CN116655655A - Tetrafused ring compound, and pharmaceutical composition and application thereof - Google Patents

Tetrafused ring compound, and pharmaceutical composition and application thereof Download PDF

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Publication number
CN116655655A
CN116655655A CN202210152068.6A CN202210152068A CN116655655A CN 116655655 A CN116655655 A CN 116655655A CN 202210152068 A CN202210152068 A CN 202210152068A CN 116655655 A CN116655655 A CN 116655655A
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compound
alkyl
cycloalkyl
alkoxy
independently selected
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方华祥
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Wuhan Yuxiang Medical Technology Co ltd
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Wuhan Yuxiang Medical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

The invention belongs to the field of pharmaceutical chemistry, and relates to a tetrafused ring compound, a pharmaceutical composition and application thereof. The compound is shown as a formula I and has good SOS1 inhibition activity, so that the compound can be used as an SOS1 inhibitor for preventing and/or treating diseases (such as cancers) over-expressed by SOS 1. The four-parallel ring compound of the invention has excellent biological activity and patentability, and has great drug development prospect.

Description

Tetrafused ring compound, and pharmaceutical composition and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a tetracyclic compound, a pharmaceutical composition containing the compound and application of the compound in the field of medicines.
Background
Starting from the discovery by the end of 1982 that the RAS family gtpases (which comprise members KRAS, NRAS, and HRAS) are associated with cancer, the incidence in human cancers is as high as 20% -30%. The RAS proteins act as molecular switches that cycle between an active GTP-bound state and an inactive GDP-bound state. Activated by guanine nucleotide exchange factor (GEF), the RAS in its GTP-bound state interacts with a number of effectors. Returning to the inactive state is driven by Gtpase Activating Proteins (GAPs), which down-regulate the active RAS by accelerating weak intrinsic gtpase activity by up to 5 orders of magnitude.
Whether mutant RAS proteins require GEF activity to be fully activated remains to be fully investigated and may vary from one particular mutation to another. The most studied protein of RAS sevenless son (SOS), two human isoforms SOS1 and SOS2 are known. Attempts to recognize RAS-SOS interactions of hydrocarbon binding peptides by inhibiting peptide mimicking the nanomolar affinity orthotopic SOS helix, but with only low cellular activity. Fragment-based screening, rational design, and high throughput screening methods have led to the identification of small molecule addressing KRAS-SOS1 interactions resulting in moderate micromolar affinities.
SOS1 protein consists of 1333 amino acids (150 kDa). SOS1 is a multidomain protein having two N-terminal Histone Domains (HD) in tandem, followed by a Dbl homology Domain (DH), a Pleckstrin homology domain (PH), a helical junction (HL), a RAS Exchange Motif (REM), a CDC25 homology domain and a C-terminal proline-rich domain (PR). SOS1 has two binding sites for RAS family proteins; a catalytic site that binds to a GDP-bound RAS family protein to promote guanine nucleotide exchange; an allosteric site that binds GTP-bound RAS family proteins, which results in a further increase in catalytic GEF function of SOS 1. Published data indicate that SOS1 is critically involved in mutant KRAS activation and oncogenic signaling in cancer (Jeng et al, nat. Commun.,2012, 3:1168). Depletion of SOS1 levels reduced proliferation and survival of tumor cells harboring KRAS mutations, whereas no effect was observed in KRAS wild-type cell lines. The effect of SOS1 loss cannot be complemented by SOS1 introduced with catalytic site mutations, demonstrating the important role of SOS1GEF activity in KRAS mutant cancer cells.
SOS1 is critically involved in activation of RAS family protein signaling in cancer by mechanisms other than RAS family protein mutation. SOS1 interacts with the adaptor protein Grb2 and the resulting SOS1/Grb2 complex binds to activated/phosphorylated receptor tyrosine kinases (e.g., EGFR, erbB2, erbB3, erbB4, PDGFR-A/B, FGFR1/2/3, IGF1R, INSR, ALK, ROS, trkA, trkB, trkC, RET, c-MET, VEGFR1/2/3, AXL) (Pierre et al, biochem. Phacol., 2011,82 (9): 1049-56). SOS1 is also recruited to other phosphorylated cell surface receptors such as T Cell Receptor (TCR), B Cell Receptor (BCR) and monocyte colony stimulating factor receptor (Salojin et al J.biol. Chem.2000,275 (8): 5966-75). This localization of SOS1 to the plasma membrane proximal to the RAS family proteins enables SOS1 to promote RAS family protein activation. SOS1 activation of RAS family proteins can also be mediated through SOS1/Grb2 interactions with BCR-ABL oncoproteins common in chronic myeloid leukemia.
SOS1 is also a GEF for activating GTPase RAC1 (Ras-related C3 botulinum toxin substrate 1) (Innocenti et al, J.cell biol.,2002,156 (1): 125-36). As with RAS family proteins, RAC1 is involved in the pathogenesis of a variety of human cancers and other diseases (Bid et al mol. Cancer ter.2013, 12 (10): 1925-34).
Herein, we describe novel SOS1 inhibitor compounds that bind to the SOS1 catalytic site and at the same time prevent interaction with RAS family proteins and their activation. This results in a significant inhibition of the interaction of SOS1 with RAS family proteins, in particular KRAS (with low number of units nanomolar IC50 activity), and thus significantly reduces ERK phosphorylation in KRAS mutant cancer cell lines.
The selective SOS1 inhibitor compounds described herein are expected to provide pharmacological benefits to patients suffering from cancers associated with dependence on RAS family protein signaling. Such cancers contemplated to be targeted by SOS1 inhibitor compounds include those that exhibit alterations (mutations, gene amplification, overexpression) in components of the RAS family protein pathway (proteins, genes) such as KRAS, NRAS, HRAS, receptor tyrosine kinases (e.g., EGFR, erbB2, erbB3, erbB4, PDGFR-a/B, FGFR1/2/3, IGF1R, INSR, ALK, ROS, trkA, trkB, trkC, RET, c-MET, VEGFR1/2/3, AXL), GAP (e.g., NF 1), and SOS1. In addition, given the role of SOS1 in RAC1 activation, cancers that exhibit a dependency on RAC1 are expected to be targeted by SOS1 inhibitor compounds. Furthermore, SOS1 inhibitor compounds are expected to also provide pharmacological benefits in other diseases associated with dysregulation of RAS family protein pathways such as neurofibromatosis, noonan Syndrome (NS), cardiac skin syndrome (CFC), and hereditary gum fibromatosis type 1.
In addition to inhibition and potency, the compounds disclosed herein exhibit good solubility, excellent DMPK properties, and good selectivity for kinases of the human kinase group.
Disclosure of Invention
Problems to be solved by the invention
The invention aims to provide a tetrafused ring compound used as an SOS1 inhibitor with a novel structure, which shows good inhibition activity on tumor cells, has good patentability and has wide drug development prospect.
Solution for solving the problem
In a first aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite, or prodrug thereof,
wherein, the liquid crystal display device comprises a liquid crystal display device,
ring A is selected from C 6 -C 10 Aryl, 5 to 6 membered monocyclic heteroaryl, or 9 to 10 membered bicyclic heteroaryl;
m is any integer from 0 to 5;
x and Y are each independently selected from CR 7 Or N;
Z 1 and Z 2 Each independently selected from-O-, -C (R) 7 ) 2 -or-NR 7 -；
L 1 、L 2 And L 3 Each independently is independently selected from- (CH) 2 ) n -or- (CH) 2 ) n -O-(CH 2 ) p -O-(CH 2 ) o -; wherein, if present, each n, o and p is independently any integer from 0 to 3;
R 1 and R is 2 Each independently selected from hydrogen or C 1 -C 8 Alkyl, orR is as follows 1 And R is 2 Together with the carbon atom to which it is attached form C 3 -C 6 Cycloalkyl; the alkyl and cycloalkylalkyl groups are each optionally substituted with at least 1R 8 Substitution; alternatively, R 1 Or R is 2 A 4-8 membered saturated carbocyclic or heterocyclic ring with ring A;
R 3 selected from hydrogen, halogen, cyano, hydroxy, amino, -NH (R) 7 )、-C(＝O)-NH(R 7 )、C 1 -C 6 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 6 Cycloalkyl, 3-to 8-membered heterocycloalkyl, C 1 -C 3 Alkoxy or C 1 -C 6 A haloalkyl group; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy and haloalkyl are each optionally substituted with at least 1R 8 Substitution;
if present, each R 4 Each independently selected from hydrogen, halogen, cyano, hydroxy, amino, -NH (R) 7 )、-C(＝O)-NH(R 7 )、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 3-to 8-membered heterocycloalkyl, C 1 -C 3 Alkoxy or C 1 -C 6 A haloalkyl group; the alkyl, cycloalkyl, heterocycloalkyl, alkoxy and haloalkyl groups are each optionally substituted with at least 1R 8 Substitution;
R 5 and R is 6 Each independently selected from hydrogen, halogen, cyano, hydroxy, amino, -N (R) 8 )(R 9 )、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 3-to 8-membered heterocycloalkyl, C 1 -C 3 Alkoxy or C 1 -C 6 A haloalkyl group; the alkyl, cycloalkyl, heterocycloalkyl, alkoxy and haloalkyl groups are each optionally substituted with at least 1R 8 Substitution;
if present, each R 7 Each independently selected from hydrogen, halogen, cyano, hydroxy, amino, -N (R) 8 )(R 9 )、-C(＝O)-N(R 8 )(R 9 )、-C(＝O)-R 8 、-C(＝O)-OR 8 、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 3-to 8-membered heterocycloalkyl, C 6 -C 10 Aryl, 5-to 10-membered heteroaryl, C 1 -C 3 Alkoxy or C 1 -C 6 Haloalkyl, said alkyl, cycloalkyl, heterocycloalkyl, alkoxy and haloalkyl each optionally being substituted with at least 1R 8 Substitution;
if present, each R 8 And R is 9 Each independently selected from hydrogen, halogen, cyano, hydroxy, amino, carbamoyl, C 1 -C 6 Alkyl, C 1 -C 6 Heteroalkyl, C 3 -C 8 Cycloalkyl, 3-to 14-membered heterocycloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, C 6 -C 10 Aryl, 5-to 6-membered monocyclic heteroaryl or 9-to 10-membered bicyclic heteroaryl, or R 8 And R is 9 Together with the nitrogen atom to which it is attached, form a 5-to 6-membered heterocycloalkyl; the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkoxy, aryl, monocyclic heteroaryl, and bicyclic heteroaryl are each optionally substituted with at least 1R 10 Substitution;
R 1 to R 9 The hetero atoms or hetero atom groups contained in the hetero alkyl group, the hetero cycloalkyl group, the hetero alkoxy group and the hetero aryl group are each independently selected from the group consisting of-C (=O) N (R) 10 )-、-N(R 10 )-、-NH-、-N＝、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O) 2 -or-N (R) 10 )C(＝O)N(R 10 ) -the number of heteroatoms or heteroatoms groups is each independently selected from 1, 2 or 3;
if present, each R 10 Each independently selected from hydrogen, chlorine, fluorine, cyano, hydroxy, amino, isopropyl, cyclopropyl, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, 2-difluoroethoxy, 2-trifluoroethoxy or phenyl.
Preferably, the compound is a compound shown as a formula I-1 or I-2,
therein, m, X, Y, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 And R is 7 As defined in formula I.
More preferably, the compound is a compound represented by formula I-1-1 or I-2-1,
therein, m, X, Y, R 4 、R 5 、R 6 And R is 7 As defined in formula I.
In a second aspect, the present invention provides a compound as shown in formula I, formula I-1, formula I-2, formula I-1-1 or formula I-2-1, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof:
in a third aspect, the present invention provides a pharmaceutical composition comprising a compound according to the first or second aspect or one or more of its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, metabolites or prodrugs thereof.
Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.
In a fourth aspect, the present invention provides the use of a compound according to the first or second aspect or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof or a pharmaceutical composition according to the third aspect for the manufacture of a medicament for the prevention and/or treatment of a disease caused by overexpression of SOS 1.
In a fifth aspect, the present invention provides the use of a compound according to the first or second aspect or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition according to the third aspect, for the manufacture of a SOS1 inhibitor medicament.
In a sixth aspect, the present invention provides the use of a compound according to the first or second aspect or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof or a pharmaceutical composition according to the third aspect in the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
Preferably, the cancer is any one or more of pancreatic cancer, colorectal cancer and lung cancer.
In a seventh aspect, the present invention provides a method for preventing and/or treating a disease or disorder caused by SOS1 overexpression, comprising administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a compound according to the first or second aspect or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition according to the third aspect.
ADVANTAGEOUS EFFECTS OF INVENTION
The invention provides a series of tetrafused ring compounds with novel structure, which are proved by related enzyme and cell activity tests to have excellent cell proliferation inhibition activity, and in vitro experiments, the compounds have good cell proliferation inhibition activity on IC 50 The value reaches the nM level, and can be well applied to various tumors. At the same time, the compounds of the present invention have very good inhibition of KRAS: SOS1 activation, which can reach nM levels, and are suitable for the preparation of SOS1 inhibitors for the prevention and/or treatment of diseases or disorders associated with SOS1 activation, such as cancer (including but not limited to pancreatic cancer, colorectal cancer and lung cancer).
Detailed Description
General terms and definitions
Unless stated to the contrary, the terms used in the present invention have the following meanings.
"alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms, which may be, for example, straight and branched chain groups of 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In the present invention, "alkyl" may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, and various branched isomers thereof, and the like. Non-limiting examples also include, but are not limited to, methylene, ethylene, propylene, butylene, and various branched isomers thereof. In addition, in the present invention, "alkyl" may be optionally substituted or unsubstituted.
"alkoxy" refers to an "-O-alkyl" group, where "alkyl" is defined above.
"alkenyl" refers to unsaturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms and at least 1 carbon-carbon double bond, and may be, for example, straight and branched chain groups of 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In the present invention, "alkenyl" may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, vinyl (-ch=ch) 2 ) Propen-1-yl (-ch=ch-CH) 3 ) Propylene-2-yl (-C (CH) 3 )＝CH 2 ) Buten-1-yl (-ch=ch-CH) 2 -CH 3 ) Buten-2-yl (-C (C) 2 H 5 )＝CH 2 ) 1-Methylpropen-1-yl (-C (CH) 3 )＝CH-CH 3 ) And various branched isomers thereof. Non-limiting examples also include, but are not limited to, 1-vinylidene (= c=ch 2 ) 1, 2-ethenylene (-ch=ch-), 1-propenylene (=)C＝CH-CH 3 ) 1, 2-propenylidene (-Ch=c (CH) 3 ) (-), 1, 3-propenylidene (-ch=ch-CH) 2 (-) and various branched isomers thereof. In addition, in the present invention, "alkenyl" may be optionally substituted or unsubstituted.
"alkynyl" refers to unsaturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms and at least 1 carbon-carbon triple bond, and may be, for example, straight and branched chain groups of 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In the present invention, "alkynyl" may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, ethynyl (-c≡ch), propynyl (-c≡c-cH) 3 ) Butynyl groupPentynyl->And various branched isomers thereof. Non-limiting examples also include, but are not limited to, ethynylene (-c≡c-), propynylene->Sulbutylkynyl->And various branched isomers thereof. In addition, in the present invention, "alkynyl" may be optionally substituted or unsubstituted.
"Heteroalkyl" means a saturated aliphatic hydrocarbon group including straight and branched chain groups of 2 to 20 atoms, for example, straight and branched chain groups which may be 2 to 18 atoms, 2 to 12 atoms, 2 to 8 atoms, 2 to 6 atoms or 2 to 4 atoms, wherein one or more of the atoms is selected from nitrogen, oxygen or S (O) m (wherein m is 0, 1 or 2) and the balance is carbon. In the present invention, "heteroalkyl" may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, methoxymethyl (2-oxopropyl), methylthiomethyl (2-thiapropyl), methylaminomethyl (2-azaPropyl) and various branched isomers thereof. In addition, in the present invention, "heteroalkyl" may be optionally substituted or unsubstituted.
"cycloalkyl" refers to a saturated or partially unsaturated, mono-or polycyclic aliphatic hydrocarbon group comprising 3 to 12 ring atoms, which may be, for example, 3 to 12, 3 to 10, or 3 to 6 ring atoms (i.e., 3 to 6 membered rings). Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. In the present invention, "cycloalkyl" may be optionally substituted or unsubstituted.
"Heterocyclyl" means a saturated or partially unsaturated, mono-or polycyclic aliphatic hydrocarbon radical comprising 3 to 20 ring atoms, which may be, for example, 3 to 16, 3 to 12, 3 to 10 or 3 to 6 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) m (wherein m is 0, 1 or 2) and the remaining ring atoms are carbon. Preferably the heterocycloalkyl group comprises 3 to 12 ring atoms, of which 1 to 4 ring atoms are heteroatoms, more preferably 3 to 10 ring atoms, most preferably 5 or 6 ring atoms, of which 1 to 4, preferably 1 to 3, more preferably 1 to 2 are heteroatoms. Non-limiting examples of monocyclic heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Non-limiting examples of polycyclic heterocycloalkyl groups include, but are not limited to, spiro or bridged heterocycloalkyl groups.
"halogen" means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
"haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group substituted with one or more halogen atoms, which may be the same or different, examples of preferred alkyl or alkoxy groups include, but are not limited to: trifluoromethyl, trifluoroethyl, trifluoromethoxy.
"cyano" refers to the "-CN" group.
"hydroxy" refers to an "-OH" group.
"amino" means "-NH- 2 "group".
"carbamoyl" means "- (c=o) -NH 2 "group".
"aryl" refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6 to 14 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains rings of 3 to 7 atoms and has one or more points of attachment to the remainder of the molecule. Examples include, but are not limited to: phenyl, naphthyl, anthracene, and the like. Preferably, the aryl group is a carbocyclic ring system of 6 to 10 or 6 to 7 ring atoms.
"heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring systems containing 5 to 14 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each ring system contains a ring of 5 to 7 atoms and has one or more points of attachment to the remainder of the molecule. The term "heteroaryl" may be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". Examples include, but are not limited to: furyl, imidazolyl, 2-pyridyl, 3-pyridyl, thiazolyl, purinyl, and quinolinyl. Preferably, the heteroaryl group is a ring system of 5 to 10 ring atoms.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents.
By "pharmaceutically acceptable salts" is meant salts prepared from the compounds of the present invention with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups (e.g., carboxyl or sulfonic groups), the base addition salts may be obtained by contacting the free form thereof with a sufficient amount of a base in pure solution or in a suitable inert solvent. Non-limiting examples of pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, ammonium, calcium, magnesium, organic amine salts, or the like. When the compounds of the present invention contain relatively basic functional groups (e.g., amino or guanidino), the acid addition salts may be obtained by contacting the free form with a sufficient amount of an acid in a pure solution or in a suitable inert solvent. Non-limiting examples of pharmaceutically acceptable acid addition salts include, but are not limited to, inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodide, nitrate, carbonate, bicarbonate, phosphate, monohydrogen phosphate, dihydrogen phosphate, phosphite, sulfate, bisulfate, etc.), organic acid salts (e.g., acetate, propionate, isobutyrate, malonate, succinate, suberate, maleate, fumarate, citrate, tartrate, lactate, mandelate, benzoate, phthalate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, glucuronate, etc.), and amino acid salts (e.g., arginate, etc.). Specific forms of pharmaceutically acceptable salts can also be found in Berge et al, "Pharmaceutical Salts", journal of Pharmaceutical Science,1977, 66:1-19). Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts. Preferably, the salt is contacted with a base or acid in a conventional manner to isolate the parent compound, thereby regenerating the neutral form of the compound. The parent form of a compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents. According to an embodiment of the present invention, the pharmaceutically acceptable salt of the compound of formula I is preferably an acid addition salt, preferably a hydrochloride, hydrobromide, phosphate or sulfate salt, more preferably a hydrochloride salt.
"pharmaceutical composition" refers to a pharmaceutically acceptable composition comprising one or more compounds of formula I or a pharmaceutically acceptable form thereof (e.g., salts, hydrates, solvates, stereoisomers, tautomers, metabolites, prodrugs, etc.), as well as other components (e.g., pharmaceutically acceptable excipients).
In the present invention, "pharmaceutically acceptable excipients" refers to auxiliary materials widely used in the field of pharmaceutical production. The main purpose of the use of auxiliary substances is to provide a pharmaceutical composition which is safe to use, stable in nature and/or has specific functionalities, and to provide a method so that the active ingredient can be dissolved at a desired rate after administration of the drug to a subject, or so that the active ingredient is effectively absorbed in the subject to whom it is administered. Pharmaceutically acceptable excipients may be inert fillers or may be functional ingredients that provide some function to the pharmaceutical composition (e.g., to stabilize the overall pH of the composition or to prevent degradation of the active ingredients in the composition). Non-limiting examples of pharmaceutically acceptable excipients include, but are not limited to, binders, suspending agents, emulsifiers, diluents (or fillers), granulating agents, binders, disintegrants, lubricants, anti-adherent agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents, sweetening agents, and the like.
The pharmaceutical compositions of the present invention may be prepared using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, milling, encapsulating, entrapping and/or lyophilizing processes.
In the present invention, the purpose of the pharmaceutical composition is to promote the administration to a living body, facilitate the absorption of an active ingredient, and further exert biological activity. The pharmaceutical compositions of the present invention may be administered by any form including injection (intra-arterial, intravenous, intramuscular, intraperitoneal, subcutaneous), mucosal, oral (oral solid, oral liquid), rectal, inhalation, implantation, topical (e.g. ocular) administration, and the like. Non-limiting examples of oral solid formulations include, but are not limited to, powders, capsules, lozenges, granules, tablets, and the like. Non-limiting examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, tinctures, elixirs, solutions, and the like. Non-limiting examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Non-limiting examples of parenteral formulations include, but are not limited to, solutions for injection, dry powders for injection, suspensions for injection, emulsions for injection, and the like. The pharmaceutical compositions of the invention may also be formulated in controlled-or delayed-release dosage forms (e.g. liposomes or microspheres).
Preferably, the compounds of the present invention or pharmaceutical compositions comprising the same are administered orally or intravenously to an individual in need thereof. Depending on the specific circumstances of the subject, other routes of administration may also be employed or even preferred. For example, transdermal administration would be a very important mode of administration for patients with amnesia or irritability to oral medications. In the present invention, the route of administration can be varied or adjusted in any suitable manner to meet the nature of the drug, the convenience of the patient and medical personnel, and other related factors.
The compound or pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof or the pharmaceutical composition containing the compound has excellent SOS1 enzyme activity and cell proliferation inhibition activity, can be used as an SOS1 inhibitor, is used for preventing and/or treating diseases or symptoms caused by over-expression of SOS1, and has good clinical application and medical application. Preferably, non-limiting examples of diseases or conditions caused by SOS1 overexpression are cancers, including but not limited to pancreatic, colorectal and lung cancers.
The following examples are provided to further illustrate the invention and are not intended to limit the scope of the invention. Various changes and modifications to the specific embodiments of the invention will be apparent to those skilled in the art without departing from the spirit and scope of the invention.
The preparation of the compounds of the present invention may be accomplished by synthetic methods well known to those skilled in the art, including but not limited to the specific embodiments listed below, embodiments formed in combination with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention. The known starting materials used in the present invention may be synthesized by methods known in the art or purchased through conventional commercial means (e.g., from Shaohuan chemical technology, beijing coupling technology, etc.). Unless otherwise indicated, the reactions were carried out under argon or nitrogen atmosphere. The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times. The reaction temperature is room temperature and the temperature range is 20-30 ℃. Monitoring of the progress of the reaction may be accomplished by synthetic methods well known to those skilled in the art, including but not limited to Thin Layer Chromatography (TLC). Thin layer chromatography silica gel plates using Qingdao ocean GF254 silica gel plates, the developer system includes but is not limited to A: methylene chloride and methanol systems; b: petroleum ether and ethyl acetate system, and the volume ratio of the solvent can be adjusted according to the polarity of the compound.
The isolation and purification of the compounds of the present invention may be accomplished by synthetic methods well known to those skilled in the art, including, but not limited to, column Chromatography (CC), high Performance Liquid Chromatography (HPLC), ultra-high performance liquid chromatography (UPLC), and the like. Column chromatography typically uses Qingdao ocean 200-300 mesh silica gel as a carrier, and eluent systems include, but are not limited to, A: methylene chloride and methanol systems; b: the volume ratio of the petroleum ether to the ethyl acetate can be adjusted according to the polarity of the compound, and a small amount of acidic or alkaline tailing-preventing agent can be added for adjustment. HPLC spectra were determined using an Agilent 1200DAD HPLC chromatograph (column: sunfire C18,150X 4.6mm,5 μm) or a Waters 2695-2996HPLC chromatograph (column: gimini C18,150X 4.6mm,5 μm).
Structural identification of the compounds of the present invention may be accomplished by methods well known to those skilled in the art, including but not limited to Nuclear Magnetic Resonance (NMR), mass Spectrometry (MS), and the like. NMR spectra were measured using Bruker AVANCE-400 or Varian Oxford-300 nuclear magnetic instruments using deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDC 1) 3 ) Or deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS), chemical shift of 10 -6 (ppm). MS spectra employed Agilent SQD (ESI) mass spectrometer (model: 6110) or Shimadzu SQD (ESI)Mass spectrometer (model 2020).
Preparation and functional verification of target compounds
Example 1: preparation of Compound 1
The synthetic route is as follows:
the first step: synthesis of Compound 1B
Compound 1A (4 g,18.4 mmol) and DIPEA (4.8 g,36.8 mmol) were dissolved in DMF (40 mL), tert-butyl (R) -3- (hydroxymethyl) piperazine-1-carboxylate (4.0 g,18.4 mmol) was added under ice-bath, and the reaction solution was reacted at 80℃for 1h. TLC showed that after the reaction was completed, the reaction solution was filtered, and the filtrate was dried by spin-drying, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1 (volume ratio)), to give compound 1B (5.4 g, yellow oil, yield 71%).
MS(ESI):m/z 414.2[M+1] + 。
And a second step of: synthesis of Compound 1C
Compound 1B (4.4 g,10.6 mmol) was dissolved in DMF (40 mL), naH (0.43 g,12.7 mmol) was added under ice-bath, and the temperature was raised to 30℃for 1h. TLC showed that after the reaction was completed, quenched by pouring ice water, extracted with ethyl acetate, washed with brine, and the organic phase was dried over anhydrous sodium sulfate and spin-dried to give compound 1C (4.2 g, yellow oil, 95% yield).
MS(ESI):m/z 394.2[M+1] + 。
And a third step of: synthesis of Compound 1D
Compound 1C (4.1 g,10.4 mmol) was dissolved in methanol (50 mL), 10% wet Pb/C (0.51 g, 10%) was added to the reaction mixture, and after the addition, the gas was replaced with nitrogen three times, and after the gas was replaced with hydrogen three times, the hydrogen pressure was maintained at 50psi and the reaction was carried out at 25℃for 5 hours. TLC showed that after the reaction was completed, the reaction solution was filtered, and the filtrate was dried by spin-drying, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1 (volume ratio)), to give compound 1D (3.5 g, pale yellow solid, yield 92.0%).
MS(ESI):m/z 364.2[M+1] + 。
Fourth step: synthesis of Compound 1E
Compound 1D (3.63 g,10.0 mmol) was added to EA (20 mL), and 8% HCl-EA (10 mL) was added dropwise over ice and reacted at room temperature for 12h. TLC showed that after the reaction was completed, the reaction mixture was dried by spin-drying to give the hydrochloride salt of compound 1E (2.8 g, white solid, 94% yield).
MS(ESI):m/z 264.2[M+1] + 。
Fifth step: synthesis of Compound 1F
The hydrochloride salt of compound 1E (1.4 g,4.7 mmol) was added to DCM (15 mL), then TEA (950 mg,9.4 mmol) and cyclopropylcarbonyl chloride (600 mg,5.6 mmol) were added and the reaction was allowed to react at room temperature for 30min. After TLC showed that the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1:1 (volume ratio)) to give compound 1F (1.4 g, pale yellow solid, yield 92.5%).
MS(ESI):m/z 332.2[M+1] + 。
Sixth step: synthesis of Compound 1G
Compound 1F (1.1 g,3.32mmol,1.0 eq) was dissolved in diiodomethane (20 ml, 18V), and isopentyl nitrite (0.778 g,6.65mmol,2.0 eq) and potassium iodide (1.65 g,10.0mmol,3.0 eq) were added to the reaction solution in this order at room temperature. After the reaction was warmed to 80 ℃ and stirred for 16h, TLC showed the reaction to end. After cooling the reaction to room temperature, it was poured into 60ml of water and extracted with dichloromethane (40 ml x 2). The combined organic phases were washed with water (50 ml), saturated brine (20 ml), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by chromatography on a silica gel column (eluent: petroleum ether/ethyl acetate=5/1, 3/1, 1/1) to give compound 1G (0.8G, brown oil, yield 54.5%).
MS(ESI):m/z 443.0[M+1] + 。
Seventh step: synthesis of Compound 1H
Compound 1G (0.8G, 1.81 mmol) was dissolved in twoTo the reaction mixture was added, in order, tri-n-butyl (1-ethoxyvinyl) tin (980 mg,2.72 mmol), pd (dppf) Cl, as a compound, in an oxygen hexaring (10 ml, 12V) at room temperature 2 DCM (100 mg,0.1 mmol). After the addition was completed, the system was replaced with nitrogen gas for 3 times, and the reaction solution was raised to 100℃and stirred for 3 hours. TLC showed the end of the reaction, after the system had cooled to room temperature, 5ml of potassium fluoride solution (8%, w/w) and 4ml of hydrochloric acid solution (4M) were added to the reaction solution and stirred at room temperature for 30min. The reaction mixture was poured into 40ml of water, and extracted with ethyl acetate (20 ml. Times.3). The combined organic phases were washed with water (20 ml), saturated brine (10 ml), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1 to 1/1 (volume ratio)) to give compound 1H (460 mg, pale yellow oil, yield 70.7%).
MS(ESI):m/z 359.2[M+H] + 。
Eighth step: synthesis of Compound 1I
Compound 1H (460.0 mg,1.28 mmol) was dissolved in ethanol (15.0 mL), then 98% by mass of hydrazine hydrate (324 mg,6.4 mmol) was added thereto, concentrated sulfuric acid (1 drop) was further added to the reaction mixture at room temperature, and after the addition was completed, the reaction mixture was heated to 80℃and stirred for 3 hours. After TLC showed that the reaction was completed, sodium bicarbonate solid (30.0 mg) was added to the reaction solution, and purified directly by chromatography on a silica gel column (eluent: dichloromethane/methanol=30/1 to 20/1 (volume ratio)) to give compound 1I (320 mg, yellow solid powder, yield 73.5%).
MS(ESI):m/z 341.0[M+1] + 。
Eighth step: synthesis of Compound 1J
Compound 1I (0.32 g,0.94 mmol) was dissolved in toluene (5 ml), and N, N-diisopropylethylamine (242 mg,1.89 mmol) and phosphorus oxychloride (430 mg,2.82 mmol) were added to the reaction liquid at room temperature in this order. The reaction solution was heated to 110℃and stirred for 16h. TLC showed little residue of starting material, and the reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml. Times.3). The combined organic phases were washed successively with water (20 ml), saturated brine (10 ml), dried over anhydrous sodium sulfate and concentrated, and the residue was purified by thin layer chromatography (eluent: dichloromethane/methanol=10/1, (volume ratio)) to give compound 1J (100 mg, pale yellow solid, yield 29.7%).
MS(ESI):m/z 359.2[M+H] + 。
Ninth step: synthesis of Compound 1
Compound 1J (100 mg,0.28 mmol) was dissolved in toluene (2 ml), and to the reaction solution was added, in order, compound (R) -1- (3- (difluoromethyl) -2-fluorophenyl) ethan-1-amine (80 mg,0.42 mmol), potassium t-butoxide (107 mg,0.56 mmol), BINAP (35 mg,0.056 mmol), pd 2 (dba) 3 (27 mg,0.028 mmol) and after the addition was completed, nitrogen was replaced three times, the reaction was heated to 100℃and stirred for 4h. After TLC showed that the reaction was completed, the reaction solution was poured into 15ml of water and extracted with ethyl acetate (10 ml. Times.3). The combined organic phases were washed with water (10 ml), saturated brine (5 ml), dried over anhydrous sodium sulfate and concentrated, and the residue was purified by thin layer chromatography (eluent: dichloromethane/methanol=10/1 (volume ratio)) to give the crude product, which was further prepared by reverse phase HPLC (Waters Sunfire OBD 100×30 mm,5 μm, mobile phase a:0.1% aqueous trifluoroacetic acid, mobile phase B: acetonitrile, gradient: 10% acetonitrile running 1min,52% -52% acetonitrile running 10min,95% acetonitrile running 14min,10% acetonitrile running 16min ended) to give compound 1 (7 mg, pale yellow solid, yield 19%).
MS(ESI):m/z 512.2[M+H] + 。
1 H-NMR(400MHz,DMSO-d 6 ):δ(ppm)7.73(s,1H),7.57(t,J＝7.2Hz,1H),7.46(t,J＝6.8Hz,1H),7.40-7.09(m,4H),5.75-5.65(m,1H),4.59-4.43(m,3H),4.24(s,1H),4.08(s,1H),3.30-3.19(m,2H),3.12-2.86(m,2H),2.48(s,3H),2.13(s,1H),1.60(d,J＝7.2Hz,3H),0.89-0.72(m,4H)。
Example 2: preparation of Compound 2
Synthesis of Compound 2 reference the procedure for the synthesis of Compound 1 in example 1 was followed, wherein (S) -3- (2-hydroxyethyl) piperazine-1-carboxylic acid tert-butyl ester was used instead of (R) -3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester, to synthesize Compound 2.
MS(ESI):m/z 526.2[M+1] + 。
1 H-NMR(400MHz,DMSO-d 6 ):δ(ppm)7.79(s,1H),7.57(t,J＝7.4Hz,1H),7.44(t,J＝7.8Hz,1H),7.39-7.33(m,1H),7.26-7.19(m,2H),7.23(t,J＝54.3Hz,1H),5.72-5.62(m,1H),4.56-4.47(m,1H),4.34-4.17(m,1H),4.08-3.97(m,1H),3.90-3.67(m,1H),3.53-3.40(m,3H),3.30-3.24(m,2H),2.47(s,3H),2.21-1.98(m,2H),1.94-1.83(m,1H),1.58(d,J＝7.0Hz,3H),0.83-0.71(m,4H)。
Example 3: preparation of Compound 3
Synthesis of Compound 3 was synthesized by substituting acetyl chloride for cyclopropylcarbonyl chloride in the synthesis procedure of Compound 2 in reference example 2.
MS(ESI):m/z 500.2[M+1] + 。
1 H-NMR(400MHz,DMSO-d 6 ):δ(ppm)7.78(d,J＝4.1Hz,1H),7.57(t,J＝7.2Hz,1H),7.44(t,J＝9Hz,1H),7.36(d,J＝6.8Hz,1H),7.27-7.19(m,2H),7.22(t,J＝54.0Hz,1H),5.71-5.63(m,1H),4.54-4.45(m,1H),4.34-4,24(m,1H),4.11-3.68(m,2H),3.65-3.39(m,5H),2.47(s,3H),2.18-2.04(m,4H),1.96-1.87(m,1H),1.58(d,J＝7.0Hz,3H)。
Example 4: preparation of Compound 4
Synthesis of Compound 4 was synthesized by the synthetic procedure of Compound 1 in reference example 1, in which acetyl chloride was used instead of cyclopropylcarbonyl chloride.
MS(ESI):m/z 486.2[M+1] + 。
1 H-NMR(400MHz,DMSO-d 6 ):δ(ppm)7.70(s,1H),7.54(t,J＝7.4Hz,1H),7.44(t,J＝9Hz,1H),7.25-7.18(m,2H),7.21(t,J＝54.0Hz,1H),7.15(s,1H),5.74-5.61(m,1H),4.55-4.40(m,4.2Hz,2H),4.23-4.17(m,1H),4.08-3.96(m,2H),3.30-3.13(m,2H),3.03-2.80(m,2H),2.45(s,3H),2.09(d,J＝7.6Hz,3H),1.58(d,J＝7.0Hz,3H)。
Example 5: preparation of Compound 5
The synthetic route is as follows:
the first step: synthesis of Compound 5A
Compound 4 (2.0 g,4.1 mmol) was added to ethanol (20 mL), concentrated hydrochloric acid (4 mL) was added, then warmed to 90 ℃, reacted for 12h, TLC showed the end of the reaction, and dried by spin to give crude hydrochloride of compound 5A (2.2 g, white solid) which was used directly in the next step without further purification.
And a second step of: synthesis of Compound 5
The crude hydrochloride of compound 5A (0.27 g,0.5 mmol) was added to DCM (2 mL), then triethylamine (100 mg,1.0 mmol) was added to the reaction solution, the reaction solution was cooled to 0 ℃ and triphosgene (298 mg,1.0 mmol) was added in portions, and after the addition was completed, the reaction was carried out at 0 ℃ for 30min. After TLC showed that the reaction was completed, dimethylamine hydrochloride (81.5 mg,1.0 mmol) was further added, triethylamine (100 mg,1.0 mmol) was added, and after completion of the addition, the reaction mixture was warmed to room temperature and stirred for 1h. TLC showed that after the reaction was completed, water (50 mL) was added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (5 ml×2), the organic phases were combined, dried, and the residue was purified by HPLC (Waters Sunfire OBD 100×30 mm,5 μm, mobile phase a:0.1% aqueous trifluoroacetic acid, mobile phase B: acetonitrile, gradient: 10% acetonitrile running 1min,52% -52% acetonitrile running 10min,95% acetonitrile running 14min,10% acetonitrile running 16min completed) to give compound 5 (85.0 mg, white solid, yield 33.0%).
MS(ESI):m/z 515.2[M+1] + 。
1 H-NMR(400MHz,DMSO):δ(ppm)7.70(s,1H),7.55(t,J＝7.3Hz,1H),7.44(t,J＝9.1Hz,1H),7.35(d,J＝6.8Hz,1H),7.25-7.16(m,2H),7.23(t,J＝54.0Hz,1H),5.77-5.56(m,1H),4.48(dd,J＝10.9,2.8Hz,1H),4.22-3.96(m,2H),3.74-3.61(m,3H),3.03-2.92(m,2H),2.81(s,6H),2.58(t,J＝11.8Hz,1H),2.46(s,3H),1.58(d,J＝7.0Hz,3H)。
Example 6: preparation of Compound 6
The synthetic route is as follows:
crude hydrochloride of compound 5A (0.27 g,0.5 mmol) and 1-bromo-2-methoxyethane (138 mg,1.0 mmol) were added to DMF (5.0 mL), followed by potassium carbonate (138 mg,1.0 mmol), reacted overnight at room temperature, TLC showed the remaining part of the starting material, continued to be added with 2-bromo-N, N-dimethylacetamide (166 mg,1.0 mmol) and potassium carbonate (138 mg,1.0 mmol), reacted for 3h, TLC showed the end of the reaction, water (50 mL) was added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (15 ml×2), the organic phase was combined, dried, the residue was prepared purified by HPLC (Waters Sunfire OBD 100×30 mm,5 μm, mobile phase a:0.1% aqueous trifluoroacetic acid solution, mobile phase B: acetonitrile, gradient: 10% acetonitrile running 1min,52% -52% acetonitrile running to 10min,95% acetonitrile running to 14min, 16% running to end of 6.31 mg) to give a white solid (6.77%).
MS(ESI):m/z 502.2[M+1] + 。
1 H-NMR(400MHz,DMSO-d 6 ):δ(ppm)7.64(s,1H),7.55(t,J＝7.4Hz,1H),7.44(t,J＝7.1Hz,1H),7.23(t,J＝54.3Hz,1H),7.21(t,J＝7.5Hz,2H),7.11(s,1H),5.73-5.61(m,1H),4.38(dd,J＝10.8,3.0Hz,1H),4.11(d,J＝12.1Hz,1H),4.00(dd,J＝10.8,9.0Hz,1H),3.49(t,J＝5.7Hz,2H),3.28-3.23(m,1H),3.25(s,3H),3.14-2.97(m,2H),2.95-2.83(m,1H),2.63-2.52(m,2H),2.44(s,3H),2.32-2.21(m,1H),1.83(t,J＝10.9Hz,1H),1.57(d,J＝7.0Hz,3H)。
Example 7: preparation of Compound 7
Synthesis of Compound 7 reference the procedure for the synthesis of Compound 5 in example 5 was followed, wherein in the second step methyl chloroformate was used instead of dimethylamine hydrochloride, to synthesize Compound 7.
MS(ESI):m/z 502.2[M+1] + 。
1 H-NMR(300MHz,DMSO-d 6 ):δ(ppm)7.71(s,1H),7.54(t,J＝7.5Hz,1H),7.44(t,J＝9.0Hz,1H),7.29-7.17(m,2H),7.23(t,J＝54.0Hz,1H),7.15(s,1H),5.74-5.59(m,1H),4.48(dd,J＝10.9,2.7Hz,1H),4.24-4.00(m,4H),3.65(s,3H),3.31-3.25(m,1H),3.21-3.04(m,1H),2.96-2.87(m,1H),2.80-2.65(m,1H),2.45(s,3H),1.58(d,J＝7.0Hz,3H)。
Example 8: preparation of Compound 8
The synthetic route is as follows:
the first step: synthesis of Compound 8
Crude hydrochloride of compound 5A (0.27 g,0.5 mmol) and 1-cyanocyclopropane-1-carboxylic acid (191 mg,1.72 mmol) were added to DMF (5.5 mL), the reaction mixture was cooled to 0deg.C, T3P (272 mg,2.24 mmol) was added dropwise to the reaction mixture, triethylamine (0.52 g,5.16 mmol) was added dropwise, and the mixture was heated to 25deg.C and reacted for 1h. After the completion of the reaction, TLC showed that ethyl acetate (20 mL) and saturated brine (20 mL) were further added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (20 mL. Times.2), the organic phases were combined, dried, and spin-dried, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20:1 (volume ratio)), and the column purified product was further purified by HPLC (Waters Sunfire OBD 100×30 mm,5 μm, mobile phase A:0.1% aqueous trifluoroacetic acid solution, mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1min,52% -52% acetonitrile for 10min,95% acetonitrile for 14min, and 10% acetonitrile for 16 min) to give compound 8 (60 mg, off-white solid, two-step yield: 22.1%).
MS(ESI):m/z 537.2[M+1] + 。
1 H-NMR(400MHz,DMSO-d6):δ(ppm)7.72(s,1H),7.54(t,J＝7.6Hz,1H),7.44(d,J＝7.2Hz,1H),7.24(dd,J＝13.3,7.6Hz,3H),7.23(t,J＝54.1Hz,1H),7.17(s,1H),5.74-5.61(m,1H),4.59-4.33(m,3H),4.26(d,J＝12.3Hz,1H),4.11(t,J＝9.9Hz,1H),3.46-3.35(m,2H),3.15-2.93(m,2H),2.46(s,3H),1.69-1.54(m,4H),1.58(d,J＝7.2Hz,2H)。
Example 9: preparation of Compound 9
Synthesis of Compound 9 reference the procedure for the synthesis of Compound 6 in example 6 was followed, wherein 2-bromo-1, 1-trifluoroethane was used instead of 1-bromo-2-methoxyethane, to synthesize Compound 9.
MS(ESI):m/z 526.2[M+1] + 。
1 H-NMR(400MHz,DMSO-d 6 ):δ(ppm)7.66(s,1H),7.55(t,J＝7.3Hz,1H),7.44(t,J＝9.0Hz,1H),7.25-7.17(m,2H),7.21(t,J＝54.0Hz,1H),5.75-5.60(m,1H),4.39(dd,J＝10.9,3.0Hz,1H),4.14(d,J＝12.2Hz,1H),4.01(dd,J＝10.9,8.7Hz,1H),3.39-3.32(m,2H),3.29-3.26(m,1H),3.13(d,J＝11.5Hz,1H),3.05-2.99(m,1H),2.96-2.91(m,1H),2.69-2.61(m,1H),2.44(s,3H),2.25(t,J＝11.0Hz,1H),1.59(d,J＝6.0Hz,3H)。
Experimental example 1: P-ERK experiments
1. Experimental materials:
DLD-1 cells were purchased from the Living technologies Co., ltd; 1640 medium was purchased from Biological Industries; fetal bovine serum was purchased from Biosera; advanced Phospho-ERK1/2 (THR 202/TYR 204) KIT was purchased from Cisbio.
2. The experimental method comprises the following steps:
DLD-1 cells were seeded in a transparent 96-well cell culture plate, 80. Mu.L of cell suspension per well, each well containing 8000 DLD-1 cells, and the cell plate was placed in a carbon dioxide incubator and incubated overnight at 37 ℃;
the test compound was diluted to 2mM with 100% DMSO as the first concentration, and then 5-fold diluted to the 8 th concentration, i.e., from 2mM to 0.026. Mu.M, with a pipette. Adding 2 mu L of compound into 78 mu L of cell starvation culture medium, uniformly mixing, adding 20 mu L of compound solution into corresponding cell plate holes, and placing the cell plate back into a carbon dioxide incubator for further incubation for 1 hour, wherein the concentration of the compound is 10 mu M to 0.128nM and the concentration of DMSO is 0.5%;
after the incubation is finished, 50 mu L of cell lysate is added into each hole, and the mixture is incubated for 30 minutes by shaking at room temperature;
Phospho-ERK1/2 Eu Cryptate antibody and Phospho-ERK1/2 d2 anti-body were diluted 20-fold using Detection buffer;
taking 16 mu L of cell lysate supernatant to a new 384 white micro-well plate, adding 2 mu L of Phospho-ERK1/2 Eu Cryptate antibody diluent and 2 mu L of Phospho-ERK1/2 d2 anti-body diluent, and incubating for 4 hours at normal temperature;
HTRF extraction was read at 320nm, emision at 315 nm,665nm using a multi-label analyzer after incubation.
3. Data analysis:
raw data was converted to inhibition ratio, IC, using the equation (Sample-Min)/(Max-Min) ×100% 50 The values of (a) can be obtained by curve fitting with four parameters (log (inhibitor) vs. response-Variable slope mode in GraphPad Prism). The inhibitory activities of the KRAS-SOS1 inhibitor BI-3406 on DLD-1 cell phosphorylation, which are commonly used in the art, of the compounds 1 to 9 prepared by the present invention are shown in Table 1.
TABLE 1 test results of the inhibitory Activity of the inventive Compounds against the phosphorylation of DLD-1 cells IC 50 Data
Numbering of compounds IC 50 (nM)
Control compound BI-3406 24.16
Compound 1 2.29
Compound 2 22.58
Compound 3 13.33
Compound 4 2.34
Compound 5 20.14
Compound 6 20.07
Compound 7 5.30
Compound 8 53.34
Compound 9 30.86
As shown in Table 1, the compounds of the present invention have an inhibitory effect on the phosphorylation of DLD-1 cells, and more unexpectedly, the compounds 1, 4 and 7 show extremely excellent activity results relative to the control compound BI-3406, and have a good clinical application prospect.
While embodiments of the present invention have been illustrated and described above, it will be appreciated that the above described embodiments are illustrative and should not be construed as limiting the invention. Variations, modifications, substitutions, and alterations are also possible in the above described embodiments without departing from the principles and spirit of the invention, and such variations, modifications, substitutions, and alterations are to be within the scope of this disclosure.

Claims (10)

1. A compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite, or prodrug thereof,
wherein, the liquid crystal display device comprises a liquid crystal display device,
ring A is selected from C 6 -C 10 Aryl, 5 to 6 membered monocyclic heteroaryl, or 9 to 10 membered bicyclic heteroaryl;
m is any integer from 0 to 5;
x and Y are each independently selected from CR 7 Or N;
Z 1 and Z 2 Each independently selected from-O-, -C (R) 7 ) 2 -or-NR 7 -；
L 1 、L 2 And L 3 Each independently is independently selected from- (CH) 2 ) n -or- (CH) 2 ) n -O-(CH 2 ) p -O-(CH 2 ) o -; wherein, if present, each n, o and p is independently any integer from 0 to 3;
R 1 and R is 2 Each independently selected from hydrogen or C 1 -C 8 Alkyl, or R 1 And R is 2 Together with the carbon atom to which it is attached form C 3 -C 6 Cycloalkyl; the alkyl and cycloalkylalkyl groups are each optionally substituted with at least 1R 8 Substitution; alternatively, R 1 Or R is 2 A 4-8 membered saturated carbocyclic or heterocyclic ring with ring A;
R 3 selected from hydrogen, halogen, cyano, hydroxy, amino, -NH (R) 7 )、-C(＝O)-NH(R 7 )、C 1 -C 6 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 3 -C 6 Cycloalkyl, 3-to 8-membered heterocycloalkyl, C 1 -C 3 Alkoxy or C 1 -C 6 A haloalkyl group; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy and haloalkyl are each optionally substituted with at least 1R 8 Substitution;
if present, each R 4 Each independently selected from hydrogen, halogen, cyano, hydroxy, amino, -NH (R) 7 )、-C(＝O)-NH(R 7 )、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 3-to 8-membered heterocycloalkyl, C 1 -C 3 Alkoxy or C 1 -C 6 A haloalkyl group; the alkyl, cycloalkyl, heterocycloalkyl, alkoxy and haloalkyl groups are each optionally substituted with at least 1R 8 Substitution;
R 5 and R is 6 Each independently selected from hydrogen, halogen, cyano, hydroxy, amino, -N (R) 8 )(R 9 )、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 3-to 8-membered heterocycloalkyl, C 1 -C 3 Alkoxy or C 1 -C 6 A haloalkyl group; the alkyl, cycloalkyl, heterocycloalkyl, alkoxy and haloalkyl groups are each optionally substituted with at least 1R 8 Substitution;
if present, each R 7 Each independently selected from hydrogen, halogen, cyano, hydroxy, amino, -N (R) 8 )(R 9 )、-C(＝O)-N(R 8 )(R 9 )、-C(＝O)-R 8 、-C(＝O)-OR 8 、C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 3-to 8-membered heterocycloalkyl, C 6 -C 10 Aryl, 5-to 10-membered heteroaryl, C 1 -C 3 Alkoxy or C 1 -C 6 Haloalkyl, said alkyl, cycloalkyl, heterocycloalkyl, alkoxy and haloalkyl each optionally being substituted with at least 1R 8 Substitution;
if present, each R 8 And R is 9 Each independently selected from hydrogen, halogen, cyano, hydroxy, amino, carbamoyl, C 1 -C 6 Alkyl, C 1 -C 6 Heteroalkyl, C 3 -C 8 Cycloalkyl, 3-to 14-membered heterocycloalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Haloalkoxy, C 6 -C 10 Aryl, 5-to 6-membered monocyclic heteroaryl or 9-to 10-membered bicyclic heteroaryl, or R 8 And R is 9 Together with the nitrogen atom to which it is attached, form a 5-to 6-membered heterocycloalkyl; the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkoxy, aryl, monocyclic heteroaryl, and bicyclic heteroaryl are each optionally substituted with at least 1R 10 Substitution;
R 1 to R 9 The hetero atoms or hetero atom groups contained in the hetero alkyl group, the hetero cycloalkyl group, the hetero alkoxy group and the hetero aryl group are each independently selected from the group consisting of-C (=O) N (R) 10 )-、-N(R 10 )-、-NH-、-N＝、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O) 2 -or-N (R) 10 )C(＝O)N(R 10 ) -the number of heteroatoms or heteroatoms groups is each independently selected from 1, 2 or 3;
if present, each R 10 Each independently selected from hydrogen, chlorine, fluorine, cyano, hydroxy, amino, isopropyl, cyclopropyl, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, 2-difluoroethoxy, 2-trifluoroethoxy or phenyl.
2. A compound according to claim 1, wherein the compound is a compound of formula I-1 or I-2,
therein, m, X, Y, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 And R is 7 As defined in claim 1.
3. A compound according to claim 1 or 2, wherein the compound is a compound of formula I-1-1 or I-2-1,
therein, m, X, Y, R 4 、R 5 、R 6 And R is 7 As defined in claim 1.
4. The following compounds or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, metabolites or prodrugs thereof:
5. a pharmaceutical composition comprising a compound according to any one of claims 1 to 4, or one or more of its pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, metabolites or prodrugs.
6. The pharmaceutical composition of claim 5, further comprising at least one pharmaceutically acceptable excipient.
7. Use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof or a pharmaceutical composition according to claim 5 or 6 for the manufacture of a medicament for the prevention and/or treatment of a disease caused by SOS1 overexpression.
8. Use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof or a pharmaceutical composition according to claim 5 or 6 for the preparation of a SOS1 inhibitor.
9. Use of a compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof or a pharmaceutical composition according to claim 5 or 6 for the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
10. The use according to claim 9, wherein the cancer is any one or more of pancreatic cancer, colorectal cancer and lung cancer.
CN202210152068.6A 2022-02-18 2022-02-18 Tetrafused ring compound, and pharmaceutical composition and application thereof Pending CN116655655A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115806560A (en) * 2022-12-20 2023-03-17 武汉誉祥医药科技有限公司 Azatetracyclic compounds, pharmaceutical compositions and uses thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115806560A (en) * 2022-12-20 2023-03-17 武汉誉祥医药科技有限公司 Azatetracyclic compounds, pharmaceutical compositions and uses thereof

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