I-31, 1 eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1, 1 eq).
1H NMR(400MHz,DMSO-d 6)δ13.16(s,1H),8.08(d,J＝8.5Hz,3H),7.92(s,1H),7.12(d,J＝8.7Hz,4H),5.82(s,1H),4.98(s,1H),4.57(s,2H),3.84(s,3H),3.53(d,J＝40.5Hz,1H),2.88(s,1H),2.68(d,J＝4.6Hz,3H),2.14(s,1H),2.05–1.95(m,2H),1.71(s,2H)；MS:ESI(+)[M+1] +553.0。 1 H NMR (400MHz, DMSO-d 6 ) δ 13.16 (s, 1H), 8.08 (d, J = 8.5 Hz, 3H), 7.92 (s, 1H), 7.12 (d, J = 8.7 Hz, 4H) ,5.82(s,1H),4.98(s,1H),4.57(s,2H),3.84(s,3H),3.53(d,J=40.5Hz,1H),2.88(s,1H),2.68( d, J=4.6 Hz, 3H), 2.14 (s, 1H), 2.05-1.95 (m, 2H), 1.71 (s, 2H); MS: ESI(+)[M+1] + 553.0.
实施例6Example 6
化合物6:2-(4-(6-氯-7-((1-(2,5-二氟苄基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺Compound 6: 2-(4-(6-chloro-7-((1-(2,5-difluorobenzyl)piperidin-4-yl)amino)-3hydro-imidazole[4,5-b] (Pyridin-2-yl)phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000167
Figure PCTCN2020116696-appb-000167
通用方法E:相关化合物5-氯-N 4-(1-(2,5-二氟苯基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-32,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。 General method E: Related compound 5-chloro-N 4 -(1-(2,5-difluorophenyl)piperidin-4-yl)-3-nitropyridine-2,4-diamine (I-32 ,1eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1,1eq).
1H NMR(400MHz,DMSO-d 6)δ8.08(dd,J＝11.2,4.3Hz,3H),7.91(s,1H),7.73(d,J＝469.0Hz,10H),7.27(tq,J＝11.8,4.5,4.0Hz,2H),7.18(td,J＝8.8,8.3,4.4Hz,1H),7.14–7.08(m,2H),5.81(d,J＝8.9Hz,1H),5.05–4.88(m,1H),4.57(s,2H),3.59(s,2H),2.89(d,J＝11.0Hz,2H),2.68(d,J＝4.6Hz,3H),2.30–2.18(m,2H),2.08(s,3H),1.99(dd,J＝10.0,5.5Hz,3H),1.77–1.63(m,2H),1.24(d,J＝3.3Hz,2H)；MS:ESI(+)[M+1] +541.0。 1 H NMR (400MHz, DMSO-d 6 ) δ8.08 (dd, J = 11.2, 4.3 Hz, 3H), 7.91 (s, 1H), 7.73 (d, J = 469.0 Hz, 10H), 7.27 (tq, J = 11.8, 4.5, 4.0 Hz, 2H), 7.18 (td, J = 8.8, 8.3, 4.4 Hz, 1H), 7.14-7.08 (m, 2H), 5.81 (d, J = 8.9 Hz, 1H), 5.05 –4.88(m,1H),4.57(s,2H),3.59(s,2H), 2.89(d,J=11.0Hz,2H), 2.68(d,J=4.6Hz,3H), 2.30–2.18( m, 2H), 2.08 (s, 3H), 1.99 (dd, J = 10.0, 5.5 Hz, 3H), 1.77-1.63 (m, 2H), 1.24 (d, J = 3.3 Hz, 2H); MS: ESI (+)[M+1] + 541.0.
实施例7Example 7
化合物7:2-(4-(6-氯-7-((1-(3-氟-4-甲氧基苄基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺Compound 7: 2-(4-(6-chloro-7-((1-(3-fluoro-4-methoxybenzyl)piperidin-4-yl)amino)-3hydro-imidazole [4,5 -b)pyridin-2-yl)phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000168
Figure PCTCN2020116696-appb-000168
通用方法E:相关化合物5-氯-N 4-(1-(3-氟-4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-33,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。 General method E: Related compound 5-chloro-N 4 -(1-(3-fluoro-4-methoxybenzyl)piperidin-4-yl)-3-nitropyridine-2,4-diamine ( I-33, 1 eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1, 1 eq).
1H NMR(400MHz,DMSO-d 6)δ8.07(d,J＝8.7Hz,3H),7.91(s,1H),7.21–7.04(m,5H),5.78(d,J＝8.9Hz,1H),4.96(d,J＝11.0Hz,1H),4.57(s,2H),3.83(s,3H),3.46(s,2H),2.86(d,J＝11.1Hz,2H),2.68(d,J＝4.6Hz,3H),2.14(t,J＝11.2Hz,2H),1.99(d,J＝11.5Hz,2H),1.68(q,J＝11.6Hz,2H)；MS:ESI(+)[M+1] +553.0。 1 H NMR(400MHz,DMSO-d 6 )δ8.07(d,J=8.7Hz,3H),7.91(s,1H),7.21-7.04(m,5H),5.78(d,J=8.9Hz, 1H), 4.96 (d, J = 11.0 Hz, 1H), 4.57 (s, 2H), 3.83 (s, 3H), 3.46 (s, 2H), 2.86 (d, J = 11.1 Hz, 2H), 2.68 ( d, J = 4.6 Hz, 3H), 2.14 (t, J = 11.2 Hz, 2H), 1.99 (d, J = 11.5 Hz, 2H), 1.68 (q, J = 11.6 Hz, 2H); MS: ESI ( +)[M+1] + 553.0.
实施例8Example 8
化合物8:2-(4-(6-氯-7-((1-(3,5-二氟-4-甲氧基苄基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺Compound 8: 2-(4-(6-chloro-7-((1-(3,5-difluoro-4-methoxybenzyl)piperidin-4-yl)amino)-3hydro-imidazole[ 4,5-b)pyridin-2-yl)phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000169
Figure PCTCN2020116696-appb-000169
通用方法E:相关化合物5-氯-N 4-(1-(3,5-二氟-4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-34,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。 General method E: Related compound 5-chloro-N 4 -(1-(3,5-difluoro-4-methoxybenzyl)piperidin-4-yl)-3-nitropyridine-2,4- Diamine (I-34, 1eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1, 1eq).
1H NMR(400MHz,DMSO-d 6)δ13.15(s,1H),8.14–8.02(m,3H),7.92(s,1H),7.20–7.02(m,4H),5.82(d,J＝8.9Hz,1H),5.05–4.88(m,1H),4.57(s,2H),3.91(s,3H),3.50(s,2H),2.86(d,J＝11.1Hz,2H),2.68(d,J＝4.6Hz,3H),2.18(t,J＝11.5Hz,2H),2.00(d,J＝11.7Hz,2H),1.71(q,J＝11.8Hz,2H)；MS:ESI(+)[M+1] +570.9。 1 H NMR (400MHz, DMSO-d 6 ) δ 13.15 (s, 1H), 8.14-8.02 (m, 3H), 7.92 (s, 1H), 7.20-7.02 (m, 4H), 5.82 (d, J =8.9Hz,1H),5.05–4.88(m,1H),4.57(s,2H),3.91(s,3H),3.50(s,2H),2.86(d,J=11.1Hz,2H),2.68 (d, J = 4.6Hz, 3H), 2.18 (t, J = 11.5Hz, 2H), 2.00 (d, J = 11.7Hz, 2H), 1.71 (q, J = 11.8Hz, 2H); MS: ESI (+)[M+1] + 570.9.
实施例9Example 9
化合物9:2-(4-(6-氯-7-((1-(2,4-二氟苄基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺Compound 9: 2-(4-(6-chloro-7-((1-(2,4-difluorobenzyl)piperidin-4-yl)amino)-3hydro-imidazole[4,5-b] (Pyridin-2-yl)phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000170
Figure PCTCN2020116696-appb-000170
通用方法E:相关化合物5-氯-N 4-(1-(2,4-二氟苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-35,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。 General method E: Related compound 5-chloro-N 4 -(1-(2,4-difluorobenzyl)piperidin-4-yl)-3-nitropyridine-2,4-diamine (I-35 ,1eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1,1eq).
1H NMR(400MHz,DMSO-d 6)δ8.08(dd,J＝11.4,4.5Hz,3H),7.91(s,1H),7.48(q,J＝8.3Hz,1H),7.22(td,J＝9.8,2.6Hz,1H),7.16–7.05(m,3H),5.80(d,J＝8.8Hz,1H),4.95(d,J＝11.0Hz,1H),4.57(s,2H),3.56(s,2H),2.88(d,J＝11.2Hz,2H),2.68(d,J＝4.6Hz,3H),2.26–2.14(m,2H),1.99(d,J＝11.7Hz,2H),1.67(q,J＝11.7,11.3Hz,2H)；MS:ESI(+)[M+1] +541.0。 1 H NMR (400MHz, DMSO-d 6 ) δ8.08 (dd, J = 11.4, 4.5 Hz, 3H), 7.91 (s, 1H), 7.48 (q, J = 8.3 Hz, 1H), 7.22 (td, J = 9.8, 2.6 Hz, 1H), 7.16–7.05 (m, 3H), 5.80 (d, J = 8.8 Hz, 1H), 4.95 (d, J = 11.0 Hz, 1H), 4.57 (s, 2H), 3.56 (s, 2H), 2.88 (d, J = 11.2 Hz, 2H), 2.68 (d, J = 4.6 Hz, 3H), 2.26-2.14 (m, 2H), 1.99 (d, J = 11.7 Hz, 2H) ), 1.67 (q, J=11.7, 11.3 Hz, 2H); MS: ESI(+)[M+1] + 541.0.
实施例10Example 10
化合物10:2-(4-(6-氯-7-((1-((4-甲氧基苯基)磺酰基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺Compound 10: 2-(4-(6-chloro-7-((1-((4-methoxyphenyl)sulfonyl)piperidin-4-yl)amino)-3hydro-imidazole [4,5 -b)pyridin-2-yl)phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000171
Figure PCTCN2020116696-appb-000171
通用方法E:相关化合物5-氯-N 4-(1-((4-甲氧基苯基)磺酰基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-36,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。 General method E: Related compound 5-chloro-N 4 -(1-((4-methoxyphenyl)sulfonyl)piperidin-4-yl)-3-nitropyridine-2,4-diamine ( I-36, 1 eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1, 1 eq).
1H NMR(400MHz,DMSO-d 6)δ8.09(d,J＝5.3Hz,1H),7.92(d,J＝9.2Hz,3H),7.80–7.72(m,2H),7.29–7.20(m,2H),7.05(d,J＝8.8Hz,2H),6.03(d,J＝8.8Hz,1H),4.86(d,J＝8.6Hz,1H),4.57(s,2H),3.90(s,3H),3.71(d,J＝11.4Hz,2H),2.69(d,J＝4.7Hz,3H),2.38(t,J＝11.7Hz,2H),2.06(d,J＝12.0Hz,2H),1.82–1.65(m,2H)；MS:ESI(+)[M+1] +584.9。 1 H NMR (400MHz, DMSO-d 6 ) δ 8.09 (d, J = 5.3 Hz, 1H), 7.92 (d, J = 9.2 Hz, 3H), 7.80-7.72 (m, 2H), 7.29-7.20 ( m, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.03 (d, J = 8.8 Hz, 1H), 4.86 (d, J = 8.6 Hz, 1H), 4.57 (s, 2H), 3.90 ( s, 3H), 3.71 (d, J = 11.4 Hz, 2H), 2.69 (d, J = 4.7 Hz, 3H), 2.38 (t, J = 11.7 Hz, 2H), 2.06 (d, J = 12.0 Hz, 2H), 1.82–1.65 (m, 2H); MS: ESI(+)[M+1] + 584.9.
实施例11Example 11
化合物11:2-(4-(6-氯-7-((1-(环丙基磺酰基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺Compound 11: 2-(4-(6-chloro-7-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-3hydro-imidazole[4,5-b]pyridine-2 -Yl)phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000172
Figure PCTCN2020116696-appb-000172
通用方法E:相关化合物5-氯-N 4-(1-(环丙基磺酰基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-37,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。 General method E: Related compound 5-chloro-N 4 -(1-(cyclopropylsulfonyl)piperidin-4-yl)-3-nitropyridine-2,4-diamine (I-37, 1eq) And 2-(4-formylphenoxy)-N-methylacetamide (I-1, 1eq).
1H NMR(400MHz,DMSO-d 6)δ8.15–8.04(m,3H),7.94(s,1H),7.17–7.07(m,2H),6.02(d,J＝8.8Hz,1H),5.17–5.01(m,1H),4.56(s,2H),3.73(d,J＝12.0Hz,2H),3.05(dd,J＝13.2,10.8Hz,2H),2.67(d,J＝4.6Hz,4H),2.12(d,J＝11.2Hz,2H),1.75(qd,J＝12.1,4.1Hz,2H),1.04(ddt,J＝9.8,6.0,3.5Hz,2H),1.01–0.94(m,2H)；MS:ESI(+)[M+1] +519.0。 1 H NMR(400MHz,DMSO-d 6 )δ8.15-8.04(m,3H),7.94(s,1H),7.17-7.07(m,2H), 6.02(d,J=8.8Hz,1H), 5.17–5.01(m,1H),4.56(s,2H),3.73(d,J=12.0Hz,2H),3.05(dd,J=13.2,10.8Hz,2H),2.67(d,J=4.6Hz ,4H), 2.12(d,J=11.2Hz,2H),1.75(qd,J=12.1,4.1Hz,2H),1.04(ddt,J=9.8,6.0,3.5Hz,2H),1.01-0.94( m, 2H); MS: ESI(+)[M+1] + 519.0.
实施例12Example 12
化合物12:2-(4-(6-氯-7-((1-((1-甲基-1氢-吲哚氮唑-5-基)亚甲基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺Compound 12: 2-(4-(6-Chloro-7-((1-((1-methyl-1hydro-indoleazol-5-yl)methylene)piperidin-4-yl)amine )-3hydro-imidazole[4,5-b]pyridin-2-yl)phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000173
Figure PCTCN2020116696-appb-000173
通用方法E:相关化合物5-氯-N 4-(1-((1-甲基-1氢-吲哚氮唑-5-基)亚甲基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-38,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。 General method E: Related compound 5-chloro-N 4 -(1-((1-methyl-1hydro-indoleazol-5-yl)methylene)piperidin-4-yl)-3-nitro Pyridine-2,4-diamine (I-38, 1eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1, 1eq).
1H NMR(400MHz,DMSO-d 6)δ13.14(s,1H),8.12–8.05(m,3H),8.00(d,J＝0.9Hz,1H),7.91(s,1H),7.66(s,1H),7.60(d,J＝8.6Hz,1H),7.41(dd,J＝8.6,1.5Hz,1H),7.15–7.09(m,2H),5.79(d,J＝8.8Hz,1H),5.04–4.89(m,1H),4.57(s,2H),4.04(s,3H),3.62(s,2H),2.90(d,J＝11.2Hz,2H),2.69(d,J＝4.6Hz,3H),2.17(t,J＝11.6Hz,2H),1.99(d,J＝10.6Hz,3H),1.68(q,J＝11.8Hz,2H)；MS:ESI(+)[M+1] +559.0。 1 H NMR (400MHz, DMSO-d 6 ) δ 13.14 (s, 1H), 8.12-8.05 (m, 3H), 8.00 (d, J = 0.9 Hz, 1H), 7.91 (s, 1H), 7.66 ( s, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.41 (dd, J = 8.6, 1.5 Hz, 1H), 7.15-7.09 (m, 2H), 5.79 (d, J = 8.8 Hz, 1H ),5.04–4.89(m,1H),4.57(s,2H),4.04(s,3H),3.62(s,2H), 2.90(d,J=11.2Hz,2H), 2.69(d,J= 4.6Hz,3H), 2.17(t,J=11.6Hz,2H),1.99(d,J=10.6Hz,3H),1.68(q,J=11.8Hz,2H); MS: ESI(+)[M +1] + 559.0.
实施例13Example 13
化合物13:2-(4-(7-((1-(苯并呋喃-5-基亚甲基)哌啶-4-基)氨)-6-氯-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺Compound 13: 2-(4-(7-((1-(benzofuran-5-ylmethylene)piperidin-4-yl)amino)-6-chloro-3hydro-imidazole [4,5- b)Pyridin-2-yl)phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000174
Figure PCTCN2020116696-appb-000174
通用方法E:相关化合物N 4-(1-(苯并呋喃-5-基亚甲基)哌啶-4-基)-5-氯-3-硝基吡啶-2,4-二胺(I-39,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。 General method E: Related compound N 4 -(1-(benzofuran-5-ylmethylene)piperidin-4-yl)-5-chloro-3-nitropyridine-2,4-diamine (I -39,1eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1,1eq).
1H NMR(400MHz,DMSO-d 6)δ13.14(s,1H),8.13–8.05(m,3H),7.98(d,J＝2.2Hz,1H),7.92(s,1H),7.61(s,1H),7.55(d,J＝8.5Hz,1H),7.35–7.27(m,1H),7.16–7.08(m,2H),6.95(dd,J＝2.2,0.9Hz,1H),5.80(d,J＝8.8Hz,1H),5.04–4.87(m,1H),4.57(s,2H),3.62(s,2H),2.90(d,J＝11.2Hz,2H),2.69(d,J＝4.6Hz,3H),2.18(s,2H),2.00(d,J＝11.9Hz,2H),1.69(q,J＝11.6Hz,2H)；MS:ESI(+)[M+1] +545.0。 1 H NMR (400MHz, DMSO-d 6 ) δ 13.14 (s, 1H), 8.13-8.05 (m, 3H), 7.98 (d, J = 2.2 Hz, 1H), 7.92 (s, 1H), 7.61 ( s,1H),7.55(d,J=8.5Hz,1H),7.35-7.27(m,1H),7.16-7.08(m,2H),6.95(dd,J=2.2,0.9Hz,1H),5.80 (d,J=8.8Hz,1H),5.04–4.87(m,1H),4.57(s,2H),3.62(s,2H),2.90(d,J=11.2Hz,2H),2.69(d, J = 4.6Hz, 3H), 2.18 (s, 2H), 2.00 (d, J = 11.9 Hz, 2H), 1.69 (q, J = 11.6 Hz, 2H); MS: ESI (+) [M+1] + 545.0.
实施例14Example 14
化合物14:2-(4-(6-氯-7-((1-(4-(N-甲基甲基磺酰胺)苄基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺Compound 14: 2-(4-(6-chloro-7-((1-(4-(N-methylmethylsulfonamide)benzyl)piperidin-4-yl)amino)-3hydro-imidazole[ 4,5-b)pyridin-2-yl)phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000175
Figure PCTCN2020116696-appb-000175
通用方法E:相关化合物N-(4-((4-((2-氨-5-氯-3-硝基吡啶-4-基)氨)哌啶-1-基)亚甲基)苯基)-N-甲基甲基磺酰胺(I-40,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。General method E: related compound N-(4-((4-((2-amino-5-chloro-3-nitropyridin-4-yl)amino)piperidin-1-yl)methylene)phenyl )-N-methylmethylsulfonamide (I-40, 1eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1, 1eq).
1H NMR(400MHz,DMSO-d 6)δ13.15(s,1H),8.18–7.99(m,3H),7.97–7.85(m,1H),7.45–7.30(m,4H),7.19–7.06(m,2H),5.81(d,J＝8.7Hz,1H),4.98(s,1H),4.62–4.50(m,2H),3.53(d,J＝6.1Hz,2H),3.26–3.19(m,3H),2.96–2.82(m,5H),2.68(q,J＝4.5Hz,3H),2.17(s,2H),2.00(d,J＝11.8Hz,3H),1.70(d,J＝12.0Hz,2H)；MS:ESI(+)[M+1] +612.0。 1 H NMR (400MHz, DMSO-d 6 ) δ 13.15 (s, 1H), 8.18-7.99 (m, 3H), 7.97-7.85 (m, 1H), 7.45-7.30 (m, 4H), 7.19-7.06 (m, 2H), 5.81 (d, J = 8.7 Hz, 1H), 4.98 (s, 1H), 4.62-4.50 (m, 2H), 3.53 (d, J = 6.1 Hz, 2H), 3.26-3.19 ( m, 3H), 2.96–2.82 (m, 5H), 2.68 (q, J = 4.5 Hz, 3H), 2.17 (s, 2H), 2.00 (d, J = 11.8 Hz, 3H), 1.70 (d, J =12.0Hz, 2H); MS: ESI(+)[M+1] + 612.0.
实施例15Example 15
化合物15:2-(4-(6-氯-7-((2-((4-甲氧基苄基)(亚甲基)氨)乙基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺Compound 15: 2-(4-(6-Chloro-7-((2-((4-methoxybenzyl)(methylene)amino)ethyl)amino)-3hydro-imidazole [4,5 -b)pyridin-2-yl)phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000176
Figure PCTCN2020116696-appb-000176
通用方法E:相关化合物5-氯-N 4-(2-((4-甲氧基苄基)(亚甲基)氨)乙基)-3-硝基吡啶-2,4-二胺(I-41,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。 General method E: Related compound 5-chloro-N 4 -(2-((4-methoxybenzyl)(methylene)amino)ethyl)-3-nitropyridine-2,4-diamine ( I-41, 1 eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1, 1 eq).
1H NMR(400MHz,DMSO-d 6)δ7.73–7.65(m,2H),7.61(s,1H),7.20–7.17(m,2H),6.82(d,J＝8.1Hz,2H),6.69(d,J＝8.2Hz,2H),6.49(s,2H),5.82(s,1H),4.62(d,J＝3.9Hz,3H),4.49(d,J＝8.1Hz,2H),3.77(d,J＝5.7Hz,4H),3.27(s,2H),2.74(dd,J＝4.8,2.0Hz,5H),2.06(q,J＝7.1Hz,1H),1.92(s,3H)；MS:ESI(+):[M+H] +:509.0。 1 H NMR(400MHz,DMSO-d 6 )δ7.73-7.65(m,2H), 7.61(s,1H), 7.20-7.17(m,2H), 6.82(d,J=8.1Hz,2H), 6.69(d,J=8.2Hz,2H),6.49(s,2H),5.82(s,1H),4.62(d,J=3.9Hz,3H), 4.49(d,J=8.1Hz,2H), 3.77(d,J=5.7Hz,4H), 3.27(s,2H), 2.74(dd,J=4.8,2.0Hz,5H), 2.06(q,J=7.1Hz,1H),1.92(s,3H ); MS: ESI(+): [M+H] + : 509.0.
实施例16Example 16
化合物16:2-(4-(6-氯-7-((1-(甲基磺酰基)哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺Compound 16: 2-(4-(6-Chloro-7-((1-(methylsulfonyl)piperidin-4-yl)amino)-3hydro-imidazole[4,5-b]pyridine-2- (Phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000177
Figure PCTCN2020116696-appb-000177
通用方法E:相关化合物5-氯-N 4-(1-(甲基磺酰基)哌啶--4-基)-3-硝基吡啶-2,4-二胺(I-42,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。 General method E: Related compound 5-chloro-N 4 -(1-(methylsulfonyl)piperidin-4-yl)-3-nitropyridine-2,4-diamine (I-42, 1eq) And 2-(4-formylphenoxy)-N-methylacetamide (I-1, 1eq).
1H NMR(400MHz,DMSO-d 6)δ13.18(s,1H),8.10(dd,J＝8.7,6.5Hz,3H),7.94(s,1H),7.17–7.05(m,2H),6.01(d,J＝8.9Hz,1H),5.06(q,J＝10.3Hz,1H),4.56(s,2H),3.68(d,J＝12.1Hz,2H),2.97(s,5H),2.67(d,J＝4.6Hz,3H),2.12(d,J＝11.7Hz,2H),1.75(qd,J＝12.2,4.1Hz,2H)；MS:ESI(+):[M+H] +:493.0。 1 H NMR (400MHz, DMSO-d 6 ) δ 13.18 (s, 1H), 8.10 (dd, J = 8.7, 6.5 Hz, 3H), 7.94 (s, 1H), 7.17-7.05 (m, 2H), 6.01 (d, J = 8.9 Hz, 1H), 5.06 (q, J = 10.3 Hz, 1H), 4.56 (s, 2H), 3.68 (d, J = 12.1 Hz, 2H), 2.97 (s, 5H), 2.67(d,J＝4.6Hz,3H), 2.12(d,J＝11.7Hz,2H), 1.75(qd,J＝12.2,4.1Hz,2H); MS: ESI(+): [M+H] + : 493.0.
实施例17Example 17
化合物17:(R)-2-(4-(6-氯-7-((1-甲基哌啶-3-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)苯氧基)-N-甲基乙酰胺Compound 17: (R)-2-(4-(6-chloro-7-((1-methylpiperidin-3-yl)amino)-3hydro-imidazole[4,5-b]pyridine-2- (Phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000178
Figure PCTCN2020116696-appb-000178
通用方法E:相关化合物(R)-5-氯-N 4-(1-甲基哌啶-3-基)-3-硝基吡啶-2,4-二胺(I-43,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。 General method E: Related compound (R)-5-chloro-N 4 -(1-methylpiperidin-3-yl)-3-nitropyridine-2,4-diamine (I-43, 1eq) and 2-(4-Formylphenoxy)-N-methylacetamide (I-1, 1eq).
1H NMR(400MHz,DMSO-d 6)δ13.18(s,1H),8.17–8.03(m,3H),7.95(s,1H),7.23–7.00(m,2H),5.84(d,J＝9.2Hz,1H),5.28–5.14(m,1H),4.56(s,2H),2.68(d,J＝4.6Hz,4H),2.33(s,2H),2.23(s,3H),2.08(s,1H),1.82–1.48(m,4H)；MS:ESI(+)[M+1] +429.0。 1 H NMR (400MHz, DMSO-d 6 ) δ 13.18 (s, 1H), 8.17-8.03 (m, 3H), 7.95 (s, 1H), 7.23-7.00 (m, 2H), 5.84 (d, J =9.2Hz,1H),5.28–5.14(m,1H),4.56(s,2H),2.68(d,J=4.6Hz,4H),2.33(s,2H),2.23(s,3H),2.08 (s, 1H), 1.82–1.48 (m, 4H); MS: ESI(+)[M+1] + 429.0.
实施例18Example 18
化合物18:2-((5-(6-氯-7-((1-甲基哌啶-4-基)氨)-3氢-咪唑[4,5-b]吡啶-2-基)吡啶-2-基)氧基)-N-甲基乙酰胺Compound 18: 2-((5-(6-Chloro-7-((1-methylpiperidin-4-yl)amino)-3hydro-imidazole[4,5-b]pyridin-2-yl)pyridine -2-yl)oxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000179
Figure PCTCN2020116696-appb-000179
通用方法E:相关化合物5-氯-N 4-(1-甲基哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-5,1eq)和2-((5-甲酰基吡啶-2-基)氧基)-N-甲基乙酰胺(I-6,1eq)。 General method E: Related compounds 5-chloro-N 4 -(1-methylpiperidin-4-yl)-3-nitropyridine-2,4-diamine (I-5, 1eq) and 2-(( 5-Formylpyridin-2-yl)oxy)-N-methylacetamide (I-6, 1 eq).
1H NMR(400MHz,DMSO-d 6)δ8.41(d,J＝2.6Hz,1H),8.29–8.21(m,1H),8.16(dd,J＝9.6,2.5Hz,1H),7.93(s,1H),6.58(d,J＝9.5Hz,1H),6.01(d,J＝8.4Hz,1H),4.98(s,1H),4.60(s,2H),2.65(d,J＝4.5Hz,5H),2.16–1.89(m,5H),1.80(d,J＝12.4Hz,2H)；MS:ESI(+):[M+H] +:430.0。 1 H NMR(400MHz,DMSO-d 6 )δ8.41(d,J=2.6Hz,1H), 8.29–8.21(m,1H), 8.16(dd,J=9.6,2.5Hz,1H), 7.93( s, 1H), 6.58 (d, J = 9.5 Hz, 1H), 6.01 (d, J = 8.4 Hz, 1H), 4.98 (s, 1H), 4.60 (s, 2H), 2.65 (d, J = 4.5 Hz, 5H), 2.16–1.89 (m, 5H), 1.80 (d, J=12.4 Hz, 2H); MS: ESI(+): [M+H] + : 430.0.
实施例19Example 19
化合物19:2-(4-(4-((1-(4-甲氧基苄基)哌啶-4-基)氨)-1氢-咪唑[4,5-c]吡啶-2-基)苯氧基)-N-甲基乙酰胺Compound 19: 2-(4-(4-((1-(4-methoxybenzyl)piperidin-4-yl)amino)-1hydro-imidazole[4,5-c]pyridin-2-yl )Phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000180
Figure PCTCN2020116696-appb-000180
通用方法E:相关化合物N 2-(1-(4-甲氧基苄基)哌啶-4-基)-3-硝基吡啶-2,4-二胺(I-44,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。 General method E: Related compounds N 2 -(1-(4-methoxybenzyl)piperidin-4-yl)-3-nitropyridine-2,4-diamine (I-44, 1eq) and 2 -(4-Formylphenoxy)-N-methylacetamide (I-1, 1eq).
1H NMR(400MHz,DMSO-d 6)δ8.12–8.04(m,3H),7.69(d,J＝5.8Hz,1H),7.37(s,2H),7.13(d,J＝8.8Hz,2H),6.98(s,2H),6.76(d,J＝5.2Hz,1H),4.56(s,2H),3.78(s,3H),2.68(d,J＝4.6Hz,3H),2.00(dt,J＝13.0,7.1Hz,4H),1.76(s,2H).MS:ESI(+)[M+1] +501.3。 1 H NMR(400MHz,DMSO-d 6 )δ8.12–8.04(m,3H), 7.69(d,J=5.8Hz,1H), 7.37(s,2H), 7.13(d,J=8.8Hz, 2H), 6.98 (s, 2H), 6.76 (d, J = 5.2 Hz, 1H), 4.56 (s, 2H), 3.78 (s, 3H), 2.68 (d, J = 4.6 Hz, 3H), 2.00 ( dt, J=13.0, 7.1 Hz, 4H), 1.76 (s, 2H). MS: ESI(+)[M+1] + 501.3.
实施例20Example 20
化合物20:2-(4-(6-((1-(4-甲氧基苄基)哌啶-4-基)氨)-3氢-咪唑[4,5-c]吡啶-2-基)苯氧基)-N-甲基乙酰胺Compound 20: 2-(4-(6-((1-(4-methoxybenzyl)piperidin-4-yl)amino)-3hydro-imidazole[4,5-c]pyridin-2-yl )Phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000181
Figure PCTCN2020116696-appb-000181
通用方法E:相关化合物N 2-(1-(4-甲氧基苄基)哌啶-4-基)-5-硝基吡啶-2,4-二胺(I-45,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。 General method E: Related compounds N 2 -(1-(4-methoxybenzyl)piperidin-4-yl)-5-nitropyridine-2,4-diamine (I-45, 1eq) and 2 -(4-Formylphenoxy)-N-methylacetamide (I-1, 1eq).
1H NMR(400MHz,DMSO-d 6)δ12.35(s,1H),8.35(s,1H),8.08(s,1H),8.03(d,J＝8.5Hz,2H),7.23–7.20(m,2H),7.11(d,J＝8.6Hz,2H),6.91–6.87(m,2H),6.42(s,1H),4.55(s,2H),3.40(s,2H),2.78(d,J＝11.5Hz,1H),2.67(d,J＝4.6Hz,3H),2.04–1.99(m,3H),1.91(d,J＝12.2Hz,2H),1.44(d,J＝13.6Hz,2H)；MS:ESI(+)[M+1] +501.0。 1 H NMR (400MHz, DMSO-d 6 ) δ 12.35 (s, 1H), 8.35 (s, 1H), 8.08 (s, 1H), 8.03 (d, J = 8.5 Hz, 2H), 7.23-7.20 ( m, 2H), 7.11 (d, J = 8.6 Hz, 2H), 6.91-6.87 (m, 2H), 6.42 (s, 1H), 4.55 (s, 2H), 3.40 (s, 2H), 2.78 (d ,J=11.5Hz,1H),2.67(d,J=4.6Hz,3H),2.04-1.99(m,3H),1.91(d,J=12.2Hz,2H),1.44(d,J=13.6Hz ,2H); MS: ESI(+)[M+1] + 501.0.
实施例21Example 21
化合物21:2-(4-(6-((1-(4-甲氧基苄基)哌啶-4-基)氨)-9氢-嘌呤-8-基)苯氧基)-N-甲基乙酰胺Compound 21: 2-(4-(6-((1-(4-methoxybenzyl)piperidin-4-yl)amino)-9hydro-purin-8-yl)phenoxy)-N- Methylacetamide
Figure PCTCN2020116696-appb-000182
Figure PCTCN2020116696-appb-000182
通用方法E:相关化合物N 4-(1-(4-甲氧基苄基)哌啶-4-基)-5-硝基嘧啶-4,6-二胺(I-46,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。 General method E: Related compounds N 4 -(1-(4-methoxybenzyl)piperidin-4-yl)-5-nitropyrimidine-4,6-diamine (I-46, 1eq) and 2 -(4-Formylphenoxy)-N-methylacetamide (I-1, 1eq).
1H NMR(400MHz,DMSO-d 6)δ8.15–8.07(m,2H),8.04(s,1H),7.89(s,1H),7.26–7.20(m,2H),6.95(d,J＝8.5Hz,2H),6.93–6.86(m,2H),4.48(s,2H),3.74(s,3H),3.40(s,2H),2.81(d,J＝11.1Hz,2H),2.68(d,J＝4.5Hz,4H),2.02(dd,J＝13.2,5.8Hz,4H),1.88(d,J＝12.3Hz,2H),1.57(q,J＝11.3,10.9Hz,2H)；MS:ESI(+)[M+1] +502.0。 1 H NMR (400MHz, DMSO-d 6 ) δ 8.15-8.07 (m, 2H), 8.04 (s, 1H), 7.89 (s, 1H), 7.26-7.20 (m, 2H), 6.95 (d, J =8.5Hz, 2H), 6.93–6.86 (m, 2H), 4.48 (s, 2H), 3.74 (s, 3H), 3.40 (s, 2H), 2.81 (d, J = 11.1Hz, 2H), 2.68 (d, J = 4.5Hz, 4H), 2.02 (dd, J = 13.2, 5.8 Hz, 4H), 1.88 (d, J = 12.3 Hz, 2H), 1.57 (q, J = 11.3, 10.9 Hz, 2H) ; MS: ESI(+)[M+1] + 502.0.
实施例22Example 22
化合物22:2-(4-(4-((1-(4-甲氧基苄基)哌啶-4-基)氨)-1H-苯并[d]咪唑-2-基)苯氧基)-N-甲基乙酰胺Compound 22: 2-(4-(4-((1-(4-methoxybenzyl)piperidin-4-yl)amino)-1H-benzo(d)imidazol-2-yl)phenoxy )-N-Methylacetamide
Figure PCTCN2020116696-appb-000183
Figure PCTCN2020116696-appb-000183
通用方法E:相关化合物N 1-(1-(4-甲氧基苄基)哌啶-4-基)-2-硝基苯基-1,3-二胺(I-47,1eq)and 2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。硅胶柱纯化,洗脱液EtOAc/MeOH/TEA(250:1:2)。 General method E: Related compound N 1 -(1-(4-methoxybenzyl)piperidin-4-yl)-2-nitrophenyl-1,3-diamine (I-47, 1eq) and 2-(4-Formylphenoxy)-N-methylacetamide (I-1, 1eq). Purification by silica gel column, eluent EtOAc/MeOH/TEA (250:1:2).
1H NMR(400MHz,Chloroform-d)δ8.00(t,J＝9.3Hz,2H),7.25(d,J＝8.2Hz,2H),7.02(ddd,J＝23.9,11.7,8.2Hz,4H),6.88–6.84(m,2H),6.64(s,1H),6.30(d,J＝8.4Hz,1H),4.55–4.52(m,2H),3.81(s,3H),3.49(s,3H),3.28(dtd,J＝15.8,8.5,7.9,6.3Hz,1H),2.94–2.87(m,5H),2.79(q,J＝7.2Hz,4H),2.21–2.10(m,4H),1.66–1.58(m,2H)；MS:ESI(+):[M+H] +:500.1。 1 H NMR (400MHz, Chloroform-d) δ8.00 (t, J = 9.3Hz, 2H), 7.25 (d, J = 8.2Hz, 2H), 7.02 (ddd, J = 23.9, 11.7, 8.2Hz, 4H ), 6.88–6.84(m,2H), 6.64(s,1H), 6.30(d,J=8.4Hz,1H), 4.55–4.52(m,2H), 3.81(s,3H), 3.49(s, 3H), 3.28 (dtd, J = 15.8, 8.5, 7.9, 6.3 Hz, 1H), 2.94-2.87 (m, 5H), 2.79 (q, J = 7.2 Hz, 4H), 2.21-2.10 (m, 4H) ,1.66–1.58(m,2H); MS: ESI(+): [M+H] + : 500.1.
实施例23Example 23
化合物23:2-(4-(5-氯-4-((1-(4-甲氧基苄基)哌啶-4-基)氨)-1氢-苯并[d]咪唑-2-基)苯氧基)-N-甲基乙酰胺Compound 23: 2-(4-(5-chloro-4-((1-(4-methoxybenzyl)piperidin-4-yl)amino)-1hydro-benzo(d)imidazole-2- (Phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000184
Figure PCTCN2020116696-appb-000184
通用方法E:相关化合物6-氯-N 1-(1-(4-甲氧基苄基)哌啶-4-基)-2-硝基苯基-1,3-二胺(I-48,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。硅胶柱纯化,洗脱液EtOAc/MeOH/TEA(200:1:2). General method E: Related compound 6-chloro-N 1 -(1-(4-methoxybenzyl)piperidin-4-yl)-2-nitrophenyl-1,3-diamine (I-48 ,1eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1,1eq). Purified by silica gel column, eluent EtOAc/MeOH/TEA (200:1:2).
1H NMR(400MHz,Chloroform-d)δ8.07–7.93(m,2H),7.26(d,J＝6.8Hz,3H),7.02(t,J＝9.7Hz,3H),6.87(d,J＝8.1Hz,2H),6.64(s,1H),6.30(d,J＝8.4Hz,1H),4.55(s,2H),3.81(s,3H),3.50(d,J＝8.8Hz,3H),2.95(dd,J＝9.9,6.0Hz,5H),2.16(dd,J＝35.9,12.0Hz,4H),1.70–1.59(m,2H)；MS:ESI(+)[M+1] +534.1。 1 H NMR(400MHz,Chloroform-d)δ8.07–7.93(m,2H), 7.26(d,J=6.8Hz,3H), 7.02(t,J=9.7Hz,3H), 6.87(d,J ＝8.1Hz, 2H), 6.64 (s, 1H), 6.30 (d, J = 8.4 Hz, 1H), 4.55 (s, 2H), 3.81 (s, 3H), 3.50 (d, J = 8.8 Hz, 3H ), 2.95(dd,J=9.9,6.0Hz,5H), 2.16(dd,J=35.9,12.0Hz,4H),1.70–1.59(m,2H); MS: ESI(+)[M+1] + 534.1.
实施例24Example 24
化合物24:2-(4-(7-氯-4-((1-(4-甲氧基苄基)哌啶-4-基)氨)-1氢-苯并[d]咪唑-2-基)苯氧基)-N-甲基乙酰胺Compound 24: 2-(4-(7-chloro-4-((1-(4-methoxybenzyl)piperidin-4-yl)amino)-1hydro-benzo(d)imidazole-2- (Phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000185
Figure PCTCN2020116696-appb-000185
通用方法E:相关化合物4-氯-N 1-(1-(4-甲氧基苄基)哌啶-4-基)-2-硝基苯基-1,3-二胺(I-49,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。硅胶柱纯化,洗脱液EtOAc/MeOH/TEA(200:1:2)。 General method E: Related compound 4-chloro-N 1 -(1-(4-methoxybenzyl)piperidin-4-yl)-2-nitrophenyl-1,3-diamine (I-49 ,1eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1,1eq). Purification by silica gel column, eluent EtOAc/MeOH/TEA (200:1:2).
1H NMR(400MHz,Chloroform-d)δ7.86(d,J＝8.3Hz,2H),7.16(d,J＝8.4Hz,2H),7.01(d,J＝8.5Hz,1H),6.86–6.81(m,2H),6.79–6.74(m,2H),6.70–6.54(m,2H),4.68(d,J＝40.5Hz,1H),4.41(s,2H),4.28(d,J＝40.9Hz,1H),3.71(s,3H),3.43(s,2H),2.82(dd,J＝15.1,7.8Hz,5H),2.14(td,J＝11.2,10.0,4.7Hz,2H),2.01(d,J＝10.0Hz,2H),1.51(d,J＝34.4Hz,2H)；MS:ESI(+)[M+1] +534.1。 1 H NMR (400MHz, Chloroform-d) δ 7.86 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.5 Hz, 1H), 6.86- 6.81(m,2H), 6.79–6.74(m,2H), 6.70–6.54(m,2H), 4.68(d,J=40.5Hz,1H), 4.41(s,2H), 4.28(d,J= 40.9Hz, 1H), 3.71 (s, 3H), 3.43 (s, 2H), 2.82 (dd, J = 15.1, 7.8 Hz, 5H), 2.14 (td, J = 11.2, 10.0, 4.7 Hz, 2H), 2.01 (d, J = 10.0 Hz, 2H), 1.51 (d, J = 34.4 Hz, 2H); MS: ESI (+) [M+1] + 534.1.
实施例25Example 25
化合物32:2-(4-(5-氯-4-((1-(4-(三甲基硅烷基)苄基)哌啶-4-基)氨)-1氢-苯并[d]咪唑-2-基)苯氧基)-N-甲基乙酰胺Compound 32: 2-(4-(5-chloro-4-((1-(4-(trimethylsilyl)benzyl)piperidin-4-yl)amino)-1hydro-benzo[d] (Imidazol-2-yl)phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000186
Figure PCTCN2020116696-appb-000186
通用方法E:相关化合物6-氯-2-硝基-N 1-(1-(4-(三甲基硅烷基)苄基)哌啶-4-基)苯-1,3-二胺(I-51,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。硅胶柱纯化,洗脱液:EtOAc/MeOH/TEA(200:1:2)。 General method E: Related compound 6-chloro-2-nitro-N 1 -(1-(4-(trimethylsilyl)benzyl)piperidin-4-yl)benzene-1,3-diamine ( I-51, 1 eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1, 1 eq). Purification by silica gel column, eluent: EtOAc/MeOH/TEA (200:1:2).
1H NMR(400MHz,Chloroform-d)δ7.58–7.52(m,2H),7.50(d,J＝7.6Hz,2H),7.32(d,J＝7.6Hz,2H),7.13(d,J＝8.7Hz,1H),7.05(dd,J＝8.8,7.2Hz,3H),6.61(s,1H),4.71(s,2H),4.58(s,2H),4.23(tt,J＝12.3,4.2Hz,1H),3.53(s,2H),3.03(d,J＝11.4Hz,2H),2.94(d,J＝4.9Hz,3H),2.71–2.53(m,2H),2.01(t,J＝12.3Hz,2H),1.85–1.76(m,2H),0.27(s,9H)；MS:ESI(+):[M+H] +:576.22。 1 H NMR (400MHz, Chloroform-d) δ 7.58–7.52 (m, 2H), 7.50 (d, J = 7.6 Hz, 2H), 7.32 (d, J = 7.6 Hz, 2H), 7.13 (d, J =8.7Hz, 1H), 7.05 (dd, J = 8.8, 7.2 Hz, 3H), 6.61 (s, 1H), 4.71 (s, 2H), 4.58 (s, 2H), 4.23 (tt, J = 12.3, 4.2Hz, 1H), 3.53 (s, 2H), 3.03 (d, J = 11.4 Hz, 2H), 2.94 (d, J = 4.9 Hz, 3H), 2.71-2.53 (m, 2H), 2.01 (t, J = 12.3 Hz, 2H), 1.85-1.76 (m, 2H), 0.27 (s, 9H); MS: ESI (+): [M+H] + : 576.22.
实施例26Example 26
化合物33:2-(4-(5-氯-4-((1-(2,5-二氟苄基)哌啶-4-基)氨)-1氢-苯并[d]咪唑-2-基)苯氧基)-N-甲基乙酰胺Compound 33: 2-(4-(5-chloro-4-((1-(2,5-difluorobenzyl)piperidin-4-yl)amino)-1hydro-benzo(d)imidazole-2 -Yl)phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000187
Figure PCTCN2020116696-appb-000187
通用方法E:相关化合物6-氯-N 1-(1-(2,5-二氟苄基)哌啶-4-基)-2-硝基苯基-1,3-二胺(I-52,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。硅胶柱纯化,洗脱液:EtOAc/MeOH/TEA(200:1:2)。 General method E: Related compound 6-chloro-N 1 -(1-(2,5-difluorobenzyl)piperidin-4-yl)-2-nitrophenyl-1,3-diamine (I- 52,1eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1,1eq). Purification by silica gel column, eluent: EtOAc/MeOH/TEA (200:1:2).
1H NMR(400MHz,Chloroform-d)δ7.57–7.49(m,2H),7.15(dd,J＝11.9,7.1Hz,2H),7.07–6.91(m,5H),6.63(s,1H),4.72(s,2H),4.58(s,2H),4.22(tt,J＝12.4,4.3Hz,1H),3.58(d,J＝1.5Hz,2H),3.02(d,J＝11.3Hz,2H),2.94(d,J＝5.0Hz,3H),2.62(qd,J＝12.5,3.9Hz,2H),2.12–2.05(m,2H),1.88–1.78(m,2H)；MS:ESI(+):[M+H] +:540.2。 1 H NMR (400MHz, Chloroform-d) δ 7.57-7.49 (m, 2H), 7.15 (dd, J=11.9, 7.1 Hz, 2H), 7.07-6.91 (m, 5H), 6.63 (s, 1H) ,4.72(s,2H),4.58(s,2H),4.22(tt,J＝12.4,4.3Hz,1H),3.58(d,J＝1.5Hz,2H),3.02(d,J＝11.3Hz, 2H), 2.94(d,J=5.0Hz,3H), 2.62(qd,J=12.5,3.9Hz,2H), 2.12–2.05(m,2H),1.88–1.78(m,2H); MS: ESI (+):[M+H] + : 540.2.
实施例27Example 27
化合物34:2-(4-(5-氯-4-((1-((1-甲基-1氢-吲哚-5-基)亚甲基)哌啶-4-基)氨)-1氢-苯并[d]咪唑-2-基)苯氧基)-N-甲基乙酰胺Compound 34: 2-(4-(5-chloro-4-((1-((1-methyl-1hydro-indol-5-yl)methylene)piperidin-4-yl)amino)- 1Hydro-benzo[d]imidazol-2-yl)phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000188
Figure PCTCN2020116696-appb-000188
通用方法E:相关化合物6-氯-N 1-(1-((1-甲基-1氢-吲哚-5-基)亚甲基)哌啶-4-基)-2-硝基苯基-1,3-二胺(I-53,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq).硅胶柱纯化,洗脱液:EtOAc/MeOH/TEA(100:1:1)。 General method E: related compound 6-chloro-N 1 -(1-((1-methyl-1hydro-indol-5-yl)methylene)piperidin-4-yl)-2-nitrobenzene 1,3-diamine (I-53, 1eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1, 1eq). Purification by silica gel column, eluent: EtOAc/MeOH/TEA (100:1:1).
1H NMR(400MHz,Chloroform-d)δ7.95(d,J＝0.9Hz,1H),7.61(t,J＝1.1Hz,1H),7.56–7.52(m,2H),7.45–7.37(m,2H),7.13(d,J＝8.7Hz,1H),7.06–7.02(m,3H),6.62(s,1H),4.71(s,2H),4.58(s,2H),4.23(tt,J＝12.4,4.3Hz,1H),4.08(s,3H),3.63(s,2H),3.03(d,J＝11.4Hz,2H),2.94(d,J＝4.9Hz,3H),2.61(qd,J＝12.5,4.0Hz,2H),2.07–1.97(m,3H),1.84–1.77(m,2H),1.28–1.22(m,1H)；MS:ESI(+):[M+H] +:558.2。 1 H NMR (400MHz, Chloroform-d) δ 7.95 (d, J = 0.9Hz, 1H), 7.61 (t, J = 1.1Hz, 1H), 7.56–7.52 (m, 2H), 7.45–7.37 (m ,2H),7.13(d,J=8.7Hz,1H),7.06-7.02(m,3H),6.62(s,1H),4.71(s,2H),4.58(s,2H),4.23(tt, J = 12.4, 4.3 Hz, 1H), 4.08 (s, 3H), 3.63 (s, 2H), 3.03 (d, J = 11.4 Hz, 2H), 2.94 (d, J = 4.9 Hz, 3H), 2.61 ( qd,J=12.5,4.0Hz,2H),2.07–1.97(m,3H),1.84–1.77(m,2H),1.28–1.22(m,1H); MS:ESI(+):[M+H ] + :558.2.
实施例28Example 28
化合物35:2-(4-(5-氯-4-((1-(4-(N-甲基甲基磺酰氨)苄基)哌啶-4-基)氨)-1氢-苯并[d]咪唑-2-基)苯氧基)-N-甲基乙酰胺Compound 35: 2-(4-(5-chloro-4-((1-(4-(N-methylmethylsulfonamide)benzyl)piperidin-4-yl)amino)-1hydro-benzene And [d]imidazol-2-yl)phenoxy)-N-methylacetamide
Figure PCTCN2020116696-appb-000189
Figure PCTCN2020116696-appb-000189
通用方法E:相关化合物N-(4-((4-((3-氨-6-氯-2-硝基苯基)氨)哌啶-1-基)亚甲基)苯基)-N-甲基甲基磺酰胺(I-54,1eq)和2-(4-甲酰基苯氧基)-N-甲基乙酰胺(I-1,1eq)。硅胶柱纯化,洗脱液:EtOAc/MeOH/TEA(100:1:1)。General Method E: Related Compound N-(4-((4-((3-Amino-6-chloro-2-nitrophenyl)amino)piperidin-1-yl)methylene)phenyl)-N -Methyl methylsulfonamide (I-54, 1eq) and 2-(4-formylphenoxy)-N-methylacetamide (I-1, 1eq). Purification by silica gel column, eluent: EtOAc/MeOH/TEA (100:1:1).
1H NMR(400MHz,Chloroform-d)δ7.60–7.51(m,2H),7.41–7.31(m,4H),7.13(d,J＝8.7Hz,1H),7.09–6.98(m,3H),6.64(s,1H),4.72(s,2H),4.58(s,2H),4.24(tt,J＝12.2,4.3Hz,1H),3.51(s,2H),3.33(s,3H),3.05–2.97(m,2H),2.94(d,J＝5.0Hz,3H),2.86(s,3H),2.63(ddt,J＝21.1,12.5,7.2Hz,2H),2.07–1.98(m,3H),1.88–1.76(m,2H),1.30–1.23(m,2H)；MS:ESI(+):[M+H] +:611.2。 1 H NMR(400MHz, Chloroform-d) δ7.60–7.51(m,2H), 7.41–7.31(m,4H), 7.13(d,J=8.7Hz,1H), 7.09–6.98(m,3H) ,6.64(s,1H),4.72(s,2H),4.58(s,2H), 4.24(tt,J＝12.2,4.3Hz,1H),3.51(s,2H),3.33(s,3H), 3.05–2.97 (m, 2H), 2.94 (d, J = 5.0 Hz, 3H), 2.86 (s, 3H), 2.63 (ddt, J = 21.1, 12.5, 7.2 Hz, 2H), 2.07–1.98 (m, 3H), 1.88–1.76 (m, 2H), 1.30–1.23 (m, 2H); MS: ESI(+): [M+H] + : 611.2.
生物学测定以及效果实施例：Examples of biological assays and effects:
效果实施例1Effect Example 1
实验材料：Experimental Materials:
1.细胞株及培养条件：1. Cell lines and culture conditions:
细胞株名称Cell line name 培养条件Culture condition
人慢性淋巴细胞白血病K562Human chronic lymphocytic leukemia K562 RPMI-1640+10％FBSRPMI-1640+10%FBS
人急性淋巴细胞白血病JurkatHuman Acute Lymphoblastic Leukemia Jurkat RPMI-1640+10％FBSRPMI-1640+10%FBS
人白血病HL-60Human Leukemia HL-60 RPMI-1640+10％FBSRPMI-1640+10%FBS
人肺腺癌A549Human lung adenocarcinoma A549 DMDM+10％FBSDMDM+10%FBS
人肺腺癌H1299Human lung adenocarcinoma H1299 RPMI-1640+10％FBSRPMI-1640+10%FBS
人三阴性乳腺癌MDA-MB-231Human triple negative breast cancer MDA-MB-231 L-15+10％FBSL-15+10%FBS
人三阴性乳腺癌MDA-MB-468Human triple negative breast cancer MDA-MB-468 DMDM+10％FBSDMDM+10%FBS
人卵巢癌细胞A2780Human ovarian cancer cell A2780 DMDM+10％FBSDMDM+10%FBS
人卵巢癌细胞OVCAR-3Human ovarian cancer cell OVCAR-3 DMDM+10％FBSDMDM+10%FBS
人卵巢癌细胞SK-OV-3Human ovarian cancer cell SK-OV-3 DMDM+10％FBSDMDM+10%FBS
人乳腺癌阿霉素耐药株MDA-MB-231/AdrHuman breast cancer resistant to adriamycin MDA-MB-231/Adr DMDM+10％FBSDMDM+10%FBS
人肺癌紫杉醇耐药株A549/TaxolHuman lung cancer paclitaxel-resistant strain A549/Taxol DMDM+10％FBSDMDM+10%FBS
人卵巢癌紫杉醇耐药株A2780/TaxolHuman Ovarian Cancer Paclitaxel Resistant Strain A2780/Taxol DMDM+10％FBSDMDM+10%FBS
人白细胞长春新碱耐药株HL60/VCRHuman leukocyte vincristine resistant strain HL60/VCR RPMI-1640+10％FBSRPMI-1640+10%FBS
2.商业可获得的试剂：RPMI-1640(批号：1970736)、DMEM(批号：2027913)及L-15培养基(批号：AD18274267)均购自Gibco公司；CCK8细胞活力检测试剂盒(批号：EG20190416)由南京恩晶生物科技有限公司提供。2. Commercially available reagents: RPMI-1640 (batch number: 1970736), DMEM (batch number: 2027913) and L-15 medium (batch number: AD18274267) were purchased from Gibco; CCK8 cell viability detection kit (batch number: EG20190416) ) Provided by Nanjing Enjing Biotechnology Co., Ltd.
3.实验方法：CCK8法检测受试物对各细胞体外增殖活性的影响：取对数生长期细胞进行实验。细胞经消化、计数、制成1×10 5个/mL的细胞悬液，接种于96孔板中(100μL/孔)，置于37℃，5％CO 2培养箱中培养24小时；每孔加入含相应浓度的受试物，同时设立阴性对照组及空白组，每组3复孔；将板置于培养箱中培养72h后，显微镜下观察各组细胞形态，每孔加入10μL CCK8溶液，在细胞培养箱内继续孵育4小时，450nm下测定吸光值，并计算增殖抑制率。 3. Experimental method: CCK8 method to detect the effect of the test substance on the proliferation activity of each cell in vitro: Take logarithmic growth phase cells for experiment. The cells were digested and counted to prepare a cell suspension of 1×10 5 cells/mL, seeded in a 96-well plate (100 μL/well), and placed in a 37°C, 5% CO 2 incubator for 24 hours; each well Add the test substance with the corresponding concentration, and set up a negative control group and a blank group at the same time, each group has 3 duplicate holes; after the plate is placed in an incubator for 72 hours, the cell morphology of each group is observed under a microscope, and 10 μL of CCK8 solution is added to each well. Continue to incubate for 4 hours in the cell incubator, measure the absorbance at 450 nm, and calculate the proliferation inhibition rate.
表1列出了部分化合物对所列肿瘤细胞体外活性的结果。Table 1 lists the results of in vitro activities of some compounds on the listed tumor cells.
表1：8种受试物对各肿瘤细胞体外增殖活性IC 50(μM)汇总。 Table 1: Summary of the in vitro proliferation activity IC 50 (μM) of 8 test substances on each tumor cell.
Figure PCTCN2020116696-appb-000190
Figure PCTCN2020116696-appb-000190
Figure PCTCN2020116696-appb-000191
Figure PCTCN2020116696-appb-000191
效果实施例2Effect Example 2
实验材料：Experimental Materials:
1.细胞株及培养条件：1. Cell lines and culture conditions:
细胞株名称Cell line name 培养条件Culture condition
人套细胞系淋巴瘤细胞株Z138Human mantle cell line lymphoma cell line Z138 DMEM+10％FBSDMEM+10%FBS
人弥漫大B淋巴瘤细胞WSU-DLCL2Human diffuse large B lymphoma cell WSU-DLCL2 RPMI-1640+10％FBSRPMI-1640+10%FBS
人弥漫大B淋巴瘤细胞DOHH-2Human Diffuse Large B Lymphoma Cell DOHH-2 RPMI-1640+10％FBSRPMI-1640+10%FBS
人***癌细胞株PC-3Human prostate cancer cell line PC-3 RPMI-1640+10％FBSRPMI-1640+10%FBS
人***癌细胞株DU145Human prostate cancer cell line DU145 MEM+10％FBSMEM+10%FBS
人套细胞淋巴瘤细胞株Jeko-1Human mantle cell lymphoma cell line Jeko-1 RPMI-1640+10％FBSRPMI-1640+10%FBS
人胰腺癌细胞株BXPC-3Human pancreatic cancer cell line BXPC-3 DMEM+10％FBSDMEM+10%FBS
2.受试药物及试剂：2. Test drugs and reagents:
RPMI-1640、DMEM及MEM培养基购自Gibco公司；RPMI-1640, DMEM and MEM medium were purchased from Gibco;
CCK8细胞活力检测试剂盒由南京恩晶生物科技有限公司提供，批号：EG20190416。The CCK8 cell viability test kit was provided by Nanjing Enjing Biotechnology Co., Ltd., batch number: EG20190416.
3.仪器：3. Apparatus:
生物洁净安全柜，苏州净化设备有限公司，型号：BHC-1300A/B2；Biological clean safety cabinet, Suzhou Purification Equipment Co., Ltd., model: BHC-1300A/B2;
二氧化碳培养箱，日本三洋SANYO，型号：MCO-15AC；Carbon dioxide incubator, SANYO, Japan, model: MCO-15AC;
荧光倒置生物显微镜，南京江南永新光学有限公司，型号：XD-202；Fluorescence inverted biological microscope, Nanjing Jiangnan Yongxin Optics Co., Ltd., model: XD-202;
酶标仪，Thermo scientific，型号，MUTISKAN MK3。Microplate reader, Thermoscientific, model, MUTISKAN MK3.
4.实验方法：4. Experimental method:
CCK8法检测受试物对各细胞体外增殖活性的影响：The CCK8 method detects the effect of the test substance on the proliferation activity of each cell in vitro:
取对数生长期细胞进行实验。细胞经消化、计数、制成1×10 5个/mL的细胞悬液，接种于96孔板中(100μL/孔)，置于37℃，5％CO 2培养箱中培养24小时；每孔加入含相应浓度的受试物，同时设立阴性对照组及空白组，每组3复孔；将板置于培养箱中培养72h后，显微镜下观察各组细胞形态，每孔加入10μL CCK8溶液，在细胞培养箱内继续孵育2-4小时，450nm下测定吸光值，并计算增殖抑制率。 Take logarithmic growth phase cells for experiment. The cells were digested and counted to prepare a cell suspension of 1×10 5 cells/mL, seeded in a 96-well plate (100 μL/well), and placed in a 37°C, 5% CO 2 incubator for 24 hours; each well Add the test substance with the corresponding concentration, and set up a negative control group and a blank group at the same time, each group has 3 duplicate holes; after the plate is placed in an incubator for 72 hours, the cell morphology of each group is observed under a microscope, and 10 μL of CCK8 solution is added to each well. Continue to incubate for 2-4 hours in the cell incubator, measure the absorbance at 450nm, and calculate the proliferation inhibition rate.
表2：受试物对各肿瘤细胞体外增殖活性IC 50汇总(单位：μM)。 Table 2: Summary of the IC 50 of the in vitro proliferation activity of the test substances on each tumor cell (unit: μM).
受试物Test substance PC-3PC-3 BXPC-3BXPC-3 DU145DU145 Z138Z138 jeko-1jeko-1 WSU-DLCL2WSU-DLCL2 DOHH-2DOHH-2
H1H1 0.51700.5170 0.79160.7916 2.1602.160 0.58710.5871 0.61070.6107 0.68810.6881 0.51820.5182
H2H2 0.94150.9415 0.66690.6669 4.8154.815 0.67490.6749 1.2181.218 0.97180.9718 0.49330.4933
H3H3 0.74770.7477 0.59650.5965 3.2243.224 0.46970.4697 0.59950.5995 0.49800.4980 0.41890.4189
H4H4 0.62750.6275 0.71500.7150 1.8921.892 0.51770.5177 1.3851.385 0.49940.4994 0.31420.3142
H5H5 0.23330.2333 0.34330.3433 1.3921.392 0.39130.3913 0.49130.4913 0.30350.3035 0.26050.2605
1212 0.066890.06689 0.11650.1165 0.55980.5598 0.15240.1524 0.21790.2179 0.10480.1048 0.085960.08596
23twenty three 9.7459.745 7.0197.019 58.8158.81 13.7413.74 9.5309.530 12.5112.51 20.7720.77
Figure PCTCN2020116696-appb-000192
Figure PCTCN2020116696-appb-000192
效果实施例3化合物对裸鼠异种移植肿瘤生长的影响Effect Example 3 The effect of the compound on the growth of xenograft tumors in nude mice
试验中采用的对照化合物H1为WO2016124553实施例中的化合物。The control compound H1 used in the experiment is the compound in the examples of WO2016124553.
取生长旺盛期的肿瘤，在无菌条件下，肿瘤细胞接种于BALB/c裸小鼠右侧腋窝皮 下，细胞接种量为5×10 6。裸小鼠移植瘤用游标卡尺测量移植瘤直径，待肿瘤生长至100mm 3左右时挑选生长状态良好且肿瘤大小均一性较好荷瘤裸鼠分组给药。给药结束后脱颈处死裸鼠，手术剥取瘤块称重，抗肿瘤活性的评价指标为抑瘤率(％)，计算公式为：抑瘤率(％)＝(模型组瘤重-给药组瘤重/模型组瘤重*100％)，结果如表3所示。 Take the tumors in the vigorous growth stage, under aseptic conditions, inoculate the tumor cells into the right axilla of BALB/c nude mice subcutaneously, and the cell inoculation amount is 5×10 6 . The diameter of the transplanted tumor in nude mice was measured with a vernier caliper. When the tumor grew to about 100mm 3 , the tumor-bearing nude mice with good growth status and good tumor size uniformity were selected for group administration. After the end of the administration, the nude mice were killed by removing the neck and surgically stripping the tumor mass. The evaluation index of anti-tumor activity was the tumor inhibition rate (%). The calculation formula was: tumor inhibition rate (%) = (model group tumor weight-given) Tumor weight in drug group/tumor weight in model group*100%), the results are shown in Table 3.
表3化合物对人***癌PC-3裸鼠异种移植肿瘤生长的影响(Mean±SD,n＝8)Table 3 Effects of Compounds on the Growth of Human Prostate Cancer PC-3 Xenograft Tumor in Nude Mice (Mean±SD, n=8)
Figure PCTCN2020116696-appb-000193
Figure PCTCN2020116696-appb-000193
与模型组比较， *p<0.05, **p<0.01。 Compared with the model group, * p<0.05, ** p<0.01.
根据上述数据可知，两种化合物对人***癌PC-3裸鼠异种移植瘤生长有明显的抑制作用。对PC-3异种移植瘤的抗肿瘤活性从强到弱顺序为：化合物12＞化合物H1。According to the above data, the two compounds have a significant inhibitory effect on the growth of human prostate cancer PC-3 xenograft tumors in nude mice. The order of anti-tumor activity against PC-3 xenograft tumors from strong to weak is: compound 12>compound H1.
效果实施例4Effect Example 4
受试药物：化合物H5，化合物12，化合物23。Test drugs: Compound H5, Compound 12, Compound 23.
药物配置：Drug configuration:
溶媒：5％DMSO、25％聚乙二醇(PEG400)、70％生理盐水。Solvent: 5% DMSO, 25% polyethylene glycol (PEG400), 70% normal saline.
动物：animal:
来源、种系、品系：ICR小鼠，由南通大学提供(实验动物生产许可证：SCXK(苏)2016-0010)；实验动物使用许可证：SYXK(苏)2017-0035。Source, strain, strain: ICR mice, provided by Nantong University (Experimental animal production license: SCXK (苏)2016-0010); Laboratory animal use license: SYXK (苏)2017-0035.
日龄：采购时4-6周，开始给药时6-8周Age: 4-6 weeks at the time of purchase, 6-8 weeks at the start of dosing
体重：18-20gWeight: 18-20g
性别：雌雄各半Gender: half male and half
实验方法：experimental method:
实验动物雌雄各半，随机分成三组，即化合物H5(4500mg/kg)，化合物12(4500mg/kg)，化合物23(4500mg/kg)。每组10只动物，雌雄各半。各组动物单次灌胃给药，给药体积为0.2ml/10g体重。给药后观察动物状态，记录死亡数，存活动物继续观察。The experimental animals were half male and half male and randomly divided into three groups, namely compound H5 (4500 mg/kg), compound 12 (4500 mg/kg), and compound 23 (4500 mg/kg). There are 10 animals in each group, half male and half male. The animals in each group were given a single intragastric administration, and the administration volume was 0.2ml/10g body weight. Observe the state of the animals after the administration, record the number of deaths, and continue to observe the surviving animals.
实验结果：Experimental results:
化合物H5、化合物12、化合物23对小鼠的急性毒性动物存活情况的影响见表4。化合物H5、化合物12、化合物23对急性毒性动物体重情况的影响见表5。The effects of compound H5, compound 12, and compound 23 on the survival of acutely toxic animals in mice are shown in Table 4. The effects of compound H5, compound 12, and compound 23 on the body weight of acutely toxic animals are shown in Table 5.
表4:化合物H5、化合物12、化合物23对小鼠的急性毒性动物存活情况的影响Table 4: Effects of Compound H5, Compound 12, and Compound 23 on the Survival Status of Acute Toxic Animals in Mice
Figure PCTCN2020116696-appb-000194
Figure PCTCN2020116696-appb-000194
表5:化合物H5、化合物12、化合物23对小鼠的急性毒性实验小鼠体重的影响(g)Table 5: Effect of Compound H5, Compound 12, and Compound 23 on Mouse Body Weight in Acute Toxicity Experiment (g)
组别Group 单次给药剂量Single dose 给药前体重Body weight before administration 给药后一周体重Body weight one week after administration
化合物H 5Compound H 5 4500mg/kg4500mg/kg 22.4±0.622.4±0.6 24.8±0.824.8±0.8
化合物12Compound 12 4500mg/kg4500mg/kg 22.3±0.322.3±0.3 24.4±0.524.4±0.5
化合物23Compound 23 4500mg/kg4500mg/kg 21.9±0.221.9±0.2 24.5±1.024.5±1.0
结论：in conclusion:
化合物H5的半数致死剂量(LD50)为4500mg/kg左右；化合物12和化合物23的半数致死剂量(LD50)大于4500mg/kg。The median lethal dose (LD50) of compound H5 is about 4500 mg/kg; the median lethal dose (LD50) of compound 12 and compound 23 is greater than 4500 mg/kg.
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。Although the specific embodiments of the present invention are described above, those skilled in the art should understand that these are only examples, and various changes or modifications can be made to these embodiments without departing from the principle and essence of the present invention. modify. Therefore, the protection scope of the present invention is defined by the appended claims.

Claims (15)

  1. 一种如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐；A heteroaryl compound as shown in formula I, its tautomer, stereoisomer or pharmaceutically acceptable salt;
    Figure PCTCN2020116696-appb-100001
    Figure PCTCN2020116696-appb-100001
    其中，
    Figure PCTCN2020116696-appb-100002
    表示咪唑环中的不饱和键；     among them,
    Figure PCTCN2020116696-appb-100002
    Represents the unsaturated bond in the imidazole ring;
    X和Y独立地为
    Figure PCTCN2020116696-appb-100003
    X and Y are independently
    Figure PCTCN2020116696-appb-100003
    R 4独立地为H、F、Cl、Br、I、或未取代或被一个或多个R 4a取代的C 1-C 4烷基；当所述的取代为多个时，相同或不同； R 4 is independently H, F, Cl, Br, I, or a C 1 -C 4 alkyl group that is unsubstituted or substituted with one or more R 4a ; when the substitutions are multiple, they are the same or different;
    R 2独立地为C 1-C 6烷基； R 2 is independently C 1 -C 6 alkyl;
    n为0、1、2、3或4；n is 0, 1, 2, 3 or 4;
    W独立地为连接键、-O-(C 1-C 3亚烷基)-、-S-(C 1-C 3亚烷基)-或-N(R W1)-(C 1-C 3亚烷基)-； W is independently a linkage, -O-(C 1 -C 3 alkylene)-, -S-(C 1 -C 3 alkylene)- or -N(R W1 )-(C 1 -C 3 Alkylene)-;
    R W1独立地为H或C 1-C 4烷基； R W1 is independently H or C 1 -C 4 alkyl;
    R 3独立地为-C(＝O)-NR 3aR 3a’或-NR 3b-C(＝O)-R 3b’； R 3 is independently -C(=O)-NR 3a R 3a' or -NR 3b -C(=O)-R 3b' ;
    R 3a、R 3a’、R 3b和R 3b’独立地为H或C 1-C 6烷基； R 3a , R 3a' , R 3b and R 3b' are independently H or C 1 -C 6 alkyl;
    R 1独立地为
    Figure PCTCN2020116696-appb-100004
    R 1 is independently
    Figure PCTCN2020116696-appb-100004
    R 5和R 5’独立地为H或C 1-C 6烷基； R 5 and R 5'are independently H or C 1 -C 6 alkyl;
    o、p1和q1独立地为1、2或3；p2和q2独立地为1或2；o, p1 and q1 are independently 1, 2 or 3; p2 and q2 are independently 1 or 2;
    L 1独立地为-SO 2-或C 1-C 3亚烷基； L 1 is independently -SO 2 -or C 1 -C 3 alkylene;
    L 2独立地为C 1-C 3亚烷基； L 2 is independently C 1 -C 3 alkylene;
    R a和R b独立地为未取代或被一个或多个R a1取代的C l-C 6烷基、未取代或被一个或多个R a2取代的C 3～C 6环烷基、未取代或被一个或多个R a3取代的C 2～C 9杂环烷基、未取代或被一个或多个R a4取代的C 6～C 10芳基、或、未取代或被一个或多个R a5取代的C 2～C 9杂芳基；所述的C 2～C 9杂环烷基中，杂原子选自N、O或S中的一种或多种，杂原子数 为1～3个；所述的C 2～C 9杂芳基中，杂原子选自N、O或S中的一种或多种，杂原子数为1～4个；当所述的取代为多个时，相同或不同； R a and R b are independently unsubstituted or substituted with one or more substituents R a1 is C l -C 6 alkyl, unsubstituted or substituted with one or more R a2 is C 3 ~ C 6 cycloalkyl group, is not unsubstituted or substituted with one or more R a3 is C 2 ~ C 9 heterocycloalkyl, unsubstituted or substituted with one or more R a4 is C 6 ~ C 10 aryl group, or an unsubstituted or substituted by one or more A C 2 ～C 9 heteroaryl group substituted by R a5 ; in the C 2 ～C 9 heterocycloalkyl group, the heteroatom is selected from one or more of N, O or S, and the number of heteroatoms is 1. ～3; In the C 2 ～C 9 heteroaryl group, the heteroatom is selected from one or more of N, O or S, and the number of heteroatoms is 1 to 4; when the substitution is more When, same or different;
    R a1、R a2、R a3、R a4和R a5独立地为H、F、Cl、Br、I、未取代或被一个或多个R 1a-1取代的C l-C 6烷基、未取代或被一个或多个R 1a-2取代的C l-C 6烷基-O-、
    Figure PCTCN2020116696-appb-100005
    -N(R b2)SO 2-R b2’或-N(R b3R b3’)；当所述的取代为多个时，相同或不同；     R a1 , R a2 , R a3 , R a4 and R a5 are independently H, F, Cl, Br, I, unsubstituted or substituted by one or more R 1a-1 C 1 -C 6 alkyl, unsubstituted C 1 -C 6 alkyl-O- substituted or substituted with one or more R 1a-2,
    Figure PCTCN2020116696-appb-100005
    -N(R b2 )SO 2 -R b2' or -N(R b3 R b3' ); when there are multiple substitutions, they are the same or different;
    R c独立地为
    Figure PCTCN2020116696-appb-100006
    R c is independently
    Figure PCTCN2020116696-appb-100006
    R b1、R b1’、R b1”、R b2’、R c2、R c2’、R c2”、R c3’和R c4独立地为C l-C 6烷基；R b2、R b3、R b3’和R c3独立地为H或C l-C 6烷基； R b1 , R b1 ' , R b1 " , R b2' , R c2 , R c2 ' , R c2" , R c3' and R c4 are independently C 1 -C 6 alkyl groups; R b2 , R b3 , R b3' and R c3 are independently H or C 1 -C 6 alkyl;
    R c1独立地为H、F、Cl、Br、I、未取代或被一个或多个R c1-1取代的C l-C 6烷基、或未取代或被一个或多个R c1-2取代的C l-C 6烷基-O-；当所述的取代为多个时，相同或不同； R c1 independently is H, F, Cl, Br, I, unsubstituted or substituted with one or more R c1-1 is C l -C 6 alkyl, or unsubstituted or substituted by one or more R c1-2 Substituted C 1 -C 6 alkyl-O-; when there are multiple substitutions, they are the same or different;
    R 4a、R 1a-1、R 1a-2、R c1-1和R c1-2独立地为F、Cl、Br或I； R 4a , R 1a-1 , R 1a-2 , R c1-1 and R c1-2 are independently F, Cl, Br or I;
    带“*”碳原子表示为非手性碳原子或手性碳原子，当为手性碳原子时，为S构型、R构型或它们的混合物。A carbon atom with "*" means an achiral carbon atom or a chiral carbon atom. When it is a chiral carbon atom, it is in the S configuration, R configuration or a mixture thereof.
  2. 如权利要求1所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐，其特征在于，
    Figure PCTCN2020116696-appb-100007
    为
    Figure PCTCN2020116696-appb-100008
    The heteroaryl compound represented by formula I, its tautomer, stereoisomer or pharmaceutically acceptable salt according to claim 1, characterized in that:
    Figure PCTCN2020116696-appb-100007
    for
    Figure PCTCN2020116696-appb-100008
    和/或，所述的未取代或被一个或多个R 4a取代的C 1-C 4烷基里的C 1-C 4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, the C 1 -C 4 alkyl group in the C 1 -C 4 alkyl group that is unsubstituted or substituted by one or more R 4a is independently methyl, ethyl, n-propyl, isopropyl Base, n-butyl, isobutyl, sec-butyl or tert-butyl;
    和/或，R 4a、R 1a-1、R 1a-2、R c1-1和R c1-2独立地为F或Cl； And/or, R 4a , R 1a-1 , R 1a-2 , R c1-1 and R c1-2 are independently F or Cl;
    和/或，R 2独立地为C 1-C 6烷基里的C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, R 2 is independently the C 1 -C 6 alkyl group in the C 1 -C 6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Sec-butyl or tert-butyl;
    和/或，n为0或1；And/or, n is 0 or 1;
    和/或，W位于环
    Figure PCTCN2020116696-appb-100009
    的间位或对位；     And/or, W is in the ring
    Figure PCTCN2020116696-appb-100009
    的分位 or counterpoint;
    和/或，W独立地为-O-(C 1-C 3亚烷基)-、-S-(C 1-C 3亚烷基)-或-N(R W1)-(C 1-C 3亚烷基)-里的C 1-C 3亚烷基独立地为-CH 2-、-CH 2CH 2-、-CH(CH 3)-、-CH(CH 3)CH 2-或-C(CH 3) 2-； And/or, W is independently -O-(C 1 -C 3 alkylene)-, -S-(C 1 -C 3 alkylene)- or -N(R W1 )-(C 1 -C 3 alkylene)-C 1 -C 3 alkylene is independently -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )-, -CH(CH 3 )CH 2 -or- C(CH 3 ) 2 -;
    和/或，R W1独立地为C 1-C 4烷基里的C 1-C 4烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, R W1 is independently a C 1 -C 4 alkyl group and the C 1 -C 4 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Sec-butyl or tert-butyl;
    和/或，R 3a、R 3a’、R 3b和R 3b’独立地为C 1-C 6烷基里的C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, R 3a , R 3a' , R 3b and R 3b' are independently C 1 -C 6 alkyl in C 1 -C 6 alkyl and independently are methyl, ethyl, n-propyl, iso Propyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
    和/或，R 5和R 5’独立地为C 1-C 6烷基里的C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, R 5 and R 5'are independently C 1 -C 6 alkyl and C 1 -C 6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, sec-butyl or tert-butyl;
    和/或，o为1或2；And/or, o is 1 or 2;
    和/或，p为1或2；And/or, p is 1 or 2;
    和/或，q为1或2；And/or, q is 1 or 2;
    和/或，L 1和L 2独立地为C 1-C 3亚烷基里的C 1-C 3亚烷基独立地为-CH 2-、-CH 2CH 2-、-CH(CH 3)-、-CH(CH 3)CH 2-或-C(CH 3) 2-； And/or, L 1 and L 2 are independently C 1 -C 3 alkylene in C 1 -C 3 alkylene independently -CH 2 -, -CH 2 CH 2 -, -CH (CH 3 )-, -CH(CH 3 )CH 2 -or -C(CH 3 ) 2 -;
    和/或，所述的未取代或被一个或多个R a1取代的C l-C 6烷基里的C l-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And / or, the unsubstituted or substituted with one or more R a1 is C l -C 6 alkyl group in the C l -C 6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, Base, n-butyl, isobutyl, sec-butyl or tert-butyl;
    和/或，所述的未取代或被一个或多个R a2取代的C 3～C 6环烷基里的C 3～C 6环烷基为环丙基、环丁基、环戊基或环己基； And/or, the C 3 ～C 6 cycloalkyl group in the C 3 ～C 6 cycloalkyl group that is unsubstituted or substituted by one or more Ra2 is cyclopropyl, cyclobutyl, cyclopentyl or Cyclohexyl
    和/或，所述的未取代或被一个或多个R a3取代的C 2～C 9杂环烷基里的C 2～C 9杂环烷基为C 3～C 6杂环烷基，其中的杂原子为N，杂原子数为1或2个； And/or, the C 2 to C 9 heterocycloalkyl in the C 2 to C 9 heterocycloalkyl group that is unsubstituted or substituted with one or more Ra3 is a C 3 to C 6 heterocycloalkyl group, The heteroatom is N, and the number of heteroatoms is 1 or 2;
    和/或，所述的未取代或被一个或多个R a4取代的C 6～C 10芳基里的C 6～C 10芳基为苯基或萘基； And/or, the C 6 ～C 10 aryl group in the C 6 ～C 10 aryl group substituted by one or more R a4 is phenyl or naphthyl;
    和/或，所述的未取代或被一个或多个R a5取代的C 2～C 9杂芳基里的C 2～C 9杂芳基为C 2～C 9杂芳基独立地为吡啶基、苯并呋喃基或吲唑基； And/or, the C 2 ～C 9 heteroaryl group in the C 2 ～C 9 heteroaryl group substituted with one or more Ra5 is C 2 ～C 9 heteroaryl group independently is pyridine Group, benzofuranyl or indazolyl;
    和/或，R a1、R a2、R a3、R a4和R a5独立地为未取代或被一个或多个R 1a-1取代的C l-C 6烷基、未取代或被一个或多个R 1a-2取代的C l-C 6烷基-O-里的C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, R a1 , R a2 , R a3 , R a4 and R a5 are independently unsubstituted or substituted with one or more R 1a-1 C 1 -C 6 alkyl, unsubstituted or one or more a R 1a-2 substituted C l -C 6 alkyl Lane -O- C 1 -C 6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , Sec-butyl or tert-butyl;
    和/或，R b1、R b1’、R b1”、R b2’、R c2、R c2’、R c2”、R c3’、R c4、R b2、R b3、R b3’和R c3独立地为C l-C 6烷基里的C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And/or, R b1 , R b1' , R b1" , R b2' , R c2 , R c2' , R c2 " , R c3' , R c4 , R b2 , R b3 , R b3' and R c3 are independent The C 1 -C 6 alkyl group in the C 1 -C 6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl ；
    和/或，R c1独立地为未取代或被一个或多个R c1-1取代的C l-C 6烷基、或未取代或被一个或多个R c1-2取代的C l-C 6烷基-O-里的C 1-C 6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基； And / or, R c1 independently is unsubstituted or substituted with one or more R c1-1 is C l -C 6 alkyl, or unsubstituted or substituted by one or more R c1-2 substituted C l -C The C 1 -C 6 alkyl group in 6 alkyl-O- is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
    和/或，当带“*”碳原子为手性碳时，为构型R或S构型。And/or, when the carbon atom with "*" is a chiral carbon, it is in the R or S configuration.
  3. 如权利要求2所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐，其特征在于，
    Figure PCTCN2020116696-appb-100010
    选自：
    Figure PCTCN2020116696-appb-100011
    Figure PCTCN2020116696-appb-100012
    The heteroaryl compound represented by formula I, its tautomer, stereoisomer or pharmaceutically acceptable salt according to claim 2, characterized in that:
    Figure PCTCN2020116696-appb-100010
    Selected from:
    Figure PCTCN2020116696-appb-100011
    Figure PCTCN2020116696-appb-100012
    和/或，R 4独立地为H或Cl； And/or, R 4 is independently H or Cl;
    和/或，n为0；And/or, n is 0;
    和/或，W位于环
    Figure PCTCN2020116696-appb-100013
    的对位；     And/or, W is in the ring
    Figure PCTCN2020116696-appb-100013
    Counterpoint
    和/或，W中，所述的-O-(C 1-C 3亚烷基)-独立地为-O-(CH 2)-； And/or, in W, the -O-(C 1 -C 3 alkylene)- is independently -O-(CH 2 )-;
    和/或，-C(＝O)-NR 3aR 3a’独立地为-C(＝O)-NHCH 3； And/or, -C(=O)-NR 3a R 3a' is independently -C(=O)-NHCH 3 ;
    和/或，
    Figure PCTCN2020116696-appb-100014
    独立地为
    Figure PCTCN2020116696-appb-100015
    and / or,
    Figure PCTCN2020116696-appb-100014
    Independently
    Figure PCTCN2020116696-appb-100015
    和/或，
    Figure PCTCN2020116696-appb-100016
    独立地为
    Figure PCTCN2020116696-appb-100017
    and / or,
    Figure PCTCN2020116696-appb-100016
    Independently
    Figure PCTCN2020116696-appb-100017
    和/或，所述的未取代或被一个或多个R a5取代的C 2～C 9杂芳基里的C 2～C 9杂芳基独立地为
    Figure PCTCN2020116696-appb-100018
    And/or, the C 2 ～C 9 heteroaryl group in the C 2 ～C 9 heteroaryl group substituted with one or more R a5 is independently
    Figure PCTCN2020116696-appb-100018
    和/或，L 1中，所述的C 1-C 3亚烷基独立地为亚甲基； And/or, in L 1 , the C 1 -C 3 alkylene group is independently methylene;
    和/或，L 2独立地为亚甲基； And/or, L 2 is independently methylene;
    和/或，
    Figure PCTCN2020116696-appb-100019
    独立地为
    Figure PCTCN2020116696-appb-100020
    and / or,
    Figure PCTCN2020116696-appb-100019
    Independently
    Figure PCTCN2020116696-appb-100020
    和/或，-N(R b2)SO 2-R b2’和
    Figure PCTCN2020116696-appb-100021
    独立地为-N(CH 3)SO 2-CH 3；     And/or, -N(R b2 )SO 2 -R b2' and
    Figure PCTCN2020116696-appb-100021
    Independently -N(CH 3 )SO 2 -CH 3 ;
    和/或，
    Figure PCTCN2020116696-appb-100022
    为
    Figure PCTCN2020116696-appb-100023
    and / or,
    Figure PCTCN2020116696-appb-100022
    for
    Figure PCTCN2020116696-appb-100023
    和/或，
    Figure PCTCN2020116696-appb-100024
    为
    Figure PCTCN2020116696-appb-100025
    and / or,
    Figure PCTCN2020116696-appb-100024
    for
    Figure PCTCN2020116696-appb-100025
    和/或，
    Figure PCTCN2020116696-appb-100026
    为
    Figure PCTCN2020116696-appb-100027
    and / or,
    Figure PCTCN2020116696-appb-100026
    for
    Figure PCTCN2020116696-appb-100027
    和/或，当带“*”碳原子为手性碳时，为构型R构型。And/or, when the carbon atom with "*" is a chiral carbon, it is in the R configuration.
  4. 如权利要求3所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐，其特征在于，
    Figure PCTCN2020116696-appb-100028
    选自：
    Figure PCTCN2020116696-appb-100029
    Figure PCTCN2020116696-appb-100030
    The heteroaryl compound represented by formula I, its tautomer, stereoisomer or pharmaceutically acceptable salt according to claim 3, characterized in that:
    Figure PCTCN2020116696-appb-100028
    Selected from:
    Figure PCTCN2020116696-appb-100029
    Figure PCTCN2020116696-appb-100030
    和/或，-W-R 3为
    Figure PCTCN2020116696-appb-100031
    And/or, -WR 3 is
    Figure PCTCN2020116696-appb-100031
    和/或，所述的未取代或被一个或多个R a4取代的C 6～C 10芳基选自：
    Figure PCTCN2020116696-appb-100032
    Figure PCTCN2020116696-appb-100033
    And/or, the C 6 -C 10 aryl group that is unsubstituted or substituted by one or more R a4 is selected from:
    Figure PCTCN2020116696-appb-100032
    Figure PCTCN2020116696-appb-100033
    和/或，所述的未取代或被一个或多个R a5取代的C 2～C 9杂芳基选自：
    Figure PCTCN2020116696-appb-100034
    Figure PCTCN2020116696-appb-100035
    And/or, the C 2 -C 9 heteroaryl group that is unsubstituted or substituted by one or more Ra5 is selected from:
    Figure PCTCN2020116696-appb-100034
    Figure PCTCN2020116696-appb-100035
    和/或，
    Figure PCTCN2020116696-appb-100036
    为
    Figure PCTCN2020116696-appb-100037
    Figure PCTCN2020116696-appb-100038
    and / or,
    Figure PCTCN2020116696-appb-100036
    for
    Figure PCTCN2020116696-appb-100037
    Figure PCTCN2020116696-appb-100038
    和/或，
    Figure PCTCN2020116696-appb-100039
    为
    Figure PCTCN2020116696-appb-100040
    and / or,
    Figure PCTCN2020116696-appb-100039
    for
    Figure PCTCN2020116696-appb-100040
    和/或，
    Figure PCTCN2020116696-appb-100041
    为
    Figure PCTCN2020116696-appb-100042
    and / or,
    Figure PCTCN2020116696-appb-100041
    for
    Figure PCTCN2020116696-appb-100042
    和/或，
    Figure PCTCN2020116696-appb-100043
    为
    Figure PCTCN2020116696-appb-100044
    and / or,
    Figure PCTCN2020116696-appb-100043
    for
    Figure PCTCN2020116696-appb-100044
  5. 如权利要求4所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐，其特征在于，
    Figure PCTCN2020116696-appb-100045
    为
    Figure PCTCN2020116696-appb-100046
    Figure PCTCN2020116696-appb-100047
    The heteroaryl compound represented by formula I, its tautomer, stereoisomer or pharmaceutically acceptable salt according to claim 4, characterized in that:
    Figure PCTCN2020116696-appb-100045
    for
    Figure PCTCN2020116696-appb-100046
    Figure PCTCN2020116696-appb-100047
    和/或，R 1独立地为
    Figure PCTCN2020116696-appb-100048
    And/or, R 1 is independently
    Figure PCTCN2020116696-appb-100048
    和/或，L 1独立地为C 1-C 3亚烷基； And/or, L 1 is independently C 1 -C 3 alkylene;
    和/或，L 2独立地为C 1-C 3亚烷基； And/or, L 2 is independently C 1 -C 3 alkylene;
    和/或，R a独立地为未取代或被一个或多个R a4取代的C 6～C 10芳基； And/or, R a is independently a C 6 -C 10 aryl group that is unsubstituted or substituted with one or more R a4;
    和/或，R b独立地为未取代或被一个或多个R a1取代的C l-C 6烷基、未取代或被一个或多个R a2取代的C 3～C 6环烷基、或未取代或被一个或多个R a4取代的C 6～C 10芳基； And / or, R b is independently unsubstituted or substituted with one or more R a1 is C l -C 6 alkyl, unsubstituted or substituted with one or more R a2 is C 3 ~ C 6 cycloalkyl, C 6 ～C 10 aryl groups that are either unsubstituted or substituted with one or more R a4;
    和/或，R c独立地为
    Figure PCTCN2020116696-appb-100049
    And/or, R c is independently
    Figure PCTCN2020116696-appb-100049
    和/或，W为-O-(C 1-C 3亚烷基)-； And/or, W is -O-(C 1 -C 3 alkylene)-;
    和/或，R 3为-C(＝O)-NR 3aR 3a’。 And/or, R 3 is -C(=O)-NR 3a R 3a' .
  6. 如权利要求1-5中任一项所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐，其特征在于，所述的如式I所示的杂芳基类化合物为如式Ia所示：The heteroaryl compound of formula I, its tautomers, stereoisomers or pharmaceutically acceptable salts according to any one of claims 1 to 5, wherein said The heteroaryl compound as shown in formula I is as shown in formula Ia:
    Figure PCTCN2020116696-appb-100050
    Figure PCTCN2020116696-appb-100050
    其中，R 1为
    Figure PCTCN2020116696-appb-100051
    R c独立地为
    Figure PCTCN2020116696-appb-100052
    Where R 1 is
    Figure PCTCN2020116696-appb-100051
    R c is independently
    Figure PCTCN2020116696-appb-100052
    R 2、R 3、R 4a、R a、R b、R 5、R 5’、L 1、L 2、R c2、R c2’、R c2”、R c3、R c3’、R c4、W、o、p1、q1、p2、q2和n的定义均如权利要求1-5中任一项所述。 R 2 , R 3 , R 4a , R a , R b , R 5 , R 5 ' , L 1 , L 2 , R c2 , R c2' , R c2 " , R c3 , R c3 ' , R c4 , W , O, p1, q1, p2, q2 and n are defined as in any one of claims 1-5.
  7. 如权利要求1-5中任一项所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐，其特征在于，所述的如式I所示的杂芳基类化合物为如式Ib所示：The heteroaryl compound of formula I, its tautomers, stereoisomers or pharmaceutically acceptable salts according to any one of claims 1 to 5, wherein said The heteroaryl compound as shown in formula I is as shown in formula Ib:
    Figure PCTCN2020116696-appb-100053
    Figure PCTCN2020116696-appb-100053
    其中，X和Y独立地为
    Figure PCTCN2020116696-appb-100054
    或者，Y独立地为
    Figure PCTCN2020116696-appb-100055
    X独立地为
    Figure PCTCN2020116696-appb-100056
    Figure PCTCN2020116696-appb-100057
    R 1、R 2、R 3、R 4、W和n的定义均如权利要求1-5中任一项所述。     Where X and Y are independently
    Figure PCTCN2020116696-appb-100054
    Or, Y is independently
    Figure PCTCN2020116696-appb-100055
    X is independently
    Figure PCTCN2020116696-appb-100056
    Figure PCTCN2020116696-appb-100057
    The definitions of R 1 , R 2 , R 3 , R 4 , W and n are as described in any one of claims 1-5.
  8. 如权利要求1-5中任一项所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐，其特征在于，所述的如式I所示的杂芳基类化合物选自如下结构：The heteroaryl compound of formula I, its tautomers, stereoisomers or pharmaceutically acceptable salts according to any one of claims 1 to 5, wherein said The heteroaryl compound represented by formula I is selected from the following structures:
    Figure PCTCN2020116696-appb-100058
    Figure PCTCN2020116696-appb-100058
  9. 一种药物组合物，其特征在于，其包括如权利要求1-8中任一项所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐，和，至少一种药用辅料。A pharmaceutical composition, characterized in that it comprises the heteroaryl compound represented by formula I according to any one of claims 1-8, its tautomers, stereoisomers or pharmaceuticals Acceptable salt, and, at least one pharmaceutical excipient.
  10. 一种如权利要求1-8中任一项所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐、或者如权利要求9所述的药物组合物在制备酪氨酸激酶样孤儿受体1抑制剂，或者在制备用于预防和/或***的药物中的应用；A heteroaryl compound as shown in formula I according to any one of claims 1-8, its tautomers, stereoisomers or pharmaceutically acceptable salts, or as claimed 9. Application of the pharmaceutical composition in the preparation of tyrosine kinase-like orphan receptor 1 inhibitors, or in the preparation of drugs for the prevention and/or treatment of tumors;
    所述的药物可通过调节ROR1活性预防和/或***；所述的肿瘤可为血癌，如慢性淋巴细胞性白血病，急性骨髓性白血病，急性淋巴母细胞性白血病或者细胞淋巴瘤，以及实体肿瘤，例如，肺癌，卵巢癌，乳腺癌或者胰腺癌；The drugs can prevent and/or treat tumors by regulating the activity of ROR1; the tumors can be blood cancers, such as chronic lymphocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia or cell lymphoma, and solid tumors , For example, lung cancer, ovarian cancer, breast cancer or pancreatic cancer;
    所述的肿瘤的细胞可为人慢性髓系白血病细胞K562、人急性淋巴细胞白血病Jurkat细胞、人原髓细胞白血病细胞HL-60、人肺腺癌细胞A549、人肺腺癌细胞H1299、人三阴性乳腺癌MDA-MB-231细胞、人三阴性乳腺癌MDA-MB-468细胞、人卵巢癌细胞A2780、人卵巢癌细胞OVCAR-3、人卵巢癌细胞SK-OV-3、人乳腺癌阿霉素耐药株MDA-MB-231/Adr、人肺癌紫杉醇耐药株A549/Taxol、人卵巢癌紫杉醇耐药株A2780/Taxol和人白细胞长春新碱耐药株HL60/VCR中的一种或多种。The tumor cells can be human chronic myeloid leukemia cells K562, human acute lymphoblastic leukemia Jurkat cells, human promyelocytic leukemia cells HL-60, human lung adenocarcinoma cells A549, human lung adenocarcinoma cells H1299, human triple negative Breast cancer MDA-MB-231 cells, human triple-negative breast cancer MDA-MB-468 cells, human ovarian cancer cell A2780, human ovarian cancer cell OVCAR-3, human ovarian cancer cell SK-OV-3, human breast cancer adriamycin One or more of the drug-resistant strain MDA-MB-231/Adr, human lung cancer-resistant paclitaxel-resistant strain A549/Taxol, human ovarian cancer-resistant paclitaxel-resistant strain A2780/Taxol, and human leukocyte vincristine-resistant strain HL60/VCR Kind.
  11. 如权利要求10所述的应用；其特征在于，所述的肿瘤为***癌；The use of claim 10; wherein the tumor is prostate cancer;
    和/或，所述的肿瘤的细胞为人套细胞系淋巴瘤细胞株Z138、人弥漫大B淋巴瘤细胞WSU-DLCL2、人弥漫大B淋巴瘤细胞DOHH-2、人***癌细胞株PC-3、人***癌细胞株DU145、人套细胞淋巴瘤细胞株Jeko-1和人胰腺癌细胞株BXPC-3中的一种或多种。And/or, the cells of the tumor are human mantle cell line lymphoma cell line Z138, human diffuse large B lymphoma cell WSU-DLCL2, human diffuse large B lymphoma cell DOHH-2, and human prostate cancer cell line PC-3 One or more of human prostate cancer cell line DU145, human mantle cell lymphoma cell line Jeko-1 and human pancreatic cancer cell line BXPC-3.
  12. 一种如权利要求1-8中任一项所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐在制备药物中的应用。A kind of heteroaryl compound as shown in formula I according to any one of claims 1-8, its tautomer, stereoisomer or pharmaceutically acceptable salt is used in the preparation of medicine application.
  13. 一种用于预防和/或治疗哺乳动物中，与酪氨酸激酶样孤儿受体1的活性调节或混乱状况有关的疾病的方法，通过对需要此种治疗的哺乳动物喂服有效量的如权利要求1-8中任一项所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐或者如权利要求9所述的药物组合物；所述的与酪氨酸激酶样孤儿受体1的活性调节或混乱状况有关的疾病例如恶性增生型失调，肥胖相关代谢并发症，自身免疫性疾病或炎症。A method for preventing and/or treating diseases related to the regulation or disorder of tyrosine kinase-like orphan receptor 1 activity in mammals by administering an effective amount of such as The heteroaryl compound represented by formula I according to any one of claims 1-8, its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, or the heteroaryl compounds according to claim 9 Pharmaceutical composition; the diseases related to the activity regulation or disorder of tyrosine kinase-like orphan receptor 1, such as malignant proliferative disorders, obesity-related metabolic complications, autoimmune diseases or inflammation.
  14. 一种用于预防和/或治疗癌症的方法，其包括给受试者施用有效剂量的如权利要求1-8中任一项所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐或者如权利要求9所述的药物组合物。A method for the prevention and/or treatment of cancer, which comprises administering to a subject an effective dose of the heteroaryl compound of formula I according to any one of claims 1-8, and their mutual Mutants, stereoisomers or pharmaceutically acceptable salts or the pharmaceutical composition according to claim 9.
  15. 一种治疗剂，其包括如权利要求1-8中任一项所述的如式I所示的杂芳基类化合物、其互变异构体、立体异构体或药学上可接受的盐或者如权利要求9所述的药物组合物。A therapeutic agent, which comprises the heteroaryl compound represented by formula I, its tautomer, stereoisomer or pharmaceutically acceptable salt according to any one of claims 1-8 Or the pharmaceutical composition of claim 9.
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