WO2022028506A1 - Sos1抑制剂、包含其的药物组合物及其用途 - Google Patents

Sos1抑制剂、包含其的药物组合物及其用途 Download PDF

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WO2022028506A1
WO2022028506A1 PCT/CN2021/110746 CN2021110746W WO2022028506A1 WO 2022028506 A1 WO2022028506 A1 WO 2022028506A1 CN 2021110746 W CN2021110746 W CN 2021110746W WO 2022028506 A1 WO2022028506 A1 WO 2022028506A1
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compound
ring
alkyl
alkylene
membered
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PCT/CN2021/110746
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French (fr)
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赵焰平
王红军
张道广
王晓倩
侯翠柳
冯泽旺
张嘉雪
张磊
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北京泰德制药股份有限公司
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Priority to CN202180057482.2A priority Critical patent/CN116194446A/zh
Publication of WO2022028506A1 publication Critical patent/WO2022028506A1/zh

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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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • 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

Definitions

  • the present invention relates to SOS1 inhibitors, pharmaceutical compositions containing them, and their use for preventing or treating diseases.
  • 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.
  • KRAS Kerrsten murine sarcoma virus oncogene homolog
  • HRAS Hardvey murine sarcoma virus oncogene
  • NRAS nerveroblastoma RAS virus oncogene homolog
  • GTPase activating protein GTPase activating protein
  • GAP GTPase activating protein
  • GAP GTPase activating protein
  • GEF Guanine nucleotide exchange factor
  • SOS1 protein Son of Sevenless 1
  • Activated RAS protein can activate multiple signal transductions such as RAF/MEK/ERK (MAPK) pathway and PI3K/AKT/mTOR pathway by activating a series of downstream effector proteins (including RAF and phosphatidylinositol kinase PI3K, etc.) pathways, thereby regulating a variety of cellular processes such as cell proliferation, survival, metabolism, motility, angiogenesis, immunity, and growth.
  • Mutation of RAS family proteins can inhibit their intrinsic GTPase activity and GAP-induced GTPase activity, resulting in persistent activation of RAS proteins, which in turn leads to persistent activation of downstream effector pathways of RAS proteins.
  • RAS is the most frequently mutated oncogene in human cancers.
  • KRAS mutations are widely present in a variety of human cancers, including lung, colorectal, and pancreatic cancer. HRAS mutations and NRAS mutations also occur. in different human cancer types. Mutation, overexpression and gene amplification of RAS protein are potential mechanisms of resistance to various anticancer drugs (eg, EGFR antibodies cetuximab and panitumumab, EGFR tyrosine kinase inhibitor osimertinib).
  • anticancer drugs eg, EGFR antibodies cetuximab and panitumumab, EGFR tyrosine kinase inhibitor osimertinib.
  • SOS1 is the human homolog of the Drosophila SOS protein.
  • SOS1 protein is a multi-domain protein composed of 1333 amino acids, consisting of N-terminal domain, Dbl homology domain (Dbl homology, DH), Pleckstrin substrate protein homology domain (Pleckstrin homology, PH), RAS exchange Motif (Ras exchanger motif, REM), CDC25 homology domain and C-terminal domain, among which REM and CDC25 homology domain together form a catalytic domain, which is the catalytic function of SOS1 protein to play a guanine nucleotide exchange factor the required part.
  • SOS1 has a critical role in the activation and signaling of mutant RAS proteins in RAS-mutant cancers, and SOS1 knockout inhibits the survival and proliferation of KRAS-mutant tumor cells, and is re-expressed in SOS1-knockout KRAS-mutant tumor cells Catalytic site mutant SOS1, tumor cells could not restore survival and proliferation, demonstrating that the guanine nucleotide exchange catalytic activity of SOS1 is critical for the survival and proliferation of KRAS mutant tumor cells.
  • SOS1 can also participate in the signal activation and transduction process of tumor cells through other mechanisms.
  • SOS1 can bind to growth factor receptor-binding protein Grb2 to form a SOS1-Grb2 complex, which in turn binds to activated receptor tyrosine kinases (such as 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 recruited by other cell surface membrane receptors (such as TCR, BCR, CSF1R).
  • SOS1 acts as a guanine nucleotide exchange factor to activate the GTPase RAC1, which is associated with a variety of human cancers and other diseases.
  • SOS1 mutations are present in embryonal rhabdomyosarcoma, Sertolioma, cutaneous granulosa cell tumor, and lung adenocarcinoma, and overexpression of the SOS1 protein has also been found in bladder and prostate cancers.
  • SOS2 is a homologue of SOS1 in mammalian cells and also functions as a guanine nucleotide exchange factor.
  • Mouse knockout model studies have shown that germline knockout of SOS1 can lead to the death of mouse embryos in the second trimester, while adult mice continue to survive after knockout of SOS1. None of the mice exhibited any apparent phenotypic changes, while adult mice with SOS1/2 double knockout died rapidly, suggesting that selective targeting of SOS1 may achieve a high therapeutic index for SOS1-regulated RAS-mutant tumors.
  • Inhibiting the binding of SOS1 catalytic site to RAS protein can block SOS1-mediated RAS protein activation, thereby inhibiting RAS protein downstream signaling (such as ERK phosphorylation activation, etc.).
  • SOS1 inhibitors with such a mechanism of action can inhibit mutant RAS.
  • Protein-dependent tumor cells such as KRAS mutant tumor cell lines have inhibitory effects (eg, inhibition of proliferation, survival, metastasis, etc.).
  • the present invention provides compounds useful as SOS1 inhibitors, which have excellent inhibitory activity against SOS1.
  • the SOS1 inhibitor of the present invention can inhibit the interaction and activation of SOS1 and RAS protein, especially has a significant inhibitory effect on the interaction between SOS1 and KRAS mutant protein, and can be used for carrying RAS and upstream and downstream proteins (including KRAS, NRAS, HRAS, Receptor tyrosine kinases (eg 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 (eg, NF1) and SOS1) mutated cancer patients provide pharmacological benefit.
  • RAS upstream and downstream proteins
  • Receptor tyrosine kinases eg EGFR, ErbB2/3/4, PDGFR-A/B, FGFR1/2/3,
  • SOS1 inhibitors in RAC1-dependent cancers and other diseases associated with dysregulation of RAS signaling pathway such as neurofibromas, Noonan syndrome (NS), cardio-facial-cutaneous syndrome (CFC) and hereditary gingival fibrosis type 1 Pharmacological benefits will also be provided in tumors.
  • the compounds of the invention also have better physicochemical properties (eg solubility, physical and/or chemical stability), improved pharmacokinetic properties (eg improved bioavailability, suitable half-life and duration of action), improved safety (lower toxicity and/or fewer side effects, wider therapeutic window) and other more excellent properties.
  • physicochemical properties eg solubility, physical and/or chemical stability
  • improved pharmacokinetic properties eg improved bioavailability, suitable half-life and duration of action
  • improved safety lower toxicity and/or fewer side effects, wider therapeutic window
  • 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 Said compound has the structure of formula (I):
  • R 5 and R 6 at each occurrence are each independently selected from H, C 1-6 alkyl, C 3-10 cyclohydrocarbyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl; and
  • n is an integer selected from 0, 1, 2, 3 and 4.
  • compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N- Oxides, isotopically-labeled compounds, metabolites or prodrugs and one or more pharmaceutically acceptable carriers, the pharmaceutical composition is preferably a solid preparation, semi-solid preparation, liquid preparation or gaseous preparation.
  • Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or pro- Use of the medicament or the pharmaceutical composition of the present invention in the preparation of a medicament for use as an SOS1 inhibitor.
  • Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or pro- A drug or a pharmaceutical composition of the present invention for use as an SOS1 inhibitor.
  • Another aspect of the present invention provides a method of preventing or treating SOS1-related diseases, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, Polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions of the invention.
  • alkylene refers to a saturated divalent hydrocarbon radical, preferably a saturated divalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon.
  • the alkyl group has 1 to 12, eg, 1 to 6, carbon atoms.
  • C 1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl) , isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl) optionally substituted by 1 or more (such as 1 to 3) suitable substituents
  • halogen substituted where the group is referred to as "haloalkyl”
  • haloalkyl eg CH2F , CHF2 , CF3 , CCl3 , C2F5 , C2
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).
  • alkenyl means a linear or branched monovalent hydrocarbon group containing one double bond and having 2-6 carbon atoms (“C 2-6 alkenyl”).
  • the alkenyl groups are, for example, vinyl, 1-propenyl, 2-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.
  • the compound of the present invention contains an alkenylene group, the compound may exist in pure E (ent ought) form, pure Z (zusammen) form, or any mixture thereof.
  • alkynyl refers to 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.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) , cyclooctyl, cyclononyl, or bicyclic, including spiro, fused, or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.)), which are optionally substituted with 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl
  • cyclooctyl cyclonony
  • the cycloalkyl group has 3 to 15 carbon atoms.
  • C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, cyclopropyl, cyclobutyl, cyclopentyl or cyclo) of 3 to 6 ring carbon atoms hexyl), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, eg methyl substituted cyclopropyl.
  • cyclohydrocarbylene refers to rings having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbons Atoms saturated (ie, “cycloalkylene” and “cycloalkyl") or unsaturated (ie having one or more double and/or triple bonds in the ring) monocyclic or polycyclic (including spirocycles) , fused or bridged systems) hydrocarbon rings including, but not limited to ()cyclopropylidene (ring), ()cyclobutylidene (ring), ()cyclopentylene (ring), ()cyclopentylene Hexyl (ring), ()cycloheptylidene (ring), ()cyclooctyl (ring), ()cyclononyl (ring), ()cyclohexenyl (ring) and the like.
  • heterocyclyl As used herein, the terms “heterocyclyl”, “heterocyclylene” and “heterocycle” mean having, for example, 3-10 (suitably 3-8, more suitably 3-6) Ring atoms in which at least one ring atom is a heteroatom selected from N, O, and S and the remaining ring atoms are saturated (ie, heterocycloalkyl) or partially unsaturated (ie, have one or more within the ring double and/or triple bonds) cyclic groups.
  • a "3-10 membered (sub)heterocycle (radical)" is one having 2-9 (eg, 2, 3, 4, 5, 6, 7, 8, or 9) ring carbon atoms and is independently selected from N A saturated or partially unsaturated (sub)heterocycle (radical) of one or more (eg 1, 2, 3 or 4) heteroatoms of , O and S.
  • heterocyclylenes and heterocycle(radicals) include, but are not limited to: ()oxiranyl, ()aziridinyl, (azetidinyl), ()oxygenide Heterocyclobutyl (oxetanyl), ()tetrahydrofuranyl, ()dioxolinyl (dioxolinyl), ()pyrrolidine, ()pyrrolidone, ()imidazolidinylene, () ) Pyrazolidine, () Pyrrolidene, () Tetrahydropyranyl, () Piperidinyl, () Morpholinyl, () Dithianyl (dithianyl), () Thiomorpholinyl, ()piperazinylidene or (trithianylidene)trithianyl.
  • the groups also encompass bicyclic ring systems, including spiro, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-nitrogen Heterobicyclo[2.2.2]octane, etc.).
  • Heterocyclylene and heterocycle(radicals) may be optionally substituted with one or more (eg, 1, 2, 3, or 4) suitable substituents.
  • the terms "()arylene” and "aromatic ring” refer to an all-carbon monocyclic or fused ring polycyclic aromatic group having a conjugated pi electron system.
  • C 6-10 ()arylene” and “C 6-10 aromatic ring” mean an aromatic group containing 6 to 10 carbon atoms, such as ()phenylene (benzene ring) or ()naphthylene (naphthalene ring).
  • the ()arylene and aromatic rings are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (eg, halogen, -OH, -CN, -NO2 , C1-6 alkyl, etc.) .
  • the ()arylene and aromatic rings are optionally fused with another ring (eg, a C 3-10 hydrocarbon ring, a 3-10 membered heterocyclic ring, or a 5-14 membered heteroaromatic ring), for example, the fused group is
  • heteroarylidene and heteroaryl ring refer to monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contain at least one heteroatom (such as oxygen, nitrogen, etc.) which may be the same or different or sulfur) and, in addition, can be benzo-fused in each case.
  • heteroatom such as oxygen, nitrogen, etc.
  • "()heteroarylene” or “heteroaromatic ring” is selected from ()thienylene, ()furanyl, ()pyrrolylene, ()oxazolylylene, ()thiazolylylene, ()imidazolylidene, ()pyrazolylidene, ()isoxazolylidene, ()isothiazolylidene, ()oxadiazolylidene, ()triazolylidene, ()thiadiazolylidene etc., and their benzo derivatives; or ()pyridylene, ()pyridazinylene, ()pyrimidinylene, ()pyrazinylene, ()triazinylene, etc., and their benzos derivative.
  • the "()heteroarylene” and “heteroaromatic ring” may also optionally be combined with another ring (eg, a C3-10 hydrocarbon ring, a 3-10 membered heterocyclic ring, a C6-10 aromatic ring, or a 5- 14-membered heteroaromatic ring) condensed, the condensed group is for example
  • aralkyl preferably refers to an aryl or heteroaryl substituted alkyl group, wherein said aryl, heteroaryl and alkyl groups are as defined herein.
  • the aryl group can have 6-14 carbon atoms
  • the heteroaryl group can have 5-14 ring atoms
  • the alkyl group can have 1-6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • halo or halogen group is defined to include F, Cl, Br or I.
  • substituted means that one or more (eg, one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the designated group, provided that no more than the designated atom is present in the normal valences in the case and the substitutions form stable compounds. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • substituent can be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be independently and/or together independently Selected optional substituents are substituted. If a nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be independently selected optional substitution of substituents.
  • each substituent is selected independently of the other.
  • each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
  • the point of attachment of a substituent can be from any suitable position on the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically-labeled compounds that are identical to the compounds of the present invention, except that one or more atoms have the same atomic number but an atomic mass or mass number different from the atomic mass that predominates in nature or atomic substitution of mass numbers.
  • isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (eg, deuterium (2H), tritium ( 3H )); isotopes of carbon (eg, 11C , 13C , and14C ) ; isotopes of chlorine (eg 36 Cl); isotopes of fluorine (eg 18 F); isotopes of iodine (eg 123 I and 125 I); isotopes of nitrogen (eg 13 N and 15 N); isotopes of oxygen (eg 15 O) , 17 O and 18 O); isotopes of phosphorus (eg 32 P); and isotopes of sulfur (eg 35 S).
  • isotopes of hydrogen eg, deuterium (2H), tritium ( 3H )
  • isotopes of carbon eg, 11C , 13C , and14C
  • isotopes of chlorine eg 36
  • Certain isotopically-labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies (eg, assays).
  • the radioisotopes tritium (ie 3 H) and carbon-14 (ie 14 C) are particularly useful for this purpose due to their ease of incorporation and ease of detection.
  • Substitution with positron emitting isotopes such as11C , 18F , 15O , and13N can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies.
  • Isotopically labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using an appropriate isotopically labeled reagent in place of the previously employed non-labeled reagent.
  • Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, eg, D2O , acetone-d6, or DMSO - d6.
  • stereoisomer refers to isomers formed due to at least one asymmetric center. In compounds having one or more (eg, one, two, three or four) asymmetric centers, it may give rise to racemic mixtures, single enantiomers, diastereomeric mixtures and individual of diastereomers. Certain individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention may exist as mixtures of two or more structurally distinct forms in rapid equilibrium (often referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of this application covers all such in any ratio (eg 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% %) of isomers or mixtures thereof.
  • Solid lines may be used in this article solid wedge or virtual wedge
  • the chemical bonds of the compounds of the present invention are depicted.
  • 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 are included (eg, a specific enantiomer, racemic mixture, etc.).
  • the use of real or dashed wedges to delineate bonds to asymmetric carbon atoms is intended to indicate that the indicated stereoisomer exists.
  • real and imaginary wedges are used to define relative, rather than absolute, stereochemistry.
  • the compounds of the present invention are intended to be available as stereoisomers (which include cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotational isomers, conformational isomers, atropisomers and mixtures thereof).
  • stereoisomers which include cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotational isomers, 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 (eg, racemic mixtures and pairs of diastereomers).
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the present invention may exist in free form for use in therapy, or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs which are administered to patients in need thereof After administration, the compounds of the invention or their metabolites or residues can be provided directly or indirectly. Accordingly, references herein to "compounds of the present invention" are 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 which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camphorsulphonate , citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate Salt, Hyphenate, Hydrochloride/Chloride, Hydrobromide/Bromide, Hydroiodide/Iodide, Isethionate, Lactate, Malate, Maleic Acid salt, malonate, mesylate, methyl sulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitic acid Salt, Pamoate, Phosphat
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinate salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, Potassium, sodium, tromethamine and zinc salts.
  • esters means an ester derived from each of the compounds of the general formula in this application, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release free acid or alcohol forms of the present invention) compound).
  • the compounds of the present invention may themselves also be esters.
  • the compounds of the present invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the present invention comprise a polar solvent as a structural element of the crystal lattice of the compound, in particular for example water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, in particular for example water, methanol or ethanol.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • Nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires available lone pairs of electrons to oxidize to oxides; Nitrogen-containing heterocycles. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl Hydrogen peroxides such as t-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane are used to oxidize heterocycles and tertiary amines.
  • peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA)
  • hydrogen peroxide alkyl Hydrogen peroxides such as t-butyl hydroperoxide
  • sodium perborate and dioxiranes such as dimethyldioxirane
  • metabolites of the compounds of the present invention ie substances formed in the body upon administration of the compounds of the present invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like, of the administered compound.
  • the present invention includes metabolites of the compounds of the present invention, including compounds prepared by methods of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity when administered into or onto the body can be converted into compounds of the invention having the desired activity, for example, by hydrolytic cleavage.
  • prodrugs will be functional derivatives of the compound that are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • prodrugs of the present invention can be obtained, for example, by using certain moieties known to those skilled in the art as “pro-moiety (eg as described in “Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" Prepared by substituting appropriate functional groups present in the compounds of the present invention.
  • the present invention also encompasses compounds of the present invention that contain protecting groups.
  • protecting groups In 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 relevant molecule, thereby forming chemically protected forms of the compounds of the present invention. This can be accomplished with conventional protecting groups, such as 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. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein the compound has the structure of formula (I):
  • R 5 and R 6 at each occurrence are each independently selected from H, C 1-6 alkyl, C 3-10 cyclohydrocarbyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl; and
  • n is an integer selected from 0, 1, 2, 3 and 4.
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein the compound has the structure of formula (II):
  • Ring A is and
  • n is an integer selected from 0, 1, 2 or 3.
  • -LR 2 is selected from
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs 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.
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein each occurrence of R 1 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 cyclic hydrocarbon group, saturated or partially unsaturated 3-10 membered heterocyclyl, C 6-10 aryl and 5-14 membered heteroaryl,
  • the alkylene, alkyl, cyclohydrocarbyl, heterocyclyl, aryl, and heteroaryl groups are optionally one or more independently selected from halogen, -OH, C 3-6 cyclohydrocarbyl, 3-10 membered Substituent substitution of heterocyclyl, C 6-10 aryl
  • each occurrence of R 1 is independently selected from CF 3 , NH 2 , And m is 1 or 2.
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof ,in selected from
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein R 3 is selected from H and C 1-6 alkyl; preferably, R 3 is methyl.
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein R 4 is selected from H and C 1-6 alkyl; preferably, R 4 is H.
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein the compound has the structure of formula (III):
  • the present invention encompasses compounds resulting from any combination of the various embodiments.
  • the present invention provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof , wherein the compound is selected from:
  • compositions and methods of treatment are provided.
  • the present invention provides pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate,
  • a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate The N-oxide, isotope-labeled compound, metabolite or prodrug and one or more pharmaceutically acceptable carriers, the pharmaceutical composition is preferably a solid preparation, semi-solid preparation, liquid preparation or gaseous preparation.
  • the pharmaceutical composition may further comprise one or more other therapeutic agents.
  • the present invention provides compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites thereof Or prodrug or use of the pharmaceutical composition of the present invention in the preparation of a medicament for use as an inhibitor of SOS1.
  • the present invention provides compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites thereof or a prodrug or a pharmaceutical composition of the present invention, which acts as a SOS1 inhibitor.
  • the present invention provides a method of preventing or treating an SOS1-related disease, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer thereof body, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug or pharmaceutical composition of the present invention.
  • the SOS1-related disease includes cancer (eg, pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid 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 carcinoma, glioblastoma, renal carcinoma, and sarcoma), RAS disorders (eg, neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple spots (NSML), capillary Vascular malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facial-cutaneous syndrome (CFC), Leggers syndrome and hereditary gingival fibr
  • cancer
  • “Pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered and which, within the scope of sound medical judgment, is suitable for contact with humans and/or tissue from other animals without undue toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can 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, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously.
  • 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, etc.
  • Water is an exemplary carrier when the pharmaceutical composition is administered intravenously.
  • Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, nonfat dry milk, glycerin, propylene glycol, water, Ethanol etc.
  • 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 saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
  • compositions of the present invention may act systemically and/or locally.
  • they may be administered by a suitable route, for example by injection (eg intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, transdermal Nasal, transmucosal, topical, in ophthalmic formulations or by inhalation.
  • 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.
  • an effective amount refers to the amount of a compound which, when administered, will alleviate to some extent one or more symptoms of the condition being treated.
  • Dosage regimens can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values 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 specific dosing regimen should be adjusted over time according to the needs of the individual and the professional judgment of the person administering or supervising the administration of the composition.
  • the amount of the compound of the invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. In general, an effective dose will range from about 0.0001 to about 50 mg per kg of body weight per day, eg, from about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, eg, about 0.7 mg/day to about 700 mg/day.
  • dose levels not higher than the lower end of the foregoing ranges may be sufficient, while in other cases larger doses may be employed without causing any deleterious side effects, provided that the larger dose is first
  • the dose is divided into several smaller doses to be administered throughout the day.
  • the content or amount of the compound of the present invention in the pharmaceutical composition may be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, such as 1.5 mg, 2mg, 4mg, 10mg, 25mg, etc.
  • treating means reversing, alleviating, inhibiting the progression of the disorder or condition to which such term applies or one or more symptoms of such disorder or condition, or Such a disorder or condition or one or more symptoms of such a disorder or condition is prevented.
  • an “individual” as used herein includes a human or non-human animal.
  • exemplary human subjects include human subjects (referred to as patients) or normal subjects with a disease (eg, a disease described herein).
  • Non-human animals in the present invention include all vertebrates such as non-mammals (eg birds, amphibians, reptiles) and mammals such as non-human primates, livestock and/or domesticated animals (eg sheep, dogs) , cats, cows, pigs, etc.).
  • compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents.
  • Thin-layer chromatography was performed using Huanghai brand HSGF 254 (5 ⁇ 20em) silica gel plates, and thin-layer preparative chromatography was performed using GF 254 (0.4-0.5nm) silica plates produced in Yantai.
  • reaction was detected by thin layer chromatography (TLC) or LC-MS, and the developing solvent systems used included dichloromethane and methanol system, n-hexane and ethyl acetate system, and petroleum ether and ethyl acetate system. Different polarities adjust the developing agent system (by adjusting the volume ratio of the solvent or adding triethylamine, etc.).
  • BiotageInitiator+ 400W, RT ⁇ 300°C microwave reactor was used.
  • the eluent system includes dichloromethane and methanol system and n-hexane and ethyl acetate system, and the eluent system is adjusted according to the polarity of the compound to be separated (by adjusting the volume ratio of the solvent or adding triethylamine, etc. conduct).
  • reaction temperature is room temperature (20°C to 30°C).
  • the reagents used in the examples were purchased from companies such as Acros Organics, Aldrich Chemical Company or Shanghai Bide Pharmaceutical Technology Co., Ltd.
  • Step 1 Dissolve acetamidine (2.4 g, 23.1 mmol) in methanol (50 mL), add sodium methoxide (3.2 g, 58.4 mmol) and 1-(tert-butyl) 3-methyl 4-oxopiperidine -1,3-Dicarboxylate (5.0 g, 19.5 mmol). The reaction solution was stirred at 60°C for 6 hours.
  • the third step Dissolve 301-2 (2.0 g, 7.1 mmol) in dimethyl sulfoxide (20 mL), add (R)-1-(3-nitro-5-(trifluoromethyl)phenyl) Ethan-1-amine hydrochloride (2.3 g, 8.5 mmol) and N,N-diisopropylethylamine (2.7 g, 21.3 mmol), and the reaction solution was stirred at 150° C. for 16 hours.
  • the fourth step: 301-3 (1.7g, 3.5mmol) was dissolved in dioxane (20mL), hydrochloric acid (4M, solution in dioxane) (5mL) was added, and the reaction solution was stirred at room temperature, The reaction of the raw materials was monitored by TLC, and the solvent was removed by concentration under reduced pressure to obtain compound 301-4 (1.3 g), which was a white solid with a yield of 90%.
  • the fifth step dissolve 301-4 (150mg, 0.4mmol) in methanol (5mL), add cyclobutanone (50mg, 0.7mmol), anhydrous zinc chloride (145mg, 1.0mmol) and sodium cyanoborohydride ( 68 mg, 1.0 mmol), and the reaction was stirred at room temperature for 15 hours. The reaction was quenched by adding water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2 ⁇ 20 mL), and the organic phase was concentrated under reduced pressure to obtain compound 301-5 (120 mg) as a yellow solid with a yield of 76%.
  • Step 6 Dissolve 301-5 (120mg, 0.3mmol) in ethanol (5mL) and water (2mL), add iron powder (157mg, 2.8mmol) and ammonium chloride (150mg, 2.8mmol), put the reaction solution in Stir at 90°C for 2 hours.
  • the first step dissolve 301-4 (130mg, 0.3mmol) in methanol (5mL), add tetrahydro-4H-pyran-4-one (60mg, 0.6mmol), anhydrous zinc chloride (121mg, 0.9mmol) ) and sodium cyanoborohydride (61 mg, 0.9 mmol), and the reaction solution was stirred at room temperature for 15 hours.
  • the reaction was quenched by adding water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2 ⁇ 20 mL), and the organic phase was concentrated under reduced pressure to obtain compound 302-1 (110 mg) as a yellow solid with a yield of 76%.
  • Step 2 Dissolve 302-1 (110mg, 0.2mmol) in ethanol (5mL) and water (2mL), add iron powder (135mg, 2.4mmol) and ammonium chloride (129mg, 2.4mmol), put the reaction solution in Stir at 90°C for 2 hours.
  • the first step Compound 301-2 (2.0 g, 7.1 mmol) was dissolved in dimethyl sulfoxide (20 mL), and (R)-1-(5-bromothiophen-2-yl) ethan-1-amine salt was added acid (2.0 g, 8.5 mmol) and N,N-diisopropylethylamine (2.7 g, 21.3 mmol), and the reaction solution was stirred at 150° C. for 16 hours.
  • Step 2 Dissolve 303-1 (1.7g, 3.8mmol) in dioxane ⁇ water (5:1) (30mL), add (2-((dimethylamino)methyl)phenyl)boronic acid (1.0 g, 5.7 mmol), tetrakis(triphenylphosphine)palladium (462 mg, 0.4 mmol) and potassium carbonate (1.6 g, 11.4 mmol), and the reaction solution was stirred at 100° C. for 16 hours.
  • the third step Dissolve 303-2 (1.7 g, 3.0 mmol) in dioxane (20 mL), add hydrochloric acid (4M, a solution in dioxane) (5 mL), and stir the reaction solution at room temperature. TLC After monitoring the reaction of the raw materials, the solvent was removed by concentration under reduced pressure to obtain compound 303-3 (1.0 g) as a white solid with a yield of 83%.
  • ESI-MS 408[M+H] + .
  • the fourth step dissolve 303-3 (120mg, 0.3mmol) in methanol (5mL), add cyclobutanone (43mg, 0.6mmol), anhydrous zinc chloride (130mg, 0.9mmol) and sodium cyanoborohydride ( 61 mg, 0.9 mmol), and the reaction was stirred at room temperature for 15 hours.
  • the first step Dissolve 301-4 (130 mg, 0.3 mmol) in methanol (5 mL), add N,N-dimethyl-4-oxocyclohexane-1-carboxamide (101 mg, 0.6 mmol), no Aqueous zinc chloride (121 mg, 0.9 mmol) and sodium cyanoborohydride (61 mg, 0.9 mmol), and the reaction was stirred at room temperature for 15 hours. The reaction was quenched by adding water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2 ⁇ 20 mL), and the organic phase was concentrated under reduced pressure to obtain compound 304-1 (110 mg) as a yellow solid with a yield of 69%.
  • ESI-MS 535[M+H] + .
  • Step 2 Dissolve 304-1 (110mg, 0.2mmol) in ethanol (5mL) and water (2mL), add iron powder (135mg, 2.4mmol) and ammonium chloride (129mg, 2.4mmol), put the reaction solution in Stir at 90°C for 2 hours.
  • the first step Compound 301-4 (130 mg, 0.3 mmol) was dissolved in methanol (5 mL), 1-acetylpiperidin-4-one (85 mg, 0.6 mmol), anhydrous zinc chloride (121 mg, 0.9 mmol) were added ) and sodium cyanoborohydride (61 mg, 0.9 mmol), and the reaction solution was stirred at room temperature for 15 hours. The reaction was quenched by adding water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2 ⁇ 20 mL), and the organic phase was concentrated under reduced pressure to obtain compound 306-1 (130 mg) as a yellow solid with a yield of 86%.
  • ESI-MS 507[M+H] + .
  • Step 2 Dissolve 306-1 (130mg, 0.3mmol) in ethanol (5mL) and water (2mL), add iron powder (135mg, 2.4mmol) and ammonium chloride (129mg, 2.4mmol), put the reaction solution in Stir at 90°C for 2 hours.
  • Step 1 Dissolve tetrahydro-2H-pyridine-4-carboxylic acid (40 mg, 0.9 mmol) in N,N-dimethylformamide (3 mL), add HATU (137 mg, 0.4 mmol), N,N - Diisopropylethylamine (116 mg, 0.9 mmol) and compound 301-4 (130 mg, 0.3 mmol), the reaction solution was stirred at room temperature for 15 hours. It was diluted with water (10 mL), extracted with ethyl acetate (2 ⁇ 20 mL), and the organic phase was concentrated under reduced pressure to obtain compound 308-1 (110 mg) as a yellow solid with a yield of 74%.
  • Step 2 Dissolve 308-1 (110mg, 0.2mmol) in ethanol (5mL) and water (2mL), add iron powder (135mg, 2.4mmol) and ammonium chloride (129mg, 2.4mmol), put the reaction solution in Stir at 90°C for 2 hours.
  • Tetrahydro-2H-pyran-4-carboxylic acid (40 mg, 0.9 mmol) was dissolved in N,N-dimethylformamide (3 mL), HATU (137 mg, 0.4 mmol), N,N-diisopropyl were added Ethylamine (116 mg, 0.9 mmol) and compound 303-3 (100 mg, 0.3 mmol), the reaction solution was stirred at room temperature for 15 hours.
  • the first step Compound 301-4 (130 mg, 0.3 mmol) was dissolved in methanol (5 mL), tetrahydro-2H-pyran-4-carbaldehyde (68 mg, 0.6 mmol), anhydrous zinc chloride (121 mg, 0.9 mmol) were added mmol) and sodium cyanoborohydride (61 mg, 0.9 mmol), and the reaction was stirred at room temperature for 15 hours. The reaction was quenched by adding water, concentrated under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (2 ⁇ 20 mL), and the organic phase was concentrated under reduced pressure to obtain compound 310-1 (110 mg) as a yellow solid with a yield of 76%.
  • Step 2 Dissolve 310-1 (110mg, 0.2mmol) in ethanol (5mL) and water (2mL), add iron powder (135mg, 2.4mmol) and ammonium chloride (129mg, 2.4mmol), put the reaction solution in Stir at 90°C for 2 hours.
  • the first step Compound 301-2 (1.0 g, 3.5 mmol) was dissolved in dimethyl sulfoxide (20 mL), and (R)-1-(4-bromothiophen-2-yl) ethan-1-amine salt was added acid (1.0 g, 4.2 mmol) and N,N-diisopropylethylamine (1.4 g, 10.2 mmol), and the reaction solution was stirred at 150° C. for 16 hours.
  • Step 2 Dissolve 312-1 (900 mg, 2.0 mmol) in dioxane ⁇ water (5:1) (15 mL), add (2-((dimethylamino)methyl)phenyl)boronic acid ( 534 mg, 3.0 mmol), tetrakis(triphenylphosphine)palladium (231 mg, 0.2 mmol) and potassium carbonate (823 mg, 6.0 mmol), and the reaction solution was stirred at 100°C for 16 hours.
  • the third step Dissolve 312-2 (450 mg, 0.9 mmol) in dioxane (5 mL), add hydrochloric acid (4M, a solution in dioxane) (3 mL), and stir the reaction solution at room temperature. TLC After monitoring the completion of the reaction of the raw materials, the solvent was removed by concentration under reduced pressure to obtain compound 312-3 (300 mg) as a white solid with a yield of 82%.
  • ESI-MS 408[M+H] + .
  • the fourth step dissolve 312-3 (100mg, 0.3mmol) in methanol (5mL), add 1-acetylpiperidin-4-one (71mg, 0.5mmol), anhydrous zinc chloride (116mg, 0.8mmol) and sodium cyanoborohydride (54 mg, 0.8 mmol), and the reaction was stirred at room temperature for 15 hours.
  • This assay can be used to examine the potency of compounds to inhibit the protein-protein interaction between SOS1 and KRAS G12C . This demonstrates the molecular mode of action of the compound. Low IC50 values indicate high potency of the SOS1 inhibitor compound in this assay setup below.
  • Assay Plate ProxiPlate-384Plus, purchased from PerkinElmer (Cat. No. 6008280)
  • Assay buffer PPI, purchased from Cisbio (Cat. No. 61DB10RDF)
  • Dissolve the compound to be tested in DMSO prepare a stock solution with a concentration of 10 mM, and dilute the compound concentration with DMSO to 2 mM as the starting concentration of the assay, serially dilute the compound solution with a 2 mM starting concentration 3 times, and dilute a total of 10 concentrations, using Labcyte
  • the Echo instrument transferred 0.1 ⁇ L of compound solutions of each concentration to a 384-well assay plate (duplicate, double wells);
  • Each plate contains the following controls:
  • IC50 values were calculated and analyzed using a 4-parameter regression equation. The measurement results are shown in the table below.

Abstract

式（I）的SOS1抑制剂、包含其的药物组合物、及其用于预防或治疗疾病的用途。

Description

SOS1抑制剂、包含其的药物组合物及其用途 发明领域
本发明涉及SOS1抑制剂、包含其的药物组合物、及其用于预防或治疗疾病的用途。
发明背景
RAS家族蛋白是由RAS基因编码的小GTP酶，包括KRAS(Kirsten鼠肉瘤病毒致癌基因同源物)、HRAS(Harvey鼠肉瘤病毒致癌基因)和NRAS(神经母细胞瘤RAS病毒致癌基因同源物)及其任何突变体。在细胞内，RAS蛋白在失活和激活状态之间转变，当与鸟嘌呤核苷二磷酸(GDP)结合时，RAS蛋白处于失活状态，当与鸟嘌呤核苷三磷酸(GTP)结合时，RAS蛋白被激活。RAS蛋白的固有GTP酶活性较弱，且内在的GDP-GTP核苷酸交换速率较低，其失活与激活状态之间的转换受到两类因子的调节：GTP酶激活蛋白(GTPase activating protein，GAP)，可催化与RAS蛋白结合的GTP水解为GDP，使RAS蛋白失活；鸟嘌呤核苷酸交换因子(Guanine nucleotide exchange factor，GEF)，包括SOS1蛋白(Son of Sevenless 1)等，可催化RAS蛋白与GTP的结合，从而促进RAS蛋白的激活。激活状态下的RAS蛋白可通过激活一系列下游效应蛋白(包括RAF和磷脂酰肌醇激酶PI3K等)来激活RAF/MEK/ERK(MAPK)通路和PI3K/AKT/mTOR通路等多条信号转导通路，从而调控细胞增殖、存活、代谢、运动、血管生成、免疫和生长等多种细胞过程。RAS家族蛋白突变可抑制其固有GTP酶活性和GAP诱导的GTP酶活性，导致RAS蛋白的持续激活，进而导致RAS蛋白下游效应通路的持续激活。RAS是人类癌症中最常出现突变的致癌基因，KRAS突变(如G12、G13和Q61等)广泛存在于包括肺癌、结直肠癌和胰腺癌等多种人类癌症中，HRAS突变和NRAS突变同样出现在不同人类癌症类型中。RAS蛋白突变、过表达及基因扩增是针对多种抗癌药物(如EGFR抗体西妥昔单抗和帕尼单抗、EGFR酪氨酸激酶抑制剂奥希替尼)的潜在耐药机制。
SOS蛋白最早发现于果蝇中，SOS1是果绳SOS蛋白的人类同源物。SOS1蛋白是由1333个氨基酸组成的多结构域蛋白，由N-末端结构域、Dbl同源结构域(Dbl homology，DH)、Pleckstrin底物蛋白同源结构域(Pleckstrin homology，PH)、RAS交换基序(Ras exchanger motif，REM)、CDC25同源结构域和C-末端结构域构成，其中REM和CDC25同源结构域共同组成催化功能域，是SOS1蛋白发挥鸟嘌呤核苷酸交换因子催化功能的必须部分。研究表明SOS1在RAS突变的癌症中对突变型RAS蛋白的激活和信号转导具有关键作用，SOS1敲除会抑制KRAS突变肿瘤细胞的存活和增殖，在SOS1敲除的KRAS突变肿瘤细胞中重新表达催化位点突变型SOS1，肿瘤细胞无法恢复存活和增殖，证明SOS1的鸟嘌呤核苷酸交换催化活性对KRAS突变肿瘤细胞的存活和增殖具有关键作用。除了调控突变型RAS蛋白，SOS1也可通过其它机制参与肿瘤细胞的信号激活与传导过程。SOS1可结合生长因子受体结合蛋白Grb2形成SOS1-Grb2复合物，进而结合活化的受体酪氨酸激酶(如EGFR、ErbB2/3/4、VEGFR1/2/3、PDGFR-A/B、FGFR1/2/3、IGF1R、ALK、ROS1、TRK-A/B/C、RET、c-MET、AXL等)，或者被其他细胞表面的膜受体(如TCR、BCR、CSF1R)所募集。SOS1可作为鸟嘌呤核苷酸交换因子激活GTP酶RAC1，RAC1与多种人类癌症及其他疾病相关。研究表明，SOS1突变存在于胚胎性横纹肌肉瘤、睾丸支持细胞瘤、皮肤颗粒细胞瘤和肺腺癌中，在膀胱癌和前列腺癌中也发现了SOS1蛋白的过表达。
SOS2是哺乳动物细胞中SOS1的同源物，同样具有鸟嘌呤核苷酸交换因子功能。小鼠基因敲除模型研究表明，SOS1种系敲除可导致小鼠胚胎在妊娠中期死亡，而成年小鼠在SOS1敲除后可继续存活，相比之下，SOS2敲除对胚胎及成熟小鼠均无任何明显的表型变化，而SOS1/2双敲除的成年小鼠会迅速死亡，这表明对于受到SOS1调控的RAS突变肿瘤，选择性靶向SOS1可能会实现较高的治疗指数。
抑制SOS1催化位点与RAS蛋白结合可阻断SOS1介导的RAS蛋白激活，进而抑制RAS蛋白下游信号传导(如ERK的磷酸化激活等)，具有此类作用机制的SOS1抑制剂对突变型RAS蛋白依赖的肿瘤细胞如KRAS突变肿瘤细胞系具有抑制作用(如抑制增殖、存活、转移等)。
发明概述
本发明提供用作SOS1抑制剂的化合物，其具有对SOS1的优异的抑制活性。本发明的SOS1抑制剂可抑制SOS1与RAS蛋白的相互作用及激活，尤其是对SOS1和KRAS突变蛋白相互作用具有 显著的抑制作用，可为携带RAS及上下游蛋白(包括KRAS、NRAS、HRAS、受体酪氨酸激酶(如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(如NF1)和SOS1)突变的癌症患者提供药理学益处。此外，SOS1抑制剂在RAC1依赖性的癌症及RAS信号通路失调相关的其他疾病如神经纤维瘤、努南综合征(NS)、心-面-皮肤综合征(CFC)和1型遗传性牙龈纤维瘤中也将提供药理学益处。
本发明的化合物还具有更好的物理化学性质(例如溶解度、物理和/或化学稳定性)、改善的药物代谢动力学性质(例如改善的生物利用度、合适的半衰期和作用持续时间)、改善的安全性(较低的毒性和/或较少的副作用，较宽的治疗窗)等更优异的性质。
本发明的一个方面提供化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物具有式(I)的结构：
Figure PCTCN2021110746-appb-000001
其中：
X 1、X 2、X 3和X 4各自独立地选自C＝O、CH 2、CHR、C(R) 2和N-L-R 2，优选地，X 1、X 2、X 3和X 4中至少一个为N-L-R 2；
L选自直接键、C 1-6亚烷基、C(＝O)、O、S(＝O)、S(＝O) 2和NR 4；
环B选自C 3-10烃环、3-10元杂环、C 6-10芳环和5-14元杂芳环，所述烃环和杂环中至多2个环成员为C(＝O)；
R和R 1在每次出现时各自独立地选自卤素、-NH 2、-CN、-NO 2、-OH、-O-C 1-6烷基、C 1-6烷基、卤代C 1-6烷基、C 1-6亚烷基-OH、卤代C 1-6亚烷基-OH、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基，所述环烃基和杂环基中至多2个环成员为C(＝O)，当m大于1和/或n大于1时，两个R 1和/或两个R连同其所连接的原子任选地共同构成C 3-10烃环、3-10元杂环、C 6-10芳环或5-14元杂芳环，所述烃环和杂环中至多2个环成员为C(＝O)；
R 2选自H、C 1-6烷基、卤代C 1-6烷基、C 1-6亚烷基-OH、卤代C 1-6亚烷基-OH、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R 5、-OC(＝O)R 5、-C(＝O)OR 5、-OR 5、-SR 5、-S(＝O)R 5、-S(＝O) 2R 5、-S(＝O) 2NR 5R 6、-NR 5R 6、-C(＝O)NR 5R 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 5R 6、-C 1-6亚烷基-NR 5R 6、-C 1-6亚烷基-O(P＝O)(OH) 2和-O-C 1-6亚烷基-NR 5R 6；
R 3和R 4各自独立地选自H、卤素、-NH 2、-CN、-NO 2、-OH、-O-C 1-6烷基、-O-(3-10元杂环基)、C 1-6烷基、卤代C 1-6烷基、C 1-6亚烷基-OH、卤代C 1-6亚烷基-OH、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R 5、-OC(＝O)R 5、-C(＝O)OR 5、-OR 5、-SR 5、-S(＝O)R 5、-S(＝O) 2R 5、-S(＝O) 2NR 5R 6、-NR 5R 6、-C(＝O)NR 5R 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 5R 6、-C 1-6亚烷基-NR 5R 6、-C 1-6亚烷基-O(P＝O)(OH) 2和-O-C 1-6亚烷基-NR 5R 6；
上述基团在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、氧代、-NH 2、-CN、-NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、＝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) 2R 5、-S(＝O) 2NR 5R 6、-NR 5R 6、-C(＝O)NR 5R 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 5R 6、-C 1-6亚烷基-NR 5R 6和-O-C 1-6亚烷基-NR 5R 6，所述烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、氧代、-NH 2、-CN、-NO 2、C 1-6烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；
R 5和R 6在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、 5-14元杂芳基和C 6-12芳烷基；并且
m为选自0、1、2、3和4的整数。
本发明的另一方面提供药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药以及一种或多种药学上可接受的载体，所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。
本发明的另一方面提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物在制备用作SOS1抑制剂的药物中的用途。
本发明的另一方面提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物，其用作SOS1抑制剂。
本发明的另一方面提供预防或治疗SOS1相关疾病的方法，所述方法包括向需要其的个体给药有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物。
发明详述
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
如本文中所使用，术语“亚烷基”表示饱和二价烃基，优选表示具有1、2、3、4、5或6个碳原子的饱和二价烃基，例如亚甲基、亚乙基、亚丙基或亚丁基。
如本文中所使用，术语“烷基”定义为线性或支化饱和脂肪族烃。在一些实施方案中，烷基具有1至12个，例如1至6个碳原子。例如，如本文中所使用，术语“C 1-6烷基”指1至6个碳原子的线性或支化的基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基或正己基)，其任选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”)(例如CH 2F、CHF 2、CF 3、CCl 3、C 2F 5、C 2Cl 5、CH 2CF 3、CH 2Cl或-CH 2CH 2CF 3等)。术语“C 1-4烷基”指1至4个碳原子的线性或支化的脂肪族烃链(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。
如本文中所使用，术语“烯基”意指线性的或支化的单价烃基，其包含一个双键，且具有2-6个碳原子(“C 2-6烯基”)。所述烯基为例如乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。当本发明的化合物含有亚烯基时，所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。
如本文中所使用，术语“炔基”表示包含一个或多个三键的单价烃基，其优选具有2、3、4、5或6个碳原子，例如乙炔基或丙炔基。
如本文中所使用，术语“环烷基”指饱和的单环或多环(诸如双环)烃环(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连系统(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等))，其任选地被1或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个碳原子。例如，术语“C 3-6环烷基”指3至6个成环碳原子的饱和的单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基)，其任选地被1或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。
如本文中所使用，术语“亚环烃基”、“环烃基”和“烃环”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环碳原子的饱和(即，“亚环烷基”和“环烷基”)或不饱和的(即在环内具有一个或多个双键和/或三键)单环或多环(包括螺环、稠合或桥连系统)烃环，其包括但不限于(亚)环丙基(环)、(亚)环丁基(环)、(亚)环戊基(环)、(亚)环己基(环)、(亚)环庚基(环)、(亚)环辛基(环)、(亚)环壬基(环)、(亚)环己烯基(环)等。
如本文中所使用，术语“杂环基”、“亚杂环基”和“杂环”是指具有例如3-10个(适合地具有3-8个， 更适合地具有3-6个)环原子、其中至少一个环原子是选自N、O和S的杂原子且其余环原子是C的饱和(即，杂环烷基)或部分不饱和的(即在环内具有一个或多个双键和/或三键)环状基团。例如，“3-10元(亚)杂环(基)”是具有2-9个(如2、3、4、5、6、7、8或9个)环碳原子和独立地选自N、O和S的一个或多个(例如1个、2个、3个或4个)杂原子的饱和或部分不饱和(亚)杂环(基)。亚杂环基和杂环(基)的实例包括但不限于：(亚)环氧乙烷基、(亚)氮丙啶基、(亚)氮杂环丁基(azetidinyl)、(亚)氧杂环丁基(oxetanyl)、(亚)四氢呋喃基、(亚)二氧杂环戊烯基(dioxolinyl)、(亚)吡咯烷基、(亚)吡咯烷酮基、(亚)咪唑烷基、(亚)吡唑烷基、(亚)吡咯啉基、(亚)四氢吡喃基、(亚)哌啶基、(亚)吗啉基、(亚)二噻烷基(dithianyl)、(亚)硫吗啉基、(亚)哌嗪基或(亚)三噻烷基(trithianyl)。所述基团也涵盖双环系统，包括螺环、稠合或桥连系统(诸如8-氮杂螺[4.5]癸烷、3，9-二氮杂螺[5.5]十一烷、2-氮杂双环[2.2.2]辛烷等)。亚杂环基和杂环(基)可任选地被一个或多个(例如1个、2个、3个或4个)适合的取代基取代。
如本文中所使用，术语“(亚)芳基”和“芳环”指具有共轭π电子系统的全碳单环或稠合环多环芳族基团。例如，如本文中所使用，术语“C 6-10(亚)芳基”和“C 6-10芳环”意指含有6至10个碳原子的芳族基团，诸如(亚)苯基(苯环)或(亚)萘基(萘环)。(亚)芳基和芳环任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO 2、C 1-6烷基等)取代。(亚)芳基和芳环任选地与另一个环(例如C 3-10烃环、3-10元杂环或5-14元杂芳环)稠合，稠合的基团例如为
Figure PCTCN2021110746-appb-000002
如本文中所使用，术语“(亚)杂芳基”和“杂芳环”指单环、双环或三环芳族环系，其具有5、6、8、9、10、11、12、13或14个环原子，特别是1或2或3或4或5或6或9或10个碳原子，且其包含至少一个可以相同或不同的杂原子(所述杂原子是例如氧、氮或硫)，并且，另外在每一种情况下可为苯并稠合的。特别地，“(亚)杂芳基”或“杂芳环”选自(亚)噻吩基、(亚)呋喃基、(亚)吡咯基、(亚)噁唑基、(亚)噻唑基、(亚)咪唑基、(亚)吡唑基、(亚)异噁唑基、(亚)异噻唑基、(亚)噁二唑基、(亚)三唑基、(亚)噻二唑基等，以及它们的苯并衍生物；或(亚)吡啶基、(亚)哒嗪基、(亚)嘧啶基、(亚)吡嗪基、(亚)三嗪基等，以及它们的苯并衍生物。所述“(亚)杂芳基”和“杂芳环”还可任选地与另一个环(例如C 3-10烃环、3-10元杂环、C 6-10芳环或5-14元杂芳环)稠合，稠合的基团例如为
Figure PCTCN2021110746-appb-000003
如本文中所使用，术语“芳烷基”优选表示芳基或杂芳基取代的烷基，其中所述芳基、杂芳基和烷基如本文中所定义。通常，所述芳基可具有6-14个碳原子，所述杂芳基可具有5-14个环原子，并且所述烷基可具有1-6个碳原子。示例性芳烷基包括但不限于苄基、苯基乙基、苯基丙基、苯基丁基。
如本文中所使用，术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。
如本文中所使用，术语“含氮杂环”指饱和或不饱和的单环或双环基团，其在环中具有2、3、4、5、6、7、8、9、10、11、12或13个碳原子和至少一个氮原子，其还可任选地包含一个或多个(例如一个、两个、三个或四个)选自N、O、C＝O、S、S＝O和S(＝O) 2的环成员，其通过所述含氮杂环中的氮原子以及任一其余环原子与分子的其余部分连接，所述含氮杂环任选地为苯并稠合的，并且优选通过所述含氮杂环中的氮原子以及所稠合的苯环中的任一碳原子与分子的其余部分连接。
术语“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
如果取代基被描述为“任选地被取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。
如果取代基被描述为“独立地选自”一组，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。
如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个或10个。
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个 或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘( 2H)、氚( 3H))；碳的同位素(例如 11C、 13C及 14C)；氯的同位素(例如 36Cl)；氟的同位素(例如 18F)；碘的同位素(例如 123I及 125I)；氮的同位素(例如 13N及 15N)；氧的同位素(例如 15O、 17O及 18O)；磷的同位素(例如 32P)；及硫的同位素(例如 35S)。某些同位素标记的本发明的化合物(例如掺入放射性同位素的那些)可用于药物和/或底物组织分布研究(例如分析)中。放射性同位素氚(即 3H)及碳-14(即 14C)因易于掺入且容易检测而特别可用于该目的。用正电子发射同位素(例如 11C、 18F、 15O及 13N)进行取代可在正电子发射断层显像术(PET)研究中用于检验底物受体占据情况。被同位素标记的本发明的化合物可通过与描述于随附路线和/或实施例及制备中的那些类似的方法通过使用适当的被同位素标记的试剂代替之前采用的非标记的试剂来制备。本发明的药学上可接受的溶剂合物包括其中结晶溶剂可被同位素取代的那些，例如，D 2O、丙酮-d 6或DMSO-d 6。
术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如一个、两个、三个或四个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本发明的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。要理解，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。
本文中可使用实线
Figure PCTCN2021110746-appb-000004
实楔形
Figure PCTCN2021110746-appb-000005
或虚楔形
Figure PCTCN2021110746-appb-000006
描绘本发明的化合物的化学键。使用实线以描绘键连至不对称碳原子的键欲表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。
本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、酯、溶剂合物、N-氧化物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。
适合的酸加成盐由形成药学可接受盐的酸来形成。实例包括乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己氨磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、海苯酸盐、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐(naphthylate)、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、糖二酸盐、硬脂酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐及昔萘酸盐(xinofoate)。
适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、苄星青霉素盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺盐、甘氨酸盐、赖氨酸盐、镁盐、葡甲胺盐、乙醇胺盐、钾盐、钠盐、氨丁三醇盐及锌盐。
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts：Properties，Selection，and Use”(Wiley-VCH，2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。
如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
本领域技术人员会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成N-氧化物；本领域技术人员会识别能够形成N-氧化物的含氮杂环。本领域技术人员还会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人员熟知的，包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备N-氧化物的方法已在文献中得到广泛描述和综述，参见例如：T.L.Gilchrist，Comprehensive Organic Synthesis，vol.7，pp 748-750；A.R.Katritzky和A.J.Boulton，Eds.，Academic Press；以及G.W.H.Cheeseman和E.S.G.Werstiuk，Advances in Heterocyclic Chemistry，vol.22，pp 390-392，A.R.Katritzky和A.J.Boulton，Eds.，Academic Press。
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier，1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在T.W.Greene & P.G.M.Wuts，Protective Groups in Organic Synthesis，John Wiley & Sons，1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。
术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。
化合物
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物具有式(I)的结构：
Figure PCTCN2021110746-appb-000007
其中：
X 1、X 2、X 3和X 4各自独立地选自C＝O、CH 2、CHR、C(R) 2和N-L-R 2，优选地，X 1、X 2、X 3和X 4中至少一个为N-L-R 2；
L选自直接键、C 1-6亚烷基、C(＝O)、O、S(＝O)、S(＝O) 2和NR 4；
环B选自C 3-10烃环、3-10元杂环、C 6-10芳环和5-14元杂芳环，所述烃环和杂环中至多2个环成员为C(＝O)；
R和R 1在每次出现时各自独立地选自卤素、-NH 2、-CN、-NO 2、-OH、-O-C 1-6烷基、C 1-6烷基、卤代C 1-6烷基、C 1-6亚烷基-OH、卤代C 1-6亚烷基-OH、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基，所述环烃基和杂环基中至多2个环成员为C(＝O)，当m大于1和/或n大于1时，两个R 1和/或两个R连同其所连接的原子任选地共同构成C 3-10烃环、3-10元杂环、C 6-10芳环或5-14元杂芳环，所述烃环 和杂环中至多2个环成员为C(＝O)；
R 2选自H、C 1-6烷基、卤代C 1-6烷基、C 1-6亚烷基-OH、卤代C 1-6亚烷基-OH、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R 5、-OC(＝O)R 5、-C(＝O)OR 5、-OR 5、-SR 5、-S(＝O)R 5、-S(＝O) 2R 5、-S(＝O) 2NR 5R 6、-NR 5R 6、-C(＝O)NR 5R 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 5R 6、-C 1-6亚烷基-NR 5R 6、-C 1-6亚烷基-O(P＝O)(OH) 2和-O-C 1-6亚烷基-NR 5R 6；
R 3和R 4各自独立地选自H、卤素、-NH 2、-CN、-NO 2、-OH、-O-C 1-6烷基、-O-(3-10元杂环基)、C 1-6烷基、卤代C 1-6烷基、C 1-6亚烷基-OH、卤代C 1-6亚烷基-OH、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R 5、-OC(＝O)R 5、-C(＝O)OR 5、-OR 5、-SR 5、-S(＝O)R 5、-S(＝O) 2R 5、-S(＝O) 2NR 5R 6、-NR 5R 6、-C(＝O)NR 5R 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 5R 6、-C 1-6亚烷基-NR 5R 6、-C 1-6亚烷基-O(P＝O)(OH) 2和-O-C 1-6亚烷基-NR 5R 6；
上述基团在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、氧代、-NH 2、-CN、-NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、＝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) 2R 5、-S(＝O) 2NR 5R 6、-NR 5R 6、-C(＝O)NR 5R 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 5R 6、-C 1-6亚烷基-NR 5R 6和-O-C 1-6亚烷基-NR 5R 6，所述烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、氧代、-NH 2、-CN、-NO 2、C 1-6烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；
R 5和R 6在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；并且
m为选自0、1、2、3和4的整数。
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物具有式(II)的结构：
Figure PCTCN2021110746-appb-000008
环A为
Figure PCTCN2021110746-appb-000009
并且
n为选自0、1、2或3的整数。
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中L为直接键、-CH 2-或C(＝O)。
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中，R 2为饱和或部分不饱和的C 3-10环烃基或饱和或部分不饱和的3-10元杂环基，其中所述环烃基和杂环基任选地被一个或多个选自-C(＝O)R 5和-C(＝O)NR 5R 6的取代基取代；
优选地，R 2为环丁烷基、环己烷基、哌啶基或四氢吡喃基，其任选地被一个或多个选自-C(＝O)CH 3和-C(＝O)N(CH 3) 2的取代基取代；
更优选地，-L-R 2选自
Figure PCTCN2021110746-appb-000010
Figure PCTCN2021110746-appb-000011
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中环B为双环[1.1.1]戊烷环、2-氧杂双环[2.1.1]己烷环、苯环或噻吩环，最优选为苯环或噻吩环。
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中R 1在每次出现时各自独立地选自卤素、-NH 2、C 1-6烷基、卤代C 1-6烷基、C 1-6亚烷基-OH、卤代C 1-6亚烷基-OH、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基和5-14元杂芳基，所述亚烷基、烷基、环烃基、杂环基、芳基和杂芳基任选地被一个或多个独立地选自卤素、-OH、C 3-6环烃基、3-10元杂环基、C 6-10芳基和5-14元杂芳基的取代基取代；
当m大于1时，两个R 1连同其所连接的原子任选地共同构成C 3-10烃环、3-10元杂环、C 6-10芳环或5-14元杂芳环，所述烃环和杂环中至多2个环成员为C(＝O)，并且所述烃环、杂环、芳环和杂芳环任选地被一个或多个卤素取代；
优选地，R 1在每次出现时各自独立地选自CF 3、NH 2、
Figure PCTCN2021110746-appb-000012
并且m为1或2。
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中
Figure PCTCN2021110746-appb-000013
选自
Figure PCTCN2021110746-appb-000014
Figure PCTCN2021110746-appb-000015
Figure PCTCN2021110746-appb-000016
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中R 3选自H和C 1-6烷基；优选地，R 3为甲基。
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中R 4选自H和C 1-6烷基；优选地，R 4为H。
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物具有式(III)的结构：
Figure PCTCN2021110746-appb-000017
本发明涵盖对各个实施方案进行任意组合所得的化合物。
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物选自：
Figure PCTCN2021110746-appb-000018
Figure PCTCN2021110746-appb-000019
药物组合物和治疗方法
在一些实施方案中，本发明提供药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药以及一种或多种药学上可接受的载体，所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。在一些实施方案中，所述药物组合物还可包含一种或多种其它治疗剂。
在一些实施方案中，本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物在制备用作SOS1抑制剂的药物中的用途。
在一些实施方案中，本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物，其用作SOS1抑制剂。
在一些实施方案中，本发明提供预防或治疗SOS1相关疾病的方法，所述方法包括向需要其的个体给药有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者本发明的药物组合物。
在一些实施方案中，所述SOS1相关疾病包括癌症(例如胰腺癌、肺癌、结直肠癌、胆管癌、多发性骨髓瘤、黑素瘤、子宫癌、子宫内膜癌、甲状腺癌、急性髓性白血病、膀胱癌、尿路上皮癌、胃癌、宫颈癌、头颈部鳞状细胞癌、弥漫性大B细胞淋巴瘤、食道癌、慢性淋巴细胞白血病、肝细胞癌、乳腺癌、卵巢癌、前列腺癌、胶质母细胞瘤、肾癌和肉瘤)、RAS病(例如1型神经纤维瘤病(NF1)、努南综合征(NS)、伴有多斑的努南综合征(NSML)、毛细血管畸形-动静脉畸形综合征(CM-AVM)、科斯特洛综合征(CS)、心-面-皮肤综合症(CFC)、莱格斯综合征和遗传性牙龈纤维瘤病)。
本发明中“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
在本发明的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体，例如水和油，包括那些石油、动物、植物或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时，水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体，特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述组合物还可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。口服制剂可以包含标准载体，如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(1990)中所述。
本发明的药物组合物可以系统地作用和/或局部地作用。为此目的，它们可以适合的途径给药， 例如通过注射(如静脉内、动脉内、皮下、腹膜内、肌内注射，包括滴注)或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。
对于这些给药途径，可以适合的剂型给药本发明的药物组合物。
所述剂型包括但不限于片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂、糖浆剂。
如本文中所使用的术语“有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。
可调整给药方案以提供最佳所需响应。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。
所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量在每日每kg体重约0.0001至约50mg，例如约0.01至约10mg/kg/日(单次或分次给药)。对70kg的人而言，这会合计为约0.007mg/日至约3500mg/日，例如约0.7mg/日至约700mg/日。在一些情况下，不高于前述范围的下限的剂量水平可以是足够的，而在其它情况下，仍可在不引起任何有害副作用的情况下采用较大剂量，条件是首先将所述较大剂量分成数个较小剂量以在一整天中给药。
本发明的化合物在药物组合物中的含量或用量可以是约0.01mg至约1000mg，适合地是0.1-500mg，优选0.5-300mg，更优选1-150mg，特别优选1-50mg，例如1.5mg、2mg、4mg、10mg、25mg等。
除非另外说明，否则如本文中所使用，术语“治疗(treating)”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
在一些实施方案中，本发明的药物组合物还可以包含一种或多种另外的治疗剂或预防剂。
实施例
以下结合实施例进一步描述本发明，但提供这些实施例并非意在限制本发明的范围。
化合物的结构通过核磁共振波谱( 1H NMR)或质谱(MS)进行确证。
化学位移(δ)以百万分之一(ppm)为单位给出。 1HNMR的测定在Bruker BioSpin GmbH 400核磁仪上进行，测试溶剂为氘代甲醇(CD 3OD)、氘代氯仿(CDCl 3)或六氘代二甲基亚砜(DMSO-d 6)，内标为四甲基硅烷(TMS)。
LC-MS的测定在岛津LC-MS-2020液质联用仪(生产商：岛津，型号：岛津LC-MS-2020)上进行。
制备高效液相色谱法使用waters 2767(waters sunfire，C18，19×250mm 10um色谱柱)进行。
薄层色谱法(TLC)使用黄海牌HSGF 254(5×20em)硅胶板进行，薄层制备色谱法采用规格为烟台产GF 254(0.4～0.5nm)硅胶板进行。
采用薄层色谱法(TLC)或LC-MS检测反应，使用的展开剂体系包括二氯甲烷和甲醇体系、正己烷和乙酸乙酯体系以及石油醚和乙酸乙酯体系，根据要分离的化合物的极性不同对展开剂体系进行调节(通过调节溶剂的体积比或者加入三乙胺等进行)。
微波反应使用BiotageInitiator+(400W，RT～300℃)微波反应器。
柱色谱法一般使用于成化工200～300目硅胶为固定相。洗脱剂的体系包括二氯甲烷和甲醇体系和正己烷和乙酸乙酯体系，根据要分离的化合物的极性不同对洗脱剂体系进行调节(通过调节溶剂的体积比或者加入三乙胺等进行)。
如在实施例中无特殊说明，反应的温度为室温(20℃～30℃)。
实施例中所使用的试剂购自Acros Organics、Aldrich Chemical Company或上海毕得医药科技有限公司等公司。
本发明中的缩写具有以下含义：
缩写 含义
CCl 4 四氯化碳
DIEA/DIPEA N，N-二异丙基乙胺
DMSO 二甲基亚砜
EDC 1，2-二氯乙烷
Fe 铁
HATU O-(7-氮杂苯并三唑-1-基)-N，N，N’，N’-四甲基脲六氟磷酸盐
HCl 盐酸
H 2O 水
K 2CO 3 碳酸钾
MeOH 甲醇
MeONa 甲醇钠
NaBH 3CN 氰基硼氢化钠
NH 4Cl 氯化铵
Pd(PPh 3) 4 四(三苯基膦)钯
PPh 3 三苯基膦
TLC 薄层色谱法
r.t./rt 室温
ZnCl 2 氯化锌
实施例1：(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-环丁基-2-甲基-5，6，7，8-四氢吡啶并[4，3-d]嘧啶-4-胺(化合物301)的制备
Figure PCTCN2021110746-appb-000020
第一步：将乙脒(2.4g，23.1mmol)溶解在甲醇(50mL)中，加入甲醇钠(3.2g，58.4mmol)和1-(叔丁基)3-甲基4-氧代哌啶-1，3-二甲酸酯(5.0g，19.5mmol)。将反应液于60℃搅拌6小时。将反应物冷却，减压浓缩，加水稀释(100mL)，向体系中加入盐酸(2M)调pH值到中性，乙酸乙酯萃取(2x100mL)，将有机相减压浓缩，得到化合物301-1(5.0g)，其为白色固体，收率96％。ESI-MS：266[M+H] +.
第二步：将301-1(5.0g，18.9mmol)溶于1，2-二氯乙烷(70mL)，加入四氯化碳(3.2g，21.1mmol)和三苯基膦(5.5g，21.1mmol)，将反应物在70℃下反应8小时。将反应物冷却，将反应液减压浓缩，将浓缩物通过柱色谱法(乙酸乙酯∶石油醚＝0-60％)分离纯化，得到化合物301-2(4.7g)，其为淡黄色固体，收率89％。ESI-MS：284[M+H] +.
第三步：将301-2(2.0g，7.1mmol)溶于二甲基亚砜(20mL)，加入(R)-1-(3-硝基-5-(三氟甲基)苯基)乙-1-胺盐酸盐(2.3g，8.5mmol)和N，N-二异丙基乙胺(2.7g，21.3mmol)，将反应液于150℃下搅拌16小时。将反应物冷却，加水稀释(50mL)，乙酸乙酯萃取(100mL)，将有机相减压浓缩，将浓缩物通过柱色谱法(甲醇∶二氯甲烷＝0-8％)分离纯化，得到化合物301-3(1.7g)，其为淡黄色固体，收率50％。ESI-MS：482[M+H] +.
第四步：将301-3(1.7g，3.5mmol)溶于二氧六环(20mL)，加入盐酸(4M，二氧六环中的溶液)(5mL)，将反应液在室温下搅拌，TLC监控原料反应完全，减压浓缩去除溶剂得化合物301-4(1.3g)， 其为白色固体，收率90％。ESI-MS：382[M+H] +.
第五步：将301-4(150mg，0.4mmol)溶于甲醇(5mL)，加入环丁酮(50mg，0.7mmol)、无水氯化锌(145mg，1.0mmol)和氰基硼氢化钠(68mg，1.0mmol)，将反应液于室温下搅拌15小时。加水淬灭反应，减压浓缩，加水稀释(10mL)，用乙酸乙酯萃取(2x20mL)，将有机相减压浓缩，得化合物301-5(120mg)，其为黄色固体，收率76％。ESI-MS：436[M+H] +.
第六步：将301-5(120mg，0.3mmol)溶于乙醇(5mL)和水(2mL)，加入铁粉(157mg，2.8mmol)和氯化铵(150mg，2.8mmol)，将反应液于90℃下搅拌2小时。将反应物冷却，过滤，将滤饼用乙酸乙酯洗涤，将滤液减压浓缩，将浓缩物用水(10mL)稀释，用乙酸乙酯萃取(2x10mL)，将有机相减压浓缩，将浓缩物通过高压制备液相色谱法分离纯化，得(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-6-环丁基-2-甲基-5，6，7，8-四氢吡啶并[4，3-d]嘧啶-4-胺(53.79mg)，其为白色固体，收率49％。ESI-MS：406[M+H] +。 1H-NMR(400MHz，DMSO-d 6)δ：ppm 6.83(s，1H)，6.79-6.77(m，2H)，6.67(s，1H)，5.52-5.50(m，2H)，5.40-5.34(m，1H)，3.34-3.31(m，2H)，3.18(s，3H)，2.98-2.94(m，2H)，2.92(s，3H)，2.10-2.07(m，2H)，1.92-1.87(m，2H)，1.72-1.66(m，2H)，1.45(d，J＝4.0Hz，3H)。
实施例2：(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-2-甲基-6-(四氢-2H-吡喃-4-基)-5，6，7，8-四氢吡啶并[4，3-d]嘧啶-4-胺(化合物302)的制备
Figure PCTCN2021110746-appb-000021
第一步：将301-4(130mg，0.3mmol)溶于甲醇(5mL)，加入四氢-4H-吡喃-4-酮(60mg，0.6mmol)、无水氯化锌(121mg，0.9mmol)和氰基硼氢化钠(61mg，0.9mmol)，将反应液于室温下搅拌15小时。加水淬灭反应，减压浓缩，加水稀释(10mL)，用乙酸乙酯萃取(2x20mL)，将有机相减压浓缩，得化合物302-1(110mg)，其为黄色固体，收率76％。ESI-MS：466[M+H] +.
第二步：将302-1(110mg，0.2mmol)溶于乙醇(5mL)和水(2mL)，加入铁粉(135mg，2.4mmol)和氯化铵(129mg，2.4mmol)，将反应液于90℃下搅拌2小时。将反应物冷却，过滤，将滤饼用乙酸乙酯洗涤，将滤液减压浓缩，将浓缩物用水(10mL)稀释，用乙酸乙酯萃取(2x10mL)，将有机相减压浓缩，将浓缩物通过高压制备液相色谱法分离纯化，得(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-2-甲基-6-(四氢-2H-吡喃-4-基)-5，6，7，8-四氢吡啶并[4，3-d]嘧啶-4-胺(38.11mg)，其为白色固体，收率36％。ESI-MS：436[M+H] +。 1H-NMR(400MHz，DMSO-d 6)δ：ppm 6.83(s，1H)，6.79-6.76(m，2H)，6.68(s，1H)，5.53-5.51(m，2H)，5.41-5.33(m，1H)，3.97-3.93(m，2H)，3.39(s，2H)，3.36-3.30(m，2H)，2.76-2.73(m，2H)，2.67-2.61(m，1H)，2.58-2.56(m，2H)，2.23(s，3H)，1.83-1.80(m，2H)，1.63-1.54(m，2H)，1.45(d，J＝4.0Hz，3H)。
实施例3：(R)-6-环丁基-N-(1-(5-(2-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)-2-甲基-5，6，7，8-四氢吡啶并[4，3-d]嘧啶-4-胺(化合物303)的制备
Figure PCTCN2021110746-appb-000022
第一步：将化合物301-2(2.0g，7.1mmol)溶于二甲基亚砜(20mL)，加入(R)-1-(5-溴噻吩-2-基)乙-1-胺盐酸盐(2.0g，8.5mmol)和N，N-二异丙基乙胺(2.7g，21.3mmol)，将反应液于150℃下搅拌16小时。将反应物冷却，加水稀释(50mL)，乙酸乙酯萃取(100mL)，将有机相减压浓缩，将浓缩物通过柱色谱法(甲醇∶二氯甲烷＝0-8％)分离纯化，得到化合物303-1(1.7g)，其为淡黄色固体，收率53％。ESI-MS：453[M+H] +.
第二步：将303-1(1.7g，3.8mmol)溶于二氧六环\水(5∶1)(30mL)，加入(2-((二甲基氨基)甲基)苯基)硼酸(1.0g，5.7mmol)、四(三苯基膦)钯(462mg，0.4mmol)和碳酸钾(1.6g，11.4mmol)，将反应液于100℃下搅拌16小时。将反应物冷却，过滤，将滤液减压浓缩，加水稀释(50mL)，乙酸乙酯萃取(100mL)，将有机相减压浓缩，将浓缩物通过柱色谱法(甲醇∶二氯甲烷＝0-8％)分离纯化，得到化合物303-2 (1.5g)，其为淡黄色固体，收率78％。ESI-MS：508[M+H] +.
第三步：将303-2(1.7g，3.0mmol)溶于二氧六环(20mL)，加入盐酸(4M，二氧六环的溶液)(5mL)，将反应液在室温下搅拌，TLC监控原料反应完全，减压浓缩去除溶剂得化合物303-3(1.0g)，其为白色固体，收率83％。ESI-MS：408[M+H] +.
第四步：将303-3(120mg，0.3mmol)溶于甲醇(5mL)，加入环丁酮(43mg，0.6mmol)、无水氯化锌(130mg，0.9mmol)和氰基硼氢化钠(61mg，0.9mmol)，将反应液于室温下搅拌15小时。加水淬灭反应，减压浓缩，加水稀释(10mL)，用乙酸乙酯萃取(2x20mL)，将有机相减压浓缩，将浓缩物通过高压制备液相色谱法纯化，得(R)-6-环丁基-N-(1-(5-(2-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)-2-甲基-5，6，7，8-四氢吡啶并[4，3-d]嘧啶-4-胺(52.76mg)，其为白色固体，收率38％。ESI-MS：462[M+H] +。 1H-NMR(400MHz，DMSO-d 6)δ：ppm 7.43(d，J＝8.0Hz，1H)，7.37(d，J＝8.0Hz，1H)，7.35-7.28(m，2H)，7.15(d，J＝4.0Hz，1H)，7.00-6.96(m，2H)，5.79-5.76(m，1H)，3.37(s，2H)，3.31(s，2H)，3.19-3.11(m，2H)，2.97-2.90(m，1H)，2.52-2.51(m，2H)，2.31(s，3H)，2.13(s，6H)，2.07-2.05(m，2H)，1.90-1.83(m，2H)，1.70-1.64(m，2H)，1.61(d，J＝4.0Hz，3H)。
实施例4：(R)-4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-7，8-二氢吡啶并[4，3-d]嘧啶-6(5H)-基)-N，N-二甲基环己烷-1-甲酰胺(化合物304)的制备
Figure PCTCN2021110746-appb-000023
第一步：将301-4(130mg，0.3mmol)溶于甲醇(5mL)，加入N，N-二甲基-4-氧代环己烷-1-甲酰胺(101mg，0.6mmol)、无水氯化锌(121mg，0.9mmol)和氰基硼氢化钠(61mg，0.9mmol)，将反应液于室温下搅拌15小时。加水淬灭反应，减压浓缩，加水稀释(10mL)，用乙酸乙酯萃取(2x20mL)，将有机相减压浓缩，得化合物304-1(110mg)，其为黄色固体，收率69％。ESI-MS：535[M+H] +.
第二步：将304-1(110mg，0.2mmol)溶于乙醇(5mL)和水(2mL)，加入铁粉(135mg，2.4mmol)和氯化铵(129mg，2.4mmol)，将反应液于90℃下搅拌2小时。将反应物冷却，过滤，将滤饼用乙酸乙酯洗涤，将滤液减压浓缩，将浓缩物用水(10mL)稀释，用乙酸乙酯萃取(2x10mL)，将有机相减压浓缩，将浓缩物通过高压制备液相色谱法分离纯化，得(R)-4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-7，8-二氢吡啶并[4，3-d]嘧啶-6(5H)-基)-N，N-二甲基环己烷-1-甲酰胺(52.33mg)，其为白色固体，收率52％。ESI-MS：505[M+H] +。 1H-NMR(400MHz，DMSO-d 6)δ：ppm 9.01(d，J＝8.0Hz，1H)，6.87(s，2H)，6.76(s，1H)，5.55-5.47(m，1H)，4.22(s，2H)，3.75-3.22(m，4H)，3.03(s，3H)，2.81(s，3H)，2.63-2.58(m，1H)，2.53(s，6H)，2.25-2.23(m，2H)，1.90-1.87(m，2H)，1.67-1.61(m，2H)，1.55(d，J＝4.0Hz，3H)，1.50-1.47(m，2H)。
实施例5：(R)-4-(4-((1-(5-(2-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-2-甲基-7，8-二氢吡啶并[4，3-d]嘧啶-6(5H)-基)-N，N-二甲基环己烷-1-甲酰胺(化合物305)的制备
Figure PCTCN2021110746-appb-000024
将化合物303-3(120mg，0.3mmol)溶于甲醇(5mL)，加入N，N-二甲基-4-氧代环己烷-1-甲酰胺(101mg，0.6mmol)、无水氯化锌(130mg，0.9mmol)和氰基硼氢化钠(61mg，0.9mmol)，将反应液于室温下搅拌15小时。加水淬灭反应，减压浓缩，加水稀释(10mL)，用乙酸乙酯萃取(2x20mL)，将有机相减压浓缩，将浓缩物通过高压制备液相色谱法纯化，得(R)-4-(4-((1-(5-(2-((二甲基氨基)甲基)苯 基)噻吩-2-基)乙基)氨基)-2-甲基-7，8-二氢吡啶并[4，3-d]嘧啶-6(5H)-基)-N，N-二甲基环己烷-1-甲酰胺(135.88mg)，其为白色固体，收率81％。ESI-MS：561[M+H] +。 1H-NMR(400MHz，DMSO-d 6)δ：ppm9.03(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz，1H)，7.56-7.49(m，2H)，7.42(d，J＝8.0Hz，1H)，7.18(d，J＝4.0Hz，1H)，7.11(d，J＝4.0Hz，1H)，5.94-5.87(m，1H)，4.43(s，2H)，4.17-4.16(m，2H)，3.42-3.41(m，2H)，3.08-3.00(m，6H)，2.81(s，3H)，2.78-2.66(m，6H)，2.55(s，3H)，2.15-1.91(m，2H)，1.93-1.86(m，3H)，1.71(d，J＝4.0Hz，3H)，1.72-1.62(m，2H)，1.59-1.50(m，2H)。
实施例6：(R)-1-(4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-7，8-二氢吡啶并[4，3-d]嘧啶-6(5H)-基)哌啶-1-基)乙-1-酮(化合物306)的制备
Figure PCTCN2021110746-appb-000025
第一步：将化合物301-4(130mg，0.3mmol)溶于甲醇(5mL)，加入1-乙酰基哌啶-4-酮(85mg，0.6mmol)、无水氯化锌(121mg，0.9mmol)和氰基硼氢化钠(61mg，0.9mmol)，将反应液于室温下搅拌15小时。加水淬灭反应，减压浓缩，加水稀释(10mL)，用乙酸乙酯萃取(2x20mL)，将有机相减压浓缩，得化合物306-1(130mg)，其为黄色固体，收率86％。ESI-MS：507[M+H] +.
第二步：将306-1(130mg，0.3mmol)溶于乙醇(5mL)和水(2mL)，加入铁粉(135mg，2.4mmol)和氯化铵(129mg，2.4mmol)，将反应液于90℃下搅拌2小时。将反应物冷却，过滤，将滤饼用乙酸乙酯洗涤，将滤液减压浓缩，将浓缩物用水(10mL)稀释，用乙酸乙酯萃取(2x10mL)，将有机相减压浓缩，将浓缩物通过高压制备液相色谱法分离纯化，得(R)-1-(4-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-7，8-二氢吡啶并[4，3-d]嘧啶-6(5H)-基)哌啶-1-基)乙-1-酮(88.72mg)，其为白色固体，收率73％。ESI-MS：477[M+H] +。 1H-NMR(400MHz，DMSO-d 6)δ：ppm 8.82(d，J＝8.0Hz，1H)，6.85(s，2H)，6.76(s，1H)，5.54-5.47(m，1H)，4.59-4.55(m，1H)，4.12(s，2H)，4.04-4.00(m，1H)，3.57-3.50(m，2H)，3.11-3.55(m，3H)，2.59-2.50(m，7H)，2.12-2.09(m，2H)，2.03(s，3H)，1.70-1.67(m，2H)，1.54(d，J＝4.0Hz，3H)。
实施例7：(R)-1-(4-(4-((1-(5-(2-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-2-甲基-7，8-二氢吡啶并[4，3-d]嘧啶-6(5H)-基)哌啶-1-基)乙-1-酮(化合物307)的制备
Figure PCTCN2021110746-appb-000026
将化合物303-3(100mg，0.3mmol)溶于甲醇(5mL)，加入1-乙酰基哌啶-4-酮(71mg，0.5mmol)、无水氯化锌(116mg，0.8mmol)和氰基硼氢化钠(54mg，0.8mmol)，将反应液于室温下搅拌15小时。加水淬灭反应，减压浓缩，加水稀释(10mL)，用乙酸乙酯萃取(2x20mL)，将有机相减压浓缩，将浓缩物通过高压制备液相色谱法纯化，得(R)-1-(4-(4-((1-(5-(2-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-2-甲基-7，8-二氢吡啶并[4，3-d]嘧啶-6(5H)-基)哌啶-1-基)乙-1-酮(30.64mg)，其为白色固体，收率23％。ESI-MS：533[M+H] +。 1H-NMR(400MHz，DMSO-d 6)δ：ppm 9.70(br，1H)，7.69(d，J＝8.0Hz，1H)，7.56-7.49(m，2H)，7.42(d，J＝8.0Hz，1H)，7.16(d，J＝4.0Hz，1H)，7.08(d，J＝4.0Hz，1H)，5.91-5.84(m，1H)，4.55-4.52(m，1H)，4.43(s，2H)，4.00-3.97(m，4H)，3.44-3.30(m，2H)，3.10-3.03(m，1H)，2.97(s，2H)，2.67-2.66(m，4H)，2.58-2.50(m，7H)，2.04-2.01(m，4H)，1.69(d，J＝4.0Hz，3H)，1.66-1.52(m，2H)。
实施例8：(R)-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-7，8-二氢吡啶并[4，3-d]嘧啶-6(5H)-基)(四氢-2H-吡喃-4-基)甲酮(化合物308)的制备
Figure PCTCN2021110746-appb-000027
第一步：将四氢-2H-吡哺-4-羧酸(40mg，0.9mmol)溶于N，N-二甲基甲酰胺(3mL)，加入HATU(137mg，0.4mmol)、N，N-二异丙基乙胺(116mg，0.9mmol)和化合物301-4(130mg，0.3mmol)，将反应液于室温下搅拌15小时。加水稀释(10mL)，用乙酸乙酯萃取(2x20mL)，将有机相减压浓缩，得化合物308-1(110mg)，其为黄色固体，收率74％。ESI-MS：494[M+H] +.
第二步：将308-1(110mg，0.2mmol)溶于乙醇(5mL)和水(2mL)，加入铁粉(135mg，2.4mmol)和氯化铵(129mg，2.4mmol)，将反应液于90℃下搅拌2小时。将反应物冷却，过滤，将滤饼用乙酸乙酯洗涤，将滤液减压浓缩，将浓缩物用水(10mL)稀释，用乙酸乙酯萃取(2x10mL)，将有机相减压浓缩，将浓缩物通过高压制备液相色谱法分离纯化，得(R)-(4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基-7，8-二氢吡啶并[4，3-d]嘧啶-6(5H)-基)(四氢-2H-吡喃-4-基)甲酮(68.34mg)，其为白色固体，收率67％。ESI-MS：494[M+H] +。 1H-NMR(400MHz，DMSO-d 6)δ：ppm 9.00(d，J＝8.0Hz，1H)，6.90(s，1H)，6.85(s，1H)，6.75(s，1H)，5.57-5.49(m，1H)，4.52-4.49(m，1H)，4.44(s，2H)，3.88-3.84(m，4H)，3.45-3.39(m，2H)，3.05-3.01(m，1H)，2.99-2.83(m，2H)，2.72-2.71(m，1H)，2.51(s，3H)，1.63-1.53(m，7H)。
实施例9：(R)-(4-((1-(5-(2-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-2-甲基-7，8-二氢吡啶并[4，3-d]嘧啶-6(5H)-基)(四氢-2H-吡喃-4-基)甲酮(化合物309)的制备
Figure PCTCN2021110746-appb-000028
将四氢-2H-吡喃-4-羧酸(40mg，0.9mmol)溶于N，N-二甲基甲酰胺(3mL)，加入HATU(137mg，0.4mmol)、N，N-二异丙基乙胺(116mg，0.9mmol)和化合物303-3(100mg，0.3mmol)，将反应液于室温下搅拌15小时。加水稀释(10mL)，用乙酸乙酯萃取(2x20mL)，将有机相减压浓缩，将浓缩物通过高压制备液相色谱法纯化，得(R)-(4-((1-(5-(2-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-2-甲基-7，8-二氢吡啶并[4，3-d]嘧啶-6(5H)-基)(四氢-2H-吡喃-4-基)甲酮(66.78mg)，其为白色固体，收率51％。ESI-MS：520[M+H] +。 1H-NMR(400MHz，DMSO-d 6)δ：ppm 9.76(br，1H)，7.70(d，J＝8.0Hz，1H)，7.51-7.48(m，2H)，7.44(d，J＝8.0Hz，1H)，7.16(d，J＝4.0Hz，1H)，7.09(d，J＝4.0Hz，1H)，5.92-5.88(m，1H)，4.51-4.31(m，5H)，4.92-3.77(m，5H)，3.05-3.00(m，1H)，2.88-2.87(m，2H)，2.54(s，6H)，2.51(s，3H)，1.71(d，J＝8.0Hz，3H)，1.63-1.57(m，4H)。
实施例10：(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-2-甲基-6-((四氢-2H-吡喃-4-基)甲基)-5，6，7，8-四氢吡啶并[4，3-d]嘧啶-4-胺(化合物310)的制备
Figure PCTCN2021110746-appb-000029
第一步：将化合物301-4(130mg，0.3mmol)溶于甲醇(5mL)，加入四氢-2H-吡喃-4-甲醛(68mg，0.6mmol)、无水氯化锌(121mg，0.9mmol)和氰基硼氢化钠(61mg，0.9mmol)，将反应液于室温下搅拌15小时。加水淬灭反应，减压浓缩，加水稀释(10mL)，用乙酸乙酯萃取(2x20mL)，将有机相 减压浓缩，得化合物310-1(110mg)，其为黄色固体，收率76％。ESI-MS：480[M+H] +.
第二步：将310-1(110mg，0.2mmol)溶于乙醇(5mL)和水(2mL)，加入铁粉(135mg，2.4mmol)和氯化铵(129mg，2.4mmol)，将反应液于90℃下搅拌2小时。将反应物冷却，过滤，将滤饼用乙酸乙酯洗涤，将滤液减压浓缩，将浓缩物用水(10mL)稀释，用乙酸乙酯萃取(2x10mL)，将有机相减压浓缩，将浓缩物通过高压制备液相色谱法分离纯化，得(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-2-甲基-6-((四氢-2H-吡喃-4-基)甲基)-5，6，7，8-四氢吡啶并[4，3-d]嘧啶-4-胺(66.47mg)，其为白色固体，收率67％。ESI-MS：450[M+H] +。 1H-NMR(400MHz，DMSO-d 6)δ：ppm 8.96(d，J＝8.0Hz，1H)，6.87(s，1H)，6.85(s，1H)，6.75(s，1H)，5.53-5.49(m，1H)，4.14-4.13(m，2H)，3.89-3.85(m，2H)，3.46-3.30(m，4H)，3.11-3.04(m，4H)，2.52.2.50(m，4H)，2.14-2.13(m，1H)，1.73-1.64(m，2H)，1.54(d，J＝8.0Hz，3H)，1.31-1.20(m，3H)。
实施例11：(R)-N-(1-(5-(2-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)-2-甲基-6-((四氢-2H-吡喃-4-基)甲基)-5，6，7，8-四氢吡啶并[4，3-d]嘧啶-4-胺(化合物311)的制备
Figure PCTCN2021110746-appb-000030
将化合物303-3(100mg，0.3mmol)溶于甲醇(5mL)，加入四氢-2H-吡喃-4-甲醛(57mg，0.5mmol)、无水氯化锌(116mg，0.8mmol)和氰基硼氢化钠(54mg，0.8mmol)，将反应液于室温下搅拌15小时。加水淬灭反应，减压浓缩，加水稀释(10mL)，用乙酸乙酯萃取(2x20mL)，将有机相减压浓缩，将浓缩物通过高压制备液相色谱法纯化，得(R)-N-(1-(5-(2-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)-2-甲基-6-((四氢-2H-吡喃-4-基)甲基)-5，6，7，8-四氢吡啶并[4，3-d]嘧啶-4-胺(29.30mg)，其为白色固体，收率23％。ESI-MS：506[M+H] +。 1H-NMR(400MHz，DMSO-d 6)δ：ppm 7.44(d，J＝8.0Hz，1H)，7.38-7.37(m，1H)，7.36-7.30(m，2H)，7.15(d，J＝4.0Hz，1H)，7.01-6.96(m，2H)，5.80-5.73(m，1H)，3.84-3.81(m，3H)，3.40-3.34(m，2H)，3.29-3.19(m，4H)，2.64-2.60(m，4H)，2.35-2.34(m，2H)，2.31(s，3H)，2.14-2.11(m，7H)，1.62-1.61(m，6H)。
实施例12：(R)-1-(4-(4-((1-(4-(2-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-2-甲基-7，8-二氢吡啶并[4，3-d]嘧啶-6(5H)-基)哌啶-1-基)乙-1-酮(化合物312)的制备
Figure PCTCN2021110746-appb-000031
第一步：将化合物301-2(1.0g，3.5mmol)溶于二甲基亚砜(20mL)，加入(R)-1-(4-溴噻吩-2-基)乙-1-胺盐酸盐(1.0g，4.2mmol)和N，N-二异丙基乙胺(1.4g，10.2mmol)，将反应液于150℃下搅拌16小 时。将反应物冷却，加水稀释(50mL)，乙酸乙酯萃取(100mL)，将有机相减压浓缩，将浓缩物通过柱色谱法(甲醇∶二氯甲烷＝0～8％)分离纯化，得到化合物312-1(900mg)，其为淡黄色固体，收率56％。ESI-MS：453[M+H] +.
第二步：将312-1(900mg，2.0mmol)溶于二氧六环\水(5∶1)(15mL)，加入(2-((二甲基氨基)甲基)苯基)硼酸(534mg，3.0mmol)、四(三苯基膦)钯(231mg，0.2mmol)和碳酸钾(823mg，6.0mmol)，将反应液于100℃下搅拌16小时。将反应物冷却，过滤，将滤液减压浓缩，加水稀释(50mL)，乙酸乙酯萃取(100mL)，将有机相减压浓缩，将浓缩物通过柱色谱法(甲醇∶二氯甲烷＝0～8％)分离纯化，得到化合物312-2(450mg)，其为淡黄色固体，收率45％。ESI-MS：508[M+H] +.
第三步：将312-2(450mg，0.9mmol)溶于二氧六环(5mL)，加入盐酸(4M，二氧六环中的溶液)(3mL)，将反应液在室温下搅拌，TLC监控原料反应完全，减压浓缩去除溶剂得化合物312-3(300mg)，其为白色固体，收率82％。ESI-MS：408[M+H] +.
第四步：将312-3(100mg，0.3mmol)溶于甲醇(5mL)，加入1-乙酰基哌啶-4-酮(71mg，0.5mmol)、无水氯化锌(116mg，0.8mmol)和氰基硼氢化钠(54mg，0.8mmol)，将反应液于室温下搅拌15小时。加水淬灭反应，减压浓缩，加水稀释(10mL)，用乙酸乙酯萃取(2x20mL)，将有机相减压浓缩，将浓缩物通过高压制备液相色谱法纯化，得(R)-1-(4-(4-((1-(4-(2-((二甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)-2-甲基-7，8-二氢吡啶并[4，3-d]嘧啶-6(5H)-基)哌啶-1-基)乙-1-酮(58.03mg)，其为白色固体，收率48％。ESI-MS：533[M+H] +。 1H-NMR(400MHz，DMSO-d 6)δ：ppm 9.45(s，1H)，7.42-7.40(m，1H)，7.39-7.29(m，3H)，7.25(s，1H)，6.95(d，J＝6.0Hz，1H)，5.82-5.74(m，1H)，4.45-4.41(m，1H)，3.89-3.85(m，1H)，3.36-3.30(m，5H)，3.06-2.99(m，1H)，2.77-2.74(m，2H)，2.68-2.60(m，1H)，2.59-2.57(m，2H)，2.30(s，3H)，2.12(s，6H)，2.00(s，3H)，1.86-1.80(m，2H)，1.61(d，J＝8.0Hz，3H)，1.53-1.51(m，2H)。
生物学测定
实验例1.KRAS：：SOS1 HTRF结合分析
此测定法可用于检查化合物抑制SOS1与KRAS G12C之间的蛋白-蛋白相互作用的效力。这证明了化合物的分子作用模式。低IC 50值指示SOS1抑制剂化合物在以下这种测定设置中的高效力。
试剂：
·GST-SOS1(aa564-1049)，内部生产
·His-KRAS G12C(aa1-169)，内部生产
·MAb Anti-6his-Tb cryptate Gold，购自Cisbio(目录号61HI2TLA)
·MAb Anti-GST-XL665，购自Cisbio(目录号61GSTXLA)
测定板：ProxiPlate-384Plus，购自PerkinElmer(目录号6008280)
测定缓冲液：PPI，购自Cisbio(目录号61DB10RDF)
测定方案：
·将待测化合物溶解在DMSO中，配制储备液浓度为10mM，并用DMSO稀释化合物浓度至2mM作为测定起始浓度，对2mM起始浓度化合物溶液连续3倍稀释，共稀释10个浓度，使用Labcyte Echo仪器转移0.1μL各浓度化合物溶液至384孔测定板中(一式两份，双复孔)；
·向0.1μL化合物溶液中加入5μL特定浓度的His-KRAS G12C，在Eppendorf5810R离心机上以1000rpm离心1min；
·随后加入5μL特定浓度的GST-SOS1，同样置于Eppendorf 5810R离心机以1000rpm离心1min；
·将384孔测定板于25℃孵育15min；
·然后加入10μL MAb Anti-6his-Tb和MAb Anti-GST-XL665混合物，在Eppendorf 5810R离心机上以1000rpm离心1min；
·384孔测定板于25℃孵育2h；
·最后使用Perkin Elmer Envision 2104仪器读板，获得665/615nm信号比值。
每个板含有以下对照：
·DMSO+KRAS+SOS1+MAb Anti-6his-Tb+MAb Anti-GST-XL665
结果计算：
使用4参数回归方程计算和分析IC 50值。测定结果如下表所示。
化合物编号 SOS1-KRAS G12C相互作用测定(IC 50，nM)
301 247.4
302 116.5
303 136.6
304 83.3
305 86.7
306 54.3
307 32
309 124.1
311 117.7
312 85.4
除本文中描述的那些外，根据前述描述，本发明的各种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (13)

  1. 化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物具有式(I)的结构：
    Figure PCTCN2021110746-appb-100001
    其中：
    X 1、X 2、X 3和X 4各自独立地选自C＝O、CH 2、CHR、C(R) 2和N-L-R 2，优选地，X 1、X 2、X 3和X 4中至少一个为N-L-R 2；
    L选自直接键、C 1-6亚烷基、C(＝O)、O、S(＝O)、S(＝O) 2和NR 4；
    环B选自C 3-10烃环、3-10元杂环、C 6-10芳环和5-14元杂芳环，所述烃环和杂环中至多2个环成员为C(＝O)；
    R和R 1在每次出现时各自独立地选自卤素、-NH 2、-CN、-NO 2、-OH、-O-C 1-6烷基、C 1-6烷基、卤代C 1-6烷基、C 1-6亚烷基-OH、卤代C 1-6亚烷基-OH、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基，所述环烃基和杂环基中至多2个环成员为C(＝O)，当m大于1和/或n大于1时，两个R 1和/或两个R连同其所连接的原子任选地共同构成C 3-10烃环、3-10元杂环、C 6-10芳环或5-14元杂芳环，所述烃环和杂环中至多2个环成员为C(＝O)；
    R 2选自H、C 1-6烷基、卤代C 1-6烷基、C 1-6亚烷基-OH、卤代C 1-6亚烷基-OH、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R 5、-OC(＝O)R 5、-C(＝O)OR 5、-OR 5、-SR 5、-S(＝O)R 5、-S(＝O) 2R 5、-S(＝O) 2NR 5R 6、-NR 5R 6、-C(＝O)NR 5R 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 5R 6、-C 1-6亚烷基-NR 5R 6、-C 1-6亚烷基-O(P＝O)(OH) 2和-O-C 1-6亚烷基-NR 5R 6；
    R 3和R 4各自独立地选自H、卤素、-NH 2、-CN、-NO 2、-OH、-O-C 1-6烷基、-O-(3-10元杂环基)、C 1-6烷基、卤代C 1-6烷基、C 1-6亚烷基-OH、卤代C 1-6亚烷基-OH、C 2-6烯基、C 2-6炔基、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R 5、-OC(＝O)R 5、-C(＝O)OR 5、-OR 5、-SR 5、-S(＝O)R 5、-S(＝O) 2R 5、-S(＝O) 2NR 5R 6、-NR 5R 6、-C(＝O)NR 5R 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 5R 6、-C 1-6亚烷基-NR 5R 6、-C 1-6亚烷基-O(P＝O)(OH) 2和-O-C 1-6亚烷基-NR 5R 6；
    上述基团在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、氧代、-NH 2、-CN、-NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、＝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) 2R 5、-S(＝O) 2NR 5R 6、-NR 5R 6、-C(＝O)NR 5R 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 5R 6、-C 1-6亚烷基-NR 5R 6和-O-C 1-6亚烷基-NR 5R 6，所述烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、氧代、-NH 2、-CN、-NO 2、C 1-6烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；
    R 5和R 6在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；并且
    m为选自0、1、2、3和4的整数。
  2. 权利要求1的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物具有式(II)的结构：
    Figure PCTCN2021110746-appb-100002
    环A为
    Figure PCTCN2021110746-appb-100003
    并且
    n为选自0、1、2或3的整数。
  3. 权利要求1或2的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中L为直接键、-CH 2-或C(＝O)。
  4. 权利要求1-3中任一项的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中，R 2为饱和或部分不饱和的C 3-10环烃基或饱和或部分不饱和的3-10元杂环基，其中所述环烃基和杂环基任选地被一个或多个选自-C(＝O)R 5和-C(＝O)NR 5R 6的取代基取代；
    优选地，R 2为环丁烷基、环己烷基、哌啶基或四氢吡喃基，其任选地被一个或多个选自-C(＝O)CH 3和-C(＝O)N(CH 3) 2的取代基取代；
    更优选地，-L-R 2选自
    Figure PCTCN2021110746-appb-100004
    Figure PCTCN2021110746-appb-100005
  5. 权利要求1-4中任一项的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中环B为双环[1.1.1]戊烷环、2-氧杂双环[2.1.1]己烷环、苯环或噻吩环，最优选为苯环或噻吩环。
  6. 权利要求1-5中任一项的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中R 1在每次出现时各自独立地选自卤素、-NH 2、C 1-6烷基、卤代C 1-6烷基、C 1-6亚烷基-OH、卤代C 1-6亚烷基-OH、饱和或部分不饱和的C 3-10环烃基、饱和或部分不饱和的3-10元杂环基、C 6-10芳基和5-14元杂芳基，所述亚烷基、烷基、环烃基、杂环基、芳基和杂芳基任选地被一个或多个独立地选自卤素、-OH、C 3-6环烃基、3-10元杂环基、C 6-10芳基和5-14元杂芳基的取代基取代；
    当m大于1时，两个R 1连同其所连接的原子任选地共同构成C 3-10烃环、3-10元杂环、C 6-10芳环或5-14元杂芳环，所述烃环和杂环中至多2个环成员为C(＝O)，并且所述烃环、杂环、芳环和杂芳环任选地被一个或多个卤素取代；
    优选地，R 1在每次出现时各自独立地选自CF 3、NH 2、
    Figure PCTCN2021110746-appb-100006
    并且 m为1或2。
  7. 权利要求1-6中任一项的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中
    Figure PCTCN2021110746-appb-100007
    选自
    Figure PCTCN2021110746-appb-100008
    Figure PCTCN2021110746-appb-100009
  8. 权利要求1-7中任一项的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中R 3选自H和C 1-6烷基；优选地，R 3为甲基。
  9. 权利要求1-8中任一项的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中R 4选自H和C 1-6烷基；优选地，R 4为H。
  10. 权利要求1-9中任一项的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物具有式(III)的结构：
    Figure PCTCN2021110746-appb-100010
  11. 权利要求1-10中任一项的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物选自：
    Figure PCTCN2021110746-appb-100011
  12. 药物组合物，其包含预防或治疗有效量的权利要求1-11中任一项的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，以及药学上可接受的载体，所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。
  13. 权利要求1-11中任一项的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶 剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或者权利要求12的药物组合物在制备用作SOS1抑制剂的药物中的用途，优选地，所述药物用于预防或治疗癌症(例如胰腺癌、肺癌、结直肠癌、胆管癌、多发性骨髓瘤、黑素瘤、子宫癌、子宫内膜癌、甲状腺癌、急性髓性白血病、膀胱癌、尿路上皮癌、胃癌、宫颈癌、头颈部鳞状细胞癌、弥漫性大B细胞淋巴瘤、食道癌、慢性淋巴细胞白血病、肝细胞癌、乳腺癌、卵巢癌、前列腺癌、胶质母细胞瘤、肾癌和肉瘤)、RAS病(例如1型神经纤维瘤病(NF1)、努南综合征(NS)、伴有多斑的努南综合征(NSML)、毛细血管畸形-动静脉畸形综合征(CM-AVM)、科斯特洛综合征(CS)、心-面-皮肤综合症(CFC)、莱格斯综合征和遗传性牙龈纤维瘤病)。
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