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  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/38—Nitrogen atoms
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  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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  • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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  • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
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  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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  • 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
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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  • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
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  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

• the invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to a new class of compounds, their stereoisomers, racemates, geometric isomers, tautomers, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof , and pharmaceutical compositions containing them, which have SOS1 inhibitory activity.
• RAS proteins include KRAS (V-Ki-ras2Kirsten rat sarcoma viral oncogene homolog), HRAS (neuroblastoma RAS viral oncogene homolog) and NRAS (Harvey murine sarcoma virus oncogene), in which KRAS has two alternative splicing isoforms KRAS4A and KRAS4B .
• RAS protein is mainly distributed inside the cell membrane, and membrane localization is a key step in activating RAS.
• RAS protein requires prenylation and palmitoylation at its C-terminus, but KRAS4B lacks a palmitoylation site, and its membrane localization depends on the electrostatic interaction between the polybasic region composed of lysine and the plasma membrane (Ahearn et al., 2011; Wright and Philips, 2006).
• RAS proteins belong to the small GTPase family and exist in cells in GTP-bound or GDP-bound ways.
• RAS activation requires its transition from GDP-bound state to GTP-bound state, which is catalyzed by guanine nucleotide exchange factors GEFs (guanine nucleotide exchange factors), such as SOS1 (Son of Sevenless 1) (Chardin et al., 1993).
• GEFs guanine nucleotide exchange factors
• SOS1 Syn of Sevenless 1
• RAS activation will promote the activation of downstream effector molecules RAF, PI3K (Phosphoinositide 3-kinase) and RalGDS (Ral guanine nucleotide dissociation stimulator) to affect biological processes such as cell proliferation, growth, metabolism, migration, angiogenesis (Rodriguez-Viciana and McCormick, 2005; Young et al., 2009).
• GTPase activating proteins GAPs (GTPase activating proteins), such as NF1, can increase their hydrolysis rate to inactivate RAS.
• GAPs and GEFs strictly regulate the inactivation and activation of RAS proteins, but when RAS proteins are mutated, the regulation mechanism becomes dysregulated.
• RAS mutations mainly occur at G12, G13, and Q61. Mutations at these sites weaken endogenous and GAPs-mediated hydrolysis activities, and G13 and Q61 mutations also increase GEFs-mediated GTP exchange rate (Simanshu et al., 2017; Smith et al., 2013).
• mutant RAS still has a certain intrinsic hydrolytic activity, and the stronger the intrinsic hydrolytic activity of the RAS mutant protein, the stronger the inhibition of its upstream protein SHP2 inhibition on its activity (Hunter et al., 2015; Mainardi et al., 2018).
• the SOS1 protein has two important motifs, the RAS exchanger motif (REM) and the CDC25 homology domain (homology domain), which are the allosteric binding site and the catalytic binding site, respectively.
• REM RAS exchanger motif
• CDC25 combines with RAS-GDP to promote the exchange of GDP and GTP
• REM combines with RAS-GTP to further increase the catalytic activity of SOS1 (Freedman et al., 2006; Pierre et al., 2011).
• SOS1 plays a key role in KRAS mutant tumors, knocking down SOS1 can reduce the proliferation and viability of KRAS mutant tumor cells, but has no effect on KRAS wild-type cells (Jeng et al., 2012).
• SOS1 plays an important role in activating the RAS signaling pathway.
• the activation of tyrosine kinase receptor RTKs will activate SHP2, which will bind to the adapter protein Grb2, promote the formation of Grb2 and SOS1 complex and activate SOS1, thereby activating RAS protein (Baltanas et al., 2020).
• SOS1 mutations in tumor cells, such as embryonal rhabdomyosarcoma and lung adenocarcinoma (Denayer et al., 2010), while high expression of SOS1 exists in bladder cancer and prostate cancer (Timofeeva et al., 2009; Watanabe et al. ,2000).
• SOS1 is also present in Noonan syndrome (NS), cardio-facio-cutaneous syndrome (CFC), hereditary gingival fibromatosis and related syndromes mutation (Pierre et al., 2011).
• the homologue of SOS1, SOS2, also acts as a GEF to activate RAS proteins, and there is functional redundancy between the two.
• Knockout of SOS1 in mice is embryonic lethal (Qian et al., 2000), whereas conditional knockout of SOS1 in adult mice is viable (Baltanas et al., 2013).
• knockout of SOS2 in mice has no obvious phenotype (Esteban et al., 2000). If both SOS1 and SOS2 are knocked out in adult mice, the mice die quickly (Baltanas et al., 2013).
• Selective inhibition of a single SOS isoform, such as SOS1, may be more effective in treating diseases with SOS1-RAS activation.
• Inhibiting the binding of SOS1 catalytic site to RAS can prevent the generation of RAS-GTP mediated by SOS1 to inhibit the RAS signaling pathway.
• RAS-dependent tumors such compounds can theoretically destroy the combination of RAS and SOS, and inhibit the phosphorylation of ERK cells to have an anti-tumor effect.
• Compounds that inhibit the interaction between SOS1 and RAS can inhibit RAS activity and can be used to treat head and neck cancer, lung cancer, mediastinal tumors, gastrointestinal tract tumors, prostate cancer, testicular cancer, gynecological tumors, breast cancer, kidney and bladder cancer, endocrine system tumors , soft tissue sarcoma, osteosarcoma, rhabdoid tumor, mesothelioma, skin cancer, peripheral nervous system tumor, central nervous system tumor, lymphoma, leukemia, Noonan syndrome, cardiofacial skin syndrome, hereditary gingival fibroma disease and its associated syndromes.
• the present invention provides a compound of formula (I), its enantiomers, diastereomers, racemates, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof:
• Ring A is C 6-10 aryl, 5-10 membered heteroaryl or 4-10 membered saturated or unsaturated heterocyclic group;
• n(R 3 ) means that there are m identical or different R 3 substituents at any position of the A ring;
• n is 0-5; preferably, m is 1, 2 or 3; more preferably, m is 1 or 2;
• R O is hydrogen, halogen, C 1-4 alkyl, cyano or cyclopropyl
• R 1 is hydrogen, halogen, unsubstituted or substituted C 1-6 alkyl, unsubstituted or substituted C 3-6 cycloalkyl, unsubstituted or substituted 4-10 membered saturated or unsaturated heterocyclic group, none Substituted or substituted C 1-6 alkoxy, -CN, -COOH, -CONH 2 , -CONH-C 1-6 alkyl, amino, -NH-C 1-6 alkyl;
• R 2 is hydrogen, unsubstituted or substituted C 1-6 alkyl, unsubstituted or substituted C 3-6 cycloalkyl;
• Q 1 is N, NR 4 , -C(O)- or CR 4
• Q 2 is N, NR 5 , -C(O)- or CR 5
• Q 3 is N, NR 6 , -C(O)- or CR 6
• Q 4 is N or CH
• Q 1 , Q 2 , Q 3 and Q 4 contain at most two N atoms ; Both maintain aromaticity;
• R 4 is selected from hydrogen, unsubstituted or substituted C 1-4 alkyl, unsubstituted or substituted C 1-4 alkoxy, unsubstituted or substituted C 2-4 alkynyl, unsubstituted or substituted C 3 -6 cycloalkyl, unsubstituted or substituted 4-6 membered saturated or unsaturated heterocyclic group, halogen, cyano, amino;
• R 5 and R 6 are each independently hydrogen, unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted Or substituted C 3-6 cycloalkyl, unsubstituted or substituted 4-10 membered saturated or unsaturated heterocyclic group, unsubstituted or substituted 5-10 membered heteroaryl and 4-10 membered heterocyclic group, halogen , -CN, -COOH, -OR 7 , -NH-R 7 , -CONH-R 7 , -NHCO-R 7 , -SO 2 -R 7 , -SO 2 NH-R 7 ;
• R 7 is selected from hydrogen, unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C 3 -6 cycloalkyl, unsubstituted or substituted 4-10 membered saturated or unsaturated heterocyclic groups;
• R 1 , R 2 , R 4 , R 5 , R 6 , and R 7 means that they are substituted by one or more of the following group A substituents.
• Group A substituents include: C 1-6 Alkyl, C 1-6 haloalkyl, C 1-6 alkyl substituted by hydroxy, C 1-6 alkyl substituted by amino, C 1-6 alkyl substituted by cyano, C 1-6 alkoxy substituted C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, halogen, cyano, amino, carboxyl, -NH-C 1-6 alkyl, -NH-C 3-6 cycloalkyl, unsubstituted or C 6-10 aryl group substituted by group B substituent, 5-10 membered heteroaryl group unsubstituted or substituted by group B substituent, C 3-6 cycloalkyl group unsubstituted or substituted by group B, unsubstituted Or a 4-10 membered saturated or
• the present invention provides the compound of formula (I), its enantiomer, diastereoisomer, racemate, prodrug, hydrate, solvate or its pharmaceutical Acceptable salts on:
• R 2 is methyl or ethyl.
• the present invention provides the compound of formula (I), its enantiomer, diastereoisomer, racemate, prodrug, hydrate, solvate or its pharmaceutical Acceptable salts on:
• ring A is phenyl
• the present invention provides the compound of formula (I), its enantiomer, diastereoisomer, racemate, prodrug, hydrate, solvate or its pharmaceutical Acceptable salts on:
• n 1 or 2;
• Each R substituent is independently selected from: substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 2-4 alkynyl, substituted or unsubstituted 4-6 membered saturated or unsaturated heterocycle Base, halogen, cyano or amino; said substitution refers to being substituted by one or more substituents selected from halogen, hydroxyl, cyano, amino; preferably R 3 is selected from substituted or unsubstituted C 1- 4 alkyl and halogen, more preferably R 3 is selected from C 1-4 alkyl and halogen substituted by halogen, further preferably R 3 is selected from fluorine and difluoromethyl.
• the present invention provides the compound of formula (I), its enantiomer, diastereoisomer, racemate, prodrug, hydrate, solvate or its pharmaceutical Acceptable salts on:
• R 4 is selected from hydrogen, C 1-4 alkyl.
• the present invention provides the compound of formula (I), its enantiomer, diastereoisomer, racemate, prodrug, hydrate, solvate or its pharmaceutical Acceptable salts on:
• R 5 is selected from hydrogen or C 1-10 alkoxy, such as C 1-4 alkoxy.
• the present invention provides the compound of formula (I), its enantiomer, diastereoisomer, racemate, prodrug, hydrate, solvate or its pharmaceutical Acceptable salts on:
• R is selected from unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C 3 -6 cycloalkyl, unsubstituted or substituted 4-10 membered saturated or unsaturated heterocyclic group, unsubstituted or substituted 5-10 membered heteroaryl and 4-10 membered heterocyclic group, halogen, -CN, - COOH, -OR 7 , -NH-R 7 , -CONH-R 7 , -NHCO-R 7 , -SO 2 -R 7 , -SO 2 NH-R 7 ;
• R 7 is selected from hydrogen, unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C 3 -6 cycloalkyl, unsubstituted or substituted 4-10 membered saturated or unsaturated heterocyclic group.
• the present invention provides the compound of formula (I), its enantiomer, diastereoisomer, racemate, prodrug, hydrate, solvate or its pharmaceutical Acceptable salts on:
• the compound of the formula (I) has the structure of the following formulas (I-1-1) to (I-1-7):
• Ring A, R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m are as defined above.
• the compound of formula (I) has the structures of the above formulas (I-1-1), (I-1-2), (I-1-3), (I-1-4).
• the present invention provides the compound of formula (I), its enantiomer, diastereoisomer, racemate, prodrug, hydrate, solvate or its pharmaceutical Acceptable salts on:
• R 5 and R 6 are each independently hydrogen, unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted Or substituted C 3-6 cycloalkyl, unsubstituted or substituted 4-10 membered saturated or unsaturated heterocyclic group, unsubstituted or substituted 5-membered heteroaryl and 6-membered heterocyclic group, halogen, -CN, -COOH, -OR 7 , -NH-R 7 , -CONH-R 7 , -NHCO-R 7 , -SO 2 -R 7 , -SO 2 NH-R 7 ;
• R 7 is selected from hydrogen, unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C 3 -6 cycloalkyl, unsubstituted or substituted 4-10 membered saturated or unsaturated heterocyclic groups;
• Substitution in R 5 , R 6 , and R 7 refers to being substituted by one or more of the following group A substituents.
• Group A substituents include: C 1-6 alkyl, C 1-6 haloalkyl , C 1-6 alkyl substituted by hydroxy, C 1-6 alkyl substituted by amino, C 1-6 alkyl substituted by cyano, C 1-6 alkyl substituted by C 1-6 alkoxy, C 1 -6 alkoxy, hydroxyl, halogen, cyano, amino, carboxyl, -NH-C 1-6 alkyl, -NH-C 3-6 cycloalkyl, C 6 unsubstituted or substituted by group B substituents -10 aryl, 5-10 membered heteroaryl unsubstituted or substituted by B group substituent, C 3-6 cycloalkyl unsubstituted or substituted by B group, 4 unsubstituted or substituted by B group substituent -10-membered saturated or
• R 5 , R 6 , R 7 and the heteroaryl group in the substituent group A are selected from:
• R 5 , R 6 , R 7 and the heterocyclic group in the group A substituent are selected from:
• the 5-membered heteroaryl and 6-membered heterocyclic group is selected from
• the present invention provides the compound of formula (I), its enantiomer, diastereoisomer, racemate, prodrug, hydrate, solvate or its pharmaceutical Acceptable salts on:
• R 5 is hydrogen or C 1-10 alkoxy
• R 6 is selected from unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C 3-6 Cycloalkyl, unsubstituted or substituted 4-10 membered saturated or unsaturated heterocyclic group, unsubstituted or substituted 5-10 membered heteroaryl and 4-10 membered heterocyclic group, halogen, -CN, -COOH, -OR 7 , -NH-R 7 , -CONH-R 7 , -NHCO-R 7 , -SO 2 -R 7 , -SO 2 NH-R 7 ;
• R 7 is selected from hydrogen, unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted C 3-6 cycloalkyl, unsubstituted or substituted 4- 10-membered saturated or unsaturated heterocyclic group;
• substitution in R 6 and R 7 refers to being substituted by one or more of the following group A substituents
• group A substituents include: C 1-6 alkyl, C 1-6 haloalkyl, hydroxyl C 1-6 alkyl, amino substituted C 1-6 alkyl, cyano substituted C 1-6 alkyl, C 1-6 alkoxy substituted C 1-6 alkyl, C 1-6 alkane Oxygen, hydroxyl, halogen, cyano, amino, carboxyl, -NH-C 1-6 alkyl, -NH-C 3-6 cycloalkyl, unsubstituted or C 6-10 aryl substituted by group B substituents Group, 5-10 membered heteroaryl group unsubstituted or substituted by Group B substituent, C 3-6 cycloalkyl group unsubstituted or substituted by Group B, 4-10 membered unsubstituted or substituted by Group B substituent Saturated or unsaturated heterocyclic group, -
• the present invention provides the compound of formula (I), its enantiomer, diastereoisomer, racemate, prodrug, hydrate, solvate or its pharmaceutical Acceptable salts on:
• R 5 and R 6 are each independently unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C 3-6 cycloalkyl, unsubstituted or substituted 4-10 membered saturated or unsaturated heterocyclic group, unsubstituted or substituted 5-membered heteroaryl and 6-membered heterocyclic group, halogen, -CN, -COOH , -OR 7 , -NH-R 7 , -CONH-R 7 , -SO 2 -R 7 , -SO 2 NH-R 7 ;
• R 7 is selected from hydrogen, unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C 3 -6 cycloalkyl, unsubstituted or substituted 4-10 membered saturated or unsaturated heterocyclic groups;
• Substitution in R 5 , R 6 , and R 7 refers to being substituted by one or more of the following group A substituents.
• Group A substituents include: C 1-6 alkyl, C 1-6 haloalkyl , C 1-6 alkyl substituted by hydroxy, C 1-6 alkyl substituted by amino, C 1-6 alkyl substituted by cyano, C 1-6 alkyl substituted by C 1-6 alkoxy, C 1 -6 alkoxy, hydroxyl, halogen, cyano, amino, carboxyl, -NH-C 1-6 alkyl, -NH-C 3-6 cycloalkyl, C 6 unsubstituted or substituted by group B substituents -10 aryl, 5-10 membered heteroaryl unsubstituted or substituted by B group substituent, C 3-6 cycloalkyl unsubstituted or substituted by B group, 4 unsubstituted or substituted by B group substituent -10-membered saturated or
• R 5 , R 6 , R 7 and the heteroaryl group in the substituent group A are selected from:
• R 5 , R 6 , R 7 and the heterocyclic group in the group A substituent are selected from:
• the 5-membered heteroaryl and 6-membered heterocyclic group is selected from
• the present invention provides the compound of formula (I), its enantiomer, diastereoisomer, racemate, prodrug, hydrate, solvate or its pharmaceutical Acceptable salts on:
• the compound of formula (I) has the structure of formula (I-2) or formula (I-3); wherein each symbol and variable are as defined before and with the proviso that R is not hydrogen:
• the compound of formula (I) has the structure of formula (I-4):
• R 0 , R 1 , R 2 , Q 1 , Q 2 , Q 3 , and Q 4 are as defined above;
• R 31 , R 32 , R 33 , R 34 , and R 35 are each independently selected from: hydrogen, substituted Or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 2-4 alkynyl, substituted or unsubstituted 4-6 membered saturated or unsaturated heterocyclic group, halogen, cyano or amino; refers to being substituted by one or more substituents selected from halogen, hydroxyl, cyano, amino; preferably, R 31 is halogen, R 32 is halogenated C 1-6 alkyl, R 33 , R 34 , R 35 are hydrogen.
• R 1 is hydrogen or C 1-6 alkyl, preferably hydrogen or methyl.
• the compound of the formula (I) is selected from the following compounds:
• composition comprising:
• Another aspect of the present invention provides the compound of formula (I), its enantiomer, diastereomer, racemate, prodrug, hydrate, solvate or pharmaceutically acceptable Accepted salts, or the use of the pharmaceutical composition in the preparation of SOS1 inhibitors.
• Another aspect of the present invention provides the compound of formula (I), its enantiomer, diastereomer, racemate, prodrug, hydrate, solvate or pharmaceutically acceptable Accepted salts, or the use of the pharmaceutical composition in the preparation of medicines for preventing and/or treating diseases related to SOS1 mutation, activity or expression.
• the diseases related to SOS1 mutation, activity or expression include head and neck cancer, lung cancer, mediastinal tumor, gastrointestinal tract tumor, prostate cancer, testicular cancer, gynecological tumor, breast cancer, kidney and bladder cancer, endocrine system tumor, Soft tissue sarcoma, osteosarcoma, rhabdoid tumor, mesothelioma, skin cancer, peripheral nervous system tumor, central nervous system tumor, lymphoma, leukemia, Noonan syndrome, cardiofacial skin syndrome, hereditary gingival fibromatosis and its associated syndromes.
• the wavy line indicates the point of attachment of the group to the rest of the molecule.
• the halogen is F, Cl, Br or I.
• substituted or “substituted by” as used herein means that one or more hydrogen atoms on a given atom or group are replaced by one or more substituents selected from the given group of substituents, provided that is no more than the normal valence for that given atom.
• C 1-6 means having 1, 2, 3, 4, 5 or 6 carbon atoms
• C 1-8 means having 1, 2, 3, 4, 5, 6 , 7 or 8 carbon atoms, and so on.
• 3-8 membered heterocyclic group means that the heterocyclic group has 3-8 ring atoms, and so on "4-10 membered heterocyclic group” and so on.
• alkyl means a saturated linear or branched chain hydrocarbon moiety
• C 1-10 alkyl means a straight chain or branched chain alkyl group with 1 to 10 carbon atoms, without limitation
• Optionally include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl; preferably methyl, ethyl, propyl, isopropyl butyl, isobutyl, sec-butyl and tert-butyl.
• the C 1-10 alkyl group is preferably a C 1-6 alkyl group, more preferably a C 1-4 alkyl group.
• alkoxy denotes an alkyl group as defined herein attached through an oxygen atom.
• C 1-6 alkoxy refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, i.e., -O-(C 1-6 alkyl) group, without limitation Including methoxy, ethoxy, propoxy, isopropoxy and butoxy, etc.
• alkenyl means a straight or branched chain hydrocarbon moiety containing at least one double bond
• C 2-6 alkenyl means a moiety having at least one double bond having 2 to 6 carbon atoms
• the linear or branched alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl, and the like.
• cycloalkyl means a saturated cyclic hydrocarbon moiety
• C 3-8 cycloalkyl means a cyclic alkyl group with 3 to 8 carbon atoms in the ring, without limitation Exemplary examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and the like.
• aryl refers to a carbocyclic hydrocarbon group consisting of one ring or more, such as two fused rings, wherein at least one ring is an aromatic ring, such as C 6-10 aryl.
• aryl groups include, but are not limited to, phenyl, naphthyl, and the like.
• heterocyclyl means a non-aromatic cyclic group comprising at least one carbon atom and at least one (such as 1-3) ring heteroatoms selected from N, O, S, wherein sulfur Atoms can optionally be oxidized.
• R is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl or nitrogen protecting group (for example, benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butoxy carbonyl, acetyl, benzoyl, benzyl, p-methoxy-benzyl, p-methoxy-phenyl, 3,4-dimethoxybenzyl, etc.).
• Heterocyclic group includes monocyclic rings and bicyclic structures such as fused rings, bridged rings, and spiro rings, and may be partially or fully saturated, such as 4-10 membered saturated or unsaturated heterocyclic groups, 4-6 membered saturated or Unsaturated heterocyclic group, 3-8 membered heterocyclic group, 3-6 membered heterocyclic group, etc.; such as tetrahydrofuryl, pyrrolidinyl, oxetanyl, oxanyl, azetidinyl, cyclo Oxyethyl, aziridinyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, azepanyl, oxetane Heptyl, etc.
• the heterocyclic groups described herein can be selected from the following groups:
• the term "5-10 membered heteroaryl” means a monocyclic or bicyclic ring having 5 to 10 ring atoms, for example 5, 6 or 7 ring atoms (ie, 5-7 membered heteroaryl).
• a ring or fused polycyclic ring aromatic hydrocarbon group which contains at least one (such as 1-3) ring heteroatoms independently selected from N, O and S (such as N) in the ring, and the remaining ring atoms are carbon atoms ;
• Bicyclic heteroaryl groups include, for example, benzoxazolyl, imidazopyridyl, triazolopyridyl, benzofuryl, pyrazolopyrimidinyl, benzodioxolyl, indolyl , quinolinyl, isoquinolyl, etc.
• the substitution is mono-substitution or multiple substitution
• the multiple substitution is di-substitution, tri-substitution, tetra-substitution, or penta-substitution.
• the disubstituted means having two substituents, and so on.
• the substituents may be identical or different from each other.
• the pharmaceutically acceptable salt of the present invention may be a salt formed by an anion and a positively charged group on the compound of formula (I).
• Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, toluenesulfonate, tartrate, fumarate Acid, glutamate, glucuronate, lactate, glutarate or maleate.
• salts can be formed from cations with negatively charged groups on compounds of formula I. Suitable cations include sodium, potassium, magnesium, calcium and ammonium, such as tetramethylammonium.
• “pharmaceutically acceptable salt” refers to the salts formed by the compound of formula (I) with an acid selected from the following group: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, Sulfuric acid, nitric acid, methanesulfonic acid, sulfamic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, sorrel oxalic acid, pyruvic acid, Malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoro
• Safe and effective amount means: the amount of the active ingredient is sufficient to significantly improve the condition without causing serious side effects.
• the pharmaceutical composition contains 1-2000 mg active ingredient/dose, more preferably 10-200 mg active ingredient/dose.
• the "one dose” is a tablet.
• “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low toxicity. "Compatibility” here means that each component in the composition can be blended with the active ingredient of the present invention and with each other without significantly reducing the efficacy of the active ingredient.
• Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
• cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
• gelatin such as talc
• solid lubricants such as stearic acid , magnesium stearate
• calcium sulfate such
• the administration method of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.
• Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
• Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
• liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
• the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
• Suspensions in addition to the active ingredient, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, mixtures of these substances, and the like.
• suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, mixtures of these substances, and the like.
• compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
• Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
• the compound of the present invention can be administered alone or in combination with other therapeutic drugs (such as antineoplastic drugs).
• other therapeutic drugs such as antineoplastic drugs.
• a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
• the dosage is usually 1-2000 mg, preferably 20-500 mg.
• factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
• reaction was cooled to 40°C, a solution of compound Int-1-e (13g, 45mmol) in isopropanol (450mL) and a solution of potassium tert-butoxide (113mL, 11mmol, 0.1M) in isopropanol were added successively, and reaction 2 at 40°C Hour.
• the reaction was monitored by TLC. After the reaction was completed, the system was concentrated, and the residue was added to saturated brine (100 mL), extracted with ethyl acetate (100 mL x 3), and the organic phases were combined and dried over anhydrous sodium sulfate.
• reaction temperature was lowered to 40°C, and (R, E)-N-(1-(3-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide Int-2 was added sequentially -d (7.5g, 24mmol) in isopropanol (250mL) and potassium tert-butoxide (60mL, 2.4mmol, 0.1M) in isopropanol were reacted at 40°C for 15 hours under the protection of argon.
• compound A-16-a (0.10g, 0.48mmol), 1-(4-hydroxypiperidin-1-yl)ethanone A-16-b (68mg, 0.48mmol) were sequentially added, Triphenylphosphine (0.16g, 0.62mmol) and anhydrous toluene (10mL), replaced by nitrogen three times, stirred at 120°C for 10 minutes, diisopropyl azodicarboxylate (0.12g, 0.62mmol) was added, The stirring reaction was continued for 3 hours.
• reaction solution was cooled and poured into ice saturated ammonium chloride solution to quench, then ethyl acetate was added for extraction, and the organic phase was backwashed with saturated brine, then dried with sodium sulfate, and the organic The phase was filtered and concentrated under reduced pressure. The residue was preliminarily purified by climbing plate, and then purified by preparation to obtain compound B-1 (11.3 mg, white solid), yield: 15.9%.
• reaction solution was cooled and poured into ice saturated ammonium chloride solution to quench, then added ethyl acetate for extraction, and then the organic phase was used Saturated brine was backwashed, and then dried with sodium sulfate. After concentrated under reduced pressure, the crude product was preliminarily purified by preparative TLC, and then the crude product after preliminary purification was prepared by the acid method (TFA) to obtain white solid compound B-2 ( 4.2 mg, yield: 12.2%).
• TFA acid method
• Compound B-51-a (70mg, 0.152mmol) was dissolved in 2mL ammonia water and 1mL dioxane solution, and then reacted in a sealed tube at 80°C for 16 hours under nitrogen protection. After the reaction is complete, pour the reaction solution into ammonium chloride solution to quench, extract with ethyl acetate, backwash the organic phase with water and saturated brine, then dry with sodium sulfate, filter and concentrate under reduced pressure, and the residue is prepared by Compound B-51 (2.3 mg, yellow solid) was obtained after purification, yield: 3.3%.
• reaction solution was poured into saturated brine, and extracted three times with ethyl acetate, the organic phase was collected and dried, concentrated under reduced pressure, and the residue was purified by a glass silica gel column to obtain yellow oily compound B-62-b (40 mg, produced rate: 63%).
• Triethylamine (69 mg) and acetic anhydride (35 mg, 0.34 mmol) were added to a solution of compound B-67-b (173 mg, 0.36 mmol) in dichloromethane (10 mL), and the reaction was carried out at room temperature for 2 hours. After the reaction was complete, the organic phase was collected and dried by extraction with dichloromethane three times, concentrated under reduced pressure, and the residue was purified by a glass silica gel column to obtain compound B-67-c (173 mg, yellow oil) as a yellow oil, yield: 93%.
• Step ten
• Example 60 The synthetic route of compound B-80 (a mixture of cis and trans isomers compound B-80-P1 and compound B-80-P2):
• reaction liquid was cooled and quenched with ammonium chloride solution, then extracted with dichloromethane, then dried with sodium sulfate, and then the organic phase was filtered and concentrated under reduced pressure, and the residue was passed through prep-HPLC (NH 4 HCO 3 system) was purified to obtain white solid cis-trans isomer compound B-80-P1 and compound B-80-P2 (P1: 102.4 mg, P2: 123.5 mg, yield: 12%).
• the target compound B-103 was used to replace B-82-b in the original route to synthesize the following compound B-104.
• reaction solution is extracted with saturated ammonium chloride solution and EA, the organic phase is backwashed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue is purified by formic acid reverse phase preparation to obtain cis-trans Isomer compounds B-92-P1 and B-92-P2 (P1: 3.5 mg, P2: 14.1 mg, white solid), yield: P1: 4.8%, P2: 19.5%.
• intermediate B-111-a is used to replace B-1-c in the original route to synthesize compound B-123; use (S)-2-hydroxypropionic acid to replace the Glycolic acid, synthetic compound B-124.
• intermediates B-62-b, B-73-1 are used to replace B-1-c in the original route, and compounds B-173 and B-175 are synthesized; with (S) -2-hydroxypropionic acid replaced glycolic acid in the original route to synthesize compounds B-174 and B-176.

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