WO2021057696A1 - Composé hétéroaryle et ses applications - Google Patents

Composé hétéroaryle et ses applications 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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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 Table
    • 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 Table
    • 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.

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Abstract

L'invention concerne un composé hétéroaryle et son application. La présente invention porte sur un composé hétéroaryle représenté par la formule I et sur un tautomère, un stéréoisomère ou un sel pharmaceutiquement acceptable de celui-ci. L'invention présente une bonne activité de suppression tumorale, en particulier pour la leucémie lymphoïde chronique humaine, l'adénocarcinome pulmonaire, le cancer du sein, le cancer de l'ovaire, le cancer du sein ou le cancer du pancréas ; et il a une bonne activité inhibitrice vis-à-vis du cancer du sein, du cancer du poumon, du cancer des ovaires et de la leucémie résistant aux médicaments.
PCT/CN2020/116696 2019-09-27 2020-09-22 Composé hétéroaryle et ses applications WO2021057696A1 (fr)

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