CN116568681A - SOS1 inhibitor, pharmaceutical composition containing same and application thereof - Google Patents

SOS1 inhibitor, pharmaceutical composition containing same and application thereof Download PDF

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CN116568681A
CN116568681A CN202180081795.1A CN202180081795A CN116568681A CN 116568681 A CN116568681 A CN 116568681A CN 202180081795 A CN202180081795 A CN 202180081795A CN 116568681 A CN116568681 A CN 116568681A
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compound
ring
alkyl
pharmaceutically acceptable
cancer
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赵焰平
王红军
张道广
王晓倩
侯翠柳
冯泽旺
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Beijing Tide Pharmaceutical Co Ltd
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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

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Abstract

Description

SOS1 inhibitor, pharmaceutical composition containing same and application thereof Technical Field
The present invention relates to SOS1 inhibitors, pharmaceutical compositions comprising the same, and their use for the prevention or treatment of diseases.
Background
RAS family proteins are small gtpases encoded by the RAS gene, including KRAS (Kirsten murine sarcoma virus oncogene homolog), HRAS (Harvey murine sarcoma virus oncogene) and NRAS (neuroblastoma RAS virus oncogene homolog), and any mutants thereof. In cells, the RAS protein transitions between an inactive and an active state, being in an inactive state when bound to Guanosine Diphosphate (GDP) and being activated when bound to Guanosine Triphosphate (GTP). The intrinsic gtpase activity of RAS proteins is weak and the rate of intrinsic GDP-GTP nucleotide exchange is low, and the transition between inactive and active states is regulated by two classes of factors: gtpase activating proteins (GTPase activating protein, GAP) which catalyze the hydrolysis of GTP bound to RAS proteins to GDP, inactivating RAS proteins; guanine nucleotide exchange factors (Guanine nucleotide exchange factor, GEF), including SOS1 protein (Son of Sevenless 1), etc., catalyze the binding of RAS protein to GTP, thereby promoting activation of RAS protein. The RAS proteins in the activated state can modulate a variety of cellular processes such as cell proliferation, survival, metabolism, motility, angiogenesis, immunity and growth by activating a number of signal transduction pathways such as the RAF/MEK/ERK (MAPK) pathway and PI3K/AKT/mTOR pathway by activating a range of downstream effector proteins including RAF and phosphatidylinositol kinases PI3K, etc. RAS family protein mutations can inhibit their intrinsic gtpase activity and GAP-induced gtpase activity, resulting in sustained activation of the RAS protein, which in turn results in sustained activation of the downstream effector pathways of the RAS protein. RAS is the oncogene in which mutations occur most frequently in human cancers, KRAS mutations (such as G12, G13, and Q61, etc.) are widely present in a variety of human cancers including lung cancer, colorectal cancer, and pancreatic cancer, and HRAS mutations and NRAS mutations also occur in different human cancer types. RAS protein mutation, overexpression and gene amplification are potential drug resistance mechanisms against various anticancer drugs (such as EGFR antibody cetuximab and panitumumab, EGFR tyrosine kinase inhibitor Ornitinib).
SOS proteins were first found in Drosophila, SOS1 being a human homolog of the rope SOS protein. SOS1 protein is a multi-domain protein consisting of 1333 amino acids, consisting of an N-terminal domain, dbl homology Domain (DH), plackstrin substrate protein homology domain (Pleckstrin homology, PH), RAS exchange motif (Ras exchanger motif, REM), CDC25 homology domain and C-terminal domain, wherein REM and CDC25 homology domains together constitute a catalytic domain, which is an essential part of SOS1 protein to exert the catalytic function of guanine nucleotide exchange factor. Studies show that SOS1 plays a key role in activation and signal transduction of mutant RAS proteins in RAS-mutated cancers, SOS1 knockout can inhibit survival and proliferation of KRAS mutant tumor cells, catalytic site mutant SOS1 is re-expressed in the SOS1 knockout KRAS mutant tumor cells, and the tumor cells can not recover survival and proliferation, so that the guanine nucleotide exchange catalytic activity of SOS1 has a key role in survival and proliferation of the KRAS mutant tumor cells. In addition to modulating mutant RAS proteins, SOS1 may also be involved in the signaling and transduction processes of tumor cells by other mechanisms. SOS1 can bind to the growth factor receptor binding protein Grb2 to form SOS1-Grb2 complexes, and thereby bind to activated receptor tyrosine kinases (e.g., EGFR, erbB2/3/4, VEGFR1/2/3, PDGFR-A/B, FGFR1/2/3, IGF1R, ALK, ROS1, TRK-A/B/C, RET, C-MET, AXL, etc.), or be recruited by other cell surface membrane receptors (e.g., TCR, BCR, CSF R). SOS1 can act as a guanine nucleotide exchange factor to activate GTPase, RAC1, which is associated with a variety of human cancers and other diseases. Studies have shown that SOS1 mutations are present in embryonal rhabdomyosarcoma, testicular support cell tumors, granulocytomas of the skin, and lung adenocarcinoma, and that overexpression of SOS1 protein is also found in bladder and prostate cancers.
SOS2 is a homolog of SOS1 in mammalian cells and also has the function of a guanine nucleotide exchange factor. Mouse gene knockout model studies indicate that SOS1 germ line knockout can lead to death of mouse embryos in mid-gestation, while adult mice can continue to survive after SOS1 knockout, in contrast to SOS2 knockout without any obvious phenotypic changes for both embryos and mature mice, and SOS1/2 double knockout adult mice die rapidly, suggesting that selective targeting of SOS1 may achieve higher therapeutic index for SOS 1-regulated RAS mutant tumors.
Inhibition of SOS1 catalytic site binding to RAS protein can block SOS1 mediated RAS protein activation, and thus inhibit RAS protein downstream signaling (e.g. ERK phosphorylation activation, etc.), SOS1 inhibitors with such mechanism of action have inhibitory effect on mutant RAS protein-dependent tumor cells such as KRAS mutant tumor cell lines (e.g. inhibition of proliferation, survival, metastasis, etc.).
Disclosure of Invention
The present invention provides compounds useful as SOS1 inhibitors, which have excellent inhibitory activity against SOS 1. SOS1 inhibitors of the invention inhibit SOS1 interaction and activation with RAS proteins, and particularly have significant inhibitory effects on SOS1 and KRAS mutant protein interactions, and may provide pharmacological benefits to cancer patients harboring RAS and upstream and downstream protein (including KRAS, NRAS, HRAS, receptor tyrosine kinases (e.g., EGFR, erbB2/3/4, PDGFR-A/B, FGFR1/2/3, IGF1R, INSR, ALK, ROS, trkA/B/C, RET, C-MET, VEGFR1/2/3, AXL), GAP (e.g., NF 1), and SOS 1) mutations. Furthermore, SOS1 inhibitors would also provide pharmacological benefits in RAC 1-dependent cancers and other diseases associated with deregulation of RAS signaling pathways such as neurofibromas, noonan Syndrome (NS), cardio-facial-skin syndrome (CFC) and hereditary gingival fibromas of type 1.
The compounds of the invention also have superior properties in terms of better physicochemical properties (e.g. solubility, physical and/or chemical stability), improved pharmacokinetic properties (e.g. improved bioavailability, suitable half-life and duration of action), improved safety (lower toxicity and/or fewer side effects, wider therapeutic window), etc.
One aspect of the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of formula (I) or formula (I'):
wherein:
ring A and ring B are each independently selected from C 3-10 Hydrocarbon ring, 3-10 membered heterocycle, C 6-10 Aromatic rings and 5-14 membered heteroaromatic rings, up to 2 ring members of which are C (=o);
r and R 1 Each at each occurrence is independently selected from halogen, -NH 2 、-CN、-NO 2 、-OH、-O-C 1-6 Alkyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 alkylene-OH, halogenated C 1-6 alkylene-OH, C 2-6 Alkenyl, C 2-6 Alkynyl, saturated or partially unsaturated C 3-10 Cycloalkyl, saturated or partially unsaturated 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl groups, up to 2 ring members of the cyclic hydrocarbon and heterocyclic groups being C (=o), when m is greater than 1 and/or n is greater than 1, two R 1 And/or two R together with the atom to which they are attached optionally form C 3-10 Hydrocarbon ring, 3-10 membered heterocycle, C 6-10 An aromatic ring or a 5-14 membered heteroaromatic ring, up to 2 ring members of the hydrocarbon ring and the heterocyclic ring being C (=o);
R 2 、R 2 ’、R 3 and R is 4 Each independently selected from H, halogen, -NH 2 、-CN、-NO 2 、-OH、-O-C 1-6 Alkyl, -O- (3-10 membered heterocyclic group), C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 alkylene-OH, halogenated C 1-6 alkylene-OH, C 2-6 Alkenyl, C 2-6 Alkynyl, saturated or partially unsaturated C 3-10 Cycloalkyl, saturated or partially unsaturated 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -C (=o) R 5 、-OC(＝O)R 5 、-C(＝O)OR 5 、-OR 5 、-SR 5 、-S(＝O)R 5 、-S(＝O) 2 R 5 、-S(＝O) 2 NR 5 R 6 、-NR 5 R 6 、-C(＝O)NR 5 R 6 、-NR 5 -C(＝O)R 6 、-NR 5 -C(＝O)OR 6 、-NR 5 -S(＝O) 2 -R 6 、-NR 5 -C(＝O)-NR 5 R 6 、-C 1-6 alkylene-NR 5 R 6 、-C 1-6 alkylene-O (p=o) (OH) 2 and-O-C 1-6 alkylene-NR 5 R 6 ；
Each of the foregoing groups is optionally substituted at each occurrence with one or more substituents independently selected from the group consisting of: halogen, -OH, oxo, -NH 2 、-CN、-NO 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, =n-OR 5 、-C(＝NH)NH 2 、-C(＝O)R 5 、-OC(＝O)R 5 、-C(＝O)OR 5 、-OR 5 、-SR 5 、-S(＝O)R 5 、-S(＝O) 2 R 5 、-S(＝O) 2 NR 5 R 6 、-NR 5 R 6 、-C(＝O)NR 5 R 6 、-NR 5 -C(＝O)R 6 、-NR 5 -C(＝O)OR 6 、-NR 5 -S(＝O) 2 -R 6 、-NR 5 -C(＝O)-NR 5 R 6 、-C 1-6 alkylene-NR 5 R 6 and-O-C 1-6 alkylene-NR 5 R 6 The alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl groups are further optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -OH, oxo, -NH 2 、-CN、-NO 2 、C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 An aralkyl group;
R 5 and R is 6 Each at each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 An aralkyl group;
m is an integer selected from 0, 1, 2, 3 and 4; and is also provided with
n is an integer selected from 0, 1, 2 or 3.
In another aspect of the invention there is provided a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers, the pharmaceutical composition preferably being a solid, semi-solid, liquid or gaseous formulation.
In a further aspect the invention provides the use of a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labelled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for use as an SOS1 inhibitor.
Another aspect of the invention provides a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention, for use as a SOS1 inhibitor.
Another aspect of the present invention provides a method for preventing or treating SOS 1-related diseases, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the present invention.
Detailed Description
Definition of the definition
Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.
As used herein, the term "alkylene" means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.
As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example 1 to 6A carbon atom. For example, as used herein, the term "C 1-6 Alkyl "refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl) optionally substituted with 1 or more (such as 1 to 3) suitable substituents such as halogen (in which case the group is referred to as" haloalkyl ") (e.g., CH) 2 F、CHF 2 、CF 3 、CCl 3 、C 2 F 5 、C 2 Cl 5 、CH 2 CF 3 、CH 2 Cl or-CH 2 CH 2 CF 3 Etc.). The term "C 1-4 Alkyl "refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).
As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon radical containing one double bond and having 2 to 6 carbon atoms ("C 2-6 Alkenyl "). The alkenyl group is, for example, vinyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compounds of the present invention contain alkenylene, the compounds may exist in pure E (ipsilateral (entgegen)) form, pure Z (ipsilateral (zusammen)) form or any mixture thereof.
As used herein, the term "alkynyl" means a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.
As used herein, the term "cycloalkyl" refers to a saturated monocyclic or multicyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo [ 1.1.1:1:]amyl, bicyclo [2.2.1]Heptyl, bicyclo [3.2.1]Octyl or bicyclo [5.2.0]Nonyl, decalyl, etc.), optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-6 Cycloalkyl "refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), optionally substituted with 1 or more (such as 1 to 3) suitable substituents, e.g., methyl-substituted cyclopropyl.
As used herein, the terms "cycloalkylene", "cyclic hydrocarbon" and "hydrocarbon ring" refer to saturated (i.e., "cycloalkylene" and "cycloalkyl") or unsaturated (i.e., having one or more double and/or triple bonds within the ring) monocyclic or polycyclic (including spiro, fused or bridged systems) hydrocarbon rings having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms, including, but not limited to, cyclopropyl (ring), (cyclobutyl (ring), (cyclopentyl (ring), (cyclohexyl (ring), (cycloheptyl) ring), (cyclooctyl (ring), (cyclononyl (ring), (cyclohexenyl (ring), and the like).
As used herein, the terms "heterocyclyl", "heterocyclylene" and "heterocycle" refer to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double and/or triple bonds within the ring) cyclic group having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring atoms, at least one of which is a heteroatom selected from N, O and S, and the remaining ring atoms being C. For example, a "3-10 membered (sub) heterocyclic (group)" is a saturated or partially unsaturated (sub) heterocyclic (group) having 2-9 (e.g., 2, 3, 4, 5, 6, 7, 8, or 9) ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from N, O and S. Examples of heterocyclylene and heterocyclic (groups) include, but are not limited to: ethylene oxide, (subunit) aziridinyl, (subunit) azetidinyl (azetidinyl), (subunit) oxetanyl (oxytanyl), (subunit) tetrahydrofuranyl, (subunit) dioxolyl (dioxanyl), (subunit) pyrrolidinyl, (subunit) pyrrolidinonyl, (subunit) imidazolidinyl, (subunit) pyrazolidinyl, (subunit) pyrrolinyl, (subunit) tetrahydropyranyl, (subunit) piperidinyl, (subunit) morpholinyl, (subunit) dithianyl, (subunit) thiomorpholinyl, (subunit) piperazinyl, or (subunit) trithianyl. The groups also encompass bicyclic systems including spiro, fused or bridged systems (such as 8-azaspiro [4.5] decane, 3, 9-diazaspiro [5.5] undecane, 2-azabicyclo [2.2.2] octane, and the like). The heterocyclylene and heterocyclic (groups) may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) suitable substituents.
As used herein, the terms "(arylene) and" aromatic ring "refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, the term "C 6-10 (arylene) and "C 6-10 An aromatic ring "means an aromatic group containing 6 to 10 carbon atoms, such as a phenyl (ene ring) or a naphthyl (ene ring). The aryl (ene) and aryl rings are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO) 2 、C 1-6 Alkyl, etc.) substitution. The aryl (ene) and aromatic rings optionally being linked to another ring (e.g. C 3-10 Hydrocarbon ring, 3-10 membered heterocyclic ring or 5-14 membered heteroaromatic ring), the condensed groups being for example
As used herein, the terms "(arylene) heteroaryl" and "heteroaryl ring" refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, particularly 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom (which may be the same or different, such as oxygen, nitrogen or sulfur), and which may additionally be benzo-fused in each case. In particular, "(arylene) heteroaryl" or "heteroaryl ring" is selected from thienyl (ene) furyl (ene) pyrrolyl (ene) oxazolyl (ene) thiazolyl (ene) imidazolyl (ene) pyrazolyl (ene) isoxazolyl (ene) isothiazolyl (ene) oxadiazolyl (ene) triazolyl (ene) thiadiazolyl, and the like, and benzo derivatives thereof; or (b) Pyridinyl (ene), pyridazinyl (ene), pyrimidinyl (ene), pyrazinyl (ene), triazinyl (ene), and the like, and benzo derivatives thereof. The "(arylene) heteroaryl" and "heteroaryl ring" may also optionally be attached to another ring (e.g., C 3-10 Hydrocarbon ring, 3-10 membered heterocycle, C 6-10 Aromatic rings or 5-14 membered heteroaromatic rings) are fused, for example
As used herein, the term "aralkyl" preferably denotes aryl or heteroaryl substituted alkyl, wherein the aryl, heteroaryl and alkyl are as defined herein. Typically, the aryl group may have 6 to 14 carbon atoms, the heteroaryl group may have 5 to 14 ring atoms, and the alkyl group may have 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
As used herein, the term "halo" or "halogen" group is defined to include F, cl, br or I.
As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated mono-or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and at least one nitrogen atom in the ring, which may optionally further comprise one or more (e.g., one, two, three, or four) selected from N, O, C = O, S, S =o and S (=o) 2 Is linked to the remainder of the molecule through a nitrogen atom in the nitrogen-containing heterocycle and any remaining ring atoms, the nitrogen-containing heterocycle optionally being benzo-fused and preferably being linked to the remainder of the molecule through a nitrogen atom in the nitrogen-containing heterocycle and any carbon atom in the fused benzene ring.
The term "substitution" means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
If a substituent is described as "optionally substituted," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent any hydrogens are present) may be replaced with an independently selected optional substituent, alone and/or together. If the nitrogen of a substituent is described as optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogens are present) may each be replaced with an independently selected optional substituent.
If substituents are described as "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.
The term "one or more" as used herein means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
As used herein, unless indicated, the point of attachment of a substituent may be from any suitable position of the substituent.
When the bond of a substituent is shown as a bond through the ring connecting two atoms, then such substituent may be bonded to any ring-forming atom in the substitutable ring.
The invention also includes all pharmaceutically acceptable isotopically-labelled compounds which are identical to those of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevailing in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium @ 2 H) The tritium is 3 H) A) is provided; isotopes of carbon (e.g 11 C、 13 C, C is a metal alloy 14 C) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of chlorine (e.g 36 Cl); isotopes of fluorine (e.g 18 F) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of iodine (e.g 123 I, I 125 I) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of nitrogen (e.g 13 N is N 15 N); isotopes of oxygen (e.g 15 O、 17 O and O 18 O); isotopes of phosphorus (e.g 32 P) is as follows; isotopes of sulfur (e.g 35 S). Certain isotopically-labeled compounds of the present invention (e.g., those into which a radioisotope is incorporated) are useful in pharmaceutical and/or substrate tissue distribution studies (e.g., assays). Radioisotope tritium (i.e 3 H) Carbon-14 (i.e 14 C) Are particularly useful for this purpose because of easy incorporation and easy detection. Using positron-emitting isotopes (e.g 11 C、 18 F、 15 O and O 13 N) substitution can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. Isotopically-labeled compounds of the present invention can be prepared by processes analogous to those described in the accompanying schemes and/or in the examples and preparations by substituting an appropriate isotopically-labeled reagent for the non-labeled reagent previously employed. Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g., D 2 O, acetone-d 6 Or DMSO-d 6 。
The term "stereoisomer" refers to an isomer formed as a result of at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, they can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Specific individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as a mixture of two or more structurally distinct forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is to be understood that the scope of the present application encompasses all such isomers in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.
Solid lines may be used hereinSolid wedge shapeOr virtual wedge shapeDepicting the chemical bond of the compounds of the present invention. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom (e.g., particular enantiomers, racemic mixtures, etc.) are included. The use of a solid or virtual wedge to depict a bond to an asymmetric carbon atom is intended to indicate the presence of the stereoisomers shown. When present in a racemic mixture, real and imaginary wedges are used to define the relative stereochemistry, not the absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers (which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).
The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of any ratio of more than one polymorphs.
It will also be appreciated that certain compounds of the invention may exist in free form for use in therapy or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs which, upon administration to a patient in need thereof, are capable of providing the compounds of the invention or metabolites or residues thereof, either directly or indirectly. Thus, when reference is made herein to "a compound of the invention" it is also intended to encompass the various derivative forms of the compounds described above.
Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include acetates, adipates, aspartate, benzoate, benzenesulfonates, bicarbonates, bisulphates/sulfates, borates, camphorsulfonates, citrates, cyclohexanesulphonates, ethanedisulfonates, formates, fumarates, glucoheptonates, gluconates, glucuronates, hexafluorophosphates, maritime salts, hydrochloride/chlorides, hydrobromide/bromides, hydroiodides/iodides, isethionates, lactates, malates, maleates, malonates, methanesulfonates, methylsulfates, naphthaleneates (nathanates), 2-naphthalenesulfonates, nicotinates, nitrates, orotate, oxalates, palmates, pamonates, phosphates/hydrogen phosphates/dihydrogen phosphates, pyroglutamates, glucarates, stearates, succinates, tanninates, tartrates, tosylates, trifluoroacetates, and xinofoates (xinofoate).
Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts.
For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: properties, selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.
As used herein, the term "ester" means an ester derived from each of the compounds of the general formula in this application, including physiologically hydrolyzable esters (compounds of the present invention that can be hydrolyzed under physiological conditions to release the free acid or alcohol form). The compounds of the invention may themselves be esters.
The compounds of the invention may be present in the form of solvates (preferably hydrates) wherein the compounds of the invention comprise a polar solvent as a structural element of the compound lattice, in particular for example water, methanol or ethanol. The polar solvent, in particular water, may be present in stoichiometric or non-stoichiometric amounts.
Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires available lone pairs to oxidize to oxides; those skilled in the art will recognize nitrogen-containing heterocycles capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidizing heterocycles and tertiary amines with peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes (dioxiranes) such as dimethyl dioxirane. These methods for preparing N-oxides have been widely described and reviewed in the literature, see for example: T.L. Gilchrist, comprehensive Organic Synthesis, vol.7, pp 748-750; katritzky and a.j. Boulton, eds., academic Press; and G.W.H.Cheeseman and E.S.G.Werstiuk, advances in Heterocyclic Chemistry, vol.22, pp 390-392, A.R.Katritzky and A.J.Boulton, eds., academic Press.
Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances that form in vivo upon administration of the compounds of the invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the compound being administered. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by a process of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.
The invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity, which, when administered into or onto the body, may be converted into the compounds of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Additional information regarding the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", vol.14, ACS Symposium Series (T.Higuchi and V.stilla). Prodrugs of the invention may be prepared, for example, by replacing the appropriate functional groups present in the compounds of the invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g. "Design of Prodrugs", described in h. Bundegaard (Elsevier, 1985) ".
The invention also encompasses compounds of the invention containing a protecting group. During any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules of interest, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example those described in T.W.Greene & P.G.M.Wuts, protective Groups in Organic Synthesis, john Wiley & Sons,1991, which references are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.
The term "about" means within + -10%, preferably within + -5%, more preferably within + -2% of the stated value.
Compounds of formula (I)
In some embodiments, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of formula (I) or formula (I'):
wherein:
ring A and ring B are each independently selected from C 3-10 Hydrocarbon ring, 3-10 membered heterocycle, C 6-10 Aromatic rings and 5-14 membered heteroaromatic rings, up to 2 ring members of which are C (=o);
r and R 1 Each at each occurrence is independently selected from halogen, -NH 2 、-CN、-NO 2 、-OH、-O-C 1-6 Alkyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 alkylene-OH, halogenated C 1-6 alkylene-OH, C 2-6 Alkenyl, C 2-6 Alkynyl, saturated or partially unsaturated C 3-10 Cycloalkyl, saturated or partially unsaturated 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl groups, up to 2 ring members of the cyclic hydrocarbon and heterocyclic groups being C (=o), when m is greater than 1 and/or n is greater than 1, two R 1 And/or two R together with the atom to which they are attached optionally form C 3-10 Hydrocarbon ring, 3-10 membered heterocycle, C 6-10 An aromatic ring or a 5-14 membered heteroaromatic ring, up to 2 ring members of the hydrocarbon ring and the heterocyclic ring being C (=o);
R 2 、R 2 ’、R 3 And R is 4 Each independently selected from H, halogen, -NH 2 、-CN、-NO 2 、-OH、-O-C 1-6 Alkyl, -O- (3-10 membered heterocyclic group), C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 alkylene-OH, halogenated C 1-6 alkylene-OH, C 2-6 Alkenyl, C 2-6 Alkynyl, saturated or partially unsaturated C 3-10 Cycloalkyl, saturated or partially unsaturated 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl group、-C(＝O)R 5 、-OC(＝O)R 5 、-C(＝O)OR 5 、-OR 5 、-SR 5 、-S(＝O)R 5 、-S(＝O) 2 R 5 、-S(＝O) 2 NR 5 R 6 、-NR 5 R 6 、-C(＝O)NR 5 R 6 、-NR 5 -C(＝O)R 6 、-NR 5 -C(＝O)OR 6 、-NR 5 -S(＝O) 2 -R 6 、-NR 5 -C(＝O)-NR 5 R 6 、-C 1-6 alkylene-NR 5 R 6 、-C 1-6 alkylene-O (p=o) (OH) 2 and-O-C 1-6 alkylene-NR 5 R 6 ；
Each of the foregoing groups is optionally substituted at each occurrence with one or more substituents independently selected from the group consisting of: halogen, -OH, oxo, -NH 2 、-CN、-NO 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, =n-OR 5 、-C(＝NH)NH 2 、-C(＝O)R 5 、-OC(＝O)R 5 、-C(＝O)OR 5 、-OR 5 、 -SR 5 、-S(＝O)R 5 、-S(＝O) 2 R 5 、-S(＝O) 2 NR 5 R 6 、-NR 5 R 6 、-C(＝O)NR 5 R 6 、-NR 5 -C(＝O)R 6 、-NR 5 -C(＝O)OR 6 、-NR 5 -S(＝O) 2 -R 6 、-NR 5 -C(＝O)-NR 5 R 6 、-C 1-6 alkylene-NR 5 R 6 and-O-C 1-6 alkylene-NR 5 R 6 The alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl groups are further optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -OH, oxo, -NH 2 、-CN、-NO 2 、C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 An aralkyl group;
R 5 and R is 6 Each at each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 An aralkyl group;
m is an integer selected from 0, 1, 2, 3 and 4; and is also provided with
n is an integer selected from 0, 1, 2 or 3.
In some embodiments, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein each R is independently at each occurrence C 1-6 Alkyl or C 1-6 An alkylene-OH; preferably, R is, independently at each occurrence, methyl or-CH 2 CH 2 -OH。
In some embodiments, the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein ring a is a 3-10 membered heterocycle or a 5-14 membered heteroaryl ring comprising one or more ring members selected from-O-, -NR-, and-n=; preferably, the method comprises the steps of,is thatMost preferably, the first and second regions are,is that
In some embodiments, the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein ring B is a bicyclo [1.1.1] pentane ring, a 2-oxabicyclo [2.1.1] hexane ring, a benzene ring, or a thiophene ring, most preferably a benzene ring or a thiophene ring.
In some embodiments, the invention provides a compound or pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein R 1 Each at each occurrence is independently selected from halogen, -NH 2 、C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 alkylene-OH, halogenated C 1-6 alkylene-OH, saturated or partially unsaturated C 3-10 Cycloalkyl, saturated or partially unsaturated 3-to 10-membered heterocyclyl, C 6-10 Aryl and 5-14 membered heteroaryl, said alkylene, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally being independently selected from one or more of halogen, -OH, C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Substituents for aryl and 5-14 membered heteroaryl;
when m is greater than 1, two R 1 Optionally together with the atoms to which they are attached form C 3-10 Hydrocarbon ring, 3-10 memberedHeterocycle, C 6-10 An aromatic ring or a 5-14 membered heteroaromatic ring, up to 2 ring members of which are C (=o), and which are optionally substituted with one or more halogens;
preferably, R 1 Each at each occurrence is independently selected from CF 3 、NH 2 Andand m is 1 or 2.
In some embodiments, the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein Selected from the group consisting of
In some embodiments, the invention provides a compound or pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein R 2 And R is 2 ' each independently selected from H, -O-C 1-6 Alkyl and-O- (3-10 membered heterocyclyl); preferably, R 2 And R is 2 ' one of which is H and the other is H, -OCH 3 Or (b)
In some embodiments, the invention provides a compound or pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein R 3 And R is 4 Each independently selected from H and C 1-6 An alkyl group; preferably, R 3 Is methyl, and R 4 H.
In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of formula (II), formula (III), formula (IV), or formula (V):
the present invention encompasses compounds resulting from any combination of the various embodiments.
In some embodiments, the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein the compound is selected from the group consisting of:
Pharmaceutical compositions and methods of treatment
In some embodiments, the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers, preferably in a solid, semi-solid, liquid, or gaseous form. In some embodiments, the pharmaceutical composition may further comprise one or more additional therapeutic agents.
In some embodiments of the present invention, in some embodiments, the present invention provides the use of a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for use in the manufacture of a SOS1 inhibitor.
In some embodiments, the invention provides a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention, for use as an SOS1 inhibitor.
In some embodiments, the invention provides a method of preventing or treating SOS 1-related disorders, comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention.
In some embodiments, the SOS 1-related disease includes cancer (e.g., pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myelogenous leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular cancer, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma), RAS disease (e.g., type 1 neurofibromatosis (NF 1), noonan Syndrome (NS), noonan syndrome with multiple plaques (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), costerol Syndrome (CS), heart-face-skin syndrome (CFC), lewis syndrome, and hereditary gum fibromatosis).
By "pharmaceutically acceptable carrier" is meant a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting the tissues of humans and/or other animals within the scope of sound medical judgment without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, in particular for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition may also contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents, as desired. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
The pharmaceutical compositions of the present invention may act systematically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection (e.g. intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, nasal, transmucosal, topical, in the form of an ophthalmic formulation or by inhalation.
For these routes of administration, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms.
Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups.
The term "effective amount" as used herein refers to the amount of a compound that, upon administration, will alleviate to some extent one or more symptoms of the disorder being treated.
The dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the doses may be proportionally reduced or increased as indicated by the urgent need for a therapeutic situation. It is noted that the dosage value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions.
The amount of the compound of the invention administered will depend on the severity of the individual, disorder or condition being treated, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. Generally, an effective dose is about 0.0001 to about 50mg, for example about 0.01 to about 10 mg/kg/day per kg body weight per day (single or divided administration). For a 70kg human, this amounts to about 0.007 mg/day to about 3500 mg/day, for example about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels not higher than the lower limit of the aforementioned range may be sufficient, while in other cases larger doses may still be employed without causing any adverse side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day.
The compounds of the invention may be present in the pharmaceutical composition in an amount or in an amount of from about 0.01mg to about 1000mg, suitably from 0.1 to 500mg, preferably from 0.5 to 300mg, more preferably from 1 to 150mg, particularly preferably from 1 to 50mg, for example 1.5mg, 2mg, 4mg, 10mg, 25mg etc.
As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing such disorder or condition, or one or more symptoms of such disorder or condition to which such term applies.
As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from a disease (e.g., a disease described herein). "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
In some embodiments, the pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents.
Examples
The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.
The structure of the compound is characterized by nuclear magnetic resonance spectrum 1 H NMR) or Mass Spectrometry (MS).
Chemical shifts (δ) are given in parts per million (ppm). 1 The HNMR assay was performed on a Bruker BioSpin GmbH 400 magnetonuclear machine with deuterated methanol (CD) as the test solvent 3 OD), deuterated chloroform (CDCl) 3 ) Or hexadeuterated dimethyl sulfoxide (DMSO-d) 6 ) The internal standard is Tetramethylsilane (TMS).
LC-MS was measured on a Shimadzu LC-MS-2020 liquid chromatography-mass spectrometer (manufacturer: shimadzu, model: shimadzu LC-MS-2020).
The preparative high performance liquid chromatography was performed using waters 2767 (waters surfire, C18,19×250mm 10um column).
Thin Layer Chromatography (TLC) was performed using yellow sea brand HSGF 254 (5X 20 cm) silica gel plates, and thin layer preparative chromatography was performed using silica gel plates of the specification fume table GF 254 (0.4-0.5 nm).
The reaction was detected by Thin Layer Chromatography (TLC) or LC-MS using a developing solvent system comprising a methylene chloride and methanol system, n-hexane and ethyl acetate system, and petroleum ether and ethyl acetate system, which was adjusted according to the polarity of the compound to be separated (by adjusting the volume ratio of the solvent or adding triethylamine, etc.).
The microwave reaction was carried out using a Biotageinitator+ (400W, RT-300 ℃ C.) microwave reactor.
Column chromatography is generally used for chemical industry 200-300 mesh silica gel as stationary phase. The eluent system comprises a dichloromethane and methanol system and an n-hexane and ethyl acetate system, and is adjusted according to the polarity of the compound to be separated (by adjusting the volume ratio of the solvent or adding triethylamine, etc.).
The reaction temperature was room temperature (20 ℃ C. To 30 ℃ C.) unless otherwise specified in the examples.
The reagents used in the examples were purchased from Acros Organics, aldrich Chemical Company or Shanghai Bi medical science Co., ltd.
Abbreviations in the present invention have the following meanings:
abbreviations (abbreviations) Meaning of
ACN Acetonitrile
AcOH/CH 3 COOH Acetic acid/acetic acid
n-Bu N-butyl group
Cs 2 CO 3 Cesium carbonate
DIEA/DIPEA N, N-diisopropylethylamine
DMF N, N-dimethylformamide
DMS Dimethyl sulfate
DMSO Dimethyl sulfoxide
EtOH Ethanol
Fe Iron (Fe)
HCl Hydrochloric acid
HNO 3 Nitric acid
H 2 O Water and its preparation method
H 2 SO 4 Sulfuric acid
IPA/i-PrOH Isopropyl alcohol
K 2 CO 3 Potassium carbonate
MeOH Methanol
N 2 Nitrogen gas
NaBH 4 Sodium borohydride
Na 2 B 4 O 7 Sodium tetraborate
NH 4 Cl Ammonium chloride
NH 4 HCO 3 Ammonium bicarbonate
Pd 2 (dba) 3 Tris (dibenzylideneacetone) dipalladium
Pd(PPh 3 ) 4 Tetrakis (triphenylphosphine) palladium
Pd(PPh 3 ) 2 Cl 2 Bis (triphenylphosphine) palladium dichloride
POCl 3 Phosphorus oxychloride
rt Room temperature
t-BuONa Sodium tert-butoxide
TEA Triethylamine
TFA Trifluoroacetic acid
THF Tetrahydrofuran (THF)
Ti(OEt) 4 Titanic acid tetraethyl ester
TLC Thin layer chromatography
Example 1: preparation of (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -10-methoxy-2-methyl-7, 8-dihydro- [1,4] dioxino [2,3-g ] quinazolin-4-amine (Compound 101 a)
The first step: 101a-3 (0.50 g,2.0 mmol) was added to phosphorus oxychloride (15 mL). The reaction was heated to 100deg.C and stirred for 10 hours, concentrated directly under reduced pressure, the concentrate was dissolved in dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (3X 50 mL), and then saturated chlorinatedSodium solution was washed, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by medium pressure flash silica gel column chromatography (eluent: ethyl acetate: petroleum ether=0-30%) to give compound 101a-4 (0.3 g) as a white solid. The yield thereof was found to be 57%. ESI-MS 267[ M+H ] ] + .
And a second step of: 101a-4 (60 mg,0.2 mmol) was dissolved in isopropanol (4 mL), and (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethan-1-amine hydrochloride (81 mg,0.3 mmol) and N, N-diisopropylethylamine (77 mg,0.6 mmol) were added and the reaction stirred at 110℃under reflux for 16 h. The reaction was cooled, concentrated under reduced pressure, and the concentrate was purified by preparative TLC (eluent: 100% ethyl acetate) to give compound 101a-5 (44 mg) as a pale yellow solid in 47% yield. ESI-MS 465[ M+H ]] + .
And a third step of: 101a-5 (44 mg,0.1 mmol) was dissolved in ethanol (5 mL) and water (2 mL), iron powder (50 mg,0.9 mmol) and ammonium chloride (48 mg,2.0 mmol) were added, and the reaction was stirred at 90℃for 2 hours. The reaction was cooled, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, the concentrate was diluted with water (10 mL), extracted with ethyl acetate (2X 10 mL), the organic phase was concentrated under reduced pressure, and the concentrate was isolated and purified by high pressure preparative liquid chromatography to give (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -10-methoxy-2-methyl-7, 8-dihydro- [1, 4)]Dioxino [2,3-g]Quinazolin-4-amine (compound 101 a) (14.04 mg) as a white solid in 27% yield. ESI-MS 435[ M+H ] ] + 。 1 H-NMR(400MHz,DMSO-d 6 )δ:ppm 8.01(d,J＝8.0Hz,1H),7.68(s,1H),6.87(s,1H),6.82(s,1H),6.68(s,1H),5.54-5.48(m,3H),4.39-4.33(m,4H),3.88(s,3H),2.37(s,3H),1.51(d,J＝8.0Hz,3H)。
Example 2: preparation of (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6-methoxy-2-methyl-8, 9-dihydro- [1,4] dioxino [2,3-h ] quinazolin-4-amine (Compound 101 b)
The first step: sodium tetraborate (30.0 g,78.7 mmol) was dissolved in water (300 mL), and methyl gallate (5.0 g,27.2 mmol) was added. The reaction was stirred at room temperature for 1 hour. Sodium hydroxide (4.4 g,110.0 mmol) was dissolved in water (15 mL) and slowly added dropwise to the reaction solution at room temperature, and after the addition was completed, the reaction was stirred at room temperature for 15 minutes. Dimethyl sulfate (13.3 g,105.4 mmol) was slowly added dropwise at 0deg.C. The reaction was stirred at room temperature for 15 hours. Sulfuric acid is added dropwise until the pH value of the reaction solution is 6. The reaction was extracted with dichloromethane (3×200 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 101b-1 (3.6 g) as a pale yellow oil. The yield thereof was found to be 67%. ESI-MS 199[ M+H ]] + .
And a second step of: 101b-1 (3.6 g,21.8 mmol) and potassium carbonate (12.0 g,86.8 mmol) were dissolved in N, N-dimethylformamide (30 mL). 1, 2-dibromoethane (6.1 g,32.5 mmol) was slowly added dropwise while stirring at room temperature. The reaction was stirred at room temperature for 18 hours. The reaction solution was extracted with ethyl acetate/water (1:1, 400 mL), then the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was separated and purified by medium pressure flash column chromatography (eluent: ethyl acetate: petroleum ether=0-20%) to give compound 101b-2 (2.6 g) as a white solid. The yield thereof was found to be 53%. ESI-MS 225[ M+H ] ] + .
And a third step of: 101b-2 (2.6 g,11.6 mmol) was dissolved in acetic acid (20 mL). Nitric acid (68%, 10.0 mL) was slowly added dropwise at room temperature. The reaction was heated to 60 ℃ and stirred for 10 hours. The reaction solution was poured into ice water (200 mL), then extracted with ethyl acetate (2×200 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was separated and purified by medium pressure flash column chromatography (eluent: ethyl acetate: petroleum ether=0-20%) to give a mixture of compounds 101a-1 and 101b-3 (2.0 g) as pale yellow solid. The yield thereof was found to be 64%. ESI-MS 270[ M+H ]] + .
Fourth step: a mixture of 101a-1 and 101b-3 (2.0 g,7.4 mmol) was dissolved in ethanol/water (20 mL/20 mL). Stirring at room temperature, addingIron powder (100 mesh, 2.3g,41 mmol) and ammonium chloride (2.2 g,41 mmol) were heated to 90℃and stirred for 8 hours. The reaction was cooled, filtered through celite, the filter cake was washed with ethyl acetate (50 mL), the filtrate was concentrated under reduced pressure, extracted with ethyl acetate/water (1:1, 200 mL), then the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by medium pressure flash column chromatography (eluent: ethyl acetate: petroleum ether=0-30%) to give a mixture of compounds 101a-2 and 101b-4 (1.4 g) as pale yellow solid. The yield thereof was found to be 79%. ESI-MS 240[ M+H ] ] + .
Fifth step: a mixture of 101a-2 and 101b-4 (1.4 g,5.8 mmol) was added to acetonitrile (30 mL). A dioxane solution of hydrochloric acid (4N, 25 mL) was added with stirring at room temperature. The reaction was heated to 90 ℃ and stirred for 6 hours to yield a large amount of solids. The reaction was cooled, filtered, and the filter cake was washed with water (20 mL) and dried. Compound 101b-5 (0.49 g) was obtained as a pale yellow solid. The yield thereof was found to be 34%. ESI-MS 249[ M+H ]] + The filtrate was concentrated under reduced pressure and the concentrate was purified by reverse phase chromatography to give compound 101a-3 (0.50 g) as an off-white solid. The yield thereof was found to be 34.5%. ESI-MS 249[ M+H ]] + .
Sixth step: 101b-5 (0.49 g,2.0 mmol) was added to phosphorus oxychloride (15 mL). The reaction was heated to 100deg.C, stirred for 10 hours, concentrated under reduced pressure, the concentrate was dissolved in dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (3×50 mL), then with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by medium pressure flash column chromatography (eluent: ethyl acetate: petroleum ether=0-30%) to give compound 101b-6 (0.34 g) as a white solid. The yield thereof was found to be 64%. ESI-MS 267[ M+H ]] + .
Seventh step: 101b-6 (60 mg,0.2 mmol) was dissolved in isopropanol (4 mL), and (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethan-1-amine hydrochloride (81 mg,0.3 mmol) and N, N-diisopropylethylamine (77 mg,0.6 mmol) were added and the reaction stirred at 110℃under reflux for 16 h. The reaction was cooled, concentrated under reduced pressure, and the concentrate was purified by preparative TLC (eluent: 100%) Ethyl acetate) to give compound 101b-7 (40 mg) as a pale yellow solid in 43% yield. ESI-MS 465[ M+H ]] + .
Eighth step: 101b-7 (40 mg,0.1 mmol) was dissolved in ethanol (5 mL) and water (2 mL), iron powder (50 mg,0.9 mmol) and ammonium chloride (48 mg,2.0 mmol) were added, and the reaction was stirred at 90℃for 2 hours. The reaction was cooled, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, the concentrate was diluted with water (10 mL), extracted with ethyl acetate (2X 10 mL), the organic phase was concentrated under reduced pressure, and the concentrate was isolated and purified by high pressure preparative liquid chromatography to give (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -6-methoxy-2-methyl-8, 9-dihydro- [1, 4)]Dioxino [2,3-h]Quinazolin-4-amine (compound 101 b) (10.11 mg) was a white solid in 26% yield. ESI-MS 435[ M+H ]] + 。 1 H-NMR(400MHz,DMSO-d 6 )δ:ppm 7.96(d,J＝8.0Hz,1H),7.35(s,1H),6.87(s,1H),6.84(s,1H),6.69(s,1H),5.59-5.51(m,3H),4.32-4.31(m,4H),3.89(s,3H),2.35(s,3H),1.54(d,J＝8.0Hz,3H)。
Example 3: preparation of N- ((R) -1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-6- (((S) -tetrahydrofurane-3-yl) oxy) -8, 9-dihydro- [1,4] dioxino [2,3-h ] quinazolin-4-amine (Compound 102 a)
The first step: methyl gallate (20 g,106.61 mmol) was dissolved in N, N-dimethylformamide (100 mL) and 1, 2-dibromoethane (30.6 g,162.91 mmol) and potassium carbonate (30 g,217.22 mmol) were added. The reaction was stirred at 90 ℃ for 10h, cooled and filtered, the filter cake was washed with ethyl acetate (100 mL), water was added to the filtrate, the aqueous phase was separated, extracted with ethyl acetate (3 x100 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by medium pressure flash column chromatography (eluent: ethyl acetate: petroleum ether=30-60%) to give compound 102-1 (12.24 g) as an off-white solid . The yield thereof was found to be 54%. ESI-MS 211[ M+H ]] + .
And a second step of: 102-1 (10 g,47.62 mmol), (R) -tetrahydrofuran-3-yl 4-methylbenzenesulfonate (13.9 g,57.14 mmol) and cesium carbonate (23.3 g,71.43 mmol) are dissolved in N, N-dimethylformamide (80 mL) and stirred at 60℃for 3 hours. The reaction was cooled, filtered through celite, the filter cake was washed with ethyl acetate (100 mL), water was added to the filtrate, the aqueous phase was extracted with ethyl acetate (3 x100 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by beating with ethyl acetate to give compound 102-2 (8.9 g) as an off-white solid. The yield thereof was found to be 67%. ESI-MS 281[ M+H ]] + .
And a third step of: 102-2 (3 g,10.71 mmol) was dissolved in glacial acetic acid (15 mL). Nitric acid (3 ml) was slowly added dropwise at room temperature, warmed to 60℃and stirred for 10 hours. The reaction was cooled and then poured into water, extracted with dichloromethane (3×50 mL), washed with water, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 102-3 (3.3 g) as a brown oil. The yield thereof was found to be 94%. ESI-MS 326[ M+H ]] + .
Fourth step: 102-3 (3.3 g,10.02 mmol) was dissolved in ethanol (25 ml), iron powder (100 mesh, 5.2g,100.22 mmol), ammonium chloride (5.4 g,100.22 mmol) and water (25 ml) were added with stirring at room temperature, and the reaction was stirred at 90℃for 2 hours. The reaction was cooled, filtered through celite, the filter cake was washed with ethanol (100 mL) and ethyl acetate (100 mL), the filtrate was concentrated under reduced pressure, the remaining aqueous phase was extracted with ethyl acetate (3 x100 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give compound 102-4 (3.7 g, crude) as a brown solid. ESI-MS 296[ M+H ] ] + .
Fifth step: n (N) 2 102-4 (3.7 g), a dioxane solution (4M) of hydrochloric acid (20 mL) was dissolved in acetonitrile (20 mL) under an atmosphere. The reaction was stirred at room temperature for 2h, warmed to 90 ℃ and stirred for 10h. Cooling the reaction, filtering, eluting with dioxane, dissolving the filter cake with water, adjusting to neutrality with saturated sodium bicarbonate solution, and acetic acidEthyl ester extraction (3×50 mL), concentration followed by separation and purification by medium pressure flash column chromatography (eluent: dichloromethane: methanol=0-20%) afforded compound 102-5 (1 g) as an off-white solid. The total yield of the two steps was 33%. ESI-MS 305[ M+H ]] + .
Sixth step: 102-5 (120 mg,0.39 mmol) was dissolved in phosphorus oxychloride (3 ml). The reaction was heated to 100deg.C and stirred for 4 hours. After concentrating the system under reduced pressure, diluting with methylene chloride (20 mL), dropwise adding to a cold saturated sodium bicarbonate solution, separating the liquid, extracting the aqueous phase with methylene chloride (3×20 mL), combining the organic phases, drying over anhydrous sodium sulfate, concentrating, and separating and purifying by medium pressure flash column chromatography (eluent: methylene chloride: methanol=0-20%) to give compound 102-6 (50 mg) as a light brown solid. The yield thereof was found to be 40%. ESI-MS 323[ M+H ]] + .
Seventh step: 102-6 (50 mg,0.16 mmol) and (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethan-1-amine hydrochloride (44 mg,0.16 mmol) were dissolved in isopropanol (2 mL) and N, N-diisopropylethylamine (103 mg,0.8 mmol) was added dropwise and reacted at 110℃under reflux for 10h. The reaction was cooled, concentrated, water and ethyl acetate were added, the solution was separated, ethyl acetate (3×20 mL) was extracted, and the organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by medium pressure flash column chromatography (eluent: dichloromethane: methanol=0-20%) to give compound 102-7 (44 mg) as a white solid. The yield thereof was found to be 53%. ESI-MS 521[ M+H ] ] +
Eighth step: 102-7 (44 mg,0.084 mmol) was dissolved in ethanol (2 ml), iron powder (100 mesh, 47mg,0.85 mmol), ammonium chloride (45 g,0.85 mmol) and water (2 ml) were added with stirring at room temperature, and the reaction was stirred at 90℃for 2 hours. The reaction was cooled, filtered through celite, the filter cake was washed with ethanol (100 mL) and ethyl acetate (100 mL), the filtrate was concentrated under reduced pressure, the remaining aqueous phase was extracted with ethyl acetate (3X 100 mL), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the concentrate was dissolved with dimethyl sulfoxide (2 mL), and purified by a C18 reverse phase column (eluent: ACN:5mmol/L NH) 4 HCO 3 Aqueous = 0-40%). Lyophilization gives N- ((R) -1- (3-amino-5- (trifluoro)Methyl) phenyl) ethyl) -2-methyl-6- (((S) -tetrahydrofuran-3-yl) oxy) -8, 9-dihydro- [1,4]Dioxino [2,3-h]Quinazolin-4-amine (16 mg) as a white solid. The yield thereof was found to be 39%. ESI-MS 491[ M+H ]] + 。 1 H-NMR(400MHz,DMSO-d 6 )：δ7.89(s,1H),7.29(s,1H),6.82(s,2H),6.65(s,1H),5.52(s,3H),5.12(s,1H),4.29(s,4H),3.93(d,J＝8.1Hz,1H),3.87-3.75(m,3H),2.31(s,3H),2.25(td,J＝8.0,6.0Hz,1H),2.03-1.95(m,1H),1.50(d,J＝6.0Hz,3H)。
Example 4: preparation of (R) -N- (1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) -6-methoxy-2-methyl-8, 9-dihydro- [1,4] dioxino [2,3-h ] quinazolin-4-amine (Compound 105)
The first step: 101b-6 (110 mg,0.41 mmol) and (R) -1- (5-bromothiophen-2-yl) ethyl-1-amine hydrochloride (110 mg,0.49 mmol) were dissolved in dimethyl sulfoxide (1 mL), N-diisopropylethylamine (265 mg,2.05 mmol) was added dropwise, and the mixture was stirred at a temperature of 150℃for 10 hours. The reaction was cooled, concentrated, water and ethyl acetate were added, the mixture was separated, ethyl acetate (3X 20 mL) was extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated, the crude product was dissolved in dimethyl sulfoxide (2 mL), and purified by a C18 reverse phase column (eluent: ACN:5mmol/L NH) 4 HCO 3 Aqueous = 0-40%) to give compound 105-1 (100 mg) as a white solid. The yield thereof was found to be 67%. ESI-MS 437[ M+H ]] +
And a second step of: 105-1 (100 mg,0.23 mmol), (2- ((dimethylamino) methyl) phenyl) boronic acid (82 mg,0.46 mmol) and potassium carbonate (96 mg,0.69 mmol) were dissolved in a mixed solution (3 mL) of dioxane and water (5:1), tetrakis (triphenylphosphine) palladium (27 mg,0.02 mmol) was added under nitrogen, stirred at 100℃for 10h, the reaction cooled, concentrated, water 10mL was added, extracted with ethyl acetate (3X 20 mL), the organic phase was dried over anhydrous sodium sulphate, concentrated, the crude product obtained was dissolved with N, N-dimethylformamide (2 mL) and then subjected to a C18 reverse phase columnPurification (eluent: ACN:5mmol/L NH) 4 HCO 3 Aqueous = 40-60%), the target fractions were concentrated and lyophilized to give (R) -N- (1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) -6-methoxy-2-methyl-8, 9-dihydro- [1,4]Dioxino [2,3-h]Quinazolin-4-amine (25 mg) in 22% yield. ESI-MS 491[ M+H ]] + 。 1 H-NMR(400MHz,DMSO-d 6 )δ8.13(d,J＝8.3Hz,1H),7.45-7.41(m,1H),7.39-7.35(m,1H),7.34-7.27(m,3H),7.18(d,J＝3.6Hz,1H),7.07(d,J＝3.7,1.1Hz,1H),5.96(t,J＝7.3Hz,1H),4.31(s,4H),3.86(s,3H),3.34(s,2H),2.43(s,3H),2.11(s,6H),1.71(d,J＝6.9Hz,3H)。
Example 5: preparation of (R) -6-methoxy-2-methyl-N- (1- (3- (trifluoromethyl) phenyl) ethyl) -8, 9-dihydro- [1,4] dioxino [2,3-h ] quinazolin-4-amine (Compound 106)
101b-6 (100 mg,0.37 mmol) and (R) -1- (3- (trifluoromethyl) phenyl) ethan-1-amine hydrochloride (84 mg,0.37 mmol) were dissolved in isopropanol (4 mL), N-diisopropylethylamine (480 mg,3.74 mmol) was added dropwise, and the mixture was warmed to reflux for 10h. The reaction was cooled, concentrated, water and ethyl acetate were added, the mixture was separated, ethyl acetate (3X 20 mL) was extracted, the organic phase was dried over anhydrous sodium sulfate, concentrated, the crude product was dissolved in dimethyl sulfoxide (2 mL), and purified by a C18 reverse phase column (eluent: ACN:5mmol/L NH) 4 HCO 3 Aqueous = 0-40%). Lyophilization afforded the title compound (28 mg) as a white solid. The yield thereof was found to be 18%. ESI-MS 420[ M+H ]] + 。 1 H-NMR(400MHz,DMSO-d 6 )：δ8.01(s,1H),7.76(s,1H),7.71(s,1H),7.54(s,2H),7.35(s,1H),5.69-5.62(m,1H),4.32(s,4H),3.91(s,3H),2.29(s,3H),1.62(d,J＝6.8Hz,3H)。
Example 6: preparation of (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-7, 8-dihydro- [1,4] dioxino [2,3-g ] quinazolin-4-amine (Compound 201)
The first step: 1-bromo-3-nitro-5- (trifluoromethyl) benzene (20.0 g,74.1 mmol) was dissolved in dioxane (300 mL) and tributyl (1-ethoxyvinyl) tin (32.1 g,88.9 mmol), triethylamine (15.0 g,148.5 mmol) and Pd (PPh) 3 ) 2 Cl 2 (2.6 g,3.7 mmol) was stirred at 80℃for 16 hours under nitrogen. The reaction was cooled, hydrochloric acid (4M) (20 mL) was added to the system, stirred at room temperature for 2 hours, the system was concentrated under reduced pressure, diluted with water (100 mL), extracted with ethyl acetate (2 x100 mL), the organic phase was concentrated under reduced pressure, and the concentrate was purified by column chromatography (ethyl acetate: petroleum ether=0-30%) to give compound 201-1 (13.0 g) as a pale yellow oil in 75% yield. ESI-MS 234[ M+H ]] + .
And a second step of: 201-1 (10.0 g,42.9 mmol) was dissolved in tetrahydrofuran (150 mL), and (R) -2-methylpropane-2-sulfinamide (6.23 g,51.5 mmol) and tetraethyltitanate (19.6 g,86.0 mmol) were added and reacted under reflux for 8 hours. The reaction solution was cooled, poured into water to give a white precipitate, which was removed by filtration, the filter cake was washed with ethyl acetate, the filtrate was extracted with ethyl acetate (2×100 mL), the organic phase was concentrated under reduced pressure, and the concentrate was purified by column chromatography (ethyl acetate: petroleum ether=0-40%) to give compound 201-2 (12.9 g) as a pale yellow oil in 90% yield. ESI-MS 337[ M+H ] ] + .
And a third step of: 201-2 (12.9 g,38.4 mmol) was dissolved in tetrahydrofuran (150 mL), -sodium borohydride (2.6 g,69.1 mmol) was added at 78deg.C, the reaction was slowly warmed to room temperature, and TLC monitored the completion of the starting material reaction. The reaction was quenched with water, extracted with ethyl acetate (100 mL), the organic phase concentrated under reduced pressure, and the concentrate was purified by column chromatography (ethyl acetate: petroleum ether=0-40%) to give compound 201-3 as a pale yellow solid in 65% yield. ESI-MS 339[ M+H ]] + .
Fourth step: 201-3 (8.5 g,25.1 mmol) was dissolved in dioxane (100 mL), hydrochloric acid (4M, solution in dioxane) (15 mL) was added, the reaction was stirred at room temperature, TLC monitored complete reaction of starting material, filtered, the filter cake was washed with ethyl acetate, and the product was dried to give compound 201-4 (5.3 g) as a white solid in 78% yield. ESI-MS 235[ M+H ]] + .
Fifth step: 2, 3-Dihydrobenzo [ b ]][1,4]Dioxin-6-carboxylic acid methyl ester (10.0 g,51.5 mmol) was dissolved in acetic acid (30 mL), concentrated nitric acid (8 mL) was added under ice-water bath, and the reaction solution was stirred at 70℃for 6 hours. The reaction was cooled and poured into ice water, solid formed, filtered, the filter cake was washed with water and dried in vacuo to give compound 201-5 (10.1 g) as a pale yellow solid in yield (82%). ESI-MS 240[ M+H ] ] + .
Sixth step: 201-5 (2.2 g,9.2 mmol) was dissolved in ethanol (15 mL) and water (4 mL), iron powder (5.2 g,92.1 mmol) and ammonium chloride (4.9 g,92.1 mmol) were added, and the reaction was stirred at 90℃for 3 hours. The reaction was cooled, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, the concentrate was diluted with water (10 mL), extracted with ethyl acetate (2 x20 mL), and the organic phase was concentrated under reduced pressure to give compound 201-6 (1.8 g) as a brown solid in 94% yield. ESI-MS 210[ M+H ]] + .
Seventh step: 201-6 (1.8 g,8.6 mmol) was dissolved in acetonitrile (15 mL), concentrated hydrochloric acid was added dropwise until all solids were dissolved, and then the reaction solution was stirred at 80℃for 16 hours. The reaction was cooled, the resulting precipitate was filtered, and the filter cake was washed with acetonitrile and dried to give compound 201-7 (460 mg) as a white solid in 26% yield. ESI-MS 219[ M+H ]] + .
Eighth step: 201-7 (460 mg,2.1 mmol) was dissolved in phosphorus oxychloride (15 mL), and the reaction solution was stirred at 100℃for 4 hours. The reaction was cooled, concentrated under reduced pressure, the crude product was dissolved with dichloromethane, the organic phase was washed with saturated sodium bicarbonate solution and concentrated under reduced pressure to give compound 201-8 (350 mg) as a yellow solid in 71% yield. ESI-MS 237[ M+H ] ] + .
Ninth step: 201-8 (120 mg,0.5 mmol) was dissolved in isopropylAlcohol (4 mL), added (R) -1- (3-nitro-5- (trifluoromethyl) phenyl) ethan-1-amine hydrochloride (1-4) (177 mg,0.7 mmol) and N, N-diisopropylethylamine (194 mg,1.5 mmol) and reacted at reflux for 6 hours. The reaction was cooled, concentrated under reduced pressure, and the concentrate was purified by column chromatography (methanol: dichloromethane=0-10%) to give compound 201-9 (70 mg), yield 32%. ESI-MS 435[ M+H ]] + .
Tenth step: 201-9 (70 mg,0.2 mmol) was dissolved in ethanol (6 mL) and water (2 mL), iron powder (112 mg,2.0 mmol) and ammonium chloride (107 mg,2.0 mmol) were added, and the reaction solution was stirred at 90℃for 2 hours. The reaction was cooled, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, the concentrate was diluted with water (10 mL), extracted with ethyl acetate (2X 10 mL), the organic phase was concentrated under reduced pressure, and the concentrate was isolated and purified by high pressure preparative liquid chromatography to give (R) -N- (1- (3-amino-5- (trifluoromethyl) phenyl) ethyl) -2-methyl-7, 8-dihydro- [1, 4)]Dioxino [2,3-g]Quinazolin-4-amine (26.7 mg) was a white solid in 41% yield. ESI-MS 405[ M+H ]] + 。 1 H-NMR(400MHz,DMSO-d 6 )δ:ppm 7.96(d,J＝8.0Hz,1H),7.89(s,1H),6.97(s,1H),6.88(s,1H),6.83(s,1H),6.68(s,1H),5.52-5.48(m,3H),4.35-4.33(m,4H),2.32(s,3H),1.51(d,J＝8.0Hz,3H)。
Example 7: preparation of (R) -N- (1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) -2-methyl-7, 8-dihydro- [1,4] dioxino [2,3-g ] quinazolin-4-amine (Compound 203)
The first step: compound 201-8 (300 mg,1.3 mmol) was dissolved in isopropanol (6 mL), and (R) -1- (5-bromothiophen-2-yl) ethyl-1-amine hydrochloride (470 mg,2.0 mmol) and N, N-diisopropylethylamine (516 mg,4.0 mmol) were added and the reaction stirred at 110℃under reflux for 16h. Cooling, concentrating under reduced pressure, separating and purifying the concentrate by column chromatography (methanol: dichloromethane=0-10%) to obtain (R) -N- (1- (5-bromothiophene-2-yl) ethyl) -2-methyl-7, 8-dihydro- [1, 4)]Dioxin union[2,3-g]Quinazolin-4-amine (203-1) (203 mg) was obtained in 38% yield. ESI-MS 406[ M+H ]] +
And a second step of: 203-1 (140 mg,0.3 mmol) was dissolved in 1, 4-dioxane/water (5:1) (6 mL), and (2- ((dimethylamino) methyl) phenyl) boric acid (125 mg,0.7 mmol), tetrakis (triphenylphosphine) palladium (35 mg,0.1 mmol) and potassium carbonate (138 mg,1.0 mmol) were added and the reaction solution was reacted at 100℃for 16 hours under nitrogen. The reaction solution was cooled, filtered, the filtrate was concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (10 mL), and the organic phase was concentrated under reduced pressure, and the concentrate was separated and purified by column chromatography (methanol: dichloromethane=0 to 8%) and high pressure liquid chromatography to give (R) -N- (1- (5- (2- ((dimethylamino) methyl) phenyl) thiophen-2-yl) ethyl) -2-methyl-7, 8-dihydro- [1,4 ]Dioxino [2,3-g]Quinazolin-4-amine (compound 203) (30.43 mg), a white solid, yield 19%. ESI-MS 461[ M+H ]] + 。 1 H-NMR(400MHz,DMSO-d 6 )δ:ppm 8.13(s,1H),7.69(d,J＝8.0Hz,1H),7.55-7.48(m,3H),7.44(d,J＝4.0Hz,1H),7.21(d,J＝8.0Hz,1H),7.16(s,1H),7.11(d,J＝4.0Hz,1H),6.08～6.04(m,1H),4.48-4.41(m,6H),2.66(s,6H),2.63(s,3H),1.78(d,J＝8.0Hz,3H)。
Example 8: preparation of (R) -2- (6-methyl-8- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -1H-pyrazolo [3,4-g ] quinazolin-1-yl) ethan-1-ol (506)
The first step: 1H-indazole-6-carboxylic acid methyl ester (5.0 g,28.4 mmol) was dissolved in sulfuric acid/acetic acid mixture (1:2, 30 mL), concentrated nitric acid (8 mL) was added in an ice bath, and stirred at room temperature for 16 hours. The reaction solution was poured into ice water, extracted with ethyl acetate (2×100 mL), the organic phase was concentrated under reduced pressure, and the concentrate was purified by column chromatography (ethyl acetate: petroleum ether=0 to 60%) to give methyl 5-nitro-1H-indazole-6-carboxylate (506-1) (5.6 g), as a pale yellow oil, with a yield of 89%. ESI-MS 222[ M+H ]] +
And a second step of: 506-1 (5.6 g,25.2 mmol) was dissolvedTo acetonitrile (40 mL) were added potassium carbonate (10.4 g,75.7 mmol) and ((2-bromoethoxy) methyl) benzene (6.0 g,27.7 mmol), and the reaction was reacted at 80℃for 4 hours. The reaction solution was cooled, concentrated under reduced pressure, diluted with water (100 mL), extracted with ethyl acetate (2×100 mL), and the organic phase was concentrated under reduced pressure, and the concentrate was purified by column chromatography (ethyl acetate: petroleum ether=0 to 60%) to give methyl 1- (2- (benzyloxy) ethyl) -5-nitro-1H-indazole-6-carboxylate (506-2) (4.0 g), a pale yellow solid, yield 45%. ESI-MS 356[ M+H ] ] +
And a third step of: a solution of (506-2) (2.0 g,5.6 mmol) in methanol (20 mL) was added with a solution of iron powder (3.1 g,56.1 mmol) and ammonium chloride (3.0 g,56.1 mmol) in water (5 mL), and the reaction solution was reacted at 80℃for 3 hours. Cooled, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, the concentrate was diluted with water (10 mL), extracted with ethyl acetate (2 x20 mL), and the organic phase was concentrated under reduced pressure to give methyl 1- (2- (benzyloxy) ethyl) -5-amino-1H-indazole-6-carboxylate (506-3) (1.6 g), a brown solid, yield 89%. ESI-MS 326[ M+H ]] +
Fourth step: (506-3) (1.6 g,4.9 mmol) was dissolved in acetonitrile (15 mL), concentrated hydrochloric acid was added dropwise until the resultant precipitate was dissolved, and then the reaction solution was stirred at 80℃for 16 hours. Cooling, filtering the precipitate, washing the filter cake with acetonitrile, and drying to obtain 1- (2- (benzyloxy) ethyl) -6-methyl-1, 7-dihydro-8H-pyrazolo [3, 4-g)]Quinazolin-8-one (506-4) (400 mg), a white solid, yield 25%. ESI-MS 335[ M+H ]] +
Fifth step: (506-4) (460 mg,1.4 mmol) was dissolved in phosphorus oxychloride (15 mL), and the reaction solution was stirred at 100℃for 14 hours. Cooling, concentrating under reduced pressure, dissolving the crude product with dichloromethane, washing the organic phase with saturated sodium bicarbonate solution, concentrating under reduced pressure to obtain 1- (2- (benzyloxy) ethyl) -8-chloro-6-methyl-1H-pyrazolo [3, 4-g) ]Quinazoline (506-5) (200 mg), yellow solid in 40% yield. ESI-MS 353[ M+H ]] +
Sixth step: (506-5) (120 mg,0.3 mmol) was dissolved in toluene (5 mL), and (R) -1- (3- (trifluoromethyl) phenyl) ethan-1-amine hydrochloride (99 mg,0.4 mmol), pd was added 2 (dba) 3 (30 mg,0.1 mmol) and sodium tert-butoxide (95 m)g,1.0 mmol) under nitrogen protection at 100deg.C for 13 hours. Cooling, filtering, washing filter cake with ethyl acetate, decompressing and concentrating filtrate, separating and purifying concentrate by column chromatography (methanol: dichloromethane=0-5%) to obtain (R) -1- (2- (benzyloxy) ethyl) -6-methyl-N- (1- (3- (trifluoromethyl) phenyl) ethyl) -1H-pyrazolo [3, 4-g)]Quinazolin-8-amine (506-6) (30 mg), brown solid, yield 21%. ESI-MS 506[ M+H ]] +
Seventh step: (506-6) (30 mg,0.1 mmol) was dissolved in toluene (2 mL), trifluoroacetic acid (1 mL) was added, and the reaction mixture was reacted at 70℃for 4 hours. Cooling, concentrating under reduced pressure, dissolving the crude product with tetrahydrofuran, adding aqueous sodium hydroxide solution, stirring at 40deg.C for 1 hr, cooling, extracting with ethyl acetate (10 mL), concentrating the organic phase under reduced pressure, and separating and purifying the concentrate by high pressure liquid chromatography to obtain (R) -2- (6-methyl-8- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -1H-pyrazolo [3, 4-g) ]Quinazolin-1-yl) ethan-1-ol (506) (2.0 mg), white solid, yield 41%. ESI-MS 416[ M+H ]] + 。 1 H-NMR(400MHz,DMSO-d 6 )δ:ppm 8.74(s,1H),8.55(s,1H),8.31(s,1H),8.04(s,1H),7.85(s,1H),7.80(d,J＝8.0Hz,1H),7.62-7.56(m,2H),5.76-5.72(m,1H),4.98(t,1H),4.57(t,2H),3.93(t,2H),2.39(s,3H),1.68(d,J＝8.0Hz,3H)。
Example 9: preparation of (R) -2, 6-dimethyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -6H- [1,4] oxazin [3,2-g ] quinazolin-7 (8H) -one (Compound 507)
The first step: methyl 4-hydroxy-3-nitrobenzoate (5.9 g,30.0 mmol) was dissolved in acetone (200 mL) and potassium carbonate (20.7 g,150.0 mmol) and methyl bromoacetate (6.0 g,39.0 mmol) were added. The reaction was heated to 60 ℃ and stirred for 5 hours. The reaction was cooled, filtered and the filter cake was washed with acetone (20 mL). Concentrating the filtrate under reduced pressure, recrystallizing in petroleum ether (500 mL), filtering, washing the filter cake with petroleum ether (20 mL), and oven drying to obtain compound 507-1 (6.7 g), which isAs a pale yellow solid. The yield thereof was found to be 83%. ESI-MS 270[ M+H ]] + .
And a second step of: 507-1 (6.7 g,24.9 mmol) was dissolved in ethanol/water (100 mL/100 mL). Iron powder (100 mesh, 14.0g,250 mmol), ammonium chloride (13.4 g,250 mmol) and acetic acid (68%, 8 mL) were added with stirring at room temperature. The reaction was heated to 90 ℃ and stirred for 16 hours. The reaction was cooled, filtered through celite, the filter cake was washed with ethyl acetate (50 mL), the filtrate was concentrated under reduced pressure, extracted with ethyl acetate/water (1:1, 800 mL), then the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by medium pressure flash column chromatography (eluent: ethyl acetate: petroleum ether=0-50%) to give compound 507-2 (3.7 g) as a pale yellow solid. The yield thereof was found to be 71%. ESI-MS 208[ M+H ] ] + .
And a third step of: 507-2 (3.7 g,17.9 mmol) was dissolved in N, N-dimethylformamide (40 mL). Potassium carbonate (7.4 g,53.7 mmol) and methyl iodide (1.7 mL,26.9 mmol) were added with stirring at room temperature. The reaction was heated to 60 ℃ and stirred for 10 hours. The reaction solution was poured into ice water (200 mL), then extracted with ethyl acetate (2×200 mL), then washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 507-3 (3.4 g) as a pale yellow solid. The yield thereof was found to be 85%. ESI-MS 222[ M+H ]] + .
Fourth step: 507-3 (3.4 g,15.4 mmol) was dissolved in acetic acid (30 mL). Nitric acid (68%, 10.0 mL) was slowly added dropwise at room temperature. The reaction was heated to 60 ℃ and stirred for 10 hours. The reaction solution was poured into ice water (200 mL), then extracted with ethyl acetate (2×200 mL), then washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was separated and purified by medium pressure flash silica gel column chromatography (eluent: ethyl acetate: petroleum ether=0-50%) to give compound 507-4 (2.6 g) as pale yellow solid. The yield thereof was found to be 63%. ESI-MS 267[ M+H ]] + .
Fifth step: 507-4 (2.6 g,9.8 mmol) was dissolved in ethanol/water (20 mL/20 mL). Iron powder (100 mesh, 5.5g,98 mmol) and ammonium chloride (5.2 g, 98 mmol) was heated to 90℃and stirred for 10 hours. The reaction was cooled, filtered through celite, the filter cake was washed with ethyl acetate (50 mL), the filtrate was concentrated under reduced pressure, extracted with ethyl acetate/water (1:1, 200 mL), then the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by medium pressure flash column chromatography (eluent: ethyl acetate: petroleum ether=0-50%) to give compound 507-5 (1.7 g) as a pale yellow solid. The yield thereof was found to be 74%. ESI-MS 237[ M+H ]] + .
Sixth step: 507-5 (1.7 g,7.2 mmol) was added to acetonitrile (20 mL). A dioxane solution of hydrochloric acid (4N, 20 mL) was added with stirring at room temperature. The reaction was heated to 90 ℃ and stirred for 12 hours to yield a large amount of solids. The reaction was cooled, filtered, and the filter cake was washed with water (20 mL) and dried to give compound 507-6 (1.3 g) as an off-white solid. The yield thereof was found to be 71%. ESI-MS:246[ M+H ]] + .
Seventh step: 507-6 (1.3 g,5.3 mmol) was added to phosphorus oxychloride (25 mL). The reaction was heated to 100deg.C, stirred for 10 hours, concentrated directly under reduced pressure, the concentrate was dissolved in dichloromethane (80 mL), washed with saturated aqueous sodium bicarbonate (3×80 mL), then with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by medium pressure flash column chromatography (eluent: ethyl acetate: petroleum ether=0-30%) to give compound 507-7 (0.91 g) as a pale yellow solid. The yield thereof was found to be 65%. ESI-MS 264[ M+H ] ] + .
Eighth step: 507-7 (100 mg,0.4 mmol) was dissolved in dimethyl sulfoxide (3 mL), and (R) -1- (3- (trifluoromethyl) phenyl) ethan-1-amine hydrochloride (126 mg,0.6 mmol) and N, N-diisopropylethylamine (2.7 g,21.3 mmol) were added to stir the reaction at 130℃for 16 hours. The reaction was cooled, diluted with water (10 mL), extracted with ethyl acetate (20 mL), the organic phase concentrated under reduced pressure and the concentrate was purified by column chromatography (methanol: dichloromethane=0-8%) to give (R) -2, 6-dimethyl-4- ((1- (3- (trifluoromethyl) phenyl) ethyl) amino) -6H- [1,4]Oxazine [3,2-g]Quinazolin-7 (8H) -one (40.23 mg) was a white solid in 50% yield. ESI (electronic service provider interface)-MS:417[M+H] + 。 1 H-NMR(400MHz,DMSO-d 6 )δ:ppm 8.33(d,J＝8.0Hz,1H),7.94(s,1H),7.80(s,1H),7.75(d,J＝8.0Hz,1H),7.61-7.55(m,2H),7.09(s,1H),5.72-5.65(m,1H),4.78(s,2H),3.43(s,3H),2.34(s,3H),1.64(d,J＝8.0Hz,3H)。
Biological assays
Experimental example 1 KRAS: SOS1HTRF binding assay
This assay can be used to examine the inhibition of SOS1 and KRAS by compounds G12C Potency of the protein-protein interaction between. This demonstrates the molecular mode of action of the compounds. Low IC 50 The values indicate high efficacy of SOS1 inhibitor compounds in this assay set-up below.
Reagent:
GST-SOS1 (aa 564-1049), internal production
His-KRAS G12C (aa 1-169), internal production
MAb Anti-6HIs-Tb cryptate Gold, available from Cisbio (catalog number 61HI2 TLA)
MAb Anti-GST-XL665, available from Cisbio (catalog number 61 GSTXLA)
Assay plate: proxiPlate-384Plus, available from Perkinelmer (catalog number 6008280)
Assay buffer: PPI, available from Cisbio (catalog number 61DB10 RDF)
Measurement protocol:
dissolving a compound to be tested in DMSO to prepare a stock solution with a concentration of 10mM, diluting the compound concentration to 2mM as an initial concentration for measurement, continuously diluting the compound solution with the initial concentration of 2mM by 3 times, diluting 10 concentrations in total, and transferring 0.1 mu L of each concentration of the compound solution to a 384-well assay plate by using a Labcyte Echo instrument (in duplicate, double-well);
add 5. Mu.L of His-KRAS G12C at a specific concentration to 0.1. Mu.L of the compound solution and centrifuge on an Eppendorf 5810R centrifuge at 1000rpm for 1min;
subsequently, 5. Mu.L of GST-SOS1 was added at a specific concentration, and the mixture was centrifuged at 1000rpm for 1min in an Eppendorf 5810R centrifuge as well;
incubating 384-well assay plates for 15min at 25 ℃;
then 10. Mu.L of the mixture of MAb Anti-6his-Tb and MAb Anti-GST-XL665 was added and centrifuged at 1000rpm for 1min on an Eppendorf 5810R centrifuge;
384 well assay plates were incubated for 2h at 25 ℃;
finally, using a Perkin Elmer Envision 2104 instrument read plate, a 665/615nm signal ratio was obtained.
Each plate contained the following controls:
·DMSO+KRAS+SOS1+MAb Anti-6his-Tb+MAb Anti-GST-XL665
and (3) calculating results:
Calculation and analysis of IC using 4-parameter regression equation 50 Values. The measurement results are shown in the following table.
Numbering of compounds SOS1-KRAS G12C interaction assay (IC 50 nM)
101a 46.5
101b 18.3
102 14.9
105 21.8
201 65.1
203 65.2
506 62.0
507 81.9
Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other publications) is incorporated herein by reference in its entirety.

Claims (12)

  1. A compound, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of formula (I) or formula (I'):
    wherein:
    ring A and ring B are each independently selected from C 3-10 Hydrocarbon ring, 3-10 membered heterocycle, C 6-10 Aromatic rings and 5-14 membered heteroaromatic rings, up to 2 ring members of which are C (=o);
    r and R 1 Each at each occurrence is independently selected from halogen, -NH 2 、-CN、-NO 2 、-OH、-O-C 1-6 Alkyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 alkylene-OH, halogenated C 1-6 alkylene-OH, C 2-6 Alkenyl, C 2-6 Alkynyl, saturated or partially unsaturated C 3-10 Cycloalkyl, saturated or partially unsaturated 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl groups, up to 2 ring members of the cyclic hydrocarbon and heterocyclic groups being C (=o), when m is greater than 1 and/or n is greater than 1, two R 1 And/or two R together with the atom to which they are attached optionally form C 3-10 Hydrocarbon ring, 3-10 membered heterocycle, C 6-10 An aromatic ring or a 5-14 membered heteroaromatic ring, up to 2 ring members of the hydrocarbon ring and the heterocyclic ring being C (=o);
    R 2 、R 2 ’、R 3 and R is 4 Each independently selected from H, halogen, -NH 2 、-CN、-NO 2 、-OH、-O-C 1-6 Alkyl, -O- (3-10 membered heterocyclic group), C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 alkylene-OH, halogenated C 1-6 alkylene-OH, C 2-6 Alkenyl, C 2-6 Alkynyl, saturated or partially unsaturated C 3-10 Cycloalkyl, saturated or partially unsaturated 3-to 10-membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -C (=o) R 5 、-OC(＝O)R 5 、-C(＝O)OR 5 、-OR 5 、-SR 5 、-S(＝O)R 5 、-S(＝O) 2 R 5 、-S(＝O) 2 NR 5 R 6 、-NR 5 R 6 、-C(＝O)NR 5 R 6 、-NR 5 -C(＝O)R 6 、-NR 5 -C(＝O)OR 6 、-NR 5 -S(＝O) 2 -R 6 、-NR 5 -C(＝O)-NR 5 R 6 、-C 1-6 alkylene-NR 5 R 6 、-C 1-6 alkylene-O (p=o) (OH) 2 and-O-C 1-6 alkylene-NR 5 R 6 ；
    Each of the foregoing groups is optionally substituted at each occurrence with one or more substituents independently selected from the group consisting of: halogen, -OH, oxo, -NH 2 、-CN、-NO 2 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, =n-OR 5 、-C(＝NH)NH 2 、-C(＝O)R 5 、-OC(＝O)R 5 、-C(＝O)OR 5 、-OR 5 、-SR 5 、-S(＝O)R 5 、-S(＝O) 2 R 5 、-S(＝O) 2 NR 5 R 6 、-NR 5 R 6 、-C(＝O)NR 5 R 6 、-NR 5 -C(＝O)R 6 、-NR 5 -C(＝O)OR 6 、-NR 5 -S(＝O) 2 -R 6 、-NR 5 -C(＝O)-NR 5 R 6 、-C 1-6 alkylene-NR 5 R 6 and-O-C 1-6 alkylene-NR 5 R 6 The alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and aralkyl groups are further optionally substituted with one or more substituents independently selected from the group consisting of: halogen, -OH, oxo, -NH 2 、-CN、-NO 2 、C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 An aralkyl group;
    R 5 and R is 6 At each occurrenceEach independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 An aralkyl group;
    m is an integer selected from 0, 1, 2, 3 and 4; and is also provided with
    n is an integer selected from 0, 1, 2 or 3.
  2. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein R is independently at each occurrence C 1-6 Alkyl or C 1-6 An alkylene-OH; preferably, R is, independently at each occurrence, methyl or-CH 2 CH 2 -OH。
  3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein ring a is a 3-10 membered heterocycle or a 5-14 membered heteroaryl ring comprising one or more ring members selected from-O-, -NR-and-n=; preferably, the method comprises the steps of, Is that Most preferably, the first and second regions are,is that
  4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labelled compound, metabolite or prodrug thereof, wherein ring B is a bicyclo [1.1.1] pentane ring, a 2-oxabicyclo [2.1.1] hexane ring, a benzene ring or a thiophene ring, most preferably a benzene ring or a thiophene ring.
  5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein R 1 Each at each occurrence is independently selected from halogen, -NH 2 、C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 alkylene-OH, halogenated C 1-6 alkylene-OH, saturated or partially unsaturated C 3-10 Cycloalkyl, saturated or partially unsaturated 3-to 10-membered heterocyclyl, C 6-10 Aryl and 5-14 membered heteroaryl, said alkylene, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally being independently selected from one or more of halogen, -OH, C 3-6 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Substituents for aryl and 5-14 membered heteroaryl;
    when m is greater than 1, two R 1 Optionally together with the atoms to which they are attached form C 3-10 Hydrocarbon ring, 3-10 membered heterocycle, C 6-10 An aromatic ring or a 5-14 membered heteroaromatic ring, up to 2 ring members of which are C (=o), and which are optionally substituted with one or more halogens;
    preferably, R 1 Each at each occurrence is independently selected from CF 3 、NH 2 Andand m is 1 or 2.
  6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, whereinSelected from the group consisting of
  7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein R 2 And R is 2 ' each independently selected from H, -O-C 1-6 Alkyl and-O- (3-10 membered heterocyclyl); preferably, R 2 And R is 2 ' one of which is H and the other is H, -OCH 3 Or (b)
  8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein R 3 And R is 4 Each independently selected from H and C 1-6 An alkyl group; preferably, R 3 Is methyl, and R 4 H.
  9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of formula (II), formula (III), formula (IV), or formula (V):
  10. the compound of any one of claims 1-9, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein the compound is selected from the group consisting of:
  11. a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, and a pharmaceutically acceptable carrier, preferably in a solid, semi-solid, liquid or gaseous formulation.
  12. Use of a compound according to any one of claims 1-10, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 11, for the manufacture of a medicament for the prevention or treatment of cancer (e.g. pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myelogenous leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal carcinoma and sarcoma), RAS diseases (e.g. neurofibromatosis type 1 (NF 1), noonan Syndrome (NS), noonan syndrome with multiple spots (NSML), capillary-arteriovenous syndrome (AVM), CS-co-ordinates syndrome (CS), genetics-fibrous disease and genetics syndrome (CFC-co-morbid) of the heart-face).
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