Sos1 inhibitors, methods of making and using the same

Abstract

SOS1 inhibitor compounds represented by Formula (I) or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising them, and their use in the manufacture of medicaments for the treatment of cancer.

Description

[0001] This application claims priority to the following two earlier applications, the full text of which is incorporated herein by reference:

[0002] The prior application filed with the China National Intellectual Property Administration on March 5, 2021, with patent application number 202110246153.4 and invention title "Novel SOS1 Inhibitor and its Preparation Method and Application";

[0003] The prior application, filed on September 17, 2021 with the China National Intellectual Property Administration, with patent application number 202111094388.2 and invention title "Novel SOS1 Inhibitor and its Preparation Method and Application", is entitled "Novel SOS1 Inhibitor and its Preparation Method and Application". Technical Field

[0004] This invention belongs to the field of pharmaceutical technology and relates to SOS1 inhibitor compounds or their optical isomers, pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their use as SOS1 inhibitors. Background Technology

[0005] RAS family proteins include KRAS (V-Ki-ras2 Kirsten rat sarcoma virus oncogene homolog), NRAS (neuroblastoma RAS virus oncogene homolog), and HRAS (Harvey rat sarcoma virus oncogene), which are small GTPases present in cells in either a GTP-bound or GDP-bound state (McCormick et al., J. Mol. Med. (Berl)., 2016, 94(3): 253-8; Nimnual et al., Sci. STKE., 2002, 2002(145): pe36).

[0006] RAS family proteins play an important role in human cancers. Tumors caused by mutations in RAS proteins account for 20-30% of all human tumors and are considered to be tumorigenic drivers, particularly in lung cancer, colorectal cancer, and pancreatic cancer (Malumbres & Barbacid 2002 Nature Reviews Cancer; Pylayeva-Gupta et al. 2011 Nature Reviews Cancer).

[0007] SOS1 (son of sevenless homolog 1) is a widely expressed regulatory protein in cells. As a guanine nucleotide exchanger of RAS and RAC proteins, it plays an important regulatory role in the intracellular RAS and RAC signaling pathways. SOS1 has two binding sites for RAS family proteins: a catalytic site, which binds GDP-bound RAS family proteins to promote guanine nucleotide exchange; and an allosteric site, which binds GTP-bound RAS family proteins, leading to a further increase in SOS1's catalytic GEF function (Freedman et al., Proc. Natl. Acad. Sci. USA., 2006, 103(4 5):16692-7; Pierre et al., Biochem. Pharmacol., 2011, 82(9):1049-56). Public data indicate that SOS1 is involved in the activation of mutant KRAS and oncogenic signaling in cancer (Jeng et al., Nat. Commun., 2012, 3:1168). Depletion of SOS1 levels reduced the proliferation and survival of tumor cells carrying KRAS mutations, but no effect was observed in KRAS wild-type cell lines. The effects of SOS1 loss could not be compensated for by introducing SOS1 with catalytic site mutations, further demonstrating the important role of SOS1GEF activity in KRAS-mutant cancer cells.

[0008] In recent decades, the interaction between RAS family proteins and SOS1 has been increasingly studied. Small activating molecules have been identified that bind to the lipophilic pocket of SOS1 closely adjacent to the RAS binding site (Burns et al., Proc. Natl. Acad. Sci. 2014, 111(9):3401-6). However, the binding of these molecules appears to lead to increased nucleotide exchange, thereby activating RAS rather than inactivating it.

[0009] Although some small molecule SOS1 inhibitors have been reported in existing literature (such as patent documents WO2018 / 115380A1 and WO2018 / 172250A1), a large number of patients still cannot achieve satisfactory clinical treatment results. Therefore, there is still a need to develop SOS1 inhibitors with better activity, better selectivity, and better safety. Summary of the Invention

[0010] This invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof. These compounds can inhibit the activity of SOS1, thereby affecting its biological function.

[0011] This invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0012]

[0013] Among them, ring B is selected from

[0014]

[0015] R 1 Selected from H, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, -OC 1-6 Alkyl or C 3-6 cycloalkyl;

[0016] R 2 Selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, C 6-10 Aryl, 3-10 membered heterocyclic or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-10 Cycloalkenyl, C 6-10 Aryl, 3-10 heterocyclic or 5-10 heteroaryl are optionally R 2b and / or R 2c replace;

[0017] R 2b Selected from -OR 2c -N(R) 2c )2、-NHR 2c Halogen, hydroxyl, cyano, amino, -C(O)R 2c -C(O)N(R) 2c )2、-C(O)NHR 2c -C(O)OR 2c -S(O)2R 2c -S(O)2N(R) 2c )2、-S(O)2NHR 2c -NHC(O)R 2c or -N(C 1-4 Alkyl)C(O)R 2c ;

[0018] R 2c Selected independently from C 1-6 Alkyl, C 3-10 cycloalkyl, C 6-10Aryl, 3-10 membered heterocyclic or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 3-10 heterocyclic or 5-10 heteroaryl are optionally R 2d replace;

[0019] R 2d Selected from halogen, hydroxyl, cyano, amino, -C(O)R 2f -C(O)N(R) 2f )2、-C(O)OR 2f -S(O)2R 2f -S(O)2N(R) 2f )2、-N(C 1-4 Alkyl)R 2f -NHC(O)R 2f -N(C 1-4 Alkyl)C(O)R 2f C 3-10 cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclic or 5-10 membered heteroaryl, wherein C 3-10 cycloalkyl, C 6-10 Aryl, 3-10 heterocyclic or 5-10 heteroaryl are optionally R 2f replace;

[0020] R 2f Independently selected from H or C 1-6 alkyl;

[0021] R 3 R 4 Independently selected from H, deuterium, and C 1-3 Deuterated alkyl, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0022] R 5 Independently selected from SF5, nitro, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 3-6 cycloalkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -O-(3-8 membered heterocyclic), -S(O)2-C 1-4 Alkyl, -P(O)(R 5b )2、-C(O)R 5b -C(O)N(R) 5b )2、-C(O)OR 5b , 3-8 membered heterocyclic group or 5-10 membered heteroaryl group, wherein C 1-6 Alkyl, C3-6 cycloalkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -O-(3-8 membered heterocyclic), -S(O)2-C 1-4 Alkyl, 3-8 membered heterocyclic or 5-10 membered heteroaryl, optionally R 5a replace;

[0023] R 5a Independently selected from halogen, hydroxyl, cyano or amino groups;

[0024] R 5b Independently selected from H or C 1-6 alkyl;

[0025] n is selected from 0, 1, 2, 3 or 4;

[0026] R 6 Selected from H, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 3-6 cycloalkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -O-(3-8 membered heterocyclic), 3-8 membered heterocyclic or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 3-6 cycloalkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -O- (3-8 membered heterocyclic), 3-8 membered heterocyclic or 5-10 membered heteroaryl are optionally R 6a replace;

[0027] R 6a Selected from halogen, hydroxyl, cyano, or amino groups;

[0028] R 7 Selected from H, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 3-6 cycloalkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -O-(3-8 membered heterocyclic), 3-8 membered heterocyclic or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 3-6 cycloalkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -O- (3-8 membered heterocyclic), 3-8 membered heterocyclic or 5-10 membered heteroaryl are optionally R 7a replace;

[0029] R 7a Selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl or C1-6 Halogenated alkyl groups;

[0030] Ring A is selected from C 6-10 Aryl, 5-10 heterocyclic or 5-10 heteroaryl.

[0031] In some implementation schemes, R 1 Selected from H, halogens, C 1-6 Alkyl or C 1-6 Deuterated alkyl groups.

[0032] In some implementation schemes, R 1 Selected from H, C 1-6 Alkyl or C 1-6 Deuterated alkyl groups.

[0033] In some implementation schemes, R 1 Selected from H, halogens, C 1-3 Alkyl or C 1-3 Deuterated alkyl groups.

[0034] In some implementation schemes, R 1 Selected from H, C 1-3 Alkyl or C 1-3 Deuterated alkyl groups.

[0035] In some implementation schemes, R 1 Selected from H, halogens, CH3 or CD3.

[0036] In some implementation schemes, R 1 Selected from H, CH3 or CD3.

[0037] In some implementation schemes, R 2 Selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclic or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 3-10 heterocyclic or 5-10 heteroaryl are optionally R 2b and / or R 2c replace.

[0038] In some implementation schemes, R 2 Selected from C 1-6 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclic or 5-10 membered heteroaryl, wherein C 1-6Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 3-10 heterocyclic or 5-10 heteroaryl are optionally R 2b and / or R 2c replace.

[0039] In some implementation schemes, R 2 Selected from C 1-6 Alkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclic groups are optionally R 2b and / or R 2c replace.

[0040] In some implementation schemes, R 2 Selected from C 3-10 cycloalkyl or 3-10 membered heterocyclic groups, wherein the C 3-10 cycloalkyl or 3-10 membered heterocyclic groups are optionally R 2b and / or R 2c replace.

[0041] In some implementation schemes, R 2 Selected from C 3-6 Cycloalkyl or 4-9 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 4-9 membered heterocyclic groups are optionally R 2b and / or R 2c replace.

[0042] In some implementation schemes, R 2 Selected from C 3-6 cycloalkyl or 4-7 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 4-7-membered heterocyclic groups are optionally R 2b and / or R 2c replace.

[0043] In some implementation schemes, R 2 Selected from cyclopropyl, oxacyclobutyl, morpholino, Piperidinyl or tetrahydropyrroleyl, wherein the cyclopropyl, oxetyl, morpholinyl, Piperidinyl or tetrahydropyrrolyl is optionally replaced by R 2b and / or R 2c replace.

[0044] In some implementation schemes, R 2 Selected from cyclopropyl, oxacyclobutyl, morpholino, or The cyclopropyl, oxetyl, morpholino, or Optionally R 2b and / or R2c replace.

[0045] In some implementation schemes, R 2 Selected from cyclopropyl, morpholino, piperidinyl, or tetrahydropyrrole, wherein the cyclopropyl, morpholino, piperidinyl, or tetrahydropyrrole group is optionally R 2b and / or R 2c replace.

[0046] In some implementation schemes, R 2b Selected from -OR 2c -N(R) 2c 2. Halogen, hydroxyl, cyano, amino, -C(O)R 2c -C(O)N(R) 2c )2、-C(O)OR 2c -S(O)2R 2c -S(O)2N(R) 2c )2、-NHC(O)R 2c or -N(C 1-4 Alkyl)C(O)R 2c In some implementations, R 2b Selected from -OR 2c -N(R) 2c 2. Halogen, hydroxyl, cyano, amino, -C(O)R 2c or -C(O)NHR 2c .

[0047] In some implementation schemes, R 2b Selected from -OR 2c -N(R) 2c 2. Halogen, hydroxyl, cyano, amino or -C(O)R 2c .

[0048] In some implementation schemes, R 2b Selected from -OR 2c -N(R) 2c 2. Halogen, hydroxyl, cyano or amino.

[0049] In some implementation schemes, R 2b Selected from -OR 2c -C(O)R 2c or -C(O)NHR 2c .

[0050] In some implementation schemes, R 2b Selected from -OR 2c or -C(O)R 2c .

[0051] In some implementation schemes, R 2bSelected from -OCH3, -C(O)CH3 or -C(O)NHCH3.

[0052] In some implementation schemes, R 2b Selected from -OCH3 or -C(O)CH3.

[0053] In some implementation schemes, R 2c Selected independently from C 1-6 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclic or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 3-10 heterocyclic or 5-10 heteroaryl are optionally R 2d replace.

[0054] In some implementation schemes, R 2c Selected independently from C 1-6 Alkyl, 3-10 membered heterocyclic or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, 3-10 membered heterocyclic or 5-10 membered heteroaryl, optionally R 2d replace.

[0055] In some implementation schemes, R 2c Selected independently from C 1-6 Alkyl, 4-9 membered heterocyclic or 5-6 membered heteroaryl, wherein C 1-6 Alkyl, 4-9 membered heterocyclic or 5-6 membered heteroaryl are optionally R 2d replace.

[0056] In some implementation schemes, R 2c Selected independently from C 1-6 Alkyl or 4-9 membered heterocyclic groups, wherein the C 1-6 Alkyl or 4-9 membered heterocyclic groups are optionally R 2d Replacement. In some implementations, R 2c Selected independently from C 1-6 Alkyl or oxocyclic butyl, wherein C 1-6 Alkyl or oxoheterobutyl is optionally R 2d replace.

[0057] In some implementation schemes, R 2c It can be methyl, CH2F, CHF2, CF3 or oxetine.

[0058] In some implementation schemes, R 2c Selected independently from C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally R 2dReplacement. In some implementations, R 2c It can be methyl, CH2F, CHF2 or CF3.

[0059] In some implementation schemes, R 2d Selected from halogen, hydroxyl, cyano, amino, -C(O)R 2f -C(O)N(R) 2f )2、-C(O)OR 2f -S(O)2R 2f -S(O)2N(R) 2f )2、-N(C 1-4 Alkyl)R 2f -NHC(O)R 2f or -N(C 1-4 Alkyl)C(O)R 2f .

[0060] In some implementation schemes, R 2d Selected from halogens.

[0061] In some implementation schemes, R 2d Selected from F.

[0062] In some implementation schemes, R 3 R 4 Independently selected from H, deuterium, and C 1-3 Deuterated alkyl or C 1-6 alkyl.

[0063] In some implementation schemes, R 3 R 4 It is independently selected from H, deuterium, CH3 or CD3.

[0064] In some implementation schemes, R 3 Selected from H or deuterium, R 4 Selected from CH3 or CD3.

[0065] In some implementation schemes, R 5 Independently selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 3-6 cycloalkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -O-(3-8 membered heterocyclic), -S(O)2-C 1-4 Alkyl, -P(O)(R 5b )2、-C(O)R 5b -C(O)N(R) 5b )2、-C(O)OR 5b , 3-8 membered heterocyclic group or 5-10 membered heteroaryl group, wherein C 1-6Alkyl, C 3-6 cycloalkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -O-(3-8 membered heterocyclic), -S(O)2-C 1-4 Alkyl, 3-8 membered heterocyclic or 5-10 membered heteroaryl, optionally R 5a replace.

[0066] In some implementation schemes, R 5 Independently selected from SF5, nitro, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 3-6 cycloalkyl, -OC 1-6 Alkyl, -S(O)2-C 1-4 Alkyl, -P(O)(R 5b 2. 3-8 membered heterocyclic group or 5-10 membered heteroaryl group, wherein C 1-6 Alkyl, C 3-6 cycloalkyl, -OC 1-6 Alkyl, -S(O)2-C 1-4 Alkyl, 3-8 membered heterocyclic or 5-10 membered heteroaryl, optionally R 5a replace.

[0067] In some implementation schemes, R 5 Independently selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 3-6 cycloalkyl, -OC 1-6 Alkyl, -S(O)2-C 1-4 Alkyl, -P(O)(R 5b 2. 3-8 membered heterocyclic group or 5-10 membered heteroaryl group, wherein C 1-6 Alkyl, C 3-6 cycloalkyl, -OC 1-6 Alkyl, -S(O)2-C 1-4 Alkyl, 3-8 membered heterocyclic or 5-10 membered heteroaryl, optionally R 5a replace.

[0068] In some implementation schemes, R 5 Independently selected from SF5, nitro, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, -OC 1-6 Alkyl, -S(O)2-C 1-4 Alkyl, -P(O)(R 5b 2. Or a 3-8 member heterocyclic group, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -S(O)2-C1-4 Alkyl or 3-8 membered heterocyclic groups are optionally R 5a replace.

[0069] In some implementation schemes, R 5 Independently selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, -OC 1-6 Alkyl, -S(O)2-C 1-4 Alkyl, -P(O)(R 5b 2. Or a 3-8 member heterocyclic group, wherein the C 1-6 Alkyl, -OC 1-6 Alkyl, -S(O)2-C 1-4 Alkyl or 3-8 membered heterocyclic groups are optionally R 5a replace.

[0070] In some implementation schemes, R 5 Independently selected from SF5, nitro, cyano, halogen, C 1-6 Alkyl, -S(O)2-C 1-4 Alkyl, -P(O)(R 5b )2 or The C 1-6 Alkyl or -S(O)2-C 1-4 Alkyl groups are optionally R 5a replace.

[0071] In some implementation schemes, R 5 Independently selected from SF5, nitro, cyano, halogen, C 1-6 Alkyl, the C 1-6 Alkyl groups are optionally R 5a replace.

[0072] In some implementation schemes, R 5 Independently selected from halogens, C 1-6 Alkyl, -S(O)2-C 1-4 Alkyl, -P(O)(R 5b )2 or The C 1-6 Alkyl or -S(O)2-C 1-4 Alkyl groups are optionally R 5a replace.

[0073] In some implementation schemes, R 5 Independently selected from nitro, cyano, F, CH3, -S(O)2-CH3 or -P(O)(CH3)2, wherein the CH3 or -S(O)2-CH3 is optionally converted by R. 5a replace.

[0074] In some implementation schemes, R5 Independently selected from F, CH3, -S(O)2-CH3, or -P(O)(CH3)2, wherein the CH3 or -S(O)2-CH3 is optionally converted by R. 5a replace.

[0075] In some implementation schemes, R 5a It is independently selected from halogens or hydroxyl groups.

[0076] In some implementation schemes, R 5a It is independently selected from halogens.

[0077] In some implementation schemes, R 5a Selected independently from F.

[0078] In some implementation schemes, R 6 Selected from H or halogens.

[0079] In some implementation schemes, R 6 Selected from H.

[0080] In some implementation schemes, R 7 Selected from H, C 1-6 Alkyl, C 3-6 cycloalkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -O-(3-8 membered heterocyclic), 3-8 membered heterocyclic or 5-10 membered heteroaryl, wherein C 1-6 Alkyl, C 3-6 cycloalkyl, -OC 1-6 Alkyl, -OC 3-6 Cycloalkyl, -O- (3-8 membered heterocyclic), 3-8 membered heterocyclic or 5-10 membered heteroaryl are optionally R 7a replace.

[0081] In some implementation schemes, R 7 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic or 5-6 membered heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-7-membered heterocyclic or 5-6-membered heteroaryl groups are optionally R 7a replace.

[0082] In some implementation schemes, R 7 Selected from H, C 1-6 Alkyl or 4-7 membered heterocyclic group, wherein the C 1-6 Alkyl or 4-7 membered heterocyclic groups are optionally R 7a replace.

[0083] In some implementation schemes, R 7Selected from H, C 1-3 alkyl or tetrahydropyridyl, wherein C 1-3 Alkyl or tetrahydropyridyl is optionally replaced by R 7a replace.

[0084] In some implementation schemes, R 7 Selected from H or C 1-3 alkyl.

[0085] In some implementation schemes, R 7 Selected from H or CH3.

[0086] In some implementation schemes, R 7 Selected from H.

[0087] In some implementation schemes, R 7a Selected from C 1-6 alkyl.

[0088] In some implementation schemes, R 7a Selected from CH3.

[0089] In some implementations, n is selected from 0, 1, or 2.

[0090] In some implementations, ring A is selected from C. 6-10 Aryl, 9-10 heterocyclic or 9-10 heteroaryl.

[0091] In some implementations, ring A is selected from C. 6-10 Aryl or 9-10 membered heterocyclic group.

[0092] In some implementations, ring A is selected from...

[0093] In some implementations, ring A is selected from...

[0094] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (I-1) or a pharmaceutically acceptable salt thereof.

[0095]

[0096] in, Selected from N-CH=CC=CH or C=CH-NC=CH; rings A and R 1 R 2 R 3 R 4 R 5 R 6 n is defined as above.

[0097] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (IIa) or a pharmaceutically acceptable salt thereof.

[0098]

[0099] Among them, rings A and R 1 R 2 R 3 R 4 R 5 R 6 R 7 n is defined as above.

[0100] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (II) or a pharmaceutically acceptable salt thereof.

[0101]

[0102] Among them, rings A and R 1 R 2 R 3 R 4 R 5 R 6 n is defined as above.

[0103] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (III) or a pharmaceutically acceptable salt thereof.

[0104]

[0105] Among them, rings A and R 1 R 2 R 3 R 4 R 5 R 6 n is defined as above.

[0106] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof.

[0107]

[0108] Among them, rings A and R 1 R 2 R 3 R 4 R 5 R 6 R 7 n is defined as above.

[0109] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or pharmaceutically acceptable salts thereof.

[0110]

[0111]

[0112]

[0113] Furthermore, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0114] Furthermore, the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for the prevention or treatment of SOS1-related diseases.

[0115] Furthermore, the present invention relates to the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of SOS1-related diseases.

[0116] Furthermore, the present invention relates to a compound of formula (I) for the prevention or treatment of SOS1-related diseases, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0117] The present invention also relates to a method for treating SOS1-related diseases, the method comprising administering to a patient a therapeutically effective dose of a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0118] Furthermore, the SOS1-related diseases are selected from cancer.

[0119] On the other hand, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for the prevention or treatment of cancer.

[0120] On the other hand, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of cancer.

[0121] On the other hand, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of cancer.

[0122] On the other hand, the present invention provides a method for preventing or treating cancer, comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0123] Terminology Definitions and Explanations

[0124] Unless otherwise stated, the definitions of groups and terms recorded in this specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should fall within the scope of this specification.

[0125] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable, non-toxic salt of an acid or base, including salts of inorganic acids and bases, and salts of organic acids and bases.

[0126] The compounds of this invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers, and single isomers are all included within the scope of this invention.

[0127] The illustrations of racemic or enantiomerically pure compounds in this article are derived from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise specified, wedge-shaped and dashed lines denote the absolute configuration of a stereocenter. When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, they include E and Z geometric isomers unless otherwise specified. Similarly, all tautomers are included within the scope of this invention.

[0128] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0129] The term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, non-corresponding isomers, and conformational isomers.

[0130] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds of this invention can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form; attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the ketone form is dominant; while in phenols, the enol form is dominant. This invention encompasses all tautomeric forms of the compounds.

[0131] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or physiologically / pharmaceutical acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutical acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0132] The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on aromatic groups.

[0133] The terms “optional” or “optionally” mean that the event or condition subsequently described may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, the ethyl group “optionally” being halogenated means that the ethyl group can be unsubstituted (CH2CH3), monosubstituted (e.g., CH2CH2F), polysubstituted (e.g., CHFCH2F, CH2CHF2, etc.), or fully substituted (CF2CF3). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0134] In this article Indicates the connection site.

[0135] Term "C" 1-6"Alkyl" should be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, etc. The term "C" is also used. 1-3 "Alkyl" should be understood as a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, or 3 carbon atoms.

[0136] The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

[0137] Term "C" 3-10 "Cycloalkyl" should be understood to refer to a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, or bicyclic hydrocarbon groups such as decahydronaphthalene ring. According to the present invention, the bicyclic hydrocarbon ring includes bridged rings, spirorings, or fused ring structures. The term "C" is used to describe the cycloalkyl group. 3-8 "Cycloalkyl" should be understood to refer to a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 8 atoms. The term "C"... 3-6 "Cycloalkyl" should be understood as referring to a saturated monovalent monocyclic or bicyclic hydrocarbon ring with 3 to 6 atoms.

[0138] The term "cycloalkenyl" refers to an incompletely saturated non-aromatic carbon ring existing in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 4- to 10-membered ring. For example, the term "C4-C..." 10 Specific examples of "cycloalkenyl" include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cyclohepteneyl, and cycloheptadienyl.

[0139] Term "C" 6-10 "Aryl" should be understood as a monocyclic, bicyclic, or tricyclic hydrocarbon ring with 6, 7, 8, 9, or 10 carbon atoms that is monovalent and aromatic or partially aromatic, particularly a ring with 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring with 9 carbon atoms ("C9 aryl"), such as indenyl or indenyl; or a ring with 10 carbon atoms ("C9 aryl"). 10 Aryl), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0140] The term "3-10 membered heterocyclic group" should be understood as a saturated or partially unsaturated (not aromatic as a whole) monocyclic or bicyclic ring having 3-10 ring atoms. The bicyclic ring includes bridged rings, spirocyclic rings, and fused rings. The "heterocyclic" in the heterocyclic group includes, but is not limited to, being independently selected from N, O, S, C(=O), C(=S), S(=O), and S(O)2. Specifically, the heterocyclic group can be monocyclic, including but not limited to: 4-membered rings, such as azirmonobutylene and oxadiazonyl; 5-membered rings, such as tetrahydrofuranyl, dioxadienoyl, pyrrolyl, imidazoyl, pyrazolyl, pyrrolinyl, 2,5-dihydro-1H-pyrrolyl, 4,5-dihydrooxazolyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, piperazine, trithiaalkyl, tetrahydropyridinyl, 4H-[1,3,4]thiadiazinyl, 4H-[1,4]thiazinyl; or 7-membered rings, such as diazirmonoheptyl. The heterocyclic group may be bicyclic, including but not limited to: 5,5-membered rings, such as hexahydrocyclopentano[c]pyrrole-2(1H)-yl rings, or 5,6-membered bicyclic rings, such as hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl rings. Alternatively, a 6,6-membered bicyclic ring, such as a dihydroisoquinolinyl ring. The term "3-8-membered heterocyclic group" should be understood as a saturated or partially unsaturated monocyclic or bicyclic ring having 3-8 ring atoms. Although some bicyclic heterocyclic groups in this application partially contain a benzene ring or a heteroaromatic ring, the heterocyclic group as a whole remains non-aromatic.

[0141] The term "5-10 heteroaryl" should be understood to include such aromatic monovalent monocyclic, bicyclic, or tricyclic aromatic ring systems, particularly those with 5, 6, 9, or 10 ring atoms. The "hetero" in "heteroaryl" includes, but is not limited to, being independently selected from N, O, and S. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazoleyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzothiazolyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazoleyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo[derivatives], such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or acrylinyl, inazinyl, purinyl, etc., and their benzo[derivatives]; or cyclolinyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphthinyl, pteridinyl, carbazolyl, acrylinyl, phenazinyl, phenthiazinyl, phenoxazinyl, etc.

[0142] The term "treatment" means administering the compound or preparation described in this application to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

[0143] (i) Suppress the disease or disease state, that is, curb its development;

[0144] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0145] The term "therapeutic effective amount" means the amount of the compound of the present invention used to treat or prevent a particular disease, condition, or disorder; (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) to prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of the present invention constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by those skilled in the art based on their own knowledge and the disclosure of this invention.

[0146] The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, without limitation, binders, disintegrants, lubricants, flow aids, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or adhesion, making the formulation more suitable for direct compression. Typical examples of "pharmaceutically acceptable carriers" suitable for the above formulations include sugars, starches, cellulose, and their derivatives, which are commonly used excipients in pharmaceutical formulations.

[0147] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0148] The words “comprise,” “comprise,” or “comprise,” and their English variations such as comprises or comprising, should be understood in an open, non-exclusive sense, meaning “including but not limited to.”

[0149] This invention also includes compounds of the invention that are identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as... 2 H,3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.

[0150] The compounds of the present invention labeled with certain isotopes (e.g., using) 3 H and 14 C-labeling can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of the present invention can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0151] The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0152] Typical routes of administration of the compounds of the present invention or their pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0153] The pharmaceutical compositions of the present invention can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, emulsification, freeze drying, etc.

[0154] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present invention to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients.

[0155] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, flow aids, or flavoring agents.

[0156] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0157] In all methods of administration of the compounds of general formula I described herein, the daily dose is from 0.01 mg / kg to 200 mg / kg body weight, in the form of single or separate doses.

[0158] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0159] The chemical reactions in the specific embodiments of this invention are carried out in a suitable solvent, which must be suitable for the chemical changes of this invention and the reagents and materials required therefor. To obtain the compounds of this invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments. Detailed Implementation

[0160] The following embodiments describe the technical solutions of the invention in detail, but the scope of protection of the invention includes, but is not limited to, these embodiments.

[0161] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are measured in units of 10⁻⁶. -6 (ppm). The solvents used for NMR determination were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., with tetramethylsilane (TMS) as the internal standard; "IC 50 "Half-inhibitory concentration" refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0162] Abbreviations:

[0163] TEA: Triethylamine; TsCl: p-Toluenesulfonyl chloride; CH3CN or ACN: Acetonitrile; Xantphos: 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene; palladium(p-cinnamyl)chloride dimer: Palladium(π-cinnamyl) chloride dimer; dioxane: Dioxane; BocNH2: Tert-butyl carbamate; DMSO: Dimethyl sulfoxide; DIEA or DIPEA: N,N-Diisopropylethylamine; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-Tetramethylurea hexafluorophosphate; THF: Tetrahydrofuran; DMF: N,N-Dimethylformamide; DMF-DMA: N,N-Di(di(di(di(di(di(di(di(di(di(di(di(di(t-))))))))))))))))))))))))))))))))))))))))")))")))"))")"))")"))")")")")")")")""-""—" ... Methylformamide dimethyl acetal; DBDMH: 1,3-dibromo-5,5-dimethylhydantoin; KHMDS: potassium bis(trimethylsilyl)aminoacetate; Pd(OAc)2: palladium acetate; BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; toluene: toluene; Pd(PPh3)2Cl2: palladium bis(triphenylphosphine)dichloride; pyridine: pyridine; SmI2: samarium diiodide; Brettphos Pd G3: [(2-di-cyclohexylphosphino-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate; NaOBu-t: sodium tert-butoxide; Brettphos: 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl; DCM: dichloromethane; TFA: trifluoroacetic acid; Ac2O: acetic anhydride; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; PyAOP : (7-azabenzotriazole-1-oxo)tripyrrolephosphine hexafluorophosphate; 18-crown-6 or 18-crown-6: 1,4,7,10,13,16-hexaoxane; AcOH: acetic acid; X-phos: 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; Pd(PPh3)Cl2: bis(triphenylphosphine)palladium dichloride; BINAP: 1,1'-binaphthyl-2,2'-bis(diphenylphosphine); NBS: N-bromosuccinimide; NCS: N-chlorosuccinimide.

[0164] Example 1: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)-1,6-naphthidium-7(6H)-one

[0165]

[0166] Step 1: Synthesis of methyl 1-(1-methylcyclopropyl)-6-oxo-4-(toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylic acid

[0167]

[0168] Referring to the preparation method of intermediate E-4a on page 127 of patent CN111372932A, the difference is that C-1a in the preparation process of E-4a is replaced with 1-methylcyclopropylamine hydrochloride to obtain methyl 4-hydroxy-1-(1-methylcyclopropyl)-6-oxopyridine-3-carboxylic acid.

[0169] 1.88 g of methyl 4-hydroxy-1-(1-methylcyclopropyl)-6-oxopyridine-3-carboxylic acid was dissolved in 20 mL of acetonitrile, followed by 1.28 g of triethylamine, and then 1.61 g of p-toluenesulfonyl chloride. The reaction mixture was stirred at room temperature for 2 hours until the reaction was complete. The reaction solution was poured into water, extracted with ethyl acetate, and the organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound.

[0170] Step 2: Synthesis of methyl 4-((tert-Butoxycarbonyl)amino)-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid

[0171]

[0172] Methyl 1-(1-methylcyclopropyl)-6-oxo-4-(toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylic acid ester (500 mg), tert-butyl carbamate (310 mg), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (76.7 mg), palladium chloride (π-cinnamyl) dimer (34.3 mg), and potassium phosphate (562 mg) were added to a reaction flask, followed by dioxane (6 mL). The mixture was heated to 100 °C under argon protection and stirred for 10 hours until the reaction was complete. The reaction solution was cooled, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound.

[0173] Step 3: Synthesis of tert-butyl (5-(methoxy(methyl)carbamoyl)-1-(1-methylcyclopropyl)-2-oxo-1,2-dihydropyridin-4-yl)carbamate

[0174]

[0175] Methyl 4-((tert-Butoxycarbonyl)amino)-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid (217 mg) was added to a reaction flask and dissolved in a mixed solvent of dimethyl sulfoxide (4.00 mL) and acetonitrile (2.00 mL). Sodium hydroxide solution (539 mg, 20% w / w) was added, and the reaction was carried out at room temperature for 1 hour. N,N-diisopropylethylamine (174.0 mg), methoxymethylamine hydrochloride (69.0 mg), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.27 g) were added, and the reaction mixture was allowed to react at room temperature for 2 hours. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound.

[0176] Step 4: Synthesis of tert-butyl (5-acetyl-1-(1-methylcyclopropyl)-2-oxo-1,2-dihydropyridin-4-yl)carbamate

[0177]

[0178] 230 mg of tert-butyl (5-(methoxy(methyl)carbamoyl)-1-(1-methylcyclopropyl)-2-oxo-1,2-dihydropyridin-4-yl)carbamate was added to a reaction flask and dissolved in anhydrous tetrahydrofuran (6 mL). The mixture was cooled to 0 °C in an ice bath under argon protection, and 0.85 mL of methyl magnesium bromide was slowly added. The mixture was then slowly heated to room temperature and reacted for 6 hours. The reaction was quenched with a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound.

[0179] Step 5: Synthesis of 6-(1-methylcyclopropyl)-1,6-naphthidine-4,7(1H,6H)-dione

[0180]

[0181] (5-Acetyl-1-(1-methylcyclopropyl)-2-oxo-1,2-dihydropyridin-4-yl) tert-butyl carbamate (87 mg) was added to a reaction flask, followed by 1.5 mL of N,N-dimethylformamide dimethyl acetal. The mixture was then heated to 110 °C and reacted for 1 hour. The reaction solution was concentrated and dissolved in tetrahydrofuran (4 mL). Dilute hydrochloric acid (1.38 mL, 2 M) was added, and the resulting reaction solution was reacted overnight at 40 °C. After cooling, the pH of the reaction solution was adjusted to 8-9 with concentrated ammonia, then extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound.

[0182] Step 6: Synthesis of 4-chloro-6-(1-methylcyclopropyl)-1,6-naphthidium-7(6H)-one

[0183]

[0184] 46.7 mg of 6-(1-methylcyclopropyl)-1,6-naphthidine-4,7(1H,6H)-dione was dissolved in acetonitrile (2.1 mL), and phosphorus oxychloride (66.2 mg) and N,N-diisopropylethylamine (58.6 mg) were added. The mixture was then heated to 70 °C and reacted for 1 hour. The reaction solution was cooled and poured onto ice. The pH was adjusted to 8 with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound.

[0185] Step 7: Synthesis of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)-1,6-naphthidium-7(6H)-one

[0186]

[0187] 4-Chloro-6-(1-methylcyclopropyl)-1,6-naphthidium-7(6H)-one (50 mg) and (1R)-1-[3-(difluoromethyl)-2-fluorophenyl]ethylamine hydrochloride (48.1 mg) were dissolved in anhydrous dimethyl sulfoxide (2 mL), and N,N-diisopropylethylamine (82.6 mg) was added. The resulting reaction solution was heated to 80 °C overnight under inert gas protection. The reaction solution was cooled, filtered, and the filtrate was concentrated and purified by column chromatography to obtain the title compound.

[0188] DMSO-d6 δ H 9.24(s,1H),8.02(d,J=5.3Hz,1H),7.85(d,J=6.5Hz,1H),7.61(t,J=7.3Hz,1H),7.54(t,J=6.8Hz,1H),7.39-7.12( m,2H),6.24(s,1H),5.56(d,J=5.4Hz,1H),5.07-4.97(m,1H),1.63(d,J=6.8Hz,3H),1.56(s,3H),1.24-1.06(m,4H).

[0189] LC / MS (m / z, MH) + ):388.1

[0190] Example 2: (R)-2-chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)-1,6-naphthidium-7(6H)-one

[0191]

[0192] Step 1: Synthesis of 2,4-dihydroxy-6-(1-methylcyclopropyl)-1,6-naphthidium-7(6H)-one

[0193]

[0194] Referring to the preparation method of intermediate E-6a on page 127 of patent CN111372932A, the difference is that C-1a in the preparation process of E-4a is replaced with 1-methylcyclopropylamine, and methyl 4-acetamide-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid is prepared by the same method.

[0195] 5.00 g of methyl 4-acetamide-1-(1-methylcyclopropyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid was dissolved in 50 mL of anhydrous tetrahydrofuran. Bis(trimethylsilyl)amino potassium (1 M in THF) (56.8 mmol, 56.8 mL) was added dropwise at a controlled temperature of -80 to -78 °C using an ethanol-liquid nitrogen mixture. After the addition was complete, the mixture was allowed to return to room temperature overnight. The reaction was quenched with 50 mL of water, and extracted with 50 mL of ethyl acetate. After separation, the aqueous phase was adjusted to pH ≈ 4 with 4 N HCl. 50 mL of dichloromethane was added, resulting in the precipitation of a large amount of solid. The solid was filtered, and the filter cake was dried to obtain the title compound.

[0196] Step 2: Synthesis of 2,4-dichloro-6-(1-methylcyclopropyl)-1,6-naphthidium-7(6H)-one

[0197]

[0198] 500 mg of 2,4-dihydroxy-6-(1-methylcyclopropyl)-1,6-naphthidium-7(6H)-one was placed in 5 mL of acetonitrile, purged with argon, and 1.65 g of phosphorus oxychloride was added. The mixture was a white turbid liquid, heated to 80 °C, and stirred for 2 hours until the reaction was complete. Excess phosphorus oxychloride was removed, the mixture was diluted with acetonitrile, poured into ice, and the pH was adjusted to approximately 8 with solid sodium bicarbonate. The mixture was extracted with ethyl acetate, and the organic phase was dried to obtain the title compound.

[0199] Step 3: Synthesis of 4-chloro-6-(1-methylcyclopropyl)-1,6-naphthidine-2,7(1H,6H)-dione

[0200]

[0201] 300 mg of 2,4-dichloro-6-(1-methylcyclopropyl)-1,6-naphthidium-7(6H)-one was dissolved in 7 mL of 1,4-dioxane, and dilute hydrochloric acid (4 M) was added. The resulting reaction solution was stirred at room temperature for 1 hour. The reaction solution was poured into water, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The solution was then extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove most of the solvent. A large amount of solid precipitated out. The solid was filtered, and the filter cake was dried to give the title compound.

[0202] Step 4: Synthesis of (R)-4-(((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)-1,6-naphthidium-2,7(1H,6H)-dione

[0203]

[0204] 4-Chloro-6-(1-methylcyclopropyl)-1,6-naphthidium-2,7(1H,6H)-dione (150 mg), (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethylamine (124 mg), palladium acetate (26.9 mg), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (74.5 mg), and cesium carbonate (585 mg) were added to a reaction flask, followed by toluene (6 mL). An argon balloon was then added, and the gas was purged three times. The mixture was then placed in an oil bath at 110 °C under gas protection and reacted overnight. The reaction solution was concentrated under reduced pressure, purified by normal-phase column chromatography (dichloromethane / methanol = 10 / 1), and then subjected to reverse-phase chromatography. 18 Column purification (acetonitrile / water (containing 1‰ ammonium bicarbonate): 5%–80%) yielded the title compound.

[0205] Step 5: Synthesis of (R)-2-chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)-1,6-naphthidium-7(6H)-one

[0206]

[0207] (R)-4-(((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)-1,6-naphthidium-2,7(1H,6H)-dione (100 mg) was added to a reaction flask, followed by phosphorus oxychloride (4.8 mL). The mixture was then placed in an oil bath at 80 °C and reacted for 1 hour. The reaction solution was concentrated under reduced pressure to remove phosphorus oxychloride, then diluted with acetonitrile, poured into crushed ice, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The solution was then extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then subjected to reverse-phase C2 chromatography. 18Column purification (acetonitrile / water (containing 1‰ ammonium bicarbonate): 5%–80%), followed by lyophilization to obtain the title compound.

[0208] 1 H NMR(400MHz, DMSO-d6)δ9.25(s,1H),8.14(d,J=5.8Hz,1H),7.65(t,J=7.2Hz,1H),7.57(t,J=7.0Hz,1H),7.40-7 .13(m,2H),6.18(s,1H),5.59(s,1H),5.09-5.06(m,1H),1.63(d,J=6.8Hz,3H),1.54(s,3H),1.23-1.06(m,4H).

[0209] LC / MS (m / z, MH) + ):422.2

[0210] Example 3: Synthesis of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-6-(1-methylcyclopropyl)-1,6-naphthidium-7(6H)-one

[0211]

[0212] (R)-2-chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-(1-methylcyclopropyl)-1,6-naphthidium-7(6H)-one (67.0 mg) was added to a reaction flask, followed by the sequential addition of bis(triphenylphosphine)palladium dichloride (22.3 mg), anhydrous N,N-dimethylformamide, and tetramethyltin (114 mg). The reaction mixture was heated to 130 °C for 1.5 h under argon protection. After cooling, the reaction solution was filtered and purified by preparative HPLC (mobile phase: acetonitrile / water) to obtain the title compound.

[0213] 1 H NMR (400MHz, DMSO-d6) δ9.13(s,1H),7.67(d,J=6.8Hz,1H),7.62(t,J=7.3Hz,1H),7.55(t,J=7.0Hz,1H),7.40-7.12(m ,2H),6.15(s,1H),5.54(s,1H),5.04-4.99(m,1H),2.14(s,3H),1.62(d,J=6.8Hz,3H),1.54(s,3H),1.18-1.05(m,4H).

[0214] LC / MS (m / z, MH) + ):402.2

[0215] Example 4: ((R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-1,8-naphthidium-2(1H)-one

[0216]

[0217] Step 1: Synthesis of 4-chloro-3-(1,3-dioxolane-2-yl)-2-fluoropyridine

[0218]

[0219] 1.00 g of 4-chloro-2-fluoro-pyridine-3-carboxaldehyde and 584 mg of ethylene glycol were added to the reaction mixture, followed by 25 mL of toluene and 59.6 mg of p-toluenesulfonic acid monohydrate. The resulting reaction solution was fitted with a water separator and refluxed in an oil bath at 140 °C for 4 hours. The reaction solution was cooled, concentrated under reduced pressure, and purified by column chromatography (elution with petroleum ether / ethyl acetate gradient) to obtain the title compound.

[0220] Step 2: Synthesis of 4-chloro-3-(1,3-dioxolane-2-yl)-N-methylpyridin-2-amine

[0221]

[0222] 500 mg of 4-chloro-3-(1,3-dioxolane-2-yl)-2-fluoropyridine and methylamine hydrochloride (199 mg) were added to a reaction flask, followed by 5 mL of anhydrous dimethyl sulfoxide and then 635 mg of N,N-diisopropylethylamine. The flask was then capped and placed in an oil bath at 70 °C for 18 hours. After cooling, the reaction solution was poured into water and extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (elution with a petroleum ether / ethyl acetate gradient) to obtain the title compound.

[0223] Step 3: Synthesis of 4-chloro-2-(methylamino)nicotinaldehyde

[0224]

[0225] 305 mg of 4-chloro-3-(1,3-dioxolane-2-yl)-N-methylpyridin-2-amine was added to a reaction flask, followed by 3.2 mL of tetrahydrofuran and then 1.4 mL of dilute hydrochloric acid (2 M). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted in water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound, which was used directly in the next reaction without purification.

[0226] Step 4: Synthesis of methyl 5-chloro-1-methyl-2-oxo-1,2-dihydro-1,8-naphthidine-3-carboxylic acid

[0227]

[0228] 4-Chloro-2-(methylamino)nicotinaldehyde (800 mg) and dimethyl malonate (682 mg) were added to a three-necked reaction flask, which was then fitted with an argon balloon. The gas was purged three times. Anhydrous tetrahydrofuran (13 mL) was added under argon protection, and the mixture was then cooled to 0 °C in an ice bath. Titanium tetrachloride (1 M in DCM, 9.38 mL) and pyridine (742 mg) were added slowly in sequence. The reaction mixture was heated to 40 °C and reacted for 16 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (elution with petroleum ether / ethyl acetate gradient) to obtain the title compound.

[0229] Step 5: Synthesis of 5-chloro-1-methyl-2-oxo-1,2-dihydro-1,8-naphthidine-3-carboxylic acid

[0230]

[0231] Methyl 5-chloro-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyl-3-carboxylic acid (398 mg) was added to a reaction flask and dissolved in methanol (8 mL). Then, an aqueous solution of sodium hydroxide (2 M, 7.88 mL) was added, and the resulting reaction solution was stirred at room temperature for 1 hour. The pH of the system was adjusted to 2-3 with 2 M dilute hydrochloric acid, and a large amount of white solid precipitated out. The solid was filtered, the filter cake was washed with a small amount of water, and the filter cake was collected and dried to obtain the title compound.

[0232] Step 6: Synthesis of 3-bromo-5-chloro-1-methyl-1,8-naphthidium-2(1H)-one

[0233]

[0234] 302 mg of 5-chloro-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyl-3-carboxylic acid was added to a Shrek tube, followed by 4 mL of anhydrous pyridine. The tube was then stoppered, and an argon balloon was used to purge the gas three times. The reaction solution was cooled to 0°C in an ice bath, and 809 mg of bromine was slowly added. The reaction tube was then placed in an oil bath at 70°C for 1 hour. After cooling, the reaction solution was poured into water, and the pH of the system was adjusted to 1-2 with concentrated hydrochloric acid. The solution was then extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (elution with petroleum ether / ethyl acetate gradient) to obtain the title compound.

[0235] Step 7: Synthesis of 3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-chloro-1-methyl-1,8-naphthidin-2(1H)-one

[0236]

[0237] 294 mg of 3-bromo-5-chloro-1-methyl-1,8-naphthidin-2(1H)-one was added to a three-necked flask, followed by 167 mg of N-acetyl-4-piperidinone. An argon balloon was then attached, and the gas was purged three times. Anhydrous tetrahydrofuran (20 mL) was added under gas protection. The reaction mixture was then cooled to -78 °C, and a 0.1 M solution of samarium diiodide in tetrahydrofuran (32.3 mL) was slowly added. After the addition was complete, the reaction mixture was kept at -78 °C for 1 hour. The reaction mixture was then brought to room temperature and stirred for a period of time until the excess samarium diiodide faded. The reaction was quenched with methanol, and the reaction mixture was poured into water. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (elution with petroleum ether / ethyl acetate gradient) to obtain the title compound.

[0238] Step 8: Synthesis of 3-(1-acetyl-4-methoxypiperidin-4-yl)-5-chloro-1-methyl-1,8-naphthidin-2(1H)-one

[0239]

[0240] 55 mg of 3-(1-acetyl-4-hydroxypiperidin-4-yl)-5-chloro-1-methyl-1,8-naphthidin-2(1H)-one was added to a reaction flask, followed by 0.9 mL of anhydrous tetrahydrofuran. The mixture was then cooled to 0 °C in an ice bath, and 26.2 mg of sodium hydride (60% purity) was added. The mixture was stirred in an ice bath for 5 minutes, followed by 116 mg of iodomethane. The reaction was then brought to room temperature and allowed to proceed for 3 hours. The reaction was quenched by adding a small amount of water. The reaction solution was concentrated under reduced pressure and purified by column chromatography (elution with dichloromethane / methanol gradient) to obtain the title compound.

[0241] Step 9: Synthesis of (R)-3-(1-acetyl-4-methoxypiperidin-4-yl)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-1,8-naphthidium-2(1H)-one

[0242]

[0243] 3-(1-acetyl-4-methoxypiperidin-4-yl)-5-chloro-1-methyl-1,8-naphthidin-2(1H)-one (30 mg), (1R)-1-(3-(difluoromethyl)-2-fluoro-phenyl)ethylamine (17.8 mg), Brettphos Pd G3 (7.77 mg), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl (4.60 mg, 0.0086 mmol), and sodium tert-butoxide (24.7 mg) were added to a reaction flask. Anhydrous 1,4-dioxane (0.8 mL) was added, and an argon balloon was attached. The gas was purged three times, and the mixture was placed in an oil bath at 100 °C for 4 hours under gas protection. The reaction solution was cooled and concentrated under reduced pressure, then purified by column chromatography (dichloromethane / methanol gradient elution), followed by preparative HPLC (mobile phase: acetonitrile / water), and finally lyophilized to obtain the title compound.

[0244] DMSO-d6 δ H 8.34(d,J=2.5Hz,1H),8.04(d,J=5.8Hz,1H),7.72(d,J=6.8Hz,1H),7.64-7.55(m,1H),7.53 (t,J=7.0Hz,1H),7.30(t,J=7.7Hz,1H),7.25(t,J=54.4Hz,1H),6.14(d,J=5.5Hz,1H),5.13- 5.00(m,1H),4.34-4.31(m,1H),3.73-3.70(m,1H),3.59(s,3H),3.42-3.30(m,1H),3.13(d,J =4.3Hz,3H),2.90-2.78(m,1H),2.32-2.16(m,2H),2.10-2.00(m,5H),1.63(d,J=6.7Hz,3H).

[0245] LC / MS (m / z, MH) + ):503.2

[0246] Example 5: 3-(1-acetyl-3-methoxypyrrolidone-3-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-1,8-naphthidium-2(1H)-one

[0247]

[0248] Step 1: Synthesis of tert-butyl 3-(5-chloro-1-methyl-2-oxo-1,2-dihydro-1,8-naphthid-3-yl)-3-hydroxypyrrolidine-1-carboxylic acid

[0249]

[0250] 400 mg of 3-bromo-5-chloro-1-methyl-1,8-naphthid-2(1H)-one and 298 mg of 1-tert-butoxycarbonyl-3-pyrrolidone were added to a three-necked flask. An argon balloon was attached, and the gas was purged three times. Anhydrous tetrahydrofuran (20 mL) was added under gas protection. The reaction solution was cooled to -78 °C, and then 43.9 mL of a 0.1 M solution of samarium diiodide in tetrahydrofuran was slowly added. The resulting reaction solution was reacted at -78 °C for 1 hour. The reaction solution was then moved to room temperature and stirred for a period of time until the color of samarium diiodide faded. A small amount of methanol was added to quench the reaction, and then the mixture was poured into water. The mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (elution with petroleum ether / ethyl acetate gradient) to obtain the title compound.

[0251] Step 2: Synthesis of tert-butyl 3-(5-chloro-1-methyl-2-oxo-1,2-dihydro-1,8-naphthid-3-yl)-3-methoxypyrrolidine-1-carboxylic acid

[0252]

[0253] 60 mg of 3-(5-chloro-1-methyl-2-oxo-1,2-dihydro-1,8-naphthid-3-yl)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester was added to a reaction flask, followed by 0.8 mL of anhydrous tetrahydrofuran. The mixture was then cooled to 0 °C in an ice bath, and 25.3 mg of sodium hydride (60% purity) was added. The mixture was stirred in an ice bath for 5 minutes, followed by 112 mg of iodomethane. The reaction was then brought to room temperature and allowed to proceed for 3 hours. The reaction was quenched with a small amount of water, and the mixture was concentrated under reduced pressure and purified by column chromatography (eluting with a dichloromethane / methanol gradient) to obtain the title compound.

[0254] Step 3: Synthesis of tert-butyl 3-(5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,8-naphthid-3-yl)-3-methoxypyrrolidine-1-carboxylic acid

[0255]

[0256] 3-(5-chloro-1-methyl-2-oxo-1,2-dihydro-1,8-naphthid-3-yl)-3-methoxypyrrolidine-1-carboxylic acid tert-butyl ester (43 mg), (1R)-1-(3-(difluoromethyl)-2-fluoro-phenyl)ethylamine (22.7 mg), Brettphos Pd G3 (9.90 mg), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl (5.86 mg), and sodium tert-butoxide (31.5 mg) were added to a reaction flask, along with anhydrous 1,4-dioxane (1 mL). An argon balloon was attached, and the gas was purged three times. The mixture was then placed in an oil bath at 100 °C for 2 hours. The reaction solution was cooled, concentrated under reduced pressure, and purified by column chromatography (elution with petroleum ether / ethyl acetate gradient) to obtain the title compound.

[0257] Step 4: Synthesis of 5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-(3-methoxypyrrolidone-3-yl)-1-methyl-1,8-naphthidium-2(1H)-one

[0258]

[0259] 51 mg of 3-(5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,8-naphthid-3-yl)-3-methoxypyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in dichloromethane (0.8 mL), and 0.2 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title compound, which was used directly in the next reaction without purification.

[0260] Step 5: Synthesis of 3-(1-acetyl-3-methoxypyrrolidone-3-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-1,8-naphthidium-2(1H)-one

[0261]

[0262] The crude product 5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-(3-methoxypyrrolidone-3-yl)-1-methyl-1,8-naphthidium-2(1H)-one (40 mg) was dissolved in dichloromethane (1 mL), and N,N-diisopropylethylamine (34.7 mg) and acetic anhydride (18.3 mg) were added. The mixture was then stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified by preparative HPLC (mobile phase: acetonitrile / water) to obtain the title compound.

[0263] DMSO-d6 δ H8.42-8.40(m,1H),8.07-8.05(m,1H),7.75-7.68(m,1H),7.59-7.52(m,2H),7.39 -7.12(m,2H),6.17-6.14(m,1H),5.10-5.19(m,1H),4.38-4.25(m,1H),3.74-3.6 5(m,1H),3.62-3.61(m,3H),3.57-3.50(m,1H),3.45-3.25(m,1H),3.07-3.02(m, 3H),2.87-2.68(m,1H),2.35-2.22(m,1H),1.99-1.97(m,3H),1.66-1.65(m,3H).

[0264] LC / MS (m / z, MH) + ):489.2

[0265] Example 6: (R)-6-(1-acetylpiperidin-4-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one

[0266]

[0267] Step 1: Synthesis of 3-amino-6-bromo-2-chloroisonicotinic acid

[0268]

[0269] 5-Amino-2-bromoisonicotinic acid (0.80 g) and N-chlorosuccinimide (0.49 g) were added to 8 mL of N,N-dimethylformamide, and the mixture was stirred at 60 °C for 10 hours until the reaction was complete. The reaction solution was added dropwise to 100 mL of water, filtered, the filter cake was washed with water, collected, and dried to obtain the title compound.

[0270] Step 2: Synthesis of 6-bromo-8-chloro-2-methyl-4H-pyrido[3,4-d][1,3]oxazin-4-one

[0271]

[0272] 0.70 g of 3-amino-6-bromo-2-chloroisonicotinic acid was dissolved in 10 mL of acetic anhydride, and the reaction was completed after stirring at 120 °C for 2 hours. The reaction solution was then concentrated and used directly in the next step of the reaction.

[0273] Step 3: Synthesis of 6-bromo-8-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one

[0274]

[0275] 0.80 g of 6-bromo-8-chloro-2-methyl-4H-pyrido[3,4-d][1,3]oxazin-4-one was added to 10 mL of ammonia water and stirred at 100 °C for 2 hours until the reaction was complete. The reaction solution was concentrated to obtain the title compound.

[0276] Step 4: Synthesis of (R)-6-bromo-8-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidine-4-amine

[0277]

[0278] 6-Bromo-8-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one (200 mg), (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethylamine (138 mg) were added to a reaction flask, followed by anhydrous N,N-dimethylformamide (3.00 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (277 mg), and (7-azabenzotriazol-1-oxo)tripyrrolephosphine hexafluorophosphate (684 mg). The resulting reaction solution was stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate gradient elution) to obtain the title compound.

[0279] Step 5: Synthesis of (R)-6-bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-8(7H)-one

[0280]

[0281] (R)-6-bromo-8-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine (200 mg) was added to a reaction flask, followed by dimethyl sulfoxide (3 mL), then potassium hydroxide (296 mg, 4.49 mmol, 85% purity), water (1 mL), and 18-crown-6 (11.9 mg). The resulting reaction solution was placed in an oil bath at 80 °C and reacted overnight. After cooling, the reaction solution was poured into water, and the pH of the system was adjusted to 7-8 with dilute hydrochloric acid (2 M). The mixture was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound, which was used directly in the next reaction without purification.

[0282] Step 6: Synthesis of (R)-6-bromo-4–((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one

[0283]

[0284] Crude (R)-6-bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-8(7H)-one (200 mg) was added to a reaction flask, dissolved in N,N-dimethylformamide (3 mL), followed by the addition of potassium carbonate (97.1 mg) and methyl iodide (73.1 mg). The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (100% ethyl acetate) to obtain the title compound.

[0285] Step 7: Synthesis of (R)-6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one

[0286]

[0287] (R)-6-bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (50 mg), 1-acetyl-5,6-dihydro-2H-pyridine-4-boronic acid pinacol ester (34.2 mg), potassium carbonate (31.3 mg), and 1,1-bis(diphenylphosphine)diferro-palladium dichloride (8.29 mg) were added to a reaction flask. A mixed solvent of 1,4-dioxane (1 mL) and water (0.1 mL) was added, and an argon balloon was then placed on top. The gas was purged three times, and the mixture was placed in a 90°C oil bath under gas protection for 4 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane / methanol gradient elution) to obtain the title compound.

[0288] Step 8: Synthesis of (R)-6-(1-acetylpiperidin-4-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one

[0289]

[0290] (R)-6-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (48.0 mg) was dissolved in methanol (2 mL), and Pd / C (10 mg, 10% Pd) and acetic acid (0.098 mmol) were added. The mixture was then placed in a hydrogen balloon, and the gas was purged three times. The reaction mixture was then stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and purified by preparative HPLC (mobile phase: acetonitrile / water). The filtrate was then lyophilized to obtain the title compound.

[0291] DMSO-d6 δ H 8.19(d,J=7.2Hz,1H),7.62(t,J=7.2Hz,1H),7.50(t,J=6.9Hz,1H),7.30 (t,J=7.7Hz,1H),7.23(t,J=54.4Hz,1H),6.81(s,1H),5.71(m,1H),4.62- 4.59(m,1H),3.98-3.94(m,1H),3.59(s,3H),3.25-3.08(m,2H),2.69-2.6 3(m,1H),2.32(s,3H),2.05(s,3H),2.03-1.89(m,2H),1.68-1.53(m,5H).

[0292] LC / MS (m / z, MH) + ):488.2

[0293] Example 7: 3-(1-acetyl-3-methoxypyrrolidone-3-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-1,6-naphthidium-2(1H)-one

[0294]

[0295] Step 1: Synthesis of methyl 5-chloro-2-methoxy-1,6-naphthyl-3-carboxylic acid

[0296]

[0297] 4-Amino-2-chloronicotinaldehyde (1.00 g) and dimethyl malonate (928 mg) were added to a three-necked flask, which was then fitted with an argon balloon. The gas was purged three times. Anhydrous tetrahydrofuran (18 mL) was added under gas protection, and the mixture was cooled to 0 °C in an ice bath. A 1 M solution of titanium tetrachloride in dichloromethane (12.8 mL) and pyridine (1.01 g) were added sequentially. The resulting reaction solution was heated to 40 °C and reacted overnight. After cooling, water was added to quench the reaction, followed by extraction with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (elution with petroleum ether / ethyl acetate gradient) to obtain the title compound.

[0298] Step 2: Synthesis of 5-chloro-2-oxo-1,2-dihydro-1,6-naphthyl-3-carboxylic acid

[0299]

[0300] Methyl 5-chloro-2-methoxy-1,6-naphthyl-3-carboxylic acid (500 mg) was added to a three-necked flask, and the gas was purged three times with an argon balloon. Anhydrous dichloromethane (10 mL) was added, and the reaction solution was cooled to 0°C in an ice bath. A 2M dichloromethane solution of boron tribromide (2.97 mL) was added. The reaction solution was brought to room temperature and reacted for 3 hours. The reaction was quenched with water, and a large amount of solid precipitated. The solid was filtered, and the filter cake was dried to obtain the title compound.

[0301] Step 3: Synthesis of 3-bromo-5-chloro-1,6-naphthidium-2(1H)-one

[0302]

[0303] 260 mg of 5-chloro-2-oxo-1,2-dihydro-1,6-naphthyl-3-carboxylic acid was added to a Shrek tube, followed by 4 mL of pyridine. An argon balloon was then attached, and the gas was purged three times. The mixture was cooled to 0°C in an ice bath, and 740 mg of bromine was added. The reaction mixture was then heated to 70°C and reacted for 1 hour. After cooling, the reaction mixture was poured into water, and the pH was adjusted to 1-2 with concentrated hydrochloric acid. The mixture was then extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (eluting with a gradient of petroleum ether / ethyl acetate) to obtain the title compound.

[0304] Step 4: Synthesis of 3-bromo-5-chloro-1-methyl-1,6-naphthidium-2(1H)-one

[0305]

[0306] 150 mg of 3-bromo-5-chloro-1,6-naphthidium-2(1H)-one was added to a reaction flask, along with 2.3 mL of N,N-dimethylformamide, 160 mg (1.16 mmol) of potassium carbonate, and 86.2 mg of iodomethane. The resulting reaction mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (elution with a petroleum ether / ethyl acetate gradient) to give the title compound.

[0307] Step 5: Synthesis of tert-butyl 3-(5-chloro-1-methyl-2-oxo-1,2-dihydro-1,6-naphthid-3-yl)-3-hydroxypyrrolidine-1-carboxylic acid

[0308]

[0309] 75 mg of 3-bromo-5-chloro-1-methyl-1,6-naphthidine-2(1H)-one and 55.9 mg of 1-tert-butoxycarbonyl-3-pyrrolidone were added to a three-necked flask, which was then fitted with an argon balloon. The gas was purged three times, and anhydrous tetrahydrofuran (4 mL) was added under gas protection. The reaction solution was cooled to -78 °C, and then 8.23 ​​mL of a 0.1 M solution of samarium diiodide in tetrahydrofuran was slowly added. The resulting reaction solution was reacted at -78 °C for 1 hour. The reaction solution was then moved to room temperature and stirred for a period of time until the color of samarium diiodide faded. A small amount of methanol was added to quench the reaction, and then the mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (dichloromethane / methanol = 92 / 8) to give the title compound.

[0310] Step 6: Synthesis of tert-butyl 3-(5-chloro-1-methyl-2-oxo-1,2-dihydro-1,6-naphthid-3-yl)-3-methoxypyrrolidine-1-carboxylic acid

[0311]

[0312] 70 mg of 3-(5-chloro-1-methyl-2-oxo-1,2-dihydro-1,6-naphthid-3-yl)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester was added to a reaction flask, followed by 0.9 mL of anhydrous tetrahydrofuran. The mixture was then cooled to 0 °C in an ice bath, and 29.5 mg (0.737 mmol, 60%) of sodium hydride was added. The mixture was stirred for 5 minutes in an ice bath, followed by the addition of 131 mg (0.921 mmol) of iodomethane. The reaction was then brought to room temperature and allowed to proceed for 3 hours. The reaction was quenched by the addition of a small amount of water, and the mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 10) to give the title compound.

[0313] Step 7: Synthesis of tert-butyl 3-(5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthid-3-yl)-3-methoxypyrrolidine-1-carboxylic acid

[0314]

[0315] 3-(5-chloro-1-methyl-2-oxo-1,2-dihydro-1,6-naphthid-3-yl)-3-methoxypyrrolidine-1-carboxylic acid tert-butyl ester (40 mg, 0.102 mmol), (1R)-1-(3-(difluoromethyl)-2-fluoro-phenyl)ethylamine (21.1 mg, 0.112 mmol), sodium tert-butoxide (19.5 mg, 0.203 mmol), Brettphos Pd G3 (9.2 mg), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-triisopropyl-1,1'-biphenyl (5.5 mg) were added to a reaction flask, along with anhydrous 1,4-dioxane (2 mL). An argon balloon was then placed on the flask, the gas was purged three times, and the mixture was placed in an oil bath at 100 °C for 2 hours. The reaction solution was cooled, concentrated under reduced pressure, and purified by column chromatography (elution with petroleum ether / ethyl acetate gradient) to obtain the title compound.

[0316] Step 8: Synthesis of 5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-(3-methoxypyrrolidone-3-yl)-1-methyl-1,6-naphthidium-2(1H)-one

[0317]

[0318] 51 mg of tert-butyl 3-(5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,6-naphthid-3-yl)-3-methoxypyrrolidine-1-carboxylic acid was dissolved in dichloromethane (0.8 mL), and 0.2 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title compound, which was used directly in the next reaction without purification.

[0319] Step 9: Synthesis of 3-(1-acetyl-3-methoxypyrrolidone-3-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-1,6-naphthidium-2(1H)-one

[0320]

[0321] The crude product 5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-(3-methoxypyrrolidone-3-yl)-1-methyl-1,6-naphthidium-2(1H)-one (40 mg) was dissolved in dichloromethane (1 mL), and N,N-diisopropylethylamine (34.7 mg) and acetic anhydride (18.3 mg) were added. The mixture was then stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified by preparative HPLC (mobile phase: acetonitrile / water) to obtain the title compound.

[0322] DMSO-d6 δ H 8.37-8.29(m,1H),7.96-7.94(m,1H),7.82-7.76(m,1H),7.62-7.58(m,1H),7.49 -7.45(m,1H),7.37-7.10(m,2H),6.65-6.62(m,1H),5.71-5.65(m,1H),4.36-4.2 3(m,1H),3.75-3.63(m,2H),3.52-3.51(m,3H),3.43-3.38(m,1H),3.06-3.02(m, 3H),2.86-2.83(m,1H),2.33-2.23(m,1H),1.99-1.96(m,3H),1.59-1.57(m,3H).

[0323] LC / MS (m / z, MH) + ):489.2

[0324] Example 8: (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-3-morpholin-1,8-naphthidium-2(1H)-one

[0325]

[0326] Step 1: Synthesis of (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,8-naphthidine-3-carboxylic acid methyl ester

[0327]

[0328] Methyl 5-chloro-1-methyl-2-oxo-1,2-dihydro-1,8-naphthidine-3-carboxylic acid (500 mg), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl-1-amine (400 mg), and N,N-diisopropylethylamine (300 mg) were added to 5 mL of DMSO. The mixture was heated to 130 °C and stirred for 4 hours until the reaction was complete. The reaction solution was then added to 20 mL of water, extracted with ethyl acetate, and the organic layers were combined. The mixture was concentrated and then subjected to column chromatography (petroleum ether / ethyl acetate gradient elution) to obtain the title compound.

[0329] Step 2: Synthesis of (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,8-naphthidine-3-carboxylic acid

[0330]

[0331] Methyl (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,8-naphthidine-3-carboxylic acid (309 mg) was added to a reaction flask and dissolved in methanol (3 mL) and tetrahydrofuran (1.5 mL). Sodium hydroxide aqueous solution (2 M, 3.81 mL) was added, and the resulting reaction solution was stirred at room temperature for 3 hours. The reaction solution was diluted with water, and the pH was adjusted to 4-5 with dilute hydrochloric acid. A large amount of solid precipitated out; this solid was filtered, the filter cake was washed with water, and dried to obtain the title compound.

[0332] Step 3: Synthesis of (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-iodo-1-methyl-1,8-naphthidium-2(1H)-one

[0333]

[0334] (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,8-naphthidine-3-carboxylic acid (103 mg), iodine (267 mg), and anhydrous potassium phosphate (55.9 mg) were added to a reaction flask. Ultra-dry acetonitrile (1.3 mL) was added, and the air in the flask was purged using an argon balloon. The flask was then tightly capped and placed in an oil bath at 100°C for 6 hours. After cooling, the reaction solution was diluted with ethyl acetate, washed in a saturated sodium thiosulfate solution, and separated. The aqueous phase was extracted again with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (elution with a petroleum ether / ethyl acetate gradient) to obtain the title compound.

[0335] Step 4: Synthesis of (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-3-morpholino-1,8-naphthidium-2(1H)-one

[0336]

[0337] (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-iodo-1-methyl-1,8-naphthidium-2(1H)-one (30.0 mg), morpholine (11.1 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (6.04 mg), tris(dibenzylacetone)dipalladium (5.81 mg), and cesium carbonate (41.3 mg) were added to a reaction flask, along with dioxane (0.6 mL). The mixture was then purged three times with an argon balloon, and reacted in a 100°C oil bath for 16 hours under gas protection. After cooling, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure and purified by preparative HPLC (mobile phase: acetonitrile / water) to obtain the title compound.

[0338] Example 9: (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,8-dimethyl-3-morpholinopyrido[2,3-d]pyridazine-2(1H)-one

[0339]

[0340] Step 1: Synthesis of ethyl 2-acetyl-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate

[0341]

[0342] 1.00 g of methyl 2-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid was dissolved in 10 mL of 1,4-dioxane. 348 mg of bis(triphenylphosphine)palladium dichloride and 2.15 g of tributyl(1-ethoxyvinyl)stanane were added. The mixture was heated to 100 °C under argon protection and reacted for 6 hours. The reaction solution was then cooled to room temperature, and the pH was adjusted to 1 with 3 M dilute hydrochloric acid. The mixture was stirred for another 1 hour. 10 mL of saturated potassium fluoride solution and 10 mL of ethyl acetate were added, and the mixture was stirred for 30 minutes. The mixture was filtered, and the filtrate was separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and then subjected to column chromatography (petroleum ether / ethyl acetate gradient elution) to obtain the title compound.

[0343] Step 2: Synthesis of 1,8-dimethylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione

[0344]

[0345] Ethyl 2-acetyl-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (1.07 g) was dissolved in 10 mL of ethanol, and 5 mL of hydrazine hydrate was added. The mixture was then heated to 75 °C and reacted for 8 hours. A large amount of solid precipitated out. The reaction solution was cooled to room temperature, filtered, and the filter cake was dried to obtain the title compound.

[0346] Step 3: Synthesis of 3-bromo-5-hydroxy-1,8-dimethylpyrido[2,3-d]pyridazin-2(1H)-one

[0347]

[0348] 1,8-Dimethylpyrido[2,3-d]pyridazine-2,5(1H,6H)-dione (1.13 g) was dispersed in 10 mL of N,N-dimethylformamide, followed by the addition of dibromohydantoin (3.38 g). After reacting at room temperature for 8 hours, the reaction solution was concentrated and then subjected to column chromatography (petroleum ether / ethyl acetate gradient elution) to obtain the title compound.

[0349] Step 4: Synthesis of 3-bromo-5-chloro-1,8-dimethylpyrido[2,3-d]pyridazin-2(1H)-one

[0350]

[0351] 800 mg of 3-bromo-5-hydroxy-1,8-dimethylpyridano[2,3-d]pyridazine-2(1H)-one was dispersed in 8 mL of acetonitrile, and 2.27 g of phosphorus oxychloride was added dropwise. The temperature was then raised to 80 °C and reacted for 10 hours. The reaction solution was concentrated, diluted with acetonitrile, and poured into crushed ice. The pH was adjusted to 8 with saturated sodium bicarbonate, and the solution was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate gradient elution) to obtain the title compound.

[0352] Step 5: Synthesis of 5-chloro-1,8-dimethyl-3-morpholinopyrido[2,3-d]pyridazin-2(1H)-one

[0353]

[0354] 100 mg of 3-bromo-5-chloro-1,8-dimethylpyridano[2,3-d]pyridazin-2(1H)-one was dissolved in 1 mL of dimethyl sulfoxide, followed by the addition of morpholine (45.3 mg) and cesium fluoride (45.8 mg). The mixture was heated to 100 °C and reacted for 1 hour. The reaction solution was then cooled to room temperature, diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate gradient elution) to obtain the title compound.

[0355] Step 6: Synthesis of (R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,8-dimethyl-3-morpholinopyrido[2,3-d]pyridazine-2(1H)-one

[0356]

[0357] 5-Chloro-1,8-dimethyl-3-morpholinopyridano[2,3-d]pyridazin-2(1H)-one (50.0 mg) was dissolved in 1 mL of dimethyl sulfoxide, followed by the addition of (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl-1-amine (48.1 mg) and cesium fluoride (22.4 mg). The mixture was heated to 110 °C and reacted for 20 hours until the reaction was complete. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated sodium chloride solution, and the organic phase was dried. The organic phase was purified by preparative HPLC (mobile phase: acetonitrile / water) to obtain the title compound.

[0358] 1 H NMR (400MHz, DMSO) δ7.57(t,J=7.4Hz,1H),7.46(t,J=6.8Hz,1H),7.39-7.09(m,4H),5.71–5.62 (m,1H),3.83-3.76(m,4H),3.74(s,3H),3.36-3.30(m,4H),2.75(s,3H),1.59(d,J=7.0Hz,3H).

[0359] LC / MS (m / z, MH) + ):448.2

[0360] Example 10: 3-(1-acetyl-3-methoxypyrrolidone-3-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,8-dimethylpyrido[2,3-d]pyridazine-2(1H)-one

[0361]

[0362] Step 1: Synthesis of tert-butyl 3-(5-chloro-1,8-dimethyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-3-hydroxypyrrolidine-1-carboxylic acid

[0363]

[0364] 200 mg of 3-bromo-5-chloro-1,8-dimethylpyrido[2,3-d]pyridazine-2(1H)-one was dissolved in 5 mL of tetrahydrofuran. Under argon protection, 154 mg of tert-butyl 3-oxopyrrolidine-1-carboxylic acid was added. After cooling to -78 °C, a tetrahydrofuran solution of samarium diiodide (0.1 M, 34.66 mL) was slowly added dropwise. After the addition was complete, the reaction was continued at this temperature for 3 hours. The reaction was quenched with saturated ammonium chloride solution. The mixture was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate gradient elution) to obtain the title compound.

[0365] Step 2: Synthesis of tert-butyl 3-(5-chloro-1,8-dimethyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-3-methoxypyrrolidine-1-carboxylic acid

[0366]

[0367] 100 mg of 3-(5-chloro-1,8-dimethyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in 5 mL of tetrahydrofuran. The mixture was cooled to 0 °C, and 20.2 mg of NaH was added. The mixture was stirred for 30 minutes. Iodimethane (53.9 mg) was added dropwise. After the addition was complete, the mixture was moved to room temperature and the reaction was continued for 1 hour until the reaction was complete. The reaction solution was poured into 10 mL of ice water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate gradient elution) to obtain the title compound.

[0368] Step 3: Synthesis of tert-butyl 3-(5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,8-dimethyl-2-oxo-1,2-dihydropyridine[2,3-d]pyridazine-3-yl)-3-methoxypyrrolidine-1-carboxylic acid

[0369]

[0370] 60.0 mg of 3-(5-chloro-1,8-dimethyl-2-oxo-1,2-dihydropyrido[2,3-d]pyridazin-3-yl)-3-methoxypyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in 1 mL of dimethyl sulfoxide, followed by the addition of (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl-1-amine (55.5 mg) and cesium fluoride (19.4 mg). The reaction was carried out at 110 °C with stirring for 10 hours until completion. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol gradient elution) to obtain the title compound.

[0371] Step 4: Synthesis of 5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-(3-methoxypyrrolidone-3-yl)-1,8-dimethylpyridino[2,3-d]pyridazine-2(1H)-one

[0372]

[0373] 80.0 mg of 3-(5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,8-dimethyl-2-oxo-1,2-dihydropyridine[2,3-d]pyridazin-3-yl)-3-methoxypyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in 1 mL of 1,4-dioxane, and then 1 mL of dioxane hydrochloride solution (4M) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 30 minutes. The reaction solution was then concentrated and directly added to the next step.

[0374] Step 5: Synthesis of 3-(1-acetyl-3-methoxypyrrolidone-3-yl)-5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1,8-dimethylpyridino[2,3-d]pyridazine-2(1H)-one

[0375]

[0376] 60.0 mg of crude 5-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-(3-methoxypyrrolidone-3-yl)-1,8-dimethylpyrido[2,3-d]pyridazin-2(1H)-one was dissolved in 3 mL of dichloromethane. N,N-diisopropylethylamine (84.0 mg) and acetic anhydride (26.6 mg) were added dropwise. The reaction was continued to be stirred at room temperature for 30 minutes until the reaction was completed. The reaction solution was concentrated and purified by preparative HPLC (mobile phase: acetonitrile / water) to obtain the title compound.

[0377] 1H NMR (400MHz, DMSO) δ8.47-8.28(m,1H),7.74-7.43(m,3H),7.40-7.03(m,2H),5.72-5.05(m,1H),4.34-4.11(m,1H),3.76-3.70(m,3H) ,3.70-3.33(m,3H),3.11-3.01(m,3H),2.84-2.73(m,3H),2.70-2.53(m,1H),2.44-2.24(m,1H),2.01-1.82(m,3H),1.64-1.20(m,3H).

[0378] LC / MS (m / z, MH) + ):504.2

[0379] Example 11: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,7-dimethyl-6-morpholinopyrido[3,4-d]pyrimidin-8(7H)-one

[0380]

[0381] Step 1: Synthesis of (R)-4–((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,7-dimethyl-6-morpholinopyrido[3,4-d]pyrimidin-8(7H)-one

[0382]

[0383] (R)-6-bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2,7-dimethylpyrido[3,4-d]pyrimidin-8(7H)-one (20.0 mg), morpholine (11.9 mg), cesium carbonate (59.1 mg), tris(dibenzylacetone)palladium (4.15 mg), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (5.64 mg) were added to a reaction flask, followed by 1,4-dioxane (0.8 mL). The mixture was heated to 100 °C under gas protection and stirred for 10 hours until the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure and purified by preparative HPLC (mobile phase: acetonitrile / water) to obtain the title compound.

[0384] 1H NMR (400MHz, DMSO) δ8.11(d,J=7.2Hz,1H),7.64(t,J=7.3Hz,1H),7.50(t,J=6.9Hz,1H),7.30(t,J=7.7Hz,1H),7.23(t,J=54 .4Hz,1H),6.57(s,1H),5.72(m,1H),3.79(bs,4H),3.50(s,3H),2.98(bs,4H),2.32(d,J=6.0Hz,3H),1.59(d,J=7.1Hz,3H).

[0385] LC / MS (m / z, MH) + ):448.2

[0386] Example 12: 3-(1-acetyl-3-methoxypyrrolidone-3-yl)-1-methyl-5-(((R)-1-(2-methyl-3-nitrophenyl)ethyl)amino)-1,8-naphthidium-2(1H)-one

[0387]

[0388] The preparation method of Example 5 is referenced, except that (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethylamine in step 3 is replaced with (1R)-1-(2-methyl-3-nitrophenyl)ethylamine, and the title compound is prepared by the same method.

[0389] 1 H NMR (400MHz, DMSO) δ8.49-8.37(m,1H),8.09-7.99(m,1H),7.82-7.62(m,3H),7.44-7.35(m,1H),6.05-5.94(m,1H),5.13-4.95(m,1H),4.40-4. 22(m,1H),3.76-3.40(m,6H),3.12-2.99(m,3H),2.93-2.63(m,1H),2.5 0-2.48(m,3H),2.37-2.20(m,1H),2.04-1.89(m,3H),1.65-1.53(m,3H).

[0390] LC / MS (m / z, MH) + ):480.2

[0391] Synthesis of (1R)-1-(2-methyl-3-nitrophenyl)ethylamine:

[0392]

[0393] Step 1: Synthesis of 1-(2-methyl-3-nitrophenyl)ethyl ketone

[0394]

[0395] 5.00 g of 2-bromo-6-nitrotoluene was added to 30 ml of toluene, followed by 5.86 g of triethylamine, 10.0 g of tributyl(1-ethoxyethylene)tin, and 649 mg of bis(triphenylphosphine)palladium dichloride. The mixture was purged three times with argon and reacted at 100 °C for 16 hours until the reaction was complete. The reaction solution was cooled to room temperature, filtered, and the filtrate was distilled under reduced pressure to obtain the crude product. The crude product was then dissolved in THF, and 23.14 ml of 1 M hydrochloric acid was added at 0 °C. The reaction solution was brought back to room temperature and stirred for 15 minutes. The pH was adjusted to weakly alkaline with saturated sodium bicarbonate solution, and then 1.61 g of potassium fluoride was added. The mixture was stirred for two hours, filtered through diatomaceous earth, and the filtrate was extracted three times with ethyl acetate. The organic phases were combined, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate gradient elution) to obtain the title compound.

[0396] Step 2: (S)-2-methyl-N-(1-(2-methyl-3-nitrophenyl)ethylene)propane-2-sulfinamide

[0397]

[0398] 1-(2-methyl-3-nitrophenyl)ethyl ketone (3.35 g) was added to 90 mL of tetrahydrofuran, and (R)-(+)-tert-butylsulfinamide (3.40 g) and tetraethyl titanate (10.6 g) were added at room temperature. The mixture was purged with argon three times and reacted at 70 °C for 3 hours. After the reaction was completed, 50 mL of ice water was added, followed by dilution with ethyl acetate. The mixture was filtered through diatomaceous earth, and the filtrate was separated to obtain an organic layer. The organic layer was dried with anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate gradient elution) to obtain the title compound.

[0399] Step 3: Synthesis of 2-methyl-N-[(1R)-1-(2-methyl-3-nitrophenyl)ethyl]propane-2-sulfonamide

[0400]

[0401] (S)-2-methyl-N-(1-(2-methyl-3-nitrophenyl)ethylene)propane-2-sulfinamide (4.00 g) was added to 30 mL of tetrahydrofuran. Sodium borohydride (520 mg) was added in portions under ice bath conditions. The reaction was carried out at room temperature for 12 hours. The reaction was quenched with saturated ammonium chloride aqueous solution, diluted with ethyl acetate, extracted with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate gradient elution) to obtain the title compound.

[0402] Step 4: Synthesis of (1R)-1-(2-methyl-3-nitrophenyl)ethylamine

[0403]

[0404] 1.77 g of 2-methyl-N-[(1R)-1-(2-methyl-3-nitrophenyl)ethyl]propane-2-sulfonamide was added to 20 mL of dioxane, and 4.67 mL of 4M dioxane hydrochloride was added under ice bath conditions. The reaction was allowed to proceed for 10 minutes at room temperature until completion. The reaction solution was concentrated, and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. The solution was extracted with ethyl acetate, and the organic layers were combined and concentrated to obtain the title compound.

[0405] Example 13: 3-((1R)-1-((6-(1-acetyl-3-methoxypyrrolidone-3-yl)-8-methyl-7-oxo-7,8-dihydro-1,8-naphthidin-4-yl)amino)ethyl)-2-methylbenzonitrile

[0406]

[0407] The preparation method of Example 5 was followed, except that (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethylamine in step 3 was replaced with (R)-3-(1-aminoethyl)-2-toluenenitrile, and the title compound was prepared by the same method.

[0408] 1 H NMR (400MHz, DMSO) δ8.47-8.38(m,1H),8.06-7.98(m,1H),7.81-7.59(m,3H),7.42-7.29(m,1H),6.03-5.93(m,1H),5.06-4.93(m,1H),4.43- 4.19(m,1H),3.77-3.38(m,6H),3.13-2.99(m,3H),2.92-2.67(m,1H), 2.65(s,3H),2.37-2.21(m,1H),2.02-1.93(m,3H),1.64-1.52(m,3H).

[0409] LC / MS (m / z, MH) + ):460.2

[0410] Example 14: 3-(1-acetyl-3-methoxypyrrolidone-3-yl)-5-((R)-1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)amino)-1-methyl-1,8-naphthidium-2(1H)-one

[0411]

[0412] The preparation method of Example 5 is referenced, except that (1R)-1-(3-(difluoromethyl)-2-fluoro-phenyl)ethylamine in step 3 is replaced with (R)-1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethane-1-amine, and the title compound is prepared by the same method.

[0413] Example 15: 3-(1-acetyl-3-methoxypyrrolidone-3-yl)-5-((R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)amino)-1-methyl-1,8-naphthidium-2(1H)-one

[0414]

[0415] The preparation method of Example 5 is referenced, except that (1R)-1(-(3-(difluoromethyl)-2-fluoro-phenyl)ethylamine in step 3 is replaced with (R)-1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethane-1-amine, and the title compound is prepared by the same method.

[0416] Example 16 3-(1-acetyl-3-methoxypyrrolidone-3-yl)-1-methyl-5-(((R)-1-(3-(pentafluoro-λ6-thioalkyl)phenyl)ethyl)amino)-1,8-naphthidin-2(1H)-one

[0417]

[0418] The preparation method of Example 5 is referenced, except that (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethylamine in step 3 is replaced with (R)-1-(3-(pentafluoro-λ6-thioalkyl)phenyl)ethyl-1-amine, and the title compound is prepared by the same method.

[0419] 1 H NMR (400MHz, DMSO) δ8.42-8.37(m,1H),8.08-8.03(m,1H),8.02-7.97(m, 1H),7.80-7.69(m,3H),7.63-7.55(m,1H),6.33-6.23(m,1H),5.12-4.95 (m,1H),4.41-4.20(m,1H),3.77-3.23(m,6H),3.09-3.00(m,3H),2.89-2 .63(m,1H),2.38-2.20(m,1H),2.03-1.93(m,3H),1.63(d,J=6.7Hz,3H).

[0420] LC / MS (m / z, MH) +):547.2

[0421] Example 17 3-(1-acetyl-3-methoxypyrrolidone-3-yl)-5-(((R)-1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl))amino)-1-methyl-1,8-naphthidium-2(1H)-one

[0422]

[0423] The preparation method of Example 5 is referenced, except that (1R)-1-[3-(difluoromethyl)-2-fluoro-phenyl]ethylamine in step 3 is replaced with (R)-1-(3-(1-aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropane-2-ol, and the title compound is prepared by the same method.

[0424] 1 H NMR (400MHz, DMSO) δ8.45-8.38(m,1H),8.09-8.03(m,1H),7.79-7.68(m,1H),7.56- 7.48(m,1H),7.39-7.32(m,1H),7.28-7.21(m,1H),6.16-6.11(m,1H),5.37(br,1H), 5.12-5.00(m,1H),4.40-4.23(m,1H),3.76-3.39(m,6H),3.09-2.99(m,3H),2.90-2. 65(m,1H),2.37-2.18(m,1H),2.06-1.88(m,3H),1.65(d,J=6.3Hz,3H),1.23(s,6H).

[0425] LC / MS (m / z, MH) + ):547.2

[0426] Example 18: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-morpholino-1,6-naphthidium-7(6H)-one

[0427]

[0428] Step 1: Synthesis of methyl 4-((tert-butoxycarbonyl)amino)-1-morpholino-6-oxo-1,6-dihydropyridine-3-carboxylic acid

[0429] The preparation method of intermediates E-5a in reference WO2019122129 is used to prepare methyl 1-morpholino-6-oxo-4-(toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylic acid, except that 1-(difluoromethyl)cyclopropyl-1-amine is replaced with N-aminomorpholino.

[0430]

[0431] Methyl 1-morpholino-6-oxo-4-(toluenesulfonyloxy)-1,6-dihydropyridine-3-carboxylic acid (3.00 g), tert-butyl carbamate (1.72 g), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (425 mg), palladium chloride (π-cinnamyl) dimer (190 mg), and potassium phosphate (3.12 g) were added to a reaction flask, followed by anhydrous 1,4-dioxane (20 mL). The mixture was heated to 100 °C under argon protection and stirred for 10 hours until the reaction was complete. The reaction solution was cooled and concentrated under reduced pressure, and purified by column chromatography (elution with petroleum ether / ethyl acetate gradient) to obtain the title compound.

[0432] Step 2: Synthesis of methyl 5-bromo-4-((tert-butoxycarbonyl)amino)-1-morpholino-6-oxo-1,6-dihydropyridine-3-carboxylic acid

[0433]

[0434] Methyl 4-((tert-butoxycarbonyl)amino)-1-morpholino-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2.11 g) was added to N,N-dimethylformamide (30 mL), and N-bromosuccinimide (1.17 g) was added with stirring at room temperature. The reaction was completed after stirring at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound, which was used directly in the next reaction.

[0435] Step 3: Synthesis of tert-butyl (3-bromo-5-(methoxy(methyl)carbamoyl)-1-morpholino-2-oxo-1,2-dihydropyridin-4-yl)carbamate

[0436]

[0437] Methyl 5-bromo-4-((tert-butoxycarbonyl)amino)-1-morpholino-6-oxo-1,6-dihydropyridine-3-carboxylic acid (3.58 g) was added to a reaction flask, dissolved in dimethyl sulfoxide (30 mL) and acetonitrile (15 mL), followed by the addition of sodium hydroxide aqueous solution (4.97 g, 20% w / w). The mixture was stirred at room temperature for 4 hours. Then, N,N-diisopropylethylamine (2.14 g), dimethylhydroxylamine hydrochloride (1.05 g), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (4.69 g) were added, and the mixture was stirred at room temperature for another hour until the reaction was complete. The reaction solution was poured into water and extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove most of the solvent, resulting in the precipitation of a large amount of white solid. The solid was filtered, and the filter cake was dried to obtain the title compound.

[0438] Step 4: Synthesis of tert-butyl (5-acetyl-3-bromo-1-morpholino-2-oxo-1,2-dihydropyridin-4-yl)carbamate

[0439]

[0440] 2.20 g of tert-butyl (3-bromo-5-(methoxy(methyl)carbamoyl)-1-morpholino-2-oxo-1,2-dihydropyridin-4-yl)carbamate was added to anhydrous tetrahydrofuran (85 mL). Under argon protection, a 3M magnesium bromide solution in diethyl ether (6.36 mL) was slowly added, and the mixture was stirred for 0.5 hours. The mixture was then cooled to room temperature and stirred for 5 hours until the reaction was complete. The reaction was quenched by adding saturated ammonium chloride solution, then poured into water and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (elution with petroleum ether / ethyl acetate gradient) to obtain the title compound.

[0441] Step 5: Synthesis of 8-bromo-6-morpholino-1,6-naphthidine-4,7(1H,6H)-dione

[0442]

[0443] 250 mg of (5-acetyl-3-bromo-1-morpholino-2-oxo-1,2-dihydropyridin-4-yl)carbamate tert-butyl ester was added to a reaction flask, followed by 3 mL of N,N-dimethylformamide dimethyl acetal. The mixture was then heated to 110 °C and stirred for 1 hour. The reaction solution was concentrated and dissolved in tetrahydrofuran (4 mL). Dilute hydrochloric acid (1.49 mL, 4 M) was added, and the resulting reaction solution was reacted at 50 °C for 2 hours. The reaction solution was cooled, concentrated ammonia was added, and the pH of the system was adjusted to 8-9. The solution was then concentrated under reduced pressure, ethyl acetate was added, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure and purified by column chromatography (ethyl acetate / methanol gradient elution) to obtain the title compound.

[0444] Step 6: Synthesis of 8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-morpholino-1,6-naphthidine-4,7(1H,6H)-dione

[0445]

[0446] 32.0 mg of 8-bromo-6-morpholino-1,6-naphthidine-4,7(1H,6H)-dione, 32.8 mg of 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester, 7.12 mg of 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (7.12 mg), and 40.7 mg of potassium carbonate were added to a mixed solvent of 0.8 mL of 1,4-dioxane and 0.2 mL of water. The mixture was heated to 100 °C and stirred for 2 hours under argon protection until the reaction was complete. The reaction solution was cooled and concentrated under reduced pressure, and purified by column chromatography (dichloromethane / methanol gradient elution) to obtain the title compound.

[0447] Step 7: Synthesis of 4-chloro-8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-morpholino-1,6-naphthidium-7(6H)-one

[0448]

[0449] 20.0 mg of 8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-morpholino-1,6-naphthidine-4,7(1H,6H)-dione was added to a reaction flask and dissolved in anhydrous acetonitrile (0.5 mL). Phosphorus oxychloride (17.9 mg) and N,N-diisopropylethylamine (15.9 mg) were then added. The mixture was heated to 70 °C and stirred for 1 hour until the reaction was complete. The reaction solution was cooled and poured onto ice. The pH was adjusted to 7-8 with saturated sodium bicarbonate solution, followed by extraction with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound, which was used directly in the next reaction.

[0450] Step 8: Synthesis of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-morpholino-1,6-naphthidium-7(6H)-one

[0451]

[0452] 4-Chloro-8-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-6-morpholino-1,6-naphthidium-7(6H)-one (10.0 mg) and (1R)-1-(3-(difluoromethyl)-2-fluoro-phenyl)ethylamine (10.5 mg) were added to a reaction flask and dissolved in dimethyl sulfoxide (1 mL). Then, N,N-diisopropylethylamine (14.3 mg) was added. The mixture was heated to 100 °C under gas protection and stirred for 10 hours until the reaction was complete. The reaction solution was cooled, poured into water, and extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (dichloromethane / methanol gradient elution) to obtain the title compound.

[0453] 1 H NMR (400MHz, DMSO) δ9.27(s,1H),8.09-7.98(m,2H),7.65-7.59(m,1H),7.58-7.52(m,1H),7.34-7.29(m,1H),7.25( t,J=54.3Hz,1H),5.69-5.63(m,1H),5.52-5.45(m,1H),5.08-5.01(m,1H),3.97-3.55(m,8H),1.62(d,J=6.7Hz,3H).

[0454] LC / MS (m / z, MH) + ):514.2

[0455] Example 19(R)-5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-3-(4-methoxy-1-(oxetane-3-yl)piperidin-4-yl)-1-methyl-1,8-naphthidium-2(1H)-one

[0456]

[0457] The title compound was prepared by referring to the synthesis method of Example 4, except that N-acetyl-4-piperidinone in step 7 was replaced with 1-(oxecyclobutane-3-yl)piperidin-4-one.

[0458] 1H NMR (400MHz, DMSO-d6) δ8.33(s,1H),8.03(d,J=5.8Hz,1H),7.70(d,J=7.0Hz,1H),7.59(t,J=7.3 Hz,1H),7.53(t,J=6.9Hz,1H),7.30(t,J=7.7Hz,1H),7.25(t,J=54.4Hz,1H),6.13(d,J=5.9Hz,1 H),5.14-5.00(m,1H),4.56(t,J=6.4Hz,2H),4.46(t,J=6.0Hz,2H),3.60(s,3H),3.48-3.38(m,1 H),3.07(s,3H),2.58-2.52(m,2H),2.48-2.32(m,2H),2.20-1.95(m,4H),1.63(d,J=6.8Hz,3H).

[0459] LC / MS (m / z, MH) + ):517.2.

[0460] Example 20(R)-1-(5-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-1-methyl-2-oxo-1,2-dihydro-1,8-naphthidium-3-yl)-N,4-dimethylpiperidin-4-carboxamide

[0461]

[0462] The title compound was prepared by referring to the synthesis method of Example 8, except that morpholine in step 4 was replaced with N,4-dimethylpiperidine-4-carboxamide.

[0463] 1 H NMR(400MHz, DMSO-d6)δ7.90(d,J=5.7Hz,1H),7.68-7.61(m,1H),7.59-7.46(m,3H),7.41-7.10(m,3H),6.08(d,J=5.9Hz,1H),5.12-4.95(m,1H),3 .63(s,3H),3.46-3.33(m,2H),2.92-2.75(m,2H),2.63(d,J=4.4Hz,3H), 2.24-2.12(m,2H),1.63(d,J=6.8Hz,3H),1.60-1.47(m,2H),1.15(s,3H).

[0464] LC / MS (m / z, MH) + ):502.2.

[0465] Biological activity and related property tests

[0466] Experimental Example 1: Determination of the inhibitory activity of this invention on the proliferation of H358 cells

[0467] The effects of the compounds of this invention on the proliferation of H358 cells were evaluated using a CellTiter-Glo luminescence assay kit.

[0468] Experimental methods:

[0469] H358 cells (ATCC, CRL-5807) were cultured in RPMI 1640 (Hyclone, SH30256.01) complete medium containing 10% FBS (Gibco, 10100147) and 100 U / mL penicillin-streptomycin mixture (Gibco, 15140163). When the cells reached 80-90% confluence, they were digested, dispersed, and seeded into 96-well plates (Corning, 4515) at 3000 cells per well (180 μl RPMI 1640 complete medium). The 96-well plates were then incubated overnight at 37°C with 5% CO2.

[0470] After overnight incubation, add 20 μL of the diluted compound to each well using a multi-channel pipette. Incubate the 96-well plate at 37°C with 5% CO2. After 7 days, aspirate and discard 100 μL of the supernatant, and add 50 μL to each well. The 3D CellViability Assay liquid was shaken at 450 rpm for 30 minutes at room temperature until the cells were completely lysed. The microplate reader was then used to read the plate using the "Luminescence" setting. In this experiment, the group without cells (replaced with 1640 medium) served as the 100% inhibition group, while the group with cells but without the compound served as the 0% inhibition group.

[0471] The percentage of inhibition of H358 cell proliferation by the compound can be calculated using the following formula:

[0472] Inhibition percentage = 100 * (0% inhibition group signal value - signal value of the analyte at a specific concentration) / (0% inhibition group signal value - 100% inhibition group signal value).

[0473] Compound IC 50 The values ​​were calculated from eight concentration points using XLfit (ID Business Solutions Ltd., UK) software via the following formula:

[0474] Y=Bottom+(Top-Bottom) / (1+10^((logIC 50 -X)×slope factor))

[0475] Where Y is the inhibition percentage, X is the logarithm of the concentration of the analyte, Bottom is the minimum inhibition percentage, Top is the maximum inhibition percentage, and slope factor is the curve slope coefficient.

[0476] Experimental Results: Under the experimental conditions, the embodiments of the present invention exhibited good inhibitory activity against the proliferation of H358 cells. The specific activity test results of the test compounds are shown in Table 1.

[0477] Table 1. Results of the inhibitory activity against H358 cell proliferation in the embodiments of the present invention.

[0478] Example <![CDATA[IC 50 (nM)]]> 1 17.3 2 111.3 3 31.2 4 80.2 5 52.5 7 195.3 9 162.2 17 67.0 18 65.7

[0479] Experimental Example 2: Effects of the Compounds of the Present Invention on the p-ERK Pathway in H358 Cells

[0480] The effects of the compounds of this invention on the p-ERK pathway in H358 cells were evaluated using the Advanced phospho-ERK (Thr202 / Tyr204) cellular kit method.

[0481] The experimental methods are summarized as follows:

[0482] H358 cells (ATCC, CRL-5807) were cultured in RPMI 1640 (ThermoFisher, A1049101) complete medium containing a mixture of 10% FBS (Gibco, 10100147) and 100 U / mL penicillin-streptomycin (Gibco, 15140163). When the cell coverage in the culture vessel reached 80-90%, the cells were dispersed and seeded into 96-well plates (Corning, 3599) at 50,000 cells per well (90 μL RPMI 1640 complete medium). After standing for 5 minutes, the plates were incubated at 37°C with 5% CO2 for 6 hours, and then the medium was replaced with serum-free RPMI 1640 for overnight starvation.

[0483] After overnight incubation, add 10 μL of the diluted compound to each well using a multi-channel pipette. Incubate the 96-well plate at 37°C and 5% CO2 for 1 hour. Discard the supernatant, wash once with PBS, and add 50 μL of lysis buffer (Advanced Phospho-ERK (Thr202 / Tyr204) cellular kit, 64AERPEH) to each well. Incubate at room temperature with shaking at 450 rpm for 1 hour until cells are completely lysed. Add 16 μL of supernatant to well 384 (PE, 6007299), add the mixed antibody (d2 / Eu = 1:1), and incubate at room temperature for 4 hours. Use an HTRF reader with a ratio of Signal 665nm / Signal 620nm x 10. 4In this experiment, the group without cells (replaced with 1640 medium) was the 100% inhibition group, and the group with cells but without the compound was the 0% inhibition group.

[0484] The percentage of inhibition of the p-ERK pathway in H358 cells by the compounds of this invention can be calculated using the following formula:

[0485] Inhibition percentage = 100 * (0% inhibition group signal value - signal value of the analyte at a specific concentration) / (0% inhibition group signal value - 100% inhibition group signal value).

[0486] Compound IC 50 The values ​​were calculated from eight concentration points using XLfit (ID Business Solutions Ltd., UK) software via the following formula:

[0487] Y=Bottom+(Top-Bottom) / (1+10^((logIC 50 -X)×slope factor))

[0488] Where Y represents the inhibition percentage, X is the logarithm of the analyte concentration, Bottom is the minimum inhibition percentage, Top is the maximum inhibition percentage, and the slope factor is the curve slope coefficient. The default fitted curve is used to fit the slope of the S-shaped curve to determine the IC50. 50 value.

[0489] Table 2. Results of p-ERK inhibition tests on the compounds of this invention.

[0490] Example <![CDATA[IC 50 (nM)]]> 1 41.9 2 81.3 3 80.2 5 141.8 8 206.3 10 181.7 14 45.0 16 137.0 17 42.9

[0491] Experimental Example 3: Determination of the inhibitory activity of SOS1 binding to KRAS G12D in this embodiment of the invention

[0492] The effect of the compounds of the present invention on the inhibition of KRASG12D::SOS1 binding was evaluated using KRAS-G12D / SOS1BINDING ASSAY KITS (Cisbio, catalog number: 63ADK000CB21PEH).

[0493] Experimental methods:

[0494] The positive control BAY-293 and the test compound (10 mM stock solution) were diluted 5-fold to 0.1 mM using 100% DMSO and serially diluted 11 times at a 1:3 ratio in a 384-well plate. 0.1 μL of each serially diluted compound solution was transferred to a 384-well plate using an Echo converter, with two replicates for each compound. The plates were centrifuged at 1000 rpm for 1 min. 5 μL of 4X KRAS G12D (final concentration 1X) and GTP solution (final concentration 10 μM, Sigma, catalog number: V900868) were transferred to the 384-well plate. The plates were centrifuged at 1000 rpm for 1 min and incubated at 25°C for 15 min. 5 μL of 4X SOS1 solution (final concentration 1X) was transferred to the 384-well plate. The plates were centrifuged at 1000 rpm for 1 min and incubated at 25°C for 45 min. The final concentrations of BAY-293 compounds were 10, 3.33, 1.11, 0.37, 0.12, 0.04, 0.014, 0.0046, 0.0015, 0.0005, 0.00017, and 0 μM. The final concentrations of the analyte compounds were also 10, 3.33, 1.11, 0.37, 0.12, 0.04, 0.014, 0.0046, 0.0015, 0.0005, 0.00017, and 0 μM. The final concentration of DMSO was 0.5% for all compounds. 10 μL of the 2X assay solution was transferred to a 384 reaction plate, centrifuged at 1000 rpm for 1 min, and incubated at 4°C for 180 min. The excitation wavelength (665 nm) and emission wavelength (615 nm) were read using an Envision multi-mode microplate reader. The 665 / 615 ratio signal intensity was used to characterize the enzyme activity.

[0495] Data processing method: The compound IC was fitted using a nonlinear regression equation derived from Graphpad Prism 8. 50 :

[0496] Negative control: DMSO

[0497] Positive control: 10 μM BAY-293

[0498] The IC of the compound is obtained using the following nonlinear fitting formula. 50 (Half-maximal inhibitory concentration):

[0499] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0500] X: Log value of compound concentration

[0501] Y:665 / 615 Ratio

[0502] Experimental Results: Under the experimental conditions, the tested compounds exhibited good inhibitory activity against KRASG12D::SOS1 binding. The specific activity test results for the tested compounds are shown in Table 3.

[0503] Table 3. Results of the inhibitory activity test on KRAS G12D::SOS1 binding in the embodiments of this patent.

[0504] Example <![CDATA[IC 50 (nM)]]> 1 4.97 5 5.16 18 8.93

Claims

1. A compound of formula (IV) or a pharmaceutically acceptable salt thereof, (IV) in, R 1 selected from H, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, -O-C1-6alkyl or C 3-6 cycloalkyl; R 2 Selected from 3-10 member heterocyclic groups, wherein the 3-10 member heterocyclic group is optionally R 2b or R 2c replace; R 2b Selected from -OR 2c -N(R) 2c 2. Halogen, hydroxyl, cyano, amino, -C(O)R 2c or -C(O)NHR 2c ; R 2c Independently selected from methyl; R 3 R 4 Independently selected from H, deuterium, and C 1-3 Deuterated alkyl, C1-6 alkyl or C 1-6 Halogenated alkyl groups; R 5 Independently selected from SF5, nitro, cyano, halogen, C1-6 alkyl, -S(O)2-C 1-4 Alkyl, -P(O)(R 5b )2 or The C1-6 alkyl or -S(O)2-C 1-4 Alkyl groups are optionally R 5a replace; R 5a Independently selected from halogen, hydroxyl, cyano or amino groups; R 5b Independently selected from H or C1-6 alkyl groups; n is selected from 0, 1, 2, 3 or 4; R 6 Selected from H or halogen; R 7 Selected from H or C1-3 alkyl groups; Ring A is selected from , or .

2. The compound of formula (IV) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: R 1 Selected from H, halogens, C 1-6 Alkyl or C 1-6 Deuterated alkyl groups.

3. The compound of formula (IV) according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that: R 1 Selected from H, halogens, C 1-3 Alkyl or C 1-3 Deuterated alkyl groups.

4. The compound of formula (IV) according to claim 3, characterized in that: R 1 Selected from H, halogens, CH3 or CD3.

5. The compound of formula (IV) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: R 3 R 4 Independently selected from H, deuterium, and C 1-3 Deuterated alkyl or C1-6 alkyl.

6. The compound of formula (IV) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: R 3 Selected from H or deuterium, R 4 Selected from CH3 or CD3.

7. The compound of formula (IV) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: R 6 Selected from H.

8. The compound of formula (IV) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: n is selected from 0, 1, or 2.

9. The following compounds or their pharmaceutically acceptable salts, or .

10. A pharmaceutical composition comprising a compound of any one of claims 1-8 (IV) or a pharmaceutically acceptable salt thereof, or a compound of claim 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. Use of the compound of any one of formula (IV) of claims 1-8 or a pharmaceutically acceptable salt thereof, or the compound of claim 9 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 10 in the preparation of a medicament for the prevention or treatment of SOS1-related diseases.

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