Substituted pyrimidopyridinone inhibitors and methods of making and using the same

Abstract

This invention relates to substituted pyrimidine and pyridinone inhibitors, their preparation methods, and applications. Specifically, the compounds of this invention have the structure shown in formula (I). This invention also discloses the preparation method of the compounds and their use as SOS1 inhibitors. The compounds of this invention exhibit excellent selective inhibition of SOS1 and possess better pharmacodynamic and pharmacokinetic properties, as well as lower toxicity.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals, specifically relating to a substituted pyrimidine and pyridinone inhibitor, its preparation method, and its application. Background Technology

[0002] Lung cancer is one of the leading causes of cancer death in humans. Based on cell type, lung cancer can be divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).

[0003] Currently, the main treatments for NSCLC include chemotherapy drugs, molecularly targeted drugs, and tumor immunotherapy. Chemotherapy drugs primarily include gemcitabine, paclitaxel, and platinum-based drugs; however, these drugs generally suffer from poor selectivity and high toxicity, leading to severe side effects. In recent years, molecularly targeted drugs have gradually become a research hotspot due to their higher selectivity, relatively fewer side effects, and ability to achieve precise treatment. Existing molecularly targeted drugs for NSCLC include EGFR inhibitors (such as afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, pyrotinib, rociletinib, osimertinib, etc.), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, oxacarinib, etc.), and VEGFR inhibitors (Sorafenib, regorafenib, cabozantinib, sunitinib, donafenib, etc.) (Current Medicinal Chemistry, 2019, 26, 1-39).

[0004] KRAS mutations occur in 20-40% of lung adenocarcinomas. The most common mutations occur at codons 12 and 13, with the most frequent mutations including G12C, G12V, and G12D. To date, no drugs targeting KRAS mutations have been approved for marketing.

[0005] Intracellularly, the KRAS protein transitions between inactive and activated states. When KRAS binds to guanosine diphosphate (GDP), it is inactive; when it binds to guanosine triphosphate (GTP), it is activated and can activate downstream signaling pathways. This switching between inactive and activated states is regulated by two classes of factors. One class consists of guanine nucleotide exchange factors (GEFs), which catalyze the binding of KRAS to GTP, thereby promoting KRAS activation; SOS1 is one such protein. The other class consists of GTPase activators (GAPs), which promote the hydrolysis of GTP bound to KRAS into GDP, thereby inhibiting KRAS activity.

[0006] To date, three major classes of RAS-specific GEFs have been identified, with SOS protein being the primary participant in tumors. SOS protein is widely expressed in vivo, containing two subtypes, SOS1 and SOS2. Published data indicate that SOS1 plays a crucial role in mutant KRAS activation and oncogenic signaling. Decreased SOS1 levels lead to reduced proliferation and survival of tumor cells carrying KRAS mutations, while KRAS wild-type cell lines are unaffected. The effects of SOS1 loss cannot be salvaged by introducing an SOS1 variant with a catalytic mutation, highlighting the important role of SOS1 GEF activity in KRAS-mutant cancer cells (see WO2019122129A1).

[0007] Since both mutant and wild-type KRAS bind to GTP in a manner dependent on SOS1, selectively inhibiting SOS1 can prevent the interaction between SOS1 and KRAS, thereby ultimately inhibiting KRAS activation, regardless of whether KRAS is mutated or not.

[0008] Because the target protein of SOS1 is pathologically associated with a variety of diseases, there is a current need for novel SOS1 inhibitors for clinical treatment. Highly selective and highly active SOS1 inhibitors could more effectively treat diseases such as cancer caused by KRAS mutations, and have the potential to reduce off-target effects, thus creating a more urgent clinical need. Summary of the Invention

[0009] The purpose of this invention is to provide a novel class of compounds that selectively inhibit SOS1 and / or have better pharmacodynamic properties, and their uses.

[0010] In a first aspect, the present invention provides a compound of formula (I), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs:

[0011]

[0012] In the formula:

[0013] Z is selected from the following group, either substituted or unsubstituted: C1-C 18 Alkylene, deuterated C1-C 18 Alkylene and halogenated C1-C 18 Alkylene; wherein the substitution refers to the substitution by one or more (e.g., 2, 3, or 4) R a replace;

[0014] W is selected from the following group, either substituted or unsubstituted: C3-C 20 Cycloalkylene, 4-20 membered heterocyclic alkylene; wherein, the substitution refers to being replaced by one or more (e.g., 2, 3 or 4) R a replace;

[0015] R 1 Selected from the group consisting of: hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, and substituted or unsubstituted 4-6 membered heterocyclic groups; wherein, the substitution refers to being substituted by one or more (e.g., 2, 3, or 4) R a replace;

[0016] R 2 Whether the two are the same or different, each is independently selected from the following group: -(CH2) m O(CH2) p R 7 -(CH2) m SR 7 -(CH2) m COR 7 -(CH2) m C(O)OR 7 -(CH2) m S(O) q R 7 -(CH2) m NR 7 R 8 -(CH2) m C(O)NR 7 R 8 -(CH2) m NR 7 C(O)R 8 -(CH2) m NR 7 C(O)NR 8 R 9 -(CH2) m S(O) q NR 7 R 8 -(CH2) m NR 7 S(O)q R 8 -(CH2) m NR 7 S(O) q NR 8 R 9 In CH2, the H can be optionally substituted; R 7 R 8 and R 9 Each is independently selected from the following group: hydrogen, substituted or unsubstituted C1-C 18 Alkyl, substituted or unsubstituted C3-C 20 Cycloalkyl, substituted or unsubstituted 4-20 membered heterocyclic groups and substituted or unsubstituted C1-C 18 Alkyl group; or in -(CH2) m NR 7 R 8 -(CH2) m C(O)NR 7 R 8 -(CH2) m S(O) q NR 7 R 8 In the middle, R 7 and R 8 The N atom attached to it cyclizes to form a substituted or unsubstituted 4-20 membered heterocyclic group; or in -(CH2) m NR 7 C(O)R 8 -(CH2) m NR 7 C(O)NR 8 R 9 -(CH2) m NR 7 S(O) q R 8 -(CH2) m NR 7 S(O) q NR 8 R 9 In the middle, R 8 and R 9 The N atom attached to it cyclizes to form a substituted or unsubstituted 4-20 membered heterocyclic group, or R 7 and R 8 The adjacent atoms cyclize to form substituted or unsubstituted 4-20 membered heterocyclic groups; wherein, the substitution refers to the presence of one or more (e.g., 2, 3, or 4) R groups. a replace;

[0017] R 3 Selected from the following group of substituent or unsubstituted groups: C3-C 18Cycloalkyl, 4-20 membered heterocyclic groups, C6-C 14 Aryl, 5-14 membered heteroaryl; wherein, the substitution refers to being replaced by one or more R a replace;

[0018] R 4 and R 5 Each group is independently selected from the following group: C1-C6 alkyl, C3-C6 cycloalkyl, and 4-6 membered heterocyclic groups; wherein, the substitution refers to being substituted by one or more (e.g., 2, 3, or 4) R groups. a replace;

[0019] R 6 Selected from the group consisting of: hydrogen, deuterium, halogen, amino, cyano, substituted or unsubstituted C1-C6 alkyl and substituted or unsubstituted C3-C6 cycloalkyl; wherein, the substitution refers to being substituted by one or more (e.g., 2, 3 or 4) R a replace;

[0020] Among them, R a Selected from the following group: deuterium, substituted or unsubstituted C1-C 18 Alkyl, deuterated C1-C 18 Alkyl, halogenated C1-C 18 Alkyl, halogenated C1-C 18 Alkyl hydroxyl, substituted or unsubstituted C3-C 20 Cycloalkyl, substituted or unsubstituted C1-C 18 Alkoxy, deuterated C1-C 18 Alkoxy, halogenated C1-C 18 Alkoxy, substituted or unsubstituted C6-C 14 Aryl, substituted or unsubstituted 5-14 membered heteroaryl, substituted or unsubstituted 4-20 membered heterocyclic groups, halogen, nitro, hydroxyl, oxo, cyano, ester, amino, amide, sulfonamide, and urea; wherein, R a The substitution mentioned herein refers to substitution by one or more (such as 2, 3 or 4) groups selected from the group consisting of: deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, halogen, nitro, hydroxyl, oxo, cyano, ester, amino, amide, sulfonamide and urea;

[0021] m can be 1, 2, 3, 4 or 5 independently;

[0022] n can be 1, 2, 3, 4 or 5 independently;

[0023] p can be 0, 1, 2, 3, 4 or 5 independently;

[0024] q is either 1 or 2.

[0025] In another preferred embodiment, the compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs have the structure shown in general formula (II):

[0026]

[0027] In the formula, R 1 R 2 R 3 R 4 R 5 The definitions of Z, W, and n are as described above.

[0028] In another preferred embodiment, the compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs have the structure shown in general formula (III):

[0029]

[0030] In the formula, R 1 R 2 R 3 R 4 The definitions of Z, W, and n are as described above.

[0031] In another preferred embodiment, the compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs have the structure shown in general formula (IV):

[0032]

[0033] In the formula, R 1 R 2 R 3 R 4 The definitions of Z, W, and n are as described above.

[0034] In another preferred embodiment, the compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs have the structure shown in formula (V):

[0035]

[0036] In the formula,

[0037] R 10 and R 11 Each group is independently selected from the following group, either substituted or unsubstituted: H, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, and halo-C1-C6 alkyl; or R 10 and R 11Together with the C linked to it, they cyclize to form substituted or unsubstituted C3-C6 cycloalkyl groups or substituted or unsubstituted 4-6 membered heterocyclic groups;

[0038] The substitution refers to substitution by one or more (e.g., 2, 3, or 4) groups selected from the group consisting of: deuterium, C1-C 18 Alkyl, deuterated C1-C 18 Alkyl, halogenated C1-C 18 Alkyl, halogenated C1-C 18 Alkyl hydroxyl, C3-C 20 cycloalkyl, C1-C 18 Alkoxy, deuterated C1-C 18 Alkoxy, halogenated C1-C 18 Alkoxy, C6-C 14 Aryl, 5-14 membered heteroaryl, 4-20 membered heterocyclic, halogen, oxo, nitro, hydroxy, cyano, ester, amino, amide, sulfonamide or urea;

[0039] t can be 1, 2, 3, 4, 5, or 6;

[0040] R 1 R 2 R 3 The definitions of W and n are as described above.

[0041] In another preferred embodiment, in Formula IV, W is selected from: substituted or unsubstituted C3-C6 cycloalkyl sub-alkyl or substituted or unsubstituted 3-6 membered heterocyclic sub-alkyl groups; wherein, the substitution refers to being replaced by one or more (e.g., 2, 3, or 4) groups selected from the group consisting of: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halo-C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic, halogen, nitro, hydroxyl, oxo, cyano, ester, amino, amide, sulfonamide, and urea.

[0042] In another preferred embodiment, in formula IV, W is selected from:

[0043] Among them, R m Selected from: H, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halo-C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic, halogen, nitro, hydroxyl, oxo, cyano, ester, amino, amide, sulfonamide, and urea;

[0044] R b Selected from: H, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, acyl or sulfonyl group;

[0045] n1 can be 0, 1, 2, 3 or 4.

[0046] In another preferred embodiment, the compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs have the structure shown in formula (VI).

[0047]

[0048] In the formula,

[0049] R 10 R 11 R 12 and R 13 Each group is independently selected from the following group, either substituted or unsubstituted: H, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, and halo-C1-C6 alkyl; or R 10 and R 11 Cyclically bonded to the C to form a substituted or unsubstituted C3-C6 cycloalkyl group or a substituted or unsubstituted 4-6 membered heterocyclic group; or R 12 and R 13 Together with the C linked to it, they cyclize to form substituted or unsubstituted C3-C6 cycloalkyl groups or substituted or unsubstituted 4-6 membered heterocyclic groups;

[0050] R 14 Selected from: OR 15 SR 15 COR 15 C(O)OR 15 S(O)R 15 S(O)2R 15 NR 15 R 16 C(O)NR 15 R 16 NR 15 C(O)R 16 NR 15 C(O)NR 16 R 17 S(O)NR 15 R 16 S(O)2NR 15 R 16 NR 15 S(O)R 16 NR 15 S(O)2R16 NR 15 S(O)NR 16 R 17 NR 15 S(O)2NR 16 R 17 Among them, R 15 R 16 and R 17 Each is independently selected from the group consisting of: hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocyclic groups, and substituted or unsubstituted C1-C6 alkoxy groups; or in NR 15 R 16 C(O)NR 15 R 16 S(O)NR 15 R 16 S(O)2NR 15 R 16 In the middle, R 15 and R 16 The N atom attached to it cyclizes to form a substituted or unsubstituted 4-6 membered heterocyclic group; or in NR 15 C(O)R 16 NR 15 C(O)NR 16 R 17 NR 15 S(O)R 16 NR 15 S(O)2R 16 NR 15 S(O)NR 16 R 17 NR 15 S(O)2NR 16 R 17 In the middle, R 16 and R 17 The N atom attached to it cyclizes to form a substituted or unsubstituted 4-6 membered heterocyclic group, or R 15 and R 16 It can cyclize with adjacent atoms to form substituted or unsubstituted 4-6 membered heterocyclic groups;

[0051] U is selected from: CR 18 R 19 NR b O;

[0052] R 18 R 19 and R mEach is independently selected from: H, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halo-C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic, halogen, nitro, hydroxyl, oxo, cyano, ester, amino, amide, sulfonamide, and urea; or R 18 R 19 It can cyclize with adjacent C to form C3-C6 cycloalkyl or 4-6 membered heterocyclic groups;

[0053] R b Selected from: H, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic group, acyl or sulfonyl group;

[0054] R 10 R 11 R 12 R 13 R 15 R 16 and R 17 The substitution referred to herein means being replaced by one or more groups selected from the group consisting of: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halo-C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic, halogen, nitro, hydroxyl, oxo, cyano, ester, amino, amide, sulfonamide, and urea;

[0055] n1 is 0, 1, 2, 3 or 4;

[0056] n2 and n3 are each independently 0, 1, 2, 3 or 4; and n2 and n3 are not both 0 at the same time;

[0057] n4 is 1, 2, 3, 4 or 5;

[0058] R 1 and R 3 The definition is as described above.

[0059] In another preferred embodiment, the compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs have the structure shown in formula (VII):

[0060]

[0061] In the formula, R 1 R3 R 10 R 11 R 12 R 13 R 14 R m The definitions of U, n1, n2, n3, and n4 are as described above.

[0062] In another preferred embodiment, in formulas I-VII, the compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, wherein R 3 Selected from the group consisting of substituted or unsubstituted groups: phenyl or 5-6-membered heteroaryl, wherein the substitution refers to being replaced by one or more (e.g., 2, 3, or 4) groups selected from the group consisting of: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halo-C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic, halogen, nitro, hydroxyl, oxo, cyano, ester, amino, amide, sulfonamide, and urea.

[0063] In another preferred embodiment, in equations I-VII, R 3 Selected from the group consisting of substituted or unsubstituted groups: phenyl, pyridyl, pyrimidinyl, pyridazinyl, wherein the substitution refers to being substituted by one or more (e.g., 2, 3, or 4) groups selected from the group consisting of: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halo-C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic, halogen, nitro, hydroxyl, oxo, cyano, ester, amino, amide, sulfonamide, and urea.

[0064] In another preferred embodiment, in equations I-VII, R 3 Selected from:

[0065]

[0066] In another preferred embodiment, R 1 Selected from the following group: hydrogen, deuterium, halogen, cyano, C1-C6 alkyl.

[0067] In another preferred embodiment, R 1 R 2 R 3 R 4 R 5 R 6Z, W, n, R 10 R 11 R 12 R 13 R 14 R m U, t, n1, n2, n3 and n4 are the functional groups corresponding to the specific compounds in the examples.

[0068] In another preferred embodiment, the compound, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, wherein the compound is selected from the group consisting of:

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076] A second aspect of the present invention provides a method for preparing a compound of formula (II), its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, comprising the steps of:

[0077]

[0078] (i) In an inert solvent (such as toluene), compound X-1 is reacted with ethylene glycol to give compound X-2;

[0079] (ii) In an inert solvent (such as dimethyl sulfoxide) and in the presence of a base (such as potassium carbonate, DIPEA, TEA or DMAP), the compound of formula X-2 reacts with the compound of formula X-3 to give the compound of formula X-4.

[0080] (iii) In the presence of a base (such as DIPEA, TEA or DMAP), the compound of formula X-4 reacts with the compound of formula X-5 to give the compound of formula X-6.

[0081] (iv) In an inert solvent (such as a mixture of dimethyl sulfoxide and acetonitrile), in the presence of a base (such as NaOH or LiOH), the compound of formula X-6 undergoes a hydrolysis reaction to give the compound of formula X-7.

[0082] (v) In an inert solvent (such as N,N-dimethylformamide), in the presence of a condensing agent (such as HATU) and a base (such as DIPEA, TEA, or DMAP), the compound of formula X-7 undergoes a condensation reaction with an amine (formula X-8) to give the compound of formula X-9.

[0083] (vi) In an inert solvent (such as isopropanol), the compound of formula X-9 undergoes deprotection and cyclization reaction under acidic conditions (such as hydrochloric acid) to give the compound of general formula (II).

[0084] In the formula,

[0085] R 1 R 2 R 3 R 4 R 5 The definitions of Z, W, and n are as described above.

[0086] In a third aspect, the present invention provides a pharmaceutical composition comprising i) one or more compounds described in the first aspect, stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof; and ii) a pharmaceutically acceptable carrier.

[0087] In another preferred embodiment, the pharmaceutical composition further includes one or more therapeutic agents selected from the group consisting of: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009, or biosimilars of the above-mentioned drugs), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F...). 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomabtiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Ocalatinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omip BTK inhibitors (such as alisib, Buparlisib, etc.), EGFR inhibitors (such as Afatinib, Gefitinib, Erlotinib, Lapatinib, Dacomitinib, Icotinib, Canertinib, Sapitinib, Naquotinib, Pyrotinib, Rociletinib, Osimertinib, etc.), VEGFR inhibitors (such as Sorafenib, Pazopanib, Regorafenib, Sitravatinib, Ningetinib, Cabozantinib, Sunitinib, Donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, Vorinostat, Fimepinostat, Droxinostat, Entinostat, Dacinostat, Quisinostat, Tacedinaline, etc.), CDK inhibitors (such as Palbociclib). Ingredients include Ribociclib, Abemaciclib, Milciclib, Trilaciclib, Lerociclib, etc., MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.), mTOR inhibitors (such as Vistusertib), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) or combinations thereof.

[0088] In another preferred embodiment, a method for preparing a pharmaceutical composition is provided, comprising the steps of: mixing a pharmaceutically acceptable carrier with a compound described in the first aspect of the present invention, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, thereby forming a pharmaceutical composition.

[0089] In another preferred embodiment, the compounds of the present invention can be prepared into powders, tablets, granules, capsules, solutions, emulsions, suspensions, etc.

[0090] In a fourth aspect, the present invention provides the use of the compound described in the first aspect, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates or prodrugs, or the pharmaceutical composition described in the third aspect, for the preparation of a medicament or pharmaceutical composition for the prevention and / or treatment of diseases related to SOS1 activity or expression levels.

[0091] In another preferred embodiment, the disease is cancer.

[0092] In another preferred embodiment, the cancer is selected from: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colon cancer, melanoma, lymphoma, leukemia, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, and skin cancer.

[0093] In a fifth aspect, the present invention provides a method for non-diagnostic, non-therapeutic inhibition of SOS1, comprising the steps of administering to a desired patient an effective amount of the compound described in the first aspect above, its stereoisomers, tautomers, crystal forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs, or administering the pharmaceutical composition described in the third aspect.

[0094] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0095] Through long-term and in-depth research, the inventors unexpectedly discovered a new class of compounds that selectively inhibit SOS1 and / or have better pharmacodynamic properties. Based on this, the inventors completed this invention.

[0096] the term

[0097] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0098] The term "alkyl" refers to a straight-chain, branched, or cyclic alkane group containing 1-20 carbon atoms, such as 1-18 carbon atoms, with a particular emphasis on 1-18 carbon atoms. Typical "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, etc. Amyl, isopentyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, etc.

[0099] The term "C1-C18 alkyl" refers to straight-chain, branched, or cyclic alkyl groups, including those with 1-18 carbon atoms, such as methyl, ethyl, propyl, and isopropyl. n-Butyl, tert-Butyl, isobutyl (e.g.) ), n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl. "Substituted alkyl" refers to an alkyl group in which one or more positions are substituted, particularly 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogens (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl groups containing Cl3), nitrile, nitro, oxygen (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e ,P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC (=O)NR b R c NR b C(=O)OR e ,NR d C(=O)NR b R c NR d S(=O)2NRb R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e R appears here a R can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, or aromatic rings. b R c and R d It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic, or aromatic ring, or R. b and R c Together with N atoms, it can form heterocycles; R e It can independently represent hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, or aromatic rings. The above-mentioned typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, or aromatic rings, can be optionally substituted.

[0100] The term "alkylene" refers to a group formed by removing one hydrogen atom from an alkyl group, such as methylene, ethylene, propylene, and isopropylene (e.g., methylene, ethylene, propylene, isopropylene). ), butylide (such as) ), pentylene (e.g.) ), hexyl (such as) ), subheptagen (such as )wait.

[0101] The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon compound group comprising 1-4 rings, each containing 3-8 carbon atoms. "Substituted cycloalkyl" refers to a cycloalkyl group in which one or more positions are substituted, particularly 1-4 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogens (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl groups containing Cl3), nitrile, nitro, oxygen (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e ,P(=O)2OR e NR b R c NR b S(=O)2R e NRb P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC (=O)NR b R c NR b C(=O)OR e ,NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e R appears here a R can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, or aromatic rings. b R c and R d It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic, or aromatic ring, or R. b and R c Together with N atoms, it can form heterocycles; R e The group can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aromatic rings. The aforementioned typical substituents can be optionally substituted. Typical substitutions also include spirocyclic, bridged-cyclic, or fused-ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spirocyclic heterocyclic (excluding heteroaromatic rings), bridged-cyclic alkyl, bridged-cyclic alkenyl, bridged-cyclic heterocyclic (excluding heteroaromatic rings), fused-cyclic alkyl, fused-cyclic alkenyl, fused-cyclic heterocyclic, or fused-cyclic aromatic rings, wherein the aforementioned cycloalkyl, cycloalkenyl, heterocyclic, and heterocyclic aryl groups can be optionally substituted. Any two or more atoms on the ring can be further cyclically linked with other cycloalkyl, heterocyclic, aryl, and heteroaromatic groups.

[0102] The term "cycloalkylene" refers to a group formed by removing two hydrogen atoms from a cycloalkyl group, such as: wait.

[0103] The term "alkylene cycloalkylene" refers to the group formed by removing two hydrogen atoms from the aforementioned cycloalkyl or alkylcycloalkyl groups. "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkyl C1-C18 alkylene" has the same meaning. Preferably, it refers to C1-C6 alkylene C3-C12 cycloalkylene, including but not limited to: wait.

[0104] The term "heterocyclic group" refers to a fully saturated or partially unsaturated cyclic group (including, but not limited to, 3-7 membered monocyclic rings, 6-11 membered bicyclic rings, or 8-16 membered tricyclic systems) in which at least one heteroatom is present in a ring containing at least one carbon atom. Each heterocycle containing a heteroatom may have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, or sulfur atoms, wherein the nitrogen or sulfur atom may be oxidized or quaternized. The heterocyclic group may be attached to any heteroatom or carbon residue in a ring or cyclic molecule. Typical monocyclic heterocycles include, but are not limited to, nitrogen-containing heterocyclic butyl, pyrrolyl, oxoheterocyclic butyl, pyrazolinyl, imidazolinyl, imidazolinyl, oxazolinyl, isoxazolinyl, thiazolinyl, isothiazolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylyl, hexahydroacoxaneyl, 4-piperidinoneyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxaneyl, and tetrahydro-1,1-dioxothiophene, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring; the heterocyclic group can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylic acid ester groups, wherein any two or more atoms on the ring can be further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

[0105] The term "subheterocyclic group" refers to the group formed by removing two hydrogen atoms from the above-mentioned heterocyclic group, including but not limited to:

[0106] wait.

[0107] The term "heterocyclic alkylene" refers to a group formed by removing two hydrogen atoms from a cycloalkyl or alkylcycloalkyl group. "4-20 membered heterocyclic alkylene C1-C18 alkylene" or "C1-C18 alkylene 4-20 membered heterocyclic alkylene" has the same meaning, preferably 4-12 membered heterocyclic alkyl C1-6 alkylene, including but not limited to: wait.

[0108] The term "aryl" refers to an aromatic cyclic hydrocarbon compound group having 1-5 rings, particularly monocyclic and bicyclic groups such as phenyl, biphenyl, or naphthyl. Any aryl group containing two or more aromatic rings (bicyclic, etc.) can have its aromatic rings linked by single bonds (e.g., biphenyl) or fused (e.g., naphthalene, anthracene, etc.). "Substituted aryl" refers to an aryl group where one or more positions are substituted, particularly 1-3 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: hydrogen, deuterium, halogens (e.g., monohalogenated or polyhalogenated substituents, the latter such as trifluoromethyl or alkyl groups containing Cl3), nitrile, nitro, oxygen (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic ring, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e ,P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC (=O)NR b R c NR b C(=O)OR e ,NR d C(=O)NR b R c NR d S(=O)2NRb R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e R appears here a R can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, or aromatic rings. b R c and R d It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic, or aromatic ring, or R. b and R c Together with N atoms, it can form heterocycles; R e It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aromatic rings. The above-mentioned typical substituents can be optionally substituted. Typical substitutions also include fused-ring substituents, especially fused-ring alkyl, fused-ring alkenyl, fused-ring heterocyclic, or fused-ring aromatic rings, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic, and heterocyclic aryl groups can be optionally substituted.

[0109] The term "heteroaryl" refers to a heteroaryl system comprising 1-4 heteroatoms and 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur. Heteroaryl groups are preferably 5- to 10-membered rings, more preferably 5- or 6-membered, such as pyrroloyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, and tetrazolyl. "Heteroaryl" can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, deuteralkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylic acid ester groups.

[0110] The term "C1-C18 alkoxy" refers to a straight-chain, branched, or cyclic alkoxy group having 1 to 18 carbon atoms, and includes, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups. C1-C8 alkoxy groups are preferred, and C1-C6 alkoxy groups are more preferred.

[0111] The term "C1-C18 alkeneoxy" refers to the group obtained by removing one hydrogen atom from a "C1-C18 alkoxy".

[0112] The term "halogen" or "halogen" refers to chlorine, bromine, fluorine, and iodine.

[0113] The term "halogenation" refers to the replacement of a substance with a halogen.

[0114] The term "deuteration" refers to being replaced by deuterium.

[0115] The term "hydroxyl group" refers to a group containing the structure OH.

[0116] The term "nitro" refers to a group containing the structure NO2.

[0117] The term "cyano" refers to a group containing the structure CN.

[0118] The term "ester group" refers to a group with the structure -COOR, where R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic.

[0119] The term "amine" refers to a group with the structure -NRR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R and R' can be the same or different in dialkylamine segments.

[0120] The term "amide group" refers to a group with the structure -CONRR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R and R' can be the same or different in dialkylamine segments.

[0121] The term "sulfonamide group" refers to a group with the structure -SO2NRR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R and R' can be the same or different in dialkylamine segments.

[0122] The term "ureido" refers to a group with the structure -NRCONR'R", where R, R', and R" can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R, R', and R" can be the same or different in dialkylamine segments.

[0123] The term "alkylaminoalkyl" refers to a group with the structure -RNHR', where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R and R' can be the same or different.

[0124] The term "dialkylaminoalkyl" refers to a group with the structure -RNHR'R", where R, R', and R" can independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic, as defined above. R, R', and R" can be the same or different in the dialkylamine segment.

[0125] The term "heterocyclic alkyl" refers to a group with the structure -RR', where R can independently represent an alkyl or substituted alkyl, a cycloalkyl or substituted cycloalkyl, a cycloalkenyl or substituted cycloalkenyl, an aryl or substituted aryl; and R' represents a heterocycle or a substituted heterocycle.

[0126] In this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are stable or chemically feasible combinations. Such substituents include, but are not limited to, halogens, hydroxyl groups, cyano groups, carboxyl groups (-COOH), C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, and C1-C6 ureyl groups, etc.

[0127] Unless otherwise stated, it is assumed that any heteroatom in a suboptimal valence state has enough hydrogen atoms to compensate for its valence state.

[0128] When the substituent is a non-terminal substituent, it is a subunit of the corresponding group. For example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclic corresponds to heterocyclic, alkoxy corresponds to alkoxy, etc.

[0129] Active ingredients

[0130] As used herein, “compound of the present invention” refers to a compound of formula I, and also includes stereoisomers or optical isomers of a compound of formula I, pharmaceutically acceptable salts, prodrugs or solvates.

[0131] The compound of formula (I) of the present invention has the following structure:

[0132]

[0133] In the formula, R 1R 2 R 3 R 4 R 5 R 6 The definitions of Z, W, and n are as described above.

[0134] Preferably, the compound has the structure shown in formula (II):

[0135]

[0136] In the formula, R 1 R 2 R 3 R 4 R 5 The definitions of Z, W, and n are as described above.

[0137] Preferably, the compound has the structure shown in general formula (III):

[0138]

[0139] In the formula, R 1 R 2 R 3 R 4 The definitions of Z, W, and n are as described above.

[0140] Preferably, the compound has the structure shown in general formula (IV):

[0141]

[0142] In the formula, R 1 R 2 R 3 R 4 The definitions of Z, W, and n are as described above.

[0143] Preferably, the compound has the structure shown in formula (V):

[0144]

[0145] In the formula, R 1 R 2 R 3 R 10 R 11 The definitions of W and n are as described above.

[0146] Preferably, the compound has the structure shown in formula (VI).

[0147]

[0148] In the formula, R 1R 3 R 10 R 11 R 12 R 13 R 14 R m The definitions of U, n1, n2, n3, and n4 are as described above.

[0149] Preferably, the compound has the structure shown in formula (VII):

[0150]

[0151] In the formula, R 1 R 3 R 10 R 11 R 12 R 13 R 14 R m The definitions of U, n1, n2, n3, and n4 are as described above.

[0152] Preferably, in the above formulas, R 3 Selected from the following group, substituted or unsubstituted: phenyl or 5-6 membered heteroaryl; more preferably, R 3 Selected from the group consisting of substituted or unsubstituted groups: phenyl, pyridyl, pyrimidinyl, pyridazinyl, wherein the substitution refers to being substituted by one or more (e.g., 2, 3, or 4) groups selected from the group consisting of: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halo-C1-C6 alkoxy, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic, halogen, nitro, hydroxyl, oxo, cyano, ester, amino, amide, sulfonamide, and urea; more preferably, R 3 Selected from:

[0153]

[0154] R 1 Selected from the following group: hydrogen, deuterium, halogen, cyano, C1-C6 alkyl.

[0155] Salts that may form from the compounds of this invention are also within the scope of this invention. Unless otherwise stated, compounds of this invention are understood to include their salts. The term "salt" as used herein refers to a salt formed from an inorganic or organic acid and a base in an acidic or basic form. Furthermore, when a compound of this invention contains a basic segment, it includes, but is not limited to, pyridine or imidazole; when it contains an acidic segment, it includes, but is not limited to, carboxylic acids; and any zwitterions ("internal salts") that may form are included within the scope of the term "salt." Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, although other salts are also useful, for example, for separation or purification steps in the preparation process. Compounds of this invention may form salts, for example, by reacting compound I with a certain amount, such as an equimolar amount, of an acid or base, precipitating it in a medium, or by freeze-drying it in an aqueous solution.

[0156] The compounds of this invention contain basic fragments, including but not limited to amines, pyridines, or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (such as acetic acid or trihaloacetic acids, such as trifluoroacetic acid), adipates, alginates, ascorbic acid salts, aspartate salts, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphor salts, camphor sulfonates, cyclopentanepropionate, diethylene glycol salts, dodecyl sulfates, ethanesulfonates, fumarates, glucono-2-phosphates, glycerol phosphates, hemisulfates, heptarates, hexanoates, hydrochlorides, hydrobromide, and hydroiodide. Salts, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectates, persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphates, picrates, neopentanoates, propionates, salicylates, succinates, sulfates (e.g., those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoates, etc.

[0157] Some compounds of this invention may contain acidic fragments, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (such as organic amines), such as benzylamine, dicyclohexylamine, hepatopanylamine (a salt formed with N,N-di(dehydroabietic)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can react with quaternary ammonium halides, such as small alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl halides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long-chain halides (e.g., chlorides, bromides, and iodides of decyl, dodecyl, tetradecyl, and tetradecyl halides), aralkyl halides (e.g., benzyl and phenyl bromides), etc.

[0158] The prodrugs and solvates of the compounds in this invention are also included within the scope of this invention. The term "prodrug" here refers to a compound that, in the course of treatment of a related disease, undergoes a chemical transformation through metabolism or a chemical process to produce the compounds, salts, or solvates of this invention. The compounds of this invention include solvates, such as hydrates.

[0159] The compounds, salts, or solvates of this invention may exist in tautomer forms (e.g., amides and imine ethers). All such tautomers are part of this invention.

[0160] All stereoisomers of compounds (e.g., those with asymmetric carbon atoms due to various substitutions), including their enantiomers and diastereomeric forms, are within the scope of this invention. The independent stereoisomers of the compounds in this invention may not coexist with other isomers (e.g., possessing special activity as a pure or substantially pure optical isomer), or may be mixtures, such as racemates, or mixtures formed with all other stereoisomers or a portion thereof. The chiral center of this invention has two configurations, S or R, as defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974. Racemic forms can be resolved by physical methods, such as stepwise crystallization, or by derivatization into diastereomers followed by crystallization, or by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to conventional methods, such as recrystallization after salting with an optically active acid.

[0161] The compounds of this invention, obtained sequentially through preparation, separation, and purification, have a weight content equal to or greater than 90%, for example, equal to or greater than 95%, or equal to or greater than 99% (“very pure” compounds), as listed in the text description. Such “very pure” compounds of this invention are also included as part of this invention.

[0162] All configurational isomers of the compounds of this invention are included within the scope of this invention, whether in mixtures, pure or very pure forms. The definition of compounds in this invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic compounds.

[0163] Throughout the specification, groups and substituents can be selected to provide stable fragments and compounds.

[0164] Specific functional groups and chemical terminology definitions are detailed below. For the purposes of this invention, chemical elements are defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75. th The definitions in Ed. are consistent. The definitions of specific functional groups are also described there. In addition, the basic principles of organic chemistry, as well as specific functional groups and reactivity, are explained in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the full contents of which are included in the references.

[0165] Some compounds of this invention may exist in specific geometric or stereoisomeric forms. This invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Additionally, the asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers and mixtures thereof are included in this invention.

[0166] According to the present invention, the ratio of isomers in a mixture of isomers can be varied. For example, a mixture containing only two isomers can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios readily understood by those skilled in the art, as well as ratios for mixtures of more complex isomers, are also within the scope of the present invention.

[0167] This invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms with different atomic weights or mass numbers. Examples of isotopes that can be included in the compounds of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively as follows: 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. The compounds of this invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, wherein the isotopes or other isotopic atoms of the aforementioned compounds are all within the scope of this invention. Certain isotopically labeled compounds of this invention, for example... 3 H and 14 Radioactive isotopes of carbon are also included, and are useful in tissue distribution experiments of drugs and substrates. Tritium, i.e. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. They are the preferred isotopes. In addition, heavier isotopes such as deuterium are used for substitution. 2 H, due to its excellent metabolic stability, offers advantages in certain therapies, such as increasing half-life or reducing dosage in vivo, and therefore may be preferred in some cases. Isotopically labeled compounds can be prepared using general methods, by replacing the non-isotopic reagent with an readily available isotopically labeled reagent, according to the scheme described in the examples.

[0168] To design the synthesis of a specific enantiomer of the compound of this invention, it can be prepared asymmetrically or derivatized with a chiral auxiliary. The resulting diastereomeric mixture is then separated, and the chiral auxiliary is removed to obtain the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomer salt, which is then separated by conventional methods such as separation crystallization or chromatography to obtain the pure enantiomer.

[0169] As described herein, the compounds of this invention can be expanded with any number of substituents or functional groups. Generally, whether the term "substitution" appears before or after the term "optional," the general formula for substituents in the formulations of this invention refers to replacing a hydrogen radical with a substituent of a specified structure. When multiple positions in a particular structure are replaced by multiple specific substituents, each position of the substituent can be the same or different. The term "substitution" as used herein includes all permissible substitutions in organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched-unbranched, carbocyclic, and heterocyclic, aromatic and non-aromatic organic compounds. In this invention, heteroatomic nitrogen may be supplemented with hydrogen substituents or any permissible organic compound described above to complete its valence state. Furthermore, this invention is not intended to limit permissible substituted organic compounds in any way. This invention considers the combination of substituents and variable groups to be beneficial in the treatment of diseases, such as infectious or proliferative diseases, in the form of stable compounds. The term "stable" here refers to a compound that is stable enough to maintain the integrity of its structure when tested over a sufficiently long period of time, preferably remaining effective over a sufficiently long period of time, and is used here for the purposes described above.

[0170] The compounds involved in this application and their pharmaceutically acceptable salt metabolites, as well as prodrugs that can be converted in vivo into structures of the compounds involved in this application and their pharmaceutically acceptable salts, are also included in the claims of this application.

[0171] Preparation method

[0172] The preparation methods of the compounds of formula (I) of the present invention are described in more detail below, but these specific methods do not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0173] Typically, the preparation process of the compounds of the present invention is as follows, wherein the raw materials and reagents used can be purchased commercially unless otherwise specified.

[0174]

[0175] (i) In an inert solvent (such as toluene), compound X-1 is reacted with ethylene glycol to give compound X-2;

[0176] (ii) In an inert solvent (such as dimethyl sulfoxide) and in the presence of a base (such as potassium carbonate, DIPEA, TEA or DMAP), the compound of formula X-2 reacts with the compound of formula X-3 to give the compound of formula X-4.

[0177] (iii) In the presence of a base (such as DIPEA, TEA or DMAP), the compound of formula X-4 reacts with the compound of formula X-5 to give the compound of formula X-6.

[0178] (iv) In an inert solvent (such as a mixture of dimethyl sulfoxide and acetonitrile), in the presence of a base (such as NaOH or LiOH), the compound of formula X-6 undergoes a hydrolysis reaction to give the compound of formula X-7.

[0179] (v) In an inert solvent (such as N,N-dimethylformamide), in the presence of a condensing agent (such as HATU) and a base (such as DIPEA, TEA, or DMAP), the compound of formula X-7 undergoes a condensation reaction with an amine (formula X-8) to give the compound of formula X-9.

[0180] (vi) In an inert solvent (such as isopropanol), the compound of formula X-9 undergoes deprotection and cyclization reaction under acidic conditions (such as hydrochloric acid) to give the compound of general formula (II).

[0181] In the formula,

[0182] R 1 R 2 R 3 R 4 R 5 Z, W, and n are defined as described above.

[0183] Pharmaceutical Compositions and Administration

[0184] The pharmaceutical compositions described in this invention are used to prevent and / or treat the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, and metabolic disease.

[0185] The compound of formula (I) can be used in combination with other known drugs for treating or improving similar symptoms. When administered in combination, the original drug's administration method and dosage can remain unchanged, while the compound of formula I is taken simultaneously or subsequently. When the compound of formula I is taken concurrently with one or more other drugs, a pharmaceutical composition containing one or more known drugs and the compound of formula I is preferred. Drug combination also includes taking the compound of formula I with one or more other known drugs during overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of either drug alone.

[0186] Drugs or active ingredients that can be used in combination with compounds of general formula (I) include, but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, CD20 antibodies (such as rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritumomab, 90In-ibritumomab, ibritumomab tiuxetan, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, etc.),OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01), ALK inhibitors (such as Ceritinib, Alectinib, Brigatinib, Lorlatinib, Ocalatinib), PI3K inhibitors (such as Idelalisib, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (such as Ibrutinib, Ti... EGFR inhibitors (such as afatinib, acalabrutinib, zanubrutinib, vecabrutinib, etc.), VEGFR inhibitors (such as sorafenib, pazopanib, regorafenib, sitravatinib, ningetinib, cabozantinib, sunitinib, donafenib, etc.), HDAC inhibitors (such as givinostat, tucidinostat, vorinostat, fimepinostat, droxinostat, entinostat, dacinostat, quisinostat, tacedinaline, etc.), and CDK inhibitors (such as palbociclib, ribociclib, A...). bemaciclib, Milciclib, Trilaciclib, Lerociclib, etc.; MEK inhibitors (such as Selumetinib (AZD6244), Trametinib (GSK1120212), PD0325901, U0126, Pimasertib (AS-703026), PD184352 (CI-1040), etc.); mTOR inhibitors (such as Vistusertib), SHP2 inhibitors (such as RMC-4630, JAB-3068, TNO155, etc.) or combinations thereof.

[0187] The dosage forms of the pharmaceutical compositions of the present invention include (but are not limited to): injections, tablets, capsules, aerosols, suppositories, films, pellets, topical liniments, controlled-release or sustained-release or nano-formulations.

[0188] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0189] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0190] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0191] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in the dosage forms of capsules, tablets, and pills.

[0192] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0193] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0194] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0195] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0196] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0197] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0198] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0199] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0200] The present invention also provides a method for preparing a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with a compound of general formula (I) or its crystal form, a pharmaceutically acceptable salt, a hydrate or a solvate of the present invention, thereby forming a pharmaceutical composition.

[0201] The present invention also provides a treatment method comprising the steps of: administering to a subject requiring treatment a compound of general formula (I) as described in the present invention, or a crystal form thereof, a pharmaceutically acceptable salt, hydrate or solvate thereof, or administering a pharmaceutical composition as described in the present invention for selectively inhibiting SOS1.

[0202] Compared with the prior art, the present invention has the following main advantages:

[0203] (1) The compound has a good selective inhibitory effect on SOS1;

[0204] (2) The compound has better in vitro and in vivo pharmacodynamics, pharmacokinetic properties and lower toxicity.

[0205] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0206] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0207] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).

[0208] NMR was performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used for the determination included deuterated dimethyl sulfoxide (DMSO-d6), deuterated acetone (CD3COCD3), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). Tetramethylsilane (TMS) was used as the internal standard. Chemical shifts were measured in parts per million (ppm).

[0209] Liquid chromatography-mass spectrometry (LC-MS) was performed using a Waters SQD2 mass spectrometer. HPLC determinations were performed using an Agilent 1100 high-performance chromatograph (Microsorb 5micron C18 100x3.0mm column).

[0210] Thin-layer chromatography (TLC) uses Qingdao GF254 silica gel plates, with a thickness of 0.15-0.20 mm for TLC and 0.4-0.5 mm for preparative TLC. Column chromatography typically uses Qingdao 200-300 mesh silica gel as the support.

[0211] The starting materials used in the embodiments of the present invention are all known and commercially available, or can be synthesized using or in accordance with literature reported in the field.

[0212] Unless otherwise specified, all reactions in this invention are carried out under the protection of a dry inert gas (such as nitrogen or argon) by continuous magnetic stirring, and the reaction temperature is [degrees Celsius].

[0213] Example

[0214] Example 1: Preparation of (R)-4-((1-(3-trifluoromethyl-2-fluorophenyl)ethyl)amino)-6-((1-((dimethylamino)methyl)cyclopropyl)methyl)-8-fluoro-2-methylpyrido[4,3-d]pyrimidin-7(6H)-one

[0215]

[0216] Step 1: Preparation of 4,6-dichloro-5-(1,3-dioxolane-2-yl)-2-methylpyrimidine

[0217] 4,6-Dichloro-2-methylpyrimidin-5-carboxaldehyde (1.0 g, 5.26 mmol) was added to toluene (50 mL), followed by ethylene glycol (326 mg, 5.26 mmol) and p-toluenesulfonic acid (90 mg, 0.53 mmol). The reaction mixture was purged with nitrogen three times and then refluxed for 3 hours. The toluene was concentrated off, and 20 mL of dichloromethane and 50 mL of saturated sodium carbonate solution were added. The mixture was then extracted with dichloromethane (3 x 20 mL). The combined organic phases were dried, filtered, and concentrated. The residue was separated by silica gel column chromatography (PE:EA = 20:1 to 10:1) to give the target product (1.3 g, yield: 100%).

[0218] LC-MS: m / z 235 (M+H) + .

[0219] Step 2: Preparation of dimethyl 2-(6-chloro-5-(1,3-dioxapentan-2-yl)-2-methylpyrimidin-4-yl)-2-fluoromalonate

[0220] 4,6-Dichloro-5-(1,3-dioxolane-2-yl)-2-methylpyrimidine (1.2 g, 5.13 mmol) was added to dimethyl sulfoxide (12 mL), followed by potassium carbonate (1.42 g, 10.3 mmol) and dimethyl 2-fluoromalonate (769 mg, 5.13 mmol). The reaction mixture was purged with nitrogen once, and then reacted at 50 °C for 2 hours. After cooling, the resulting reaction mixture was diluted with 100 mL of water and extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the target product (1.78 g, yield: 99%). No further purification was required; the product was used directly in the next reaction.

[0221] LC-MS: m / z 349 (M+H) + .

[0222] Step 3: Preparation of methyl 2-(6-(((R)-1-(3-trifluoromethyl-2-fluorophenyl)ethyl)amino)-5-(1,3-dioxolane-2-yl)-2-methylpyrimidin-4-yl)-2-fluoroacetate

[0223] Dimethyl 2-(6-chloro-5-(1,3-dioxapentan-2-yl)-2-methylpyrimidin-4-yl)-2-fluoromalonate (1.78 g, 5.11 mmol) was dissolved in dimethyl sulfoxide (10 mL), and triethylamine (1.03 g, 10.22 mmol) and 1-(3-trifluoromethyl-2-fluorophenyl)ethylamine (1.06 g, 5.11 mmol) were added. The reaction mixture was purged with nitrogen once, and then heated to 80 °C for 16 hours. After cooling to room temperature, 50 mL of ice water and 50 mL of saturated ammonium chloride solution were added to the reaction mixture, and then extracted with ethyl acetate (3 x 100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the target product (2.36 g, yield: 100%). No purification was required for use in the next reaction.

[0224] LC-MS: m / z 462 (M+H) + .

[0225] Step 4: Preparation of 2-(6-(((R)-1-(3-trifluoromethyl-2-fluorophenyl)ethyl)amino)-5-(1,3-dioxolane-2-yl)-2-methylpyrimidin-4-yl)-2-fluoroacetic acid

[0226] Methyl 2-(6-((((R)-1-(3-trifluoromethyl-2-fluorophenyl)ethyl)amino)-5-(1,3-dioxolane-2-yl)-2-methylpyrimidin-4-yl)-2-fluoroacetate (2.36 g, 5.12 mmol) was added to a mixed solvent of dimethyl sulfoxide (10 mL) and acetonitrile (5 mL), followed by the addition of 20% sodium hydroxide aqueous solution (4.1 mL, 20.48 mmol). The reaction mixture was allowed to react at room temperature for 1 hour, then filtered. The filtrate was separated by preparative chromatography to obtain the target product (870 mg, yield: 38%).

[0227] LC-MS: m / z 448 (M+H) + .

[0228] Step 5: Preparation of 2-(5-(1,3-dioxapentan-2-yl)-6-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrimidin-4-yl)-2-fluoro-N-((1-(hydroxymethyl)cyclopropyl)methyl)acetamide

[0229] 2-(6-(((R)-1-(3-trifluoromethyl-2-fluorophenyl)ethyl)amino)-5-(1,3-dioxolane-2-yl)-2-methylpyrimidin-4-yl)-2-fluoroacetic acid (100 mg, 0.22 mmol) was added to N,N-dimethylformamide (5 mL), followed by 1-(aminomethyl)cyclopropyl)methanol (45 mg, 0.44 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluracil hexafluorophosphate (167 mg, 0.44 mmol), and N,N-diisopropylethylamine (114 mg, 0.88 mmol). The reaction mixture was stirred at room temperature for 16 hours, then 30 mL of water and 30 mL of saturated ammonium chloride solution were added, followed by extraction with ethyl acetate (3 x 50 mL). The combined organic phases were dried and concentrated, and the residue was separated by preparative chromatography to obtain the target product (70 mg, yield: 60%).

[0230] LC-MS: m / z 531 (M+H) + .

[0231] Step 6: Preparation of (R)-8-fluoro-4-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-6-((1-(hydroxymethyl)cyclopropyl)methyl)-2-methylpyridin[4,3-d]pyrimidin-7(6H)-one

[0232] 2-(5-(1,3-dioxapentan-2-yl)-6-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrimidin-4-yl)-2-fluoro-N-((1-(hydroxymethyl)cyclopropyl)methyl)acetamide (60 mg, 0.11 mmol) was added to isopropanol (3 mL), followed by the addition of 5N concentrated hydrochloric acid (0.1 mL). The reaction solution was reacted at 50°C for 1 hour, then concentrated, and the residue was separated by preparative chromatography to obtain the target product (40 mg, yield: 78%).

[0233] LC-MS: m / z 469 (M+H) + .

[0234] Step 7: Preparation of (R)-1-((8-fluoro-4-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7-oxopyridin[4,3-d]pyrimidin-6(7H)-yl)methyl)cyclopropane-1-aminocarboxaldehyde

[0235] (R)-8-fluoro-4-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-6-((1-(hydroxymethyl)cyclopropyl)methyl)-2-methylpyridin[4,3-d]pyrimidin-7(6H)-one (20 mg, 0.04 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of sodium bicarbonate (17 mg, 0.20 mmol) and Dys-Martin reagent (36 mg, 0.08 mmol). The mixture was stirred overnight at room temperature, followed by the addition of 1.5 N sodium hydroxide (2 mL) and stirring for 10 minutes, then the addition of saturated sodium bicarbonate aqueous solution (50 mL), and extraction with dichloromethane (50 mL). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the target product (20 mg, yield: 99%). No further purification was required; the product was used directly in the next reaction.

[0236] LC-MS: m / z 467 (M+H) + .

[0237] Step 8: Preparation of (R)-6-((1-((dimethylamino)methyl)cyclopropyl)methyl)-8-fluoro-4-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyridin[4,3-d]pyrimidin-7(6H)-one

[0238] (R)-1-((8-fluoro-4-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl-7-oxopyridin[4,3-d]pyrimidin-6(7H)-yl)methyl)cyclopropane-1-aminocarboxaldehyde (20 mg, 0.04 mmol) was dissolved in methanol (10 mL), followed by the addition of 2 M dimethylaminetetrahydrofuran solution (0.1 mL, 0.20 mmol) and sodium cyanoborohydride (13 mg, 0.20 mmol). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was separated by preparative chromatography to obtain the target product (1.52 mg, yield: 8%).

[0239] LC-MS: m / z 496 (M+H) + . 1 H NMR (400MHz, DMSO) δ9.03 (s, 1H), 8.88 (d, J = 8.8Hz, 1H), 7.80-7.83 (t, J = 7.8Hz, 1H), 7.66-7.69 (t, J = 7.7Hz, 1H), 7.37-7.41 (t, J = 7.4Hz, 1H), 5. 72-5.76(m,1H),4.16-4.17(m,1H),2.25(s,3H),2.15(s,3H),1.99-2.0 0(m,2H),1.59(d,J=1.59Hz,3H),1.25(s,3H),0.81(s,2H),0.34(s,2H).

[0240] The following compounds were synthesized using different starting materials according to the method of Example 1:

[0241] Example 2 (R)-4-((1-(3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl)ethyl)amino)-6-((1-((dimethylamino)methyl)cyclopropyl)methyl)-8-fluoro-2-methylpyridin[4,3-d]pyrimidin-7(6H)-one

[0242]

[0243] LC-MS: m / z 536 (M+H) + . 1H NMR(400MHz, DMSO)δ9.10(s,1H),8.89(s,1H),7.68–7.56(m,1H),7.37–7.30(m,1H),7.24(t,J=7.7Hz,1H),5 .85–5.70(m,1H),5.34(s,1H),2.36–1.98(m,10H),1.54(m,3H),1.26–1.14(m,9H),0.84(s,2H),0.40(s,2H).

[0244] Example 3(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-fluoro-2-methyl-6-((1-((dimethylamino)methyl)cyclopropyl)methyl)pyridin[4,3-d]pyrimidin-7(6H)-one

[0245]

[0246] LC-MS: m / z 493 (M+H) + .

[0247] Example 4 (R)-4-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-8-fluoro-2-methyl-6-((1-(morpholinomethyl)cyclopropyl)methyl)pyridine[4,3-d]pyrimidine-7(6H)-one

[0248]

[0249] LC-MS: m / z 550 (M+H) + . 1 H NMR (400MHz, DMSO) δ9.06 (s, 1H), 8.73 (d, J = 7.3Hz, 1H), 8.21 (s, 1H), 7.59 (s ,1H),7.55(d,J=7.5Hz,1H),7.50–7.32(m,2H),5.73–5.59(m,1H),4.14(q,J =13.5Hz,2H),3.84(t,J=14.2Hz,2H),3.27(s,4H),2.31(s,3H),2.28–2.07( m, 6H), 1.56 (t, J = 12.0Hz, 3H), 0.84 (d, J = 4.6Hz, 2H), 0.37 (d, J = 4.5Hz, 2H).

[0250] Example 5(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-fluoro-2-methyl-6-((1-((4-methylpiperazin-1-yl)methyl)cyclopropyl)methyl)pyridin[4,3-d]pyrimidine-7(6H)-ketocarbamate

[0251]

[0252] LC-MS: m / z 548 (M+H) + . 1 H NMR (400MHz, DMSO) δ8.98(s,1H),8.56(d,J=7.9Hz,1H),8.19(s,1H),6.84(d,J=6.2Hz,2H),6.73(s,1H),5.56(m,3H),4.17–4.04(m ,2H),2.56–2.44(m,8H),2.32(s,3H),2.14(m,2H),1.91(s,3H),1.53(d,J=7.0Hz,3H),0.84(dd,J=18.5,10.0Hz,2H),0.35(s,2H).

[0253] Example 6(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-fluoro-2-methyl-6-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methyl)pyridine[4,3-d]pyrimidine-7(6H)-ketocarbamate

[0254]

[0255] LC-MS: m / z 519 (M+H) + . 1 H NMR (400MHz, DMSO) δ9.00(s,1H),8.62(d,J=7.8Hz,1H),8.22(s,1H),6.84(d,J=4.6Hz,2H),6.72(s,1H ),5.66–5.37(m,3H),4.15(s,2H),2.37–2.11(m,9H),1.47(m,7H),0.80(d,J=4.9Hz,2H),0.35(s,2H).

[0256] Example 7(R)-4-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-8-fluoro-6-((1-(hydroxymethyl)cyclopropyl)methyl)-2-methylpyridin[4,3-d]pyrimidin-7(6H)-one

[0257]

[0258] LC-MS: m / z 481 (M+H) + . 1 H NMR (400MHz, DMSO) δ8.97(s,1H),8.82(d,J=7.6Hz,1H),7.63–7.51(m,2H),7.50–7.36(m,2H),5.67(m,2H),4.64(m,1H),4.18(q,J= 13.5Hz, 2H), 3.84 (t, J = 14.1Hz, 2H), 3.21 (t, J = 7.6Hz, 2H), 2.30 (s, 3H), 1.59 (d, J = 7.0Hz, 3H), 0.69 (d, J = 2.9Hz, 2H), 0.47 (s, 2H).

[0259] Example 8 (R)-8-fluoro-4-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-6-((1-(hydroxymethyl)cyclopropyl)methyl)-2-methylpyridin[4,3-d]pyrimidin-7(6H)-one

[0260]

[0261] LC-MS: m / z 469 (M+H) + . 1 H NMR (400MHz, DMSO) δ9.01 (s, 1H), 8.89 (d, J = 6.7Hz, 1H), 7.78 (t, J = 7.3Hz, 1 H),7.67(t,J=7.2Hz,1H),7.39(t,J=7.8Hz,1H),5.81–5.66(m,1H),4.68(t, J=5.7Hz,1H),4.25(d,J=13.5Hz,1H),4.14(d,J=13.5Hz,1H),3.28–3.16(m, 2H), 2.23 (s, 3H), 1.61 (d, J = 7.1Hz, 3H), 0.71 (d, J = 6.4Hz, 2H), 0.48 (s, 2H).

[0262] Example 9 (R)-8-fluoro-6-((1-(methoxymethyl)cyclopropyl)methyl)-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyridine[4,3-d]pyrimidin-7(6H)-one

[0263]

[0264] LC-MS: m / z 519 (M+H) + . 1H NMR (400MHz, DMSO) δ9.03 (d, J = 7.1Hz, 1H), 8.94 (s, 1H), 8.57 (s, 1H), 8.38 (s, 1H), 8.30 (s, 1H), 5.71 (m, 1H), 4.25–4 .09(m,2H),3.19–3.11(m,4H),3.05(m,1H),2.26(s,3H),1.64(d,J=7.0Hz,3H),0.80(d,J=2.8Hz,2H),0.50(s,2H).

[0265] Example 10(R)-4-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-8-fluoro-6-((1-(methoxymethyl)cyclopropyl)methyl)-2-methylpyridin[4,3-d]pyrimidin-7(6H)-one

[0266]

[0267] LC-MS: m / z 477 (M+H) + . 1 H NMR (400MHz, DMSO) δ8.94 (s, 1H), 8.85 (d, J = 7.7Hz, 1H), 7.65–7.52 (m, 2H), 7.49–7.37 (m, 2H), 5.64 (m, 2H), 4.15 (q, J = 13. 5Hz,2H),3.83(t,J=14.1Hz,2H),3.17–3.04(m,5H),2.31(s,3H),1.56(t,J=10.8Hz,3H),0.85–0.69(m,2H),0.49(s,2H).

[0268] Example 11(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-fluoro-6-((1-(methoxymethyl)cyclopropyl)methyl)-2-methylpyridin[4,3-d]pyrimidin-7(6H)-one

[0269]

[0270] LC-MS: m / z 480 (M+H) + . 1H NMR (400MHz, DMSO) δ8.92(s,1H),8.75(d,J=7.8Hz,1H),8.34(s,1H),6.84(d,J=7.7Hz,2H),6.72(s,1H),5.69–5.45(m,3 H),4.15(dd,J=29.7,13.5Hz,2H),3.17–2.99(m,5H),2.30(s,3H),1.52(d,J=7.0Hz,3H),0.84–0.68(m,2H),0.48(s,2H).

[0271] Example 12(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-6-((1-((cyclopropyl(methyl)amino)methyl)cyclopropyl)methyl)-8-fluoro-2-methylpyridin[4,3-d]pyrimidine-7(6H)-ketocarbamate

[0272]

[0273] LC-MS: m / z 529 (M+H) + . 1 H NMR (400MHz, DMSO) δ8.81(s,1H),8.65(d,J=7.4Hz,1H),8.39(brs,2H),6.84(d,J=9.1Hz,2H),6.72(s,1H),5.64–5.44(m,3H),4. 03(s,2H),2.39–2.24(m,4H),2.23–1.99(m,5H),1.54(d,J=6.9Hz,3H),1.43(s,2H),0.89(m,1H),0.75(m,1H),0.48–0.20(m,4H).

[0274] Example 13(R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-8-fluoro-6-((1-(((2-methoxyethyl)(methyl)amino)methyl)cyclopropyl)methyl)-2-methylpyridin[4,3-d]pyrimidine-7(6H)-ketocarbamate

[0275]

[0276] LC-MS: m / z 537 (M+H) + . 1H NMR (400MHz, DMSO) δ8.69(s,1H),8.29(d,J=7.8Hz,1H),8.07(s,1H),6.63–6.55(m,2H),6.48(s,1H),5.38–5.24(m,3H),3.90 (s,2H),2.88(m,5H),2.23(m,2H),2.07(s,3H),1.97–1.77(m,5H),1.28(d,J=7.0Hz,3H),0.55(d,J=5.6Hz,2H),0.09(s,2H).

[0277] Example 14 Biological Test Evaluation

[0278] The following biological test examples further illustrate the invention, but these examples are not intended to limit the scope of the invention.

[0279] Compounds against KRAS G12C Inhibition experiment on binding to SOS1.

[0280] Experimental steps

[0281] (1) Gradual dilution of the test compound: 10 mM stock solution (dissolved in 100% DMSO) was added to the 384-well test plate, and the final DMSO content was 0.25%.

[0282] (2) Add 5 μL of Tag1-SOS1 solution to the test plate, and add 5 μL of dilution buffer to the control group. Add 5 μL of Tag2-KRAS solution to the test plate. G12C Solution.

[0283] (4) Add 10 μL of Anti-Tag1-Tb3+ and Anti-Tag2-XL665 detection solutions to the test plate. Centrifuge at 1000 rpm for 1 minute and incubate at room temperature for 2 hours.

[0284] (5) Reading the board

[0285] (6) Finally, the IC50 of the compound was calculated using GraphPad Prism software. 50 The values ​​were calculated, and the fitted curve was plotted.

[0286] The compounds in the embodiments of this invention affect KRAS G12C The inhibitory activity of the enzyme and SOS1 binding is shown in Table 1.

[0287] Table 1 Inhibitory activity of compounds in the embodiments of the present invention

[0288]

[0289]

[0290] As can be seen from Table 1:

[0291] The compounds in the embodiments of this invention are effective for KRAS. G12C The binding to SOS1 showed good inhibitory activity.

[0292] Pharmacokinetic testing and evaluation

[0293] Male SD rats, weighing approximately 220g, were fasted overnight and then administered a solution of the compound of the present invention at a concentration of 10mg / kg [using CMC / TW80 as a carrier] via gavage. Blood samples were collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12, 24, 36, and 48 hours after administration of the compound of the present invention, and the concentration of the compound of the present invention in plasma was determined by LC / MS / MS.

[0294] The test results show that the compound of this invention has good pharmacokinetic characteristics.

[0295] Antitumor pharmacodynamic evaluation

[0296] 100uL containing 5x10 6 MIA PaCa-2 tumor cell suspension was subcutaneously inoculated into the right posterior abdomen of nude mice. The health status of the mice was monitored daily, and measurements were taken when the tumor grew to a palpable size. The tumor volume was calculated using the formula: 0.5 x L x W. 2 Where L and W represent the length and width of the tumor, respectively. The tumor is approximately 150 mm long. 3 Mice were randomly assigned to groups. Mice were administered a CMC-Na suspension containing the appropriate dose (15, 50 mg / kg) of the compound daily by gavage, while their general condition was monitored. Tumors were measured three times a week, and body weight was measured twice a week.

[0297] The test results show that the compound of the present invention has good anti-tumor effects.

[0298] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts: (I) In the formula: Z stands for: methylene or deuterated methylene; W is ; R 1 Selected from the following group: hydrogen, deuterium, halogen, cyano, C1-C6 alkyl; R 2 For: -(CH2) m NR 7 R 8 ;in, R 7 and R 8 Each is independently selected from the following group: hydrogen, substituted or unsubstituted C1-C 18 Alkyl, substituted or unsubstituted C3-C 20 Cycloalkyl; or in -(CH2) m NR 7 R 8 In the middle, R 7 and R 8 The N atom attached to it cyclizes to form a substituted or unsubstituted 4-20 membered heterocyclic group; wherein, the substitution refers to being substituted by one or more R atoms. a replace; R 3 Selected from the group consisting of substituted or unsubstituted groups: phenyl or 5-6-membered heteroaryl, wherein the substitution refers to substitution by one or more groups selected from the group consisting of: deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halo-C1-C6 alkoxy, halogen, hydroxyl, oxo, cyano, amino, amide, sulfonamide, and urea; R 4 and R 5 Each is independently a substituted or unsubstituted C1-C6 alkyl group; wherein the substitution means being substituted by one or more groups selected from the group consisting of: deuterium, halogen; R 6 Selected from the group consisting of: hydrogen, deuterium, halogen, amino, cyano, substituted or unsubstituted C1-C6 alkyl and substituted or unsubstituted C3 cycloalkyl; wherein, the substitution means being substituted by one or more groups selected from the group consisting of: deuterium, halogen; Among them, R a Selected from the following group: deuterium, substituted or unsubstituted C1-C 18 Alkyl, substituted or unsubstituted C3-C 20 Cycloalkyl, substituted or unsubstituted C1-C 18 Alkoxy, halogen, hydroxyl, oxo, cyano, amino, amide, sulfonamide, and urea groups; among which, R a The substitution mentioned herein refers to substitution by one or more groups selected from the group consisting of: deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, halogen, nitro, hydroxyl, oxo, cyano, amino, amide, sulfonamide, and urea. m is 1; n is 1, 2, 3, 4 or 5; Furthermore, the term "amino" refers to -NRR', where R and R' are independently hydrogen or alkyl; the term "amide" refers to -CONRR', where R and R' are independently hydrogen or alkyl; the term "sulfonamide" refers to -SO2NRR', where R and R' are independently hydrogen or alkyl; the term "urea" refers to -NRCONR'R", where R, R', and R" are independently hydrogen or alkyl; wherein the alkyl group is selected from: methyl, ethyl, and propyl.

2. The compound of claim 1, its stereoisomers, tautomers, or pharmaceutically acceptable salts, characterized in that, It has the structure shown in general formula (II): (II) In the formula, R 1 R 2 R 3 R 4 R 5 The definitions of Z, W, and n are as described in claim 1.

3. The compound of claim 1, its stereoisomers, tautomers, or pharmaceutically acceptable salts, characterized in that, It has the structure shown in general formula (III): (III) In the formula, R 1 R 2 R 3 R 4 The definitions of Z, W, and n are as described in claim 1.

4. The compound of claim 1, its stereoisomers, tautomers, or pharmaceutically acceptable salts, characterized in that, It has the structure shown in general formula (IV): (IV) In the formula, R 1 R 2 R 3 The definitions of Z, W, and n are as described in claim 1.

5. The compound of claim 1, its stereoisomers, tautomers, or pharmaceutically acceptable salts, characterized in that, R 2 -(CH2) m NR 7 R 8 ;in, R 7 and R 8 Each is independently selected from the following group: hydrogen, substituted or unsubstituted C1-C 18 Alkyl groups and substituted or unsubstituted C3 cycloalkyl groups, wherein the C1-C18 alkyl groups are selected from the group consisting of methyl, ethyl, propyl, and isopropyl; or, in -(CH2) m NR 7 R 8 In the middle, R 7 and R 8 The N atom attached thereto cyclizes to form a substituted or unsubstituted 4-20 membered heterocyclic group, wherein the 4-20 membered heterocyclic group is selected from the group consisting of pyrrolidinyl, piperazine, and morpholino; wherein the substitution refers to being formed by one or more substituents selected from the group consisting of deuterium, deuterated C1-C... 18 Alkyl, halogenated C1-C 18 Alkyl, deuterated C1-C 18 Alkoxy and halogenated C1-C 18 alkoxy group, and the aforementioned; C1-C 18 The alkyl group is selected from the group consisting of methyl, ethyl, propyl, and isopropyl, wherein the C1-C 18 Alkoxy groups are selected from the following group: methoxy, ethoxy, propoxy, and isopropoxy; m is 1.

6. The compound of claim 1, its stereoisomers, tautomers, or pharmaceutically acceptable salts, characterized in that, R a In the context, the substituted or unsubstituted C1-C 18 Alkyl groups are: deuterated C1-C 18 Alkyl, halogenated C1-C 18 Alkyl or halogenated C1-C 18 Alkyl hydroxyl; the substituted or unsubstituted C1-C 18 The alkoxy group is deuterated C1-C. 18 Alkoxy or halogenated C1-C 18 Alkyl group.

7. The compound of claim 1, its stereoisomers, tautomers, or pharmaceutically acceptable salts, characterized in that, R 3 Selected from: 。 8. The compound of claim 1, its stereoisomers, tautomers, or pharmaceutically acceptable salts, characterized in that, R 3 Selected from: 。 9. The compound of claim 1, its stereoisomers, tautomers, or pharmaceutically acceptable salts, characterized in that, R 3 Selected from: 。 10. A compound, its stereoisomers, tautomers, or pharmaceutically acceptable salts, characterized in that, The compounds are selected from the group consisting of:

11. The compound of claim 10, its stereoisomers, tautomers, or pharmaceutically acceptable salts, characterized in that, The compounds are selected from the group consisting of: , , , , , , and .

12. A pharmaceutical composition, characterized in that, It comprises i) one or more compounds according to any one of claims 1-11, their stereoisomers, tautomers, or pharmaceutically acceptable salts; and ii) a pharmaceutically acceptable carrier.

13. Use of a compound, its stereoisomer, tautomer, or pharmaceutically acceptable salt, or the pharmaceutical composition of claim 12, as described in any one of claims 1-11, characterized in that, Used to prepare drugs for the prevention and / or treatment of diseases related to SOS1 activity or expression levels.

14. The use as described in claim 13, characterized in that, The disease in question is cancer.

15. The use as described in claim 14, characterized in that, The cancers mentioned are selected from: leukemia, skin cancer, and colorectal cancer.

16. The use as described in claim 14, characterized in that, The cancers mentioned are selected from: lung cancer, breast cancer, prostate cancer, esophageal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, melanoma, lymphoma, brain tumor, myeloma, soft tissue sarcoma, and pancreatic cancer.

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