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WO2025153057A1 - Composition pharmaceutique comprenant un inhibiteur de braf et utilisation d'une composition pharmaceutique en médecine - Google Patents

Composition pharmaceutique comprenant un inhibiteur de braf et utilisation d'une composition pharmaceutique en médecine

Info

Publication number
WO2025153057A1
WO2025153057A1 PCT/CN2025/072990 CN2025072990W WO2025153057A1 WO 2025153057 A1 WO2025153057 A1 WO 2025153057A1 CN 2025072990 W CN2025072990 W CN 2025072990W WO 2025153057 A1 WO2025153057 A1 WO 2025153057A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
content
alkoxy
mmol
halogenated
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/072990
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English (en)
Chinese (zh)
Inventor
蒋炜
王利
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Haisco Pharmaceutical Group Co Ltd
Original Assignee
Haisco Pharmaceutical Group Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Haisco Pharmaceutical Group Co Ltd filed Critical Haisco Pharmaceutical Group Co Ltd
Publication of WO2025153057A1 publication Critical patent/WO2025153057A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • MAP kinases are a family of serine/threonine kinases that respond to a variety of extracellular growth signals. For example, growth hormone, epidermal growth factor, platelet-derived growth factor, and insulin are all thought to participate in mitogenic stimulation of the MAPK pathway. Activation of this pathway at the receptor level initiates a signaling cascade whereby Ras GTPase exchanges GDP for GTP. Next, Ras activates Raf kinase (also known as MAPKKK), which in turn activates MEK (MAPKK).
  • MAPKKK Raf kinase
  • the BRAF protein is a member of the RAF family of serine/threonine kinases that participates in cascades of the Ras Raf MEK extracellular signal-regulated kinase (ERK) pathway or the mitogen-activated protein kinase (MAPK)/ERK signaling pathway that affect cell division and differentiation. Mutations in the BRAF gene can lead to uncontrolled growth and subsequent tumor formation. BRAF is mutated and/or overactivated in common human cancers such as melanoma, colorectal cancer, thyroid cancer, non-small cell lung cancer, and ovarian cancer and their metastatic cancers, and primary brain tumors. Although some BRAF inhibitors produce excellent extracranial responses, cancers may still develop brain metastases during or following BRAF inhibitor therapy.
  • Brain metastases remain a substantial contributor to overall cancer mortality in subjects with advanced cancer, and despite multimodality treatment and advances in systemic therapy, which includes combinations of surgery, radiation therapy, chemotherapy, immunotherapy, and/or targeted therapies, the prognosis remains poor.
  • the blood-brain barrier is a highly selective physical transport and metabolic barrier that separates the CNS from the blood.
  • the BBB prevents certain drugs from entering brain tissue and is a limiting factor for the delivery of many peripherally administered agents to the CNS.
  • Many drugs commonly used to treat cancer cannot cross the blood-brain barrier. This means that these drugs cannot penetrate the brain and therefore cannot effectively kill cancer cells in the brain.
  • Current treatments for subjects with brain tumors include surgical resection, radiation therapy, and/or chemotherapy using agents such as temozolomide and/or bevacizumab.
  • both P gp and BCRP are expressed in endothelial cells lining the blood-brain capillaries
  • the activity of both P gp and BCRP in the BBB plays a key role in preventing most kinase inhibitors from distributing into the brain parenchyma. Therefore, kinase inhibitors are generally not suitable for the treatment of tumors or cancers in the brain, which is protected by the BBB. Therefore, there remains a need for treatment of tumors with BRAF mutations. In addition, there remains an unmet need for the treatment of CNS tumors, including CNS tumors with BRAF mutations.
  • Ring A is a 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from N, S, and O, and the heteroaryl group is optionally substituted by 1-2 groups selected from halogen, C 1-4 alkoxy, -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , CN, C 1-4 alkyl, halogenated C 1-4 alkoxy, and halogenated C 1-4 alkyl. In some embodiments, it is a 5-membered heteroaryl group.
  • the heteroaryl group is selected from pyrazolyl, oxazolyl, imidazolyl, triazole, thiazolyl, isoxazolyl, isothiazolyl, pyrrolyl, pyridinyl, pyrimidinyl, etc.
  • # means to select a point to connect with Y
  • n is selected from 0 or 1;
  • X 2 is N or CR 3 ; in some embodiments, X 2 is N; in some embodiments, X 2 is CR 3 ;
  • X 3 is N or CR 31 ; in some embodiments, X 3 is N or CH;
  • X 4 is N or CR 32 ; In some embodiments, X 4 is N or CH;
  • X 5 is N or CR 33 ; in some embodiments, X 5 is N or CH;
  • X 7 is CR 7 or N; in some embodiments, X 7 is N; in some embodiments, X 7 is CH;
  • R 1 , R 2 and R 4 are independently H, halogen, OH, -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , CN, C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, halogenated C 1-4 alkyl, C 2-4 alkenyl or C 2-4 alkynyl;
  • the -NHC 1-4 alkyl includes -NH methyl, -NH ethyl, -NH isopropyl, -NH propyl, -NH butyl, the -N(C 1-4 alkyl) 2 includes dimethylamino, diethylamino, etc.;
  • R 3 , R 31 , R 32 , and R 33 are independently H, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl , C 1-4 alkoxy, halogenated C 1-4 alkoxy, -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , CN, or C 3-6 cycloalkyl.
  • R 7 , R 8 , and R 9 are independently H, halogen, -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo-C 1-4 alkyl, C 1-4 alkoxy , or halo-C 1-4 alkoxy; in some embodiments, R 7 , R 8 , and R 9 are independently H, halogen, -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo- C 1-4 alkyl, C 1-4 alkoxy, or halo-C 1-4 alkoxy; in some embodiments, R 7 is H or halogen; in some embodiments, R 8 is halogen, OH, NH 2 , -NHC 1-4 alkyl, -N(
  • Y is C 1-2 alkylene, O or NR y ; in some embodiments, Y is O; in some embodiments, Y is NH; in some embodiments, Y is methylene or ethylene;
  • M is C 1-2 alkylene, O or NR m ; in some embodiments, M is NH; in some embodiments, M is methylimino, ethylimino, propylimino or isopropylimino;
  • the above groups are optionally substituted by 1-3 groups selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, halo-C 1-4 alkoxy, OH, NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 and halo-C 1-4 alkyl;
  • R is a 4-10 membered saturated heterocycloalkyl group containing 1-3 heteroatoms selected from N, S, and O, and is optionally substituted by 1-3 groups selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, OH, NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , and halo-substituted C 1-4 alkyl;
  • the pharmaceutical composition or pharmaceutical preparation comprises 1-1000 mg of active ingredient M, and the excipient comprises one or more of a filler, a binder, a glidant, a lubricant, and a disintegrant;
  • the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 5-600 mg of active ingredient M;
  • the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 5-400 mg of active ingredient M;
  • the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 20-800 mg of active ingredient M;
  • the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 20-400 mg of active ingredient M;
  • the pharmaceutical composition or pharmaceutical preparation of the present invention comprises 10 mg of active ingredient M;
  • the pharmaceutical composition or pharmaceutical preparation of any one of the embodiments of the present invention comprises the active ingredient M and a pharmaceutical excipient in any of the foregoing embodiments, wherein the content of the active ingredient M is 0.5%-99%; in some embodiments, 1%-90%; in some embodiments, 1%-80%; in some embodiments, 1%-70%; in some embodiments, 1%-60%; in some embodiments, 1%-50%; in some embodiments, 1%-40%; in some embodiments, 1%-30%; in some embodiments, 1%-20%; in some embodiments, 1%-10%; in some embodiments, 5%-90%; in some embodiments, 5%-80%; in some embodiments, 5%-70%; in some embodiments, 5 %-60%; in some embodiments, 5%-45%; in some embodiments, 5%-40%; in some embodiments, 5%-30%; in some embodiments, 5%-20%; in some embodiments, 5%-10%; in some embodiments, 10%-90%; in some embodiments, 10%-80%; in
  • Any pharmaceutical composition or pharmaceutical preparation of the present invention comprises the active ingredient M in any of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, and a disintegrant.
  • the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, and a disintegrant.
  • any pharmaceutical composition or pharmaceutical preparation of the present invention comprises the active ingredient M in any of the aforementioned embodiments and a pharmaceutical excipient, wherein the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and a pH regulator.
  • the pharmaceutical excipient comprises a filler, a binder, a glidant, a lubricant, a disintegrant, and a pH regulator.
  • the present invention relates to a pharmaceutical composition and a pharmaceutical preparation, wherein the binder is selected from one or more of povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethyl cellulose or sodium carboxymethyl cellulose; in some embodiments, the binder is selected from one or more of hydroxypropyl methylcellulose, methylcellulose or sodium carboxymethyl cellulose; in some embodiments, the binder is selected from hydroxypropyl methylcellulose.
  • the present invention relates to a pharmaceutical composition and a pharmaceutical preparation, wherein the glidant is selected from one or more of talc, silicon dioxide, micro-powder silica gel, polyethylene glycol or magnesium dodecyl sulfate; in some embodiments, the glidant is selected from one or more of silicon dioxide or micro-powder silica gel; in some embodiments, the glidant is selected from colloidal silicon dioxide.
  • the present invention relates to a pharmaceutical composition and a pharmaceutical preparation.
  • the surfactant is selected from sodium lauryl sulfate.
  • the present invention relates to a pharmaceutical composition and a pharmaceutical preparation, wherein the pH regulator is selected from magnesium oxide.
  • the present invention relates to a pharmaceutical composition and a pharmaceutical preparation, comprising:
  • active ingredient M in an amount of 0.5%-99%; in some embodiments, 1%-90%; in some embodiments, 1%-80%; in some embodiments, 1%-70%; in some embodiments, 1%-60%; in some embodiments, 1%-50%; in some embodiments, 1%-40%; in some embodiments, 1%-30%; in some embodiments, 1%-20%; in some embodiments, 1%-10%; in some embodiments, 5%-90%; in some embodiments, 5%-80%; in some embodiments, 5%-70%; in some embodiments, 5%-60%; in some embodiments, 5%-45%; in some embodiments, 5%-40 %; in some embodiments, 5%-30%; in some embodiments, 5%-20%; in some embodiments, 5%-10%; in some embodiments, 10%-90%; in some embodiments, 10%-80%; in some embodiments, 10%-70%; in some embodiments, 10%-60%; in some embodiments, 10%-50%; in some embodiments, 10%-40%; in some embodiments, 1%
  • a filler wherein the filler is one or more of microcrystalline cellulose, silicified microcrystalline cellulose or sorbitol, and the content is 10%-90%; in some embodiments, the content is 10%-80%; in some embodiments, the content is 10%-70%; in some embodiments, the content is 10%-60%; in some embodiments, the content is 10%-50%; in some embodiments, the content is 10%-40%; in some embodiments, the content is 10%-30%; in some embodiments, the content is 10%-20%; in some embodiments, the content is 30%-80%; in some embodiments, the content is 40%-80%; in some embodiments, the content is 37%; in some embodiments, the content is 40%; in some embodiments, the content is 72.5%; in some embodiments, the content is 80%;
  • a binder wherein the binder is one or more of hydroxypropyl methylcellulose, methylcellulose or sodium carboxymethylcellulose, and the content is 1%-50%; in some embodiments, the content is 1%-40%; in some embodiments, the content is 1%-30%; in some embodiments, the content is 1%-20%; in some embodiments, the content is 1%-15%; in some embodiments, the content is 1%-10%; in some embodiments, the content is 1%-6%; in some embodiments, the content is 1%-5%; in some embodiments, the content is 1%-4%; in some embodiments, the content is 1%-3%; in some embodiments, the content is 1%-2.5%; in some embodiments, the content is 1.5%-2.5%; in some embodiments, the content is 2%-2.5%; in some embodiments, the content is 2%; in some embodiments, the content is 2.5%; in some embodiments, the content is 3%;
  • a glidant which is one or more of silicon dioxide or micro-powdered silica gel, and has a content of 0.5%-10%; in some embodiments, the content is 0.5%-5%; in some embodiments, the content is 0.5%-4%; in some embodiments, the content is 0.5%-3%; in some embodiments, the content is 0.5%-2%; in some embodiments, the content is 1%-2%; in some embodiments, the content is 0.5%; in some embodiments, the content is 1%; in some embodiments, the content is 2%; in some embodiments, the content is 3%;
  • the lubricant is sodium stearyl fumarate, the content is 0.1%-10%; in some embodiments, the content is 0.1%-8%; in some embodiments, the content is 0.1%-6%; in some embodiments, the content is 0.1%-5%; in some embodiments, the content is 0.5%-2.0%; in some embodiments, the content is 0.5%-1%; in some embodiments, the content is 0.5%; in some embodiments, the content is 0.6%; in some embodiments, the content is 0.7%; in some embodiments, the content is 0.8%; in some embodiments, the content is 0.9%; in some embodiments, the content is 1.0%.
  • the solubilizer is one or more of cyclodextrin or hydroxypropyl beta-cyclodextrin, and the content is 5%-50%; in some embodiments, the content is 10%-50%; in some embodiments, the content is 10%-45%; in some embodiments, the content is 10%-40%; in some embodiments, the content is 30%-50%; in some embodiments, the content is 30%-45%; in some embodiments, the content is 10%; in some embodiments, the content is 20%; in some embodiments, the content is 30%; in some embodiments, the content is 32%; in some embodiments, the content is 40%; in some embodiments, the content is 42.5%; in some embodiments, the content is 45%;
  • the surfactant is sodium dodecyl sulfate, and the content is 1%-40%; in some embodiments, the content is 1%-30%; in some embodiments, the content is 1%-20%; in some embodiments, the content is 5%-20%; in some embodiments, the content is 10%-20%; in some embodiments, the content is 10%-15%; in some embodiments, the content is 5%; in some embodiments, the content is 10%; in some embodiments, the content is 15%; in some embodiments, the content is 20%;
  • the pH adjuster is magnesium oxide, and the content is 1%-50%; in some embodiments, the content is 10%-50%; in some embodiments, the content is 1%-10%; in some embodiments, the content is 1%-9%; in some embodiments, the content is 1%-8%; in some embodiments, the content is 1%-6%; in some embodiments, the content is 1%-5%; in some embodiments, the content is 1%; in some embodiments, the content is 2%; in some embodiments, the content is 2.5%; in some embodiments, the content is 3%; in some embodiments, the content is 4%; in some embodiments, the content is 5%.
  • the pharmaceutical preparation as described above is characterized in that the binder can be added in a solution state or in a powder state; the disintegrant can be added internally, externally, or both internally and externally.
  • the present invention also provides an application of a pharmaceutical composition or a pharmaceutical preparation in preparing drugs related to treating cancer.
  • the formulation specifications of the pharmaceutical composition or pharmaceutical preparation of the present invention include but are not limited to 1-1000 mg, 2-1000 mg, 3-1000 mg, 4-1000 mg, 5-1000 mg, 6-1000 mg, 10-1000 mg, 20-1000 mg, 25-1000 mg, 30-1000 mg, 40-1000 mg, 50-1000 mg, 60-1000 mg, 70-1000 mg, 75-1000 mg, 80-1000 mg, 90-1000 mg, 100-1000 mg, 200-1000 mg, 300-1000 mg, 400-1000 mg, 1000mg, 1-900mg, 2-900mg, 3-900mg, 4-900mg, 5-900mg, 6-900mg, 10-900mg, 20-900mg, 25-900mg, 30-900mg, 40-900mg, 50-900mg, 60-900mg, 70-900mg, 75-900mg, 80-900mg, 90-900mg, 100-900mg, 200-900mg, 300-900mg, 400-900mg, 1-800mg, 2-800mg, 3-1000 mg, 4-
  • Alkoxy refers to -O-alkyl.
  • -OC 1-8 alkyl For example, -OC 1-8 alkyl, -OC 1-6 alkyl, -OC 1-4 alkyl or -OC 1-2 alkyl.
  • Specific non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyloxy and cyclobutyloxy, etc.; the alkoxy group may be optionally substituted with a substituent.
  • alkenyl group may be optionally further substituted by a substituent.
  • Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl and 4-decynyl, etc.; the alkynyl group may be optionally substituted with a substituent.
  • Cycloalkyl refers to a saturated or partially unsaturated, non-aromatic carbocyclic hydrocarbon group that does not contain ring heteroatoms. Cycloalkyl can be monocyclic, bicyclic or polycyclic. The bicyclic or polycyclic rings can be cyclic, spirocyclic, bridged or a combination thereof. The bicyclic or polycyclic rings can include one or more aromatic rings, but the ring system as a whole is not aromatic, and the connection site can be on the aromatic ring or on the non-aromatic ring.
  • Carbocycle or “carbocyclyl” refers to a saturated, partially unsaturated, or aromatic carbocycle, including aryl and cycloalkyl.
  • the carbocycle can be monocyclic, bicyclic or polycyclic, including bridged rings, cyclocyclic rings and spirocyclic rings and their combinations.
  • the carbocycle usually has 3 to 12 carbon atoms, or 3-10 carbon atoms, or 3-6 carbon atoms.
  • the heterocycloalkyl group is a 3-20-membered ring.
  • it is usually a 3-15-membered ring, or a 3-10-membered ring, or a 3-8-membered ring, or a 3-6-membered ring;
  • it is a bicyclic or polycyclic heterocycloalkyl group, it is usually a 5-12-membered ring, or a 5-11-membered ring, or a 6-9-membered ring.
  • the heteroatoms N and S therein include their oxidation states.
  • heterocycloalkyl examples include azetidinyl, morpholinyl, piperazinyl, piperidinyl, tetrahydropyranyl, oxetanyl, pyranyl, azocycloolyl, azocyclohexenyl, oxolyl, oxenyl, and the like, and the heterocycloalkyl may be optionally substituted with a substituent.
  • Heterocycle or “heterocyclyl” refers to a saturated or unsaturated, aromatic or non-aromatic ring containing 1 to 4 heteroatoms selected from N, O or S and their oxidation states, and its meaning includes heteroaryl and heterocycloalkyl. Heterocycles include monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic heterocycles and bicyclic spiro heterocycles or their combinations. It is usually a 3-12 membered heterocycle or a 5-12 membered heterocycle, or a 5-7 membered heterocycle.
  • the heterocyclic group may be attached to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, piperazinyl, azepanyl, pyridinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl , dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazoly
  • Heterocyclylene refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic divalent heterocyclic group. Non-limiting examples include wait.
  • the spiro ring is a trispirotri (indicating a three-membered ring spirotricyclic ring), a trispirotetra, a trispiropenta, a trispirohexa, a tetraspirotetra, a tetraspiropenta, a tetraspirohexa, a pentaspiropenta or a pentaspirohexa.
  • spiro rings include The spiro ring may be optionally substituted with a substituent.
  • alkyl optionally substituted with F means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.
  • “Pharmaceutically acceptable salt” refers to a salt of the compound of the present invention which retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.
  • Preparation specifications refers to the weight of the main drug contained in each vial, tablet or other unit preparation.
  • Carrier refers to a system that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug and deliver the drug to the targeted organ.
  • Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.
  • Excipient refers to a substance that is not a therapeutic agent in itself but is used as a diluent, adjuvant, binder and/or vehicle and is added to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate the formation of a compound or pharmaceutical composition into a unit dosage form for administration.
  • pharmaceutical excipients can serve a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents and sweeteners.
  • glycols such as propylene glycol
  • polyols such as glycerol, sorbitol, mannitol and polyethylene glycol
  • esters such as ethyl oleate and ethyl laurate
  • agar such as agar
  • buffers such as magnesium hydroxide and aluminum hydroxide
  • Co-crystal refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components.
  • Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF 254 or Qingdao GF 254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;
  • RuPhos-Pd-G3 Catalyst with CAS No. 1445085-77-7.
  • Step 1 In a 50 mL reaction bottle, 1A (800 mg, 5.99 mmol), triethylamine (1.82 g, 17.97 mmol) and dichloromethane (10 mL) were added in sequence. After the addition, the mixture was stirred at 0°C for 20 minutes, and a dichloromethane (7 mL) solution of aminosulfonyl chloride (692 mg, 5.99 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 1 h.
  • Step 2 In a 50 mL reaction bottle, 1C (250 mg, 0.8 mmol, preparation method refer to WO2021116050A1), 1B (160 mg, 0.9 mmol), cesium carbonate (310 mg, 0.96 mmol) and N, N-dimethylformamide (10 mL) were added in sequence. After the addition, the mixture was stirred at 80 ° C for 18 hours. Ethyl acetate (50 mL) was added to the reaction solution, and then washed with water (40 mL ⁇ 2). The organic layer was washed with The residue was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • 1C 250 mg, 0.8 mmol, preparation method refer to WO2021116050A1
  • 1B 160 mg, 0.9 mmol
  • cesium carbonate 310 mg, 0.96 mmol
  • N, N-dimethylformamide 10 mL
  • Step 1 In a 50 mL reaction bottle, 2A (520 mg, 4.34 mmol), triethylamine (2.19 g, 21.64 mmol) and dichloromethane (10 mL) were added in sequence. After the addition, the mixture was stirred at 0°C for 20 minutes, and a solution of aminosulfonyl chloride (500 mg, 4.34 mmol) in dichloromethane (7 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 1 h.
  • 2A 520 mg, 4.34 mmol
  • triethylamine 2.19 g, 21.64 mmol
  • dichloromethane 10 mL
  • Step 2 Referring to the reaction operation of step 2 of Example 1, compound 2 (60 mg, yield 16%) was obtained by separation and purification.
  • Step 1 In a 250 mL nitrogen-protected three-necked flask, 4A (4.0 g, 26.08 mmol) was dissolved in dry tetrahydrofuran (80 mL), triphosgene (2.94 g, 9.91 mmol) was slowly added under an ice bath, and the mixture was stirred at 70°C for 4 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the residue was purified by slurrying with petroleum ether, and the solid was filtered and dried to obtain 4B (3.86 g, yield
  • Step 4 In a 100 mL single-mouth bottle, 4D (2.4 g, 12.49 mmol) was dissolved in dry N, N-dimethylformamide (40 mL). Cesium carbonate (4.88 g, 14.99 mmol) was slowly added under an ice bath. After the addition, the mixture was stirred at room temperature for 0.5 h. Under an ice bath, a solution of 2,3,6-trifluorobenzonitrile (2.32 g, 14.99 mmol) in N, N-dimethylformamide (10 mL) was slowly added dropwise. After the addition, the mixture was stirred at room temperature for 1 h.
  • reaction solution was poured into ice water (250 mL), stirred for 30 min, filtered, and the obtained solid was dried and purified by slurrying with a mixed solvent of petroleum ether (100 mL) and ethyl acetate (10 mL). The solid was filtered and dried to obtain 4E (3.6 g, yield 88%).
  • Step 2 Referring to the second step of Example 1, compound 5 (12 mg, yield 1%) was obtained by synthesis, separation and purification.
  • Step 1 In a 50 mL reaction bottle, add 6A (synthesis method reference: WO2017/1660, 2017, A1) (620 mg, 5.38 mmol), triethylamine (1633.21 mg, 16.14 mmol) and dichloromethane (20 mL) in sequence, stir at 0 ° C for 20 minutes after addition, slowly drop aminosulfonyl chloride (622 mg, 5.38 mmol) in dichloromethane (10 mL) solution, and stir at room temperature for 1-2 hours.
  • 6A synthesis method reference: WO2017/1660, 2017, A1
  • 6A synthesis method reference: WO2017/1660, 2017, A1
  • triethylamine (1633.21 mg, 16.14 mmol
  • dichloromethane 20 mL
  • Step 2 Referring to the second step of Example 1, compound 6 (8 mg, yield 1%) was obtained by synthesis, separation and purification.
  • Step 1 Refer to step 2 of Example 1 for synthesis, separation and purification to obtain compound 7 (58 mg, yield: 8%).
  • Step 1 Refer to step 2 of Example 1 for synthesis, separation and purification to obtain compound 8 (0.3 g, yield: 42%).
  • Step 1 Add 9A (25 g, 184.46 mmol) and sodium formate (15.55 g, 21.51 mmol) into a 250 mL single-necked bottle and react at 130° C. for 2 hrs. After the reaction is complete, cool to room temperature and filter to obtain 9B (22.0 g, yield 94%).
  • Step 2 In a 250 mL single-necked bottle, 2-amino-5-hydroxybenzoic acid (1.0 g, 6.52 mmol) was added to 9B (6 mL, 36.2 mmol) and reacted at 150°C for 21 hrs. After the reaction was complete, it was cooled to room temperature and filtered. The filter cake was washed twice with ethyl acetate (1 mL), and then the filter cake was concentrated to obtain 9C (1.3 g, yield 82%).
  • Step 1 Add 10A (20 g, 184.46 mmol) to ethyl formate (20 mL) and react overnight at 55° C. After the reaction is complete, cool to room temperature and concentrate the reaction solution to obtain the residue 10B (3.1 g, yield 12%).
  • Step 2 In a 25 mL single-mouth bottle, 2-amino-5-hydroxybenzoic acid (0.5 g, 3.31 mmol) was added to 10B (3.1 mL, 28.4 mmol) and reacted at 150°C for 21 hours. After the reaction was complete, it was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (0.5 mL ⁇ 2), and then the filter cake was concentrated to obtain 10C (0.70 g, yield 94%).
  • Step 3 In a 25 mL single-mouth bottle, 10C (0.70 g, 3.09 mmol) was dissolved in dry N, N-dimethylformamide (6 mL). Cesium carbonate (2.01 g, 6.17 mmol) was slowly added under an ice bath. After the addition, the reaction was stirred at room temperature for 0.5 h. In an ice bath, 2,3,6-trifluorobenzonitrile (0.51 g, 3.20 mmol) was slowly added dropwise. After the addition, the reaction was stirred at room temperature overnight.
  • Step 4 In a 25 mL single-mouth bottle, 10E (0.50 g, 1.38 mmol) was dissolved in dry N, N-dimethylformamide (5 mL), and cesium carbonate (0.90 g, 2.76 mmol) and 1B (0.24 g, 1.38 mmol) were slowly added under an ice bath, and stirred at 100 ° C for 4 hours.
  • Step 2 In a 100 mL reaction bottle, 11B (7.0 g, 82.26 mmol) and 4A (1.5 g, 9.83 mmol) were added in sequence, and stirred at 145 °C for 10 hours. After the reaction was completed, the mixture was filtered and the obtained solid was purified by slurrying with ethyl acetate. The solid was filtered and dried to obtain 11C (1.5 g, yield 75%).
  • Step 3 In a 100 mL reaction bottle, 11C (1.5 g, 7.42 mmol) was dissolved in dry N,N-dimethylformamide (20 mL), and cesium carbonate (3.63 g, 11.13 mmol) was added under ice bath, and the mixture was reacted at room temperature for 0.5 h. A solution of 2,3,6-trifluorobenzonitrile (1.28 g, 8.16 mmol) in N,N-dimethylformamide (15 mL) was slowly added dropwise under ice bath, and the mixture was reacted at room temperature for 2 h.
  • Step 2 In a 50 mL reaction bottle, 1C (1.58 g, 5.04 mmol), 13B (500 mg, 2.52 mmol), cesium carbonate (2.46 g, 7.62 mmol) and N,N-dimethylformamide (15 mL) were added in sequence. After the addition, the mixture was stirred at 100 °C for 12 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure.
  • Step 2 In a 50 mL reaction bottle, 1C (490 mg, 1.56 mmol), 14B (0.30 g crude product), cesium carbonate (1.52 mg, 4.67 mmol) and N,N-dimethylformamide (5 mL) were added in sequence. After the addition, the mixture was stirred at 100 °C for 18 hours. Ethyl acetate (50 mL) was added to the reaction solution, which was then washed with water (40 mL ⁇ 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 3 In a 100 mL single-mouth bottle, 15D (crude product) was dissolved in dry N,N-dimethylformamide (10 mL). Cesium carbonate (2.27 g, 6.97 mmol) and 1C (300 mg, 0.96 mmol) were slowly added under ice bath, and the mixture was stirred at 100 °C for 6 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to obtain an oily liquid.
  • Step 1 In a 100 mL single-mouth bottle, 3-(trifluoromethyl)azetidine hydrochloride (16A) (0.25 g, 1.55 mmol) was dissolved in dry acetonitrile (15 mL), and 15B (0.47 g, 1.55 mmol) was added. After the addition, the mixture was stirred at 30°C for 1 h. After the reaction was complete, the reaction solution was concentrated to obtain a solid, which was the crude compound 16C. No purification was required and the next step was carried out directly.
  • Step 2 Compound 16C (crude product) and dichloromethane (12 ml) were added to a single-necked bottle, and trifluoroacetic acid (3 ml) was added, and the mixture was reacted at room temperature for 2 hours. After concentration, compound 16D was obtained, which was directly used for the next step without purification.
  • Step 3 In a 100 mL single-mouth bottle, 16D (crude product) was dissolved in dry N,N-dimethylformamide (10 mL). Cesium carbonate (2.02 g, 6.20 mmol) and 1C (300 mg, 0.96 mmol) were slowly added under ice bath, and the mixture was stirred at 100 °C for 6 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to obtain an oily liquid.
  • Step 1 In a 100 mL single-mouth bottle, 2-azabicyclo[3.1.0]hexane hydrochloride (17A) (0.47 g, 3.97 mmol) was dissolved in dry acetonitrile (25 mL), and 15B (1.2 g, 3.97 mmol) was added. After the addition, the mixture was stirred at 70°C for 4 h. After the reaction was complete, the reaction solution was concentrated to obtain a solid, which was the crude compound 17B. The crude compound 17B was directly used for the next step without purification.
  • 2-azabicyclo[3.1.0]hexane hydrochloride (17A) (0.47 g, 3.97 mmol) was dissolved in dry acetonitrile (25 mL), and 15B (1.2 g, 3.97 mmol) was added. After the addition, the mixture was stirred at 70°C for 4 h. After the reaction was complete, the reaction solution was concentrated to obtain a solid, which was the crude compound 17B. The crude compound 17
  • Step 3 In a 100 mL single-mouth bottle, 17C (217 mg, 1.34 mmol) was dissolved in dry N,N-dimethylformamide (10 mL). Cesium carbonate (655 mg, 2.01 mmol) was slowly added under ice bath, and the mixture was stirred at 50°C for 0.5 h. In an ice bath, a solution of 1C (420 mg, 1.34 mmol) in N,N-dimethylformamide (5 mL) was slowly added dropwise, and the mixture was stirred at 100°C for 2 h.
  • reaction solution was filtered and the filtrate was concentrated to obtain an oily liquid which was separated and purified by preparative liquid chromatography (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm ⁇ 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1/1000 trifluoroacetic acid); gradient: 20%-80% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 17 (56 mg, yield: 9%).
  • preparative liquid chromatography instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm ⁇ 150 mm
  • mobile phase composition mobile phase A: acetonitrile
  • mobile phase B water (containing 1/1000 trifluoroacetic acid); gradient: 20%-80% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 17 (56 mg, yield: 9%).
  • Step 1 In a 50 mL reaction bottle, 18A (500 mg, 5.08 mmol), triethylamine (1.54 g, 15.24 mmol) and dichloromethane (10 mL) were added in sequence, stirred at 0°C for 20 minutes, and a solution of aminosulfonyl chloride (1.17 g, 10.16 mmol) in dichloromethane (7 mL) was slowly added dropwise, and stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain 18B (500 mg, crude product).
  • Step 2 In a 50 mL reaction bottle, 1C (1.76 g, 5.62 mmol), 18B (500 mg, 2.81 mmol), cesium carbonate (2.75 g, 8.37 mmol) and N,N-dimethylformamide (15 mL) were added in sequence. After the addition, the mixture was stirred at 100 °C for 12 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure.
  • Step 1 In a 50 mL reaction bottle, 19A (500 mg, 4.49 mmol), triethylamine (1.36 g, 13.47 mmol) and dichloromethane (10 mL) were added in sequence. After the addition, the mixture was stirred at 0°C for 20 minutes, and a solution of aminosulfonyl chloride (520 mg, 4.49 mmol) in dichloromethane (7 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 1-2 h.
  • Step 2 In a 100 mL reaction bottle, 1C (0.9 g, 2.87 mmol), 19B (0.6 g, 3.16 mmol), cesium carbonate (1.12 g, 3.44 mmol) and N,N-dimethylformamide (20 mL) were added in sequence. After the addition, the mixture was stirred at 80 °C for 18 hours. Ethyl acetate (100 mL) was added to the reaction solution, and then washed with water (40 mL ⁇ 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 1 Take a 500mL reaction bottle, dissolve trimethyl sulfoxide iodide (100.45g, 456.62mmol) in tert-butanol (350mL) at room temperature, then add potassium tert-butoxide (45.0g, 401.83mmol), react at 50°C for 1h, then cool to room temperature, slowly add 20A (40.0g, 182.65mmol), after the addition is complete, react at 50°C for 48h. After the reaction was complete, saturated ammonium chloride solution (20 mL) was added to quench, water (50 mL) was added, and ethyl acetate (150 mL ⁇ 2) was used for extraction.
  • Preparative chromatographic separation conditions instrument SFC Prep 150AP; chromatographic column: Daicel AD-H (19 mm ⁇ 250 mm); mobile phase system: A for CO 2 and B for MeOH; gradient: B 10%; 5. flow rate: 45 mL/min.
  • Step 4 In a 50mL reaction bottle, add 1C (407.4mg, 1.30mmol), 20D (500mg, 2.60mmol), cesium carbonate (813.8mg, 2.60mmol) and N,N-dimethylformamide (10mL) in sequence at room temperature, and stir at 100°C for 12 hours after addition. After the reaction is complete, add water (10mL) and extract with ethyl acetate (30mL ⁇ 2). The combined organic phase is washed with saturated brine (10mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and the residue is prepared by preparative liquid phase after the filtrate is concentrated. HPLC separation method: 1.
  • Step 2 In a 100 mL reaction bottle, 22B (0.6 g, 3.01 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium ethanethiolate (0.50 g, 5.94 mmol) was added. The reaction solution was replaced with nitrogen three times, and then heated to 130 °C for 10 hours. After the reaction was completed, the solution was filtered and the filtrate was concentrated to obtain 22C (0.45 g, yield 80%).
  • Step 3 In a 100 mL reaction bottle, 22C (0.45 g, 2.43 mmol) was dissolved in N, N-dimethylformamide (10 mL), and cesium carbonate (1.20 g, 3.75 mmol) was slowly added in an ice-water bath. After stirring at room temperature for 0.5 hours, a solution of 2,3,6-trifluorobenzonitrile (0.38 g, 2.43 mmol) in N, N-dimethylformamide (5 mL) was slowly added dropwise in an ice-water bath, and reacted at room temperature for 1 hour.
  • Step 4 In a 100 mL reaction bottle, 22D (0.25 g, 0.78 mmol), 1B (0.21 g, 1.17 mmol), cesium carbonate (0.51 g, 1.56 mmol) and N,N-dimethylformamide (15 mL) were added in sequence. After the addition, the mixture was stirred at 100 °C for 12 hours. Ethyl acetate (30 mL) was added to the reaction solution, which was then washed with water (30 mL ⁇ 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 1 23A (1.00 g, 9.11 mmol) and acetic acid (15 mL) were added to a single-mouth bottle, followed by 3-ethoxy-2-methyl-2-propenoic acid ethyl ester (2.88 g, 18.22 mmol), and heated under reflux for 16 hours. After the reaction was completed as monitored by LCMS, the acetic acid was removed by rotation, and the remaining solid was slurried with ethyl acetate (20 mL). The solid was filtered and dried to obtain the product 23B (1.2 g, 74.7%).
  • Step 2 23B (0.20 g, 1.14 mmol) was dissolved in N,N-dimethylformamide (5 mL), and then cesium carbonate (0.74 g, 2.27 mmol) was added. 2,3,6-trifluorobenzonitrile (0.23 g, 1.48 mmol) was added under stirring at 0°C, and the temperature was slowly raised to room temperature for 2 h. After the reaction was completed, the reaction solution was poured into water (15 mL) to precipitate a large amount of solid, which was filtered and dried to obtain product 23C (0.12 g, 33.6%).
  • Step 1 In a 50 mL reaction bottle, 24A (1.2 g, 10.95 mmol), triethylamine (3.32 g, 32.85 mmol) and acetonitrile (20 mL) were added in sequence, stirred for 30 minutes after the addition, 15B (4.97 g, 16.43 mmol) was slowly added dropwise, and stirred at 40 degrees Celsius for 3 hours. The reaction solution was concentrated under reduced pressure to obtain 24B (1 g, crude product).
  • Step 2 In a 50 mL reaction bottle, 24B (0.8 g, 3.17 mmol) and dichloromethane (6 mL) were added in sequence, trifluoroacetic acid (2 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain 24C (0.8 g, crude product).
  • Step 3 In a 50 mL reaction bottle, 24C (0.8 g, 5.26 mmol), cesium carbonate (2.57 g, 7.89 mmol) and N,N-dimethylformamide (15 mL) were added in sequence, and the mixture was stirred at 50 °C for 2 hours, and then 4E (2.08 g, 6.31 mmol) was added, and the mixture was stirred at 80 °C for 12 hours.
  • reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by preparative liquid phase (instrument: waters2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm ⁇ 150 mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing one thousandth of trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to obtain compound 24 (91.8 mg, yield 3.79%).
  • preparative liquid phase instrument: waters2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm ⁇ 150 mm
  • mobile phase composition mobile phase A: acetonitrile
  • mobile phase B water (containing one thousandth of trifluoroacetic acid)
  • gradient 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes
  • Step 2 In a 20 mL microwave tube, 26A (1.5 g, 8.58 mmol) was dissolved in triethyl orthoformate (10 mL), the reaction solution was heated to 185 °C for 2 hours, and after the reaction was completed, the reaction mixture was filtered and the filter cake was dried to obtain 26B (1.6 g, yield 89%).
  • Step 3 In a 100 mL reaction bottle, 26B (1.5 g, 7.20 mmol) was dissolved in N, N-dimethylformamide (20 mL), and cesium carbonate (3.52 g, 10.80 mmol) was slowly added in an ice-water bath. After stirring at room temperature for 30 minutes, a solution of 2,3,6-trifluorobenzonitrile (1.36 g, 8.64 mmol) in N, N-dimethylformamide (5 mL) was slowly added dropwise in an ice-water bath. After the addition was complete, the mixture was reacted at room temperature for 2 hours.
  • Step 1 In a 100 mL single-mouth bottle, 27A (1.0 g, 8.96 mmol) was dissolved in dry acetonitrile (15 mL), and 15B (2.71 g, 8.96 mmol) and triethylamine (1.81 g, 17.96 mmol) were added and stirred at 30°C for 1 h. After the reaction was complete, the reaction solution was concentrated to obtain a solid, which was compound 27C, which was directly used for the next step without purification.
  • Step 3 In a 100 mL single-mouth bottle, 27D (0.45 g, 2.92 mmol) was dissolved in dry N, N-dimethylformamide (6 mL), and cesium carbonate (0.95 g, 2.92 mmol) and 4E (800 mg, 2.43 mmol) were slowly added and stirred at 80 ° C for 6 h. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to obtain an oily liquid.
  • the reaction solution was filtered, the filter cake was added with N, N-dimethylformamide (4 mL), the filtrate was concentrated, and then dissolved with water (15 mL) and ethyl acetate (10 mL).
  • the aqueous phase was extracted once with ethyl acetate (10 mL), and the pH was adjusted to about 7 with a saturated ammonium chloride solution.
  • the aqueous phase was extracted with dichloromethane (20 mL ⁇ 3), and the organic phase was dried and concentrated with anhydrous sodium sulfate to obtain a crude product of 40A, which was directly used for the next step.
  • Step 2 The crude product 40A was separated by chiral SFC to obtain P1 (retention time: 14.73 min, set as compound 40) and P2 (retention time: 24.02 min, set as compound 41).
  • Separation method Instrument name: Waters 150SFC; Chromatographic column: AD; Mobile phase: A for CO 2 and B for IPA+MeOH (0.05% NH 3 ⁇ H 2 O); Flow rate: 42 mL/min; Column pressure: 100 bar; Column temperature: 25°C; Absorption wavelength: 220 nm Cycle time: 40 min).
  • Step 3 In a 25 mL single-necked bottle, add 42C (0.250 g, 1.18 mmol) and cesium carbonate (0.577 g, 1.77 mmol) to dry N,N-dimethylformamide (5 mL), and react at 50 ° C for 30 min. Then, add 10E (0.429 g, 1.18 mmol) in N,N-dimethylformamide (2 mL) dropwise at 50 ° C. After the addition, stir and react at 80 ° C overnight.
  • reaction solution was filtered and the filtrate was purified by preparative liquid phase purification (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 150mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1/1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to separate and purify compound 42 (110 mg, yield 17%).
  • preparative liquid phase purification instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 150mm
  • mobile phase composition mobile phase A: acetonitrile
  • mobile phase B water (containing 1/1000 trifluoroacetic acid)
  • gradient 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes
  • Step 1 In a 100 mL single-mouth bottle, 10C (700 mg, 3.09 mmol), 39A (720 mg, 3.09 mmol), and cesium carbonate (1.53 g, 4.63 mmol) were dissolved in dry N,N-dimethylformamide (25 mL), and stirred at room temperature for 2 h.
  • Step 3 In a 100 mL single-necked bottle, 43D (800 mg, 1.81 mmol), 1B (400 mg, 2.26 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (154 mg, 0.36 mmol), allylpalladium chloride (99 mg, 0.27 mmol), and potassium carbonate (625 mg, 4.25 mmol) were dissolved in dry methyltetrahydrofuran (40 mL). After the addition, nitrogen was replaced and the reaction was stirred at 70 °C for 5 h.
  • Step 1 44A (4.5 g, 23.13 mmol) and isopropanol (50 mL) were added to a 250 mL single-mouth bottle, and then triethylamine (4.68 g, 46.26 mmol) and isopropanolamine (2.08 g, 27.76 mmol) were added, and the mixture was reacted at 80°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated, slurried with ethyl acetate (50 mL), filtered, and the filter cake was washed with petroleum ether (50 mL) to obtain 44B (5.30 g, yield 98%).
  • Step 6 In a 25 mL single-necked bottle, 1B (0.21 g, 1.16 mmol) and cesium carbonate (0.47 g, 1.46 mmol) were added to dry N,N-dimethylformamide (5 mL), and reacted at 50 ° C for 30 min. Then, a solution of 44F (0.36 g, 0.97 mmol) in N,N-dimethylformamide (1 mL) was added dropwise at 50 ° C. After the addition, the mixture was stirred at 80 ° C for 4 hrs. After the reaction was completed, the reaction solution was filtered and the filter cake was washed with N,N-dimethylformamide (2 mL).
  • Step 1 45A (10 g, 61.33 mmol) and N,N-dimethylformamide (100 mL) were added to a 250 mL single-mouth bottle, and N,N-diisopropylethylamine (15.85 g, 122.64 mmol) and 1-fluoro-2-iodoethane (12.80 g, 73.63 mmol) were slowly added dropwise at 0-5°C, and reacted at 80°C overnight. After the reaction was complete, the reaction solution was added dropwise to water (500 mL), and a large amount of solid precipitated. After stirring for 30 minutes, the mixture was filtered, and the filter cake was washed with water (100 mL) and petroleum ether (50 mL), and the filter cake was concentrated to obtain 45B (10.0 g, yield 78%).
  • Step 2 In a 500 mL single-mouth bottle, 45B (10 g, 47.81 mmol) was dissolved in dichloromethane (260 mL) and methanol (26 mL), and hydrazine hydrate (5.98 g, 95.62 mmol) was slowly added dropwise at room temperature. After the addition, the mixture was reacted at room temperature for 2.5 hrs.
  • reaction solution was filtered, the filtrate was washed with 5N ammonia water (200 mL), extracted with dichloromethane (200 mL ⁇ 2), the organic phase was dried over anhydrous sodium sulfate and concentrated, the residue was dissolved in ethanol (50 mL), concentrated hydrochloric acid (8 mL) was added, stirred for 30 min and concentrated, the residue was slurried with ethyl acetate (30 mL), and filtered to obtain 45C (1.90 g, yield 34%).
  • Step 4 In a 100 mL single-necked bottle, 45D (0.2 g, 0.93 mmol) was added to triethyl orthoformate (3 mL) and N,N-dimethylformamide (3 mL), and reacted at 150°C for 4 hrs. After the reaction was complete, the mixture was cooled to room temperature and the reaction solution was concentrated to obtain crude 45E, which was directly used for the next step.
  • Step 6 In a 25 mL single-necked bottle, add 1B (0.21 g, 1.20 mmol) and cesium carbonate (0.49 g, 1.5 mmol) to dry N,N-dimethylformamide (8 mL), and react at 50 ° C for 30 min. Then, add 45F (0.36 g, 1.00 mmol) in N,N-dimethylformamide (2 mL) dropwise at 50 ° C. After the addition, stir the reaction at 80 ° C overnight.
  • reaction solution was filtered and the filtrate was purified by preparative liquid phase purification (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 150mm); mobile phase composition: mobile phase A: acetonitrile; mobile phase B: water (containing 1/1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes) to separate and purify compound 45 (83.0 mg, yield 16%).
  • preparative liquid phase purification instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19mm ⁇ 150mm
  • mobile phase composition mobile phase A: acetonitrile
  • mobile phase B water (containing 1/1000 trifluoroacetic acid); gradient: 20%-70% acetonitrile isocratic elution; cycle time: 15 minutes
  • Step 2 In a 25 mL single-mouth bottle, 46A (2.30 g, 6.82 mmol) was dissolved in dry acetonitrile (50 mL), and tert-butyl nitrite (0.71 g, 6.89 mmol) and copper bromide (1.54 g, 6.90 mmol) were slowly added in sequence at 0-5°C, and the reaction was stirred overnight at room temperature after the addition was completed.
  • reaction solution was concentrated, and saturated sodium bicarbonate (100 mL) was added to quench the reaction, and dissolved with ethyl acetate (100 mL), then filtered, and the filtrate was extracted with ethyl acetate (100 mL ⁇ 2), and the organic phase was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated.
  • Step 3 Add 46B (0.80 g, 1.99 mmol), 1B (0.46 g, 2.59 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.10 g, 0.20 mmol), potassium carbonate (0.41 g, 2.98 mmol) and tris(dibenzyl-BASE acetone)dipalladium (0.11 g, 0.19 mmol) to dry 1,4-dioxane (16 mL), blow with nitrogen for 2 min and then react in microwave at 120 °C for 1 hr.
  • Step 1 In a 250 mL single-mouth bottle, compound 5B (0.55 g, 3.39 mmol) was dissolved in dry N,N-dimethylformamide (10 mL), cesium carbonate (1.42 g, 4.36 mmol) was added, and the mixture was reacted at 50°C for 0.5 h. Then, a solution of 26C (1 g, 2.90 mmol) in N,N-dimethylformamide (10 mL) was added dropwise, and the reaction solution was stirred at 85°C for 12 h. After the reaction, ethyl acetate (100 mL) was added, and then washed with water (70 mL ⁇ 2).
  • Step 1 In a 100 mL single-necked bottle, 39D (500 mg, 1.18 mmol), 5B (230 mg, 1.42 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (100 mg, 0.24 mmol), allylpalladium chloride (65 mg, 0.18 mmol), and potassium carbonate (571 mg, 4.13 mmol) were dissolved in dry methyltetrahydrofuran (40 mL). After the addition, nitrogen was replaced and the reaction was stirred at 70 °C for 5 h.
  • Step 1 Dissolve 43D (800 mg, 1.81 mmol), 5B (352 mg, 2.17 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (80 mg, 0.18 mmol), and potassium carbonate (876 mg, 6.33 mmol) in dry 1,4-dioxane (40 mL), add allylpalladium chloride (33 mg, 0.09 mmol), replace nitrogen after addition, and stir at 85°C for 10 h.
  • the inhibition rate of the compound on BRAF V600E was calculated.
  • the Graphpad software log (inhibitor) vs. response--Variable slope (four parameters) equation was used for fitting analysis to calculate the IC 50 value of the sample.
  • the compounds of the present invention such as the compounds in the examples, have very good enzyme activity, with IC 50 ⁇ 100 nM.
  • the inhibitory activity of some compounds on BRAF V600E is shown in Table 1.
  • A indicates IC 50 ⁇ 10 nM
  • B indicates 10 nM ⁇ IC 50 ⁇ 50 nM
  • C indicates 50 nM ⁇ IC 50 ⁇ 100 nM.
  • the compounds of the present invention show high inhibitory activity at the cellular level.
  • mice On the day of the experiment, ICR mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and fed 4 hours after administration.
  • Reference compound 1 is compound Example 1 in document WO2021116055A1;
  • the compounds of the present invention such as the compounds in the examples, have good pharmacokinetic characteristics in mice and have better brain penetration properties than the control compounds.
  • mice Male beagle dogs, about 8-11 kg, 6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.
  • test method On the test day, beagle dogs were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration, and were fed 4 hours after administration. Administration was performed according to Table 5.
  • Reference compound 1 is compound Example 1 in document WO2021116055A1;
  • the compounds of the present invention such as the compounds in the examples, have good pharmacokinetic characteristics in beagle dogs.
  • mice Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • 0.1 ml of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm and 4°C for 10 min to collect plasma.
  • the time points for blood collection in the venous group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h; the time points for blood collection in the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. All samples were stored at -80°C before analysis and testing.
  • Reference compound 1 is compound Example 1 in document WO2021116055A1; -: not applicable.
  • the compounds of the present invention such as the compounds in the examples, have good bioavailability and pharmacokinetic characteristics in rats.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
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Abstract

La présente invention concerne une composition pharmaceutique ou une préparation pharmaceutique. La composition pharmaceutique ou la préparation pharmaceutique comprend une quantité thérapeutiquement efficace d'un principe actif M et d'un excipient pharmaceutiquement acceptable, le principe actif M étant choisi parmi un composé tel que représenté dans la formule générale I ou un stéréoisomère, un tautomère, un produit deutéré, un solvate, un promédicament, un métabolite, un sel pharmaceutiquement acceptable ou un cristal eutectique de celui-ci, et la composition pharmaceutique ou la préparation pharmaceutique comprenant de 1 à 1 000 mg du principe actif M. La présente invention concerne également une utilisation de la composition pharmaceutique ou de la préparation pharmaceutique dans la préparation d'un médicament associé pour le traitement de cancers.
PCT/CN2025/072990 2024-01-17 2025-01-17 Composition pharmaceutique comprenant un inhibiteur de braf et utilisation d'une composition pharmaceutique en médecine Pending WO2025153057A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012118492A1 (fr) * 2011-03-01 2012-09-07 Array Biopharma Inc. Sulfonamides hétérocycliques en tant qu'inhibiteurs de raf
CN111247152A (zh) * 2017-09-20 2020-06-05 璧辰医药技术股份有限公司 作为激酶抑制剂的环状亚氨基嘧啶衍生物
US20200407344A1 (en) * 2019-06-28 2020-12-31 Array Biopharma Inc. Compounds for the treatment of braf-associated diseases and disorders
US20220298119A1 (en) * 2019-12-10 2022-09-22 Hoffmann-La Roche Inc. Methylquinazolinone derivatives
WO2023105371A1 (fr) * 2021-12-08 2023-06-15 Array Biopharma Inc. Forme cristalline de n-(2-chloro-3-((5-chloro-3-méthyl-4-oxo-3,4-dihydroquinazolin-6-yle) amino)-4-fluorophényl)-3-fluoroazétidine-1-sulfonamide
WO2023183470A1 (fr) * 2022-03-24 2023-09-28 Vibliome Therapeutics, Llc Modulateurs de protéines kinases
WO2024017294A1 (fr) * 2022-07-19 2024-01-25 西藏海思科制药有限公司 Préparation et utilisation d'un dérivé de quinazolinone en tant qu'inhibiteur de kinase

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012118492A1 (fr) * 2011-03-01 2012-09-07 Array Biopharma Inc. Sulfonamides hétérocycliques en tant qu'inhibiteurs de raf
CN111247152A (zh) * 2017-09-20 2020-06-05 璧辰医药技术股份有限公司 作为激酶抑制剂的环状亚氨基嘧啶衍生物
US20200407344A1 (en) * 2019-06-28 2020-12-31 Array Biopharma Inc. Compounds for the treatment of braf-associated diseases and disorders
CN114026073A (zh) * 2019-06-28 2022-02-08 Array生物制药公司 用于治疗braf相关的疾病和障碍的喹唑啉-4-酮衍生物
US20220298119A1 (en) * 2019-12-10 2022-09-22 Hoffmann-La Roche Inc. Methylquinazolinone derivatives
WO2023105371A1 (fr) * 2021-12-08 2023-06-15 Array Biopharma Inc. Forme cristalline de n-(2-chloro-3-((5-chloro-3-méthyl-4-oxo-3,4-dihydroquinazolin-6-yle) amino)-4-fluorophényl)-3-fluoroazétidine-1-sulfonamide
WO2023183470A1 (fr) * 2022-03-24 2023-09-28 Vibliome Therapeutics, Llc Modulateurs de protéines kinases
WO2024017294A1 (fr) * 2022-07-19 2024-01-25 西藏海思科制药有限公司 Préparation et utilisation d'un dérivé de quinazolinone en tant qu'inhibiteur de kinase

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