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CN117843567A - Diazaaryl ring substituted benzene derivatives, compositions and uses thereof - Google Patents

Diazaaryl ring substituted benzene derivatives, compositions and uses thereof Download PDF

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Publication number
CN117843567A
CN117843567A CN202311504919.XA CN202311504919A CN117843567A CN 117843567 A CN117843567 A CN 117843567A CN 202311504919 A CN202311504919 A CN 202311504919A CN 117843567 A CN117843567 A CN 117843567A
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substituted
unsubstituted
butyl
alkyl
amino
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王元勋
张虎
孙士勇
许冬明
王瑞瑞
许鹭
万小波
李台威
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Commadison Beijing Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • 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
    • C07D401/14—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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The application discloses a benzene derivative substituted by diaza aromatic ring, which is shown as a general formula (I), wherein the definition of each substituent is shown in the specificationAnd (3) a book. The derivatives are useful as inhibitors of hematopoietic progenitor kinase 1 (HPK 1), as pharmaceuticals for anti-cancer use, compositions containing them and methods of preparation.

Description

Diazaaryl ring substituted benzene derivatives, compositions and uses thereof
Technical Field
The present disclosure relates to diazaaryl ring substituted benzene derivatives, which are inhibitors of hematopoietic progenitor kinase 1 (hpk 1), useful in the treatment or amelioration of abnormal cell proliferative diseases, such as cancer, and pharmaceutically acceptable salts thereof, as well as compositions containing them and their use in therapy.
Background
The discovery of immune checkpoints and their inhibition have become a new approach to targeting cancer against tumors by exploiting the immune system itself. While checkpoint therapies such as PD1/PDL1 show great promise in several tumor types, only a small fraction of cancer patients respond, and new therapies are still needed to treat a wider range of patients.
T cells are critical in the cancer immune cycle (Nature, 541 (2017), 321-330;Nature reviews immunology,20, (2020), 651-668); they are effector cells that recognize and kill tumor cells. In cancer patients, T cells are depleted and become nonfunctional by being driven into the tumor microenvironment by chronic exposure to antigen. In addition, inhibitory signals in tumors such as PGE2, tnfβ, adenosine, etc. prevent the function of these cells. Thus, therapies that enhance T cell function and resuscitate the function of depleted T cells thus achieve improved tumor control.
HPKl (hematopoietic progenitor kinase 1), also known as mitogen-activated protein kinase 1 (MAP 4K 1), is a Ste 20-related serine/threonine kinase expressed only in hematopoietic cells, acting as a negative regulator of T cell signaling and tumor cytokine production. Loss of HPK1 or inactivation of kinases causes enhanced activation of T cells, resulting in increased cytokine secretion and proliferation (Nat. Immunol.,8 (2007), 84-91; cell report, 25 (2018), 80-94). HPK1 can also inhibit T cell signaling in response to immunosuppressive prostaglandin E2 (PGE 2) by Protein Kinase A (PKA) (Blood, 101 (2003), 3687-89; j.biol. Chem.,282 (2007), 34693-99;Cancer Immunol.Immunother.59 (2010), 419-29). Furthermore, HPK1 has also been reported to act as a negative regulator in other immune cells such as B cells, dendritic cells and NK cells (elife, 2020,9). In conclusion, it is reasonable to target HPK1 small molecule kinase inhibitors for cancer immunotherapy.
HPK1 inhibitors can be used alone or in combination with other therapeutic agents to treat cancer. HPK1 inhibitors can be used in combination with PD-1, PD-L1 or CTLA4 and have a synergistic effect. Other combinations may include radiation, chemotherapy, surgery, tumor targeting agents or other immune targeting agents.
Patents on HPK1 inhibitors include WO2016/205942A1, WO2018/167147A1, WO2020/061377A1, WO2020/069402A1, WO2018/102366A1, WO2018/228923A1, WO2020/092528A1, WO2020/100027A1, WO2021/026180A1, etc.
SUMMARY
The present application provides a diazaaromatic ring substituted benzene derivative which is useful as an inhibitor of hematopoietic progenitor kinase 1 (HPK 1), as a medicament, compositions containing them and methods of preparation.
In a first aspect of the present application, there is provided a diazaaryl ring substituted benzene derivative of formula (I):
wherein,
y is O, S, NH, NR a Or SO 2 The method comprises the steps of carrying out a first treatment on the surface of the Here, R is a Is unsubstituted C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl or C 1 -C 6 Alkoxy C 1 -C 6 An alkyl group;
R 1 to R 4 Each independently selected from hydrogen, deuterium, halogen, nitro, cyano, hydroxy, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl and C 1 -C 6 Alkoxy C 1 -C 6 An alkyl group; optionally R 1 And R is R 2 Together with the carbon atoms to which they are attached or R 3 And R is R 4 And the carbon atoms to which they are attached together form an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heterocycloalkyl, an unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl;
R 5 To R 8 Each independently selected from hydrogen, deuterium, -C (O) NR 13 R 14 Halogen, nitro, cyano, hydroxy, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl and C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl;
R 9 and R is 10 Each independently selected from hydrogen, deuterium, halogen, nitro, cyano, hydroxy, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
R 11 selected from hydrogen, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl; unsubstituted or substituted C 2 -C 8 A heterocyclic group;
R 12 selected from hydrogen, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 1 -C 6 Alkanoyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
alternatively, R 11 And R is R 12 And N attached thereto together form an unsubstituted or substituted 3 to 6 membered heterocycloalkyl, or an unsubstituted or substituted 5 to 6 membered heteroaryl; optionally, the 3-to 6-membered heterocycloalkyl or 5-to 6-membered heteroaryl is substituted with NH, NR b O, S or SO 2 Interrupted (the interval refers to NH, NR between adjacent ring atoms of a heterocycloalkyl or heteroaryl group) b O, S or SO 2 Linking), where R b Is unsubstituted C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl or C 1 -C 6 Alkoxy C 1 -C 6 An alkyl group;
R 13 and R is 14 Each independently selected from hydrogen, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
m is N or C (R) 15 ) The method comprises the steps of carrying out a first treatment on the surface of the Here, R is 15 Is hydrogen, halogen, nitro, cyano, hydroxy, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl and C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; alternatively, R 15 And R is R 11 And the carbon atoms and nitrogen atoms to which they are attached together form a nitrogen-containing five-to seven-membered heterocyclic ring;
or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof.
In a second aspect of the present application, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof, and a pharmaceutically acceptable diluent, excipient and/or inert carrier.
In a third aspect of the present application, there is provided a compound of formula (I) or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof, or a pharmaceutical composition thereof, for use as a medicament. In some embodiments of the present application, the present application provides a compound of formula (I) or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof, or a pharmaceutical composition thereof, for use in treating cancer.
In a fourth aspect of the present application, there is provided the use of a compound of formula (I) or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for use as an HPK1 inhibitor; in some embodiments of the present application, the present application provides the use of a compound of formula (I) or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment or prevention of cancer.
In a fifth aspect of the present application, there is provided a method of preventing or treating cancer comprising administering to a subject in need thereof a compound of formula (I) or an optical isomer, stable isotope variant, pharmaceutically acceptable salt, or hydrate thereof, or a pharmaceutical composition thereof.
In a sixth aspect of the present application, there is provided a process for the preparation of a compound of formula (I) or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof, and intermediate compounds thereof.
Detailed description of the preferred embodiments
Terminology
As used herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine.
As used herein, the term "C 1 -C 6 Alkyl "includes straight or branched chain saturated hydrocarbon groups having 1, 2, 3, 4, 5 or 6 carbon atoms; for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, (2-methyl) butan-3-yl, pent-2-yl, 2-methylbutyl, neopentyl, n-hexyl, 2-methylpentyl and the like.
As used herein, the term "C 2 -C 6 Alkenyl "means a straight or branched hydrocarbon chain consisting of only carbon and hydrogen atomsA group containing at least one double bond, having two to six carbon atoms, linked to the rest of the molecule by a single bond. C (C) 2 -C 6 Examples of alkenyl groups include, but are not limited to, vinyl, prop-1-enyl, but-1-enyl, pent-4-enyl, and pent-1, 4-dienyl.
As used herein, the term "C 2 -C 6 Alkynyl "refers to a straight or branched hydrocarbon chain group consisting of only carbon and hydrogen atoms, containing at least one triple bond, having two to six carbon atoms, and attached to the remainder of the molecule by a single bond. C (C) 2 -C 6 Examples of alkynyl groups include, but are not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-4-ynyl, and pent-1, 4-dialkynyl.
As used herein, the term "C 1 -C 6 Alkoxy "means having the formula-OR 100 Wherein R is a group of 100 Is C as defined above 1 -C 6 An alkyl group. C (C) 1 -C 6 Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy and hexoxy.
As used herein, the term "C 1 -C 6 Alkoxy C 1 -C 6 Alkyl "means having the formula-R 100 -O-R 100 Wherein R is a group of 100 Each independently is C as above 1 -C 6 An alkyl group. The oxygen atom may be bonded to any carbon atom in any alkyl group. C (C) 1 -C 6 Alkoxy C 1 -C 6 Examples of alkyl groups include, but are not limited to: methoxy-methyl, methoxy-ethyl, ethoxy-ethyl, 1-ethoxy-propyl and 2-methoxy-butyl.
The term "halo C", as used herein 1 -C 6 Alkyl "means C as defined above substituted by one or more halogen groups as defined above 1 -C 6 An alkyl group. Halogenated C 1-6 Examples of alkyl groups include, but are not limited to: trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2-trifluoroethyl, 1, 3-diBromoprop-2-yl, 3-bromo-2-fluoropropyl, and 1, 4-trifluorobutan-2-yl.
The term "halo C", as used herein 1 -C 6 Alkoxy "means C as above substituted by one or more halogen groups as above 1 -C 6 An alkoxy group. Halogenated C 1 -C 6 Examples of alkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy and 2, 2-trifluoroethoxy.
As used herein, the term "C 3 -C 10 Cycloalkyl "refers to a monocyclic or bicyclic saturated hydrocarbon group having from three to ten carbon atoms, while the hydrocarbon group consists of only carbon and hydrogen atoms; bridged rings and spiro rings may be included. C (C) 3 -C 10 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
As used herein, the term "C 2 -C 8 Heterocyclyl "means a saturated or partially saturated heterocyclic group and is preferably monocyclic or polycyclic (in the case of polycyclic, in particular bicyclic, tricyclic or spiro ring); and has 3 to 16, more preferably 4 to 15, most preferably 5 to 10 and most preferably 5 or 6 ring atoms; wherein one or more, preferably one to four, especially one or two, ring atoms are heteroatoms (the remaining ring atoms being carbon). Heterocyclyl groups may include fused or bridged rings as well as spiro rings. C (C) 2 -C 8 Examples of heterocyclyl groups include dihydrofuryl, dioxanyl, dithianyl, dihydropyrrole, dihydropyranyl, oxathiolyl, dithianyl, oxathiolyl, thiomorpholinyl, oxiranyl, aziridinyl, glycinyl, oxepinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, azetidinyl, oxepinyl, azepanyl, thiepinyl, dioxanyl, diazepinyl. A non-limiting example of a spiroheterocyclyl group is azaspiro [2.3 ]Hexaalkyl or azaspiro [3.4]Octyl. Non-limiting examples of bridged heterocycles are azabicyclo [1.1.1]A pentyl group.
As used herein, the term "heteroaryl" refers to a 5-14 membered monocyclic or bicyclic aromatic ring system having 1 to 8 heteroatoms. Each heteroatom is independently selected from: o, N and S, where S and N can be oxidized to various oxidation states. Typically, heteroaryl groups are 5-10 membered ring systems (e.g., 5-or 6-membered monocyclic or 8-10 membered bicyclic). Typically, the monocyclic heteroaryl group contains 5 or 6 ring members selected from carbon atoms and 1 to 4 heteroatoms, and typical monocyclic heteroaryl groups include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxa-2, 3-diazolyl, oxa-2, 4-diazolyl, oxa-2, 5-diazolyl, oxa-3, 4-diazolyl, thia-2, 3-diazolyl, thia-2, 4-diazolyl, thia-2, 5-diazolyl, thia-3, 4-diazolyl, 3-, 4-or 5-isothiazolyl, 2-, 4-or 5-oxazolyl, 3-, 4-or 5-isoxazolyl, 3-or 5-1,2, 4-triazolyl, 4-or 5-1,2, 3-triazolyl, tetrazolyl, 2-, 3-or 4-pyridyl, 3-or 4-pyridazinyl, 2-, 3-, 4-or 5-pyrazinyl, 2-, 4-or 5-pyrimidinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, oxazolopyridinyl, imidazopyridinyl, imidazopyrimidinyl, naphthyridinyl, 5,6,7, 8-tetrahydro-1, 6-naphthyridinyl, 5,6,7, 8-tetrahydroisoquinolinyl, 5,6,7, 8-tetrahydroquinolinyl, 6, 7-dihydro-5H-cyclopenta [ b ] pyridinyl, 6, 7-dihydro-5H-cyclopenta [ c ] pyridinyl, 1,4,5, 6-tetrahydrocyclopenta [ c ] pyrazolyl, 2,4,5, 6-tetrahydrocyclopenta [ c ] pyrazolyl, 5, 6-dihydro-4H-pyrrolo [1,2-b ] [1,2,4] triazolyl, 5,6, 7-dihydro-5H-pyrrolo [1,2-b ] [1,2,4] triazolyl, 5,6, 7-tetrahydro- [1, 4, 6-tetrahydro-cyclopenta [ c ] pyridinyl, 1,4, 6-tetrahydro-4, 5-H ] pyrrolyl, 1,2, 4-b ] triazolyl, 6,7, 6-tetrahydrocyclopenta [ c ] pyrazolyl, 1,4, 6-dihydro-4H-pyrrolyl.
As used herein, the term "aryl" refers to an aromatic hydrocarbon group having 6 to 20 carbon atoms in the ring moiety. Typically, an aryl group is a monocyclic, bicyclic or tricyclic aryl group having 6 to 20 carbon atoms. Non-limiting examples include phenyl and naphthyl.
As used herein, the term "optical isomers" includes R and S enantiomers, diastereomers, geometric isomers, rotamers, conformational isomers and tautomers, including compounds that exhibit more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs). Also included are acid or base addition salts in which the counterion is optically active, e.g., D-lactate or L-lysine, or racemic, e.g., DL-tartrate or DL-arginine.
As used herein, the term "subject" or "individual" refers to mammals, primates (e.g., humans (male or female)), dogs, rabbits, guinea pigs, rats, and mice. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
As used herein, the term "treatment" of any disease or disorder refers to alleviation or amelioration of the disease or disorder (i.e., slowing or arresting the progression of the disease or at least one clinical symptom thereof); or alleviating or ameliorating at least one physical parameter or biomarker associated with the disease or disorder, including a physical parameter or biomarker that may not be discernable by the patient.
As used herein, the term "prevention" of any disease or disorder refers to the prophylactic treatment of a disease or disorder; or delay the onset or progression of a disease or disorder.
As used herein, a subject is "in need of" such treatment if the subject would benefit biologically, medically, or quality of life from the treatment.
As used herein, the term "therapeutically effective amount" of a compound of the present application refers to an amount of a compound of the present application that will induce a biological or medical response (e.g., a decrease or inhibition of enzymatic or protein activity, or improve symptoms, alleviate a disorder, slow or delay disease progression or prevent a disease, etc.) in a subject.
As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise, e.g., reference to "the compound" includes reference to one or more compounds.
As used herein, the term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention, and are typically not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and/or base salts due to the presence of amino and/or carboxyl groups or groups similar thereto; wherein pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids; inorganic acids from which salts may be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; organic acids from which salts may be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like; pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases; inorganic bases from which salts may be derived include, for example, ammonium salts and metals from columns I to XII of the periodic Table of the elements. In certain embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts; organic bases from which salts may be derived include, for example, primary, secondary and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; basic ion exchange resins, and the like. Some organic amines include isopropylamine, benzathine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
As used herein, the term "stable isotopic variant" represents a stable non-labeled form as well as isotopically labeled forms of the compound. Isotopically-labeled compounds have structures described by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic or mass number. Isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, for example. Furthermore, the incorporation of certain isotopes, particularly deuterium (i.e., 2H or D), may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements or improved therapeutic index or tolerability. It is to be understood that deuterium is considered in this context to be a substituent of the compounds of the present invention. Can be incorporated intoOther examples of isotopes of the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, phosphorus, fluorine, chlorine, and iodine, such as respectively 3 H、 11 C、 13 C、 14 C、 15 N、 18 O、 18 F、 31 P、 32 P、 35 S、 36 Cl、 123 I、 124 I、 125 I. Accordingly, it is to be understood that the present invention includes compounds incorporating one or more of any of the above isotopes, including, for example, radioisotopes, such as 3 H and 14 c, or incorporating therein non-radioactive isotopes, e.g. 2 H and 13 those of C. Such isotopically-labeled compounds are useful in metabolic studies (with 14 C) Kinetic studies of the reaction (e.g. using 2 H or 3 H) Detection or imaging techniques (such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT), including drug or substrate tissue distribution assays), or for radiation therapy of a patient. In particular the number of the elements to be processed, 18 f or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and preparations, using an appropriate isotopically-labeled reagent in place of the unlabeled previously used reagent.
As used herein, the term "pharmaceutical composition" refers to a compound of the invention, or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof, in a form suitable for oral or parenteral administration, and at least one pharmaceutically acceptable carrier.
As used herein, the term "pharmaceutically acceptable carrier" refers to a substance that can be used to prepare or use a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof, as known to those skilled in the art (see, e.g., remington The Science and Practice of Pharmacy [ leimington: pharmaceutical science and practice ], 22 nd edition, pharmaceutical Press [ pharmaceutical publishing company ],2013, pages 1049-1070).
In an embodiment of the present application of the first aspect, the present application provides a diazaaryl ring substituted benzene derivative as shown in formula (I):
wherein,
y is O, S, NH, NR a Or SO 2 The method comprises the steps of carrying out a first treatment on the surface of the Here, R is a Is unsubstituted C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl or C 1 -C 6 Alkoxy C 1 -C 6 An alkyl group;
R 1 to R 4 Each independently selected from hydrogen, deuterium, halogen, nitro, cyano, hydroxy, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl and C 1 -C 6 Alkoxy C 1 -C 6 An alkyl group; here, the substituted C 2 -C 6 Alkenyl, substituted C 2 -C 6 Alkynyl or substituted C 1 -C 6 Alkoxy is substituted with one or more groups selected from group a; optionally R 1 And R is R 2 Together with the carbon atoms to which they are attached or R 3 And R is R 4 And the carbon atoms to which they are attached together form an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heterocycloalkyl, an unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl;
R 5 to R 8 Each independently selected from hydrogen, deuterium, -C (O) NR 13 R 14 Halogen, nitro, cyano, hydroxy, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl and C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; here, the substituted C 2 -C 6 Alkenyl, substituted C 2 -C 6 Alkynyl, substituted C 1 -C 6 Alkoxy, substituted C 3 -C 10 Cycloalkyl, substituted C 2 -C 8 Heterocyclyl, substituted aryl or substituted heteroaryl is substituted with one or more groups selected from group a;
R 9 and R is 10 Each independently selected from hydrogen, deuterium, halogen, nitro, cyano, hydroxy, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; here, the substituted C 2 -C 6 Alkenyl, substituted C 2 -C 6 Alkynyl, substituted C 1 -C 6 Alkoxy, substituted C 3 -C 10 Cycloalkyl, substituted C 2 -C 8 Heterocyclyl, substituted aryl or substituted heteroaryl is substituted with one or more groups selected from group a;
R 11 Selected from hydrogen, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl; unsubstituted or substituted C 2 -C 8 A heterocyclic group; here, the substituted C 2 -C 6 Alkenyl, substituted C 2 -C 6 Alkynyl or substituted C 1 -C 6 Alkoxy, substituted C 3 -C 10 Cycloalkyl, substituted C 2 -C 8 The heterocyclic group is substituted with one or more groups selected from group A;
R 12 selected from hydrogen, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 1 -C 6 Alkanoyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; said substituted C 2 -C 6 Alkenyl, substituted C 2 -C 6 Alkynyl, substituted C 1 -C 6 Alkoxy, substituted C 1 -C 6 Alkanoyl, substituted C 3 -C 10 Cycloalkyl, substituted C 2 -C 8 Heterocyclyl, substituted aryl or substituted heteroaryl is substituted with one or more groups selected from group a;
Alternatively, R 11 And R is R 12 And N attached thereto together form an unsubstituted or substituted 3 to 6 membered heterocycloalkyl, or an unsubstituted or substituted 5 to 6 membered heteroaryl; optionally, the 3-to 6-membered heterocycloalkyl or 5-to 6-membered heteroaryl is substituted with NH, NR b 、O、SOr SO 2 Interval (interleaved), where R b Is unsubstituted C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl or C 1 -C 6 Alkoxy C 1 -C 6 An alkyl group;
R 13 and R is 14 Each independently selected from hydrogen, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; here, the substituted C 2 -C 6 Alkenyl, substituted C 2 -C 6 Alkynyl, substituted C 3 -C 10 Cycloalkyl, substituted C 2 -C 8 Heterocyclyl, substituted aryl or substituted heteroaryl is substituted with one or more groups selected from group a;
m is N or C (R) 15 ) The method comprises the steps of carrying out a first treatment on the surface of the Here, R is 15 Is hydrogen, halogen, nitro, cyano, hydroxy, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl and C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; alternatively, R 15 And R is R 11 And the carbon atom and nitrogen atom attached thereto together form a nitrogen-containing five-to seven-membered heterocyclic ring, optionally substituted with one or more groups selected from group a;
or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof;
here, the group a groups are: halogen, nitro, cyano, hydroxy, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 3 -C 10 Cycloalkyl, C 3 -C 10 Cycloalkoxy radicals C 2 -C 8 Heterocyclyl, C 2 -C 8 Heteroepoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, optionally C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 3 -C 10 Cycloalkyl, C 3 -C 10 Cycloalkoxy radicals C 2 -C 8 Heterocyclyl, C 2 -C 8 Heteroepoxy, aryl, aryloxy, heteroaryl and heteroaryloxy are further substituted.
In some embodiments of the first aspect of the present application, the present application provides diazaaryl ring substituted benzene derivatives of formula (I):
Wherein,
y is O, S, NH, NR a Or SO 2 Here, R is a Is unsubstituted C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl or C 1 -C 6 Alkoxy C 1 -C 6 An alkyl group;
R 1 to R 4 Each independently selected from hydrogen, fluorine, chlorine, nitro, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethenyl, propenyl, ethynyl, propynyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl and C 1 -C 6 Alkoxy C 1 -C 6 An alkyl group; optionally R 1 And R is R 2 Together with the carbon atoms to which they are attached or R 3 And R is R 4 And the carbon atoms to which they are attached together form an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heterocycloalkyl, an unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl;
R 5 is-C (O) NR 13 R 14 And R is 6 To R 8 Each independently selected from hydrogen, halogen, nitro, cyano, hydroxy, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl and C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; alternatively, R 5 To R 8 Each independently selected from hydrogen, halogen, nitro, cyano, hydroxy, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl and C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl;
R 9 and R is 10 Each independently selected from hydrogen, deuterium, halogen, nitro, cyano, hydroxy, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl group,Unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
R 11 selected from hydrogen, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl; unsubstituted or substituted C 2 -C 8 A heterocyclic group;
R 12 selected from hydrogen, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 1 -C 6 Alkanoyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
alternatively, R 11 And R is R 12 And N attached thereto together form an unsubstituted or substituted 3 to 6 membered heterocycloalkyl, or an unsubstituted or substituted 5 to 6 membered heteroaryl; optionally, the 3-to 6-membered heterocycloalkyl or 5-to 6-membered heteroaryl is substituted with NH, NR b O, S or SO 2 Interval (interleaved), where R b Is unsubstituted C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl or C 1 -C 6 Alkoxy C 1 -C 6 An alkyl group;
R 13 and R is 14 Each independently selected from hydrogen, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
m is N or C (R) 15 ) The method comprises the steps of carrying out a first treatment on the surface of the Here, R is 15 Is hydrogen, halogen, nitro, cyano, hydroxy, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl and C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; alternatively, R 15 And R is R 11 And the carbon atoms and nitrogen atoms to which they are attached together form a nitrogen-containing five-to seven-membered heterocyclic ring;
or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof.
In some embodiments of the first aspect of the present application, provided herein are polysubstituted benzene derivatives of formula (I), wherein Y is O, S, NH, NR a Or SO 2 Here, R is a Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In some embodiments of the first aspect of the present application, provided herein are polysubstituted benzene derivatives of formula (I), wherein Y is O, S, NH, NCH 3 Or SO 2 。
In some embodiments of the first aspect of the present application, the present application provides a polysubstituted benzene derivative as represented by formula (I), wherein Y is O.
In some embodiments of the first aspect of the present application, provided herein are diazaaryl-ring-substituted benzene derivatives of formula (I), wherein R 1 To R 4 Wherein at least one of the others is hydrogen, and each of the others is independently selected from hydrogen, deuterium, fluorine, chlorine, nitro, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethenyl, propenyl, ethynyl, and propynyl; alternatively, R 1 And R is R 2 Together with the carbon atoms to which they are attached or R 3 And R is R 4 And the carbon atoms to which they are attached together form an unsubstituted or substituted cyclopentylalkyl, unsubstituted or substituted cyclohexenyl, unsubstituted or substituted heterocyclylalkyl, unsubstituted or substituted cyclohexenyl, unsubstituted or substituted phenyl, unsubstituted or substituted heteroaryl, and R 3 And R is R 4 Or R is 1 And R is R 2 Each independently selected from the group consisting of hydrogen, fluorine, chlorine, nitro, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethenyl, propenyl, ethynyl, and propynyl.
In some embodiments of the first aspect of the present application, provided herein are diazaaryl-ring-substituted benzene derivatives of formula (I), wherein R 1 Selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, nitro, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethenyl, propenyl, ethynyl, and propynyl, R 2 To R 4 Are all hydrogen.
In some embodiments of the first aspect of the present application, provided herein are diazaaryl-ring-substituted benzene derivatives of formula (I), wherein R 1 Is hydrogen, fluorine, chlorine or methyl, R 2 To R 4 Are all hydrogen.
In some embodiments of the first aspect of the present application, provided herein are polysubstituted benzenes of formula (I)Derivatives, wherein R 1 And R is 2 Each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, nitro, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethenyl, propenyl, ethynyl, and propynyl; and R is 3 And R is R 4 And the carbon atoms to which they are attached form unsubstituted or substituted cyclopentylalkyl, unsubstituted or substituted cyclohexenyl, unsubstituted or substituted tetrahydroimidazolyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted tetrahydrofuranyl, unsubstituted or substituted piperazinyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted tetrahydropyranyl, unsubstituted or substituted phenyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted pyridinyl, or unsubstituted or substituted pyrimidinyl.
In some embodiments of the first aspect of the present application, provided herein are polysubstituted benzene derivatives of formula (I), wherein R 1 Is hydrogen, fluorine, chlorine or methyl, R 2 Is hydrogen; and R is 3 And R is R 4 And the carbon atoms to which they are attached together form a cyclopentenyl, cyclohexenyl, tetrahydroimidazolyl, pyrrolidinyl, tetrahydrofuranyl, piperazinyl, piperidinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridinyl, or pyrimidinyl group.
In some embodiments of the first aspect of the present application, provided herein are polysubstituted benzene derivatives of formula (I), wherein R 1 Is hydrogen, fluorine, chlorine or methyl, R 2 Is hydrogen; and R is 3 And R is R 4 And the carbon atoms to which they are attached together form a cyclohexenyl, piperidinyl, or pyridyl group.
In some embodiments of the first aspect of the present application, provided herein are diazaaryl-ring-substituted benzene derivatives of formula (I), wherein R 5 To R 8 Each independently selected from hydrogen, deuterium, halogen, nitro, cyano, hydroxy, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl and C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, optionally R 5 To R 8 At least one of which is other than hydrogen.
In some embodiments of the first aspect of the present application, provided herein are diazaaryl-ring-substituted benzene derivatives of formula (I), wherein R 5 To R 8 Each independently selected from hydrogen, deuterium, unsubstituted and substituted aryl and unsubstituted or substituted heteroaryl, and R 5 To R 8 At least one of which is other than hydrogen.
In some embodiments of the first aspect of the present application, provided herein are diazaaryl-ring-substituted benzene derivatives of formula (I), wherein R 5 To R 8 Each independently selected from hydrogen, deuterium, unsubstituted or substituted phenyl and unsubstituted or substituted naphthyl, and R 5 To R 8 At least one of which is other than hydrogen; here, the substituted phenyl or substituted naphthyl means substituted with one or more groups selected from group a; the group A is as follows: halogen, nitro, cyano, hydroxy, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 3 -C 10 Cycloalkyl, C 3 -C 10 Cycloalkoxy radicals C 2 -C 8 Heterocyclyl, C 2 -C 8 Heteroepoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, optionally C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 3 -C 10 Cycloalkyl, C 3 -C 10 Cycloalkoxy radicals C 2 -C 8 Heterocyclyl, C 2 -C 8 Heteroepoxy, aryl, aryloxy, heteroaryl and heteroaryloxy are further substituted.
In some embodiments of the first aspect of the present application, provided herein are diazaaryl-ring-substituted benzene derivatives of formula (I), wherein R 5 To R 8 Each independently selected from hydrogen and halophenyl.
In some embodiments of the first aspect of the present application, provided herein are diazaaryl-ring-substituted benzene derivatives of formula (I), wherein R 5 To R 8 Each independently selected from hydrogen and fluorophenyl.
In some embodiments of the first aspect of the present application, provided herein are diazaaryl-ring-substituted benzene derivatives of formula (I), wherein R 5 、R 6 And R is 7 Is hydrogen and R 8 Is a fluorophenyl group, preferably a 3-fluorophenyl group.
In some embodiments of the first aspect of the present application, provided herein are diazaaryl-ring-substituted benzene derivatives of formula (I), wherein R 5 is-C (O) NR 13 R 14 And R is 6 To R 8 Are all hydrogen;
R 13 and R is 14 Each independently selected from hydrogen, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.
In some embodiments of the first aspect of the present application, provided herein are diazaaryl-ring-substituted benzene derivatives of formula (I), wherein R 5 is-C (O) NR 13 R 14 And R is 6 To R 8 Are all hydrogen;
R 13 and R is 14 Each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, and cycloHexyl, cycloheptyl, tetrahydropyranyl, morpholinyl, phenyl and naphthyl; here, the cyclopentyl, cyclohexyl, cycloheptyl, tetrahydropyranyl, morpholinyl, phenyl and naphthyl groups are optionally substituted with one or more groups selected from group a;
the group A is as follows: fluoro, chloro, bromo, nitro, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, trifluoromethyl, methoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azaspiro [2.3] hexanyl, or azaspiro [3.4] octanyl, pyrrolidinyloxy, piperidinyloxy, azaspiro [2.3] hexyloxy, azaspiro [3.4] octanyl, optionally, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, trifluoromethyl, methoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azaspiro [2.3] hexlkyl, azaspiro [3.4] octyl, pyrrolidinyloxy, piperidinyloxy, azaspiro [2.3] hexoxy, or azaspiro [3.4] octyloxy is further selected from: fluorine, chlorine, bromine, iodine, nitro, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, amino, monomethylamino, and dimethylamino.
In some embodiments of the first aspect of the present application, provided herein are diazaaryl-ring-substituted benzene derivatives of formula (I), wherein R 5 is-C (O) NR 13 R 14 And R is 6 To R 8 Are all hydrogen;
R 13 and R is 14 Each independently selected from hydrogen, methyl, ethyl, cyclohexyl, substitutedCyclohexyl, morpholinyl, tetrahydropyranyl, phenyl, substituted phenyl, naphthyl and substituted naphthyl; here, the substituted cyclohexyl, substituted phenyl or substituted naphthyl means substituted with one or more groups selected from group a; the group A is as follows: fluorine, chlorine, bromine, iodine, nitro, cyano, hydroxyl, methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, ethynyl, N-propoxy, dimethylamino-substituted N-butyl, dimethylamino-substituted isobutyl, dimethylamino-substituted sec-butyl, amino-substituted N-butyl, amino-substituted isobutyl, amino-substituted sec-butyl, cyclobutoxy, amino-substituted cyclobutoxy, piperidinyloxy, N-methylpiperidinyloxy, pyrrolidinyloxy, azaspiro [3.4 ]]An octyloxy group.
In some embodiments of the first aspect of the present application, provided herein are diazaaryl-ring-substituted benzene derivatives of formula (I), wherein R 5 is-C (O) NR 13 R 14 And R is 6 To R 8 Are all hydrogen;
R 13 and R is 14 Are all methyl groups; alternatively, R 13 Is hydrogen and R 14 Is methyl, phenyl or substituted phenyl, cyclohexyl or substituted cyclohexyl, tetrahydropyranyl or naphthyl, where the substituted cyclohexyl is 4, 4-difluorocyclohexyl and the substituted phenyl is 4-fluorophenyl, 4-tolyl, 3-chlorophenyl, 3-fluorophenyl, 3, 4-difluorophenyl, 3-alkynylphenyl, 3-trifluoromethylphenyl, 2- (3- (N, N-dimethylamino) propoxy) phenyl, 2- (3- (N, N-dimethylamino) propoxy) -4-fluorophenyl, 2- (N-methylpiperidin-4-yloxy) phenyl, 2- ((4-aminobutan-2-yl) oxy) -4-fluorophenyl, 2- (3-aminocyclobutoxy) -4-fluorophenyl, 2- ((pyrrolidin-2-yl) oxy) -4-fluorophenyl, 2- ((4-aminobutan-2-yl) oxy) -4-fluorophenyl, 2- ((4-aminopiperan-2-yl) oxy) or 2- ((3.5) spiro [3. - ((3-spiro ]]Oct-2-yl) oxy) -4-fluorophenyl.
In some embodiments of the first aspect of the present application, provided herein are diaza-aromatic ring-substituted benzene derivatives of formula (I), wherein M is N or C (R 15 ) The method comprises the steps of carrying out a first treatment on the surface of the Here, R is 15 Hydrogen, fluoro, chloro, nitro, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethenyl, propenyl, ethynyl or propynyl; alternatively, R 15 And R is R 11 And the carbon atom and nitrogen atom to which they are attached together form a nitrogen-containing five-or six-membered heterocyclic ring;
R 9 and R is 10 Each independently selected from hydrogen, fluorine, chlorine, nitro, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethenyl, propenyl, ethynyl, or propynyl.
In some embodiments of the first aspect of the present application, provided herein are diaza-aromatic ring-substituted benzene derivatives of formula (I), wherein M is N or C (R 15 ) The method comprises the steps of carrying out a first treatment on the surface of the Here, R is 15 Hydrogen, fluorine or chlorine; alternatively, R 15 And R is R 11 And the carbon atom and nitrogen atom to which they are attached together form a pyrrole ring or pyridine ring;
R 9 and R is 10 Are all hydrogen.
In some embodiments of the first aspect of the present application, provided herein are diazaaryl-ring-substituted benzene derivatives of formula (I), wherein R 11 Is hydrogen; r is R 12 Selected from hydrogen, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 1 -C 6 Alkanoyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.
In some embodiments of the first aspect of the present application, provided herein are diazaaryl-ring-substituted benzene derivatives of formula (I), wherein R 11 Is hydrogen;R 12 selected from the group consisting of unsubstituted or substituted formyl, unsubstituted or substituted acetyl, unsubstituted or substituted propionyl, unsubstituted or substituted n-butyryl, unsubstituted or substituted isobutyryl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted pyridinyl and unsubstituted or substituted naphthyridinyl, wherein the substituted formyl, substituted acetyl, substituted propionyl, substituted n-butyryl, substituted isobutyryl, substituted pyrazolyl, substituted pyridinyl or substituted naphthyridinyl is substituted with one or more groups selected from the group consisting of: fluorine, chlorine, bromine, nitro, cyano, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azaspiro [2.3 ]Hexaalkyl, azaspiro [3.4]Octyl.
In some embodiments of the first aspect of the present application, provided herein are diazaaryl-ring-substituted benzene derivatives of formula (I), wherein R 11 Is hydrogen; r is R 12 Selected from the group consisting of acetyl, piperidine substituted acetyl, pyrrolidinyl substituted acetyl, aziridinyl substituted acetyl, cyclopropoyl, methylpyrazolyl, pyrazolyl, pyridinyl, naphthyridinyl, and substituted naphthyridinyl, where the substituted naphthyridinyl is substituted with one or more groups selected from the group consisting of: methyl and methoxy.
In some embodiments of the first aspect of the present application, provided herein are diazaaryl-ring-substituted benzene derivatives of formula (I), wherein R 11 Selected from unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 A heterocyclic group; r is R 12 Selected from unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 1 -C 6 Alkanoyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl.
In some embodiments of the first aspect of the present application, provided herein are diazaaryl-ring-substituted benzene derivatives of formula (I), wherein R 11 And R is 12 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.
In some embodiments of the first aspect of the present application, provided herein are diazaaryl-ring-substituted benzene derivatives of formula (I), wherein R 11 And R is 12 Is methyl.
In some embodiments of the first aspect of the present application, provided herein are diazaaryl-ring-substituted benzene derivatives of formula (I), wherein R 11 And R is R 12 And N attached thereto together form an unsubstituted or substituted aziridinyl, an unsubstituted or substituted azetidinyl, an unsubstituted or substituted pyrrolidinyl, an unsubstituted or substituted piperidinyl, an unsubstituted or substituted pyrrolyl, an unsubstituted or substituted imidazolyl, an unsubstituted or substituted pyridinyl, or an unsubstituted or substituted pyrimidinyl, optionally, the unsubstituted or substituted aziridinyl, the unsubstituted or substituted azetidinyl, the unsubstituted or substituted pyrrolidinyl, the unsubstituted or substituted piperidinyl, the unsubstituted or substituted pyrrolyl, the unsubstituted or substituted imidazolyl Said unsubstituted or substituted pyridinyl, or said unsubstituted or substituted pyrimidinyl is substituted with NH, NR b O, S or SO 2 Interval (interleaved), where R b Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl.
In some embodiments of the first aspect of the present application, provided herein are polysubstituted benzene derivatives of formula (I), wherein R 11 And R is R 12 And the N to which they are attached together form aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, 4-methylpiperazinyl, pyrrolyl, imidazolyl, pyridinyl or pyrimidinyl.
In some embodiments of the first aspect of the present application, the present application provides the following compounds, or optical isomers, stable isotopic variants, pharmaceutically acceptable salts, or hydrates thereof:
in a second aspect of the present application, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof, and a pharmaceutically acceptable diluent, excipient and/or inert carrier.
In some embodiments of the second aspect, the pharmaceutical composition may be formulated into any of the clinically or pharmaceutically acceptable dosage forms, such as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injectable solutions, injectable sterile powders and injectable concentrated solutions), suppositories, inhalants or sprays, and the like.
In some embodiments of the present application, the above pharmaceutical compositions may be administered orally, parenterally, rectally, or pulmonary, etc., to a patient or subject in need of such treatment. For oral administration, the pharmaceutical composition may be formulated into oral preparations, for example, into conventional oral solid preparations such as tablets, capsules, pills, granules, etc.; can also be made into oral liquid preparation such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. may be added. For parenteral administration, the pharmaceutical preparations may also be formulated as injections, including injectable solutions, injectable sterile powders and injectable concentrated solutions. When the injection is prepared, the conventional method in the existing pharmaceutical field can be adopted for production, and when the injection is prepared, no additive can be added, and the proper additive can be added according to the property of the medicine. For rectal administration, the pharmaceutical composition may be formulated as suppositories and the like. For pulmonary administration, the pharmaceutical composition may be formulated as an inhalant or spray, etc.
In a third aspect of the present application, there is provided a compound of formula (I) or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof, or a pharmaceutical composition thereof, for use as a medicament. In some embodiments of the present application, the present application provides a compound of formula (I) or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof, or a pharmaceutical composition thereof, for use in treating cancer.
In a fourth aspect of the present application, there is provided the use of a compound of formula (I) or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for use as an HPK1 inhibitor; in some embodiments of the present application, the present application provides the use of a compound of formula (I) or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment or prevention of cancer.
In a fifth aspect of the present application, there is provided a method of preventing or treating cancer comprising administering to a subject in need thereof a compound of formula (I) or an optical isomer, stable isotope variant, pharmaceutically acceptable salt, or hydrate thereof, or a pharmaceutical composition thereof.
In some embodiments of the third through fifth aspects of the present application, the cancer includes, but is not limited to, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, thyroid cancer, female genital tract cancer, lymphoma, neurofibroma, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, small-cell lung cancer, non-small-cell lung cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, leukemia, glioma or sarcoma, and the like.
In some embodiments of the third to fifth aspects of the present application, the compound of formula (I) or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof, or a pharmaceutical composition thereof is administered in combination with a PD-1/PD-L1/CTLA-4 antibody or a PD-1/PD-L1/CTLA-4 inhibitor.
In a sixth aspect of the present application, there is provided a process for the preparation of a compound of formula (I) or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof, and intermediate compounds thereof.
Detailed Description
Nuclear magnetic resonance apparatus: bruker ASCEND400M;
LCMS：AB SCIEX 3200Q TRAP LC/MS/MS System。
abbreviations (abbreviations)
ACN acetonitrile
HATU 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate
DIEA ethyl diisopropylamine
DMSO dimethyl sulfoxide
DMF dimethylformamide
THF tetrahydrofuran
DCM dichloromethane
Boc
Boc 2 O di-tert-butyl dicarbonate
EA ethyl acetate
PE Petroleum ether
Pd 2 (dba) 3 Tridibenzylidene acetone dipalladium
Xanthos 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene
TFA trifluoroacetic acid
K 2 CO 3 Potassium carbonate
Cs 2 CO 3 Cesium carbonate
DMAP 4-dimethylaminopyridine
NCS N-chlorosuccinimide
TEA triethylamine
PyBOP hexafluorophosphate benzotriazol-1-yl-oxy-tripyrrolidinylphosphine
Pd/C palladium carbon
MeOH methanol
NaOH sodium hydroxide
H 2 O water
Fe iron powder
EtOH ethanol
TCFH N, N, N, N-tetramethyl chloroformidine hexafluorophosphate
NMI N-methylimidazole
NH 4 Cl ammonium chloride
LiOH lithium hydroxide
Pd(Ph 3 P) 4 Tetratriphenylphosphine palladium
rt room temperature
Example 1
Intermediate 1
2- ((4- ((2- ((tert-Butoxycarbonyl) amino) -3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) nicotinic acid
Step 1: synthesis of 4- (2-fluoro-4-nitrophenoxy) pyridin-2-amine
To a solution of 2-aminopyridine-4-ol (SM 1) (20.0 g,0.18mol and 1, 2-difluoro-4-nitrobenzene (28.9 g,0.18 mol) in acetonitrile (200 mL) was added potassium carbonate (37.7 g,0.27 mol) and the reaction temperature was 20 ℃ C..the mixture was stirred at 55 ℃ C. For 3 hours and then filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel chromatography, eluting with ethyl acetate/petroleum ether (from 0 to 80% ethyl acetate over 30 minutes) to give 4- (2-fluoro-4-nitrophenoxy) pyridin-2-amine (23.4 g, yield 51%) as a pale yellow solid.
LCMS(ESI+):m/z 250.0(M+1)
Step 2: 3-chloro-4- (2-fluoro-4-nitrophenoxy) pyridin-2-amine and 5-chloro-4- (2-fluoro-4-nitrophenoxy) pyridin-2-amine
To a solution of 4- (2-fluoro-4-nitrophenoxy) pyridin-2-amine (18.4 g,73.8 mmol) in ACN (400 ml) was added N-chlorosuccinimide (11.8 g,88.5 mmol) at a reaction temperature of 20 ℃. After stirring the reaction at 20℃for 16 hours, it was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate/petroleum ether (from 0 to 40% ethyl acetate in 20 min) to give a mixture of 3-chloro-4- (2-fluoro-4-nitrophenoxy) pyridin-2-amine and 5-chloro-4- (2-fluoro-4-nitrophenoxy) pyridin-2-amine (1:2) (15.9 g, yield 72%) as a yellow solid.
LCMS(ESI+):m/z 284.1(M+1)
Step 3: (Boc) (5-chloro-4- (2-fluoro-4-nitrophenoxy) pyridin-2-yl) carbamic acid tert-butyl ester And (tert-butoxycarbonyl) (3-chloro-4- (2-fluoro-4-nitrophenoxy) pyridin-2-yl) carbamic acid tert-butyl ester
To a solution of 3-chloro-4- (2-fluoro-4-nitrophenoxy) pyridin-2-amine and 5-chloro-4- (2-fluoro-4-nitrophenoxy) pyridin-2-amine (15.9 g,56.1 mmol), di-tert-butyl dicarbonate (36.7 g,168 mmol) and triethylamine (28.4 g, 281mmol) in acetonitrile (400 ml) was added 4-dimethylaminopyridine (1.37 g,11.2 mmol) at a reaction temperature of 20 ℃. The reaction mixture was stirred at 40 ℃ for 16 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate/petroleum ether (from 0 to 40% ethyl acetate over 30 minutes) to give tert-butyl (tert-butoxycarbonyl) (5-chloro-4- (2-fluoro-4-nitrophenoxy) pyridin-2-yl) carbamate (9.7 g, yield 33%) as a yellow solid, while tert-butyl (tert-butoxycarbonyl) (3-chloro-4- (2-fluoro-4-nitrophenoxy) pyridin-2-yl) carbamate (4.7 g, yield 16%) was also obtained as a yellow solid.
LCMS(ESI+):m/z 483.9(M+1)，LCMS(ESI+):m/z 505.9(M+Na)
Step 4: (4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-yl) (t-butoxycarbonyl) carbamic acid tert-butyl ester
Tert-butyl (tert-butoxycarbonyl) (3-chloro-4- (2-fluoro-4-nitrophenoxy) pyridin-2-yl) carbamate (4.7 g,9.7 mmol) was dissolved in ethyl acetate (150 ml) at 20 ℃. Palladium on carbon (2.06 g,1.9 mmol) was then added. The reaction mixture was stirred under hydrogen for 1.5 hours and then filtered. The filtrate was concentrated under reduced pressure to give tert-butyl (4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-yl) (tert-butoxycarbonyl) carbamate (4 g, yield 86%) as a brown solid.
LCMS(ESI+):m/z 454.0(M+1)
Step 5:2- ((4- ((2-di (t-butoxycarbonyl) amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) Nicotinic acid methyl ester
Tert-butyl (4- (4-amino-2-fluorophenoxy) -3-chloropyridin-2-yl) (tert-butoxycarbonyl) carbamate (3.8 g,8.4 mmol), methyl 2-bromonicotinate (2.18 g,10.0 mmol), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (0.97 g,1.6 mmol) and cesium carbonate (5.47 g,16.8 mmol) were dissolved in dioxane (150 ml). Tridibenzylideneacetone dipalladium (0.77 g,0.8 mmol) was then added at 20 ℃. The reaction mixture was stirred at 100℃for 2 hours, then quenched with water (100 ml) and then extracted with ethyl acetate (200 ml. Times.2). After the organic phases are combined, the drying agent Na is used 2 SO 4 And filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with ethyl acetate/n-hexane solution (20 min from 0 to 30% ethyl acetate) to give methyl 2- ((4- ((2-di (t-butoxycarbonyl) amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) nicotinate (3.9 g, yield 75%) as a pale yellow solid.
LCMS(ESI+):m/z 589.0(M+1)
Step 6:2- ((4- ((2- ((tert-Butoxycarbonyl) amino) -3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) Nicotinic acid
Methyl 2- ((4- ((2-di (t-Butoxycarbonyl) amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) nicotinate (3.9 g,6.6 mmol) was dissolved in methanol (100 ml) and tetrahydrofuran (50 ml) and then added at 20℃to the solution in H 2 Sodium hydroxide (0.79 g,19.8 mmol) in O (20 ml). The reaction mixture was stirred at 20 ℃ for 1 hour and then adjusted to ph=7 with 1N hydrochloric acid solution. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with methanol and dichloromethane (30 min from 0 to 10% methanol) to give 2- ((4- ((2- ((tert-butoxycarbonyl) amino) -3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) nicotinic acid (2.8 g, 80% yield) as a pale yellow solid.
LCMS(ESI+):m/z 475.0(M+1)
1 H NMR(400MHz,DMSO)δ13.77(s,1H),10.67(s,1H),9.50(s,1H),8.47(dd,J＝4.8,2.0Hz,1H),8.30(dd,J＝7.6,2.0Hz,1H),8.24-8.11(m,2H),7.55-7.44(m,1H),7.37(t,J＝9.2Hz,1H),6.97(dd,J＝7.6,4.8Hz,1H),6.64(dd,J＝5.6,0.8Hz,1H),1.46(s,9H)。
Synthesis method one:
example 2
Compound 1
2- [ (4- [ (2-amino-3-chloropyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (3-chlorophenyl) pyridine-3-carboxamide
Step 1: n- (3-chloro- (4- [ (3- [ (3-chlorophenyl) carbamoyl ] pyridin-2-yl) amino ] -2-fluorophenoxy) pyridin-2-yl) carbamic acid tert-butyl ester
To a solution of 2- [ (4- [ (2- { [ (tert-butoxy) carbonyl ] amino } -3-chloropyridin-4-yl) oxy ] -3-fluorophenyl) amino ] nicotinic acid (0.15 g,0.32 mmol) in tetrahydrofuran (2 ml) were added 3-chloroaniline (0.041 g,0.32 mmol) and N, N-diisopropylethylamine (0.083 g,0.64 mmol), followed by 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.18 g,0.48 mmol). The reaction was stirred at 25℃overnight. To the reaction mixture was added 1mL of water to quench the reaction, followed by extraction with ethyl acetate (30 mL. Times.3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was isolated and purified on silica gel (petroleum ether: ethyl acetate=1:1) to give tert-butyl N- (3-chloro- (4- [ (3- [ (3-chlorophenyl) carbamoyl ] pyridin-2-yl) amino ] -2-fluorophenoxy) pyridin-2-yl) carbamate (100 mg, yield: 54.17%) as a brown solid.
Step 2: synthesis of 2- [ (4- [ (2-amino-3-chloropyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (3-chlorophenyl) pyridine-3-carboxamide
To a solution of tert-butyl N- (3-chloro- (4- [ (3-chlorophenyl) carbamoyl ] pyridin-2-yl) amino ] -2-fluorophenoxy) pyridin-2-yl) carbamate (100 mg,0.17 mmol) in methylene chloride (2 mL) at 25℃was added trifluoroacetic acid (1 mL). The reaction was stirred at room temperature overnight. The reaction solution was concentrated to give a crude product, which was dissolved in 2mL of methylene chloride, the pH was adjusted to 8 with saturated aqueous sodium bicarbonate, and methylene chloride (30 mL. Times.3) was added for extraction. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product. The crude product was isolated and purified using a reverse phase preparative column to give 2- [ (4- [ (2-amino-3-chloropyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (3-chlorophenyl) pyridine-3-carboxamide (20 mg, yield: 24.13%) as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.65(s,1H),10.33(s,1H),8.46-8.40(m,1H),8.27(dd,J＝7.9,1.8Hz,1H),8.10(dd,J＝13.5,2.5Hz,1H),7.95(d,J＝2.0Hz,1H),7.76(d,J＝5.7Hz,1H),7.65(d,J＝8.2Hz,1H),7.44(q,J＝8.6,8.1Hz,2H),7.27(t,J＝9.0Hz,1H),7.22(d,J＝8.0Hz,1H),7.04(dd,J＝7.8,4.9Hz,1H),6.41(s,2H),5.92(d,J＝5.7Hz,1H).
LCMS(ESI+):m/z 484.0(M+H) +
Example 3
Compound 2
2- [ (4- [ (2-amino-3-chloropyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N-phenylpyridine-3-carboxamide was synthesized according to one of the synthetic methods in 67.22% yield as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.49(d,J＝9.3Hz,2H),8.42(d,J＝4.8Hz,1H),8.29(d,J＝7.7Hz,1H),8.11(dd,J＝13.8,2.5Hz,1H),7.74(dd,J＝9.9,6.9Hz,3H),7.41(q,J＝8.0Hz,3H),7.27(t,J＝9.1Hz,1H),7.17(t,J＝7.4Hz,1H),7.03(dd,J＝7.7,4.9Hz,1H),6.39(s,2H),5.93(d,J＝5.7Hz,1H).
Example 4
Compound 3
2- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -N-p-tolyl nicotinamide was synthesized according to the general method of synthesis in 50.90% yield as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.55(s,1H),10.43(s,1H),8.42(d,J＝4.7Hz,1H),8.28(dd,J＝7.8,1.8Hz,1H),8.15-8.07(m,1H),7.75(d,J＝5.6Hz,1H),7.61(d,J＝8.0Hz,2H),7.45-7.38(m,1H),7.26(t,J＝9.1Hz,1H),7.20(d,J＝8.0Hz,2H),7.02(dd,J＝7.8,4.8Hz,1H),6.40(s,2H),5.93(d,J＝5.7Hz,1H),2.31(s,3H).
Example 5
Compound 4
2- [ (4- [ (2-amino-3-chloropyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (4-fluorophenyl) pyridine-3-carboxamide was synthesized according to the general method for synthesis in 59.26% yield as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.56(s,1H),10.47(s,1H),8.43(dd,J＝4.9,1.7Hz,1H),8.28(dd,J＝7.8,1.8Hz,1H),8.11(dd,J＝13.7,2.5Hz,1H),7.74(dd,J＝8.4,5.3Hz,3H),7.46-7.39(m,1H),7.25(q,J＝9.3Hz,3H),7.03(dd,J＝7.7,4.8Hz,1H),6.41(s,2H),5.92(d,J＝5.7Hz,1H).
Example 6
Compound 5
2- [ (4- [ (2-amino-3-chloropyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N-cyclohexylpyridine-3-carboxamide was synthesized according to the general procedure in 56.69% yield as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ11.12(s,1H),8.58(d,J＝7.8Hz,1H),8.36(dd,J＝4.9,1.7Hz,1H),8.19-8.08(m,2H),7.75(d,J＝5.7Hz,1H),7.41-7.33(m,1H),7.26(t,J＝9.0Hz,1H),6.94(dd,J＝7.7,4.9Hz,1H),6.41(s,2H),5.92(d,J＝5.7Hz,1H),3.81(s,1H),1.85(s,2H),1.76(s,2H),1.63(d,J＝12.6Hz,1H),1.39-1.26(m,4H),1.16-1.13(m,1H).
Example 7
Compound 6
2- [ (4- [ (2-amino-3-chloropyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (3, 4-difluorophenyl) pyridine-3-carboxamide was synthesized according to the general procedure in 14.44% yield as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.69(s,1H),10.32(s,1H),8.43(dd,J＝4.8,1.8Hz,1H),8.26(dd,J＝7.8,1.8Hz,1H),8.10(dd,J＝13.8,2.5Hz,1H),7.96-7.86(m,1H),7.76(d,J＝5.7Hz,1H),7.53-7.40(m,3H),7.27(t,J＝9.0Hz,1H),7.04(dd,J＝7.8,4.9Hz,1H),6.41(s,2H),5.92(d,J＝5.7Hz,1H).
Example 8
Compound 7
2- [ (4- [ (2-amino-3-chloropyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (4, 4-difluorocyclohexyl) pyridine-3-carboxamide was synthesized according to the general method of synthesis in 34.89% yield as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ11.03(s,1H),8.65(d,J＝7.6Hz,1H),8.37(d,J＝4.8Hz,1H),8.17(d,J＝7.7Hz,1H),8.12(dd,J＝13.8,2.4Hz,1H),7.75(d,J＝5.6Hz,1H),7.36(d,J＝9.0Hz,1H),7.26(t,J＝9.0Hz,1H),6.96(dd,J＝7.8,4.9Hz,1H),6.41(s,2H),5.92(d,J＝5.7Hz,1H),4.08-4.01(m,1H),2.12-1.90(m,6H),1.67(q,J＝12.0,10.8Hz,2H).
Example 9
Compound 8
2- [ (4- [ (2-amino-3-chloropyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (3-cyanophenyl) pyridine-3-carboxamide was synthesized according to one of the methods of synthesis in 10.09% yield as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.58(s,1H),10.38(s,1H),8.43(dd,J＝4.7,2.1Hz,1H),8.28(dd,J＝7.8,2.0Hz,1H),8.11(dd,J＝13.7,2.5Hz,1H),7.94(d,J＝2.0Hz,1H),7.75(t,J＝7.3Hz,2H),7.49-7.37(m,2H),7.27(dt,J＝8.5,4.9Hz,2H),7.04(dd,J＝7.8,5.0Hz,1H),6.41(s,2H),5.92(d,J＝5.7Hz,1H).
Example 10
Compound 9
2- [ (4- [ (2-amino-3-chloropyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (2- (3- (dimethylamino) propoxy) phenyl) pyridine-3-carboxamide was synthesized according to the general procedure of synthesis in the yield: 5.91% as brown solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.77(s,1H),9.96(s,1H),8.43(d,J＝4.8Hz,1H),8.32(d,J＝7.7Hz,1H),8.10(dd,J＝13.7,2.5Hz,1H),7.75(d,J＝5.6Hz,1H),7.58(d,J＝7.8Hz,1H),7.38(d,J＝8.6Hz,1H),7.25(q,J＝8.7,8.1Hz,2H),7.11(d,J＝8.2Hz,1H),7.06-6.95(m,2H),6.41(s,2H),5.91(d,J＝5.7Hz,1H),4.04(t,J＝6.1Hz,2H),2.30(t,J＝7.1Hz,2H),2.02(s,6H),1.80(p,J＝6.7Hz,2H).LCMS(ESI+):m/z 551.0(M+H) +
Example 11
Compound 10
2- [ (4- [ (2-amino-3-chloropyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (2- [ (1-methylpiperidin-4-yl) oxy ] phenyl) pyridine-3-carboxamide was synthesized according to the general method for synthesis, yield: 16.83% as an off-white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.77(s,1H),9.87(s,1H),8.44(dd,J＝4.8,1.9Hz,1H),8.32(d,J＝7.7Hz,1H),8.10(dd,J＝13.6,2.5Hz,1H),7.75(d,J＝5.7Hz,1H),7.62(d,J＝7.8Hz,1H),7.38(d,J＝9.0Hz,1H),7.31-7.19(m,2H),7.16(d,J＝8.2Hz,1H),7.08-6.95(m,2H),6.41(s,2H),5.91(d,J＝5.7Hz,1H),4.45(s,1H),2.46(s,2H),2.16(s,2H),2.07(d,J＝10.0Hz,3H),1.87(d,J＝13.7Hz,2H),1.67(d,J＝8.7Hz,2H).LCMS(ESI+):m/z 563.0(M+H) +
Example 12
Compound 11
2- [ (4- [ (2-amino-3-chloropyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (naphthalen-1-yl) pyridine-3-carboxamide was synthesized according to the general procedure in 35.01% yield as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.88(s,1H),10.76(s,1H),8.56(d,J＝7.8Hz,1H),8.48(d,J＝4.8Hz,1H),8.13(d,J＝13.6Hz,1H),8.04-7.98(m,2H),7.92(d,J＝7.8Hz,1H),7.74(d,J＝5.6Hz,1H),7.66-7.54(m,4H),7.38(d,J＝8.9Hz,1H),7.25(t,J＝9.0Hz,1H),7.08(dd,J＝7.6,4.8Hz,1H),6.41(s,2H),5.91(d,J＝5.6Hz,1H).
Example 13
Compound 12
2- [ (4- [ (2-amino-3-chloropyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (3-trifluoromethylphenyl) pyridine-3-carboxamide was synthesized according to the general method of synthesis in the yield: 18.84% as white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.80(s,1H),10.29(s,1H),8.44(dd,J＝4.8,1.9Hz,1H),8.29(dd,J＝7.8,1.9Hz,1H),8.22(s,1H),8.10(dd,J＝13.6,2.5Hz,1H),7.99(d,J＝8.3Hz,1H),7.75(d,J＝5.7Hz,1H),7.64(t,J＝8.0Hz,1H),7.52(d,J＝7.8Hz,1H),7.46(d,J＝8.9Hz,1H),7.28(t,J＝9.0Hz,1H),7.05(dd,J＝7.7,5.0Hz,1H),6.45(s,2H),5.91(d,J＝5.7Hz,1H).
LCMS(ESI+):m/z 518.1(M+H) +
Example 14
Compound 13
2- ((4- ((2-amino-3-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -N- (2- (3- (dimethylamino) propoxy) -4-fluorophenyl) nicotinamide was synthesized according to the general procedure as follows: 36.18% as yellow solid.
1 H NMR(400MHz,DMSO-d 6 )δ11.13-10.66(m,1H),10.21-9.78(m,1H),8.43(dd,J＝4.8,1.8Hz,1H),8.32(d,J＝7.7Hz,1H),8.10(dd,J＝13.6,2.5Hz,1H),7.75(d,J＝5.7Hz,1H),7.50(dd,J＝8.7,6.4Hz,1H),7.38(dd,J＝9.1,2.4Hz,1H),7.26(t,J＝9.1Hz,1H),7.03(td,J＝9.6,8.4,3.7Hz,2H),6.82(td,J＝8.5,2.6Hz,1H),6.40(s,2H),5.91(d,J＝5.7Hz,1H),4.05(t,J＝6.0Hz,2H),2.27(t,J＝7.2Hz,2H),2.01(s,6H),1.78(p,J＝6.6Hz,2H).
LCMS(ESI+):m/z 569.2(M+H)+
Example 15
Intermediate 2
2- ((4- ((2-acetamidopyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinic acid
Step 1: n- (4- (4-amino-2-chlorophenoxy) pyridin-2-yl) acetamide
N- (4- (2-chloro-4-nitrophenoxy) pyridin-2-yl) acetamide (4.0 g,13.0 mmol) and iron powder (2.18 g,39.0 mmol) were dissolved in ethanol (200 ml) and water (20 ml) and ammonium chloride (3.48 g,65.0 mmol) was added at 20 ℃. The reaction mixture was stirred at 80 ℃ for 1 hour and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with methanol/dichloromethane (methanol increased from 0 to 10% over 20 minutes) to give N- (4- (4-amino-2-chlorophenoxy) pyridin-2-yl) acetamide (3.3 g, 86% yield) as a yellow solid.
LCMS(ESI+):m/z 278.0(M+1)
Step 2:2- ((4- ((2-Acetaminopyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinic acid methyl ester
N- (4- (4-amino-2-chlorophenoxy) pyridin-2-yl) acetamide (3.3 g,11.9 mmol), methyl 2-bromonicotinate (3.08 g,14.2 mmol), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (1.38 g,2.3 mmol) and cesium carbonate (7.75 g,23.8 mmol) were dissolved in dioxane (100 ml) and dibenzylideneacetone dipalladium (1.09 g,1.1 mmol) was added at 20 ℃. The reaction mixture was stirred at 100℃for 6 hours. And then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/petroleum ether (40 minutes to increase ethyl acetate from 0 to 75%) to give methyl 2- ((4- ((2-acetamidopyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinate (3.8 g, 73% yield) as a white solid.
LCMS(ESI+):m/z 413.0(M+1)
Step 3:2- ((4- ((2-acetamidopyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinic acid
Methyl 2- ((4- ((2-acetamidopyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinate (3.8 g,9.2 mmol) was dissolved in methanol (70 ml) and tetrahydrofuran (70 ml), followed by addition of lithium hydroxide monohydrate (1.93 g,46.0 mmol) (35 ml) dissolved in water at 20 ℃. The reaction mixture was stirred at 20℃for 0.5 hours and then brought to pH 5 with 3N hydrochloric acid. Filtration under reduced pressure collected the filter cake to give 2- ((4- ((2-acetamidopyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinic acid (3.39, yield 83%) as a white solid
1 H NMR(400MHz,DMSO-d 6 ):δ13.73(s,1H),10.58(d,J＝17.6Hz,2H),8.46(dd,J＝4.8,2.0Hz,1H),8.32-8.25(m,2H),8.18(d,J＝5.6Hz,1H),7.69-7.59(m,2H),7.32(d,J＝8.8Hz,1H),6.96(dd,J＝7.6,4.8Hz,1H),6.64(dd,J＝5.6,2.4Hz,1H),2.04(s,3H).
LCMS(ESI+):m/z 399.0(M+1)
And a synthesis method II:
example 16
Compound 14
Synthesis of N- (2- ((5-azaspiro [3.4] oct-2-yl) oxy) -4-fluorophenyl) -2- ((4- ((2-acetamidopyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinamide, yield: 32, which is white solid in shape
To a 20mL three-necked flask was added 2- ((4- ((2-acetamidopyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinic acid (100.0 mg,0.25 mmol), DMF (5.0 mL), DIEA (81.43 mg,0.63 mmol), HATU (144.5 mg,0.38 mmol) and after stirring at room temperature for 30min 2- (2-amino-5-fluorophenoxy) -5-azaspiro [3.4] was added]Tert-butyl octane-5-carboxylate (92.5 mg,0.27 mmol) was stirred overnight at room temperature. Ethyl acetate (10 ml) was added to the reaction system, followed by washing with water (10 ml. Times.3) and washing with a saturated aqueous sodium chloride solution (10 ml. Times.2). The organic phase was concentrated, DCM (5 mL) was added, and TFA (1 mL) was added after stirring to dissolve. After stirring at room temperature for 30min, the reaction solvent was removed by concentration under reduced pressure. The system was dissolved in 10mL ethyl acetate and taken up in saturated Na 2 CO 3 The aqueous solution was washed to ph=8 and the organic phase was concentrated. Purification by reverse phase preparative column gave 50mg (yield: 32%) of a white solid, N- (2- ((5-azaspiro [3.4 ])]Oct-2-yl) oxy) -4-fluorophenyl) -2- ((4- ((2-acetamidopyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinamide.
1 H NMR(400MHz,DMSO-d 6 )δ10.56(s,1H),8.48-8.38(m,2H),8.32(d,J＝7.6Hz,1H),8.25-8.15(m,2H),7.60(d,J＝13.7Hz,3H),7.29(d,J＝8.9Hz,1H),7.10-6.95(m,1H),6.93-6.76(m,2H),6.62(d,J＝5.8Hz,1H),4.82(p,J＝6.5Hz,1H),3.10(s,2H),3.00(t,J＝7.3Hz,2H),2.06(d,J＝15.0Hz,5H),1.86(t,J＝7.3Hz,2H)
LCMS(ESI+):m/z 617.0(M+1)
Example 17
Compound 15
2- [ (3-chloro-4- ((2-acetamidopyridin-4-yl) oxy) phenyl) amino ] -N- (2- (3- (dimethylamino) propoxy) -4-fluorophenyl) pyridine-3-carboxamide was synthesized according to synthesis general procedure two, yield: 15.82% as white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.55(s,1H),8.44(d,J＝4.9Hz,1H),8.32(d,J＝7.8Hz,1H),8.24(d,J＝2.5Hz,1H),8.18(d,J＝5.6Hz,1H),7.64-7.56(m,2H),7.51(t,J＝7.6Hz,1H),7.29(d,J＝8.8Hz,1H),7.03(td,J＝9.5,8.1,3.8Hz,2H),6.82(td,J＝8.3,2.3Hz,1H),6.61(dd,J＝5.9,2.3Hz,1H),4.05(t,J＝6.1Hz,2H),2.27(t,J＝7.1Hz,2H),2.02(d,J＝9.7Hz,8H),1.79(q,J＝6.6Hz,2H).
LCMS(ESI+):m/z 593.0(M+1)
Example 18
Compound 16
2- [ (3-chloro-4- [ (2-acetamidopyridin-4-yl) oxy ] phenyl) amino ] -N- (2- (2- (dimethylamino) ethoxy) -4-fluorophenyl) pyridine-3-carboxamide was synthesized according to synthesis procedures in 11.48% yield as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.56(s,1H),10.43(s,2H),8.44(d,J＝4.8Hz,1H),8.24(d,J＝2.9Hz,2H),8.18(d,J＝5.7Hz,1H),7.71(dd,J＝8.7,6.4Hz,1H),7.61(dd,J＝8.9,2.5Hz,2H),7.30(d,J＝8.8Hz,1H),7.13(dd,J＝10.7,2.8Hz,1H),7.04(dd,J＝7.7,4.9Hz,1H),6.87(td,J＝8.6,2.7Hz,1H),6.62(dd,J＝5.9,2.4Hz,1H),4.15(t,J＝5.6Hz,2H),2.59-2.52(m,2H),2.13(s,6H),2.03(s,3H).
Example 19
Compound 17
2- [ (3-chloro-4- ((2-acetamidopyridin-4-yl) oxy) phenyl) amino ] -N- (4-fluoro-2- [ (1-methylpiperidin-4-yl) oxy ] phenyl) pyridine-3-carboxamide was synthesized according to the synthesis method II in 13.18% yield, which was characterized as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.80(s,1H),10.55(s,1H),9.92(s,1H),8.44(d,J＝4.9Hz,1H),8.32(d,J＝7.8Hz,1H),8.25(d,J＝2.6Hz,1H),8.18(d,J＝5.7Hz,1H),7.64-7.55(m,2H),7.58-7.50(m,1H),7.29(d,J＝8.8Hz,1H),7.15-7.08(m,1H),7.04(dd,J＝7.8,4.9Hz,1H),6.86-6.77(m,1H),6.61(d,J＝5.6Hz,1H),4.51(s,1H),2.42(s,2H),2.17(s,2H),2.04(s,6H),1.90-1.81(m,2H),1.67(s,2H),1.68-1.64(m,2H).
Example 20
Compound 18
2- ((4- ((2-acetamidopyridin-4-yl) oxy) -3-chlorophenyl) amino) -N- (4-fluorophenyl) nicotinamide was synthesized according to synthesis method two in 18.92% yield as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.56(d,J＝4.5Hz,2H),10.45(s,1H),8.43(dd,J＝4.9,1.9Hz,1H),8.31-8.22(m,2H),8.18(d,J＝5.5Hz,1H),7.80-7.71(m,2H),7.67-7.60(m,2H),7.29(d,J＝8.9Hz,1H),7.24(td,J＝8.2,7.6,2.2Hz,2H),7.03(dd,J＝7.9,5.0Hz,1H),6.63(dd,J＝5.8,2.3Hz,1H),2.04(s,3H).
Example 21
Compound 19
2- ((4- ((2-acetamidopyridin-4-yl) oxy) -3-chlorophenyl) amino) -N- (2- ((1 s,3 s) -3-aminocyclobutoxy) -4-fluorophenyl) nicotinamide was synthesized according to synthesis method two in 47% yield as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.54(s,1H),8.44(dd,J＝4.9,1.7Hz,1H),8.32(d,J＝7.7Hz,1H),8.25(d,J＝2.6Hz,1H),8.18(d,J＝5.7Hz,1H),7.59(ddd,J＝14.9,6.9,4.5Hz,3H),7.29(d,J＝8.8Hz,1H),7.03(dd,J＝7.8,4.8Hz,1H),6.90-6.79(m,2H),6.63(dd,J＝5.8,2.4Hz,1H),4.50(p,J＝7.0Hz,1H),3.21(t,J＝7.8Hz,1H),2.81(dh,J＝10.2,3.4Hz,2H),2.02(d,J＝14.2Hz,5H),1.23(s,1H)
LCMS(ESI+):m/z 577.0(M+1)
Example 22
Compound 20
N- (2- ((5-azaspiro [3.4] oct-2-yl) oxy) -4-fluorophenyl) -2- ((4- ((2-acetamidopyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinamide was synthesized according to synthesis method II in 34% yield as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.73(s,1H),10.57(s,1H),9.97(s,1H),8.44(d,J＝4.8Hz,1H),8.31(d,J＝8.6Hz,1H),8.25(d,J＝2.5Hz,1H),8.18(d,J＝5.9Hz,1H),7.70-7.52(m,3H),7.29(d,J＝8.8Hz,1H),7.11-6.99(m,1H),6.94-6.77(m,2H),6.64(dd,J＝5.8,2.4Hz,1H),4.91-4.76(m,1H),3.12(t,J＝7.1Hz,2H),3.06(s,2H),2.69(s,2H),2.11(t,J＝9.5Hz,2H),2.00(d,J＝24.5Hz,5H),1.24(s,1H)
LCMS(ESI+):m/z 617.0(M+1)
Example 23
Compound 21
(S) -2- ((4- ((2-acetamidopyridin-4-yl) oxy) -3-chlorophenyl) amino) -N- (4-fluoro-2- (pyrrolidin-3-yloxy) phenyl) nicotinamide was synthesized according to synthesis method two in 29% yield, which was a white solid in character.
1 H NMR(400MHz,DMSO-d 6 )δ10.55(s,1H),8.96(s,2H),8.44(dd,J＝4.8,1.8Hz,1H),8.30(dd,J＝7.7,1.8Hz,1H),8.23(d,J＝2.6Hz,1H),8.18(d,J＝5.7Hz,1H),7.71(dd,J＝8.8,6.4Hz,1H),7.66-7.58(m,2H),7.29(d,J＝8.8Hz,1H),7.17(dd,J＝10.8,2.7Hz,1H),7.03(dd,J＝7.7,4.8Hz,1H),6.90(td,J＝8.6,2.7Hz,1H),6.64(dd,J＝5.8,2.4Hz,1H),5.29-5.19(m,1H),3.46(dd,J＝13.1,4.4Hz,1H),3.37-3.22(m,4H),2.19(ddt,J＝13.6,9.5,5.2Hz,2H),2.03(s,3H)
LCMS(ESI+):m/z 577.0(M+1)
Example 24
Compound 22
(R) -2- ((4- ((2-acetamidopyridin-4-yl) oxy) -3-chlorophenyl) amino) -N- (4-fluoro-2- (pyrrolidin-3-yloxy) phenyl) nicotinamide was synthesized according to synthesis method two in 38% yield which was a white solid.
1H NMR(400MHz,DMSO-d6)δ10.55(s,1H),10.24(s,2H),8.44(dd,J＝4.8,1.8Hz,1H),8.28(dd,J＝7.8,1.9Hz,1H),8.21(dd,J＝19.0,4.2Hz,2H),7.71(dd,J＝8.8,6.4Hz,1H),7.67-7.54(m,2H),7.29(d,J＝8.8Hz,1H),7.15(dd,J＝10.9,2.8Hz,1H),7.02(dd,J＝7.7,4.8Hz,1H),6.89(td,J＝8.5,2.7Hz,1H),6.64(dd,J＝5.7,2.4Hz,1H),5.20(t,J＝4.6Hz,1H),3.39(dd,J＝13.0,4.4Hz,2H),3.25-3.20(m,2H),2.26-2.09(m,2H),2.03(s,3H),1.24(s,1H)
LCMS(ESI+):m/z 577.0(M+1)
Example 25
Compound 23
(S) -2- ((4- ((2-acetamidopyridin-4-yl) oxy) -3-chlorophenyl) amino) -N- (2- ((4-aminobutan-2-yl) oxy) -4-fluorophenyl) nicotinamide was synthesized according to synthesis method two in 41% yield as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.57(s,1H),8.44(d,J＝4.9Hz,1H),8.35-8.22(m,2H),8.18(d,J＝5.7Hz,1H),7.64-7.49(m,3H),7.30(d,J＝8.8Hz,1H),7.06(ddd,J＝24.5,9.6,4.0Hz,2H),6.84(td,J＝8.5,2.7Hz,1H),6.64(dd,J＝6.0,2.5Hz,1H),4.68(q,J＝6.1Hz,1H),2.89(dq,J＝12.7,7.6Hz,2H),2.69(s,2H),2.03(s,3H),1.88(q,J＝7.6Hz,2H),1.25(d,J＝6.3Hz,3H)，LCMS(ESI+):m/z 579.0(M+1)
Example 26
Intermediate 3
2- ((4- ((2-aminopyridin-4-yl) oxy) -3-chlorophenyl) amino) -N- (4-fluorophenyl) nicotinamide
Step 1:4- (2-chloro-4-nitrophenoxy) pyridin-2-amine
2-aminopyridin-4-ol (5.0 g,45.4 mmol) and 2-chloro-1-fluoro-4-nitrobenzene (8.8 g,49.9 mmol) were dissolved in dimethyl sulfoxide (300 ml), followed by addition of potassium carbonate (9.4 g,68.1 mmol) at 20 ℃. The reaction mixture was stirred at 60℃for 3 hours, then quenched with water (500 ml) and filtered. The filtrate was extracted with ethyl acetate (500 ml) and quenched with water (200 ml. Times.5). The organic phases were combined, dried over sodium persulfate and then filtered. The filtrate was concentrated under reduced pressure to give 4- (2-chloro-4-nitrophenoxy) pyridin-2-amine (11.3 g, yield 88%) as a yellow solid.
LCMS(ESI+):m/z 266.0(M+1)
Step 2: (tert-Butoxycarbonyl) (4- (2-chloro-4-nitrophenoxy) pyridin-2-yl) carbamic acid tert-butyl ester
4- (2-chloro-4-nitrophenoxy) pyridin-2-amine (2.0 g,7.5 mmol), di-tert-butyl dicarbonate (4.9 g,22.5 mmol) and triethylamine (3.8 g,37.5 mmol) were dissolved in THF (100 ml) and then 4-dimethylaminopyridine (0.18 g,1.5 mmol) was added at 20 ℃. The reaction mixture was stirred at 40 ℃ for 16 hours and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with ethyl acetate/petroleum ether solvent (0 to 15% in 20 minutes) to give tert-butyl (tert-butoxycarbonyl) (4- (2-chloro-4-nitrophenoxy) pyridin-2-yl) carbamate (1.3 g, yield 34%) as a brown solid.
LCMS(ESI+):m/z 466.1(M+1)
Step 3: (4- (4-amino-2-chlorophenoxy) pyridin-2-yl) (t-butoxycarbonyl) carbamic acid tert-butyl ester
Tert-butyl (tert-butoxycarbonyl) (4- (2-chloro-4-nitrophenoxy) pyridin-2-yl) carbamate (1.3 g,2.8 mmol) was dissolved in ethyl acetate (100 ml) and palladium on carbon (0.3 g,0.2 mmol) was then added at 20 ℃. The reaction mixture was stirred under a hydrogen atmosphere at 20 ℃ for 1.5 hours, and then filtered. The filtrate was concentrated under reduced pressure to give tert-butyl (4- (4-amino-2-chlorophenoxy) pyridin-2-yl) (tert-butoxycarbonyl) carbamate (1.1 g, yield 85%) as a pale yellow solid.
LCMS(ESI+):m/z 436.1(M+1)
Step 4:2- ((4- ((2- (bis (t-butoxycarbonyl) amino) pyridin-4-yl) oxy) -3-chlorophenyl) amino) smoke Acid methyl ester
Tert-butyl (4- (4-amino-2-chlorophenoxy) pyridin-2-yl) (tert-butoxycarbonyl) carbamate (11.4 g,26.0 mmol) and methyl 2-bromopyridine-3-carboxylate (6.18 g,28.6 mmol) were dissolved in dioxane (300 ml), then tris dibenzylideneacetone dipalladium (2.38 g,2.6 mmol), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (3.01 g,5.2 mmol) and cesium carbonate (16.9 g,0.052 mmol) were added at 25 ℃. The reaction was heated to 100℃and stirred for 4 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with ethyl acetate and petroleum ether solvent (0 to 30% in 20 min) to give methyl 2- ((4- ((2- (bis (t-butoxycarbonyl) amino) pyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinate (13 g, yield 87%) as a yellow solid.
LCMS(ESI+):m/z 571.1(M+1)
Step 5:2- ((4- ((2- ((tert-Butoxycarbonyl) amino) pyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinic acid
Methyl 2- ((4- ((2- (bis (t-butoxycarbonyl) amino) pyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinate (13.0 g,22.7 mmol) was dissolved in tetrahydrofuran (100 ml), water (50 ml) and methanol (50 ml) and then lithium hydroxide monohydrate (4.76 g,113.5 mol) was added at 25 ℃. The reaction was stirred at 25℃for 1 hour. The reaction mixture was concentrated under reduced pressure and the pH was adjusted to 2-3 with 1N hydrochloric acid. The mixture was filtered to give 2- ((4- ((2- ((tert-butoxycarbonyl) amino) pyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinic acid (9.6 g, yield 87%) as a white solid.
LCMS(ESI+):m/z 457.1(M+1)
Step 6: (4- (2-chloro-4- ((3- ((4-fluorophenyl) amino) methyl)Acyl) pyridin-2-yl) amino) phenoxy) pyri-dine Pyridin-2-yl) carbamic acid tert-butyl ester
2- ((4- ((2- ((tert-Butoxycarbonyl) amino) pyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinic acid (7.0 g,15.3 mmol) and 4-fluoroaniline (2.2 g,19.8 mmol) were dissolved in dimethylformamide (150 ml), then benzotriazol-1-yl-oxy-tripyrrolidinylphosphine hexafluorophosphate (10.4 g,19.8 mmol) and 4-dimethylaminopyridine (1.9 g,15.3 mmol) were added at 20 ℃. The reaction mixture was stirred at 20℃for 2 hours, then diluted with water (50 ml) and extracted with dichloromethane (500 ml. Times.3). The organic phases were combined and then taken up in Na 2 SO 4 Drying and filtering. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with methanol in dichloromethane solvent (0 to 5% methanol in 10 min) to give tert-butyl (4- (2-chloro-4- ((3- ((4-fluorophenyl) carbamoyl) pyridin-2-yl) amino) phenoxy) pyridin-2-yl) carbamate (7.5 g, 84% yield) as a white solid.
LCMS(ESI+):m/z 550.1(M+1)
Step 7:2- ((4- ((2-aminopyridin-4-yl) oxy) -3-chlorophenyl) amino) -N- (4-fluorophenyl) nicotinamide
Tert-butyl (4- (2-chloro-4- ((3- ((4-fluorophenyl) carbamoyl) pyridin-2-yl) amino) phenoxy) pyridin-2-yl) carbamate (7.5 g,13.6 mmol) was dissolved in dichloromethane (60 ml) and trifluoroacetic acid (77.5 g,0.68 mol) was added at 20 ℃. The reaction mixture was stirred at 20 ℃ for 1 hour, then diluted with water (300 ml) and extracted with DCM (500 ml×2). The organic phases were combined, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with methanol in dichloromethane solvent (0 to 5% methanol in 30 min) to give 2- ((4- ((2-aminopyridin-4-yl) oxy) -3-chlorophenyl) amino) -N- (4-fluorophenyl) nicotinamide (4.1315 g, 65% yield) as a white solid.
LCMS(ESI+):m/z 449.9(M+1)
1 H NMR(400MHz,DMSO-d 6 ):δ10.55(s,1H),10.40(s,1H),8.42(dd,J＝4.8,1.6Hz,1H),8.27(dd,J＝7.6,1.6Hz,1H),8.20(d,J＝2.8Hz,1H),7.82-7.70(m,3H),7.60(dd,J＝8.8,2.8Hz,1H),7.27-7.18(m,3H),7.02(dd,J＝7.6,4.8Hz,1H),6.14(dd,J＝5.6,2.4Hz,1H),5.95(s,2H),5.80-5.67(m,1H).
And (3) a synthesis method III:
example 27
Compound 24
Step 1: (3S) -3- { [ (4- (2-chloro-4- [ (4-fluorophenyl) carbamoyl)]Pyridin-2-yl) amino groups]Benzene Oxy) pyridin-2-yl) carbamoyl]Methyl } pyrrolidine-1-carboxylic acid tert-butyl ester
To a solution of 2- ((4- ((2-aminopyridin-4-yl) oxy) -3-chlorophenyl) amino) -N- (4-fluorophenyl) nicotinamide (200 mg,0.44 mmol) in acetonitrile (10 ml) was added 2- [ (3S) -1- [ (tert-butoxy) carbonyl ] pyrrolidin-3-yl ] acetic acid (110.97 mg,0.48 mmol), 1-methyl-1H-imidazole (126.43 mg,1.54 mmol), N, N, N, N-tetramethyl chloroformyl amine hexafluorophosphate (246.91 mg,0.88 mmol), and the mixture was stirred at room temperature for 16 hours. LCMS showed good reaction. The mixture was concentrated under reduced pressure, and the residue was purified with a methanol/dichloromethane (0-2.5%) eluting silica gel column to give tert-butyl (3S) -3- { [ (4- (2-chloro-4- [ (3- [ (4-fluorophenyl) carbamoyl ] pyridin-2-yl) amino ] phenoxy) pyridin-2-yl) carbamoyl ] methyl } pyrrolidine-1-carboxylate (216 mg, yield 73.49%).
LCMS(ESI+):m/z 661.3(M+1)
Step 2:2- [ (3-chloro-4- [ (2- (2- [ (3S) -pyrrolidin-3-yl)]Acetamido) pyridin-4-yl) oxy]Benzene Radical) amino group]-N- (4-fluorophenyl) pyridine-3-carboxamide
To a solution of tert-butyl (3S) -3- { [ (4- (2-chloro-4- [ (3- [ (4-fluorophenyl) carbamoyl ] pyridin-2-yl) amino ] phenoxy) pyridin-2-yl) carbamoyl ] methyl } pyrrolidine-1-carboxylate (216 mg,0.33 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (5 ml) and the mixture was stirred at room temperature for 2 hours. LCMS showed good reaction. The mixture was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran and ethyl acetate, the organic phase was concentrated, and the residue was purified by C18 column to give 2- [ (3-chloro-4- [ (2- (2- [ (3S) -pyrrolidin-3-yl ] acetamido) pyridin-4-yl) oxy ] phenyl) amino ] -N- (4-fluorophenyl) pyridine-3-carboxamide (80 mg, yield 43.65%) as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.65-10.64(m,2H),10.45(s,1H),8.43(dd,J＝4.9,1.8Hz,1H),8.36(d,J＝6.2Hz,1H),8.32-8.23(m,2H),8.19(d,J＝5.7Hz,1H),7.80-7.70(m,2H),7.68-7.59(m,2H),7.30(d,J＝8.8Hz,1H),7.24(t,J＝8.9Hz,2H),7.03(ddd,J＝6.5,4.9,1.6Hz,1H),6.66(dd,J＝5.8,2.4Hz,1H),3.25-3.22(m,2H),3.12-3.11(m,1.5H),3.10-3.00(m,1.5H),2.68-2.66(dd,J＝11.6,8.0Hz,1H),2.46(s,2H),2.08-1.98(m,1.5H),1.47-1.44(m,1.5H).
LCMS(ESI+):m/z 561.4(M+1)
Example 28
Compound 25
(S) -2- ((3-chloro-4- ((2- (2- (pyrrolidin-2-yl) acetamido) pyridin-4-yl) oxy) phenyl) amino) -N- (4-fluorophenyl) nicotinamide was synthesized according to synthesis method three in 10.25% yield which was a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.87(s,1H),10.62(s,1H),10.44(s,1H),8.43(dd,J＝4.8,1.8Hz,1H),8.35(s,1H),8.32-8.22(m,2H),8.20(d,J＝5.7Hz,1H),7.80-7.70(m,2H),7.65(dd,J＝8.8,2.6Hz,1H),7.59(d,J＝2.3Hz,1H),7.33-7.19(m,3H),7.03(dd,J＝7.7,4.8Hz,1H),6.70(dd,J＝5.8,2.4Hz,1H),3.52-3.48(m,1H),2.95-2.88(m,2H),2.64-2.54(m,2H),1.94-1.89(m,1H),1.79-1.64(m,2H),1.43-1.34(m,1H).
Example 29
Compound 26
(R) -2- ((3-chloro-4- ((2- (2- (pyrrolidin-2-yl) acetamido) pyridin-4-yl) oxy) phenyl) amino) -N- (4-fluorophenyl) nicotinamide was synthesized according to synthesis method three in 24.44% yield which was a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.87(s,1H),10.66-10.61(m,1H),10.45(s,1H),8.43(dd,J＝4.8,1.8Hz,1H),8.34(s,1H),8.29(dd,J＝7.8,1.8Hz,1H),8.25(d,J＝2.6Hz,1H),8.20(d,J＝5.7Hz,1H),7.80-7.70(m,2H),7.65(dd,J＝8.9,2.6Hz,1H),7.59(d,J＝2.4Hz,1H),7.30(d,J＝8.9Hz,1H),7.30-7.19(m,2H),7.03(dd,J＝7.7,4.8Hz,1H),6.72(dd,J＝5.7,2.4Hz,1H),3.55(s,1H),3.02-2.93(m,2H),2.70(t,J＝5.9Hz,2H),1.97(d,J＝9.4Hz,1H),1.83-1.76(m,1H),1.70(s,1H),1.42(t,J＝9.8Hz,1H).
Example 30
Compound 27
2- ((4- ((2- (2- (azetidin-3-yl) acetamido) pyridin-4-yl) oxy) -3-chlorophenyl) amino) -N- (4-fluorophenyl) nicotinamide was synthesized according to synthesis method three in 22.94% yield as a white solid.
1 H NMR(400MHz,DMSO-d6)δ10.68(s,1H),10.62(s,1H),10.45(s,1H),8.43(dd,J＝4.9,1.7Hz,1H),8.39(s,1H),8.32-8.23(m,2H),8.19(d,J＝5.7Hz,1H),7.80-7.70(m,2H),7.64(dd,J＝8.9,2.6Hz,1H),7.56(d,J＝2.4Hz,1H),7.32-7.20(m,3H),7.03(dd,J＝7.7,4.8Hz,1H),6.67(dd,J＝5.7,2.4Hz,1H),3.90(t,J＝9.2Hz,2H),3.63(t,J＝8.8Hz,2H),3.03(p,J＝8.2Hz,1H),2.74(d,J＝7.6Hz,2H).
Example 31
Compound 28
2- ((3-chloro-4- ((2- (2- (piperidin-4-yl) acetamido) pyridin-4-yl) oxy) phenyl) amino) -N- (4-fluorophenyl) nicotinamide was synthesized according to synthesis method three in 25.88% yield as a white solid.
1 H NMR(400MHz,DMSO-d6)δ10.66(s,1H),10.61(s,1H),10.47(s,1H),8.46-8.41(m,1H),8.39(d,J＝4.2Hz,1H),8.33-8.24(m,2H),8.19(d,J＝5.7Hz,1H),7.81-7.71(m,2H),7.65(dt,J＝6.4,3.0Hz,2H),7.30(d,J＝8.7Hz,1H),7.24(td,J＝8.7,1.5Hz,2H),7.03(ddd,J＝7.3,4.9,1.9Hz,1H),6.67(dd,J＝5.7,2.5Hz,1H),3.17(d,2H),2.76(t,J＝12.5Hz,2H),2.31(d,J＝7.0Hz,2H),2.01-1.91(m,1H),1.76-1.67(m,2H),1.31(q,J＝12.7Hz,2H).
Example 32
Compound 29
(S) -2- ((3-chloro-4- ((2- (2- (piperidin-3-yl) acetamido) pyridin-4-yl) oxy) phenyl) amino) -N- (4-fluorophenyl) nicotinamide was synthesized according to the general method of synthesis in 33.55% yield as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.63(s,2H),10.45(s,1H),8.43(dd,J＝4.9,1.8Hz,1H),8.37-8.22(m,3H),8.19(d,J＝5.7Hz,1H),7.80-7.70(m,2H),7.65(dd,J＝9.8,3.5Hz,1H),7.63(s,1H),7.31-7.19(m,3H),7.03(ddd,J＝7.8,4.8,1.2Hz,1H),6.66(dd,J＝5.8,2.4Hz,1H),3.09(s,2H),2.65(t,J＝12.2Hz,1H),2.45(d,J＝12.1Hz,1H),2.31-2.22(m,2H),2.04(s,1H),1.69(d,J＝11.0Hz,2H),1.52(d,J＝12.2Hz,1H),1.17-1.11(m,1H).
Example 33
Intermediate 4-1
Step 1:4- (2-fluoro-4-nitrophenoxy) pyridin-2-amine
To a solution of 2-aminopyridin-4-ol (20 g,181.64 mmol) in acetonitrile (200 ml) was added 1, 2-difluoro-4-nitrobenzene (28.90 g,181.64 mmol) and potassium carbonate (37.66 g,272.46 mmol). The mixture was then heated to 60 ℃ and stirred for 12 hours. The mixture was added to 500ml of water, and then the mixture was cooled to room temperature. The mixture was filtered, and the solid was dried under reduced pressure to give 4- (2-fluoro-4-nitrophenoxy) pyridin-2-amine (29 g, yield 64.07%).
LCMS(ESI+):m/z 250.2(M+1)
Step 2: n- (4- (2-fluoro-4-nitrophenoxy) pyridin-2-yl) acetamide
To a solution of 4- (2-fluoro-4-nitrophenoxy) pyridin-2-amine (5 g,20.06 mmol) in dichloromethane (100 ml) was added triethylamine (6.09 g,60.18 mmol), the mixture was cooled to 0 ℃ and a solution of acetyl chloride (3.94 g,50.15 mmol) in dichloromethane (20 ml) was added dropwise. The mixture was then warmed to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in 50ml of tetrahydrofuran and 10ml of water, followed by addition of 50ml of a saturated lithium hydroxide solution. The mixture was stirred until the diacetyl compound was converted to the target compound, then 150ml of ethyl acetate was added. The organic layer was separated and washed with 50ml brine. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and the residue was purified by a silica gel column to give N- (4- (2-fluoro-4-nitrophenoxy) pyridin-2-yl) acetamide (5.35 g, yield 91.56%) as a yellow solid.
LCMS(ESI+):m/z 292.14(M+1)
Step 3: n- (4- (4-amino-2-fluorophenoxy) pyridin-2-yl) acetamide
To a solution of N- (4- (2-fluoro-4-nitrophenoxy) pyridin-2-yl) acetamide (5 g,17.17 mmol) in tetrahydrofuran (50 ml) was added palladium on carbon (0.91 g,0.86mmol, content 10%). The hydrogen was replaced three times. The mixture was stirred at room temperature overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give crude N- (4- (4-amino-2-fluorophenoxy) pyridin-2-yl) acetamide (4.5 g, yield 100.33%).
LCMS(ESI+):m/z 262.7(M+1)
Step 4:2- [ (4- [ (2-Acetaminopyridin-4-yl) oxy ] -3-fluorophenyl) amino ] pyridine-3-carboxylic acid methyl ester
To a solution of N- (4- (4-amino-2-fluorophenoxy) pyridin-2-yl) acetamide (1 g,3.83 mmol) in 1, 4-dioxane (20 ml) was added methyl 2-bromopyridine-3-carboxylate (992.87 mg,4.60 mmol), cesium carbonate (2495.78 mg,7.66 mmol), dimethyl diphenylphosphinoxa-ne (443.22 mg,0.77 mmol) and (1E, 4E) -1, 5-diphenylpenta-1, 4-dien-3-one palladium (220.22 mg,0.38 mmol) with nitrogen three substitutions. The mixture was then heated to 100 ℃ and stirred overnight. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by a silica gel column to give methyl 2- [ (4- [ (2-acetamidopyridin-4-yl) oxy ] -3-fluorophenyl) amino ] pyridine-3-carboxylate (230 mg, yield 15.16%).
LCMS(ESI+):m/z 397.8(M+1)
Step 5:2- [ (4- [ (2-acetaminopyridine)-4-yl) oxy]-3-fluorophenyl) amino group]Pyridine-3-carboxylic acid
To a solution of methyl 2- [ (4- [ (2-acetamidopyridin-4-yl) oxy ] -3-fluorophenyl) amino ] pyridine-3-carboxylate (230 mg,0.58 mmol) was added lithium hydroxide hydrate (48.67 mg,1.16 mmol) in 5ml tetrahydrofuran and 10ml water and the mixture was stirred at room temperature overnight. Concentrating the mixture to remove tetrahydrofuran, then adding saturated citric acid solution, and adjusting the pH value to 1-2. The mixture was filtered and the solid was washed with water, and then the solid was dried to give 2- [ (4- [ (2-acetamidopyridin-4-yl) oxy ] -3-fluorophenyl) amino ] pyridine-3-carboxylic acid (180 mg, yield 81.13%).
LCMS(ESI+):m/z 383.4(M+1)
Synthesis method four:
example 34
Compound 30
2- [ (4- [ (2-Acetaminopyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (4-fluoro-2- [ (1-methylpiperidin-4-yl) oxy ] phenyl) pyridine-3-carboxamide
To a solution of 2- [ (4- [ (2-acetamidopyridin-4-yl) oxy ] -3-fluorophenyl) amino ] pyridine-3-carboxylic acid (210 mg,0.55 mmol) in acetonitrile (10 ml) was added 4-fluoro-2- [ (1-methylpiperidin-4-yl) oxy ] aniline (135.68 mg,0.61 mmol), 1-methyl-1H-imidazole (158.04 mg,1.93 mmol) and N, N, N, N-tetramethyl chloroformidine hexafluorophosphate (231.48 mg,0.83 mmol). The mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure and the residue was purified using a prepared thin layer chromatography Plate (PLC) to give the target compound. The title compound was recrystallized from 1.5ml DMSO and 0.5ml water to give 2- [ (4- [ (2-acetamidopyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (4-fluoro-2- [ (1-methylpiperidin-4-yl) oxy ] phenyl) pyridine-3-carboxamide (48 mg, yield 14.85%) as a yellow solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.86(s,1H),10.58(s,1H),9.95(s,1H),8.46(dd,J＝4.9,1.7Hz,1H),8.35(d,J＝7.8Hz,1H),8.20(d,J＝5.8Hz,1H),8.15(dd,J＝13.7,2.5Hz,1H),7.69(d,J＝2.4Hz,1H),7.55(dd,J＝8.7,6.5Hz,1H),7.41(dd,J＝9.1,2.5Hz,1H),7.30(t,J＝9.0Hz,1H),7.13(dd,J＝11.1,2.8Hz,1H),7.06(dd,J＝7.7,4.8Hz,1H),6.84(td,J＝8.5,2.7Hz,1H),6.70(dd,J＝5.8,2.4Hz,1H),4.53(m,1H),2.44(m,2H),2.22-2.18(m,2H),2.06(s,6H),1.90-1.84(m,2H),1.72-1.64(m,2H).
LCMS(ESI+):m/z 589.2(M+1)
Example 35
Compound 31
Synthesis of 2- [ (3-fluoro-4- [ (2-acetamidopyridin-4-yl) oxy ] phenyl) amino ] -N- (2- (3- (dimethylamino) propoxy) -4-fluorophenyl) pyridine-3-carboxamide according to the Synthesis method IV, yield: 14.82% as white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.57(s,1H),8.47-8.41(m,1H),8.33(d,J＝7.8Hz,1H),8.18(d,J＝5.7Hz,1H),8.13(dd,J＝13.8,2.4Hz,1H),7.67(s,1H),7.50(dd,J＝8.7,6.4Hz,1H),7.39(d,J＝9.4Hz,1H),7.28(t,J＝8.9Hz,1H),7.03(td,J＝9.2,8.1,3.7Hz,2H),6.87-6.77(m,1H),6.68(dd,J＝5.9,2.2Hz,1H),4.05(t,J＝6.1Hz,2H),2.27(t,J＝7.2Hz,2H),2.02(d,J＝10.3Hz,8H),1.78(p,J＝6.5Hz,2H).
LCMS(ESI+):m/z 577.0(M+H) +
Example 36
Compound 32
Synthesis of 2- ((4- ((2-acetamidopyridin-4-yl) oxy) -3-fluorophenyl) amino) -N- (4-fluorophenyl) nicotinamide according to synthesis method four gave a yield of 17.46% which was a white solid.
1H NMR(400MHz,DMSO-d6)δ10.57(s,2H),10.49(s,1H),8.43(dd,J＝4.8,1.8Hz,1H),8.28(dd,J＝7.8,1.8Hz,1H),8.19(d,J＝5.8Hz,1H),8.13(dd,J＝13.7,2.4Hz,1H),7.79-7.71(m,2H),7.67(s,1H),7.47-7.40(m,1H),7.27(dt,J＝17.5,8.9Hz,3H),7.03(dd,J＝7.7,4.9Hz,1H),6.69(dd,J＝5.8,2.2Hz,1H),2.04(s,3H).
Example 37
Compound 33
2- ((4- ((2-acetamidopyridin-4-yl) oxy) -3-fluorophenyl) amino) -N- (2- (3- (dimethylamino) propoxy) phenyl) nicotinamide was synthesized according to synthesis four with a yield of 32.77% as a white solid.
1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),10.56(s,1H),9.97(s,1H),8.44(dd,J＝4.8,1.8Hz,1H),8.33(dd,J＝7.7,1.9Hz,1H),8.18(d,J＝5.7Hz,1H),8.12(dd,J＝13.6,2.5Hz,1H),7.66(d,J＝2.4Hz,1H),7.58(dd,J＝7.9,1.7Hz,1H),7.40(dd,J＝8.9,2.5Hz,1H),7.33-7.20(m,2H),7.11(dd,J＝8.4,1.3Hz,1H),7.06-6.95(m,2H),6.68(dd,J＝5.7,2.5Hz,1H),4.05(t,J＝6.1Hz,2H),2.47(s,2H),2.16(s,6H),2.03(s,3H),1.86(p,J＝6.5Hz,2H).
Example 38
Intermediate 4-2
Intermediate 4-2 synthesis is similar to intermediate 4-1
Five synthetic methods: similar to the synthesis method
Example 39
Compound 34
Synthesis of N- (2- (3- (dimethylamino) propoxy) -4-fluorophenyl) -2- [ (4- [ (2-acetamidopyridin-4-yl) oxy ] -3-methylphenyl) amino ] pyridine-3-carboxamide
The synthesis of N- (2- (3- (dimethylamino) propoxy) -4-fluorophenyl) -2- [ (4- [ (2-acetamidopyridin-4-yl) oxy ] -3-methylphenyl) amino ] pyridine-3-carboxamide according to synthesis general procedure five or four was similar to the synthesis of 2- [ (3-chloro-4- [ (2-acetamidopyridin-4-yl) oxy ] phenyl) amino ] -N- (2- (3- (dimethylamino) propoxy) -4-fluorophenyl) pyridine-3-carboxamide (compound 31), yield: 8.81% as yellow solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.72(s,1H),10.50(s,1H),9.87(s,1H),8.39(d,J＝4.7Hz,1H),8.29(d,J＝7.7Hz,1H),8.14(d,J＝5.8Hz,1H),7.75-7.68(m,1H),7.59(t,J＝3.6Hz,2H),7.50(dd,J＝8.7,6.5Hz,1H),7.07-7.01(m,2H),6.94(dd,J＝7.7,4.9Hz,1H),6.82(td,J＝8.6,2.5Hz,1H),6.55(dd,J＝5.8,2.3Hz,1H),4.05(t,J＝6.1Hz,2H),2.29(t,J＝7.1Hz,2H),2.08(s,3H),2.02(t,J＝2.3Hz,9H),1.80(q,J＝7.0Hz,2H).
LCMS(ESI+):m/z 573.7(M+H) +
Example 40
Compound 35
Synthesis of 2- [ (4- [ (2-acetamidopyridin-4-yl) oxy ] -3-methylphenyl) amino ] -N- (4-fluoro-2- [ (1-methylpiperidin-4-yl) oxy ] phenyl) pyridine-3-carboxamide
In analogy to the synthesis of 2- [ (4- [ (2-acetamidopyridin-4-yl) oxy ] -3-methylphenyl) amino ] -N- (4-fluoro-2- [ (1-methylpiperidin-4-yl) oxy ] phenyl) pyridine-3-carboxamide and 2- [ (3-chloro-4- ((2-acetamidopyridin-4-yl) oxy) phenyl) amino ] -N- (2- (3- (dimethylamino) propoxy) -4-fluorophenyl) pyridine-3-carboxamide according to the general procedure five or four, the yields: 8.63% as yellow solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.67(s,1H),10.50(s,1H),9.87(s,1H),8.39(d,J＝4.7Hz,1H),8.29(d,J＝7.7Hz,1H),8.17-8.11(m,1H),7.72(dd,J＝8.7,2.7Hz,1H),7.60(t,J＝2.6Hz,2H),7.53(dd,J＝8.7,6.5Hz,1H),7.11(dd,J＝11.0,2.7Hz,1H),7.04(d,J＝8.6Hz,1H),6.96(dd,J＝7.6,4.8Hz,1H),6.82(td,J＝8.5,2.5Hz,1H),6.55(dd,J＝5.8,2.3Hz,1H),4.51(s,1H),2.43(s,2H),2.18(dt,J＝10.4,6.2Hz,2H),2.08(s,3H),2.04(d,J＝4.9Hz,6H),1.90-1.81(m,2H),1.67(t,J＝6.6Hz,2H).
LCMS(ESI+):m/z 585.5(M+1)
Example 41
Compound 36
2- ((4- ((2-acetamidopyridin-4-yl) oxy) -3-methylphenyl) amino) -N- (4-fluorophenyl) nicotinamide was synthesized according to synthesis methods five or four in 25.15% yield as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.52(d,J＝8.5Hz,2H),10.39(s,1H),8.42-8.35(m,1H),8.26(dd,J＝7.8,2.0Hz,1H),8.15(dd,J＝5.8,1.5Hz,1H),7.79-7.70(m,3H),7.68-7.58(m,2H),7.24(td,J＝8.9,1.7Hz,2H),7.04(dd,J＝8.7,1.5Hz,1H),6.96(ddd,J＝7.1,4.9,1.6Hz,1H),6.57(dt,J＝5.9,2.0Hz,1H),2.09(d,J＝2.4Hz,3H),2.03(d,J＝1.6Hz,3H).
Example 42
Intermediate 5-1
Step one: n- (4- (2-fluoro-4- [ (3- [ (4-fluorophenyl) carbamoyl)]Pyridin-2-yl) amino groups]Phenoxy group) Pyridin-2-yl) carbamic acid tert-butyl ester
To a solution of 2- [ (4- [ (2- { [ (tert-butoxy) carbonyl ] amino } pyridin-4-yl) oxy ] -3-fluorophenyl) amino ] pyridine-3-carboxylic acid (1.84 g,4.18 mmol) in tetrahydrofuran (50 ml) was added 4-fluoroaniline (0.56 g,5.02 mmol), ethyldiisopropylamine (1.08 g,8.36 mmol) and 2- (7-aza-1H-benzotriazol-1-yl) -1, 3-tetramethylurea hexafluorophosphate (3.97 g,10.45 mmol), and the mixture was stirred at room temperature for 48 hours. The mixture was added to ethyl acetate (50 ml), washed with water (50 ml) and saturated brine (50 ml), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to give crude t-butyl N- (4- (2-fluoro-4- [ (3- [ (4-fluorophenyl) carbamoyl ] pyridin-2-yl) amino ] phenoxy) pyridin-2-yl) carbamate (2.1 g, yield 94.21%).
LCMS(ESI+):m/z 534.4(M+1)
Step two: 2- [ (4- [ (2-aminopyridin-4-yl) oxy]-3-fluorophenyl) amino group]N- (4-fluorophenyl) pyridine- 3-carboxamide
To a solution of tert-butyl N- (4- (2-fluoro-4- [ (3- [ (4-fluorophenyl) carbamoyl ] pyridin-2-yl) amino ] phenoxy) pyridin-2-yl) carbamate (2.1 g,3.94 mmol) was added dichloromethane (20 ml), trifluoroacetic acid (10 ml), and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by a silica gel column eluting with methanol/methylene chloride (0 to 7.5%) to give 2- [ (4- [ (2-aminopyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (4-fluorophenyl) pyridine-3-carboxamide (1.31 g, yield 76.79%). LCMS (ESI+): M/z 433.9 (M+1)
Synthesis method six:
example 43
Compound 37 synthetic route:
2- [ (4- [ (2-Cyclopropanamidopyridin-4-yl) oxy)]-3-fluorophenyl) amino group]-N- (4-fluorophenyl) pyri-dine Pyridine-3-carboxamides
To a solution of 2- [ (4- [ (2-aminopyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (4-fluorophenyl) pyridine-3-carboxamide (150 mg,0.35 mmol) in acetonitrile (10 ml) was added cyclopropanecarboxylic acid (33.14 mg,0.39 mmol), 1-methyl-1H-imidazole (100.57 mg,1.22 mmol), N, N-tetramethyl chloroformidine hexafluorophosphate (196.41 mg,0.70 mmol) and the mixture was stirred at room temperature for 32 hours. LCMS showed 46% of the target compound, the remainder starting. The mixture was concentrated under reduced pressure, and the residue was purified with a C18 column to give 2- [ (4- [ (2-cyclopropylaminopyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (4-fluorophenyl) pyridine-3-carboxamide (42 mg, yield 24.20%).
LCMS(ESI+):m/z 503.1(M+1)
1 H NMR(400MHz,DMSO-d 6 )δ10.87(s,1H),10.57(s,1H),10.49(s,1H),8.43(dd,J＝4.9,1.8Hz,1H),8.28(dd,J＝7.8,1.9Hz,1H),8.20(d,J＝5.7Hz,1H),8.13(dd,J＝13.6,2.5Hz,1H),7.81-7.70(m,2H),7.65(d,J＝2.4Hz,1H),7.48-7.40(m,1H),7.26(dt,J＝15.5,9.0Hz,3H),7.03(dd,J＝7.7,4.8Hz,1H),6.72(dd,J＝5.7,2.4Hz,1H),1.96(p,J＝6.2Hz,1H),0.79-0.72(m,4H).
Example 44
Compound 38
(R) -2- ((3-fluoro-4- ((2- (2- (pyrrolidin-3-yl) acetamido) pyridin-4-yl) oxy) phenyl) amino) -N- (4-fluorophenyl) nicotinamide was synthesized according to the general method in 20.79% yield as a white solid.
1H NMR (400 MHz, methanol-d 4) delta 8.37 (dt, J=4.9, 1.5Hz, 1H), 8.21 (ddd, J=7.7, 1.8,1.0Hz, 1H), 8.15 (d, J=5.9 Hz, 1H), 8.09 (dd, J=13.5, 2.4Hz, 1H), 7.74-7.65 (m, 2H), 7.63 (s, 1H), 7.33 (ddt, J=8.9, 2.6,1.3Hz, 1H), 7.22-7.07 (m, 3H), 6.94 (ddd, J=7.8, 4.9,1.3Hz, 1H), 6.72 (ddd, J=6.0, 2.5,1.1Hz, 1H), 3.54 (dd, J=11.7.2 Hz, 1H), 3.38 (ddd, 12.6, 1.3Hz, 1H), 7.22-7.07 (m, 3H), 6.94 (ddd, J=7.8, 4.9, 1.9, 1.3Hz, 1H), 3.54 (ddd, 1.7.7.4 Hz, 1H), 3.38 (ddd, 2.4.8, 1Hz, 1H), 3.4.4.7.7 (2 Hz, 1H), 3.4.7.7 (2H).
Example 45
Compound 39
(S) -2- ((3-fluoro-4- ((2- (2- (pyrrolidin-3-yl) acetamido) pyridin-4-yl) oxy) phenyl) amino) -N- (4-fluorophenyl) nicotinamide was synthesized according to the general method in 12.75% yield which was a white solid.
1 H NMR (400 MHz, methanol-d) 4 )δ8.37(dt,J＝5.4,2.1Hz,1H),8.20(dt,J＝7.8,1.8Hz,1H),8.15(d,J＝5.9Hz,1H),8.08(dd,J＝13.9,2.4Hz,1H),7.73-7.66(m,2H),7.65(s,1H),7.33(d,J＝8.5Hz,1H),7.22-7.10(m,2H),7.14-7.07(m,1H),6.94(ddd,J＝8.6,5.1,2.4Hz,1H),6.71(dt,J＝5.3,2.6Hz,1H),3.54(dd,J＝11.6,7.2Hz,1H),3.38(ddd,J＝12.1,8.6,4.0Hz,1H),3.28-3.16(m,1H),2.94(dd,J＝11.7,8.5Hz,1H),2.72(q,J＝6.4,5.8Hz,1H),2.67(d,J＝6.1Hz,1H),2.67-2.53(m,1H),2.26(dq,J＝12.4,7.3,6.9Hz,1H),1.71(dq,J＝13.0,8.8Hz,1H).
Synthesis method seven:
example 46
Compound 40
2- [ (3-fluoro-4- [ (2- [ (1-methyl-1H-pyrazol-4-yl) amino)]Pyridin-4-yl) oxy]Phenyl) amino group ]- N- (4-fluorophenyl) pyridine-3-carboxamideTo 2- [ (2-aminopyridin-4-yl) oxy)]-3-fluorophenyl) amino group]To a solution of-N- (4-fluorophenyl) pyridine-3-carboxamide (100 mg,0.23 mmol) was added 4-bromo-1-methyl-1H-pyrazole (44.44 mg,0.28 mmol), di-tert-butyl- [3, 6-dimethoxy-2- [2,4, 6-tris (propyl-2-yl) phenyl]Phenyl group]Phosphine (6.69 mg,0.014 mmol), cesium carbonate (149.88 mg,0.46 mmol), tris (dibenzylideneacetone) dipalladium (0) (6.32 mg,0.0069 mmol), the mixture was heated to 110 ℃ under nitrogen in a sealed tube and the mixture was stirred at 110 ℃ overnight. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column and C18 column to give 2- [ (3-fluoro-4- [ (2- [ (1-methyl-1H-pyrazol-4-yl) amino)]Pyridin-4-yl) oxy]Phenyl) amino group]-N- (4-fluorophenyl) pyridine-3-carboxamide (53 mg, yield 44.73%). LCMS (ESI+): M/z 514.0 (M+1)
1 H NMR(400MHz,DMSO-d6)δ10.56(s,1H),10.46(s,1H),8.76(s,1H),8.42(dd,J＝4.8,1.9Hz,1H),8.28(dd,J＝7.8,1.9Hz,1H),8.15-8.04(m,1H),8.00(d,J＝5.8Hz,1H),7.88(s,1H),7.82-7.70(m,2H),7.47-7.37(m,1H),7.33-7.19(m,4H),7.03(dd,J＝7.7,4.8Hz,1H),6.32(dd,J＝5.8,2.3Hz,1H),6.01(d,J＝2.3Hz,1H),3.77(s,3H).
Example 47
Compound 41
2- ((3-fluoro-4- ((2- (pyridin-2-ylamino) pyridin-4-yl) oxy) phenyl) amino) -N- (4-fluorophenyl) nicotinamide was synthesized according to synthesis method seven in 55.19% yield as a white solid.
1 H NMR(400MHz,DMSO-d6)δ10.57(s,1H),10.47(s,1H),9.71(s,1H),8.46-8.40(m,1H),8.28(d,J＝7.8Hz,1H),8.12(dd,J＝12.9,4.2Hz,3H),7.75(dt,J＝8.9,4.4Hz,2H),7.71-7.59(m,2H),7.48-7.39(m,2H),7.30(t,J＝8.9Hz,1H),7.25(t,J＝8.8Hz,2H),7.03(dd,J＝7.8,4.8Hz,1H),6.84(t,J＝6.5Hz,1H),6.48-6.44(m,1H).
Example 48
Compound 42
2- (3-fluoro-4- ((2- (5, 6,7, 8-tetrahydro-1, 6-naphthyridin-2-yl) amino) pyridin-4-yl) oxy) phenyl) amino) -N- (4-fluorophenyl) nicotinamide was synthesized according to synthesis method seven in 36.53% yield as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.64(s,1H),10.52(s,1H),9.68(s,1H),8.44(dd,J＝4.8,1.8Hz,1H),8.30(dd,J＝7.8,1.8Hz,1H),8.26(s,1H),8.17(dd,J＝13.6,2.5Hz,1H),8.10(d,J＝5.8Hz,1H),7.81-7.71(m,3H),7.49-7.42(m,1H),7.35-7.20(m,4H),7.15(d,J＝8.4Hz,1H),7.03(dd,J＝7.7,4.8Hz,1H),6.59(dd,J＝5.7,2.4Hz,1H),2.88(t,J＝6.1Hz,2H),2.54(m,2H),2.47(d,J＝5.9Hz,2H).
Example 49
Compound 43
2- (3-fluoro-4- ((2- (6-methyl-5, 6,7, 8-tetrahydro-1, 6-naphthyridin-2-yl) amino) pyridin-4-yl) oxy) phenyl) amino) -N- (4-fluorophenyl) nicotinamide was synthesized according to synthesis method seven in 20.13% yield as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.58(s,1H),10.52(s,1H),9.60(d,J＝2.3Hz,1H),8.43(dd,J＝4.9,1.8Hz,1H),8.30(dd,J＝7.8,1.9Hz,1H),8.13-8.10(d,J＝4Hz,1H),8.08(d,J＝5.7Hz,1H),7.77(ddd,J＝9.1,5.3,2.6Hz,3H),7.46(dt,J＝8.9,1.7Hz,1H),7.34-7.22(m,3H),7.23(d,J＝2.5Hz,1H),7.06(ddd,J＝14.6,8.1,3.6Hz,2H),6.59(dd,J＝5.7,2.4Hz,1H),3.30(s,2H)2.48-2.42(m,2H),2.41-2.34(m,2H),2.17(d,J＝4.9Hz,3H).
Example 50
Intermediate 6-1
Step 1: n- [4- (2-fluoro-4-nitrophenoxy) pyridin-2-yl]Carbamic acid tert-butyl ester
Tert-butyl N- (4-hydroxypyridin-2-yl) carbamate (1.5 g,7.1 mmol) and 1, 2-difluoro-4-nitrobenzene (1.24 g,7.8 mmol) were dissolved in acetonitrile (30 ml) and then potassium carbonate (1.96 g,14.2 mmol) was added at 25 ℃. The reaction mixture was warmed to 80 ℃ and stirred at 80 ℃ for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel chromatography and eluted with ethyl acetate/petroleum ether (from 0 to 20% in 20 min) to give tert-butyl N- [4- (2-fluoro-4-nitrophenoxy) pyridin-2-yl ] carbamate (1.8 g, yield 79%) as a white solid. LCMS (ESI+): M/z 350.1 (M+1)
Step 2: n- (4- (4-amino-2-fluorophenoxy) pyridin-2-yl) carbamic acid tert-butyl ester
Tert-butyl N- [4- (2-fluoro-4-nitrophenoxy) pyridin-2-yl ] carbamate (2.3 g,6.6 mmol) and palladium on carbon (0.70 g,6.6 mmol) were dissolved in ethyl acetate (100 ml) and stirred continuously under hydrogen at 25℃for 2 hours, then filtered and concentrated to give tert-butyl N- (4- (4-amino-2-fluorophenoxy) pyridin-2-yl) carbamate (1.8 g, 81% yield) as a white solid.
LCMS(ESI+):m/z 320.0(M+1)
Step 3:2- ((4- ((2- ((tert-Butoxycarbonyl) amino) pyridin-4-yl) oxy) -3-fluorophenyl) amino) nicotinic acid Methyl ester
A reactor containing tert-butyl N- (4- (4-amino-2-fluorophenoxy) pyridin-2-yl) carbamate (1.0 g,3.1 mmol), methyl 2-bromopyridine-3-carboxylate (0.80 g,3.7 mmol), tris (dibenzylideneacetone) dipalladium (0.28 g,0.31 mmol), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (0.36 g,0.62 mmol), cesium carbonate (2.02 g,6.2 mmol) and dioxane (50 ml) was placed in an oil bath heated to 90 ℃. The reaction mixture was stirred continuously at 100℃for 2 hours. The reaction mixture was concentrated and purified by silica gel chromatography and eluted with ethyl acetate/petroleum ether (from 0 to 30% in 20 min with ethyl acetate) to give methyl 2- ((4- ((2- ((tert-butoxycarbonyl) amino) pyridin-4-yl) oxy) -3-fluorophenyl) amino) nicotinate (0.72 g, 51% yield) as a yellow oily liquid.
LCMS(ESI+):m/z 455.0(M+1)
Step 4 2- ((4- ((2- ((tert-Butoxycarbonyl) amino) pyridin-4-yl) oxy) -3-fluorophenyl) amino) nicotinic acid
Lithium hydroxide (87.12 mg,3.63 mmol) was added to a solution of methyl 2- ((4- ((2- ((tert-butoxycarbonyl) amino) pyridin-4-yl) oxy) -3-fluorophenyl) amino) nicotinate (550 mg,1.21 mmol) in THF (10 ml) and water (5 ml). The reaction mixture was stirred continuously at 25 ℃ for 12 hours, then pH was adjusted to 5 with 1N hydrochloric acid and filtered to give 2- ((4- ((2- ((tert-butoxycarbonyl) amino) pyridin-4-yl) oxy) -3-fluorophenyl) amino) nicotinic acid (238 mg, yield 44%).
LCMS(ESI+):m/z 441.0(M+1)
1 H NMR(400MHz,DMSO):δ12.13(s,1H),9.84(s,1H),8.38-8.17(m,3H),8.12(d,J＝5.7Hz,1H),7.32(tt,J＝18.0,9.2Hz,3H),6.86(dd,J＝7.5,4.9Hz,1H),6.62(dd,J＝5.7,2.3Hz,1H),1.48-1.33(m,9H).
Example 51
Compound 44
Step one: n- (4- (2-fluoro-4- [ (3- [ (phenyl) carbamoyl ] pyridin-2-yl) amino ] phenoxy) pyridin-2-yl) carbamic acid tert-butyl ester
2- [ (4- [ (2- { [ (tert-Butoxy) carbonyl ] amino } pyridin-4-yl) oxy ] -3-fluorophenyl) amino ] pyridine-3-carboxylic acid (160 mg,0.36 mmol), aniline (33.53 mg,0.36 mmol), HATU (177.95 mg,0.47 mmol) and ethyldiisopropylamine (93.05 mg,0.72 mmol) were added sequentially to tetrahydrofuran (5 mL) and stirred under nitrogen at room temperature for 16 h. TLC and LCMS showed complete reaction. The reaction mixture was concentrated and purified by silica gel flash column chromatography PE/EA (30%) to give tert-butyl N- (4- (2-fluoro-4- [ (3- [ (phenyl) carbamoyl ] pyridin-2-yl) amino ] phenoxy) pyridin-2-yl) carbamate (160 mg, yield 81.16%, purity 95%) as a white solid.
Step two: 2- [ (4- [ (2-aminopyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N-phenylpyridine-3-carboxamide
Trifluoroacetic acid (1.53 g,13.42 mmol) was added to N- (4- (2-fluoro-4- [ (3- [ (phenyl) carbamoyl)]Pyridin-2-yl) amino groups]A solution of tert-butyl phenoxy) pyridin-2-yl carbamate (119.39 mg,0.22 mmol) in dichloromethane (4 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated and taken up in NaHCO 3 The reaction was quenched with water, extracted with DCM (20 mL. Times.3) and the organic phase was taken up in Na 2 SO 4 Drying, filtration, concentration and purification by preparative thin plate chromatography (25:1 volume ratio of dichloromethane to methanol) yields 2- [ (4- [ (2-aminopyridin-4-yl) oxy]-3-fluorophenyl) amino group]-N-phenylpyridine-3-carboxamide (60 mg, yield 63.68%, purity 97%). The character is white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.48(d,J＝15.8Hz,2H),8.42(d,J＝4.9Hz,1H),8.29(d,J＝7.7Hz,1H),8.09(d,J＝13.6Hz,1H),7.83-7.77(m,1H),7.73(d,J＝8.1Hz,2H),7.40(t,J＝8.1Hz,3H),7.24(t,J＝9.2Hz,1H),7.16(t,J＝7.4Hz,1H),7.03(dd,J＝7.6,5.0Hz,1H),6.20-6.14(m,1H),5.96(s,2H),5.82(s,1H).
Step three: 2- [ (4- [ (2-Acetaminopyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N-phenylpyridine-3-carboxamide
Acetyl chloride (7.54 mg,0.096 mmol) was dissolved in tetrahydrofuran (1 mL) and added dropwise to a solution of 2- [ (4- [ (2-aminopyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N-phenylpyridine-3-carboxamide (40 mg,0.096 mmol) and ethyldiisopropylamine (18.61 mg,0.14 mmol) in tetrahydrofuran (5 mL) at 0 degrees celsius, the mixture was then allowed to warm to room temperature and stirred for 4 hours. The reaction was quenched with methanol (2 mL) and concentrated to give the crude product. The crude product was purified by preparative thin plate chromatography (volume ratio of dichloromethane to methanol 25:1) to give 2- [ (4- [ (2-acetamidopyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N-phenylpyridine-3-carboxamide (20 mg, 44.50% yield, 98% purity). It is a white solid in shape.
1 H NMR(400MHz,DMSO-d 6 )δ10.55(s,1H),10.51(d,J＝5.3Hz,2H),8.46-8.40(m,1H),8.29(d,J＝7.9Hz,1H),8.19(d,J＝5.7Hz,1H),8.13(dd,J＝13.6,2.4Hz,1H),7.74(d,J＝8.0Hz,2H),7.67(d,J＝2.0Hz,1H),7.48-7.36(m,3H),7.29(t,J＝8.9Hz,1H),7.17(t,J＝7.5Hz,1H),7.03(dd,J＝7.8,4.9Hz,1H),6.69(dd,J＝5.7,2.4Hz,1H),2.04(s,3H).
Example 52
Compound 45
Step one: n- (4- (2-fluoro-4- [ (3- [ (tetrahydro-2H-pyran-4-yl) carbamoyl)]Pyridin-2-yl) ammonia Base group]Phenoxy) pyridin-2-yl) carbamic acid tert-butyl ester
To a solution of 2- [ (4- [ (2- { [ (tert-butoxy) carbonyl ] amino } pyridin-4-yl) oxy ] -3-fluorophenyl) amino ] pyridine-3-carboxylic acid (150 mg,0.34 mmol) in tetrahydrofuran (5 ml) was added tetrahydro-2H-pyran-4-amine hydrochloride (46.79 mg,0.34 mmol), N-diisopropylethylamine (131.82 mg,1.02 mmol), 2- (7-aza-1H-benzotriazol-1-yl) -1, 3-tetramethylurea hexafluorophosphate (193.92 mg,0.51 mmol) and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was added to 10ml of methylene chloride and washed with water, and the separated organic layer was concentrated under reduced pressure, and the residue was purified by a silica gel column to give tert-butyl N- (4- (2-fluoro-4- [ (3- [ (tetrahydro-2H-pyran-4-yl) carbamoyl ] pyridin-2-yl) amino ] phenoxy) pyridin-2-yl) carbamate (145 mg, yield 81.32%).
LCMS(ESI+):m/z 524.5(M+1)
Step two: 2- [ (4- [ (2-Ammonia)Pyridin-4-yl) oxy]-3-fluorophenyl) amino group]N- (tetrahydro-2H-pyran) 4-yl) pyridine-3-carboxamide
To a solution of tert-butyl N- (4- (2-fluoro-4- [ (3- [ (tetrahydro-2H-pyran-4-yl) carbamoyl ] pyridin-2-yl) amino ] phenoxy) pyridin-2-yl) carbamate (145 mg,0.28 mmol) was added trifluoroacetic acid (4 ml), and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, the residue was dissolved in 10ml of methylene chloride and washed with sodium hydrogencarbonate solution, then the methylene chloride phase was concentrated under reduced pressure, and the residue was purified by silica gel column to give 2- [ (4- [ (2-aminopyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (tetrahydro-2H-pyran-4-yl) pyridine-3-carboxamide (110 mg, yield 93.80%).
LCMS(ESI+):m/z 424.6(M+1)
Step three: 2- [ (4- [ (2-Acetaminopyridin-4-yl) oxy)]-3-fluorophenyl) amino group]-N- (tetrahydro-2H-pyri-dine) Pyran-4-yl) pyridine-3-carboxamide
To a solution of 2- [ (4- [ (2-aminopyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (tetrahydro-2H-pyran-4-yl) pyridine-3-carboxamide (110 mg,0.26 mmol) in dichloromethane (10 ml) was added triethylamine (78.93 mg,0.78 mmol), the mixture was cooled to 0℃and then acetyl chloride (40.82 mg,0.52 mmol) was added dropwise at 0-5℃and the mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated under reduced pressure, and the residue was dissolved in 10ml of methanol, 4ml of tetrahydrofuran, and 4ml of saturated potassium carbonate solution. The mixture was stirred at room temperature for 24 hours. The mixture was concentrated under reduced pressure, 10ml of tetrahydrofuran was added to the residue and washed with brine, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column to give 2- [ (4- [ (2-acetamidopyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (tetrahydro-2H-pyran-4-yl) pyridine-3-carboxamide (42 mg, yield 34.39%).
LCMS(ESI+):m/z 466.6(M+1)
1 H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.56(s,1H),8.68(d,J＝7.6Hz,1H),8.41-8.35(m,1H),8.21-8.10(m,3H),7.66(s,1H),7.41-7.35(m,1H),7.28(t,J＝9.0Hz,1H),7.00-6.92(m,1H),6.72-6.66(m,1H),4.14-4.00(m,1H),3.90(dt,J＝11.0,3.7Hz,2H),3.40(t,J＝11.6Hz,2H),2.04(s,3H),1.84-1.76(m,2H),1.61(qd,J＝12.1,4.5Hz,2H).
Example 53
Intermediate 6-2
Example 54
Compound 46
Step one: 2-chloro-4- (3-fluorophenyl) pyridine
2-chloro-4-iodopyridine (500 mg,2.09mmol,1 eq), (3-fluorophenyl) boronic acid (350 mg,2.5mmol,1.2 eq), tetrakis (triphenylphosphine) palladium (24 mg,0.02mmol,0.01 qr) and sodium carbonate (440 mg,0.44mmol,2 eq) were added to a mixture of 1, 4-dioxane (20 ml) and water (4 ml) under nitrogen. The reaction was stirred at 80 degrees celsius for 6 hours. After the reaction was completed, 20mL of water was added, and extraction was performed 3 times with 20mL of ethyl acetate each. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give a crude product. The crude product was washed with 10% n-hexane in ethyl acetate to give 2-chloro-4- (3-fluorophenyl) pyridine (30 mg, yield 69%, white solid).
Step two: 2- [ (4- (2-fluoro-4- [ (4- (3-fluorophenyl) pyridin-2-yl) amino ] phenoxy) pyridin-2-yl) amino ] -5,6,7, 8-tetrahydro-1, 6-naphthyridine-6-carboxylic acid tert-butyl ester
2- [ (4- (4-amino-2-fluorophenoxy) pyridin-2-yl) amino ] -5,6,7, 8-tetrahydro-1, 6-naphthyridine-6-carboxylic acid tert-butyl ester (200 mg,0.44mmol,1 eq), 2-chloro-4- (3-fluorophenyl) pyridine (120 mg,0.57mmol,1.3 eq), tris (dibenzylideneacetone) dipalladium (0) (40 mg,0.044mmol,0.1 eq), cesium carbonate (290 mg,0.88mmol,2 eq) were added to 5mL of 1, 4-dioxane under nitrogen protection, and the reaction was stirred for 8h at 100 ℃. After the reaction was completed, 10mL of water was added and extracted three times with 10mL of ethyl acetate each time. The organic phases were combined and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography to give tert-butyl 2- [ (4- (2-fluoro-4- [ (4- (3-fluorophenyl) pyridin-2-yl) amino ] phenoxy) pyridin-2-yl) amino ] -5,6,7, 8-tetrahydro-1, 6-naphthyridine-6-carboxylate (100 mg, white solid).
Step three: n- (4- (2-fluoro-4- ((4- (3-fluorophenyl) pyridin-2-yl) amino) phenoxy) pyridin-2-yl) -5,6,7, 8-tetrahydro-1, 6-naphthyridin-2-amine
Tert-butyl 2- [ (4- (2-fluoro-4- [ (4- (3-fluorophenyl) pyridin-2-yl) amino ] phenoxy) pyridin-2-yl) amino ] -5,6,7, 8-tetrahydro-1, 6-naphthyridin-6-carboxylate (100 mg) was added to 50% trifluoroacetic acid in dichloromethane, stirred at room temperature for 5h, after which the solvent was distilled off, the reaction pH was adjusted to ph=8 with saturated ammonium bicarbonate solution, extracted three times with ethyl acetate, 10ml each time, the organic phases were combined and dried with anhydrous sodium sulfate, and after evaporation of the solvent the crude product was purified by flash column chromatography on silica gel to give N- (4- (2-fluoro-4- ((4- (3-fluorophenyl) pyridin-2-yl) amino) phenoxy) pyridin-2-yl) -5,6,7, 8-tetrahydro-1, 6-naphthyridin-2-amine (30 mg, white solid).
1 H NMR(400MHz,DMSO-d 6 )δ9.58(d,J＝16.1Hz,2H),8.30(d,J＝5.4Hz,1H),8.15(dd,J＝13.9,2.5Hz,1H),8.08(d,J＝5.8Hz,1H),7.75(d,J＝2.3Hz,1H),7.59(td,J＝6.7,3.4Hz,3H),7.44(dd,J＝9.0,2.5Hz,1H),7.40-7.24(m,4H),7.18(d,J＝5.3Hz,1H),7.14(d,J＝7.7Hz,2H),6.57(dd,J＝5.7,2.4Hz,1H),3.76(s,2H),2.83(s,2H),2.46(d,J＝5.7Hz,2H).
Example 55
Compound 47
N- (4- (2-fluoro-4- ((4- (3-fluorophenyl) pyridin-2-yl) amino) phenoxy) pyridin-2-yl) acetamide
N- (4- (4-amino-2-fluorophenoxy) pyridin-2-yl) acetamide (200 mg,0.44mmol,1 eq), 2-chloro-4- (3-fluorophenyl) pyridine (120 mg,0.57mmol,1.3 eq), tris (dibenzylideneacetone) dipalladium (0) (40 mg,0.044mmol,0.1 eq), cesium carbonate (290 mg,0.88mmol,2 eq) was added to 5mL of 1, 4-dioxane under nitrogen and the reaction mixture stirred at 100℃for 8h. After the reaction was completed, 10mL of water was added and extracted three times with 10mL of ethyl acetate each time. The organic phases were combined and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography to give N- (4- (2-fluoro-4- ((4- (3-fluorophenyl) pyridin-2-yl) amino) phenoxy) pyridin-2-yl) acetamide (100 mg, white solid).
1 H NMR(400MHz,DMSO-d 6 )δ10.55(s,1H),9.54(s,1H),8.30(d,J＝5.4Hz,1H),8.18(d,J＝5.7Hz,1H),8.11(dd,J＝13.9,2.5Hz,1H),7.66(d,J＝2.4Hz,1H),7.58(td,J＝6.4,3.5Hz,3H),7.42(dt,J＝8.9,1.7Hz,1H),7.38-7.23(m,2H),7.18(dd,J＝5.4,1.6Hz,1H),7.12(d,J＝1.6Hz,1H),6.69(dd,J＝5.8,2.4Hz,1H),2.03(s,3H).
Example 56
Intermediate 6-3
Intermediate 6-3 Synthesis of intermediate 1
Example 57
Compound 48 synthetic route:
2- [ (4- [ (3-chloro-2-acetamidopyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (4-methylphenyl) pyridine-3-carboxamide
To a solution of 2- [ (4- [ (2-amino-3-chloropyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (4-methylphenyl) pyridine-3-carboxamide (46 mg,0.099 mmol) in dichloromethane (5 ml) was added triethylamine (25.04 mg,0.25 mmol). The mixture was cooled to 0℃and then acetyl chloride (15.54 mg,0.20 mmol) was added dropwise at 0-5 ℃. The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was dissolved in methanol (10 ml) and tetrahydrofuran (4 ml), then potassium carbonate (136.83 mg,0.99 mmol) was added to an aqueous solution (4 ml), and the mixture was stirred at room temperature for 3 days. The mixture was concentrated under reduced pressure to remove the organic solvent, then the mixture was extracted with dichloromethane, and the dichloromethane layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column to give 2- [ (4- [ (3-chloro-2-acetamidopyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (4-methylphenyl) pyridine-3-carboxamide (15 mg, yield 29.90%).
LCMS(ESI+):m/z 506.5(M+1)
1 H NMR(400MHz,DMSO-d 6 )δ10.52(s,1H),10.38(s,1H),10.18(s,1H),8.36(d,J＝4.7Hz,1H),8.25-8.18(m,1H),8.13(dd,J＝5.7,1.2Hz,1H),8.14-8.05(m,1H),7.54(d,J＝8.0Hz,2H),7.44-7.36(m,1H),7.29(t,J＝9.0Hz,1H),7.13(d,J＝8.1Hz,2H),6.96(dd,J＝7.7,5.0Hz,1H),6.59(d,J＝5.6Hz,1H),2.24(s,3H),2.02(d,J＝1.2Hz,3H).
Example 58
Compound 49 synthetic route:
2- [ (4- [ (2-acetamido-3-chloropyridin-4-yl) oxy)]-3-fluorophenyl) amino group]-N- (4-fluorophenyl) pyri-dine Pyridine-3-carboxamides
To a solution of 2- [ (4- [ (2-amino-3-chloropyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (4-fluorophenyl) pyridine-3-carboxamide (30 mg,0.064 mmol) in tetrahydrofuran (5 ml) was added triethylamine (16.19 mg,0.16 mmol), the mixture was cooled to 0℃and acetyl chloride (10.05 mg,0.13 mmol) was added dropwise at 0-5 ℃. The mixture was stirred at 0-5 ℃ for 30 minutes, then warmed to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in 10ml of methanol, 4ml of tetrahydrofuran, and 4ml of saturated potassium carbonate solution. The mixture was stirred at room temperature for 24 hours to convert the diacetyl compound to the target compound. The mixture was concentrated under reduced pressure, 10ml of tetrahydrofuran was added to the residue and washed with brine, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was eluted with ethyl acetate/dichloromethane (0% to 75%) to give 2- [ (4- [ (2-acetamido-3-chloropyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (4-fluorophenyl) pyridine-3-carboxamide (12 mg, yield 36.70%).
LCMS(ESI+):m/z 510.1(M+1)
1 H NMR(400MHz,DMSO-d 6 )δ10.58(s,1H),10.50(s,1H),10.26(s,1H),8.47-8.41(m,1H),8.29(dd,J＝7.7,1.8Hz,1H),8.20(d,J＝5.5Hz,1H),8.21-8.12(m,1H),7.79-7.71(m,2H),7.48(d,J＝9.2Hz,1H),7.36(t,J＝9.0Hz,1H),7.25(t,J＝8.7Hz,2H),7.05(dd,J＝7.8,4.8Hz,1H),6.66(d,J＝5.6Hz,1H),2.09(s,3H).
Example 59
Intermediate 6-4
2- ((4- ((2- ((tert-Butoxycarbonyl) amino) -5-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) cigaretteAcid(s)
Step 1: (4- (4-amino-2-fluorophenoxy) -5-chloropyridin-2-yl) (t-butoxycarbonyl) carbamic acid tert-butyl ester
Tert-butyl (tert-butoxycarbonyl) (5-chloro-4- (2-fluoro-4-nitrophenoxy) pyridin-2-yl) carbamate (9.7 g,20.0 mmol) was dissolved in ethyl acetate (200 ml) and palladium on carbon (4.26 g,4.0 mmol) was added. The reaction mixture was stirred at 20℃for 1.5 hours and then filtered. The filtrate was concentrated under reduced pressure to give tert-butyl (4- (4-amino-2-fluorophenoxy) -5-chloropyridin-2-yl) (tert-butoxycarbonyl) carbamate (8.7 g, yield 91%) as a brown solid.
LCMS(ESI+):m/z 454.0(M+1)
Step 2:2- ((4- ((2- (Di (t-Butoxycarbonyl) amino) -5-chloropyridin-4-yl) oxy) -3-fluorophenyl) ammonia Methyl nicotinate
Tert-butyl (4- (4-amino-2-fluorophenoxy) -5-chloropyridin-2-yl) (tert-butoxycarbonyl) carbamate (5.0 g,11.0 mmol), methyl 2-bromonicotinate (2.85 g,13.2 mmol), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (1.27 g,2.2 mmol) and cesium carbonate (7.17 g,22 mmol) were dissolved in dioxane (150 ml) and tris (dibenzylideneacetone) dipalladium (1.01 g,1.1 mmol) was added at 20 ℃. The reaction mixture was stirred at 100℃for 2 hours, then the elimination reaction was carried out with water (100 ml) and extraction was carried out with ethyl acetate (200 ml. Times.2). Combining the organic phases and then passing through Na 2 SO 4 And (5) drying and filtering. The filtrate was concentrated under reduced pressure. Passing the residue through silica gel column layerPurification by chromatography eluting with ethyl acetate/n-hexane solution (increasing from 0 to 25% ethyl acetate over 20 minutes) afforded methyl 2- ((4- ((2- (di (tert-butoxycarbonyl) amino) -5-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) nicotinate (4.15 g, 60% yield) as a pale yellow solid.
LCMS(ESI+):m/z 589.0(M+1)
Step 3:2- ((4- ((2- ((tert-Butoxycarbonyl) amino) -5-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) Nicotinic acid
Methyl 2- ((4- ((2- (di (t-butoxycarbonyl) amino) -5-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) nicotinate (4.15 g,7.0 mmol) was dissolved in methanol (100 ml) and tetrahydrofuran (200 ml), then sodium hydroxide (0.84 g,21 mmol) dissolved in water (20 ml) was added at 20 ℃. The reaction mixture was stirred at 20 ℃ for 1 hour and then acidified with 1N hydrochloric acid to ph=7. The reaction mixture was filtered. Filtration gave 2- ((4- ((2- ((tert-butoxycarbonyl) amino) -5-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) nicotinic acid (3.38 g, 97% yield) as a pale yellow solid.
1 H NMR(400MHz,DMSO-d 6 )δ12.22(s,1H),9.99(s,1H),8.35-8.29(m,1H),8.27(dd,J＝6.4,2.0Hz,1H),8.24(d,J＝2.0Hz,1H),7.43-7.37(m,1H),7.34(t,J＝8.8Hz,1H),7.27(s,1H),6.87(dd,J＝7.6,4.8Hz,1H),1.35(s,9H).LCMS(ESI+):m/z 474.9(M+1)
Eight methods of synthesis
Example 60
Compound 50
2- [ (4- [ (2- { [ (tert-Butoxy) carbonyl ] amino } -5-chloropyridin-4-yl) oxy ] -3-fluorophenyl) amino ] pyridine-3-carboxylic acid (160 mg,0.34 mmol), 4-methylaniline (36.43 mg,0.34 mmol), HATU (168.06 mg,0.44 mmol) and ethyldiisopropylamine (87.88 mg,0.68 mmol) were added sequentially to tetrahydrofuran (5 mL), nitrogen protected, and stirred for 16 h at room temperature. TLC and LCMS showed complete reaction. The mixture was concentrated and purified by flash column chromatography on silica gel (PE/EA (30%)) to give tert-butyl N- (5-chloro-4- (2-fluoro-4- [ (3- [ (4-methylphenyl) carbamoyl ] pyridin-2-yl) amino ] phenoxy) pyridin-2-yl) carbamate (160 mg, 79.99% yield, 95% purity) as a yellow solid.
HCl (4M in methanol) (5 mL) was added to N- (5-chloro-4- (2-fluoro-4- [ (3- [ (4-methylphenyl)) carbamoyl) in methanol (1 mL) at room temperature]Pyridin-2-yl) amino groups]Phenoxy) pyridin-2-yl) carbamic acid tert-butyl ester (140 mg,0.24mmol, 95% purity). The mixture was then stirred at room temperature for 16 hours. TLC indicated that it had been converted to complete. The mixture was stirred at 40℃for a further 16 hours. The reaction mixture was concentrated and taken up with NaHCO 3 (aqueous) quench, extract with DCM (20 mL. Times.3), and pass through Na 2 SO 4 Dried, concentrated and purified by TLC (DCM/MeOH 25:1) to give 2- [ (4- [ (2-amino-5-chloropyridin-4-yl) oxy) as a solid]-3-fluorophenyl) amino group]-N- (4-methylphenyl) pyridine-3-carboxamide (80 mg, 73.13%) as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.56(s,1H),10.44(s,1H),8.42(dd,J＝4.7,1.7Hz,1H),8.29(dd,J＝7.8,1.9Hz,1H),8.14(dd,J＝13.7,2.5Hz,1H),7.91(s,1H),7.61(d,J＝8.2Hz,2H),7.45(dt,J＝8.9,1.6Hz,1H),7.31(t,J＝9.1Hz,1H),7.20(d,J＝8.1Hz,2H),7.03(dd,J＝7.7,4.9Hz,1H),6.12(s,2H),5.78(s,1H),2.31(s,3H).
Example 61
Compound 51
2- [ (4- [ (2- { [ (tert-Butoxy) carbonyl ] amino } -5-chloropyridin-4-yl) oxy ] -3-fluorophenyl) amino ] pyridine-3-carboxylic acid (160 mg,0.34mmol, purity 100%), aniline (31.66 mg,0.34mmol, purity 100%), HATU (168.06 mg,0.44mmol, purity 100%) and ethyldiisopropylamine (87.88 mg,0.68mmol, purity 100%) were mixed in tetrahydrofuran (5 mL) at room temperature under nitrogen and stirred for 16 hours. TLC and LCMS indicated the reaction was complete. The mixture was concentrated and purified by flash column chromatography on silica gel PE/EA (30%) to give tert-butyl N- (5-chloro-4- (2-fluoro-4- [ (3- (phenylcarbamoyl) pyridin-2-yl) amino ] phenoxy) pyridin-2-yl) carbamate (160 mg, yield 82.03%) as a white solid.
HCl (4M in methanol) (5 mL) was added to N- (5-chloro-4- (2-fluoro-4- [ (3- (phenylcarbamoyl) pyridin-2-yl)) amino group in methanol (1 mL) at room temperature]Phenoxy) pyridin-2-yl) carbamic acid tert-butyl ester (80 mg,0.14mmol, 95% purity). The mixture was then stirred at room temperature for 16 hours. TLC indicated complete conversion. The mixture was stirred at 40℃for a further 16 hours. The reaction mixture was concentrated and taken up with NaHCO 3 (aqueous) quench, extract with DCM (20 mL. Times.3), and pass through Na 2 SO 4 Dried, concentrated and purified by TLC (DCM/MeOH 25:1) to give 2- [ (4- [ (2-amino-5-chloropyridin-4-yl) oxy) as a solid]-3-fluorophenyl) amino group]-N-phenylpyridine-3-carboxamide (40 mg, 64.35% yield, 100% purity) as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.48(d,J＝15.8Hz,2H),8.42(d,J＝4.9Hz,1H),8.29(d,J＝7.7Hz,1H),8.09(d,J＝13.6Hz,1H),7.83-7.77(m,1H),7.73(d,J＝8.1Hz,2H),7.40(t,J＝8.1Hz,3H),7.24(t,J＝9.2Hz,1H),7.16(t,J＝7.4Hz,1H),7.03(dd,J＝7.6,5.0Hz,1H),6.20-6.14(m,1H),5.96(s,2H),5.82(s,1H)
Example 62
Intermediate 7
Intermediate 7 was prepared according to the synthetic method of intermediate 1.
Example 63
Compound 52
Step 1: (4- (2-chloro-4- ((3- (methylcarbamoyl) pyridin-2-yl) amino) phenoxy) pyridin-2-yl) carbamic acid tert-butyl ester
To a 25mL three-necked flask was added successively 2- ((4- ((2- ((tert-butoxycarbonyl) amino) pyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinic acid (200.0 mg,0.44 mmol), DMF (5.0 mL), DIEA (173.8 mg,1.32 mmol), HATU (252 mg,0.66 mmol), methylamine hydrochloride (32.4 mg,0.48 mmol) after stirring at room temperature for 30min and stirring overnight at room temperature. Ethyl acetate (10 ml) was added to the reaction system, followed by washing with water (10 ml. Times.3) and saturated aqueous sodium chloride (10 ml. Times.2). The organic phase was concentrated and purified by normal phase silica gel column (ethyl acetate: petroleum ether=1:5) to give 170mg (yield: 82.6%) of tert-butyl 4- (2-chloro-4- ((3- (methylcarbamoyl) pyridin-2-yl) amino) phenoxy) pyridin-2-yl) carbamate as a white solid.
Step 2:2- ((4- ((2-aminopyridin-4-yl) oxy) -3-chlorophenyl) amino) -N-methylnicotinamide
To (4- (2-chloro-4- ((3- (methylcarbamoyl) pyridin-2-yl) amino) phenoxy) pyridin-2-yl) carbamic acid tert-butyl esterTo a solution of the ester (170 mg,0.46 mmol) in DCM (4 mL) was added 1mL of trifluoroacetic acid and the mixture was stirred at room temperature for 30min. The reaction was concentrated, and ethyl acetate (10 mL) was added. Saturated Na for organic phase 2 CO 3 The aqueous solution was washed until the aqueous phase was neutral in pH. The organic phase was concentrated to give crude 2- ((4- ((2-aminopyridin-4-yl) oxy) -3-chlorophenyl) amino) -N-methylnicotinamide (120 mg, 89.7% yield).
Step 3:2- ((4- (2-chloro-4- ((3- (methylcarbamoyl) pyridin-2-yl) amino) phenoxy) pyridin-2 ] Group) amino) -7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylic acid tert-butyl ester
To a 25mL reaction flask was added successively 2- ((4- ((2-aminopyridin-4-yl) oxy) -3-chlorophenyl) amino) -N-methylnicotinamide (120 mg,0.32 mmol), tert-butyl 2-chloro-7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylate (94.3 g,0.35 mmol), cesium carbonate (325 mg,1.0 mmol), xantphos (34.7 mg.0.06 mmol), pd 2 dba 3 (27.5 mg,0.03 mmol), 1, 4-dioxane (5 mL) was replaced with nitrogen three times. The reaction was then allowed to warm to 100.+ -. 2 ℃ and stirred overnight. Filtration, 50mL of ethyl acetate was added, and the mixture was washed with water (30 mL. Times.2) and saturated NaCl solution (30 mL. Times.2). The organic phase was concentrated and purified by column over silica gel to give 130mg (yield: 67%) of 2- ((4- (2-chloro-4- ((3- (methylcarbamoyl) pyridin-2-yl) amino) phenoxy) pyridin-2-yl) amino) -7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylic acid tert-butyl ester as a white solid.
Step 4:2- ((3-chloro-4- ((2- ((5, 6,7, 8-tetrahydro-1, 6-naphthyridin-2-yl) amino) pyridin-4-yl) oxy) Group) phenyl) amino) -N-methylnicotinamide
To 2- ((4- (2-chloro-4- ((3- (methylcarbamoyl) pyridin-2-yl) amino) phenoxy) pyridin-2-yl)) To a solution of tert-butyl amino) -7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylate (130 mg,0.26 mmol) in DCM (5 mL) was added 1mL trifluoroacetic acid and stirred at room temperature for 30min. The reaction was concentrated, and ethyl acetate (10 mL) was added. Saturated Na for organic phase 2 CO 3 The aqueous solution was washed until the aqueous phase was neutral in pH. The organic phase was concentrated and purified by reverse phase preparation apparatus to give 2- ((3-chloro-4- ((2- ((5, 6,7, 8-tetrahydro-1, 6-naphthyridin-2-yl) amino) pyridin-4-yl) oxy) phenyl) amino) -N-methylnicotinamide (50 mg, 46% yield).
1 H NMR(400MHz,DMSO-d 6 )δ11.21(s,1H),9.74(s,1H),8.85(d,J＝4.8Hz,1H),8.38(dd,J＝4.8,1.8Hz,1H),8.28(d,J＝2.6Hz,1H),8.19-8.12(m,2H),8.11(d,J＝5.8Hz,1H),7.65(d,J＝2.4Hz,1H),7.60(dd,J＝8.9,2.6Hz,1H),7.38(d,J＝8.5Hz,1H),7.31(d,J＝8.8Hz,1H),7.21(d,J＝8.5Hz,1H),6.95(dd,J＝7.8,4.8Hz,1H),6.59(dd,J＝5.8,2.4Hz,1H),3.99(s,2H),3.06(t,J＝6.1Hz,2H),2.84(d,J＝4.5Hz,3H),2.59(d,J＝6.2Hz,2H).,LC-MS:m/z[M+H] + ＝502.
Example 64
Compound 53
Step 1: (4- (2-chloro-4- ((3- (phenylcarbamoyl) pyridin-2-yl) amino) phenoxy) pyridin-2-yl) Carbamic acid tert-butyl ester
To a 25mL three-necked flask was added successively 2- ((4- ((2- ((tert-butoxycarbonyl) amino) pyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinic acid (200.0 mg,0.44 mmol), DMF (5.0 mL), DIEA (173.8 mg,1.32 mmol), HATU (252 mg,0.66 mmol), aniline (44.64 mg,0.48 mmol) was added after stirring at room temperature for 30min and stirring overnight at room temperature. Ethyl acetate (10 ml) was added to the reaction mass, which was washed with water (10 ml. Times.3) and saturated aqueous sodium chloride (10 ml. Times.2). The organic phase was concentrated and purified by normal phase silica gel column (ethyl acetate: petroleum ether=1:5) to give 190mg (yield: 81.5%) of tert-butyl 4- (2-chloro-4- ((3- (phenylcarbamoyl) pyridin-2-yl) amino) phenoxy) pyridin-2-yl) carbamate as a white solid.
Step 2:2- ((4- ((2-aminopyridin-4-yl) oxy) -3-chlorophenyl) amino) -N-phenylnicotinamide
To a solution of tert-butyl (4- (2-chloro-4- ((3- (phenylcarbamoyl) pyridin-2-yl) amino) phenoxy) pyridin-2-yl) carbamate (190 mg,0.34 mmol) in DCM (4 mL) was added 1mL of trifluoroacetic acid and stirred at room temperature for 30min. The reaction was concentrated, and ethyl acetate (10 mL) was added. Saturated Na for organic phase 2 CO 3 The aqueous solution was washed until the aqueous phase was neutral in pH. The organic phase was concentrated to give crude 2- ((4- ((2-aminopyridin-4-yl) oxy) -3-chlorophenyl) amino) -N-phenylnicotinamide (140 mg, 91% yield).
Step 3:2- ((4- (2-chloro-4- ((3- (phenylcarbamoyl) pyridin-2-yl) amino) phenoxy) pyridin-2 ] Group) amino) -7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylic acid tert-butyl ester
To a 25mL reaction flask was added successively 2- ((4- ((2-aminopyridin-4-yl) oxy) -3-chlorophenyl) amino) -N-phenylnicotinamide (140 mg,0.32 mmol), tert-butyl 2-chloro-7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylate (94.3 g,0.35 mmol), cesium carbonate (325 mg,1.0 mmol), xantphos (34.7 mg,0.06 mmol), pd 2 dba 3 (27.5 mg,0.03 mmol), 1, 4-dioxane (5 mL) was replaced with nitrogen three times. The reaction was then allowed to warm to 100.+ -. 2 ℃ and stirred overnight. Filtration, 50mL of ethyl acetate was added, and the mixture was washed with water (30 mL. Times.2) and saturated NaCl solution (30 mL. Times.2). Concentrating the organic phase, purifying with silica gel column to obtain To 170mg (yield: 79%) of a white solid, namely tert-butyl 2- ((4- (2-chloro-4- ((3- (phenylcarbamoyl) pyridin-2-yl) amino) phenoxy) pyridin-2-yl) amino) -7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylate.
Step 4:2- ((3-chloro-4- ((2- ((5, 6,7, 8-tetrahydro-1, 6-naphthyridin-2-yl) amino) pyridin-4-yl) oxy) Group) phenyl) amino) -N-phenyl nicotinamide
To a solution of 2- ((4- (2-chloro-4- ((3- (phenylcarbamoyl) pyridin-2-yl) amino) phenoxy) pyridin-2-yl) amino) -7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylic acid tert-butyl ester (170 mg,0.26 mmol) in DCM (5 mL) was added 1mL trifluoroacetic acid and stirred at room temperature for 30min. The reaction was concentrated, and ethyl acetate (10 mL) was added. Saturated Na for organic phase 2 CO 3 The aqueous solution was washed until the aqueous phase was neutral in pH. The organic phase was concentrated and purified by reverse phase preparation apparatus to give 2- ((3-chloro-4- ((2- ((5, 6,7, 8-tetrahydro-1, 6-naphthyridin-2-yl) amino) pyridin-4-yl) oxy) phenyl) amino) -N-phenylnicotinamide (70 mg, 49% yield).
1 H NMR(400MHz,DMSO-d 6 )δ10.56(s,1H),10.49(s,1H),9.68(d,J＝2.3Hz,1H),8.44(dd,J＝4.8,1.8Hz,1H),8.34-8.26(m,2H),8.23(d,J＝3.1Hz,1H),8.10(d,J＝5.7Hz,1H),7.77-7.71(m,2H),7.66(td,J＝5.3,4.5,2.6Hz,2H),7.45-7.36(m,2H),7.32(dd,J＝8.4,5.6Hz,2H),7.21-7.14(m,2H),7.03(dd,J＝7.7,4.8Hz,1H),6.57(dd,J＝5.7,2.4Hz,1H),3.87(d,J＝3.8Hz,2H),2.95(q,J＝5.3Hz,2H),2.54(d,J＝4.5Hz,2H),LC-MS:m/z[M+H] + Example 65 =564
Compound 54
Step 1: (4- (2-chloro-4- ((3- (dimethylcarbamoyl) pyridin-2-yl) amino) phenoxy) pyridin-2- Radical) carbamic acid tert-butyl ester
To a 25mL three-necked flask was added successively 2- ((4- ((2- ((tert-butoxycarbonyl) amino) pyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinic acid (200.0 mg,0.44 mmol), DMF (5.0 mL), DIEA (173.8 mg,1.32 mmol), HATU (252 mg,0.66 mmol), dimethylamine hydrochloride (39.12 mg,0.48 mmol) after stirring at room temperature for 30min and stirring overnight at room temperature. Ethyl acetate (10 ml) was added to the reaction system, followed by washing with water (10 ml. Times.3) and saturated aqueous sodium chloride (10 ml. Times.2). The organic phase was concentrated and purified by normal phase silica gel column (ethyl acetate: petroleum ether=1:5) to give 180mg (yield: 83.7%) of tert-butyl 4- (2-chloro-4- ((3- (dimethylcarbamoyl) pyridin-2-yl) amino) phenoxy) pyridin-2-yl) carbamate as a white solid.
Step 2:2- ((4- ((2-aminopyridin-4-yl) oxy) -3-chlorophenyl) amino) -N, N-dimethylnicotinamide
To a solution of tert-butyl (4- (2-chloro-4- ((3- (dimethylcarbamoyl) pyridin-2-yl) amino) phenoxy) pyridin-2-yl) carbamate (180 mg,0.37 mmol) in DCM (4 mL) was added 1mL of trifluoroacetic acid and stirred at room temperature for 30min. The reaction was concentrated, and ethyl acetate (10 mL) was added. Saturated Na for organic phase 2 CO 3 The aqueous solution was washed until the aqueous phase was neutral in pH. The organic phase was concentrated to give 2- ((4- ((2-aminopyridin-4-yl) oxy) -3-chlorophenyl) amino) -N, N-dimethyl nicotinamide (127 mg, 89% yield).
Step 3:2- ((4- (2-chloro-4- ((3- (dimethylcarbamoyl) pyridin-2-yl) amino) phenoxy) pyridine ] 2-ylamino) -7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylic acid tert-butyl ester
To a 25mL reaction flask was added sequentially 2- ((4- ((2-aminopyridin-4-yl) oxy) -3-chlorophenyl) amino) -N, N-dimethylnicotinamide (127 mg,0.33 mmol), tert-butyl 2-chloro-7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylate (96.9 g,0.36 mmol), cesium carbonate (325 mg,1.0 mmol), xantphos (40.5 mg,0.07 mmol), pd 2 dba 3 (28.2 mg,0.03 mmol), 1, 4-dioxane (5 mL) was replaced with nitrogen three times. The reaction was then allowed to warm to 100.+ -. 2 ℃ and stirred overnight. Filtration, 50mL of ethyl acetate was added, and the mixture was washed with water (30 mL. Times.2) and saturated NaCl solution (30 mL. Times.2). The organic phase was concentrated and purified by column over silica gel to give 133mg (yield: 65.2%) of 2- ((4- (2-chloro-4- ((3- (dimethylcarbamoyl) pyridin-2-yl) amino) phenoxy) pyridin-2-ylamino) -7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylic acid tert-butyl ester as a white solid.
Step 4:2- ((3-chloro-4- ((2- ((5, 6,7, 8-tetrahydro-1, 6-naphthyridin-2-yl) amino) pyridin-4-yl) oxy) Group) phenyl) amino) -N, N-dimethyl nicotinamide
To a solution of 2- ((4- (2-chloro-4- ((3- (dimethylcarbamoyl) pyridin-2-yl) amino) phenoxy) pyridin-2-ylamino) -7, 8-dihydro-1, 6-naphthyridine-6 (5H) -carboxylic acid tert-butyl ester (133 mg,0.22 mmol) in DCM (5 mL) was added 1mL trifluoroacetic acid and stirred at room temperature for 30min the reaction was concentrated, ethyl acetate (10 mL) was added the organic phase was taken up in saturated Na 2 CO 3 The aqueous solution was washed until the aqueous phase was neutral in pH. The organic phase was concentrated and purified by reverse phase preparation apparatus to give 2- ((3-chloro-4- ((2- ((5, 6,7, 8-tetrahydro-1, 6-naphthyridin-2-yl) amino) pyridin-4-yl) oxy) phenyl) amino) -N, N-dimethyl nicotinamide (40 mg, 36.0% yield).
1 H NMR(400MHz,DMSO-d 6 )δ9.68(s,1H),8.62(s,1H),8.29(dd,J＝4.9,1.9Hz,1H),8.11-8.04(m,2H),7.69(dd,J＝8.9,2.6Hz,1H),7.67-7.63(m,2H),7.34(d,J＝8.5Hz,1H),7.27(d,J＝8.9Hz,1H),7.19(d,J＝8.5Hz,1H),6.94(dd,J＝7.4,4.9Hz,1H),6.56(dd,J＝5.7,2.4Hz,1H),3.90(s,2H),3.07-2.88(m,8H),2.54(t,J＝6.3Hz,2H).
LCMS(ESI+):m/z 516.0(M+1)
Example 66
Compound 55
2- [ (4- [ (2-Acetaminopyridin-4-yl) oxy)]Phenyl) amino group]-N- (4-fluorophenyl) pyridine-3-carboxamide Is synthesized by (a)
To a solution of 2- [ (4- [ (2-acetamidopyridin-4-yl) oxy ] phenyl) amino ] pyridine-3-carboxylic acid (200 mg,0.55 mmol) in tetrahydrofuran (5 ml) was added 4-fluoroaniline (64.17 mg,0.58 mmol), ethyldiisopropylamine (142.16 mg,1.1 mmol), 2- (7-aza-1H-benzotriazol-1-yl) -1, 3-tetramethyluronium hexafluorophosphate (313.69 mg,0.83 mol), and the mixture was stirred at room temperature for 16 hours. LCMS showed good reaction. The mixture was concentrated under reduced pressure, and the residue was purified with a silica gel column to give 2- [ (4- [ (2-acetamidopyridin-4-yl) oxy ] phenyl) amino ] -N- (4-fluorophenyl) pyridine-3-carboxamide (70 mg, yield 27.88%).
LCMS(ESI+):m/z 459.2(M+1)
1 H NMR(400MHz,DMSO-d 6 )δ10.53(d,J＝2.9Hz,2H),10.39(s,1H),8.38(dd,J＝4.8,1.8Hz,1H),8.26(dd,J＝7.8,1.8Hz,1H),8.16(d,J＝5.7Hz,1H),7.84-7.70(m,4H),7.67(d,J＝2.4Hz,1H),7.24(t,J＝8.9Hz,2H),7.16-7.09(m,2H),6.97(dd,J＝7.7,4.8Hz,1H),6.64(dd,J＝5.7,2.4Hz,1H),2.03(s,3H).
Example 67
Compound 56
Step 1:4- (2-chloro-4-nitrophenoxy) -1H-pyrrolo [2,3-b]Pyridine compound
To 1H-pyrrolo [2,3-b]Na was added to a solution of pyridin-4-ol (5.0 g,37.3 mmol) in DMF (15 mL) 2 CO 3 (15.2 g,110 mmol) and the temperature of the reaction system was lowered to 0 ℃. After stirring at 0deg.C for 1 hour, 2-chloro-1-fluoro-4-nitrobenzene (6.5 g,37.0 mmol) was added in portions. The reaction was then stirred at room temperature for 2 hours. After the reaction was completed, pure water (500 mL) was added dropwise to the reaction system, and after the solid was completely precipitated, the mixture was filtered. After purification of the filter cake by a silica gel column (EA/pe=1:3), a yellow solid was obtained, namely 4- (2-chloro-4-nitrophenoxy) -1H-pyrrolo [2,3-b]Pyridine (3.2 g, 33% yield).
Step 2:4- ((1H-pyrrolo [2, 3-b)]Pyridin-4-yl) oxy) -3-chloroaniline
To a solution of 4- (2-chloro-4-nitrophenoxy) -1H-pyrrolo [2,3-b ] pyridine (3.0 g,10.4 mmol) in absolute ethanol (10 mL) was added 10mL of water and ammonium chloride (5.60 g,105.6 mmol), and the mixture was stirred until the reaction system was clear. Iron powder (928 mg.52 mmol) was added to the reaction system. Stirring was maintained at 75℃for 8 hours. After the reaction was completed, the mixture was filtered, 50ml of ethyl acetate was added, the mixture was separated, and the organic phase was washed once with saturated NaCl (50 ml). The organic phase was concentrated to give crude 4- ((1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) -3-chloroaniline (2.5 g, 93% yield)
LCMS(ESI+):m/z 260.0(M+1)
Step 3:2- ((4- ((1H-pyrrolo [2, 3-b)]Pyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinic acid methyl ester
To a 50mL reaction flask was added sequentially 4- ((1H-pyrrolo [2, 3-b)]Pyridin-4-yl) oxy) -3-chloroaniline (2.5 g,6.3 mmol), methyl 2-bromonicotinate (1.4 g,6.5 mmol), cesium carbonate (5.9 g,18.1 mmol), xantphos (694 mg,1.2 mmol), pd 2 dba 3 (549 mg,0.6 mmol), 1, 4-dioxane (30 mL) followed by nitrogen substitution three times. The reaction was then allowed to warm to 100.+ -. 2 ℃ and stirred overnight. Filtration, 50mL of ethyl acetate was added, and the mixture was washed with water (30 mL. Times.2) and saturated NaCl solution (30 mL. Times.2). The organic phase was concentrated and purified by column on silica gel to give 3.6g (yield: 95%) of a white solid, 2- ((4- ((1H-pyrrolo [2, 3-b)]Pyridin-4-yl) oxy) -3-chlorophenyl) amino) methyl nicotinate.
Step 4:2- ((4- ((1H-pyrrolo [2, 3-b)]Pyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinic acid
Methyl 2- ((4- ((1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinate (3.6 g,9.5 mmol) was dissolved in 30ml THF and formulated 4.5% aqueous lithium hydroxide solution (0.7 g, water: 15 ml) was added and stirred at 30℃for 3 hours. Ethyl acetate (50 ml) was added, and the organic phase was collected by separation. The organic phase was concentrated to give 3.0g (yield: 87%) of crude solid, 2- ((4- ((1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinic acid.
1 H NMR(400MHz,DMSO-d 6 )δ11.76(s,1H),10.94(s,1H),8.43(d,J＝4.8Hz,1H),8.29(d,J＝6.7Hz,2H),8.07(d,J＝5.5Hz,1H),7.62(d,J＝8.9Hz,1H),7.43-7.26(m,2H),6.93(dd,J＝7.7,4.9Hz,1H),6.32(d,J＝5.5Hz,1H),6.22(d,J＝3.4Hz,1H).
Step 5:2- ((4- ((1H-pyrrolo [2, 3-b)]Pyridin-4-yl) oxy) -3-chlorophenyl) amino) -N- (4-fluoro Phenyl) nicotinamide
To a 50mL three-necked flask was added 2- ((4- ((1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) -3-chlorophenyl) amino) nicotinic acid (200.0 mg,0.53 mmol), DMF (5.0 mL), DIEA (171.2 mg,1.3 mmol), HATU (302 mg,0.79 mmol), and after stirring at room temperature for 30min, 4-fluoroaniline (64.7 mg,0.58 mmol) was added and stirring at room temperature overnight. Ethyl acetate (10 ml) was added to the reaction mass, which was washed with water (10 ml. Times.3) and saturated aqueous sodium chloride (10 ml. Times.2). The organic phase was concentrated and purified by reverse phase chromatography (acetonitrile: water=1:5) to give 70mg (14.7%) of 2- ((4- ((1H-pyrrolo [2,3-b ] pyridin-4-yl) oxy) -3-chlorophenyl) amino) -N- (4-fluorophenyl) nicotinamide as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ11.74(s,1H),10.56(s,1H),10.43(s,1H),8.43(dd,J＝4.9,1.7Hz,1H),8.33-8.18(m,2H),8.06(d,J＝5.5Hz,1H),7.75(dd,J＝8.9,5.1Hz,2H),7.62(dd,J＝8.9,2.6Hz,1H),7.36(t,J＝3.0Hz,1H),7.33-7.20(m,3H),7.02(dd,J＝7.7,4.8Hz,1H),6.31(d,J＝5.5Hz,1H),6.25-6.16(m,1H)
LCMS(ESI+):m/z 474.0(M+1)
Example 68
Compound 57
Step 1: 3-fluoro-4- ((triisopropylsilyl) oxy) aniline
Imidazole (1.12 g,16.5 mmol) was added to a solution of 4-amino-2-fluorophenol (700 mg,5.5 mmol) in ACN (15 mL) and the temperature of the system was lowered to 0deg.C. After slowly adding triisopropylchlorosilane (1.16 g,6.05 mmol), stirring at room temperature for 5h. The reaction solvent was concentrated and ethyl acetate (50 mL) was added. The organic phase was washed with water (30 mL. Times.2) and saturated brine (30 mL. Times.2), and concentrated to give crude 3-fluoro-4- ((triisopropylsilyl) oxy) aniline (1.37 g, yield: 87.8%).
Step 2:2- ((3-fluoro-4- ((triisopropylsilyl) oxy) phenyl) amino) nicotinic acid methyl ester
To a 50mL reaction flask was added 3-fluoro-4- ((triisopropylsilyl) oxy) aniline (900 mg,3.18 mmol), methyl 2-bromonicotinate (751 mg,3.5 mmol), cesium carbonate (3.1 g,9.54 mmol), xantphos (367.6 mg,0.6 mmol), pd in this order 2 dba 3 (274.5 mg,0.3 mmol), 1, 4-dioxane (20 mL) followed by nitrogen substitution three times. The reaction was then allowed to warm to 100.+ -. 2 ℃ and stirred overnight. Filtration, 50mL of ethyl acetate was added, and the mixture was washed with water (30 mL. Times.2) and saturated NaCl solution (30 mL. Times.2). The organic phase was concentrated and purified by a silica gel column to give 1.0g (yield: 76%) of methyl 2- ((3-fluoro-4- ((triisopropylsilyl) oxy) phenyl) amino) nicotinate as a white solid.
Step 3 methyl 2- ((3-fluoro-4-hydroxyphenyl) amino) nicotinate
To a solution of methyl 2- ((3-fluoro-4- ((triisopropylsilyl) oxy) phenyl) amino) nicotinate (1.0 g,2.4 mmol) in THF (15 mL) was added TBAF (941.3 mg,3.6 mmol) and the system temperature was raised to 70 ℃ and stirred for 8h. The reaction solvent was concentrated and ethyl acetate (40 mL) was added. The organic phase was washed with water (20 mL. Times.2) and saturated brine (20 mL. Times.2), and concentrated to give methyl 2- ((3-fluoro-4-hydroxyphenyl) amino) nicotinate (560 mg, yield: 89%) as a crude product.
Step 4:2- ((4- ((2-chloropyrimidin-4-yl) oxy) -3-fluorophenyl) amino) nicotinic acid methyl esterEsters of
To a solution of methyl 2- ((3-fluoro-4-hydroxyphenyl) amino) nicotinate (560 mg,2.13 mmol) in DMF (10 mL) was added K 2 CO 3 (828.0 mg,6.0 mmol), 2, 4-dichloropyrimidine (317.0 mg,2.13 mmol) and the system was warmed to 70℃and stirred overnight. Ethyl acetate (30 mL) and water (30 mL) were added, the solution was separated, and the organic phase was collected. The organic phase was washed with water (20 mL. Times.3) and saturated brine (20 mL. Times.2), and concentrated to give crude methyl 2- ((4- ((2-chloropyrimidin-4-yl) oxy) -3-fluorophenyl) amino) nicotinate (750 mg, yield: 93.4%).
Step 5:2- ((4- ((2-chloropyrimidin-4-yl) oxy) -3-fluorophenyl) amino) nicotinic acid
To methyl 2- ((4- ((2-chloropyrimidin-4-yl) oxy) -3-fluorophenyl) amino) nicotinate (200 mg,0.53 mmol) in THF/H 2 To a solution of O (1:1, 10 mL) was added LiOH (31.6 mg,5.0 mmol) and the mixture was stirred at room temperature for 3 hours. Concentrated, ethyl acetate (30 mL) was added. The aqueous phase was pH adjusted to ph=3 with saturated aqueous citric acid, separated and the organic phase was collected. The organic phase was concentrated to give crude 2- ((4- ((2-chloropyrimidin-4-yl) oxy) -3-fluorophenyl) amino) nicotinic acid (140 mg, yield: 73%).
Step 6:2- ((4- ((2-chloropyrimidin-4-yl) oxy) -3-fluorophenyl) amino) -N- (4-fluorophenyl) nicotinamide
To a 25mL three-necked flask was added successively 2- ((4- ((2-chloropyrimidin-4-yl) oxy) -3-fluorophenyl) amino) nicotinic acid (140.0 mg,0.39 mmol), DMF (6.0 mL), DIEA (128.7 mg,1.0 mmol), HATU (220 mg,0.58 mmol), and after 30min stirring at room temperature, 4-fluoroaniline (52.1 mg,0.47 mmol) was added and stirred overnight at room temperature. Ethyl acetate (10 ml) was added to the reaction system, followed by washing with water (10 ml. Times.3) and saturated aqueous sodium chloride (10 ml. Times.2). The organic phase was concentrated and purified by silica gel chromatography (EA: pe=1:5) to give 120mg (yield: 68.1%) of 2- ((4- ((2-chloropyrimidin-4-yl) oxy) -3-fluorophenyl) amino) -N- (4-fluorophenyl) nicotinamide as a white solid.
Step 7:2- ((3-fluoro-4- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) Pyrimidin-4-yl) oxy) phenyl) -amino-N- (4-fluorophenyl) nicotinamide
To a solution of 2- ((4- ((2-chloropyrimidin-4-yl) oxy) -3-fluorophenyl) amino) -N- (4-fluorophenyl) nicotinamide (120 mg,0.27 mmol) in isopropanol (3 mL) was added 6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-amine (51.8 mg,0.27 mmol), after p-toluenesulfonic acid (70.5 mg,0.41 mmol), the system was warmed to 80℃and stirred overnight. Concentrated, ethyl acetate (30 mL) was added. Saturated Na for organic phase 2 CO 3 The aqueous solution was washed three times and the organic phase was collected. The organic phase was concentrated to give crude 2- ((3-fluoro-4- ((2- ((6-methoxy-2-methyl-1, 2,3, 4-tetrahydroisoquinolin-7-yl) amino) pyrimidin-4-yl) oxy) phenyl) amino) -N- (4-fluorophenyl) nicotinamide (60.0 mg, yield: 37%) as a white solid by flash column chromatography on silica gel.
1 H NMR(400MHz,DMSO-d 6 )δ10.68(s,1H),10.56(s,1H),8.45(dd,J＝4.8,1.8Hz,1H),8.37(d,J＝5.5Hz,1H),8.29(dd,J＝7.8,1.9Hz,1H),8.23(dd,J＝13.6,2.5Hz,1H),7.88(s,1H),7.78-7.71(m,2H),7.50-7.44(m,1H),7.36-7.21(m,4H),7.03(dd,J＝7.7,4.9Hz,1H),6.68(s,1H),6.61(d,J＝5.6Hz,1H),3.78(s,3H),3.02(s,2H),2.66(s,2H),2.42(s,2H),1.98(s,3H).
Example 69
Compound 58
Preparation of 2- [ (4- [ (2-aminopyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N-phenylpyridine-3-carboxamide according to example 51 procedure two
Example 70
Compound 59
Acetyl chloride (6.75 mg,0.086 mmol) was dissolved in tetrahydrofuran (1 mL) and then added dropwise to a solution of 2- [ (4- [ (2-amino-5-chloropyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (4-methylphenyl) pyridine-3-carboxamide (40 mg,0.086 mmol) and ethyldiisopropylamine (16.67 mg,0.13 mmol) in tetrahydrofuran (5 mL) at 0deg.C and stirred for 1h at 0deg.C. Gradually warmed to room temperature and stirred at 25℃for 4 hours. Quench the reaction with methanol (2 mL) and concentrate. The residue was concentrated and purified by Pre-TLC (DCM/MeOH 25:1) to give 2- [ (4- [ (5-chloro-2-acetamidopyridin-4-yl) oxy ] -3-fluorophenyl) amino ] -N- (4-methylphenyl) pyridine-3-carboxamide as a white solid (20 mg, yield 44.93%, purity 98%).
1 H NMR(400MHz,DMSO-d 6 )δ10.68(s,1H),10.61(s,1H),10.46(s,1H),8.43(d,J＝4.8Hz,1H),8.38(s,1H),8.29(d,J＝7.8Hz,1H),8.18(dd,J＝13.9,2.5Hz,1H),7.66-7.59(m,3H),7.47(d,J＝8.9Hz,1H),7.35(t,J＝9.0Hz,1H),7.20(d,J＝8.1Hz,2H),7.04(dd,J＝7.8,4.9Hz,1H),2.31(s,3H),1.99(s,3H).
Example 71
Compound 60
2- ((4- ((2-acetamido-5-chloropyridin-4-yl) oxy) -3-fluorophenyl) amino) -N-phenylnicotinamide
The process of reference example 70 was carried out by reacting compound 51 with acetyl chloride.
Yield 40%, purity 95%, white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.52(d,J＝6.9Hz,2H),10.26(s,1H),8.44(d,J＝4.8Hz,1H),8.29(d,J＝7.8Hz,1H),8.23-8.13(m,2H),7.73(d,J＝7.9Hz,2H),7.48(d,J＝8.6Hz,1H),7.44-7.32(m,3H),7.17(t,J＝7.4Hz,1H),7.05(t,J＝6.3Hz,1H),6.66(d,J＝5.7Hz,1H),2.09(s,3H).
Example 72
Compound 61
(R) -2- ((3-chloro-4- ((2- (2- (piperidin-3-yl) acetamido) pyridin-4-yl) oxy) phenyl) amino) -N- (4-fluorophenyl) nicotinamide
With reference to the procedure of example 32, (R) -2- ((3-chloro-4- ((2- (2- (piperidin-3-yl) acetamido) pyridin-4-yl) oxy) phenyl) amino) -N- (4-fluorophenyl) nicotinamide was synthesized according to the general method of synthesis in 18.79% purity 95% as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ10.61(s,2H),10.45(s,1H),8.43(dd,J＝4.9,1.8Hz,1H),8.35(s,1H),8.32-8.23(m,2H),8.19(d,J＝5.7Hz,1H),7.80-7.70(m,2H),7.65(dd,J＝8.9,2.5Hz,2H),7.29(d,J＝8.8Hz,1H),7.24(t,J＝8.9Hz,2H),7.03(dd,J＝7.7,4.9Hz,1H),6.66(dd,J＝5.7,2.4Hz,1H),3.08-3.13(m,2H),2.66(dd,J＝13.8,10.6Hz,1H),2.46(d,J＝11.8Hz,1H),2.31(d,J＝6.9Hz,2H),2.02(d,J＝28.1Hz,1H),1.80-1.65(m,2H),1.52(d,J＝13.4Hz,1H),1.22-1.07(m,1H).
Biological Activity test
In vitro hematopoietic progenitor kinase 1 (HPK 1) inhibition assay
Exemplary procedures that can be used to determine the inhibitory effect of the compounds of the invention on HPK1 in vitro are as follows. ADP-GloTM kinase assay kit from Promega was used. ADP-GloTM kinase assay is an assay that determines kinase activity by quantifying ADP produced during an enzymatic reaction. The analysis method mainly comprises two steps; first, after the enzymatic reaction is completed, the reaction is terminated by adding an equal volume of ADP-GloTM reagent and the remaining ATP is depleted. Kinase detection reagents are then added to convert ADP to ATP and the newly synthesized ATP is measured using a luciferase/luciferin reaction. The detailed procedure is as follows. Transferring the compound dilutions 20nL to 384 assay plates with Echo 655; after centrifugation, 2. Mu.L of 2 Xkinase solution was added to 384 assay plates, centrifuged at 1000rpm for 1 min and incubated at 25℃for 10 min. Then 2. Mu.L of the 2 Xsubstrate/ATP solution was added to 384 assay plates and centrifuged at 1000rpm for 1 minute. The final HPK1 enzymatic reaction consisted of the following components: 0.3nM HPK1, 10 μMATP, 0.05mg/mL MBP, 50mM HEPES, 10mM MgCl2, 0.01% Brij35, 2mM DTT, 1mM EGTA, test compound concentrations were: 30000nM, 10000nM, 3333nM, 1111nM, 370nM, 123nM, 41nM, 13nM, 4.5nM, 1.5nM. Incubate at 25℃for 60 min. Add 4. Mu.L ADP-Glo reagent to 384 assay plates, centrifuge at 1000rpm for 1 min, incubate at 25℃for 40 min. mu.L of kinase assay reagent was added to 384 assay plates, centrifuged at 1000rpm for 1 min and incubated at 25℃for 40 min. Finally, the luminescence signal is read on a BMG PHERAstar FSX microplate reader.
The inhibition ratio of each test solution was calculated by setting the reading value of the negative control to 0% inhibition ratio and the reading value of the positive control to 100% inhibition ratio.
Wherein the method comprises the steps ofMean value of positive control well values, +.>Is the average value of the values of the negative control wells.
IC of each Compound 50 By combining the data with the following nonlinearityRegression equation fitting:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50 -X)*HillSlope))
wherein X is the log of the compound concentration and Y is the compound inhibition (% inhibition)
Wherein the IC 50 The values are: a is less than or equal to 50nM,50nM<B≤500nM，C>500nM。
The experimental results show that the compound has remarkable inhibition effect on HPK 1.

Claims (18)

1. A diaza aromatic ring substituted benzene derivative of formula (I):
wherein,
y is O, S, NH, NR a Or SO 2 The method comprises the steps of carrying out a first treatment on the surface of the Here, R is a Is unsubstituted C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl or C 1 -C 6 Alkoxy C 1 -C 6 An alkyl group;
R 1 to R 4 Each independently selected from hydrogen, deuterium, halogen, nitro, cyano, hydroxy, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl and C 1 -C 6 Alkoxy C 1 -C 6 An alkyl group; optionally R 1 And R is R 2 Together with the carbon atoms to which they are attached or R 3 And R is R 4 And the carbon atoms to which they are attached together form an unsubstituted or substituted cycloalkyl, an unsubstituted or substituted heterocycloalkyl, an unsubstituted or substituted aryl, or an unsubstituted or substituted heteroaryl;
R 5 To R 8 Each independently selected from hydrogen, deuterium, -C (O) NR 13 R 14 Halogen, nitro, cyano, hydroxy, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl and C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl;
R 9 and R is 10 Each independently selected from hydrogen, deuterium, halogen, nitro, cyano, hydroxy, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
R 11 selected from hydrogen, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 A heterocyclic group;
R 12 selected from hydrogen, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 1 -C 6 Alkanoyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
alternatively, R 11 And R is R 12 And N attached thereto together form an unsubstituted or substituted 3 to 6 membered heterocycloalkyl, or an unsubstituted or substituted 5 to 6 membered heteroaryl; optionally, the 3-to 6-membered heterocycloalkyl or 5-to 6-membered heteroaryl is substituted with NH, NR b O, S or SO 2 Interval, here R b Is unsubstituted C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl or C 1 -C 6 Alkoxy C 1 -C 6 An alkyl group;
R 13 and R is 14 Each independently selected from hydrogen, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl and unsubstituted or substituted heteroaryl；
M is N or C (R) 15 ) The method comprises the steps of carrying out a first treatment on the surface of the Here, R is 15 Is hydrogen, halogen, nitro, cyano, hydroxy, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl and C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl; alternatively, R 15 And R is R 11 And the carbon atoms and nitrogen atoms to which they are attached together form a nitrogen-containing five-to seven-membered heterocyclic ring;
or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof.
2. The derivative according to claim 1, or an optical isomer, stable isotope variant, pharmaceutically acceptable salt, or hydrate thereof, wherein Y is O, S, NH, NR a Or SO 2 Here, R is a Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
preferably Y is O, S, NH, NCH 3 Or SO 2 ；
More preferably, Y is O.
3. The derivative according to claim 1 or 2, or an optical isomer, stable isotope variant, pharmaceutically acceptable salt, or hydrate thereof, wherein R 1 To R 4 Wherein at least one of the others is hydrogen, and each of the others is independently selected from hydrogen, deuterium, fluorine, chlorine, nitro, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethenyl, propenyl, ethynyl, and propynyl; alternatively, R 1 And R is 2 Each independently selected from hydrogen,Deuterium, fluorine, chlorine, nitro, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethenyl, propenyl, ethynyl and propynyl, and R 3 And R is R 4 And the carbon atoms to which they are attached form unsubstituted or substituted cyclopentylalkyl, unsubstituted or substituted cyclohexenyl, unsubstituted or substituted tetrahydroimidazolyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted tetrahydrofuranyl, unsubstituted or substituted piperazinyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted tetrahydropyranyl, unsubstituted or substituted phenyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted pyridinyl, or unsubstituted or substituted pyrimidinyl;
preferably, R 1 Selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, nitro, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethenyl, propenyl, ethynyl, and propynyl, R 2 To R 4 Are all hydrogen; alternatively, R 1 Is hydrogen, fluorine, chlorine or methyl, R 2 Is fluorine; and R is 3 And R is R 4 And the carbon atoms to which they are attached together form a cyclopentylalkyl, cyclohexenyl, tetrahydroimidazolyl, pyrrolidinyl, tetrahydrofuranyl, piperazinyl, piperidinyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridinyl, or pyrimidinyl group;
more preferably, R 1 Is hydrogen, fluorine, chlorine or methyl, R 2 To R 4 Are all hydrogen; alternatively, R 1 Is hydrogen, chlorine or methyl, R 2 Is fluorine, and R 3 And R is R 4 And the carbon atoms to which they are attached together form a cyclohexenyl, piperidinyl, or pyridyl group.
4. A derivative according to any one of claims 1 to 3, or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof, wherein R 5 To R 8 Each independently selected from hydrogen, deuterium, halogen, nitro, cyano, hydroxy, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substitutedC 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl and C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, optionally R 5 To R 8 At least one of which is other than hydrogen;
preferably, R 5 To R 8 Each independently selected from hydrogen, unsubstituted or substituted phenyl and unsubstituted or substituted naphthyl, and R 5 To R 8 At least one of which is other than hydrogen; here, the substituted phenyl or substituted naphthyl means substituted with one or more groups selected from group a; the group A is as follows: halogen, nitro, cyano, hydroxy, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 3 -C 10 Cycloalkyl, C 3 -C 10 Cycloalkoxy radicals C 2 -C 8 Heterocyclyl, C 2 -C 8 Heteroepoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, optionally C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, C 3 -C 10 Cycloalkyl, C 3 -C 10 Cycloalkoxy radicals C 2 -C 8 Heterocyclyl, C 2 -C 8 Heteroepoxy, aryl, aryloxy, heteroaryl and heteroaryloxy are further substituted;
more preferably, R 5 To R 8 Each independently selected from hydrogen and halophenyl;
more preferably, R 5 To R 8 Each independently selected from hydrogen and fluorophenyl;
more preferably, R 5 、R 6 And R is 7 Is a hydrogen gas which is used as a hydrogen gas,and R is 8 Is a fluorophenyl group, particularly preferably a 3-fluorophenyl group.
5. A derivative according to any one of claims 1 to 3, or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof, wherein R 5 is-C (O) NR 13 R 14 And R is 6 To R 8 Are all hydrogen;
R 13 and R is 14 Each independently selected from hydrogen, unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
preferably, R 13 And R is 14 Each independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydropyranyl, morpholinyl, phenyl and naphthyl; here, the cyclopentyl, cyclohexyl, cycloheptyl, tetrahydropyranyl, morpholinyl, phenyl and naphthyl groups are optionally substituted with one or more groups selected from group a;
the group A is as follows: fluoro, chloro, bromo, iodo, nitro, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, trifluoromethyl, methoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azaspiro [2.3] hexy, azaspiro [3.4] octy, pyrrolidinyloxy, piperidinyloxy, azaspiro [2.3] hexy, or azaspiro [3.4] octy, optionally the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, trifluoromethyl, methoxymethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyloxy, cyclopentyloxy, piperidinyl, piperazinyl, azaspiro [2.3] hexy, azaspiro [3.4] oxa, pyrrolidinyl, 3.3 ] oxa, piperidinyl, pyrrolidinyl, 3.3 ] oxa, or azaspiro [3.4] oxa, optionally the methyl, ethyl, n-propyl, isopropyl, tert-butoxy, trifluoromethyl: fluoro, chloro, bromo, iodo, nitro, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, amino, mono-and dimethylamino;
More preferably, R 13 And R is 14 Each independently selected from the group consisting of hydrogen, methyl, ethyl, cyclohexyl, substituted cyclohexyl, morpholinyl, tetrahydropyranyl, phenyl, substituted phenyl, naphthyl, and substituted naphthyl; here, the substituted cyclohexyl, substituted phenyl or substituted naphthyl means substituted with one or more groups selected from group a; the group A is as follows: fluorine, chlorine, bromine, iodine, nitro, cyano, hydroxyl, methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, ethynyl, N-propoxy, dimethylamino-substituted N-butyl, dimethylamino-substituted isobutyl, dimethylamino-substituted sec-butyl, amino-substituted N-butyl, amino-substituted isobutyl, amino-substituted sec-butyl, cyclobutoxy, amino-substituted cyclobutoxy, piperidinyloxy, N-methylpiperidinyloxy, pyrrolidinyloxy, azaspiro [3.4 ]]An octyloxy group;
more preferably, R 13 And R is 14 Are all methyl groups; alternatively, R 13 Is hydrogen and R 14 Is methyl, phenyl or substituted phenyl, cyclohexyl or substituted cyclohexyl, tetrahydropyranyl or naphthyl, wherein the substituted cyclohexyl is 4, 4-difluorocyclohexyl and the substituted phenyl is 4 -fluorophenyl, 4-tolyl, 3-chlorophenyl, 3-fluorophenyl, 3, 4-difluorophenyl, 3-alkynylphenyl, 3-trifluoromethylphenyl, 2- (3- (N, N-dimethylamino) propoxy) phenyl, 2- (3- (N, N-dimethylamino) propoxy) -4-fluorophenyl, 2- (N-methylpiperidin-4-yloxy) phenyl, 2- ((N-methylpiperidin-4-yl) oxy) -4-fluorophenyl, 2- ((4-aminobutan-2-yl) oxy) -4-fluorophenyl, 2- (3-aminocyclobutoxy) -4-fluorophenyl, 2- ((pyrrolidin-2-yl) oxy) -4-fluorophenyl, 2- ((4-aminobutan-2-yl) oxy) -4-fluorophenyl, or 2- ((5-azaspiro [3.4 ]]Oct-2-yl) oxy) -4-fluorophenyl.
6. The derivative according to any one of claims 1 to 5, or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof, wherein M is N or C (R 15 ) The method comprises the steps of carrying out a first treatment on the surface of the Here, R is 15 Hydrogen, fluoro, chloro, nitro, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethenyl, propenyl, ethynyl or propynyl; alternatively, R 15 And R is R 11 And the carbon atom and nitrogen atom to which they are attached together form a nitrogen-containing five-or six-membered heterocyclic ring;
R 9 and R is 10 Each independently selected from hydrogen, fluorine, chlorine, nitro, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethenyl, propenyl, ethynyl, or propynyl;
Preferably, M is N or C (R 15 ) The method comprises the steps of carrying out a first treatment on the surface of the Here, R is 15 Hydrogen, fluorine or chlorine; alternatively, R 15 And R is R 11 And the carbon atom and nitrogen atom to which they are attached together form a pyrrole ring or pyridine ring;
R 9 and R is 10 Are all hydrogen.
7. The derivative according to any one of claims 1 to 6, or an optical isomer, stable isotope variant, pharmaceutically acceptable salt, or hydrate thereof, wherein R 11 Is hydrogen; r is R 12 Selected from hydrogen, unsubstituted C 1 -C 6 Alkyl, unsubstitutedOr substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 1 -C 6 Alkanoyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl;
preferably, R 11 Is hydrogen; r is R 12 Selected from the group consisting of unsubstituted or substituted formyl, unsubstituted or substituted acetyl, unsubstituted or substituted propionyl, unsubstituted or substituted n-butyryl, unsubstituted or substituted isobutyryl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted pyridinyl and unsubstituted or substituted naphthyridinyl, wherein the substituted formyl, substituted acetyl, substituted propionyl, substituted n-butyryl, substituted isobutyryl, substituted pyrazolyl, substituted pyridinyl or substituted naphthyridinyl is substituted with one or more groups selected from the group consisting of: fluorine, chlorine, bromine, nitro, cyano, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azaspiro [2.3 ]Hexaalkyl, azaspiro [3.4]Octyl.
8. The derivative according to any one of claims 1 to 6, or an optical isomer, stable isotope variant, pharmaceutically acceptable salt, or hydrate thereof, wherein R 11 Selected from unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substitutedC of (2) 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 A heterocyclic group; and R is 12 Selected from unsubstituted C 1 -C 6 Alkyl, unsubstituted or substituted C 2 -C 6 Alkenyl, unsubstituted or substituted C 2 -C 6 Alkynyl, unsubstituted or substituted C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy C 1 -C 6 Alkyl, unsubstituted or substituted C 1 -C 6 Alkanoyl, unsubstituted or substituted C 3 -C 10 Cycloalkyl, unsubstituted or substituted C 2 -C 8 Heterocyclyl, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl; alternatively, R 11 And R is R 12 And N attached thereto form together an unsubstituted or substituted aziridinyl, an unsubstituted or substituted azetidinyl, an unsubstituted or substituted pyrrolidinyl, an unsubstituted or substituted piperidinyl, an unsubstituted or substituted pyrrolyl, an unsubstituted or substituted imidazolyl, an unsubstituted or substituted pyridinyl, or an unsubstituted or substituted pyrimidinyl, optionally said unsubstituted or substituted aziridinyl, said unsubstituted or substituted azetidinyl, said unsubstituted or substituted pyrrolidinyl, said unsubstituted or substituted piperidinyl, said unsubstituted or substituted pyrrolyl, said unsubstituted or substituted imidazolyl, said unsubstituted or substituted pyridinyl, or said unsubstituted or substituted pyrimidinyl is NH, NR b O, S or SO 2 Interval, here R b Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl;
preferably, R 11 And R is 12 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl; or,R 11 and R is R 12 And the N to which they are attached together form aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, 4-methylpiperazinyl, pyrrolyl, imidazolyl, pyridinyl or pyrimidinyl;
more preferably, R 11 And R is 12 Is methyl.
9. A compound, or an optical isomer, stable isotopic variant, pharmaceutically acceptable salt, or hydrate thereof, selected from the group consisting of:
10. a pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or an optical isomer, stable isotope variant, pharmaceutically acceptable salt, or hydrate thereof, and a pharmaceutically acceptable diluent, excipient and/or inert carrier.
11. A compound according to any one of claims 1 to 9 or an optical isomer, stable isotope variant, pharmaceutically acceptable salt, or hydrate thereof, or a pharmaceutical composition according to claim 10 for use as a medicament.
12. A compound according to any one of claims 1 to 9, or an optical isomer, stable isotope variant, pharmaceutically acceptable salt, or hydrate thereof, or a pharmaceutical composition according to claim 10, for use in the treatment or prevention of cancer.
13. Use of a compound according to any one of claims 1 to 9, or an optical isomer, stable isotope variant, pharmaceutically acceptable salt, or hydrate thereof, or a pharmaceutical composition according to claim 10, in the manufacture of a medicament for the treatment or prevention of cancer.
14. A method of preventing or treating cancer, the method comprising administering to a subject in need thereof a compound of any one of claims 1 to 9, or an optical isomer, stable isotope variant, pharmaceutically acceptable salt, or hydrate thereof, or a pharmaceutical composition of claim 10.
15. The use according to any one of claims 11 to 13, or the method of claim 14, wherein the cancer comprises, but is not limited to, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, renal cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, thyroid cancer, female genital tract cancer, lymphoma, neurofibroma, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal stromal tumor, mast cell tumor, multiple myeloma, melanoma, leukemia, glioma or sarcoma.
16. The use according to any one of claims 11 to 13, or the method according to claim 14, wherein the compound or optical isomer, stable isotope variant, pharmaceutically acceptable salt, or hydrate thereof, or the pharmaceutical composition is combined with a second therapeutic agent or radiation therapy.
17. The use or method of claim 16, wherein the second therapeutic agent is one or more of a chemotherapeutic drug, a targeted therapeutic drug, and a tumor immune drug.
18. The use or method of claim 17, wherein the second therapeutic agent is a PD-1/PD-L1/CTLA-4 antibody or a PD-1/PD-L1/CTLA-4 inhibitor.
CN202311504919.XA 2023-11-13 2023-11-13 Diazaaryl ring substituted benzene derivatives, compositions and uses thereof Pending CN117843567A (en)

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