Compounds for degrading mutant braf

Abstract

This invention provides compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which can be applied to a host in need, such as humans, to treat conditions mediated by mutant BRAF, such as cancer. These compounds effectively degrade class I, II, and III mutant BRAF proteins.

Description

Cross - Reference to Related Applications

[0001] This application claims the benefits of U.S. Provisional Application 63 / 546,727, filed October 31, 2023, and U.S. Provisional Application 63 / 599,455, filed November 15, 2023. The entire contents of each of these applications are incorporated herein by reference for all purposes. Technical Field

[0002] This invention provides compounds that degrade mutant BRAFs (such as class I, II, and / or III mutant BRAFs), as well as pharmaceutically acceptable salts, uses, compositions, and articles thereof. The compounds of this invention can be administered to a host (such as a human) in need of therapeutic treatment for conditions mediated by mutant BRAFs (such as cancer). Background Technology

[0003] BRAF is a serine / threonine protein kinase, a member of the signal transduction protein kinase family. BRAF plays a crucial role in the MAPK signaling pathway and is mutated in approximately 8% of all human cancers, including melanoma (approximately 60%), colorectal cancer (approximately 12%), and lung adenocarcinoma (approximately 5%). The most common mutation in BRAF is V600E (class I), which is present in half of malignant melanomas. This mutation overactivates ERK and acts as a monomeric signaling receptor for RAF inhibitors. Other common activating mutations include class II mutations, such as G469A; and class III mutations, such as G466V. Class II and III mutations activate ERK by promoting homodimerization or heterodimerization of RAF.

[0004] Although available BRAF inhibitors offer therapeutic benefits, the emergence of drug resistance can limit the duration of their antitumor response.

[0005] BRAF proteins provide a signaling mechanism that requires homodimerization (BRAF-BRAF) or heterodimerization with other RAF proteins (BRAF-RAF1 or BRAF-ARAF). When BRAF has a class I mutation, as observed in oncology indications with BRAF V600E / K substitution, BRAF signaling becomes independent of homodimerization and / or heterodimerization. As a monomeric protein, kinase activity becomes overactivated and drives cell proliferation signaling.

[0006] Several BRAF inhibitors have been described that inhibit monomeric BRAF but not dimeric BRAF, including vemurafenib, dabrafenib, and encorafenib. However, resistance typically develops within one year, including in cases of RAS mutations, BRAF V600E amplification, and deletions or splicing variants within the BRAF V600E gene. These inhibitors are also ineffective against non-V600 BRAF mutants (class II and III) that activate ERK by promoting homodimerization or heterodimerization of RAF.

[0007] Examples of BRAF inhibitors are described in WO2021 / 116055, WO2021 / 116050, WO2022 / 129259 and WO2022 / 258584.

[0008] Non-limiting examples of BRAF-degrading compounds include those described in WO2018 / 119448, WO2019 / 199816, WO2020 / 051564, WO2021 / 255212, WO2022 / 047145, WO2022 / 261250 and WO2024 / 119111.

[0009] Despite these achievements, novel therapeutics are still needed to treat BRAF-mediated cancers, especially those mediated by mutant BRAF. Summary of the Invention

[0011] This invention provides compounds that degrade mutant BRAFs (e.g., class I, II, and / or III mutant BRAFs) via the ubiquitin-proteasome pathway, as well as pharmaceutically acceptable salts, uses, compositions, and manufactures thereof. These compounds bind to the widely expressed E3 ligase protein cereblon (CRBN) and alter the substrate specificity of the CRBN E3 ubiquitin ligase complex, thereby inducing recruitment and ubiquitination of mutant BRAFs such as BRAF V600E. The compounds of this invention are also biochemical binders to other RAF proteins (e.g., WT BRAF, RAF1, or ARAF); however, these compounds trigger more effective targeted degradation of mutant BRAFs, such as class I mutant BRAFs (e.g., V600E), class II mutant BRAFs (e.g., G469A), class III mutant BRAFs (e.g., G466V mutation), and splice variants (e.g., p61-BRAF). V600E ) .

[0012] By degrading mutant BRAF, the compounds of the present invention can be used to treat BRAF-mediated cancers, such as melanoma, lung cancer (including, for example, non-small cell lung cancer), colorectal cancer (including, for example, microsatellite stable colorectal cancer), thyroid cancer (including, for example, undifferentiated thyroid cancer), or ovarian cancer. In some embodiments, the compounds of the present invention are used to treat solid tumors mediated by V600X mutant BRAF. Other non-limiting examples of conditions that can be treated with the compounds of the present invention include melanoma, non-small cell lung cancer, thyroid cancer, colorectal cancer, and other solid tumor malignancies with mutant BRAF driving factors.

[0013] In some aspects, the selected compounds of the present invention provide rapid and durable degradation of mutant BRAF proteins. By degrading mutant BRAF, these compounds can be used to treat BRAF-mediated cancers. For example, in A375 human melanoma xenografts, oral delivery of compounds 8, 118, 141, 156, or 180 elicited a more robust antitumor response than that of comparators such as dabrafenib or enrafenib (see example...). Figure 14 and 22 These compounds, when administered at a BID of 10 mg / kg, caused significant tumor regression in xenograft models.

[0015]

[0016]

[0017]

[0018]

[0019] The compounds of this invention can be used to treat refractory double-mutant cancers, where one oncogenic mutation is located in BRAF. For example, in some embodiments, the compounds of this invention are used to treat cancers having a BRAF mutation and a PI3K, NRAS, or MEK1 mutation. In some embodiments, the PI3K mutation is a subunit mutation, such as a mutation in the p110α protein, such as PIK3CA. H1047R Or PIK3CA P449T .

[0020] The compounds of this invention can be used to degrade class I, II, and III BRAF mutants and their splice variants. In some embodiments, the compounds of this invention can treat cancers that have developed resistance to BRAF inhibitors. For example, in some embodiments, the compounds of this invention are used to treat cancers that have acquired resistance to BRAF inhibitor therapy due to NRAS, MEK1, or PI3K mutations other than BRAF mutations.

[0021] In some embodiments, the compounds of the present invention are orally bioavailable.

[0022] In some embodiments, compounds of formulas I to XXXII are provided: (I) (II) (III) (IV) (V) (VI) (VII) (VIII) (IX) (X), (XI) (XII) (XIII) (XIV) (XV) (XVI) (XVII) (XVIII) (XIX) (XX) (XXI) (XXII) (XXIII) (XXIV) (XXV) (XXVI) (XXVII) (XXVIII) (XXIX) (XXX) (XXXI) (XXXII), Or its pharmaceutically acceptable salt; in: ring It is a spiroheterocyclic group, bridged cycloalkyl group, bridged heterocyclic group, or piperidine-1,4-diyl group containing one or two nitrogen atoms and without other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; ring It is a spiroheterocyclic group containing one nitrogen atom and one oxygen atom and no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; ring It is a bridging heterocyclic group, fused heterocyclic group, or spirocyclic group containing one or two nitrogen atoms and no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; ring It is a cycloalkyl or heterocyclic group containing one or two nitrogen atoms and zero or one oxygen atom, and containing no other heteroatoms, wherein the cycloalkyl or heterocyclic group contains one or two nitrogen atoms and zero or one oxygen atom, and contains no other heteroatoms. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; ring It is a spiroheterocyclic group containing one oxygen atom and zero or one nitrogen atom, and containing no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; ring It is a cycloalkyl group, wherein the ring is cycloalkyl. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; ring It is a spiroheterocyclic group containing one or two nitrogen atoms and zero or one oxygen atom, and containing no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; ring It is a cycloalkyl group, 3,3-difluoro-piperidine-1,4-diyl, piperazine-1,4-diyl, bridged cycloalkyl group, a bridged heterocyclic group or spirocyclic group containing one or two nitrogen atoms and one or two oxygen atoms and without other heteroatoms, wherein the cycloalkyl group, piperazine-1,4-diyl or spirocyclic group is optionally substituted by one or two independent substituents selected from halogen, alkyl and alkoxy groups; ring It is a cycloalkyl, piperidine-1,4-diyl, spiroheterocyclic group containing one or two nitrogen atoms and without other heteroatoms, wherein the cycloalkyl group is... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; ring It is a cycloalkyl group substituted with 1, 2 or 3 substituents, which are independently selected from alkyl, alkoxy, F, Cl, Br and OH; ring It is a cycloalkyl, spirocycloalkyl, or heterocyclic group containing one or two nitrogen atoms and no other heteroatoms, wherein the cycloalkyl group is a cycloalkyl group. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; ring It is a cycloalkyl, spirocycloalkyl, or heterocyclic group containing one or two nitrogen atoms and no other heteroatoms, wherein the cycloalkyl group is a cycloalkyl group. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; ring It is a heterocyclic group optionally substituted with one or two substituents, which are independently selected from halogens, alkyl groups, OH groups and alkoxy groups; A 1 Selected from -NR 2 -and-CHR 2 '-; R 1 Selected from hydrogen, alkyl, and cycloalkyl groups; R 2 Selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; or R 1 and R 2 Together with the nitrogen atom to which it is attached, it forms an optional structure via one or two R atoms. 3 Substituted heterocyclic alkyl groups; R 2 Selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; or R1 and R 2 'Together with the carbon atom to which it is attached, it forms optionally via one or two R... 3 Substituted cycloalkyl groups; Each R 3 Independently selected from hydrogen, halogen, alkyl, cycloalkyl, and alkoxy; R 4 Selected from hydrogen, alkyl, cyano, and halogen; R 5 Selected from hydrogen, alkyl, cyano, and halogen; A 2 Selected from -O-, -NH- and -(C=O)-; R 6 Selected from hydrogen, halogen, hydroxyl, amino, dialkylamino, alkoxy, alkyl, and alkoxyalkyl; R 7 Selected from hydrogen and alkyl groups; R 8 Selected from hydrogen, alkyl, cyano, halogen, and alkoxy groups; R 9 Selected from hydrogen, alkyl, cyano, halogen, and alkoxy groups; R 17 Selected from hydrogen, alkyl, cyano, hydroxyl, cycloalkyl, halogen, and alkoxy; R 18 Selected from hydrogen, alkyl, cyano, hydroxyl, cycloalkyl, halogen, and alkoxy; R 19 Selected from hydrogen, alkyl, cyano, hydroxyl, cycloalkyl, halogen, and alkoxy; A 5 It can be -CH- or -N-; A 15 Selected from the bond, -O- and -NH-, where when A 15 When it is O or NH, A 6 For CH and where A 15 When A is the key 6 For N or CH; A 6 It can be -CH- or -N-; R 60 It is isopropyl, pyrrolidine-1-yl substituted with F or OMe, or cyclopropyl; q is 0 or 1; r is 0, 1, or 2; p is 0, 1, or 2; w is 1 or 2. Non-limiting examples of compounds of the present invention include: Or its pharmaceutically acceptable salt. In another aspect, the compounds of the present invention exhibit significant blood-brain barrier permeability and can be used to treat cancers metastasized to the brain. In some aspects, a method is provided for treating BRAF-mediated cancers metastasized to the brain or central nervous system (CNS), comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need. In some embodiments, the cancers metastasized to the brain or central nervous system are colorectal cancer, melanoma, or non-small cell lung cancer. In some aspects, the compounds of the present invention are used to treat BRAF-mediated cancers, wherein the BRAF has been mutated by a wild-type mutation. There are many possibilities for BRAF mutations. In some non-limiting embodiments, the mutation is a class I mutation, a class II mutation, or a class III mutation, or any combination thereof. Non-limiting examples of class I mutations include V600 mutations, such as V600E, V600K, V600R, V600D, V600M, and V600N. Non-limiting examples of class II mutations include G469A, G469V, G469L, G469R, L597Q, and K601E. Non-limiting examples of class III mutations include G466A, G466E, G466R, G466V, S467L, G469E, N581I, D594E, D594G, and D594N. In some embodiments, the BRAF mutation is a V600 mutation, such as V600E, and the cancer has metastasized to the brain or CNS. In some embodiments, the compounds of the present invention can treat BRAF mutant-mediated conditions, wherein the mutation is not a type I, II, or III mutation. Non-limiting examples of mutations include G464I, G464R, N581T, L584F, E586K, G593D, G596C, L597R, L597S, S605I, S607F, N684T, E26A, V130M, L745L, and D284E. In some embodiments, the BRAF mutation is not a type I, II, or III mutation, and the cancer has metastasized to the brain or CNS. In some embodiments, the compounds of the present invention treat BRAF mutant-mediated conditions, wherein the mutation is a splice variant, such as p61-BRAF. V600E In some embodiments, BRAF is mutated into a splice variant, such as p61-BRAF. V600E Furthermore, the cancer may have metastasized to the brain or CNS.

[0023] In some embodiments, the compounds of the present invention are used to treat conditions mediated by two or more mutant proteins, such as those caused by BRAF. V600E / NRAS Q61K Double-mutant mediated cancers. Non-limiting examples of double-mutant cancers include colorectal cancer mediated by BRAF mutations, such as BRAF... V600E And mutations in NRAS, MEK1, or PI3K, such as BRAF. V600E / NRAS Q61R BRAF V600E / MAP2K1 P124S BRAF V600E / PIK3CA H1047R or BRAF V600E / PIK3CA P449T In some embodiments, cancer metastasis to the brain or CNS is mediated by two or more mutated proteins.

[0024] In some embodiments, the compounds of the present invention are used to treat cancers resistant to at least one BRAF inhibitor, such as cancers resistant or acquiredly resistant to BRAF inhibitors selected from dabrafenib, vemurafenib, and enrafenib. In some aspects, cancers resistant to BRAF inhibitor treatment have mutations that promote homodimerization or heterodimerization of the RAF protein. For example, in some embodiments, the compounds of the present invention are used to treat cancers having one or more mutations that promote RAF dimerization. In some embodiments, cancers having one or more mutations that promote RAF dimerization are resistant to BRAF inhibitor treatment (e.g., dabrafenib, vemurafenib, or enrafenib). In some aspects, the mutation is a mutation that promotes homodimerization of BRAF. In some embodiments, the compounds of the present invention are used to treat BRAF mutant-mediated cancers that have metastasized to the brain or CNS, wherein the cancer has one or more mutations that promote RAF dimerization.

[0025] In some embodiments, the compounds described herein are used to treat cancers that have developed escape mutations, such as BRAFV600E / NRAS. Q61KDual-mutant cancers. In other embodiments, the compounds described herein reduce phosphorylated ERK signaling, indicating inhibition of the EGFR-mediated MAPK pathway. In another embodiment, the compounds described herein are used to treat BRAFV600X colorectal cancer (CRC). In some embodiments, the compounds of the present invention are used to treat BRAF-V600X non-small cell lung cancer (NSCLC). In some embodiments, the compounds described herein show activity against antitumor mutations, such as point mutations in MEK and PI3K, splice variants (such as p61-BRAF-V600E), BRAF kinase domain replication, or BRAF amplification.

[0026] In some embodiments, the compounds described herein are used to treat melanoma. For example, in some embodiments, the compounds of the present invention are used to treat cancers driven by BRAF mutants, such as melanoma that has metastasized to the brain or CNS. In some embodiments, the compounds described herein are used to treat colorectal cancer. For example, in some embodiments, the compounds of the present invention are used to treat colorectal cancer that has metastasized to the brain or CNS. In some embodiments, the compounds described herein are used to treat non-small cell lung cancer. For example, in some embodiments, the compounds of the present invention are used to treat non-small cell lung cancer that has metastasized to the brain or CNS.

[0027] In some embodiments, the selected compounds of the present invention provide an improved efficacy and / or safety profile compared to at least one known BRAF inhibitor. For example, the degraders of the present invention, as the sole protein-binding moiety, possess inhibitory efficacy and catalytic degradation activity for proteasome degradation activated by cerebroside. This provides rapid activity of the active moiety against mutant BRAF-mediated cancers, which can rapidly "return to action" and repeatedly perform its catalytic function. In this manner, BRAF is rapidly destroyed, similar to that of a covalent suicide inhibitor, without destroying the active pharmaceutical ingredient.

[0028] In some embodiments, the degradation compound of the present invention has one or more advantages in treating BRAF-mediated conditions compared to using enzyme inhibitors alone.

[0029] In some embodiments, the amount of the compound described herein (in moles) required to treat BRAF-mediated symptoms is less than the amount of the BRAF-targeting ligand moiety alone (in moles).

[0030] In some embodiments, at least one side effect of the compound of the present invention when treating BRAF-mediated conditions is less than that of the BRAF-targeting ligand moiety alone (in molar terms).

[0031] Another aspect of the invention provides compounds described herein, or their enantiomers, diastereomers, or stereoisomers, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the manufacture of medicaments for inhibiting or preventing BRAF-mediated symptoms or for regulating or reducing the amount of BRAF.

[0032] Another aspect of the invention provides compounds as described herein, or their enantiomers, diastereomers or stereoisomers, or pharmaceutically acceptable salts, or pharmaceutical compositions thereof, for use in the manufacture of medicaments for the treatment or prevention of BRAF-mediated diseases.

[0033] In some embodiments, the selected compounds as described herein can be used to treat conditions involving abnormal cell proliferation, such as tumors or cancer, wherein BRAF is an oncogenic protein or a signaling mediator of abnormal cell proliferation pathways and its degradation attenuates abnormal cell growth.

[0034] In some embodiments, atoms in the compounds of the present invention are replaced by at least one desired isotope in an amount higher than the natural abundance of the isotope (i.e., enriched).

[0035] In some embodiments, the compounds of the present invention comprise one or more deuterium atoms. In some aspects, the chiral center of the glutarimide is deuterated.

[0036] In some embodiments, the compounds of the present invention can be used for therapeutic treatment of cancer.

[0037] In some aspects, the compounds of the present invention are used in combination with the second active agent described herein to treat mutant BRAF-mediated cancers. Non-limiting examples of molecular classes that can be used in combination with the compounds of the present invention include MEK inhibitors, immune checkpoint inhibitors, and EGFR antibodies. In some embodiments, the compounds of the present invention are used in combination with trametinib to treat mutant BRAF-mediated cancers, such as melanoma or non-small cell lung cancer. In some embodiments, the compounds of the present invention are used in combination with immune checkpoint inhibitors to treat mutant BRAF-mediated cancers. In some embodiments, the compounds of the present invention are used in combination with cetuximab or panitumumab to treat mutant BRAF-mediated cancers, such as colorectal cancer. In some embodiments, the compounds of the present invention are used in combination with nivolumab, pembrolizumab, cemiplimab, ipilimumab, relatlimab, atezolizumab, avelumab, or durvalumab to treat mutant BRAF-mediated cancers, such as colorectal cancer, melanoma, or non-small cell lung cancer. In other respects, the compounds of the present invention are used in combination with two or more additional active agents described herein to treat mutant BRAF-mediated cancers. In some embodiments, the compounds described herein are used in combination with MEK inhibitors and immune checkpoint inhibitors to treat melanoma or non-small cell lung cancer. Other features and advantages of this application will become clear from the following embodiments. Therefore, the present invention includes at least the following features: (a) The compounds of the present invention or their pharmaceutically acceptable salts or isotopic derivatives (including deuterated derivatives); (b) A method of treating a BRAF-mediated condition (such as abnormal cell proliferation, including cancer) by administering to a patient in need an effective amount of the compound of the present invention described herein or a pharmaceutically acceptable salt thereof; (c) The method of (b) wherein the BRAF mutant-mediated disease is cancer that has metastasized to the brain or CNS; (d) A compound of the present invention or a pharmaceutically acceptable salt or isotope derivative thereof (including deuterated derivatives) for the treatment of conditions mediated by mutant BRAF, such as abnormal cell proliferation, such as tumors or cancer. (e) The method as in (d), wherein the BRAF mutant-mediated disease is cancer that has metastasized to the brain or CNS; (f) Use of the compounds of the present invention or pharmaceutically acceptable salts thereof in an effective amount to treat patients (typically, humans) in need of a condition mediated by mutant BRAF, such as abnormal cell proliferation, such as tumors or cancer. (g) Use of the compounds of the present invention or pharmaceutically acceptable salts or isotopic derivatives thereof (including deuterated derivatives) for the manufacture of medicaments for the treatment of BRAF-mediated conditions (e.g., abnormal cell proliferation, such as tumors or cancers). (h) Use of the compounds of the present invention or pharmaceutically acceptable salts thereof in an effective amount to treat patients (typically, humans) in need of a condition mediated by mutant BRAF, such as abnormal cell proliferation, such as tumors or cancer. (i) as in any of (f) to (h), wherein the BRAF mutant-mediated condition is cancer that has metastasized to the brain or CNS; (j) A pharmaceutical composition comprising an amount of the compound of the present invention or a pharmaceutically acceptable salt or isotopic derivative thereof that is effective in treating a patient; and a pharmaceutically acceptable carrier or diluent; (k) A compound of the present invention as described herein, which is an enantiomer or a mixture of diastereomers (where relevant), including racemic mixtures; (l) A compound of the present invention as described herein, in an enantiomerically or diastereomeric (where relevant) enriched form, comprising a single enantiomer or diastereomeric form (i.e., greater than about 85, 90, 95, 97, or 99% purity); and (m) A method for preparing a therapeutic product containing an effective amount of the compound of the present invention as described herein or a pharmaceutically acceptable salt thereof. Attached Figure Description Figure 1 shows the changes in body weight in female BALB / c nude mice with A375 xenografts after oral administration (po) of vehicle (10 µL / g, po, BID), enrafenib (35 mg / kg, po, QD), dabrafenib (100 mg / kg, po, QD), compound 83 (10 mg / kg, po, BID), compound 93 (10 mg / kg, po, BID), compound 70 (10 mg / kg, po, BID), or compound 54 (10 mg / kg, po, BID). Data points represent group mean body weight. Error bars represent the standard error (SEM) of the mean. The x-axis represents time (days), and the y-axis represents body weight change (grams). The experiment was conducted as described in Example 6. Figure 2 shows the percentage change in body weight (BW) of female BALB / c nude mice with A375 xenografts after oral administration (po) of solvent (10 µL / g, po, BID), enrafenib (35 mg / kg, po, QD), dabrafenib (100 mg / kg, po, QD), compound 83 (10 mg / kg, po, BID), compound 93 (10 mg / kg, po, BID), compound 70 (10 mg / kg, po, BID), or compound 54 (10 mg / kg, po, BID). BW change was calculated based on the animals' body weight at the time of grouping on day 1. Data points represent the percentage change in BW from the group mean. Error bars represent the standard error (SEM) of the mean. The x-axis represents time (days), and the y-axis represents the percentage change in body weight. The experiment was conducted as described in Example 6. Figure 3 shows the in vivo efficacy of enrafenib, dabrafenib, compound 83, compound 93, compound 70, and compound 54 in female BALB / c nude mice with A375 tumors. Mice were administered the solvent (10 µL / g, po, BID), enrafenib (35 mg / kg, po, QD), dabrafenib (100 mg / kg, po, QD), compound 83 (10 mg / kg, po, BID), compound 93 (10 mg / kg, po, BID), compound 70 (10 mg / kg, po, BID), or compound 54 (10 mg / kg, po, BID) orally (po). Data points represent the group mean change in tumor volume. Error bars represent the standard error (SEM) of the mean. The x-axis represents time (days), and the y-axis represents the A375 tumor volume (mm). 3 (Unit: ). Conduct the experiment as described in Example 6. Figure 4 is a bar chart showing the plasma and liver concentrations of enrafenib, dabrafenib, compound 83, compound 93, compound 70, and compound 54 after oral administration (po) of enrafenib (35 mg / kg), dabrafenib (100 mg / kg), compound 83 (10 mg / kg), compound 93 (10 mg / kg), compound 70 (10 mg / kg), or compound 54 (10 mg / kg). Samples were collected 6 hours after the last treatment in female BALB / c nude mice with A375 tumors. The experiment was performed as described in Example 6. Figure 5 is a bar chart showing the concentrations of enrafenib in plasma, tumor, and liver following a single oral (PO) administration of 35 mg / kg. Plasma, tumor, and liver samples were collected from female BALB / c nude mice with A375 tumors at specified time points after treatment for analysis. The experiments were performed as described in Example 6. Figure 6 is a bar chart showing the concentrations of dabrafenib in plasma, tumor, and liver following a single oral (PO) administration of 100 mg / kg. Plasma, tumor, and liver samples were collected from female BALB / c nude mice with A375 tumors at specified time points after treatment for analysis. The experiments were performed as described in Example 6. Figure 7 is a bar chart showing the concentrations of compound 83 in plasma, tumor, and liver following a single oral (PO) administration of 10 mg / kg. Plasma, tumor, and liver samples were collected from female BALB / c nude mice with A375 tumors at specified time points after treatment for analysis. The experiments were performed as described in Example 6. Figure 8 is a bar chart showing the concentrations of compound 93 in plasma, tumor, and liver after a single oral (PO) administration of 10 mg / kg. Plasma, tumor, and liver samples were collected from female BALB / c nude mice with A375 tumors at specified time points after treatment for analysis. The experiments were performed as described in Example 6. Figure 9 is a bar chart showing the concentrations of compound 70 in plasma, tumor, and liver after a single oral (PO) administration of 10 mg / kg. Plasma, tumor, and liver samples were collected from female BALB / c nude mice with A375 tumors at specified time points after treatment for analysis. The experiments were performed as described in Example 6. Figure 10 is a bar chart showing the concentrations of compound 54 in plasma, tumor, and liver following a single oral (PO) administration of 100 mg / kg. Plasma, tumor, and liver samples were collected from female BALB / c nude mice with A375 tumors at specified time points after treatment for analysis. The experiments were performed as described in Example 6. Figures 11A to 11F show Western blots and matching bar graphs of BRAF and phosphorylated ERK (p-ERK) expression levels in A375 tumor samples at multiple time points following administration of solvent, enrafenib (35 mg / kg), dabrafenib (100 mg / kg), compound 83 (10 mg / kg), compound 93 (10 mg / kg), compound 70 (10 mg / kg), or compound 54 (10 mg / kg), representing the endpoint measurement of mitogen-activated protein kinase (MAPK) signaling pathway activation. Experiments were performed as described in Example 6. Figure 12 shows the changes in body weight in female BALB / c nude mice with A375 xenografts after oral administration (po) of the following solvents (10 µL / g, po, BID), dabrafenib (100 mg / kg, po, QD), compound 141 (10 mg / kg, po, QD), compound 141 (10 mg / kg, po, BID), compound 118 (10 mg / kg, po, BID), compound 156 (10 mg / kg, po, BID), or compound 180 (10 mg / kg, po, BID). Data points represent group mean body weight. Error bars represent the standard error (SEM) of the mean. The x-axis represents time (days), and the y-axis represents body weight change (grams). The experiment was conducted as described in Example 7. Figure 13 shows the percentage change in body weight (BW) of female BALB / c nude mice with A375 xenografts after oral administration (po) of the solvent (10 µL / g, po, BID), dabrafenib (100 mg / kg, po, QD), compound 141 (10 mg / kg, po, QD), compound 141 (10 mg / kg, po, BID), compound 118 (10 mg / kg, po, BID), compound 156 (10 mg / kg, po, BID), or compound 180 (10 mg / kg, po, BID). BW change was calculated based on the animals' body weight at the time of grouping on day 1. Data points represent the percentage change in BW from the group mean. Error bars represent the standard error (SEM) of the mean. The x-axis represents time (days), and the y-axis represents the percentage change in body weight. The experiment was conducted as described in Example 7. Figure 14 shows the in vivo efficacy of dabrafenib, compound 141, compound 118, compound 156, and compound 180 in female BALB / c nude mice with A375 tumors. Mice were administered the solvent (10 µL / g, po, BID), dabrafenib (100 mg / kg, po, QD), compound 141 (10 mg / kg, po, QD), compound 118 (10 mg / kg, po, BID), compound 156 (10 mg / kg, po, BID), or compound 180 (10 mg / kg, po, BID) orally (po). Data points represent the group mean change in tumor volume. Error bars represent the standard error (SEM) of the mean. The x-axis represents time (days), and the y-axis represents the A375 tumor volume (mm). 3 (Unit: ). Conduct the experiment as described in Example 7. Figure 15 is a bar chart showing the plasma and liver concentrations of dabrafenib, compound 141, compound 118, compound 156, and compound 180 after oral administration (po) of dabrafenib (100 mg / kg, po, QD), compound 141 (10 mg / kg, po, QD), compound 141 (10 mg / kg, po, BID), compound 118 (10 mg / kg, po, BID), compound 156 (10 mg / kg, po, BID), or compound 180 (10 mg / kg, po, BID). Samples were collected 6 hours after the last treatment in female BALB / c nude mice with A375 tumors. The experiment was performed as described in Example 7. Figure 16 is a bar chart showing the plasma concentrations of dabrafenib, compound 141, compound 118, compound 156, and compound 180 after a single oral (PO) administration of 100 mg / kg dabrafenib and 10 mg / kg of the other test compounds. Plasma samples were collected from female BALB / c nude mice with A375 tumors at 1 hour, 6 hours, 12 hours, and 24 hours post-treatment for analysis. The experiment was conducted as described in Example 7. Figure 17 is a bar chart showing the concentrations of dabrafenib, compound 141, compound 118, compound 156, and compound 180 in tumors after a single oral (PO) administration of 100 mg / kg dabrafenib and 10 mg / kg of the other test compounds. Tumor samples were collected from female BALB / c nude mice with A375 tumors at 1 hour, 6 hours, 12 hours, and 24 hours post-treatment for analysis. The experiments were performed as described in Example 7. Figure 18 is a bar chart showing the concentrations of dabrafenib, compound 141, compound 118, compound 156, and compound 180 in the liver after a single oral (PO) administration of 100 mg / kg dabrafenib and 10 mg / kg of the other test compounds. Liver samples were collected from female BALB / c nude mice with A375 tumors at 6 and 12 hours post-treatment for analysis. The experiments were performed as described in Example 7. Figure 19A to Figure 19E Western blots and matched bar graphs showing the expression levels of BRAF and phosphorylated ERK (p-ERK) in A375 tumor samples at multiple time points following administration of the solvent, dabrafenib (100 mg / kg), compound 141 (10 mg / kg), compound 118 (10 mg / kg), compound 156 (10 mg / kg), or compound 180 (10 mg / kg). Experiments were performed as described in Example 7. Figure 20 shows the changes in body weight in female BALB / c nude mice with A375 xenografts after oral administration (po) of the solvent (10 µL / g, po, BID), enrafenib (35 mg / kg, po, QD), compound 8 (10 mg / kg, po, BID), compound 26 (10 mg / kg, po, BID), or compound 38 (10 mg / kg, po, BID). Data points represent group mean body weight. Error bars represent the standard error (SEM) of the mean. The x-axis represents time (days), and the y-axis represents body weight change (grams). The experiment was conducted as described in Example 8. Figure 21 shows the percentage change in body weight (BW) of female BALB / c nude mice with A375 xenografts after oral administration (po) of the solvent (10 µL / g, po, BID), enrafenib (35 mg / kg, po, QD), compound 8 (10 mg / kg, po, BID), compound 26 (10 mg / kg, po, BID), or compound 38 (10 mg / kg, po, BID). BW change was calculated based on the animals' body weight at day 1. Data points represent the percentage change in BW from the group mean. Error bars represent the standard error (SEM) of the mean. The x-axis represents time (days), and the y-axis represents the percentage change in body weight. The experiment was conducted as described in Example 8. Figure 22 shows the in vivo efficacy of enrafenib, compound 8, compound 26, and compound 38 in female BALB / c nude mice with A375 tumors. Mice were administered the solvent (10 µL / g, po, BID), enrafenib (35 mg / kg, po, QD), compound 8 (10 mg / kg, po, BID), compound 26 (10 mg / kg, po, BID), or compound 38 (10 mg / kg, po, BID) orally (po). Data points represent the group mean change in tumor volume. Error bars represent the standard error (SEM) of the mean. The x-axis represents time (days), and the y-axis represents the A375 tumor volume (mm). 3 (Unit: ). Conduct the experiment as described in Example 8. Figure 23 is a bar chart showing the plasma and liver concentrations of enrafenib, compound 8, compound 26, and compound 38 after oral administration (po) of enrafenib (35 mg / kg, po, QD), compound 8 (10 mg / kg, po, BID), compound 26 (10 mg / kg, po, BID), or compound 38 (10 mg / kg, po, BID). Samples were collected 6 hours after the last treatment in female BALB / c nude mice with A375 tumors. The experiment was performed as described in Example 8. Figure 24 is a bar chart showing the plasma concentrations of enrafenib, compound 8, compound 26, compound 38, and compound 39 after a single oral (PO) administration of 35 mg / kg enrafenib and 10 mg / kg of the other test compounds. Plasma samples were collected from female BALB / c nude mice with A375 tumors at 1 hour, 6 hours, 12 hours, and 24 hours post-treatment for analysis. The experiments were performed as described in Example 8. Figure 25 is a bar chart showing the concentrations of enrafenib, compound 8, compound 26, compound 38, and compound 39 in tumors after a single oral (PO) administration of 35 mg / kg enrafenib and 10 mg / kg of the other test compounds. Tumor samples were collected from female BALB / c nude mice with A375 tumors at 1 hour, 6 hours, 12 hours, and 24 hours post-treatment for analysis. The experiments were performed as described in Example 8. Figure 26 is a bar chart showing the concentrations of enrafenib, compound 8, compound 26, compound 38, and compound 39 in the liver following a single oral (PO) administration of 35 mg / kg enrafenib and 10 mg / kg of the other test compounds. Liver samples were collected from female BALB / c nude mice with A375 tumors at 6 and 12 hours post-treatment for analysis. The experiments were performed as described in Example 8. Figures 27A to 27E show Western blots and matched bar graphs of BRAF and p-ERK expression levels in A375 tumor samples after administration of the solvent, enrafenib, compound 8, compound 26, compound 38, and compound 39. Experiments were performed as described in Example 8. Figure 28 shows the changes in body weight in female BALB / c nude mice with A375 xenografts after oral administration (po) of solvent (10 µL / g, po, BID), dabrafenib (100 mg / kg, po, QD), compound 218 (10 mg / kg, po, BID), or compound 157 (10 mg / kg, po, BID). Data points represent group mean body weight. Error bars represent the standard error (SEM) of the mean. The x-axis represents time (days), and the y-axis represents body weight change (grams). The experiment was conducted as described in Example 9. Figure 29 shows the percentage change in body weight (BW) in female BALB / c nude mice with A375 xenografts after oral administration (po) of solvent (10 µL / g, po, BID), dabrafenib (100 mg / kg, po, QD), compound 218 (10 mg / kg, po, BID), or compound 157 (10 mg / kg, po, BID). BW change was calculated based on the animals' body weight at day 1. Data points represent the percentage change in BW from the group mean. Error bars represent the standard error (SEM) of the mean. The x-axis represents time (days), and the y-axis represents the percentage change in body weight. The experiment was conducted as described in Example 9. Figure 30 shows the in vivo efficacy of dabrafenib, compound 218, and compound 157 in female BALB / c nude mice with A375 tumors. Data points represent the group mean changes in tumor volume. Error bars represent the standard error (SEM) of the mean. The x-axis represents time (days), and the y-axis represents the A375 tumor volume (mm). 3 (Unit: ). Conduct the experiment as described in Example 9. Figure 31 is a bar chart showing the plasma and liver concentrations of dabrafenib, compound 218, and compound 157 after oral administration (po) of dabrafenib (100 mg / kg, po, QD), compound 218 (10 mg / kg, po, BID), or compound 157 (10 mg / kg, po, BID). Samples were collected 6 hours after the last treatment in female BALB / c nude mice with A375 tumors. The experiment was performed as described in Example 9. Figure 32 shows the changes in body weight in female BALB / c nude mice with A375 xenografts after administration of solvent (10 µL / g, po, BID), compound 133 (10 mg / kg, po, BID), compound 144 (10 mg / kg, po, BID), or compound 198 (10 mg / kg, po, BID). Data points represent group mean body weight. Error bars represent the standard error (SEM) of the mean. The x-axis represents time (days), and the y-axis represents body weight change (grams). The experiment was conducted as described in Example 9. Figure 33 shows the percentage change in body weight (BW) of female BALB / c nude mice with A375 xenografts after oral administration (po) of the solvent (10 µL / g, po, BID), compound 133 (10 mg / kg, po, BID), compound 144 (10 mg / kg, po, BID), or compound 198 (10 mg / kg, po, BID). BW change was calculated based on the animals' body weight at the time of grouping on day 1. Data points represent the percentage change in BW from the group mean. Error bars represent the standard error (SEM) of the mean. The x-axis represents time (days), and the y-axis represents the percentage change in body weight. The experiment was conducted as described in Example 9. Figure 34 shows the in vivo efficacy of compounds 133, 144, and 198 in female BALB / c nude mice with A375 tumors. Mice were administered the solvent (10 µL / g, po, BID), compound 133 (10 mg / kg, po, BID), compound 144 (10 mg / kg, po, BID), or compound 198 (10 mg / kg, po, BID) orally (po). Data points represent the group mean change in tumor volume. Error bars represent the standard error (SEM) of the mean. The x-axis represents time (days), and the y-axis represents the A375 tumor volume (mm). 3 (Unit: ). Conduct the experiment as described in Example 9. Figure 35 is a bar chart showing the plasma and liver concentrations of compounds 133, 144, and 198 after oral administration (po) of compound 133 (10 mg / kg, po, BID), compound 144 (10 mg / kg, po, BID), or compound 198 (10 mg / kg, po, BID). Samples were collected 6 hours after the last administration in female BALB / c nude mice with A375 tumors. Experiments were performed as described in Example 9. Figure 36 is a bar chart showing the plasma concentrations of dabrafenib, compound 218, and compound 157 after a single oral (PO) administration of 100 mg / kg dabrafenib and 10 mg / kg of the other test compounds. Plasma samples were collected from female BALB / c nude mice with A375 tumors at 1 hour, 6 hours, 12 hours, and 24 hours post-treatment for analysis. The experiment was conducted as described in Example 9. Figure 37 is a bar chart showing the concentrations of dabrafenib, compound 218, and compound 157 in tumors after a single oral (PO) administration of 100 mg / kg dabrafenib and 10 mg / kg of the other test compounds. Tumor samples were collected from female BALB / c nude mice with A375 tumors at 1 hour, 6 hours, 12 hours, and 24 hours post-treatment for analysis. The experiments were performed as described in Example 9. Figure 38 is a bar chart showing the plasma concentrations of dabrafenib, compound 218, and compound 157 after a single oral (PO) administration of 100 mg / kg dabrafenib and 10 mg / kg of the remaining test compounds. Plasma samples were collected from female BALB / c nude mice with A375 tumors at 6 and 12 hours post-treatment for analysis. The experiment was performed as described in Example 9. Figures 39A to 39C Western blot and matched bar graphs show the expression levels of BRAF and p-ERK in A375 tumor samples after administration of solvent, dabrafenib, compound 218, and compound 157. Experiments were performed as described in Example 9. Figure 40 is a bar chart showing the concentrations of compounds 133, 144, and 198 in plasma samples collected from female BALB / c nude mice with A375 tumors at 1 hour, 6 hours, 12 hours, and 24 hours post-treatment. The experiment was conducted as described in Example 9. Figure 41 is a bar chart showing the concentrations of compounds 133, 144, and 198 in tumor samples collected from female BALB / c nude mice with A375 tumors at 1 hour, 6 hours, 12 hours, and 24 hours post-treatment. The experiment was conducted as described in Example 9. Figure 42 is a bar chart showing the concentrations of compounds 133, 144, and 198 in liver samples collected at 6 and 12 hours after administration. The experiment was conducted as described in Example 9. Figures 43A to 43C The bar chart shows the Western blot analysis of BRAF and p-ERK expression levels in A375 tumor samples after administration of the solvent, compound 133, compound 144, and compound 198. Experiments were performed as described in Example 9. Figure 44 is a bar chart showing the concentrations of compound 204 in plasma, tumor, and liver samples collected from female BALB / c nude mice with A375 tumors at 1 hour, 6 hours, 12 hours, and 24 hours post-treatment. The experiment was conducted as described in Example 9. Figure 45 shows a bar chart and matched protein blots, illustrating the Western blot analysis of BRAF and p-ERK expression levels in the A375 tumor sample after application of solvent and compound 204. The experiment was performed as described in Example 9. Figure 46 is a graph showing the survival percentage of the HT29 human colorectal adenocarcinoma cell line after in vitro administration of various concentrations of compounds 26 and 141. The x-axis represents the concentration in nM and the y-axis represents the survival percentage. The experiment was conducted as described in Example 11. Figure 47 shows the change in bioluminescence signal over time in a luciferase-labeled A375 human melanoma CNS tumor study after administration of the solvent, enrafenib, compound 26, and compound 141. The x-axis represents the number of days after treatment initiation, and the y-axis represents the change in bioluminescence signal. The experiment was conducted as described in Example 12. Figure 48 shows the survival rate curves of mice after administration of solvent, enrafenib, compound 26, and compound 141 in CNS tumor studies. The x-axis represents time in days, and the y-axis represents the survival probability. The experiment was conducted as described in Example 12. Figure 49 is a graph showing the concentrations of compounds 26, 141, and enrafenib in plasma during a luciferase-labeled A375 CNS xenograft pharmacokinetics (PK) study. The x-axis represents treatment time in hours, and the y-axis represents plasma concentration in ng / mL. The experiment was performed as described in Example 12. Figure 50 is a graph showing the concentrations of compounds 26, 141, and enrafenib in tumor-adjacent brain tissue during a luciferase-labeled A375 CNS xenograft pharmacokinetics (PK) study. The x-axis represents time after treatment in hours, and the y-axis represents the concentration in brain tissue in ng / mL. The experiment was performed as described in Example 12. Figure 51 is a pharmacodynamic diagram showing the degradation of BRAF protein in the inoculated CNS tumor. The x-axis represents the time after treatment in hours, and the y-axis represents BRAF in the brain tumor at a normalized ratio. V600E Concentration. Conduct the experiment as described in Example 12. Figure 52 is a bar chart showing the plasma concentration of dabrafenib after oral (PO) administration at 100 mg / kg, QD. Plasma samples from female BALB / c nude mice with A375 tumors were collected at specified time points after treatment for analysis. The experiment was performed as described in Example 13. Figure 53 is a bar chart showing the concentrations of dabrafenib in tumors and the brain after oral (PO) administration at 100 mg / kg, QD. Following treatment, tumor and brain samples were collected from female BALB / c nude mice with A375 tumors at specified time points for analysis. The experiment was performed as described in Example 13. Figure 54 is a bar chart showing the plasma concentration of compound 26 after oral (PO) administration at a BID of 1.5 mg / kg. Plasma samples from female BALB / c nude mice with A375 tumors were collected at specified time points after treatment for analysis. The experiment was performed as described in Example 13. Figure 55 is a bar chart showing the concentrations of compound 26 in tumors and the brain after oral (PO) administration at a BID of 1.5 mg / kg. Following treatment, tumor and brain samples were collected from female BALB / c nude mice with A375 tumors at specified time points for analysis. The experiments were performed as described in Example 13. Figure 56 is a bar chart showing the plasma concentration of compound 26 after oral (PO) administration at a TID of 2 mg / kg. Plasma samples from female BALB / c nude mice with A375 tumors were collected at specified time points after treatment for analysis. The experiment was performed as described in Example 13. Figure 57 is a bar chart showing the concentrations of compound 26 in tumors and the brain after oral (PO) administration at a TID of 2 mg / kg. Following treatment, tumor and brain samples were collected from female BALB / c nude mice with A375 tumors at specified time points for analysis. The experiment was performed as described in Example 13. Figure 58 is a bar chart showing the concentration of compound 26 in plasma after oral (PO) administration at a BID of 3 mg / kg. Plasma samples from female BALB / c nude mice with A375 tumors were collected at specified time points after treatment for analysis. The experiment was performed as described in Example 13. Figure 59 is a bar chart showing the concentrations of compound 26 in tumors and the brain after oral (PO) administration at a BID of 3 mg / kg. Following treatment, tumor and brain samples were collected from female BALB / c nude mice with A375 tumors at specified time points for analysis. The experiment was conducted as described in Example 13. Figure 60 is a bar chart showing the plasma concentration of compound 26 after oral (PO) administration at 6 mg / kg, QD. Plasma samples from female BALB / c nude mice with A375 tumors were collected at specified time points after treatment for analysis. The experiment was performed as described in Example 13. Figure 61 is a bar chart showing the concentrations of compound 26 in tumors and the brain after oral (PO) administration at a dose of 6 mg / kg QD. Following treatment, tumor and brain samples were collected from female BALB / c nude mice with A375 tumors at specified time points for analysis. The experiment was conducted as described in Example 13. Figure 62 is a bar chart showing the concentration of compound 26 in plasma after oral (PO) administration at a BID of 10 mg / kg. Plasma samples from female BALB / c nude mice with A375 tumors were collected at specified time points after treatment for analysis. The experiment was performed as described in Example 13. Figure 63 is a bar chart showing the concentrations of compound 26 in tumors and the brain after oral (PO) administration at a BID of 10 mg / kg. Following treatment, tumor and brain samples were collected from female BALB / c nude mice with A375 tumors at specified time points for analysis. The experiments were performed as described in Example 13. Figure 64 is a bar chart showing the plasma concentration of compound 141 after oral (PO) administration at a BID of 0.75 mg / kg. Plasma samples from female BALB / c nude mice with A375 tumors were collected at specified time points after treatment for analysis. The experiment was performed as described in Example 13. Figure 65 is a bar chart showing the concentrations of compound 141 in tumors and the brain after oral (PO) administration at a BID of 0.75 mg / kg. Following treatment, tumor and brain samples were collected from female BALB / c nude mice with A375 tumors at specified time points for analysis. The experiments were performed as described in Example 13. Figure 66 is a bar chart showing the plasma concentration of compound 141 after oral (PO) administration at a TID of 1 mg / kg. Plasma samples from female BALB / c nude mice with A375 tumors were collected at specified time points after treatment for analysis. The experiment was performed as described in Example 13. Figure 67 is a bar chart showing the concentration of compound 141 in tumors and the brain after oral (PO) administration at a TID of 1 mg / kg. Following treatment, tumor and brain samples were collected from female BALB / c nude mice with A375 tumors at specified time points for analysis. The experiment was conducted as described in Example 13. Figure 68 is a bar chart showing the plasma concentration of compound 141 after oral (PO) administration at a BID of 1.5 mg / kg. Plasma samples from female BALB / c nude mice with A375 tumors were collected at specified time points after treatment for analysis. The experiment was performed as described in Example 13. Figure 69 is a bar chart showing the concentrations of compound 141 in tumors and the brain after oral (PO) administration at a BID of 1.5 mg / kg. Following treatment, tumor and brain samples were collected from female BALB / c nude mice with A375 tumors at specified time points for analysis. The experiments were performed as described in Example 13. Figure 70 is a bar chart showing the plasma concentration of compound 141 after oral (PO) administration at a dose of 3 mg / kg QD. Plasma samples from female BALB / c nude mice with A375 tumors were collected at specified time points after treatment for analysis. The experiment was performed as described in Example 13. Figure 71 is a bar chart showing the concentrations of compound 141 in tumors and the brain after oral (PO) administration at a dose of 3 mg / kg QD. Following treatment, tumor and brain samples were collected from female BALB / c nude mice with A375 tumors at specified time points for analysis. The experiment was conducted as described in Example 13. Figure 72 is a bar chart showing the concentration of compound 141 in plasma after oral (PO) administration at a BID of 5 mg / kg. Plasma samples from female BALB / c nude mice with A375 tumors were collected at specified time points after treatment for analysis. The experiment was performed as described in Example 13. Figure 73 is a bar chart showing the concentrations of compound 141 in tumors and the brain after oral (PO) administration at a BID of 5 mg / kg. Following treatment, tumor and brain samples were collected from female BALB / c nude mice with A375 tumors at specified time points for analysis. The experiments were performed as described in Example 13. Figures 74A to 74M show Western blots and matched bar graphs of BRAF and p-ERK expression levels in A375 tumor samples after administration of solvent, dabrafenib, compound 26, or compound 141. Experiments were performed as described in Example 13. Figure 75 shows the change in body weight (BW) in female BALB / c nude mice after administration of compound 26, compound 141, or dabrafenib to the A375 xenograft. Data points represent group mean body weight. Error bars represent the standard error (SEM) of the mean. The experiment was conducted as described in Example 14. Figure 76 shows the percentage change in body weight (BW) after administration of compound 26, compound 141, or dabrafenisol to female BALB / c nude mice with A375 xenografts. BW changes were calculated based on the animals' body weight at day 1. Data points represent group mean body weight. Error bars represent the standard error (SEM) of the mean. The experiment was conducted as described in Example 14. Figure 77 shows tumor volume trace in female BALB / c nude mice with A375 xenografts after administration of compounds 26, 141, and dabrafenib. Data points represent the group mean percentage of tumor volume. Error bars represent the standard error (SEM) of the mean. The experiment was performed as described in Example 14. Figure 78 is a bar chart showing the concentrations of dabrafenib in plasma, tumors, and brain after oral (PO) administration at a dose of 100 mg / kg QD. Following treatment, plasma, tumor, and brain samples were collected from female BALB / c nude mice with A375 tumors at specified time points for analysis. The experiment was performed as described in Example 14. Figure 79 is a bar chart showing the plasma concentration of compound 26 after different oral (PO) doses. Plasma samples from female BALB / c nude mice with A375 tumors were collected at specified time points after treatment for analysis. The experiment was performed as described in Example 14. Figure 80 is a bar chart showing the concentrations of compound 26 in tumors and the brain after different oral (PO) doses. Following treatment, tumor and brain samples were collected from female BALB / c nude mice with A375 tumors at specified time points for analysis. The experiments were performed as described in Example 14. Figure 81 is a bar chart showing the plasma concentration of compound 141 after different oral (PO) doses. Plasma samples from female BALB / c nude mice with A375 tumors were collected at specified time points after treatment for analysis. The experiment was performed as described in Example 14. Figure 82 is a bar chart showing the concentrations of compound 141 in tumors and the brain after different oral (PO) doses. Following treatment, tumor and brain samples were collected from female BALB / c nude mice with A375 tumors at specified time points for analysis. The experiments were performed as described in Example 14. Figure 83 shows the results of compound 26, compound 26-NMe, compound 141, and compound 141-NMe in A375 cell viability assays. The y-axis represents cell viability (%), and the x-axis represents concentration (nM). The experiments were performed as described in Example 15. Figure 84 shows the cell viability assay results of compounds 26 and 141 in the V600K cell line (CTGlo). The y-axis represents cell viability (%), and the x-axis represents concentration (Log(nM)). The experiment was performed as described in Example 16. Figure 85 shows the prolonged survival curves of the BRAF intracranial model in CNS tumor studies after administration of solvent, enrafenib, compound 26, and compound 141. The x-axis represents time in days, and the y-axis represents the probability of survival. The experiment was conducted as described in Example 12. Detailed Implementation In some embodiments, the present invention provides compounds of formula I to formula XXXII: (I) (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII) (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII),

[0038] Or a pharmaceutically acceptable salt thereof, wherein the substituents and variables are as described herein.

[0039] It has been surprisingly found that the selected compounds of the present invention provide rapid and sustained degradation of mutant BRAF proteins. For example, when tested in the BRAF V600E degradation assay of Example 5, both compounds 26 and 141 degraded more than 50% of the BRAF V600E protein at nanomolar concentrations in just two hours.

[0040] Given the minimal inhibitory activity of the selected compounds, this robust degradation activity is remarkable. In the A375 cell bioavailability analysis of Example 15, compounds 26 and 141 were potent cytotoxic agents, both exhibiting efficacy of 30+% against cancer cell survival at a concentration of 100 nM. However, the degradation-deficient versions (N-methyl analogs) of compounds 26 and 141 showed minimal efficacy against cell survival at a concentration of 100 nM (see [link to relevant documentation]). Figure 83 This experiment shows that the selected compounds of the present invention exert their therapeutic effects by degrading mutant BRAF, rather than by degrading and inhibiting mutant BRAF.

[0041] By degrading mutant BRAF, the compounds of this invention can be used to treat BRAF-mediated cancers. For example, in A375 human melanoma xenografts, oral delivery of compounds 8, 118, 141, 156, or 180 elicited a more robust antitumor response than FDA-approved BRAF inhibitors such as dabrafenib or enrafenib (see [link to original text]). Figure 14 and 22 These compounds, when administered at a BID of 10 mg / kg, caused significant tumor regression in xenograft models.

[0042] It has also been surprisingly discovered that the compounds of the present invention have significant blood-brain barrier permeability and can be used to treat cancers that have metastasized to the brain. For example, mice with CNS tumors administered compound 26 or compound 141, as described in Example 12, had significantly longer lifespans than mice administered enrafenib. Samples obtained from mice with CNS tumors showed that BRAFV600E levels in brain tumors were much lower after administration of compound 26 or compound 141 than after administration of enrafenib (see [link to sample]). Figure 51 ).

[0043] In some aspects, a method is provided for treating BRAF-mediated cancer that has metastasized to the brain or central nervous system (CNS), comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a patient in need. In some embodiments, the cancer that has metastasized to the brain or central nervous system is colorectal cancer, melanoma, or non-small cell lung cancer. Terms

[0044] Compounds are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0045] Unless the context specifically excludes it, the compounds of the present invention may be racemic, enantiomers, mixtures of enantiomers, diastereomers, mixtures of diastereomers, tautomers, N -Oxides, isomers, such as rotational isomers, as each is specifically described.

[0046] The term "a / an" does not indicate a limitation on quantity, but rather indicates the presence of at least one of the mentioned items. The terms "or" signify "and / or". Unless otherwise specified herein, the designation of numerical ranges is intended only as a shorthand for individually referring to the individual values ​​belonging to that range, and each individual value is incorporated into the specification as if it were individually specified herein. The endpoints of all ranges are included within the range and can be combined independently. Unless otherwise specified herein or otherwise obviously contradicted by the context, all methods described herein may be performed in any suitable order. The use of exemplification or illustrative language (e.g., "such as") is intended only to better illustrate the invention and does not constitute a limitation on the scope of the invention, unless otherwise specified.

[0047] This invention includes compounds in which atoms are substituted with at least one desired isotope in an amount higher than the natural abundance of the isotope (i.e., enriched). The isotope is an atom having the same number of atoms but different mass numbers (i.e., the same number of protons but different numbers of neutrons).

[0048] Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as... 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. In some embodiments, isotopically labeled compounds can be used for metabolic studies (e.g., 14 C); Reaction kinetic studies (e.g.) 2 H or 3 H); detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution analysis, or patient radiation therapy. Specifically, via 18 F-labeled compounds are particularly useful for PET or SPECT studies. The isotope-labeled compounds and their prodrugs of the present invention can generally be prepared by replacing unlabeled reagents with readily available isotope-labeled reagents by performing the procedures described in the following processes or examples and preparations.

[0049] Isotopic substitution (e.g., deuterium substitution) can be partial or complete. Partial deuterium substitution means that at least one hydrogen atom is substituted with deuterium. In some embodiments, the isotope is enriched by 90%, 95%, or 99% or more for any isotope at any position of interest. In one embodiment, deuterium is enriched by 90%, 95%, or 99% at the desired position.

[0050] In some embodiments, substitution of hydrogen atoms with deuterium atoms may be provided in any of the compounds of the present invention. In some embodiments, substitution of hydrogen atoms with deuterium atoms occurs within one or more groups selected from any of the R or variables described herein. For example, when any group is or contains, for example, methyl, ethyl, or methoxy, alkyl residues may be deuterated (in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3, etc.). In some other embodiments, when two substituents combine to form a ring, the unsubstituted carbon may be deuterated.

[0051] In some embodiments, the compounds of the present invention are isotopically labeled. In some embodiments, at least one is independently selected from R 1 R 2 R 2' R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 17 R 18 R 19 and R 60 The R group is isotopically labeled, with one, two, or more isotopes if the valence allows. In some embodiments, the isotope label is deuterium. In some embodiments, at least one deuterium is placed on an atom where the bond breaks during the compound's metabolism in vivo, or on one, two, or three atoms away from the metabolized bond (e.g., this may be referred to as α, β, or γ, or a primary, secondary, or tertiary isotope effect). In other embodiments, the isotope label is... 13 C. In other embodiments, the isotope is labeled as 18 F.

[0052] In some non-limiting embodiments, the invention includes the solvated form of the compounds described herein. The term "solvent" refers to a molecular complex of a compound of the invention (including its salts) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a compound of the invention and water. Pharmaceutically acceptable solvates according to the invention include those in which the solvent can be isotopically substituted, such as D2O, acetone- d 6 DMSO- d 6 (Dimethyl sulfoxide). Solvents can be in liquid or solid form.

[0053] A dashed line ("-") not between two letters or symbols is used to indicate the connection point of a substituent. For example, -(C=O)NH2 is connected to a carbonyl (C=O) group.

[0054] "alkyl" refers to a branched or straight-chain saturated aliphatic hydrocarbon group. Unless otherwise specified, "alkyl" is typically a C1-C8 alkyl. In some non-limiting embodiments, the alkyl contains 1 to 12 carbon atoms, and more generally, 1 to 6 carbon atoms or 1 to 4 carbon atoms. In some non-limiting embodiments, the alkyl contains 1 to 8 carbon atoms. In some embodiments, the alkyl is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6. The specified ranges used herein indicate alkyl groups having members within the range described as independent species. For example, as used herein, the term C1-C6 alkyl indicates a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms and means that each of them is described as an independent species, and therefore, each subset is considered to be described separately. For example, as used herein, the term C1-C4 alkyl indicates a straight-chain or branched alkyl group having 1, 2, 3, or 4 carbon atoms and means that each of them is described as an independent species. Examples of alkyl groups include (but are not limited to) methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The term "alkyl" also encompasses cycloalkyl or carbocyclic groups. For example, unless the context explicitly excludes it, "cycloalkyl" or "carbocyclic" may be considered part of this definition when terms including "alkane" are used. For example, and not limited to, unless the context explicitly excludes it, the terms alkyl, alkoxy, haloalkyl, etc., may be considered to include cyclic forms of alkyl groups.

[0055] Non-limiting examples of "cycloalkyl" include dihydroindene and tetrahydronaphthalene, wherein the connection points of the groups are located on the cycloalkyl ring.

[0056] For example: It is a "cycloalkyl" compound.

[0057] However, It is an "aryl" group.

[0058] The term "alkoxy" represents a group with the formula -O-alkyl. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0059] The term "cycloalkoxy" indicates a group with the formula -O-cycloalkyl. Examples of cycloalkoxy groups include cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, cycloheptoxy, and cyclooctoxy.

[0060] "alkylene" refers to a divalent saturated hydrocarbon. For example, alkylene can have 1, 2, 3, 4, 5, 6, 7 to 8 carbon motifs, 1 to 6 carbon motifs, or a specified number of carbon atoms, such as C1-C2 alkylene, C1-C3 alkylene, C1-C4 alkylene, C1-C5 alkylene, or C1-C6 alkylene.

[0061] The term "cyano" indicates a -C≡N group.

[0062] The term "hydroxyl" indicates the -OH group.

[0063] "Halogen" and "halogen" refer independently to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0064] "Haloalkyl" refers to a branched or straight-chain alkyl group in which one or more of the aforementioned halogen atoms (up to the maximum permissible number of halogen atoms) are substituted. Unless otherwise specified, "haloalkyl" is typically a C1-C4 haloalkyl. Examples of haloalkyl include (but are not limited to) fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Perhaloalkyl" means an alkyl group in which all hydrogen atoms are substituted with halogen atoms. Examples include (but are not limited to) trifluoromethyl and pentafluoroethyl.

[0065] "Haloalkoxy" indicates a haloalkyl group as described herein that is connected via an oxygen bridge (oxygen in an alcohol group).

[0066] "Heterocyclic alkyl" refers to an alkyl group as described herein that has been substituted with a heterocyclic group as described herein.

[0067] "Aryl group" refers to an alkyl group as described herein that has been substituted with an aryl group.

[0068] Non-limiting examples of "araneyl" include: , , , , and .

[0069] In some embodiments, "aryl group" is .

[0070] In some embodiments, "aralkyl" refers to an aryl-substituted 2-carbon alkyl group.

[0071] Non-limiting examples of "araneyl" also include: , , and .

[0072] In some embodiments, "aralkyl" refers to an aryl-substituted 3-carbon alkyl group.

[0073] "Heteroarylalkyl" refers to an alkyl group substituted with a heteroaryl group as described herein.

[0074] As used herein, "aryl" refers to a group in a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., with 6, 10, or 14 π electrons in a cyclic array), which provides 6 to 14 ring carbon atoms and zero heteroatoms ("C"). 6-14 Aryl group ("C6 aryl"; for example, phenyl). In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl"; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C6 aryl"). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 cyclic carbon atoms (“C”). 14 "Aryl" (e.g., anthracene). "Aryl" also includes ring systems in which an aryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the linking group or linking point is located on the aryl ring, and in such cases, the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system. The one or more fused carbocyclic or heterocyclic groups may be 4- to 7-membered or 5- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic groups, optionally containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon, and boron to form, for example, a 3,4-methylenedioxyphenyl group. In some embodiments, an aryl group is side-attached. An example of a side-attached ring is a phenyl-substituted phenyl group.

[0075] In some embodiments, "aryl" is a 6-carbon aromatic group fused with a heterocycle, wherein the linking point is located on the aryl ring. Non-limiting examples of "aryl" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the linking point for each group is located on the aromatic ring.

[0076] For example, It is an "aryl" group.

[0077] However, It is a "heterocyclic" group.

[0078] In some embodiments, "aryl" is a 6-carbon aromatic group fused with a cycloalkyl group, wherein the linking point is located on the aryl ring. Non-limiting examples of "aryl" include dihydroindene and tetrahydronaphthalene, wherein the linking point of each group is located on the aromatic ring.

[0079] For example, It is an "aryl" group.

[0080] However, It is a "cycloalkyl" group. The terms "heterocyclic group," "heterocycle," and "heterocyclic" include saturated and partially saturated cyclic groups containing heteroatoms, which may be selected from nitrogen, sulfur, and oxygen. Heterocycles include monocyclic 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered rings, and 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, or 16-membered bicyclic systems (which may include bridged and helically fused bicyclic systems). They do not include rings containing -OO-, -OS-, or -SS- portions. Examples of saturated heterocyclic groups include saturated 3-, 4-, 5-, or 6-membered heterocyclic groups containing 1, 2, 3, or 4 nitrogen atoms [e.g., pyrrolyl, imidazolyl, piperidinyl, pyrrololinyl, piperazinel]; saturated 3-, 4-, 5-, or 6-membered heterocyclic groups containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms [e.g., morpholinyl]; and saturated 3-, 4-, 5-, or 6-membered heterocyclic groups containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen atoms [e.g., thiazolyl]. Examples of partially saturated heterocyclic groups include (but are not limited to) dihydrothiophene, dihydropyranyl, dihydrofuranyl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include (but are not limited to) pyrrolyl, imidazoalkyl, piperidinyl, pyrrololinyl, pyrazolyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazoalkyl, dihydrothiopheneyl, 2,3-dihydro-benzo[1,4]dioxanecyclohexyl, indololinyl, isoyindololinyl, dihydrobenzothiopheneyl, dihydrobenzofuranyl, isochromyl, chromanyl, 1,2-dihydroquinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 1,2,3,4-tetrahydro-quinolinyl, 2,3,4,4a,9,9a-hexahydro-1 H -3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4- a Isoquinolinyl, 3,4-dihydro-2 H-Benzo[1,4]oxazinyl, benzo[1,4]dioxane-hexyl, 2,3-dihydro-1H-1λ'-benzo[d]isothiazo-6-yl, dihydropyranyl, dihydrofuranyl, isoquinoline-1(2H)-keto, benzo[d]oxazol-2(3H)-keto, 1,3-dihydro-2 H -Benz[d]imidazol-2-keto, benzo[d]thiazol-2(3H)-keto, 1,2-dihydro-3 H -pyrazole-3-one, 2(1 H )-pyridinone group, 2-piperazinone group, indoline group and dihydrothiazolyl group.

[0081] The terms "heterocyclic group", "heterocycle" and "heterocyclic group" also include portions in which the heterocyclic group is fused / condensed with an aryl or heteroaryl group: such as unsaturated condensed heterocyclic groups containing 1, 2, 3, 4 or 5 nitrogen atoms, for example, indoline, isoindoline, unsaturated condensed heterocyclic groups containing 1 or 2 oxygen atoms and 1, 2 or 3 nitrogen atoms, unsaturated condensed heterocyclic groups containing 1 or 2 sulfur atoms and 1, 2 or 3 nitrogen atoms, and saturated, partially unsaturated and unsaturated condensed heterocyclic groups containing 1 or 2 oxygen or sulfur atoms.

[0082] Other non-limiting examples of "heterocycles" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the linkages of the groups are located on the heterocycle.

[0083] For example, It is a "heterocyclic" group.

[0084] However, It is an "aryl" group. The term "heteroaryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a ring array) and 1, 2, 3, 4, 5, or 6 heteroatoms independently selected from O, N, and S, wherein the cyclic nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Examples include (but are not limited to) 5- to 6-membered unsaturated heteromonocyclic groups containing 1, 2, 3, or 4 nitrogen atoms, such as pyrroloyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4] H- 1,2,4-Triazolyl, 1 H -1,2,3-triazolyl, 2 H-1,2,3-triazolyl]; 5- or 6-membered unsaturated heteromonocyclic groups containing oxygen atoms, such as pyranyl, 2-furanyl, 3-furanyl, etc.; 5- or 6-membered unsaturated heteromonocyclic groups containing sulfur atoms, such as 2-thienyl, 3-thienyl, etc.; 5- or 6-membered unsaturated heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl [e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; 5- or 6-membered unsaturated heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, thiadiazolyl [e.g. 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl]. Other examples include 8-, 9-, or 10-membered heteroaryl bicyclic groups, such as indazole, indolyl, imidazo[1,5-a]pyridyl, benzimidazolyl, 4(3) H )-Quinazolinyl, Quinolinyl, Isoquinolinyl, Isoindolyl, Thiophenothiopheneyl, Indolazinyl, Benzofuranyl, Isobenzofuranyl, Benzothiopheneyl, Isobenzothiopheneyl, Benzooxazolyl, Benzothiazolyl, Purinyl, Coumarinyl, Triazolyl and Triazolylpyridyl.

[0085] The term "bicyclic" refers to a ring system in which two rings are fused together, and each ring is independently selected from carbocyclic, heterocyclic, aryl, and heteroaryl rings. Bicyclic systems also include helically fused bicyclic systems. Non-limiting examples of bicyclic groups include: , , , , , , ,and .

[0086] When the term "bicyclic" is used in the context of divalent residues, the linkage point may be located on separate rings or on the same ring. In some embodiments, both linkage points are located on the same ring. In some embodiments, the two linkage points are located on different rings. Non-limiting examples of divalent bicyclic groups include: , , , , , , ,and .

[0087] "Dosage form" refers to the unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, granules, pellets, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gels, mucosal, and similar forms. "Dosage form" may also include implants, such as ocular implants. The term "sulfonyl" alone or in combination with other groups is the group -SO2-.

[0088] When referring to variables, the terms "as defined herein" and "as described herein" are incorporated by reference into the broad definition of the variable as well as the specific, more specific, and most specific definitions (if any).

[0089] The term "inhibitor" refers to a compound that competes with a specific ligand for binding to a specific receptor, reduces or prevents the binding of a specific ligand to a specific receptor, or reduces or prevents the function of a specific protein.

[0090] If one of the starting materials or compounds of this invention contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, a suitable protecting group may be introduced prior to the critical steps using methods well known in the art (e.g., as described in TW Greene and PGM Wuts, "Protective Groups in Organic Chemistry," 3rd edition, 1999, Wiley, New York). Such protecting groups may be removed later in the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butyloxycarbonyl (Boc), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethylcarbamate (Teoc), benzyloxycarbonyl (Cbz), and p-methoxybenzyloxycarbonyl (Moz). The compounds of the present invention may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers (such as racemates), mixtures of diastereomers, racemates of diastereomers, or mixtures of racemates of diastereomers.

[0091] The term "asymmetric carbon atom" refers to a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog Convention, an asymmetric carbon atom can have an "R" or "S" configuration.

[0092] As long as a chiral carbon is present in the chemical structure, the structure is intended to encompass all stereoisomers associated with that chiral carbon, as well as mixtures thereof, as long as the structure is a pure stereoisomer.

[0093] The compounds of the present invention can exist in tautomer forms, that is, structural isomers that interconvert with, especially in solution, the compounds of the present invention as illustrated herein. The compounds of the present invention are intended to cover all their existing tautomer forms.

[0094] The compounds of this invention can exist as solvates. The compounds of this invention are intended to cover all their existing solvates.

[0095] The present invention also provides pharmaceutical compositions, methods of use, and methods for preparing the above-mentioned compounds.

[0096] The compounds of this invention may contain one or more asymmetric centers and therefore may exist as racemic mixtures, mixtures of enantiomers, single enantiomers, mixtures of diastereomers, and individual diastereomers. Additional asymmetric centers may be present depending on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and this invention is intended to include all possible mixtures of optical and diastereomers, as well as pure or partially purified compounds. This invention aims to cover all such isomeric forms of these compounds. As is known in the art, the independent synthesis or chromatographic separation of these diastereomers can be achieved by appropriately modifying the methods described herein. Their absolute stereochemistry can be determined by X-ray crystallography of the crystalline products or intermediates, which, if necessary, are derivatized with reagents containing asymmetric centers of known absolute configuration. If necessary, racemic mixtures of the compounds can be separated to isolate individual enantiomers. Separation can be carried out by methods well known in the art, such as coupling a racemic mixture of compounds with an enantiomerically pure compound to form a mixture of diastereomers, and then separating the individual diastereomers by standard methods such as stepwise crystallization or chromatography.

[0097] In embodiments providing optically pure enantiomers, optically pure enantiomers mean that the compound contains more than 90% by weight of the desired isomer, particularly more than 95% by weight, or even more particularly more than 99% by weight of the desired isomer, the weight percentage being based on the total weight of the compound's isomers. Chiral pure compounds or chiral enriched compounds can be prepared by chiral selective synthesis or by separation of enantiomers. Enantiomer separation can be performed on the final product or, alternatively, on suitable intermediates. Examples of Formula I and Formula XVII

[0098] In some embodiments, the compounds of the present invention are selected from compounds of formula I and formula XVII: (I) and

[0099] (XVII), Or its pharmaceutically acceptable salt.

[0100] in:

[0101] ring It is a spiroheterocyclic group, bridged cycloalkyl group, bridged heterocyclic group, or piperidine-1,4-diyl group containing one or two nitrogen atoms and without other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0102] ring It is a spiroheterocyclic group containing one nitrogen atom and one oxygen atom and no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0103] A 1 Selected from -NR 2 -and-CHR 2 '-;

[0104] R 1 Selected from hydrogen, alkyl, and cycloalkyl groups;

[0105] R 2 Selected from hydrogen, alkyl, cycloalkyl, and haloalkyl;

[0106] or R 1 and R 2 Together with the nitrogen atom to which it is attached, it forms an optional structure via one or two R atoms. 3 Substituted heterocyclic alkyl groups;

[0107] R 2 Selected from hydrogen, alkyl, cycloalkyl, and haloalkyl;

[0108] or R 1 and R 2 'Together with the carbon atom to which it is attached, it forms optionally via one or two R... 3 Substituted cycloalkyl groups;

[0109] Each R 3 Independently selected from hydrogen, halogen, alkyl, cycloalkyl, and alkoxy;

[0110] R 4 Selected from hydrogen, alkyl, cyano, and halogen;

[0111] R 5 Selected from hydrogen, alkyl, cyano, and halogen;

[0112] A 2 Selected from -O-, -NH- and -(C=O)-;

[0113] R6 Selected from hydrogen, halogen, hydroxyl, amino, dialkylamino, alkoxy, alkyl, and alkoxyalkyl;

[0114] R 7 Selected from hydrogen and alkyl groups;

[0115] R 8 Selected from hydrogen, alkyl, cyano, halogen, and alkoxy groups;

[0116] R 9 Selected from hydrogen, alkyl, cyano, halogen, and alkoxy groups;

[0117] A 5 It can be -CH- or -N-;

[0118] R 17 Selected from hydrogen, alkyl, cyano, hydroxyl, cycloalkyl, halogen, and alkoxy;

[0119] R 18 Selected from hydrogen, alkyl, cyano, hydroxyl, cycloalkyl, halogen, and alkoxy;

[0120] R 19 Selected from hydrogen, alkyl, cyano, hydroxyl, cycloalkyl, halogen, and alkoxy;

[0121] A 15 Selected from the bond, -O- and -NH-, where when A 15 When it is O or NH, A 6 For CH and where A 15 When A is the key 6 For N or CH; and

[0122] A 6 It can be -CH- or -N-.

[0123] In some embodiments, the compound of formula I or formula XVII is selected from: and

[0124] ,

[0125] Or its pharmaceutically acceptable salt.

[0126] The present invention further provides the following:

[0127] A compound of formula I or XVII or a pharmaceutically acceptable salt thereof, used as a therapeutically active substance for treating BRAF-mediated diseases caused by mutants.

[0128] A pharmaceutical composition comprising a compound of formula I or formula XVII or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0129] Use of compounds of formula I or XVII or pharmaceutically acceptable salts thereof for the therapeutic and / or preventive treatment of cancer.

[0130] A compound of formula I or XVII or a pharmaceutically acceptable salt thereof, used for the treatment and / or prevention of cancer.

[0131] Use of a compound of formula I or formula XVII or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the therapeutic and / or preventive treatment of cancer. A method for therapeutic and / or preventive treatment of cancer, comprising administering to a patient in need an effective amount of a compound of formula I or XVII or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, the cancer is a BRAF V600X mutant tumor.

[0133] In some embodiments, the cancer is a BRAF V600E / K mutant tumor.

[0134] In some embodiments, the cancer has not been treated with targeted therapy.

[0135] In some embodiments, the cancer is selected from melanoma, colorectal cancer, and lung cancer, especially non-small cell lung cancer.

[0136] Examples of Formula II and Formula XVIII

[0137] In some embodiments, the compounds of the present invention are selected from compounds of formula II and formula XVIII: (II) and

[0138] (XVIII),

[0139] Or its pharmaceutically acceptable salt.

[0140] in:

[0141] ring It is a bridging heterocyclic group, fused heterocyclic group, or spirocyclic group containing one or two nitrogen atoms and no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0142] ring It is a cycloalkyl or heterocyclic group containing one or two nitrogen atoms and zero or one oxygen atom, and containing no other heteroatoms, wherein the cycloalkyl or heterocyclic group contains one or two nitrogen atoms and zero or one oxygen atom, and contains no other heteroatoms. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; and all other substituents as defined herein.

[0143] In some embodiments, the compound of formula II or formula XVIII is selected from: and

[0144] Or its pharmaceutically acceptable salt.

[0145] The present invention further provides the following: A compound of formula II or XVIII or a pharmaceutically acceptable salt thereof, used as a therapeutically active substance for treating BRAF-mediated diseases caused by mutants.

[0146] A pharmaceutical composition comprising a compound of formula II or XVIII or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0147] The use of compounds of formula II or XVIII or pharmaceutically acceptable salts thereof for the therapeutic and / or preventive treatment of cancer.

[0148] A compound of formula II or XVIII or a pharmaceutically acceptable salt thereof, used for the treatment and / or prevention of cancer.

[0149] Use of a compound of formula II or XVIII or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the therapeutic and / or preventive treatment of cancer. A method for therapeutic and / or preventive treatment of cancer, comprising administering to a patient in need an effective amount of a compound of formula II or XVIII or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the cancer is a BRAF V600X mutant tumor.

[0151] In some embodiments, the cancer is a BRAF V600E / K mutant tumor.

[0152] In some embodiments, the cancer has not been treated with targeted therapy.

[0153] In some embodiments, the cancer is selected from melanoma, colorectal cancer, and lung cancer, especially non-small cell lung cancer. Examples of Formula III and Formula XIX

[0154] In some embodiments, the compounds of the present invention are selected from compounds of formula III and formula XIX: (III) and

[0155] (XIX),

[0156] Or its pharmaceutically acceptable salt.

[0157] in:

[0158] ring It is a spiroheterocyclic group containing one oxygen atom and zero or one nitrogen atom, and containing no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0159] ring It is a cycloalkyl group, wherein the ring is cycloalkyl. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; and all other substituents as defined herein.

[0160] In some embodiments, the compound of formula III or formula XIX is selected from: and

[0161] Or its pharmaceutically acceptable salt.

[0162] The present invention further provides the following:

[0163] A compound of formula III or formula XIX or a pharmaceutically acceptable salt thereof, used as a therapeutically active substance for treating BRAF-mediated diseases caused by mutants.

[0164] A pharmaceutical composition comprising a compound of formula III or formula XIX or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0165] Use of compounds of formula III or XIX or pharmaceutically acceptable salts thereof for the therapeutic and / or preventive treatment of cancer.

[0166] A compound of formula III or formula XIX or a pharmaceutically acceptable salt thereof, used for the treatment and / or prevention of cancer.

[0167] Use of a compound of formula III or XIX or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the therapeutic and / or preventive treatment of cancer.

[0168] A method for treating and / or preventing cancer, comprising administering to a patient in need an effective amount of a compound of formula III or formula XIX or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the cancer is a BRAF V600X mutant tumor.

[0170] In some embodiments, the cancer is a BRAF V600E / K mutant tumor.

[0171] In some embodiments, the cancer has not been treated with targeted therapy.

[0172] In some embodiments, the cancer is selected from melanoma, colorectal cancer, and lung cancer, especially non-small cell lung cancer. Examples of Formula IV and Formula XX

[0173] In some embodiments, the compounds of the present invention are selected from compounds of formula IV and formula XX: (IV) and

[0174] (XX) Or its pharmaceutically acceptable salt.

[0175] in:

[0176] ring It is a spiroheterocyclic group containing one or two nitrogen atoms and zero or one oxygen atom, and containing no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0177] ring It is a cycloalkyl group, wherein the ring is cycloalkyl. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; and all other substituents as defined herein.

[0178] In some embodiments, compounds of formula IV or formula XX are selected from: and Or its pharmaceutically acceptable salt.

[0179] The present invention further provides the following:

[0180] A compound of formula IV or formula XX or a pharmaceutically acceptable salt thereof, used as a therapeutically active substance for the treatment of BRAF-mediated diseases caused by mutants.

[0181] A pharmaceutical composition comprising a compound of formula IV or formula XX or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0182] The use of compounds of formula IV or formula XX or pharmaceutically acceptable salts thereof for the therapeutic and / or preventive treatment of cancer.

[0183] A compound of formula IV or formula XX or a pharmaceutically acceptable salt thereof, used for the treatment and / or prevention of cancer.

[0184] Use of a compound of formula IV or formula XX or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the therapeutic and / or preventive treatment of cancer.

[0185] A method for therapeutic and / or preventive treatment of cancer, comprising administering to a patient in need an effective amount of a compound of formula IV or formula XX or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments, the cancer is a BRAF V600X mutant tumor.

[0187] In some embodiments, the cancer is a BRAF V600E / K mutant tumor.

[0188] In some embodiments, the cancer has not been treated with targeted therapy.

[0189] In some embodiments, the cancer is selected from melanoma, colorectal cancer, and lung cancer, especially non-small cell lung cancer. Examples of Formula V and Formula XXI

[0190] In some embodiments, the compounds of the present invention are selected from compounds of formula V and compounds of formula XXI: (V) and

[0191] (XXI), Or its pharmaceutically acceptable salt.

[0192] in:

[0193] ring It is a spiroheterocyclic group containing one or two nitrogen atoms and zero or one oxygen atom, and containing no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; and all other substituents as defined herein.

[0194] In some embodiments, compounds of formula V or formula XXI are selected from: and Or its pharmaceutically acceptable salt.

[0195] The present invention further provides the following:

[0196] A compound of formula V or formula XXI or a pharmaceutically acceptable salt thereof, used as a therapeutically active substance for treating BRAF-mediated diseases caused by mutants.

[0197] A pharmaceutical composition comprising a compound of formula V or formula XXI or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0198] Use of compounds of formula V or formula XXI or pharmaceutically acceptable salts thereof for the therapeutic and / or preventive treatment of cancer.

[0199] A compound of formula V or formula XXI or a pharmaceutically acceptable salt thereof, used for the treatment and / or prevention of cancer.

[0200] Use of compounds of formula V or formula XXI or pharmaceutically acceptable salts thereof in the preparation of medicaments for the therapeutic and / or preventive treatment of cancer.

[0201] A method for therapeutic and / or preventive treatment of cancer, comprising administering to a patient in need an effective amount of a compound of formula V or formula XXI or a pharmaceutically acceptable salt thereof.

[0202] In some embodiments, the cancer is a BRAF V600X mutant tumor.

[0203] In some embodiments, the cancer is a BRAF V600E / K mutant tumor.

[0204] In some embodiments, the cancer has not been treated with targeted therapy.

[0205] In some embodiments, the cancer is selected from melanoma, colorectal cancer, and lung cancer, especially non-small cell lung cancer. Examples of Formula VI and Formula XXII

[0206] In some embodiments, the compounds of the present invention are selected from compounds of formula VI and formula XXII: (VI) and

[0207] (XXII), Or its pharmaceutically acceptable salt.

[0208] in:

[0209] ring It is a spiroheterocyclic group containing one or two nitrogen atoms and zero or one oxygen atom, and containing no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0210] ring It is a cycloalkyl, piperidine-1,4-diyl, spiroheterocyclic group containing one or two nitrogen atoms and without other heteroatoms, wherein the cycloalkyl group is... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; and all other substituents as defined herein.

[0211] In some embodiments, compounds of formula VI or formula XXII are selected from: and Or its pharmaceutically acceptable salt.

[0212] The present invention further provides the following:

[0213] A compound of formula VI or XXII or a pharmaceutically acceptable salt thereof, used as a therapeutically active substance for the treatment of BRAF-mediated diseases caused by mutants.

[0214] A pharmaceutical composition comprising a compound of formula VI or formula XXII or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0215] The use of compounds of formula VI or XXII or pharmaceutically acceptable salts thereof for the therapeutic and / or preventive treatment of cancer.

[0216] A compound of formula VI or XXII or a pharmaceutically acceptable salt thereof, used for the treatment and / or prevention of cancer.

[0217] Use of compounds of formula VI or XXII or pharmaceutically acceptable salts thereof for the preparation of medicaments for the therapeutic and / or preventive treatment of cancer.

[0218] A method for therapeutic and / or preventive treatment of cancer, comprising administering to a patient in need an effective amount of a compound of formula VI or XXII or a pharmaceutically acceptable salt thereof.

[0219] In some embodiments, the cancer is a BRAF V600X mutant tumor.

[0220] In some embodiments, the cancer is a BRAF V600E / K mutant tumor.

[0221] In some embodiments, the cancer has not been treated with targeted therapy.

[0222] In some embodiments, the cancer is selected from melanoma, colorectal cancer, and lung cancer, especially non-small cell lung cancer. Examples of Formula VII and Formula XXIII

[0223] In some embodiments, the compounds of the present invention are selected from compounds of formula VII and formula XXIII: (VII) and

[0224] (XXIII), Or its pharmaceutically acceptable salt. in: ring It is a cycloalkyl group, 3,3-difluoro-piperidine-1,4-diyl, piperazine-1,4-diyl, bridged cycloalkyl group, bridged heterocyclic group, or a spiroheterocyclic group containing one or two nitrogen atoms and one or two oxygen atoms and containing no other heteroatoms, wherein the cycloalkyl group, piperazine-1,4-diyl or spiroheterocyclic group is optionally substituted by one or two substituents independently selected from halogen, alkyl and alkoxy groups; and all other substituents are as defined herein.

[0225] In some embodiments, the compound of formula VII or formula XXIII is selected from: and Or its pharmaceutically acceptable salt.

[0226] The present invention further provides the following:

[0227] A compound of formula VII or XXIII or a pharmaceutically acceptable salt thereof, used as a therapeutically active substance for treating BRAF-mediated diseases caused by mutants.

[0228] A pharmaceutical composition comprising a compound of formula VII or XXIII or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0229] The use of compounds of formula VII or XXIII or pharmaceutically acceptable salts thereof for the therapeutic and / or preventive treatment of cancer.

[0230] A compound of formula VII or XXIII or a pharmaceutically acceptable salt thereof, used for the treatment and / or prevention of cancer.

[0231] Use of compounds of formula VII or XXIII or pharmaceutically acceptable salts thereof in the preparation of medicaments for the therapeutic and / or preventive treatment of cancer.

[0232] A method for therapeutic and / or preventive treatment of cancer, comprising administering to a patient in need an effective amount of a compound of formula VII or XXIII or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, the cancer is a BRAF V600X mutant tumor.

[0234] In some embodiments, the cancer is a BRAF V600E / K mutant tumor.

[0235] In some embodiments, the cancer has not been treated with targeted therapy.

[0236] In some embodiments, the cancer is selected from melanoma, colorectal cancer, and lung cancer, especially non-small cell lung cancer. Examples of Formula VIII and Formula XXIV

[0237] In some embodiments, the compounds of the present invention are selected from compounds of formula VIII and formula XXIV: (VIII) and

[0238] (XXIV), Or its pharmaceutically acceptable salt.

[0239] in:

[0240] ring It is a spiroheterocyclic group containing one nitrogen atom and one oxygen atom and no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0241] ring It is a cycloalkyl group substituted with one, two, or three substituents, which are independently selected from alkyl, alkoxy, F, Cl, Br, and OH; and all other substituents are as defined herein.

[0242] In some embodiments, compounds of formula VIII or XXIV are selected from: and , Or its pharmaceutically acceptable salt.

[0243] The present invention further provides the following:

[0244] A compound of formula VIII or XXIV or a pharmaceutically acceptable salt thereof, used as a therapeutically active substance for the treatment of BRAF-mediated diseases caused by mutants.

[0245] A pharmaceutical composition comprising a compound of formula VIII or XXIV or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0246] Use of compounds of formula VIII or XXIV or pharmaceutically acceptable salts thereof for the therapeutic and / or preventive treatment of cancer.

[0247] A compound of formula VIII or XXIV or a pharmaceutically acceptable salt thereof, used for the treatment and / or prevention of cancer.

[0248] Use of compounds of formula VIII or XXIV or pharmaceutically acceptable salts thereof for the preparation of medicaments for the therapeutic and / or preventive treatment of cancer.

[0249] A method for therapeutic and / or preventive treatment of cancer, comprising administering to a patient in need an effective amount of a compound of formula VIII or XXIV or a pharmaceutically acceptable salt thereof.

[0250] In some embodiments, the cancer is a BRAF V600X mutant tumor.

[0251] In some embodiments, the cancer is a BRAF V600E / K mutant tumor.

[0252] In some embodiments, the cancer has not been treated with targeted therapy.

[0253] In some embodiments, the cancer is selected from melanoma, colorectal cancer, and lung cancer, especially non-small cell lung cancer. Examples of Formula IX and Formula XXV In some embodiments, the compounds of the present invention are selected from compounds of formula IX and formula XXV: (IX) and (XXV), Or its pharmaceutically acceptable salt. in: ring It is a cycloalkyl, spirocycloalkyl, or heterocyclic group containing one or two nitrogen atoms and no other heteroatoms, wherein the cycloalkyl group is a cycloalkyl group. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; ring It is a cycloalkyl, spirocycloalkyl, or heterocyclic group containing one or two nitrogen atoms and no other heteroatoms, wherein the cycloalkyl group is a cycloalkyl group. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; and all other substituents as defined herein. In some embodiments, compounds of formula IX or XXV are selected from: and Or its pharmaceutically acceptable salt. The present invention further provides the following: A compound of formula IX or XXV or a pharmaceutically acceptable salt thereof, used as a therapeutically active substance for treating BRAF-mediated diseases caused by mutants. A pharmaceutical composition comprising a compound of formula IX or XXV or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The use of compounds of formula IX or XXV or pharmaceutically acceptable salts thereof for the therapeutic and / or preventive treatment of cancer. A compound of formula IX or XXV or a pharmaceutically acceptable salt thereof, used for the treatment and / or prevention of cancer. The use of compounds of formula IX or XXV or pharmaceutically acceptable salts thereof for the preparation of medicaments for the therapeutic and / or preventive treatment of cancer. A method for therapeutic and / or preventive treatment of cancer, comprising administering to a patient in need an effective amount of a compound of formula IX or XXV or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is a BRAF V600X mutant tumor. In some embodiments, the cancer is a BRAF V600E / K mutant tumor. In some embodiments, the cancer has not been treated with targeted therapy. In some embodiments, the cancer is selected from melanoma, colorectal cancer, and lung cancer, especially non-small cell lung cancer. Examples of Formula X and Formula XXVI In some embodiments, the compounds of the present invention are selected from compounds of formula X and formula XXVI: (X) and (XXVI), Or its pharmaceutically acceptable salt.

[0254] in:

[0255] ring It is a cycloalkyl, spirocycloalkyl, or heterocyclic group containing one or two nitrogen atoms and no other heteroatoms, wherein the cycloalkyl group is a cycloalkyl group. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0256] ring It is a cycloalkyl, spirocycloalkyl, or heterocyclic group containing one or two nitrogen atoms and no other heteroatoms, wherein the cycloalkyl group is a cycloalkyl group. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; and all other substituents as defined herein.

[0257] In some embodiments, compounds of formula X or formula XXVI are selected from: and Or its pharmaceutically acceptable salt.

[0258] The present invention further provides the following:

[0259] A compound of formula X or formula XXVI, or a pharmaceutically acceptable salt thereof, used as a therapeutically active substance for treating BRAF-mediated diseases caused by mutants.

[0260] A pharmaceutical composition comprising a compound of formula X or formula XXVI or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0261] The use of compounds of formula X or XXVI or pharmaceutically acceptable salts thereof for the therapeutic and / or preventive treatment of cancer.

[0262] A compound of formula X or formula XXVI or a pharmaceutically acceptable salt thereof, used for the treatment and / or prevention of cancer.

[0263] Use of a compound of formula X or formula XXVI or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the therapeutic and / or preventive treatment of cancer.

[0264] A method for therapeutic and / or preventive treatment of cancer, comprising administering to a patient in need an effective amount of a compound of formula X or formula XXVI or a pharmaceutically acceptable salt thereof.

[0265] In some embodiments, the cancer is a BRAF V600X mutant tumor.

[0266] In some embodiments, the cancer is a BRAF V600E / K mutant tumor.

[0267] In some embodiments, the cancer has not been treated with targeted therapy. In some embodiments, the cancer is selected from melanoma, colorectal cancer, and lung cancer, especially non-small cell lung cancer. Examples of Formulas XI and XXVII

[0268] In some embodiments, the compounds of the present invention are selected from compounds of formula XI and formula XXVII: (XI) and

[0269] (XXVII), Or its pharmaceutically acceptable salt.

[0270] in:

[0271] ring It is a bridging heterocyclic group or spirocyclic group containing one or two nitrogen atoms and no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0272] ring It is a cycloalkyl group, wherein the ring is cycloalkyl. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; and all other substituents as defined herein.

[0273] In some embodiments, compounds of formula XI or formula XXVII are selected from: and Or its pharmaceutically acceptable salt.

[0274] The present invention further provides the following:

[0275] A compound of formula XI or XXVII or a pharmaceutically acceptable salt thereof, used as a therapeutically active substance for treating BRAF-mediated diseases caused by mutants.

[0276] A pharmaceutical composition comprising a compound of formula XI or XXVII or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Use of compounds of formula XI or XXVII or pharmaceutically acceptable salts thereof for the therapeutic and / or preventive treatment of cancer.

[0277] A compound of formula XI or XXVII or a pharmaceutically acceptable salt thereof, used for the treatment and / or prevention of cancer.

[0278] Use of compounds of formula XI or XXVII or pharmaceutically acceptable salts thereof for the preparation of medicaments for the therapeutic and / or preventive treatment of cancer.

[0279] A method for therapeutic and / or preventive treatment of cancer, comprising administering to a patient in need an effective amount of a compound of formula XI or XXVII or a pharmaceutically acceptable salt thereof.

[0280] In some embodiments, the cancer is a BRAF V600X mutant tumor.

[0281] In some embodiments, the cancer is a BRAF V600E / K mutant tumor.

[0282] In some embodiments, the cancer has not been treated with targeted therapy.

[0283] In some embodiments, the cancer is selected from melanoma, colorectal cancer, and lung cancer, especially non-small cell lung cancer. Examples of Formula XII and Formula XXVIII

[0284] In some embodiments, the compounds of the present invention are selected from compounds of formula XII and formula XXVIII: (XII) and (XXVIII), Or its pharmaceutically acceptable salt.

[0285] in:

[0286] ring It is a cycloalkyl group, wherein the ring is cycloalkyl. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; and all other substituents as defined herein.

[0287] In some embodiments, compounds of formula XII or XXVIII are selected from: and Or its pharmaceutically acceptable salt.

[0288] The present invention further provides the following:

[0289] A compound of formula XII or XXVIII or a pharmaceutically acceptable salt thereof, used as a therapeutically active substance for the treatment of BRAF-mediated diseases caused by mutants.

[0290] A pharmaceutical composition comprising a compound of formula XII or XXVIII or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0291] The use of compounds of formula XII or XXVIII or pharmaceutically acceptable salts thereof for the therapeutic and / or preventive treatment of cancer.

[0292] A compound of formula XII or XXVIII or a pharmaceutically acceptable salt thereof, used for the treatment and / or prevention of cancer.

[0293] Use of compounds of formula XII or XXVIII or pharmaceutically acceptable salts thereof in the preparation of medicaments for the therapeutic and / or preventive treatment of cancer.

[0294] A method for therapeutic and / or preventive treatment of cancer, comprising administering to a patient in need an effective amount of a compound of formula XII or XXVIII or a pharmaceutically acceptable salt thereof.

[0295] In some embodiments, the cancer is a BRAF V600X mutant tumor.

[0296] In some embodiments, the cancer is a BRAF V600E / K mutant tumor.

[0297] In some embodiments, the cancer has not been treated with targeted therapy.

[0298] In some embodiments, the cancer is selected from melanoma, colorectal cancer, and lung cancer, especially non-small cell lung cancer. Examples of Formula XIII and Formula XXIX

[0299] In some embodiments, the compounds of the present invention are selected from compounds of formula XIII and formula XXIX: (XIII) and

[0300] (XXIX), Or its pharmaceutically acceptable salt.

[0301] in:

[0302] ring It is a spiroheterocyclic group containing one nitrogen atom and one oxygen atom and no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0303] ring It is a cycloalkyl group, wherein the ring is cycloalkyl. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; and all other substituents as defined herein.

[0304] In some embodiments, compounds of formula XIII or XXIX are selected from: and Or its pharmaceutically acceptable salt.

[0305] The present invention further provides the following:

[0306] A compound of formula XIII or XXIX or a pharmaceutically acceptable salt thereof, used as a therapeutically active substance for the treatment of BRAF-mediated diseases caused by mutants.

[0307] A pharmaceutical composition comprising a compound of formula XIII or XXIX or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0308] The use of compounds of formula XIII or XXIX or pharmaceutically acceptable salts thereof for the therapeutic and / or preventive treatment of cancer.

[0309] A compound of formula XIII or XXIX or a pharmaceutically acceptable salt thereof, used for the treatment and / or prevention of cancer.

[0310] Use of compounds of formula XIII or XXIX or pharmaceutically acceptable salts thereof for the preparation of medicaments for the therapeutic and / or preventive treatment of cancer.

[0311] A method for therapeutic and / or preventive treatment of cancer, comprising administering to a patient in need an effective amount of a compound of formula XIII or XXIX or a pharmaceutically acceptable salt thereof.

[0312] In some embodiments, the cancer is a BRAF V600X mutant tumor.

[0313] In some embodiments, the cancer is a BRAF V600E / K mutant tumor.

[0314] In some embodiments, the cancer has not been treated with targeted therapy.

[0315] In some embodiments, the cancer is selected from melanoma, colorectal cancer, and lung cancer, especially non-small cell lung cancer. Examples of Formula XIV and Formula XXX

[0316] In some embodiments, the compounds of the present invention are selected from compounds of formula XIV and formula XXX: (XIV) and

[0317] (XXX), Or its pharmaceutically acceptable salt.

[0318] in:

[0319] ring It is a spiroheterocyclic group containing one nitrogen atom and one oxygen atom and no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0320] ring It is a cycloalkyl group, wherein the ring is cycloalkyl. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; and all other substituents as defined herein.

[0321] In some embodiments, compounds of formula XIV or formula XXX are selected from: and Or its pharmaceutically acceptable salt.

[0322] The present invention further provides the following:

[0323] A compound of formula XIV or formula XXX or a pharmaceutically acceptable salt thereof, used as a therapeutically active substance for the treatment of BRAF-mediated diseases caused by mutants.

[0324] A pharmaceutical composition comprising a compound of formula XIV or formula XXX or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0325] The use of compounds of formula XIV or formula XXX or pharmaceutically acceptable salts thereof for the therapeutic and / or preventive treatment of cancer.

[0326] A compound of formula XIV or formula XXX or a pharmaceutically acceptable salt thereof, used for the treatment and / or prevention of cancer.

[0327] The use of a compound of formula XIV or formula XXX or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the therapeutic and / or preventive treatment of cancer.

[0328] A method for therapeutic and / or preventive treatment of cancer, comprising administering to a patient in need an effective amount of a compound of formula XIV or formula XXX or a pharmaceutically acceptable salt thereof.

[0329] In some embodiments, the cancer is a BRAF V600X mutant tumor.

[0330] In some embodiments, the cancer is a BRAF V600E / K mutant tumor.

[0331] In some embodiments, the cancer has not been treated with targeted therapy.

[0332] In some embodiments, the cancer is selected from melanoma, colorectal cancer, and lung cancer, especially non-small cell lung cancer. Examples of Formula XV and Formula XXXI

[0333] In some embodiments, the compounds of the present invention are selected from compounds of formula XV and formula XXXI: (XV) and

[0334] (XXXI), Or its pharmaceutically acceptable salt.

[0335] in:

[0336] ring It is a spiroheterocyclic group containing one nitrogen atom and one oxygen atom and no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0337] ring It is a cycloalkyl group, wherein the ring is cycloalkyl. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; and all other substituents as defined herein.

[0338] In some embodiments, compounds of formula XV or formula XXXI are selected from: and Or its pharmaceutically acceptable salt.

[0339] The present invention further provides the following:

[0340] A compound of formula XV or XXXI or a pharmaceutically acceptable salt thereof, used as a therapeutically active substance for the treatment of BRAF-mediated diseases caused by mutants.

[0341] A pharmaceutical composition comprising a compound of formula XV or formula XXXI or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0342] The use of compounds of formula XV or XXXI or pharmaceutically acceptable salts thereof for the therapeutic and / or preventive treatment of cancer.

[0343] A compound of formula XV or formula XXXI or a pharmaceutically acceptable salt thereof, used for the treatment and / or prevention of cancer.

[0344] The use of compounds of formula XV or XXXI or pharmaceutically acceptable salts thereof for the preparation of medicaments for the therapeutic and / or preventive treatment of cancer.

[0345] A method for therapeutic and / or preventive treatment of cancer, comprising administering to a patient in need an effective amount of a compound of formula XV or formula XXXI or a pharmaceutically acceptable salt thereof.

[0346] In some embodiments, the cancer is a BRAF V600X mutant tumor.

[0347] In some embodiments, the cancer is a BRAF V600E / K mutant tumor.

[0348] In some embodiments, the cancer has not been treated with targeted therapy.

[0349] In some embodiments, the cancer is selected from melanoma, colorectal cancer, and lung cancer, especially non-small cell lung cancer. Examples of Formula XVI and Formula XXXII

[0350] In some embodiments, the compounds of the present invention are selected from compounds of formula XVI and formula XXXII: (XVI) and (XXXII), Or its pharmaceutically acceptable salt.

[0351] in:

[0352] ring It is a spiroheterocyclic group containing one nitrogen atom and one oxygen atom and no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0353] ring It is a heterocyclic group, which is optionally substituted by one or two independent substituents selected from halogen, alkyl, OH and alkoxy groups; and all other substituents are as defined herein.

[0354] In some embodiments, compounds of formula XVI or XXXII are selected from... and Or its pharmaceutically acceptable salt.

[0355] The present invention further provides the following:

[0356] A compound of formula XVI or XXXII or a pharmaceutically acceptable salt thereof, used as a therapeutically active substance for the treatment of BRAF-mediated diseases caused by mutants.

[0357] A pharmaceutical composition comprising a compound of formula XVI or XXXII or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0358] The use of compounds of formula XVI or XXXII or pharmaceutically acceptable salts thereof for the therapeutic and / or preventive treatment of cancer.

[0359] A compound of formula XVI or XXXII or a pharmaceutically acceptable salt thereof, used for the treatment and / or prevention of cancer.

[0360] Use of compounds of formula XVI or XXXII or pharmaceutically acceptable salts thereof for the preparation of medicaments for the therapeutic and / or preventive treatment of cancer.

[0361] A method for therapeutic and / or preventive treatment of cancer, comprising administering to a patient in need an effective amount of a compound of formula XVI or XXXII or a pharmaceutically acceptable salt thereof.

[0362] In some embodiments, the cancer is a BRAF V600X mutant tumor.

[0363] In some embodiments, the cancer is a BRAF V600E / K mutant tumor.

[0364] In some embodiments, the cancer has not been treated with targeted therapy.

[0365] In some embodiments, the cancer is selected from melanoma, colorectal cancer, and lung cancer, especially non-small cell lung cancer.

[0366] Other embodiments of the compounds of the present invention: Examples of Formulas I to XXXII

[0367] 1. A compound of the following formula: (I) (II) (III) (IV) (V) (VI) (VII) (VIII) (IX) (X), (XI) (XII) (XIII) (XIV) (XV) (XVI) (XVII) (XVIII) (XIX) (XX) (XXI) (XXII) (XXIII) (XXIV) (XXV) (XXVI) (XXVII) (XXVIII) (XXIX) (XXX) (XXXI), or

[0368] (XXXII), Or its pharmaceutically acceptable salt.

[0369] in:

[0370] ring It is a spiroheterocyclic group containing one or two nitrogen atoms and no other heteroatoms, or a piperidine-1,4-diyl group, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0371] ring It is a spiroheterocyclic group containing one nitrogen atom and one oxygen atom and no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0372] ring It is a bridging heterocyclic group or spirocyclic group containing one or two nitrogen atoms and no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0373] ring It is a cycloalkyl or heterocyclic group containing one or two nitrogen atoms and zero or one oxygen atom, and containing no other heteroatoms, wherein the cycloalkyl or heterocyclic group contains one or two nitrogen atoms and zero or one oxygen atom, and contains no other heteroatoms. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0374] ring It is a spiroheterocyclic group containing one oxygen atom and zero or one nitrogen atom, and containing no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0375] ring It is a cycloalkyl group, wherein the ring is cycloalkyl. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0376] ring It is a spiroheterocyclic group containing one or two nitrogen atoms and zero or one oxygen atom, and containing no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0377] ring It is a cycloalkyl group, 3,3-difluoro-piperidine-1,4-diyl, piperazine-1,4-diyl, or a spiroheterocyclic group containing one or two nitrogen atoms and zero or one oxygen atom and without other heteroatoms, wherein the cycloalkyl group, piperazine-1,4-diyl, or spiroheterocyclic group is optionally substituted by one or two independent substituents selected from halogen, alkyl, and alkoxy groups;

[0378] ring It is a cycloalkyl, piperidine-1,4-diyl, spiroheterocyclic group containing one or two nitrogen atoms and without other heteroatoms, wherein the cycloalkyl group is... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0379] ring It is a cycloalkyl group substituted with 1, 2 or 3 substituents, which are independently selected from alkyl, alkoxy, F, Cl, Br and OH;

[0380] ring It is a cycloalkyl, spirocycloalkyl, or heterocyclic group containing one or two nitrogen atoms and no other heteroatoms, wherein the cycloalkyl group is a cycloalkyl group. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0381] ring It is a cycloalkyl, spirocycloalkyl, or heterocyclic group containing one or two nitrogen atoms and no other heteroatoms, wherein the cycloalkyl group is a cycloalkyl group. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups;

[0382] ring It is a heterocyclic group optionally substituted with one or two substituents, which are independently selected from halogens, alkyl groups, OH groups and alkoxy groups;

[0383] A 1 Selected from -NR 2 -and-CHR 2 '-;

[0384] R 1 Selected from hydrogen, alkyl, and cycloalkyl groups;

[0385] R 2 Selected from hydrogen, alkyl, cycloalkyl, and haloalkyl;

[0386] or R 1 and R 2 Together with the nitrogen atom to which it is attached, it forms an optional structure via one or two R atoms. 3 Substituted heterocyclic alkyl groups;

[0387] R 2 Selected from hydrogen, alkyl, cycloalkyl, and haloalkyl;

[0388] or R 1 and R 2 'Together with the carbon atom to which it is attached, it forms optionally via one or two R... 3 Substituted cycloalkyl groups;

[0389] Each R 3 Independently selected from hydrogen, halogen, alkyl, cycloalkyl, and alkoxy;

[0390] R 4 Selected from hydrogen, alkyl, cyano, and halogen;

[0391] R 5 Selected from hydrogen, alkyl, cyano, and halogen;

[0392] A 2 Selected from -O-, -NH- and -(C=O)-;

[0393] R 6 Selected from hydrogen, halogen, hydroxyl, amino, dialkylamino, alkoxy, alkyl, and alkoxyalkyl;

[0394] R 7 Selected from hydrogen and alkyl groups;

[0395] R 8 Selected from hydrogen, alkyl, cyano, halogen, and alkoxy groups;

[0396] R 9 Selected from hydrogen, alkyl, cyano, halogen, and alkoxy groups;

[0397] R 17 Selected from hydrogen, alkyl, cyano, hydroxyl, cycloalkyl, halogen, and alkoxy;

[0398] R 18 Selected from hydrogen, alkyl, cyano, hydroxyl, cycloalkyl, halogen, and alkoxy;

[0399] R 19 Selected from hydrogen, alkyl, cyano, hydroxyl, cycloalkyl, halogen, and alkoxy;

[0400] A 5 It can be -CH- or -N-;

[0401] A 15 Selected from the bond, -O- and -NH-, where when A 15 When it is O or NH, A 6 For CH and where A 15 When A is the key 6 For N or CH;

[0402] R 60 It is isopropyl; pyrrolidine-1-yl substituted with F or OMe; or cyclopropyl;

[0403] q is 0 or 1;

[0404] r is 0, 1, or 2;

[0405] p is 0, 1, or 2; and

[0406] w is 1 or 2.

[0408] 2. The compound of Example 1, wherein the compound has the formula...

[0409] (I), Or its pharmaceutically acceptable salt.

[0410] 3. The compound of Example 1, wherein the compound has the formula...

[0411] (VIII), Or its pharmaceutically acceptable salt.

[0412] 4. The compound of Example 1, wherein the compound has the formula...

[0413] (XIII), Or its pharmaceutically acceptable salt.

[0414] 5. The compound of Example 1, wherein the compound has the formula...

[0415] (XVI), Or its pharmaceutically acceptable salt.

[0416] 6. The compound of Example 1, wherein the compound has the formula...

[0417] (XV), Or its pharmaceutically acceptable salt.

[0418] 7. The compound of Example 1, wherein the compound has the formula...

[0419] (XIV), Or its pharmaceutically acceptable salt.

[0420] 8. The compound of any one of Examples 1 to 7, wherein the ring for .

[0421] 9. The compound of any one of Examples 1 to 7, wherein the ring for .

[0422] 10. The compound of Example 1, wherein the compound has the formula...

[0423] (II), Or its pharmaceutically acceptable salt.

[0424] 11. The compound of Example 1, wherein the compound has the formula... (XI), Or its pharmaceutically acceptable salt.

[0425] 12. The compound as described in Example 10 or 11, wherein the ring... for , , ,or .

[0426] 13. The compound as described in Example 10 or 11, wherein the ring... for , ,or .

[0427] 14. The compound of Example 1, wherein the compound has the formula... (III), Or its pharmaceutically acceptable salt.

[0428] 15. The compound of Example 1, wherein the compound has the formula... (IV), Or its pharmaceutically acceptable salt.

[0429] 16. The compound of Example 1, wherein the compound has the formula... (XII), Or its pharmaceutically acceptable salt.

[0430] 17. The compound of any one of Examples 14 to 16, wherein the ring for .

[0431] 18. The compound of Example 1, wherein the compound has the formula... (V), Or its pharmaceutically acceptable salt.

[0432] 19. The compound of Example 1, wherein the compound has the formula... (VI), Or its pharmaceutically acceptable salt.

[0433] 20. The compound of Example 1, wherein the compound has the formula... (VII), Or its pharmaceutically acceptable salt.

[0434] 21. The compound of Example 1, wherein the compound has the formula... (IX), Or its pharmaceutically acceptable salt.

[0435] 22. The compound of Example 1, wherein the compound has the formula... (X), Or its pharmaceutically acceptable salt.

[0436] 23. The compound of any one of Examples 1 to 22, wherein A 5 It is -CH-.

[0437] 24. The compound of any one of Examples 1 to 22, wherein A 5 It is -N-.

[0438] 25. The compound of any one of Examples 1 to 24, wherein R 7 It is CH3.

[0439] 26. The compound of any one of Examples 1 to 24, wherein R 7 For H.

[0440] 27. The compound of any one of Examples 1 to 26, wherein R 8 It is CH3.

[0441] 28. The compound of any one of Examples 1 to 26, wherein R 8 For H.

[0442] 29. The compound of any one of Examples 1 to 26, wherein R 8 It is F.

[0443] 30. The compound of any one of Examples 1 to 26, wherein R 8 For CN.

[0444] 31. The compound of any one of Examples 1 to 26, wherein R 8 It is OCH3.

[0445] 32. The compound of any one of Examples 1 to 31, wherein R 9 It is CH3.

[0446] 33. The compound of any one of Examples 1 to 31, wherein R 9 For H.

[0447] 34. The compound of any one of Examples 1 to 31, wherein R 9 It is F.

[0448] 35. The compound of any one of Examples 1 to 31, wherein R 9 For CN.

[0449] 36. The compound of any one of Examples 1 to 31, wherein R 9 It is OCH3.

[0450] 37. The compound of Example 1, wherein the compound has the formula...

[0451] (XVII), Or its pharmaceutically acceptable salt.

[0452] 38. The compound of Example 1, wherein the compound has the formula... (XXIV), Or its pharmaceutically acceptable salt.

[0453] 39. The compound of Example 1, wherein the compound has the formula... (XXIX), Or its pharmaceutically acceptable salt.

[0454] 40. The compound of Example 1, wherein the compound has the formula... (XXX), Or its pharmaceutically acceptable salt.

[0455] 41. The compound of Example 1, wherein the compound has the formula... (XXXI), Or its pharmaceutically acceptable salt.

[0456] 42. The compound of Example 1, wherein the compound has the formula... (XXXII), Or its pharmaceutically acceptable salt.

[0457] 43. The compound of any one of Examples 37 to 42, wherein the ring for .

[0458] 44. The compound of any one of Examples 37 to 42, wherein the ring for .

[0459] 45. The compound of Example 1, wherein the compound has the formula...

[0460] (XVIII), Or its pharmaceutically acceptable salt.

[0461] 46. ​​The compound of Example 1, wherein the compound has the formula... (XXVII), Or its pharmaceutically acceptable salt.

[0462] 47. The compounds of Examples 45 or 46, wherein the ring for , , ,or .

[0463] 48. The compounds of Examples 45 or 46, wherein the ring for , ,or .

[0464] 49. The compound of Example 1, wherein the compound has the formula... (XIX), Or its pharmaceutically acceptable salt.

[0465] 50. The compound of Example 1, wherein the compound has the formula... (XX), Or its pharmaceutically acceptable salt.

[0466] 51. The compound of Example 1, wherein the compound has the formula... (XXVIII), Or its pharmaceutically acceptable salt.

[0467] 52. The compound of any one of Examples 49 to 51, wherein the ring for .

[0468] 53. The compound of Example 1, wherein the compound has the formula... (XXI), Or its pharmaceutically acceptable salt.

[0469] 54. The compound of Example 1, wherein the compound has the formula... (XXII), Or its pharmaceutically acceptable salt.

[0470] 55. The compound of Example 1, wherein the compound has the formula... (XXIII), Or its pharmaceutically acceptable salt.

[0471] 56. The compound of Example 1, wherein the compound has the formula... (XXV), Or its pharmaceutically acceptable salt.

[0472] 57. The compound of Example 1, wherein the compound has the formula... (XXVI), Or its pharmaceutically acceptable salt.

[0473] 58. The compound of any one of Examples 37 to 57, wherein A 6 For CH and A 15 It is -N-.

[0474] 59. The compound of any one of Examples 37 to 57, wherein A 6 For CH and A 15 It is -O-.

[0475] 60. The compound of any one of Examples 37 to 57, wherein A 6 For CH and A 15 For key.

[0476] 61. The compound of any one of Examples 37 to 57, wherein A 6 For N and A 15 For key.

[0477] 62. The compound of any one of Examples 37 to 61, wherein R 17 For H.

[0478] 63. The compound of any one of Examples 37 to 61, wherein R 17 It is CH3.

[0479] 64. The compound of any one of Examples 37 to 61, wherein R 17 It is a cyano group.

[0480] 65. The compound of any one of Examples 37 to 61, wherein R 17 It is a hydroxyl group.

[0481] 66. The compound of any one of Examples 37 to 61, wherein R 17 It is cyclopropyl.

[0482] 67. The compound of any one of Examples 37 to 61, wherein R 17 It is F.

[0483] 68. The compound of any one of Examples 37 to 61, wherein R 17 It is OCH3.

[0484] 69. The compound of any one of Examples 37 to 68, wherein R 18 For H.

[0485] 70. The compound of any one of Examples 37 to 68, wherein R 18 It is CH3.

[0486] 71. The compound of any one of Examples 37 to 68, wherein R 18 It is a cyano group.

[0487] 72. The compound of any one of Examples 37 to 68, wherein R 18 It is a hydroxyl group.

[0488] 73. The compound of any one of Examples 37 to 68, wherein R 18 It is cyclopropyl.

[0489] 74. The compound of any one of Examples 37 to 68, wherein R 18 It is F.

[0490] 75. The compound of any one of Examples 37 to 68, wherein R 18 It is OCH3.

[0491] 76. The compound of any one of Examples 37 to 75, wherein R 19 For H.

[0492] 77. The compound of any one of Examples 37 to 75, wherein R 19 It is CH3.

[0493] 78. The compound of any one of Examples 37 to 75, wherein R 19 It is a cyano group.

[0494] 79. The compound of any one of Examples 37 to 75, wherein R 19 It is a hydroxyl group.

[0495] 80. The compound of any one of Examples 37 to 75, wherein R 19 It is cyclopropyl.

[0496] 81. The compound of any one of Examples 37 to 75, wherein R 19 It is F.

[0497] 82. The compound of any one of Examples 37 to 75, wherein R 19 It is OCH3.

[0498] 83. A compound described in Table 1.

[0499] 84. A pharmaceutical composition comprising a compound as described in any one of Examples 1 to 83, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier thereof.

[0500] 85. A method of treating a BRAF mutant-mediated condition, comprising administering to a human patient in need an effective amount of a compound such as any one of Examples 1 to 83 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition such as Example 84.

[0501] 86. The method of Example 85, wherein the BRAF-mediated condition of the mutant is cancer.

[0502] 87. The method of Example 86, wherein the mutant BRAF-mediated cancer is melanoma.

[0503] 88. The method of Example 86, wherein the BRAF mutant-mediated cancer is lung cancer.

[0504] 89. The method of Example 86, wherein the mutant BRAF-mediated cancer is non-small cell lung cancer.

[0505] 90. The method of Example 86, wherein the BRAF mutant-mediated cancer is colorectal cancer.

[0506] 91. The method of Example 86, wherein the mutant BRAF-mediated cancer is microsatellite stable colorectal cancer.

[0507] 92. The method of Example 86, wherein the BRAF-mediated cancer of the mutant is thyroid cancer.

[0508] 93. The method of Example 86, wherein the BRAF mutant-mediated cancer is ovarian cancer.

[0509] 94. The method of Example 85, wherein the mutant BRAF-mediated disease is cholangiocarcinoma, Erdeheim-Chester disease, Langerhans shistiocytosis, ganglioglioma, glioma, glioblastoma, hairy cell leukemia, metanephrotic adenoma, multiple myeloma, non-small cell lung cancer, ovarian cancer, pilomyxoid astrocytoma, anaplastic pleomorphic xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, pancreatic cancer, clear cell sarcoma of the chest, salivary gland carcinoma, or microsatellite stable colorectal cancer.

[0510] 95. The method as described in any one of Examples 85 to 94, wherein the patient also receives another active agent.

[0511] 96. The method of Example 95, wherein the other active agent is a MEK inhibitor.

[0512] 97. The method of Example 96, wherein the MEK inhibitor is trametinib.

[0513] 98. The method of Example 95, wherein the other active agent is an immune checkpoint inhibitor.

[0514] 99. The method of Example 98, wherein the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, ipilimumab, relatlimab, atezolizumab, avelumab, and durvalumab.

[0515] 100. The method of Example 95, wherein the other active agent is cetuximab or panitumumab.

[0516] 101. The method as described in any one of Examples 85 to 100, wherein the mutant BRAF has the V600 mutation.

[0517] 102. The method of Example 101, wherein the V600 is mutated to V600E, V600K, V600R, V600D or V600N.

[0518] 103. The method of Example 101, wherein the V600 is mutated to V600E.

[0519] 104. The method of any one of Examples 85 to 103, wherein the mutant BRAF has a mutation selected from G469A, G469V, G469L, G469R, L597Q and K601E.

[0520] 105. The method of any one of Examples 85 to 104, wherein the mutant BRAF has a mutation selected from G466A, G466E, G466R, G466V, S467L, G469E, N581I, D594E, D594G and D594N.

[0521] 106. The method of any one of Examples 85 to 105, wherein the mutant BRAF has a mutation selected from G464I, G464R, N581T, L584F, E586K, G593D, G596C, L597R, L597S, S605I, S607F, N684T, E26A, V130M, L745L and D284E.

[0522] 107. The method as described in any one of Examples 85 to 106, wherein the mutant BRAF has a splicing mutation.

[0523] 108. The method of Example 107, wherein the splicing mutation is a p61-BRAF splicing mutation.

[0524] 109. The method of any one of Examples 85 to 108, wherein the BRAF-mediated disease of the mutant is cancer and the cancer also has an NRAS, MEK1 or PI3K mutation.

[0525] 110. The method of Example 109, wherein the cancer has an NRAS mutation.

[0526] 111. The method of Example 110, wherein the NRAS mutation is Q61K.

[0527] 112. The method of Example 110, wherein the NRAS mutation is Q61R.

[0528] 113. The method of Example 109, wherein the cancer has a MEK1 mutation.

[0529] 114. The method of Example 109, wherein the cancer has a PI3K mutation.

[0530] 115. The method of Example 114, wherein the PI3K mutation is changed to PIK3CA. H1047R Or PIK3CA P449T .

[0531] 116. The method of any one of Examples 85 to 115, wherein the mutant BRAF-mediated condition is cancer and one or more mutations promote homodimerization or heterodimerization of the RAF protein.

[0532] 117. The method of Example 116, wherein the one or more mutations promote homodimerization of the RAF protein.

[0533] 118. The method of Example 116, wherein the one or more mutations promote heterodimerization of the RAF protein.

[0534] 119. The method as described in any one of Examples 85 to 118, wherein the BRAF-mediated disease is cancer that has metastasized to the brain or CNS.

[0535] 120. The method as described in any one of Examples 85 to 118, wherein the BRAF-mediated condition is cancer that has metastasized to the brain.

[0536] 121. The method as described in any one of Examples 85 to 118, wherein the mutant BRAF-mediated condition is cancer that has metastasized to the CNS.

[0538] Non-limiting examples of compounds of the present invention

[0539] Compounds Table 1

[0540] Other examples of the compounds of the present invention include: and ; Or its pharmaceutically acceptable salt. Treatment

[0541] The compounds of the present invention, their pharmaceutically acceptable salts, or pharmaceutical compositions can be used in effective amounts to treat patients suffering from a condition mediated by mutant BRAF. In some aspects, the condition mediated by mutant BRAF is cancer. In some embodiments, the cancer mediated by mutant BRAF has metastasized to the brain or CNS.

[0542] BRAF is a serine / threonine protein kinase, a member of the signal transduction protein kinase family. BRAF V600X mutations, particularly BRAF V600E / K mutations, are commonly observed in a variety of human tumors, including melanoma, thyroid cancer, colorectal cancer, lung cancer, and others. Non-restrictive examples of V600X mutations include V600E, V600K, V600R, V600D, and V600N. Although BRAF inhibitors can provide therapeutic benefits for many of these indications clinically, the duration of the antitumor response to these drugs is limited by the acquisition of resistance.

[0543] BRAF proteins provide a signaling mechanism that requires homodimerization (BRAF-BRAF) or heterodimerization with other RAF proteins (BRAF-RAF1 or BRAF-ARAF). As observed in oncology indications with BRAF V600X substitution, when BRAF is mutated, BRAF signaling becomes independent of the production of homodimers and / or heterodimers. In this context, the kinase, as a monomeric protein, becomes overactivated and drives cell proliferation signaling.

[0544] Since classical inhibitors only block the activity of BRAF in its monomeric form and are ineffective against BRAF homodimers or heterodimers, it is not surprising that various BRAF resistance-inducing mechanisms function by restoring RAF homodimer and heterodimer-mediated signal transduction.

[0545] Targeted protein degradation induces targeted ubiquitination by recruiting E3 ligases, thereby promoting proteasome-mediated disruption of the bound target. Degradation of BRAF via targeted degradation is superior to conventional inhibition because it eliminates the BRAF V600E / K skeletal activity and, in particular, induces BRAF protein elimination. This activity prevents dimerization-mediated resistance mechanisms.

[0546] BRAF protein elimination represents a potential strategy for delaying the initiation of resistance acquisition and targeting tumors that have acquired resistance to available inhibitors. This observation offers new therapeutic opportunities for treating BRAF V600X-mutant tumors such as melanoma, colorectal cancer, and lung cancer.

[0547] Another aspect of the invention provides compounds as described herein, or their enantiomers, diastereomers, or stereoisomers, or pharmaceutically acceptable salts, hydrates, or solvates, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for the treatment or prevention of cancer in patients of need; wherein BRAF inhibition is required for the treatment or prevention of cancer.

[0548] In some aspects, the compounds of the present invention are used to treat BRAF-mediated cancers, wherein the BRAF has been mutated from the wild type. There are many possibilities for BRAF mutations. In some non-limiting embodiments, the mutation is a class I mutation, a class II mutation, or a class III mutation, or any combination thereof. Non-limiting examples of class I mutations include V600 mutations, such as V600E, V600K, V600R, V600D, and V600N. Non-limiting examples of class II mutations include G469A, G469V, G469L, G469R, L597Q, and K601E. Non-limiting examples of class III mutations include G466A, G466E, G466R, G466V, S467L, G469E, N581I, D594E, D594G, and D594N.

[0549] In some embodiments, the compounds of the present invention treat BRAF mutant-mediated conditions, wherein the mutation is not a type I, II, or III mutation. Non-limiting examples of mutations include G464I, G464R, N581T, L584F, E586K, G593D, G596C, L597R, L597S, S605I, S607F, N684T, E26A, V130M, L745L, and D284E.

[0550] In some embodiments, the BRAF mutation is an exon 11 mutation.

[0551] In some embodiments, the BRAF mutation is an exon 15 mutation.

[0552] In some embodiments, the BRAF mutation is the G464 mutation.

[0553] In some embodiments, the BRAF mutation is the G466 mutation.

[0554] In some embodiments, the BRAF mutation is the G466R mutation.

[0555] In some embodiments, the BRAF mutation is the G466E mutation.

[0556] In some embodiments, the BRAF mutation is the G469 mutation.

[0557] In some embodiments, the BRAF mutation is the G469E mutation.

[0558] In some embodiments, the BRAF mutation is the D594 mutation.

[0559] In some embodiments, the BRAF mutation is the D594A mutation.

[0560] In some embodiments, the BRAF mutation is the L597 mutation.

[0561] In some embodiments, the BRAF mutation is the L597R mutation.

[0562] In some embodiments, the BRAF mutation is the L597S mutation.

[0563] In some embodiments, the BRAF mutation is the L597Q mutation.

[0564] In some embodiments, the BRAF mutation is the V600 mutation.

[0565] In some embodiments, the BRAF mutation is the V600E mutation.

[0566] In some embodiments, the BRAF mutation is replaced by the V600K mutation.

[0567] In some embodiments, the BRAF mutation is the V600R mutation.

[0568] In some embodiments, the BRAF mutation is the V600D mutation.

[0569] In some embodiments, the BRAF mutation is replaced by the K601 mutation.

[0570] In some embodiments, the BRAF mutation is the K601E mutation.

[0571] In some embodiments, the BRAF mutation is a K601N mutation.

[0572] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is an exon 11 mutation.

[0573] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is an exon 15 mutation.

[0574] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is the G464 mutation.

[0575] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is the G466 mutation.

[0576] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is the G466R mutation.

[0577] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is the G466E mutation.

[0578] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is the G469 mutation.

[0579] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is the G469E mutation.

[0580] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is the D594 mutation.

[0581] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is the D594A mutation.

[0582] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is the L597 mutation.

[0583] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is the L597R mutation.

[0584] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is the L597S mutation.

[0585] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is the L597Q mutation.

[0586] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is the V600 mutation.

[0587] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is the V600E mutation.

[0588] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is a V600K mutation.

[0589] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is a V600R mutation.

[0590] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is the V600D mutation.

[0591] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is a K601 mutation.

[0592] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is a K601E mutation.

[0593] In some embodiments, the condition is cancer that has metastasized to the brain or CNS and the BRAF mutation is a K601N mutation.

[0594] In some embodiments, the cancer metastasizes to the brain. In some embodiments, the cancer metastasizes to the CNS.

[0595] In some embodiments, the compounds of the present invention treat BRAF mutant-mediated conditions, wherein the mutation is a splice variant, such as p61-BRAF. V600E In some embodiments, BRAF is mutated into a splice variant, such as p61-BRAF. V600E Furthermore, the cancer may have metastasized to the brain or CNS.

[0596] In some embodiments, the compounds of the present invention are used to treat conditions mediated by two or more mutant proteins, such as those caused by BRAF. V600E / NRAS Q61K Double-mutant mediated cancers. Non-limiting examples of double-mutant cancers include colorectal cancer mediated by BRAF mutations, such as BRAF... V600E And mutations in NRAS, MEK1, or PI3K, such as BRAF. V600E / PIK3CA H1047R or BRAF V600E / PIK3CA P449T In some embodiments, cancer metastasis to the brain or CNS is mediated by two or more mutated proteins.

[0597] In some embodiments, the compounds of the present invention are used to treat cancers resistant to at least one BRAF inhibitor, such as cancers resistant or acquiredly resistant to BRAF inhibitors selected from dabrafenib, vemurafenib, and encorafenib. In some aspects, cancers resistant to BRAF inhibitor treatment have mutations that promote homodimerization or heterodimerization of the RAF protein. For example, in some embodiments, the compounds of the present invention are used to treat cancers having one or more mutations that promote RAF dimerization. In some embodiments, cancers having one or more mutations that promote RAF dimerization are resistant to BRAF inhibitor treatment (e.g., dabrafenib, vemurafenib, or encorafenib). In some aspects, the mutation is a mutation that promotes homodimerization of BRAF. In some embodiments, the compounds of the present invention are used to treat BRAF mutant-mediated cancers that have metastasized to the brain or CNS, wherein the cancer has one or more mutations that promote RAF dimerization.

[0598] In some embodiments, the compounds described herein are used to treat cancers that have developed escape mutations, such as BRAFV600E / NRAS. Q61K Double-mutant cancer.

[0599] In some embodiments, the compounds described herein are used to treat melanoma. For example, in some embodiments, the compounds of the present invention are used to treat melanoma that has metastasized to the brain or CNS. In some embodiments, the compounds described herein are used to treat colorectal cancer. For example, in some embodiments, the compounds of the present invention are used to treat colorectal cancer that has metastasized to the brain or CNS.

[0600] Non-limiting examples of melanoma include non-acral cutaneous melanoma, acral melanoma, mucosal melanoma, uveal melanoma, and leptomeningeal melanoma, each of which may be primary or metastatic.

[0601] In some embodiments, the compounds of the present invention are used to treat triple-negative breast cancer, such as triple-negative breast cancer with the G464V BRAF mutant.

[0602] In some embodiments, the compounds of the present invention are used to treat lung cancer, such as lung adenocarcinoma having the G466V BRAF mutant.

[0603] In some embodiments, the compounds of the present invention are used to treat melanoma with the V600 BRAF mutant.

[0604] In some aspects, the compounds of the present invention are used to treat BRAF-mediated cancers, wherein the BRAF has been mutated from the wild type. There are many possibilities for BRAF mutations. In some non-limiting embodiments, the mutation is a class I mutation, a class II mutation, or a class III mutation, or any combination thereof. Non-limiting examples of class I mutations include V600 mutations, such as V600E, V600K, V600R, V600D, and V600N. Non-limiting examples of class II mutations include G469A, G469V, G469L, G469R, L597Q, and K601E. Non-limiting examples of class III mutations include G466A, G466E, G466R, G466V, S467L, G469E, N581I, D594E, D594G, and D594N.

[0605] In some embodiments, the compounds of the present invention treat BRAF mutant-mediated conditions, wherein the mutation is not a type I, II, or III mutation. Non-limiting examples of mutations include G464I, G464R, N581T, L584F, E586K, G593D, G596C, L597R, L597S, S605I, S607F, N684T, E26A, V130M, L745L, and D284E.

[0606] In some embodiments, the compounds of the present invention treat BRAF mutant-mediated conditions, wherein the mutation is a splice variant, such as p61-BRAF. V600E .

[0607] In some embodiments, the compounds of the present invention are used to treat conditions mediated by two or more mutant proteins, such as those caused by BRAF. V600E / NRAS Q61K Cancer mediated by double mutants.

[0608] In some embodiments, the compounds of the present invention are used to treat cancers resistant to at least one BRAF inhibitor, such as cancers resistant to or acquired to a BRAF inhibitor selected from dabrafenib, vemurafenib, and enrafenib.

[0609] In some embodiments, the compounds of the present invention are used to treat cancers that have developed escape mutations, such as BRAFV600E NRAS. Q61K Double-mutant cancer.

[0610] In some embodiments, the compounds of the present invention are used to treat melanoma.

[0611] In some embodiments, the compounds of the present invention are used to treat triple-negative breast cancer, such as triple-negative breast cancer with the G464V BRAF mutant.

[0612] In some embodiments, the compounds of the present invention are used to treat lung cancer, such as lung adenocarcinoma having the G466V BRAF mutant.

[0613] In some embodiments, the compounds of the present invention are used to treat melanoma with the V600 BRAF mutant.

[0614] In some embodiments, the compounds of the present invention are used to treat cholangiocarcinoma.

[0615] In some embodiments, the compounds of the present invention are used to treat Odheim-Chester disease.

[0616] In some embodiments, the compounds of the present invention are used to treat Langerhans cell histiocytosis.

[0617] In some embodiments, the compounds of the present invention are used to treat ganglioglioma.

[0618] In some embodiments, the compounds of the present invention are used to treat glioma.

[0619] In some embodiments, the compounds of the present invention are used to treat GIST.

[0620] In some embodiments, the compounds of the present invention are used to treat glioblastoma.

[0621] In some embodiments, the compounds of the present invention are used to treat hairy cell leukemia.

[0622] In some embodiments, the compounds of the present invention are used to treat multiple myeloma.

[0623] In some embodiments, the compounds of the present invention are used to treat non-small cell lung cancer.

[0624] In some embodiments, the compounds of the present invention are used to treat ovarian cancer.

[0625] In some embodiments, the compounds of the present invention are used to treat pilomyxoid astrocytoma.

[0626] In some embodiments, the compounds of the present invention are used to treat anaplastic pleomorphic xanthoastrocytoma.

[0627] In some embodiments, the compounds of the present invention are used to treat astrocytomas.

[0628] In some embodiments, the compounds of the present invention are used to treat thyroid cancer.

[0629] In some embodiments, the compounds of the present invention are used to treat papillary thyroid carcinoma.

[0630] In some embodiments, the compounds of the present invention are used to treat undifferentiated thyroid cancer.

[0631] In some embodiments, the compounds of the present invention are used to treat pancreatic cancer.

[0632] In some embodiments, the compounds of the present invention are used to treat clear cell sarcoma of the chest.

[0633] In some embodiments, the compounds of the present invention are used to treat salivary gland cancer.

[0634] In some embodiments, the compounds of the present invention are used to treat colorectal cancer.

[0635] In some embodiments, the compounds of the present invention are used to treat microsatellite-stabilized colorectal cancer.

[0636] In some embodiments, the compounds of the present invention are used to treat conditions selected from: cholangiocarcinoma, Odheim-Chester disease, Langerhans cell histiocytosis, ganglioglioma, glioma, GIST, glioblastoma, hairy cell leukemia, metanephrotic adenoma, multiple myeloma, lung cancer, non-small cell lung cancer, ovarian cancer, pilomyxoid astrocytoma, anaplastic pleomorphic xanthoastrocytoma, astrocytoma, thyroid cancer, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, pancreatic cancer, clear cell sarcoma of the thoracic thorax, salivary gland cancer, colorectal cancer, and microsatellite stable colorectal cancer.

[0637] Another aspect of the present invention provides a method for treating or preventing proliferative diseases. The method comprises administering to a patient in need an effective amount of a pharmaceutical composition comprising a compound as described herein, or an enantiomer, diastereomer, or stereoisomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally a pharmaceutically acceptable carrier.

[0638] In some respects, the term “treatment” as used herein means reducing the frequency or severity of at least one sign or symptom of a disease or condition experienced by a patient (i.e., palliative care) or reducing the cause or effect of a disease or condition (i.e., disease-remittent treatment).

[0639] In some aspects, the compounds of the present invention are administered non-enterically. "Non-enteric" administration of pharmaceutical compositions includes techniques such as subcutaneous (sc), intravenous (iv), intramuscular (im), intrasternal injection, or infusion.

[0640] In some embodiments, the disease or condition is cancer or a proliferative disease.

[0641] In some embodiments, BRAF-mediated symptoms are abnormal cell proliferation, including (but not limited to) solid or hematologic cancers.

[0642] In some embodiments, hematologic malignancies include acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), lymphoblastic T-cell leukemia, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, chronic neutrophilic leukemia (CNL), acute lymphoblastic T-cell leukemia, acute monocytic leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, acute megakaryoblastic leukemia, promyelocytic leukemia, mixed lineage leukemia (MLL), erythroleukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, and Burkitt's lymphoma. Lymphoma, follicular lymphoma, B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, Myc and B-cell leukemia (BCL)2 and / or BCL6 recombinant / overexpression [double-hit and triple-hit lymphoma], myelodysplastic / myeloproliferative neoplasms, mantle cell lymphoma, including bortezomib-resistant mantle cell lymphoma.

[0643] Solid tumors treatable with the compounds described herein include (but are not limited to) lung cancer, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC); breast cancer, including inflammatory breast cancer, ER-positive breast cancer (including tamoxifen-resistant ER-positive breast cancer), and triple-negative breast cancer; colon cancer; midline cancer; liver cancer; kidney cancer; prostate cancer, including castrate-resistant prostate cancer (CRPC); brain cancer, including glioma, glioblastoma, neuroblastoma, and medulloblastoma, including MYC-amplified medulloblastoma; colorectal cancer; Wilm's tumor; Ewing's sarcoma. Sarcoma; Rhabdomyosarcoma; Ependymoma; Head and neck cancer; Melanoma; Squamous cell carcinoma; Ovarian cancer; Pancreatic cancer, including pancreatic duct adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PanNET); Osteosarcoma; Giant cell tumor of bone; Thyroid cancer; Bladder cancer; Urothelial carcinoma; Vulvar cancer; Cervical cancer; Endometrial cancer; Mesothelioma; Esophageal cancer; Salivary gland cancer; Gastric cancer; Nasopharyngeal carcinoma; Buccal cancer; Oral cancer; Gastrointestinal stromal tumor (GIST); Midline NUT carcinoma; Testicular cancer; Squamous cell carcinoma; Hepatocellular carcinoma (HCC); MyCN-driven solid tumors; and Midline NUT carcinoma (NMC).

[0644] In other embodiments, the disease or symptom is a sarcoma of bone, muscle, tendon, cartilage, nerve, fat, or blood vessel.

[0645] In other embodiments, the disease or condition is soft tissue sarcoma, bone sarcoma, or osteosarcoma.

[0646] In other embodiments, the disease or condition is angiosarcoma, fibrosarcoma, liposarcoma, leiomyosarcoma, Karposi's sarcoma, osteosarcoma, gastrointestinal stromal tumor, synovial sarcoma, pleomorphic sarcoma, chondrosarcoma, Ewing's sarcoma, reticulum cell sarcoma, hemangioendothelioma, grape-like sarcoma, rhabdomyosarcoma, or embryonal rhabdomyosarcoma.

[0647] In some embodiments, the lesion is a bone, muscle, tendon, cartilage, nerve, fat, or angiosarcoma.

[0648] In other embodiments, a pharmaceutical composition comprising compounds and other therapeutic agents as described herein is administered simultaneously or sequentially.

[0649] In other embodiments, the disease or symptom is cancer. In other embodiments, cancer is lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal cell carcinoma, head and neck squamous cell carcinoma, leukemia, lymphoma, myeloma, solid tumor, hematologic cancer, or solid carcinoma.

[0650] One aspect of this application provides compounds that can be used to treat diseases, conditions, and symptoms characterized by excessive or abnormal cell proliferation. Such diseases include, but are not limited to, proliferative or hyperproliferative disorders. Examples of proliferative and hyperproliferative disorders include, but are not limited to, cancer. The term "cancer" includes (but is not limited to) the following cancers: breast cancer; ovarian cancer; cervical cancer; prostate cancer; testicular cancer; genitourinary tract cancer; esophageal cancer; laryngeal cancer; glioblastoma; neuroblastoma; gastric cancer; skin cancer; keratoacanthoma; lung cancer; epidermoid carcinoma; large cell carcinoma; small cell carcinoma; lung adenocarcinoma; bone cancer; colon cancer; colorectal cancer; adenoma; pancreatic cancer; follicular thyroid carcinoma; undifferentiated thyroid carcinoma; papillary carcinoma; seminoma; melanoma; sarcoma; bladder cancer; liver cancer and biliary tract cancer; kidney cancer; myeloid diseases; lymphatic diseases; Hodgkin's disease; hairy cell disease; buccal and pharyngeal (oral) cancer; lip cancer; tongue cancer; oral cavity cancer; pharyngeal cancer; small intestine cancer; colorectal cancer; large intestine cancer; rectal cancer; brain cancer and central nervous system cancer; chronic myeloid leukemia (CML) and leukemia. The term "cancer" includes (but is not limited to) the following cancers: myeloma, lymphoma, or cancers selected from stomach cancer, kidney cancer, and / or the following cancers: head and neck cancer, oropharyngeal cancer, non-small cell lung cancer (NSCLC), endometrial cancer, liver cancer, non-Hodgkin's lymphoma, and lung cancer.

[0651] In some respects, the term "cancer" refers to any cancer caused by the proliferation of malignant neoplasms, such as tumors, neoplasms, carcinomas, sarcomas, leukemia, lymphomas, and similar cancers. For example, cancers include (but are not limited to) mesothelioma, leukemia, and lymphomas such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, lymphomas associated with human T-cell lymphotropic virus (HTLV) (such as adult T-cell leukemia / lymphoma (ATLL)), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, lymphoma and multiple myeloma, non-Hodgkin's lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, Burkitt lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Other examples include myelodysplastic syndromes, juvenile solid tumors (such as brain tumors, neuroblastomas, retinoblastomas, Wilms' tumors, bone tumors, and soft tissue sarcomas), common solid tumors in adults (such as head and neck cancers, including those of the mouth, larynx, nasopharynx, and esophagus), genitourinary cancers (such as those of the prostate, bladder, kidneys, uterus, ovaries, and testes), lung cancers (such as small cell and non-small cell lung cancers), breast cancer, pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors associated with Gorlin's syndrome (such as medulloblastomas or meningiomas), and liver cancer.

[0652] Other exemplary forms of cancer include (but are not limited to) cancers of bone or smooth muscle, stomach cancer, small bowel cancer, rectal cancer, salivary gland cancer, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0653] Other cancers for which the compounds described herein can be used for prevention, treatment, and research include, for example, colorectal cancer, familial adenomatous polyposis, and hereditary nonpolyposis colorectal cancer or melanoma. Additionally, cancers include (but are not limited to) lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, thyroid cancer (medullary and papillary thyroid carcinoma), kidney cancer, renal parenchymal carcinoma, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, melanoma, brain tumors (such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumors), gallbladder cancer, bronchial cancer, multiple myeloma, basal carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma. In one aspect of this application, the application provides the use of one or more compounds as described herein for the manufacture of a medicament for treating cancer (including, but not limited to, the various types of cancer described herein).

[0654] In some embodiments, the compounds of this application may be used to treat cancers such as colorectal cancer, thyroid cancer, breast cancer, and lung cancer; and myeloproliferative disorders such as polycythemia vera, thrombocythemia, myelometaplasia with myelofibrosis, chronic myeloid leukemia, chronic myeloid monocytic leukemia, eosinophilia syndrome, juvenile myeloid monocytic leukemia, and systemic mast cell disease. In some embodiments, the compounds described herein may be used to treat hematopoietic disorders, specifically acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute promyelocytic leukemia, and acute lymphoblastic leukemia (ALL).

[0655] In some embodiments, the compounds described herein or their corresponding pharmaceutically acceptable salts or isotope derivatives may be used in effective amounts to treat a host, such as a human, suffering from lymphoma or a lymphocytic or myeloproliferative disorder or abnormality. For example, the compounds described herein may be administered to a host suffering from Hodgkin's lymphoma or non-Hodgkin's lymphoma. For example, the host may suffer from non-Hodgkin's lymphoma, such as (but not limited to): AIDS-related lymphoma; undifferentiated large cell lymphoma; angioimmunoblastic lymphoma; blastic NK cell lymphoma; Burkitt's lymphoma: Burkitt-like lymphoma (cleavage-free small cell lymphoma); diffuse microcleavage cell lymphoma (DSCCL); chronic lymphocytic leukemia / small lymphocytic lymphoma: cutaneous T-cell lymphoma; diffuse large B-cell lymphoma; enteropathy-type T-cell lymphoma; follicular lymphoma; hepatosplenic γ-δ T-cell lymphoma; lymphoblastic lymphoma; mantle cell lymphoma; marginal zone lymphoma; nasal T-cell lymphoma; pediatric lymphoma; peripheral T-cell lymphoma; primary central nervous system lymphoma; T-cell leukemia; transformed lymphoma; treatment-related T-cell lymphoma; Langerhans cell histiocytosis; or Waldenstrom's macroglobulinemia.

[0656] In another embodiment, the compound as described herein or its corresponding pharmaceutically acceptable salt or isotope derivative may be used in effective amounts to treat patients (e.g., humans) with Hodgkin's lymphoma, such as (but not limited to): tuberous sclerotic classical Hodgkin's lymphoma (CHL); mixed cellular CHL; lymphocyte-depleted CHL; lymphocyte-rich CHL; lymphocyte-dominant Hodgkin's lymphoma; or nodular lymphocyte-dominant HL.

[0657] This application further covers the treatment or prevention of proliferative disorders, such as hyperplasia, dysplasia, and precancerous lesions. Dysplasia is the earliest form of precancerous lesion that a pathologist can identify in a tissue section. The compound can be applied to prevent these hyperplasia, dysplasia, or precancerous lesions from continuing to grow or becoming cancerous. Examples of precancerous lesions can occur in the skin, esophageal tissue, breast, and cervical intraepithelial tissue.

[0658] Based on the foregoing, this application further provides a method for preventing or treating any of the aforementioned diseases or conditions in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of the compound as described herein, or its enantiomers, diastereomers, or stereoisomers, or pharmaceutically acceptable salts, hydrates, or solvates thereof. For any of the above uses, the required dosage will vary depending on the mode of administration, the specific symptom to be treated, and the desired effect.

[0659] Combination therapy

[0660] The compounds described herein, or their pharmaceutically acceptable salts or pharmaceutical compositions, may be used alone or in combination with another compound of the present invention or another bioactive agent or a second therapeutic agent in an effective amount to treat patients, such as humans suffering from mutant BRAF-mediated conditions (including, but not limited to, those described herein).

[0661] The terms "bioactive agent" or "another active agent" are used to describe medicines other than those selected according to the invention, which may be used in combination with or alternately with the compounds of the invention to achieve desired therapeutic outcomes. In some embodiments, the compounds of the invention and the bioactive agent are administered in vivo in a manner that ensures their activity during overlapping time periods (e.g., Cmax, Tmax, AUC, or another pharmacokinetic parameter during the overlapping time period). In another embodiment, the compounds of the invention and the bioactive agent are administered to the patient in need in a manner where there are no overlapping pharmacokinetic parameters, but one has a therapeutic effect on the therapeutic efficacy of the other.

[0662] In some embodiments, the selected compounds or their pharmaceutically acceptable salts provided herein are used in combination with another BRAF inhibitor, such as sorafenib or vemurafenib. ® ), dabrafenib (TAFINLAR) ® ) or Braftovi ® ).

[0663] In some embodiments, the bioactive agent is a MEK inhibitor. MEK inhibitors are well-known and include, for example, trametinib / GSKl120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib / AS703026 / MSC 1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), and XL-518 / GDC-0973. (1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azacyclobut-3-ol), refamateinib / BAY869766 / RDEAl 19 (N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidin-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfonamido)-4-pyridinyl]methyl]-4-methyl-7-pyrimidin-2-yloxysomn-2-one), WX-554, R04987655 / CH4987655 (3,4-Difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazacyclohexyl-2-yl)methyl)benzamide), or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-Dihydropyridine-3-carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX 02189, BIX 02188, binitinib, SL-327, TAK-733, PD318088.

[0664] In some embodiments, the MEK inhibitor is trametinib.

[0665] In some embodiments, the compounds of the present invention are used in combination with cetuximab or trametinib to treat colorectal cancer. In some embodiments, the compounds of the present invention are used in combination with cetuximab and BYL719 to treat colorectal cancer. In some embodiments, the compounds of the present invention are used in combination with cetuximab and irinotecan to treat colorectal cancer.

[0666] In some embodiments, the compounds of the present invention are used in combination with cetuximab or trametinib to treat colorectal cancer. In some embodiments, the compounds of the present invention are used in combination with cetuximab and BYL719 to treat colorectal cancer. In some embodiments, the compounds of the present invention are used in combination with cetuximab and irinotecan to treat colorectal cancer.

[0667] In some embodiments, the bioactive agent is an SHP2 inhibitor. In some embodiments, the SHP2 inhibitor is SHP099.

[0668] In some embodiments, the bioactive agent is a RAF inhibitor. Non-limiting examples of Raf inhibitors include, for example, vemurafenib (N-[3-[[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridin-2-carboxamide; 4-methylbenzenesulfonate), AZ628 (3-(2-cyanopropyl-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide), NVP-BHG712 (4-Methyl-3-(1-Methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide), RAF-265 (1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2-bromosponge alkaloid (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]aza-4,8-dione), Raf kinase inhibitor IV (2-Chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol), sorafenib N-oxide (4-[4-[[[[4-chloro-3(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide 1-oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ 628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120 and GX818 (enrafenib (BRAFTOVI) ® )).

[0669] In some embodiments, the RAF inhibitor is enrafenib.

[0670] In some embodiments, the RAF inhibitor is vemurafenib.

[0671] In some embodiments, the RAF inhibitor is dabrafenib.

[0672] In some embodiments, the bioactive agent is an EGFR inhibitor, including, for example, gefitinib (IRESSA). ® ), erlotinib (TARCEVA) ® Lapatinib (TYKERB)® Osimertinib (TAGRISSO) ® ), neratinib (NERLYNX) ® ), vandetanib (CAPRELSA) ® ), dacomitinib (VIZIMPRO) ® ), rociletinib (XEGAFRI TM Afatinib (GLOTRIF) ® GIOTRIFF TM AFANIX TM (e.g., lazertinib or nazartib). In other embodiments, the bioactive agent is an EGFR degrader.

[0673] Other examples of EGFR inhibitors include roxitinib (CO-1686), olmutinib (OLITATM), naquotinib (ASP8273), nazartinib (EGF816), PF-06747775, icotinib (BPI-2009), neratinib (HKI-272; PB272), avitinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF-06459988 (Pfizer), and tesevatinib. (XL647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, dacomitinib (PF-00299804; Pfizer), brigatinib (ALUNBRIG®), lorlatinib, and PF-06747775 (PF7775).

[0674] In some embodiments, the bioactive agent is a first-generation EGFR inhibitor, such as erlotinib, gefitinib, or lapatinib. In some embodiments, the bioactive agent is a second-generation EGFR inhibitor, such as afatinib and / or dacomitinib. In some embodiments, the bioactive agent is a third-generation EGFR inhibitor, such as osimertinib.

[0675] In some embodiments, the compounds of the present invention are administered in combination with osimertinib to patients in need.

[0676] In some embodiments, the compounds of the present invention are administered in combination with roxitinib to patients in need.

[0677] In some embodiments, the compounds of the present invention are administered in combination with avitinib to patients in need.

[0678] In some embodiments, the compounds of the present invention are administered in combination with lazatinib to patients in need.

[0679] In some embodiments, the compounds of the present invention are administered in combination with nazartinib to patients in need.

[0680] In some embodiments, the compounds of the present invention are administered in combination with EGFR antibodies (e.g., cetuximab, panitumumab, or necitumumab) to patients in need.

[0681] In some embodiments, the compounds of the present invention are administered in combination with cetuximab to patients in need.

[0682] In some embodiments, the compounds of the present invention are administered in combination with panitumumab to patients in need.

[0683] In some embodiments, the compounds of the present invention are administered in combination with nexitumab to patients in need.

[0684] In one aspect of this embodiment, the bioactive agent is an immunomodulator, including (but not limited to) checkpoint inhibitors, such as PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, T cell activation domain V-domain Ig inhibitor (VISTA) inhibitors, small molecules, peptides, nucleotides, or other inhibitors, as non-limiting examples. In some aspects, the immunomodulator is an antibody, such as a monoclonal antibody.

[0685] PD-1 inhibitors, which block the interaction between PD-1 and PD-L1 and subsequently inhibit immunosuppression by binding to the PD-1 receptor, include, for example, nivolumab (OPDIVO). ® ), pembrolizumab (KEYTRUDA) ® PD-L1 inhibitors include atezolizumab (PD-L1), AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (GlaxoSmithKline plc), and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.). PD-L1 inhibitors that block PD-1-PD-L1 interaction and subsequently inhibit immunosuppression by binding to the PD-L1 receptor include, for example, atezolizumab (TECENTRIQ). ® PD-1 and LAG-3 checkpoint inhibitors include (but are not limited to) durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab Co. Ltd.), and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibit immunosuppression include (but are not limited to) ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884, and AGEN2041 (Agenus). LAG-3 checkpoint inhibitors include (but are not limited to) BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline plc), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (GlaxoSmithKlineplc).

[0686] In some embodiments, the checkpoint inhibitor is selected from nivolumab (OPDIVO). ® ); Pembrolizumab (KEYTRUDA)® ); and pidilizumab / CT-011, MPDL3280A / RG7446; MEDI4736; MSB0010718C; BMS936559, PDL2 / lg fusion proteins (such as AMP 224) or B7-H3 inhibitors (such as MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or combinations thereof.

[0687] In another embodiment, one or more active compounds described herein may be administered in combination with or alternately with an effective amount of an estrogen inhibitor for the treatment of abnormal tissues of the female reproductive system, such as breast cancer, ovarian cancer, endometrial cancer, or uterine cancer. The estrogen inhibitor includes (but is not limited to) selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), complete estrogen receptor degraders, or another form of partial or complete estrogen antagonist or agonist. Partial anti-estrogens (such as raloxifene and tamoxifen) retain some estrogen-like effects (including estrogen-like stimulation of uterine growth), and in some cases, estrogen-like effects that actually stimulate tumor growth during breast cancer progression. In contrast, fulvestrant (a complete anti-estrogen) does not produce estrogen-like effects on the uterus and is effective against tamoxifen-resistant tumors.

[0688] Non-limiting examples of anti-estrogenic compounds are provided in WO 2014 / 19176 (assigned to Astra Zeneca); WO 2013 / 090921; WO 2014 / 203129; WO 2014 / 203132; and US 2013 / 0178445 (assigned to Olema Pharmaceuticals); and U.S. Patents 9,078,871, 8,853,423, and 8,703,810; and US 2015 / 0005286, WO 2014 / 205136, and WO 2014 / 205138.

[0689] Other non-limiting examples of anti-estrogenic compounds include: SERMS, such as aordrin, bazedoxifene, broparestriol, chlorotrianisene, and clomiphene citrate. Citrate, cyclofenil, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestrant; aromatase inhibitors, such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole; and antigonadotropins, such as leuprorelin, cetrorelix, allylestrenol, chloromadinone acetate, cyproterone acetate, and delmadinone acetate. Acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, and spironolactone.

[0690] Other estrogen ligands that may be used according to the present invention are described in U.S. Patent Nos. 4,418,068, 5,478,847, 5,393,763, and 5,457,117, WO 2011 / 156518, U.S. Patent Nos. 8,455,534 and 8,299,112, U.S. Patent Nos. 9,078,871, 8,853,423, and 8,703,810, US 2015 / 0005286, and WO 2014 / 205138, US 2016 / 0175289, US 2015 / 0258080, WO 2014 / 191726, WO 2012 / 084711, WO 2002 / 013802, WO 2002 / 004418、WO 2002 / 003992、WO 2002 / 003991、WO 2002 / 003990、WO2002 / 003989、WO 2002 / 003988、WO 2002 / 003986、WO 2002 / 003977、WO 2002 / 003976, WO2002 / 003975, WO 2006 / 078834, US 6821989, US 2002 / 0128276, US 6777424, US 2002 / 0016340, US 6326392, US 6756401, US 2002 / 0013327、US 6512002, US 6632834, US 2001 / 0056099, US 6583170, US 6479535, WO 1999 / 024027, US 6005102, EP 0802184, US5998402, US 5780497, US 5880137, WO 2012 / 048058 and WO 2007 / 087684.

[0691] In another embodiment, the active compound described herein may be administered in combination with or alternately with an effective amount of an androgen (such as testosterone) inhibitor for the treatment of abnormal tissues of the male reproductive system (such as prostate cancer or testicular cancer), the androgen inhibitor comprising (but not limited to) selective androgen receptor modulators, selective androgen receptor degraders, complete androgen receptor degraders, or other forms of partial or complete androgen antagonists. In some embodiments, the prostate cancer or testicular cancer is androgen resistant.

[0692] Non-limiting examples of antiandrogen compounds are provided in WO 2011 / 156518 and U.S. Patent Nos. 8,455,534 and 8,299,112. Other non-limiting examples of antiandrogen compounds include enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine.

[0693] In some embodiments, the bioactive agent is an ALK inhibitor. Examples of ALK inhibitors include, but are not limited to, crizotinib (XALKORI). ® alectinib (ALECENSA) ® ), ceritinib, TAE684 (NVP-TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101) and AP26113.

[0694] In some embodiments, the bioactive agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab-bemtansine conjugate, and pertuzumab.

[0695] In some embodiments, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab (GAZYVA). ® ), rituximab (RITUXAN) ® ), ofatumumab, ibritumomab, tositumomab and ocrelizumab.

[0696] In some embodiments, the bioactive agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tasocitinib.

[0697] In some embodiments, the bioactive agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclax, ABT-199 (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylthiobut-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide) (navitoclax), and ABT-263 ((R)-4-(4-(4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-N-morpholino-1-(phenylthio)but-2-yl)amino)-3((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (obatoclax mesylate, (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrolo-2-yl)methylene]-4-methoxypyrrolo-2-yl]indole; methanesulfonic acid))), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazolyl-2-ylamino)-phenyl ester), pogosin, 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-benzopyran-3-carboxylic acid ethyl ester, Nilotinib-d3, TW-37 (N-[4-[[2-(1,1-dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide), Apogossypolone (ApoG2), HA14-1, AT101, sabutoclax, gambogic acid, or G3139 (oblimersen)).

[0698] In some embodiments, the bioactive agent is a kinase inhibitor. In some embodiments, the kinase inhibitor is selected from phosphoinositol 3-kinase (PI3K) inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, or spleen tyrosine kinase (Syk) inhibitors, or combinations thereof.

[0699] Examples of PI3 kinase inhibitors include (but are not limited to) Wortmannin, demethoxyviridin, perifosine, idelalisib, pictilisib, palomid 529, ZSTK474, PWT33597, CUDC-907 and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (taselisib) (2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazolo-9-yl]pyrazol-1-yl]-2-methylpropionamide), MLN-1117 ((2R)-1-phenoxy-2-butylhydro(S)-methylphosphonate; or methyl(oxo){[(2R)-1-phenoxy-2-butyl]oxy}phosphonium), BYL-719 ((2S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK2126458 (2,4-difluoro-N-{2-(methoxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide) (omipalisib), TGX-221 ((±)-7-methyl-2-(morpholin-4-yl)-9-(l-phenylaminoethyl)-pyrido[1,2-a]pyrimidin-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-N-morpholinyl-1H-benzo[d]imidazolium-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((1-(7-methyl-2-N-morpholinyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264, GS-9820 ((S)-l-(4-(2-(2-aminopyrimidin-5-yl)-7-methyl-4-hydroxyprop-1-one), GS-1101 (5-Fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409 (N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinolin-2-yl)aminosulfonyl)phenyl)-3-methoxy-4-methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-N-morpholinylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazole), AS 252424 (5-[1-[5-(4-fluoro-2-hydroxyphenyl)-furan-2-yl]-methyl-(Z)-ylidene]-thiazolyl-2,4-dione), CZ 24832 (5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), Buparlisib (5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinylamine), GDC-0941 (2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-(N-morpholinyl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyprop-1-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-benzopyran-2-yl)-N-morpholinyl-4-onthium)-2-oxa-7,10,13,16-tetraazaoctadecane-18-ester), PF-05212384 (N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4-morpholino-1,3,5-triazin-2-yl)phenyl]urea (gedatolisib), LY3023414, BEZ235 (2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propionitrile) (dactolisib), XL-765 (N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinolin-2-yl)aminesulfonyl)phenyl)-3-methoxy-4-methylbenzamide), and GSK1059615 (5-[[4-(4-pyridyl)-6-quinolinyl]methylene]-2,4-thiazolyldione), PX886 (acetic acid [(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindene[4,[5h] isobenzopyran-10-yl]acetate (also known as sonoxixib), LY294002, AZD8186, PF-4989216, pilaralisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, apitolisib (GDC-0980; RG7422).

[0700] Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (IMBRUVICA). ®) (1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), diphenylaminopyrimidine-based inhibitors (such as AVL-101 and AVL-291 / 292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide)) (AvilaTherapeutics) (see U.S. Patent Publication No. 2011 / 0117073, which is incorporated herein by reference in its entirety), dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazolyl-5-carboxamide]), LFM-A13 (α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)acrylamide), GDC-0834 ([RN-(3-(6-(4-(1,4-dimethyl-3-oxopiazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide]), CGI-560 4-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide, CGI-1746(4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholin-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide), CNX-774(4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpyridinecarboxamide), CTA056 (7-Benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoline-6(5H)-one), GDC-0834 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopirarin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-Tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (OnoPharmaceuticals), PRT062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1-acryloylindoline-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthidium-2(1H)-one) and RN486 (6-Cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methylpiperazin-1-yl)pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinoline-1-one) and other molecules capable of inhibiting BTK activity, such as those BTK inhibitors described in Akinleye et al., Journal of Hematology & Oncology, 2013, 6:59 (the entire contents of which are incorporated herein by reference).

[0701] Syk inhibitors include (but are not limited to) cerdulatinib (4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(1H-indazole-6-yl)-N-(4-N-morpholinylphenyl)imidazo[1,2-a]pyrazin-8-amine), and fostamatinib. ([6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl phosphate dihydrogen salt), flotatinib disodium salt ((6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate sodium salt), BAY 61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamide HCl), RO9021 (6-[(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxamide), imatinib (GLEEVEC) ®; 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), astrococcus, GSK143 (2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-toluidine)pyrimidin-5-carboxamide), PP2 (1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), PRT-060318 (2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-toluidine)pyrimidin-5-carboxamide), PRT-062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112 (3,3'-((5-fluoropyrimidine-2,4-diyl)bis(azadiyl))diol), R348 (3-ethyl-4-methylpyridine), R406 (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidine-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazine-3(4H)-one), piceatannol (3-hydroxyresveratrol), YM193306 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. (See Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, 7-azaindole, leucine, ER-27319 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the full text of which is incorporated herein by reference), compound D (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the full text of which is incorporated herein by reference), PRT060318 ...).2012, 55, 3614-3643 (the full text of this article is incorporated herein by reference), luteolin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the full text of which is incorporated herein by reference), apigenin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, the full text of which is incorporated herein by reference), quercetin ... (See Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is included in the full text of this paper), fisetin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is included in the full text of this paper), and morin (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is included in the full text of this paper). .

[0702] In some embodiments, the bioactive agent is a c-MET inhibitor, such as crizotinib (XALKORI). ® CRIZONIX TM), tepotinib (XL880, EXEL-2880, GSK1363089, GSK089) or tivantinib (ARQ197).

[0703] In some embodiments, the bioactive agent is an AKT inhibitor, including (but not limited to) MK-2206, GSK690693, perifolfenoxam (KRX-0401), GDC-0068, triciribine, AZD5363, honokiol, PF-04691502, and miltefosine; and an FLT-3 inhibitor, including (but not limited to) P406, dovitinib, quizartinib (AC220), amuvatinib (MP-470), tandutinib (MLN518), ENMD-2076, and KW-2449, or combinations thereof.

[0704] In some embodiments, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include (but are not limited to) rapamycin and its analogues, everolimus (AFINITOR). ® ), temsirolimus, ridaforolimus, sirolimus, and deforolimus.

[0705] In some embodiments, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include (but are not limited to) Reolysin and siG12D LODER.

[0706] In some embodiments, the bioactive agent is an HSP inhibitor. HSP inhibitors include (but are not limited to) geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG) and radicicol.

[0707] Other bioactive compounds include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, and AZD. 1152, Enzastaurin, Vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, Aurora kinase inhibitors, PIK-1 modulators, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, focal adhesion kinase inhibitors, Map kinase (MEK) inhibitors, VEGF capture antibodies, Pemetrexed, Panitumumab, Amarabicin Rubicin, Oregomab, Lep-etu, Nolatrexed, Azd2171, Batabulin, Ofatumumab, Zanolimumab, Eotecarin, Tetrandrine, Rubitecan, Tesmilifene, Oblimersen, Ticilimumab, Ipilimumab, Gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx102, talampanel, atrasentan, Xr311. Romidesin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Liposome Doxorubicin, 5'-Deoxy-5-Fluorouracil, Vincristine, Temozolomide ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl]ethyl]benzoyl]-L-glutamic acid disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate citrate), anastrozole, exemestane, letrozole, DES (dextrin), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperidinylmethyl)-indolyl-quinolinone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate Acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetateacetate), CP-724714; TAK-165, HKI-272, lapatinib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanalide hydroxamic acid, valproic acid, trichostocin A A), FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, BCG ( Bacillus Calmette - Guerin BCG vaccine, adriamycin, bleomycin, buserelin, busulan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, GLEEVEC ®Gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitox antrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomi de), thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, fluxuridine, 5-deoxyuridine, cytosinearabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, photomycin Mithramycin, Vinblastine, Vinorelbine, Topotecan, Razoxin, Marimastat, COL-3, Neovastat, BMS-275291, Squalamine, Endostatin, SU5416, SU6668, EMD121974, Interleukin-12, IM862, Angiostatin, Vitaxin, Droloxifen, IdoxyfenSpironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezomib, paclitaxel, paclitaxel without hexadecyl polyoxyethylene ether, docetaxel, epithilone B) BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, azoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, Rapamycin, 40-O-(2-hydroxyethyl)-Rapamycin, Temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Wortmannin, ZM336372, L-779, 450, PEG-Figrastim, Darbepoetin, Erythropoietin, Granulocyte Colony-Stimulating Factor, Zolendronate, Prednisone, Cetuximab Anti-cetuximab, granulocyte-macrophage colony-stimulating factor, histamine relin, pegylated interferon α-2a, interferon α-2a, pegylated interferon α-2b, interferon α-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisoloneIbritumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, corticosteroids, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium-89, caspopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam Haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epidotin alfa, darbepoetin alfa, and mixtures thereof.

[0708] In some embodiments, the compound is administered in combination with ifosfamide.

[0709] In some embodiments, the bioactive agent is selected from (but not limited to) imatinib mesylate (GLEEVEC). ® ), dasatinib (SPRYCEL) ® ), nilotinib (TASIGNA) ® ), bosutinib (BOSULIF) ® trastuzumab (HERCEPTIN) ®), trastuzumab-DM1, pertuzumab (PERJETA) ® Lapatinib (TYKERB) ® ), Gefitinib (IRESSA) ® ), erlotinib (TARCEVA) ® ), cetuximab (ERBITUX) ® Panitumumab (VECTIBIX) ® ), vandetanib (CAPRELSA) ® ), vemurafenib (ZELBORAF) ® ), vorinostat (ZOLINZA) ® romidepsin (ISTODAX) ® Bexarotene (TAGRETIN) ® ), alitretinoin (PANRETIN) ® ), tretinoin (VESANOID) ® ), carfilizomib (KYPROLIS) ® ), Pralatrexate (FOLOTYN) ® ), bevacizumab (AVASTIN) ® ), ziv-aflibercept (ZALTRAP) ® Sorafenib (NEXAVAR) ® Sunitinib ® ), Pazopanib (VOTRIENT) ® Regorafenib (STIVARGA) ® ) and cabozantinib (COMETRIQ ® ).

[0710] In some respects, bioactive agents are anti-inflammatory agents, chemotherapeutic agents, radiation therapy agents, other therapeutic agents, or immunosuppressants.

[0711] Suitable chemotherapeutic bioactive agents include (but are not limited to) radioactive molecules, toxins (also known as cytotoxic agents, which include any agent harmful to cell viability), and liposomes or other vesicles containing chemotherapeutic compounds. Common anticancer agents include: vincristine (oncovine). ® ) or liposomal vincristine (MARQIBO) ® ), daunorubicin (daunomycin or cerubidine) ® or doxorubicin (ADRIAMYCIN) ® ), cytarabine (cytosine arabinoside, ara-C or CYTOSAR) ® L-Asparaginase (ELSPAR) ® ) or PEG-L-asparaginase (pegaspargase or ONCASPAR) ® Etoposide (VP-16), teniposide (VUMON) ® ), 6-mercaptopurine (6-MP or PURINETHOL) ® Methotrexate, Cyclophosphamide ® Prednisone, Dexamethasone ® ), imatinib (GLEEVEC) ® ), dasatinib (SPRYCEL) ® ), nilotinib (TASIGNA) ® ), bosutinib (BOSULIF) ® ) and ponatinib (ICLUSIG ® ).

[0712] Other examples of suitable chemotherapy agents include (but are not limited to) 1-dehydrotestosterone, 5-fluorouracil dacarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adenomyomycin, aldehyde-interleukin, alkylating agents, allopurinol sodium, hexamethylmelamine, amifostine, anastrozole, atracin (AMC), antimitotic agents, cis-dichlorodiamineplatin(II) (DDP, cisplatin), diaminodichloroplatinum, anthracycline, antibiotics, antimetabolites, asparaginase, BCG live. (Intrabladder), Betamethasone Sodium Phosphate and Betamethasone Acetate, Bicalutamide, Bleomycin Sulfate, Busulfan, Calcium Leucovorin, Carbazin, Capecitabine, Carboplatin, Lomustine (CCNU), Carmustine (BSNU), Chloromustine, Cisplatin, Cladribine, Colchicine, Conjugated Estrogen, Cyclophosphamide, Cyclothiophosphamide, Cytarabine, Cytochalasin B, Cetaxel, Dacarbazine, Actinomycin D, Actinomycin D (formerly Actinomycin), Daunorubicin HCl, Daunomycin Citrate, Dine Interleukin, Dextromethorphan, Dibromomannitol, Dihydroxyanthraxetine Dione, Docetaxel, Dolastron Mesylate, Doxorubicin HCl, Drowanesol, Escherichia coli L-Asparaginase, Ipecain, Eberrin-α, Erwinia L-Asparaginase, Esterified Estrogen, Estradiol, Estradiol Mustard Sodium Phosphate, Ethidium Bromide, Diethylestradiol, Etiphosphonate, Etoposide, Citrulline, Etoposide Phosphate, Filgrasting, Fluorouracil, Fluconazole, Fludarabine Phosphate, Fluuracil, Flutamide, Leucovorin, Gemcitabine HCl, Glucocorticoids, Goserelin Acetate, Leucovorin D, Granisetron HCl, Hydroxyurea, Edamycin HCl, Ifosfamide, Interferon Alpha-2b, Irinotecan HCl, Letrozole, Folic Acid Calcium, Leuprolide Acetate, Levamisole HCl, Lidocaine, Lomustine, Maytansine, Methamido Mustard HCl, Medroxyprogesterone Acetate, Megestrol Acetate, Melphalan HCl, Thiol Purine, Mesna, Methotrexate, Methyltestosterone, Photomycin, Mitomycin C, Mitotan, Mitoxantrone, Nilumethicone, Octreotide Acetate, Ondansetron HCl, Paclitaxel, Pamidronate Disodium, Pentostatin, Pilocarpine HCl, Piriformin, Carmustine Implanted Polyphenylpropionate 20 (polifeprosan 20 with carmustine implant), porphyrin sodium, procaine, procarbazine HCl, propranolol, rituximab, saxaglastine, streptozomycin, tamoxifen, paclitaxel, tenoposide, testrolide, tetracaine, thioguanine, thiotepa, toponotecan HCl, toremifene citrate, trastuzumab, retinoic acid, vararubicin, vincristine sulfate, vincristine sulfate, and vinorelbine tartrate.

[0713] In some embodiments, the compounds of the present invention are administered in combination with chemotherapeutic agents (e.g., cytotoxic agents or other compounds that can be used to treat cancer). Examples of chemotherapeutic agents include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferon, platinum coordination complexes, anthrone-substituted ureas, methylhydrazine derivatives, adrenocortical inhibitors, adrenocortical steroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), folate (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylmelamines, including altretamine and triethylenemelamine. mine), trietylenephosphoramide, triethiylenethiophosphoramide, and trimethylolomeleamine; acetogenins (especially bullatacin and bullatacinone); camptothecin (including its synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (Including its synthetic analogues adozelesin, carzelesin, and bizelesin)); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogues KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin;Spongistatin; nitrogen mustard, such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novoembichin, phenesterine, prednimustine, trofosfamide, uracil Mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics, such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, for example, Agnew, Chem. Inti. Ed Engl. 33:183-186) (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; esperamicin; and neo-cancer suppressant chromophores and related chromoproteins, aclacinomysins, actinomycin, autramycin, azaserine, bleomycins, cactinomycin C, carabicin, caminomycin, carzinophilin, chromomycinis, actinomycin D, daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine, ADRIAMYCIN; ®(Doxorubicin, including N-morpholino-doxorubicin, cyano-N-morpholino-doxorubicin, 2-N-pyrrololino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins (such as mitomycin C), mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex Metabolites such as mex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denostatin, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, deoxyfluorouridine, enocitabine, and fluorouridine; androgens such as calusterone and dromostanolone. Propionate, epitiostanol, mepitiostane, testolactone; anti-adrenergic drugs, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as folinic acid; acetylglucuronide; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate;Defofamine; Demecolcine; Diaziquone; Elfomithine; Elliptinium acetate); epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansine-like drugs such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazine; procarbazine; PSK; ® Polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofuran; spiral germanium; Alternaria ketoacid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A) A) and anguidine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactalol; piperobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; paclitaxel-like drugs, such as TAXOL ® (Paclitaxel; Bristol-Myers SquibbOncology, Princeton, NJ), ABRAXANE ® Albumin-engineered paclitaxel nanoparticle formulations without cetyl alcohol polyoxyethylene ether (American Pharmaceutical Partners, Schaumberg, IL) and TAXOTERE ®Docetaxel (Rhone-Poulenc Rorer, Antony, France); Chloranbucil; Gemzar ® Gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes, such as cisplatin, oxaliplatin, and carboplatin; vincristine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Navelbine ® Vinorelbine; Novantrone; Teniposide; Edatraxate; Daunomycin; Aminopterin; Xeloda; Ibandronate; Irinotecan (e.g., CPT-11); Topoisomerase inhibitor RFS 2000; Difluoromethylornithine (DMFO); Retinoids, such as retinoic acid; Capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Two or more chemotherapeutic agents may be administered in combination with the compounds of the present invention, or used as a mixture. Suitable dosing regimens for combination chemotherapy are known in the art. For example, combination dosing regimens are described in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999) and Douillard et al., Lancet 355(9209):1041-1047 (2000).

[0714] Other therapeutic agents that can be administered in combination with the compounds described herein may include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vtalanib, vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukine, and other similar drugs. Atlizumab, Tocilizumab, Tamromolimus, Everolimus, Lucarumumab, Dacetuzumab, HLL1, huN901-DM1, Atipremod, Natalizumab, Bortezomib, Carfilzomib, Marizomib, Tanespimycin, Saquinavir Mesylate, Ritonavir, Nelfinavir Mesylatemesylate), indinavir sulfate, belinostat, panobinostat, mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin, talmapimod, P276-00, enzatolin Staurin, Tipifarnib, Perifosine, Imatinib, Dasatinib, Lenalidomide, Thalidomide, Simvastatin, Celecoxib, Bazedoxifene, AZD4547, Rilotumumab, Oxaliplatin ® ), PD0332991, Ribocitabine (ribociclib) (LEE011), Amebaciclib (LY2835219), HDM201, Flavextane (FASLODEX) ® ), AROMASIN ® PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (ALIMTA®), and ramucirumab (IMC-1121B).

[0715] In some embodiments, the additional therapy is a monoclonal antibody (MAb). Some MAbs stimulate an immune response to destroy cancer cells. Similar to antibodies naturally produced by B cells, these MAbs can "coat" the surface of cancer cells, thereby triggering the immune system to destroy them. For example, bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor microenvironment that promotes tumor angiogenesis. When bound to bevacizumab, VEGF cannot interact with its cell receptors, thereby blocking the signaling that induces new blood vessel growth. MAbs that bind to cell surface growth factor receptors prevent the targeted receptors from sending signals that promote their normal growth. They can also trigger apoptosis and activate the immune system to destroy tumor cells.

[0716] In one aspect of the invention, the bioactive agent is an immunosuppressant. The immunosuppressant may be a calcineurin inhibitor, such as cyclosporine or ascomycin, such as cyclosporine A. ® FK506 (tacrolimus), pimecrolimus, mTOR inhibitors such as rapamycin or its derivatives such as sirolimus ® ), everolimus (CERTICAN) ® ), temsirolimus, zotarolimus, biolimus-7, biolimus-9; rapamycin analogues, such as ridaforolimus, azathioprine, campath 1H; S1P receptor modulators, such as fingolimod or their analogues; anti-IL-8 antibodies, mycophenolic acid or its salts, such as sodium salts, or their prodrugs, such as mycophenolate mofetil (CELLCEPT) ® OKT3 ORTHOCLONE OKT3 ® Prednisone, ATGAM ® THYMOGLOBULIN ® Brequinar sodium, OKT4, T10B9.A-3A, 33B3.1, deoxyspergualin, tresperimus, leflunomide (ARAVA) ® ), CTLAI-Ig, anti-CD25, anti-IL2R, basiliximab (SIMULECT) ® ), daclizumab (ZENAPAX) ® Mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, ELIDEL) ®), CTLA4lg (abatacept), belatacept, LFA3lg, etanercept (as ENBREL by Immunex) ® (For Sale), adalimumab (HUMIRA) ® ), infliximab (REMICADE) ® Anti-LFA-1 antibody, natalizumab (ANTEGREN) ® Enlimomab, gavilimomab, anti-thymocyte immunoglobulin, siplizumab, alefacept, efalizumab, pentasa, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naproxen, diclofenac, etodolac, indomethacin, aspirin, and ibuprofen.

[0717] In some embodiments, the bioactive agent is a therapeutic agent, which is a biologic, such as a cytokine (e.g., interferon or interleukin (e.g., IL-2)) used for cancer treatment. In some embodiments, the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, for example, bevacizumab (AVASTIN®). In some embodiments, the biologic is an immunoglobulin-based biologic, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that induces a targeted anti-cancer response or antagonizes important cancer antigens. Such agents include RITUXAN. ® (rituximab); ZENAPAX ® (daclizumab); SIMULECT ® (basiliximab); SYNAGIS ® (palivizumab); REMICADE ® (infliximab); HERCEPTIN ® (trastuzumab); MYLOTARG® (gemtuzumab ozogamicin); CAMPATH ® (alemtuzumab); ZEVALIN ® (Ibrimomab tiuxetan); HUMIRA ® (adalimumab); XOLAIR ® (Omalizumab); BEXXAR ® (tositumomab-l-131); RAPTIVA ® (efalizumab); ERBITUX ® (cetuximab); AVASTIN ® (bevacizumab); TYSABRI ® (natalizumab); ACTEMRA ® (tocilizumab); VECTIBIX ® (panitumumab); LUCENTIS ® (ranibizumab); SOURIS ® (eculizumab); CIMZIA ® (Petroglycolated certolizumab pegol); SIMPONI ® (golimumab); ILARIS ® (canakinumab); STELARA ® (ustekinumab); ARZERRA ® (ofatumumab); PROLIA ® (denosumab); NUMAX ® (motavizumab); ABTHRAX ® (Raxibacumab); BENLYSTA ® (belimumab); YERVOY ® (ipilimumab); ADCETRIS® (brentuximab vedotin); PERJETA ® (pertuzumab); KADCYLA ® (trastuzumab-emtansine conjugate); and GAZYVA ® (Obinutuzumab). Also includes antibody-drug conjugates.

[0718] Combination therapy may include therapeutic agents as non-pharmacological treatments. For example, compounds may be administered in addition to radiotherapy, cryotherapy, hyperthermia, and / or surgical removal of tumor tissue.

[0719] Other embodiments of the present invention

[0720] Unless the context excludes, all individual embodiments can be combined.

[0721] R 1 Implementation examples

[0722] In some embodiments, R 1 It is hydrogen.

[0723] In some embodiments, R 1 It is an alkyl group.

[0724] In some embodiments, R 1 It is a cycloalkyl group.

[0725] In some embodiments, R 1 It is a methyl group.

[0726] In some embodiments, R 1 It is an ethyl group.

[0727] In some embodiments, R 1 It is cyclopropyl.

[0728] R 2 Implementation examples

[0729] In some embodiments, R 2 It is hydrogen.

[0730] In some embodiments, R 2 It is an alkyl group.

[0731] In some embodiments, R 2 It is a cycloalkyl group.

[0732] In some embodiments, R 2 It is a methyl group.

[0733] In some embodiments, R 2 It is an ethyl group.

[0734] In some embodiments, R 2 It is cyclopropyl.

[0735] In some embodiments, R 2 It is a haloalkyl group.

[0736] In some embodiments, R 2 It is CF3.

[0737] In some embodiments, R 1 and R 2 Together with the nitrogen atom to which it is attached, it forms an optional structure via one or two R atoms. 3 Substituted heterocyclic alkyl groups. R 2' Implementation examples

[0738] In some embodiments, R 2' It is hydrogen.

[0739] In some embodiments, R 2' It is an alkyl group.

[0740] In some embodiments, R 2' It is a cycloalkyl group.

[0741] In some embodiments, R 2' It is a methyl group.

[0742] In some embodiments, R 2' It is an ethyl group.

[0743] In some embodiments, R 2' It is cyclopropyl.

[0744] In some embodiments, R 2' It is a haloalkyl group.

[0745] In some embodiments, R 2' It is CF3.

[0746] In some embodiments, R 1 and R 2 'Together with the carbon atom to which it is attached, it forms optionally via one or two R... 3 Substituted cycloalkyl groups. R 3 Implementation examples

[0747] In some embodiments, R 3 It is hydrogen.

[0748] In some embodiments, R 3 It is an alkyl group.

[0749] In some embodiments, R 3 It is a cycloalkyl group.

[0750] In some embodiments, R 3 It is a methyl group.

[0751] In some embodiments, R 3 It is an ethyl group.

[0752] In some embodiments, R 3 It is cyclopropyl.

[0753] In some embodiments, R 3 It is an alkoxy group.

[0754] In some embodiments, R 3 It is a methoxy group.

[0755] In some embodiments, R 3 It is an ethoxylated compound.

[0756] In some embodiments, R 3 It is a halogen.

[0757] In some embodiments, R 3 It is F. R 4 Implementation examples

[0758] In some embodiments, R 4 It is hydrogen.

[0759] In some embodiments, R 4 It is an alkyl group.

[0760] In some embodiments, R 4 It is a cycloalkyl group.

[0761] In some embodiments, R 4 It is a methyl group.

[0762] In some embodiments, R 4 It is an ethyl group.

[0763] In some embodiments, R 4 It is cyclopropyl.

[0764] In some embodiments, R 4 It is a halogen.

[0765] In some embodiments, R 4 It is F.

[0766] In some embodiments, R 4 It is a cyano group. R 5Implementation examples

[0767] In some embodiments, R 5 It is hydrogen.

[0768] In some embodiments, R 5 It is an alkyl group.

[0769] In some embodiments, R 5 It is a cycloalkyl group.

[0770] In some embodiments, R 5 It is a methyl group.

[0771] In some embodiments, R 5 It is an ethyl group.

[0772] In some embodiments, R 5 It is cyclopropyl.

[0773] In some embodiments, R 5 It is a halogen.

[0774] In some embodiments, R 5 It is F.

[0775] In some embodiments, R 5 It is a cyano group. R 6 Implementation examples

[0776] In some embodiments, R 6 It is hydrogen.

[0777] In some embodiments, R 6 It is an alkyl group.

[0778] In some embodiments, R 6 It is a cycloalkyl group.

[0779] In some embodiments, R 6 It is a methyl group.

[0780] In some embodiments, R 6 It is an ethyl group.

[0781] In some embodiments, R 6 It is cyclopropyl.

[0782] In some embodiments, R 6 It is a halogen.

[0783] In some embodiments, R 6 It is F.

[0784] In some embodiments, R 6 It is a hydroxyl group.

[0785] In some embodiments, R 6 It is an amino group.

[0786] In some embodiments, R 6 It is a dialkylamino group.

[0787] In some embodiments, R 6 It is an alkoxy group.

[0788] In some embodiments, R 6 It is an alkoxyalkyl group. R 7 Implementation examples

[0789] In some embodiments, R 7 It is hydrogen.

[0790] In some embodiments, R 7 It is an alkyl group.

[0791] In some embodiments, R 7 It is a methyl group.

[0792] In some embodiments, R 7 It is an ethyl group. R 8 Implementation examples

[0793] In some embodiments, R 8 It is hydrogen.

[0794] In some embodiments, R 8 It is an alkyl group.

[0795] In some embodiments, R 8 It is a cyano group.

[0796] In some embodiments, R 8 It is a halogen.

[0797] In some embodiments, R 8 It is an alkoxy group.

[0798] In some embodiments, R 8 It is fluorine.

[0799] In some embodiments, R 8 It is a methoxy group.

[0800] In some embodiments, R 8 It is an ethoxylated compound.

[0801] In some embodiments, R 8 It is a methyl group.

[0802] In some embodiments, R 8 It is an ethyl group. R9 Implementation examples

[0803] In some embodiments, R 9 It is hydrogen.

[0804] In some embodiments, R 9 It is an alkyl group.

[0805] In some embodiments, R 9 It is a cyano group.

[0806] In some embodiments, R 9 It is a halogen.

[0807] In some embodiments, R 9 It is an alkoxy group.

[0808] In some embodiments, R 9 It is fluorine.

[0809] In some embodiments, R 9 It is a methoxy group.

[0810] In some embodiments, R 9 It is an ethoxylated compound.

[0811] In some embodiments, R 9 It is a methyl group.

[0812] In some embodiments, R 9 It is an ethyl group. R 17 Implementation examples

[0813] In some embodiments, R 17 It is hydrogen.

[0814] In some embodiments, R 17 It is an alkyl group.

[0815] In some embodiments, R 17 It is a cyano group.

[0816] In some embodiments, R 17 It is a halogen.

[0817] In some embodiments, R 17 It is an alkoxy group.

[0818] In some embodiments, R 17 It is fluorine.

[0819] In some embodiments, R 17 It is a methoxy group.

[0820] In some embodiments, R 17 It is an ethoxylated compound.

[0821] In some embodiments, R 17 It is a methyl group.

[0822] In some embodiments, R 17 It is an ethyl group.

[0823] In some embodiments, R 17 It is a hydroxyl group.

[0824] In some embodiments, R 17 It is a cycloalkyl group.

[0825] In some embodiments, R 17 It is cyclopropyl. R 18 Implementation examples

[0826] In some embodiments, R 18 It is hydrogen.

[0827] In some embodiments, R 18 It is an alkyl group.

[0828] In some embodiments, R 18 It is a cyano group.

[0829] In some embodiments, R 18 It is a halogen.

[0830] In some embodiments, R 18 It is an alkoxy group.

[0831] In some embodiments, R 18 It is fluorine.

[0832] In some embodiments, R 18 It is a methoxy group.

[0833] In some embodiments, R 18 It is an ethoxylated compound.

[0834] In some embodiments, R 18 It is a methyl group.

[0835] In some embodiments, R 18 It is an ethyl group.

[0836] In some embodiments, R 18 It is a hydroxyl group.

[0837] In some embodiments, R 18 It is a cycloalkyl group.

[0838] In some embodiments, R 18 It is cyclopropyl. R 19 Implementation examples

[0839] In some embodiments, R 19 It is hydrogen.

[0840] In some embodiments, R 19 It is an alkyl group.

[0841] In some embodiments, R 19 It is a cyano group.

[0842] In some embodiments, R 19 It is a halogen.

[0843] In some embodiments, R 19 It is an alkoxy group.

[0844] In some embodiments, R 19 It is fluorine.

[0845] In some embodiments, R 19 It is a methoxy group.

[0846] In some embodiments, R 19 It is an ethoxylated compound.

[0847] In some embodiments, R 19 It is a methyl group.

[0848] In some embodiments, R 19 It is an ethyl group.

[0849] In some embodiments, R 19 It is a hydroxyl group.

[0850] In some embodiments, R 19 It is a cycloalkyl group.

[0851] In some embodiments, R 19 It is cyclopropyl. R 60 Implementation examples

[0852] In some embodiments, R 60 It is isopropyl.

[0853] In some embodiments, R 60 It is an F-substituted pyrrolidine-1-yl group.

[0854] In some embodiments, R 60 It is a pyrrolidine-1-yl group substituted with OMe.

[0855] In some embodiments, R 60 It is cyclopropyl. A 1 Implementation examples

[0856] In some embodiments, A1 It is NR2.

[0857] In some embodiments, A 1 For -CHR 2 '-.

[0858] In some embodiments, A 1 It is NH.

[0859] In some embodiments, A 1 It is NCH3.

[0860] In some embodiments, A 1 It is -CH2-. A 2 Implementation examples

[0861] In some embodiments, A 2 It is -O-.

[0862] In some embodiments, A 2 It is -NH-.

[0863] In some embodiments, A 2 It is -(C=O)-. A 5 A 6 and A 15 Implementation examples

[0864] In some embodiments, A 5 It is -CH-.

[0865] In some embodiments, A 5 It is -N-.

[0866] In some embodiments, A 6 It is -CH-.

[0867] In some embodiments, A 6 It is -N-.

[0868] In some embodiments, A 15 It is -O-.

[0869] In some embodiments, A 15 It is -N-.

[0870] In some embodiments, A 15 For key. Implementation of q

[0871] In some embodiments, q is 0.

[0872] In some embodiments, q is 1. Examples of p

[0873] In some embodiments, p is 0.

[0874] In some embodiments, p is 1.

[0875] In some embodiments, p is 2. Examples of r

[0876] In some embodiments, r is 0.

[0877] In some embodiments, r is 1.

[0878] In some embodiments, r is 2. Examples of w

[0879] In some embodiments, w is 1.

[0880] In some embodiments, w is 2.

[0881] Implementation examples

[0882] In some embodiments, ring D is optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups.

[0883] In some embodiments, ring D is substituted with a halogen substituent.

[0884] In some embodiments, ring D is substituted with two halogen substituents.

[0885] In some embodiments, cyclodextrin D is substituted with an alkyl group.

[0886] In some embodiments, ring D is substituted with two alkyl substituents.

[0887] In some embodiments, ring D is substituted with an alkoxy group.

[0888] In some embodiments, ring D is substituted with two alkoxy substituents.

[0889] In some embodiments, ring D is halogenated and alkyl-substituted.

[0890] In some embodiments, ring D is substituted with halogen and alkoxy groups.

[0891] In some embodiments, cyclodextrin D is substituted with alkyl and alkoxy groups.

[0892] In some embodiments, ring D is (2-azaspiro[3.3]heptane-2,6-diyl).

[0893] In some embodiments, ring D is (2,6-diazaspiro[3.3]heptane-2,6-diyl).

[0894] In some embodiments, ring D is (piperidine-1,4-dimethyl).

[0895] Implementation examples

[0896] In some embodiments, ring E is (1-oxa-8-azaspiro[4.5]decane-3,8-diyl).

[0897] In some embodiments, ring E is (5-oxa-2-azaspiro[3.4]octane-2,7-diyl).

[0898] Implementation examples

[0899] In some embodiments, ring F is (7-azaspiro[3.5]nonane-2,7-diyl).

[0900] In some embodiments, ring F is (3-azabicyclo[3.1.0]hexane-3,6-diyl).

[0901] In some embodiments, ring F is (3-azaspiro[5.5]undecane-3,9-diyl).

[0902] In some embodiments, ring F is (octahydrocyclopentano[c]pyrrole-2,5-diyl).

[0903] In some embodiments, ring F is (8-azaspiro[4.5]decane-2,8-diyl).

[0904] In some embodiments, ring F is (2-azaspiro[3.3]heptane-2,6-diyl).

[0905] In some embodiments, ring F is (6-azaspiro[3.4]octane-2,6-diyl).

[0906] Implementation examples

[0907] In some embodiments, ring G is (cyclohexane-1,4-diyl).

[0908] In some embodiments, ring G is (2-Fluoro-cyclohexane-1,4-diyl).

[0909] In some embodiments, ring G is (2-azaspiro[3.3]heptane-2,6-diyl).

[0910] In some embodiments, ring G is (piperidine-1,4-dimethyl).

[0911] In some embodiments, ring G is (7-azaspiro[3.5]nonane-2,7-diyl).

[0912] In some embodiments, ring G is (2-azaspiro[3.5]nonane-2,7-diyl).

[0913] In some embodiments, ring G is (3,3-Difluoro-piperidine-1,4-diyl).

[0914] In some embodiments, ring G is (1-oxa-8-azaspiro[4.5]decane-3,8-diyl).

[0915] Implementation examples

[0916] In some embodiments, ring H is (1-oxa-8-azaspiro[4.5]decane-3,8-diyl).

[0917] Implementation examples

[0918] In some embodiments, ring I is (cyclohexane-1,4-diyl).

[0919] Implementation examples

[0920] In some embodiments, ring J is (1-oxa-8-azaspiro[4.5]decane-3,8-diyl).

[0921] In some embodiments, ring J is (7-azaspiro[3.5]nonane-2,7-diyl).

[0922] In some embodiments, ring J is (2-azaspiro[3.3]heptane-2,6-diyl).

[0923] Implementation examples

[0924] In some embodiments, ring K is (2,6-diazaspiro[3.3]heptane-2,6-diyl).

[0925] In some embodiments, ring K is (3,3-Difluoro-piperidine-1,4-diyl).

[0926] In some embodiments, ring K is (piperazine-1,4-dimethyl).

[0927] Implementation examples

[0928] In some embodiments, ring L is (piperazine-1,4-dimethyl).

[0929] In some embodiments, ring L is (2-azaspiro[3.3]heptane-2,6-diyl).

[0930] In some embodiments, ring L is (2-Fluoro-cyclohexane-1,4-diyl).

[0931] In some embodiments, ring L is (cyclohexane-1,4-diyl).

[0932] In some embodiments, ring L is (piperidine-1,4-dimethyl).

[0933] Implementation examples

[0934] In some embodiments, ring M is 2-Fluoro-cyclohexane-1,4-diyl;

[0935] In some embodiments, ring M is 2-Hydroxy-cyclohexane-1,4-dimethyl.

[0936] Implementation examples

[0937] In some embodiments, ring N is (piperidine-1,4-dimethyl).

[0938] In some embodiments, ring N is (spiro[3.3]heptane-2,6-diyl).

[0939] In some embodiments, ring N is (7-azaspiro[3.5]nonane-2,7-diyl).

[0940] In some embodiments, ring N is (cyclohexane-1,4-diyl).

[0941] In some embodiments, ring N is (spiro[3.5]nonane-2,7-diyl).

[0942] In some embodiments, ring N is (2-azaspiro[3.3]heptane-2,6-diyl).

[0943] Implementation examples

[0944] In some embodiments, ring O is (cyclohexane-1,4-diyl).

[0945] In some embodiments, ring O is (3,3-Difluoro-piperidine-1,4-diyl).

[0946] In some embodiments, ring O is (2,7-diazaspiro[3.5]nonane-2,7-diyl).

[0947] In some embodiments, ring O is (2-azaspiro[3.3]heptane-2,6-diyl).

[0948] In some embodiments, ring O is (4-Hydroxypiperidine-1,4-dimethyl).

[0949] In some embodiments, ring O is (Zynebutane-1,3-diyl).

[0950] In some embodiments, ring O is (piperidine-1,4-dimethyl).

[0951] Examples of alkyl groups

[0952] In some embodiments, "alkyl" is C1-C. 10 Alkyl, C1-C9 alkyl, C1-C8 alkyl, C1-C7 alkyl, C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1-C2 alkyl.

[0953] In some embodiments, "alkyl" has one carbon atom.

[0954] In some embodiments, "alkyl" has two carbon atoms.

[0955] In some embodiments, "alkyl" has three carbons.

[0956] In some embodiments, "alkyl" has four carbon atoms.

[0957] In some embodiments, the "alkyl" has five carbons.

[0958] In some embodiments, the "alkyl" has six carbons.

[0959] Non-limiting examples of "alkyl" include: methyl, ethyl, propyl, butyl, pentyl, and hexyl.

[0960] Other non-limiting examples of "alkyl" include isopropyl, isobutyl, isopentyl, and isohexyl.

[0961] Other non-limiting examples of "alkyl" include: sec-butyl, sec-pentyl and sec-hexyl.

[0962] Other non-limiting examples of "alkyl" include tert-butyl, tert-pentyl, and tert-hexyl.

[0963] Other non-limiting examples of "alkyl" include neopentyl, 3-pentyl, and reactive pentyl.

[0964] Examples of cycloalkyl groups

[0965] In some embodiments, "cycloalkyl" refers to C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C3-C4 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl, or C6-C8 cycloalkyl.

[0966] In some embodiments, "cycloalkyl" has three carbons.

[0967] In some embodiments, "cycloalkyl" has four carbons.

[0968] In some embodiments, "cycloalkyl" has five carbons.

[0969] In some embodiments, "cycloalkyl" has six carbons.

[0970] In some embodiments, "cycloalkyl" has seven carbons.

[0971] In some embodiments, "cycloalkyl" has eight carbons.

[0972] In some embodiments, "cycloalkyl" has nine carbons.

[0973] In some embodiments, "cycloalkyl" has ten carbons.

[0974] Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl.

[0975] R1 - A 1 - SO2 - NH - ( ) Examples

[0976] In some embodiments, for .

[0977] In some embodiments, for .

[0978] In some embodiments, for .

[0979] In some embodiments, for .

[0980] In some embodiments, for .

[0981] In some embodiments, for .

[0982] In some embodiments, for .

[0983] In some embodiments, for .

[0984] In some embodiments, for .

[0985] In some embodiments, for .

[0986] In some embodiments, for .

[0987] In some embodiments, for .

[0988] In some embodiments, for .

[0989] In some embodiments, for .

[0990] In some embodiments, for .

[0991] In some embodiments, for .

[0992] In some embodiments, for .

[0993] In some embodiments, for .

[0994] In some embodiments, for .

[0995] Examples of alkyl halides

[0996] In some embodiments, "haloalkyl" is C1-C 10 Haloalkyl, C1-C9 haloalkyl, C1-C8 haloalkyl, C1-C7 haloalkyl, C1-C6 haloalkyl, C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl and C1-C2 haloalkyl.

[0997] In some embodiments, the "haloalkyl" has one carbon atom.

[0998] In some embodiments, the "haloalkyl" has one carbon atom and one halogen atom.

[0999] In some embodiments, the "haloalkyl" has one carbon atom and two halogens.

[1000] In some embodiments, the "haloalkyl" has one carbon atom and three halogens.

[1001] In some embodiments, the "haloalkyl" has two carbon atoms.

[1002] In some embodiments, the "haloalkyl" has three carbons.

[1003] In some embodiments, the "haloalkyl" has four carbons.

[1004] In some embodiments, the "haloalkyl" has five carbons.

[1005] In some embodiments, the "haloalkyl" has six carbons.

[1006] Non-limiting examples of "haloalkyl" include: , ,and .

[1007] Other non-limiting examples of "haloalkyl" include: , , , , , , , , , ,and .

[1008] Other non-limiting examples of "haloalkyl" include: , ,and .

[1009] Other non-limiting examples of "haloalkyl" include: , ,and .

[1010] Examples of heterocyclic rings

[1011] In some embodiments, "heterocyclic" refers to a cyclic ring having one nitrogen atom, one oxygen atom, and 3, 4, 5, 6, 7, or 8 carbon atoms.

[1012] In some embodiments, "heterocyclic" refers to a cyclic ring having two nitrogen atoms and 3, 4, 5, 6, 7, or 8 carbon atoms.

[1013] In some embodiments, "heterocyclic" refers to a cyclic ring having one oxygen atom and 3, 4, 5, 6, 7, or 8 carbon atoms.

[1014] In some embodiments, "heterocyclic ring" refers to a ring having one sulfur atom and 3, 4, 5, 6, 7, or 8 carbon atoms.

[1015] Non-limiting examples of "heterocycles" include azirropropane, ethylene oxide, thioheteropropane, azirrobutane, 1,3-diazaheterobutane, oxoheterobutane, and thioheterobutane.

[1016] Other non-limiting examples of "heterocyclic" compounds include pyrrolidine, 3-pyrrolidine, 2-pyrrolidine, pyrazolidine, and imidazoline.

[1017] Other non-limiting examples of "heterocycles" include tetrahydrofuran, 1,3-dioxacyclopentane, tetrahydrothiophene, 1,2-oxothiocyclopentane, and 1,3-oxothiocyclopentane.

[1018] Other non-limiting examples of "heterocyclic" include piperidine, piperazine, tetrahydropyran, 1,4-dioxane, thiazide, 1,3-dithiazide, 1,4-dithiazide, morpholine, and thiomorpholine.

[1019] Other non-limiting examples of "heterocycles" include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran, wherein the linkages of the groups are located on the heterocycle.

[1020] Non-limiting examples of "heterocycles" also include: , , , , , , , , ,and .

[1021] Other non-limiting examples of "heterocycles" include: , , , , , , ,and .

[1022] Other non-limiting examples of "heterocycles" include: , , , , , , ,and .

[1023] Non-limiting examples of "heterocycles" also include: , ,and .

[1024] Non-limiting examples of "heterocycles" also include: , , , , , , ,and .

[1025] Other non-limiting examples of "heterocycles" include: , , , , ,and .

[1026] Other non-limiting examples of "heterocycles" include: , , , , ,and .

[1027] Examples of spiroheterocyclic groups

[1028] In some embodiments, "spiroheterocyclic group" refers to a heterocyclic moiety having one nitrogen atom, one oxygen atom, and 5, 6, 7, 8, 9, or 10 carbon atoms, wherein one quaternary carbon atom is the only common member of the two rings.

[1029] In some embodiments, "spiroheterocyclic group" refers to a heterocyclic moiety having two nitrogen atoms and 5, 6, 7, 8, 9 or 10 carbon atoms, wherein one quaternary carbon atom is the only common member of the two rings.

[1030] In some embodiments, "spiroheterocyclic group" refers to a heterocyclic moiety having one oxygen atom and 5, 6, 7, 8, 9 or 10 carbon atoms, wherein one quaternary carbon atom is the only common member of the two rings.

[1031] In some embodiments, the "spiroheterocyclic group" is selected from: , , , , , , , , , .

[1032] Examples of spirocycloalkyl

[1033] In some embodiments, "spirocycloalkyl" refers to a cycloalkyl moiety having 6, 7, 8, 9, 10, or 11 carbon atoms, wherein one quaternary carbon atom is the only common member of the two rings.

[1034] In some embodiments, "spirocycloalkyl" is (spiro[3.3]heptane-2,6-diyl).

[1035] In some embodiments, "spirocycloalkyl" is (spiro[3.5]nonane-2,7-diyl).

[1036] Examples of fused bicyclic moieties (fused bicyclic groups)

[1037] In some embodiments, a "fused" bicyclic base refers to a 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, or 12-membered bicyclic base portion, wherein the two rings in this portion share two adjacent atoms, that is, the rings (which may be heterocyclic or carbocyclic) share a covalent bond.

[1038] In some embodiments, the fused bicyclic group is a fused heterocyclic group having one or two heteroatoms selected from oxygen and nitrogen.

[1039] In some embodiments, the fused bicyclic group is a fused cycloalkyl group.

[1040] In some embodiments, the fused bicyclic group contains one or two heteroatoms selected from oxygen and nitrogen and 5, 6, 7, 8, 9 or 10 carbon atoms.

[1041] In some embodiments, the fused bicyclic group contains one nitrogen atom and five carbon atoms.

[1042] In some embodiments, the fused bicyclic group contains one nitrogen atom and six carbon atoms.

[1043] In some embodiments, the fused bicyclic group contains one nitrogen atom and seven carbon atoms.

[1044] In some embodiments, the fused double-ring portion is (3-azabicyclo[3.1.0]hexane-3,6-diyl).

[1045] In some embodiments, the fused double-ring portion is (octahydrocyclopentano[c]pyrrole-2,5-diyl).

[1046] Example of a bridging double-ring section (bridging double-ring base)

[1047] In some embodiments, a “bridged” bicyclic base refers to a 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, or 11-membered bicyclic base portion, wherein the two rings in the portion share three or more atoms, and the two bridgehead atoms are separated by a bridge containing at least one atom.

[1048] In some embodiments, the bridging bicyclic group is a bridging heterocyclic group having one, two, or three heteroatoms selected from oxygen and nitrogen.

[1049] In some embodiments, the bridging bicyclic group is a bridging heterocyclic group having one nitrogen atom, one oxygen atom, and seven carbon atoms.

[1050] In some embodiments, the bridging bicyclic group is a bridging heterocyclic group having two nitrogen atoms and seven carbon atoms.

[1051] In some embodiments, the bridging bicyclic group is a bridging heterocyclic group having one oxygen atom and eight carbon atoms.

[1052] In some embodiments, the bridging bicyclic group is a bridging heterocyclic group having one nitrogen atom and eight carbon atoms.

[1053] In some embodiments, the bridging bicyclol group is a bridging cycloalkyl group.

[1054] In some embodiments, the bridging double-ring base is (3-oxa-9-azabicyclo[3.3.1]nonane-7,9-diyl).

[1055] In some embodiments, the bridging double-ring base is (3-oxabicyclo[3.3.1]nonane-7,9-diyl).

[1056] Examples of ligand moieties targeting BRAF

[1057] In some embodiments, R 1 It is CH3.

[1058] In some embodiments, A 1 It is -N(CH2CH3)-.

[1059] In some embodiments, R 4 It is a cyano group.

[1060] In some embodiments, R 4 It is F.

[1061] In some embodiments, R 5 It is F.

[1062] In some embodiments, A 2 It is O.

[1063] In some embodiments, A 2 It is NH.

[1064] In some embodiments, R 6 It is hydrogen.

[1065] In some embodiments, R 6 It is F. In some embodiments, the ligands targeting BRAF are selected from: and

[1066] In some embodiments, the ligands targeting BRAF are selected from: and

[1067] In some embodiments, the ligands targeting BRAF are selected from: and

[1068] In some embodiments, the ligands targeting BRAF are selected from: and

[1069] In some embodiments, the ligands targeting BRAF are selected from: and

[1070] In some embodiments, the ligands targeting BRAF are selected from: and .

[1071] In some embodiments, the ligands targeting BRAF are selected from: and .

[1072] In some embodiments, the ligands targeting BRAF are selected from: and .

[1073] In some embodiments, the ligands targeting BRAF are selected from:

[1074] and .

[1075] Implementation examples

[1076] In some embodiments, Selected from: .

[1077] Implementation examples

[1078] In some embodiments, Selected from: and its stereoisomers.

[1079] Examples of the hydroxycerebroside ligand moiety of the molecule

[1080] In some embodiments, the hydroxycerebroside ligand is selected from... and .

[1081] In some embodiments, the hydroxycerebroside ligand is selected from... and .

[1082] In some embodiments, the hydroxycerebroside ligand is selected from... and .

[1083] In some embodiments, the hydroxycerebroside ligand is selected from... and .

[1084] Pharmaceutical Composition

[1085] The selected compounds of the present invention, or pharmaceutically acceptable salts thereof, may be administered in pure chemical form, but are typically administered in the form of pharmaceutical compositions, including in an effective amount for a host (typically human) requiring such treatment for any of the conditions described herein. Therefore, this disclosure provides pharmaceutical compositions comprising an effective amount of the compound or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier for use in any of the purposes described herein. The pharmaceutical composition may contain the compound or salt as the sole active agent, or, in alternative embodiments, may contain the compound and at least one other active agent.

[1086] In some embodiments, the pharmaceutical composition is presented in dosage forms containing, per unit dosage form, about 0.001 mg to about 1000 mg, about 0.01 mg to about 800 mg, about 1 mg to about 800 mg, or about 200 mg to about 600 mg of an active compound, and optionally, about 0.1 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of another active agent. Examples are dosage forms having at least about or no more than 0.001, 0.005, 0.010, 0.10, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of an active compound or a salt thereof.

[1087] In some aspects, the compound of the present invention or a pharmaceutically acceptable salt thereof is administered at a dose between about 0.1 mg and about 1000 mg. In some embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof is administered at a dose between about 1 mg and about 500 mg. In some embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof is administered at a dose between about 10 mg and about 500 mg. In some embodiments, the compound of the present invention or a pharmaceutically acceptable salt thereof is administered at a dose between about 1 mg and about 250 mg.

[1088] In some embodiments, the pharmaceutical composition is in the form of a dosage form containing about 70 mg of the active compound or a salt thereof. In some embodiments, the pharmaceutical composition is in the form of a dosage form containing about 400 mg of the active compound or a salt thereof. In some embodiments, the pharmaceutical composition is in the form of a dosage form containing about 800 mg of the active compound or a salt thereof.

[1089] In some embodiments, the compound is administered twice daily to patients in need.

[1090] The compounds described herein may be administered orally, topically, systemically, non-enterically, by inhalation or spray, sublingually, via implants (including ocular implants), percutaneously, via buccal administration, rectal administration, as an ophthalmic solution, by injection (including intravenous, intra-aortic, intracranial, subdermal, intraperitoneal, and subcutaneous), via nasal, sublingual, or rectal administration, or by other means, in dosage units containing pharmaceutically acceptable conventional carriers.

[1091] Pharmaceutical compositions can be formulated in any pharmaceutically suitable form, such as solid dosage forms, liquids, aerosols, creams, gels, pills, injectable or infusion solutions, capsules, tablets, syrups, transdermal patches, subcutaneous patches, dry powders, inhalation formulations, medical devices, suppositories, buccal or sublingual formulations, non-enteral formulations, or ophthalmic solutions. Some dosage forms (such as tablets and capsules) are further divided into appropriately sized unit doses containing an adequate amount of the active ingredient (e.g., an effective amount to achieve the desired purpose).

[1092] The carrier includes excipients and diluents and should have sufficiently high purity and low toxicity to make it suitable for administration in an effective amount to the patient being treated. The carrier may be inert or may itself have pharmaceutical benefits. The amount of carrier used in conjunction with the compound is sufficient to provide a usable amount of the substance based on the unit dose of the compound.

[1093] Carrier categories include (but are not limited to) binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavoring agents, lubricants, preservatives, stabilizers, surfactants, tableting agents, and humectants. Some carriers may be listed in more than one category; for example, vegetable oils can be used as lubricants in some formulations and as diluents in others. Pharmaceutically acceptable exemplary carriers include sugars, starches, cellulose, powdered tragacanth gum, malt, gelatin; talc, and vegetable oils. Pharmaceutical compositions may include optionally present active agents that do not substantially interfere with the activity of the compounds of the present invention.

[1094] Pharmaceutical compositions / combinations may be formulated for oral administration. These compositions may contain any amount of the active compound to achieve the desired results, such as between 0.1 wt.% and 99 wt.% of the compound, typically at least about 5 wt.% of the compound. Some examples contain about 25 wt.% to about 50 wt.% or about 5 wt.% to about 75 wt.% of the compound.

[1095] In some embodiments, the LNP contains a cation or an ionization restriction. Examples include (but are not limited to): U.S. Patent Publications 20060083780 and 20060240554; U.S. Patents 5,208,036; 5,264,618; 5,279,833; 5,283,185; 5,753,613; and 5,785,992; and PCT Publication WO 96 / 10390, the descriptions of which are each incorporated herein by reference in their entirety for all purposes.

[1096] Formulations suitable for rectal administration are sometimes presented as unit-dose suppositories. These can be prepared by mixing an active compound with one or more conventional solid carriers (e.g., cocoa butter) and then shaping the resulting mixture.

[1097] Formulations suitable for topical application to the skin are preferably in the form of ointments, creams, lotions, pastes, gels, sprays, aerosols, or oils. Suitable carriers include petroleum jelly, lanolin, polyethylene glycol, alcohols, transdermal enhancers, and combinations of two or more of these.

[1098] Formulations suitable for transdermal administration can be delivered in the form of discrete patches, which are adapted to maintain close contact with the recipient's epidermis for an extended period. Formulations suitable for transdermal administration can also be delivered via iontophoresis (see, for example...). Pharmaceutical Research 3 (6):318 (1986)) and often in the form of optionally buffered aqueous solutions of the active compound. In some embodiments, microneedle patches or devices are provided for delivering drugs across or into biological tissues (especially skin). Microneedle patches or devices allow drugs to be delivered across or into the skin or other tissue barriers at clinically relevant rates with minimal or no damage, pain, or irritation to the tissue.

[1099] Suitable formulations for lung administration can be delivered via a wide range of passively driven and actively electrically driven single-dose / multi-dose dry powder inhalers (DPIs). The most commonly used devices for airway delivery include nebulizers, pre-dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. The selection of a suitable lung delivery device depends on parameters such as the nature of the drug and its formulation, the site of action, and lung pathophysiology.

[1100] In some respects, the term "pharmaceutically acceptable salt" refers to a salt that can be used in contact with human and animal tissues. Examples of suitable salts of inorganic and organic acids include (but are not limited to) acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, succinic acid, sulfuric acid, tartaric acid, trifluoroacetic acid, and the like. Specific acids include formic acid, trifluoroacetic acid, and hydrochloric acid.

[1101] In some respects, the term "pharmaceuticalally acceptable adjuvant" refers to carriers and adjuvants, such as diluents or excipients, that are compatible with other components of a formulation.

[1102] In some respects, the term "pharmaceutical composition" encompasses a product comprising a predetermined amount or proportion of a specified ingredient, and any product directly or indirectly obtained by combining a specified amount of the specified ingredient. Specifically, it encompasses a product comprising one or more active ingredients and optionally a carrier containing an inert ingredient, and any product directly or indirectly produced by the combination, compounding, or aggregation of any two or more ingredients, or by the dissociation of one or more ingredients, or by other types of reactions or interactions of one or more ingredients.

[1103] In some embodiments, the term "pharmaceuticalally acceptable excipient" refers to an ingredient that is non-therapeutic and sufficiently non-toxic, such as a disintegrant, binder, filler, solvent, buffer, tension agent, stabilizer, antioxidant, surfactant, or lubricant used in the formulation of pharmaceutical products.

[1104] Other pharmaceutical compositions

[1105] The compounds of this invention and / or their pharmaceutically acceptable salts can be used as therapeutically active substances, for example, in pharmaceutical formulations. Pharmaceutical formulations can be administered orally, for example, in the form of tablets, coated tablets, sugar-coated pills, hard and soft gelatin capsules, solutions, emulsions, or suspensions. However, they can also be administered rectally, for example, in the form of suppositories, or non-intestinally, for example, in the form of injectable solutions.

[1106] The compounds of this invention and / or their pharmaceutically acceptable salts can be treated with pharmaceutically inert inorganic or organic carriers to formulate pharmaceutical preparations. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and analogues can be used as such carriers for tablets, coated tablets, sugar-coated pills, and hard gelatin capsules. Carriers that can be used in soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and their analogues. However, depending on the nature of the active substance, a carrier is generally not required in the case of soft gelatin capsules. Carriers that can be used to formulate solutions and syrups include, for example, water, polyols, glycerin, vegetable oils and their analogues. Carriers that can be used in suppositories include, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and their analogues.

[1107] In addition, pharmaceutical preparations may contain pharmaceutically acceptable adjuvants, such as preservatives, solubilizers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts that alter osmotic pressure, buffers, masking agents, or antioxidants. They may also contain other substances with therapeutic value.

[1108] Universal synthesis

[1109] The compounds described herein can be prepared by methods known to those skilled in the art. In one non-limiting example, the described compounds can be prepared using the following procedure.

[1110] For convenience, the compounds of the present invention having stereoisomeric centers can be illustrated without showing stereochemistry. Those skilled in the art will recognize that pure enantiomers and diastereomers can be prepared by methods known in the art. Examples of methods for obtaining optically active substances include at least the following:

[1111] i) Physical separation of crystals – a technique for artificially separating macroscopic crystals of individual enantiomers. This technique can be used if individual enantiomers exist as crystals, i.e., the substance is a conglomerate and the crystals are visually apparent;

[1112] ii) Simultaneous crystallization - a technique that allows individual enantiomers to crystallize separately from a racemic solution only when the enantiomers are solid aggregates;

[1113] iii) Enzymatic resolution - a technique for partially or completely separating racemic mixtures based on the different reaction rates of enantiomers in the presence of an enzyme;

[1114] iv) Enzymatic asymmetric synthesis - a synthetic technique in which at least one step of the synthesis utilizes an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer;

[1115] v) Chemical asymmetric synthesis - A synthetic technique for synthesizing desired enantiomers from achiral precursors under conditions that produce asymmetry (i.e., chirality) in the product, which can be achieved by chiral catalysts or chiral auxiliaries.

[1116] vi) Diastereomer Separation - A technique for reacting a racemic compound with an enantiomerically pure reagent (chiral auxiliary) to convert individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization based on their more obvious structural differences, followed by removal of the chiral auxiliary to obtain the desired enantiomer;

[1117] vii) First- and second-order asymmetric transformations – A technique by which diastereomers in a racemic mixture rapidly reach equilibrium, causing the diastereomer to dominate in solution relative to the desired enantiomer. The diastereomer crystallizes preferentially over the desired enantiomer, disrupting the equilibrium so that all substances ultimately, in principle, transform from the desired enantiomer into the crystalline diastereomer. The desired enantiomer is then released from the diastereomer.

[1118] viii) Kinetic resolution - This technique refers to the partial or complete resolution (or further resolution of partially resolved compounds) of racemates based on the unequal reaction rates of enantiomers with chiral, non-racemic reagents or catalysts under kinetic conditions.

[1119] ix) Enantiomer-specific synthesis from non-racemic precursors - Synthetic techniques for obtaining desired enantiomers from non-chiral starting materials, wherein stereochemical integrity is not compromised or is only minimally compromised during synthesis;

[1120] x) Chiral liquid chromatography – a technique (including via chiral HPLC) for separating enantiomers from a racemic mixture from a liquid mobile phase based on their different interactions with the stationary phase. The stationary phase may be made of a chiral material or the mobile phase may contain another chiral material to induce different interactions;

[1121] xi) Chiral gas chromatography – a technique for separating enantiomers by volatilizing racemic mixtures and based on their different interactions with a column containing a non-racemic chiral adsorbent stationary phase in a gaseous mobile phase.

[1122] xii) Chiral solvent extraction - a technique for separating enantiomers based on the preferential solubility of an enantiomer in a specific chiral solvent;

[1123] xiii) Trans-chiral membrane transport – a technique involving contacting a racemic mixture with a membrane barrier. The barrier separates two miscible fluids, one containing the racemic mixture, and driving forces (such as concentration or pressure gradients) induce preferential transport across the membrane barrier. Separation occurs based on the non-racemic chiral properties of the membrane, which allow only one enantiomer of the racemic mixture to pass through;

[1124] xiv) In one embodiment, simulated moving bed chromatography is used. A variety of chiral stationary phases are commercially available.

[1125] Synthesis of representative compounds of the present invention

[1126] abbreviation

[1127] ACN = Acetonitrile; Boc = tert-butoxycarbonyl; dba = diphenylmethyleneacetone; COMU = (1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-N-morpholinylcarbomonium hexafluorophosphate, 1-[(1-(cyano-2-ethoxy-2-oxoethyleneaminooxy)-dimethylamino-N-morpholinyl)]-ureonium-hexafluorophosphate; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM = dichloromethane; DMAc = dimethylacetamide; DMAP = 4-dimethylaminopyridine; DMF = dimethylformamide; DMSO = dimethyl sulfoxide; dppf = 1,1'-bis(diphenylphosphino)ferrocene; ESI = electrospray ionization; EtOAc = ethyl acetate; Ex = example; HATU = Hexafluorophosphate azirconazole tetramethylureonium; HPLC = High Performance Liquid Chromatography; IPA = Isopropanol; LC-MS = Liquid Chromatography-Mass Spectrometry; MS = Mass Spectrometry; MTBE = Methyl tert-butyl ether; NBS = N-bromosuccinimide; NIS = N-iodosuccinimide; NMR = Nuclear Magnetic Resonance; PEPPSI = Pyridine-enhanced precatalyst preparation, stabilization and initiation; PG = Protecting group; pin = Pinalol group; rt = Room temperature; SFC = Supercritical Fluid Chromatography; TEA = Triethylamine; Tf = Trifluoromethanesulfonate; TFA = Trifluoroacetic acid; THF = Tetrahydrofuran; TLC = Thin Layer Chromatography; Ts = Toluenesulfonate; UPLC = Ultra-High Performance Liquid Chromatography. Example 1: Synthesis of Targeted Ligands Synthesis A1: Synthesis of (3S)-3-[6-[2-cyano-3-[[ethyl(methyl)aminesulfonyl]amino]-6-fluoro-phenoxy]-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane (A-1): Step 1:

[1128] Anhydrous triethyl orthoformate (9.36 mmol, 1.56 mL) was added to a stirred solution of 2-amino-5-hydroxybenzoic acid (1, 1.19 g, 7.80 mmol) in toluene:tetrahydrofuran (5:1), followed by the addition of tert-butyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (2, 2 g, 7.80 mmol). The resulting reaction mixture was heated in a sealed tube at 110 °C for 18 hours. After completion, the reaction mixture was cooled to room temperature. An aqueous solution of NaHCO3 was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with a saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to give the desired crude product. The crude product was further purified by silica gel chromatography using 5% methanol / dichloromethane as eluent to give tert-butyl 3-(6-hydroxy-4-oxo-quinazolin-3-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (3, 1.5 g, 3.09 mmol, 40% yield), a light brown, viscous oil. LC-MS (ES+): m / z 402.3[M+H] + . Step 2:

[1129] At room temperature, tert-butyl 3-(6-hydroxy-4-oxo-quinazolin-3-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (3, 1.8 g, 4.48 mmol) was subjected to... N,N - Potassium 2-methylprop-2-ol (603.75 mg, 5.38 mmol) and 2,3,6-trifluorobenzonitrile (4, 4.93 mmol, 569.70 µL) were added to a stirred solution of dimethylformamide / tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 14 hours. After stirring, water was added to the reaction mixture, followed by extraction with ethyl acetate. The combined organic layers were evaporated under reduced pressure to give the crude product. The crude compound was eluted with 80-90% ethyl acetate / petroleum ether and purified by silica gel column chromatography to give racemic tert-butyl 3-[6-(2-cyano-3,6-difluoro-phenoxy)-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylate. Further progress has been made in the chiral SFC method for racemic compounds, followed by purification using a Lux A1 chiral column (solvent system -30% (0.5% isopropylamine in isopropanol, temperature -35°C)) to obtain a light brown solid. S )-3-(6-(2-cyano-3,6-difluorophenoxy)-4-oxoquinazoline-3(4 H)-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (5- S First eluting isomer, 400 mg, 678.87 µmol, 15% yield) and ( R )-3-(6-(2-cyano-3,6-difluorophenoxy)-4-oxoquinazoline-3(4 H )-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (5- R Second eluted isomer, 410 mg). LC-MS (ES+): m / z 483.1[M+H- t Bu] + .

[1130] Step 3:

[1131] At room temperature, the intermediate (3S)-3-[6-(2-cyano-3,6-difluoro-phenoxy)-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (5- S (410 mg, 761.32 µmol) at N,N - Cs₂CO₃ (620.1 mg, 1.9 mmol) and [methyl(aminosulfonyl)amino]ethane (6, 157.81 mg, 1.14 mmol) were added to a solution of dimethylformamide. The resulting reaction mixture was stirred at 60 °C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with saturated NaCl solution, dried over Na₂SO₄, filtered, and evaporated under reduced pressure to give the crude product. The crude compound was purified by silica gel column chromatography using 20-50% ethyl acetate / petroleum ether as eluent to give a light brown oily (3... S 3-[6-[2-cyano-3-[[ethyl(methyl)aminesulfonyl]amino]-6-fluoro-phenoxy]-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (7,471 mg, 670.36 µmol, 88% yield). LC-MS (ES-): m / z 655.21[MH]ˉ.

[1132] Step 4:

[1133] Get (3) SA solution of tert-butyl 3-[6-[2-cyano-3-[[ethyl(methyl)aminesulfonyl]amino]-6-fluoro-phenoxy]-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (7,470 mg, 715.67 µmol) in dichloromethane was prepared, and trifluoroacetic acid (3.58 mmol, 275.69 µL) was added at 0 °C. The resulting reaction mixture was stirred at room temperature for 2 hours. After completion, the reaction solvent was removed under reduced pressure to give the crude product. The crude compound was ground with methyl tert-butyl ether to give the targeting ligand (3 S )-3-[6-[2-cyano-3-[[ethyl(methyl)aminesulfonyl]amino]-6-fluoro-phenoxy]-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane (A-1, 436 mg, 494.10 µmol, 69% yield). LC-MS (ES+): m / z 557.1[M+H] + .

[1134] Synthesizing A2: Synthesis N -[2-cyano-4-fluoro-3-[3-[(3 R )-1-oxa-8-azaspiro[4.5]dec-3-yl]-4-oxo-quinazolin-6-yl]oxy-phenyl]cyclopropanesulfonamide (A-2): Step 1:

[1135] At 0 °C, 7N methanol (7 M, 40 mL) containing ammonia was added to a well-stirred 100 mL double-necked round-bottom flask containing a thoroughly stirred solution of cyclopropanesulfonyl chloride (2a, 2 g, 14.23 mmol, 1.45 mL) in methanol (30 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the solvent was concentrated under reduced pressure to obtain a crude residue. The residue was diluted with water (10 mL), and a solid precipitate was observed. The precipitated solid compound (400 mg) was filtered. The filtrate was extracted with ethyl acetate (2 × 30 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give cyclopropanesulfonamide (2, 1.6 g, 11.89 mmol, 84% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO-) d 6): δ 6.78(s, 2H), 2.55-2.48(m, 1H), 0.92-0.88(m, 4H).

[1136] Step 2:

[1137] At room temperature, to contain (3 R )-3-[6-(2-cyano-3,6-difluoro-phenoxy)-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (1, 500 mg, 928.43 μmol) in N,N - Cs₂CO₃ (605.00 mg, 1.86 mmol) and cyclopropanesulfonamide (2, 134.98 mg, 1.11 mmol) were added to a 20 mL reaction flask containing a solution of dimethylformamide (6 mL). The reaction mixture was stirred at 65 °C for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with water (30 mL), and extracted with ethyl acetate (2 × 40 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude residue. This residue was eluted with 0-100% ethyl acetate / petroleum ether (where the compounds were eluted with 70-80% ethyl acetate / petroleum ether) and purified by rapid column chromatography (silica gel 230-400 mesh) to obtain a brown, gelatinous liquid (3... R 3-[6-[2-cyano-3-(cyclopropylsulfonylamino)-6-fluoro-phenoxy]-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (3,500 mg, 539.32 μmol, 58% yield). UPLC-MS (ES+): m / z 584.0[M-Boc+H] + .

[1138] Step 3:

[1139] At 0℃, to contain (3 R 3-[6-[2-cyano-3-(cyclopropylsulfonylamino)-6-fluoro-phenoxy]-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (3,500 mg, 781.62 μmol) was added to a 50 mL single-necked round-bottom flask containing a well-stirred solution of dichloromethane (10 mL). Trifluoroacetic acid (7.82 mmol, 598.13 μL) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the solvent was concentrated to obtain a brown, gelatinous liquid. N -[2-cyano-4-fluoro-3-[3-[(3 R)-1-oxa-8-azaspiro[4.5]dec-3-yl]-4-oxo-quinazolin-6-yl]oxy-phenyl]cyclopropanesulfonamide (A-2, 500 mg, 734.39 μmol, 94% yield, TFA salt). UPLC-MS (ES+): m / z 540.0 [M+H] + .

[1140] Synthesize A3: Synthesize N -[2-cyano-4-fluoro-3-[3-[(3 R )-1-oxa-8-azaspiro[4.5]dec-3-yl]-4-oxo-quinazolin-6-yl]oxy-phenyl]morpholine-4-sulfonamide (A-3): Step 1:

[1141] At 0 °C, thioyl chloride (172.18 mmol, 13.96 mL) was added to a well-stirred 250 mL single-necked round-bottom flask containing morpholine (1, 57.39 mmol, 5.02 mL) in acetonitrile (40 mL). The resulting reaction mixture was heated at 85 °C for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and co-distilled with toluene (2 × 50 mL) to give morpholine-4-sulfonyl chloride (2.8 g, 30.17 mmol, 53% yield) as a light brown solid. 1 H NMR (400 MHz, DMSO-) d 6 ): δ 3.79, 3.28.

[1142] Step 2:

[1143] At 0 °C, ammonium hydroxide (30% solution) (616.34 mmol, 24 mL) was added to a well-stirred 250 mL single-necked round-bottom flask containing morpholine-4-sulfonyl chloride (2.8 g, 30.17 mmol) in acetone (15 mL). The resulting reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and co-distilled with toluene (2 × 50 mL) to give a crude residue, which was purified by rapid column chromatography (silica gel 230-400 mesh, 100 g) using 0-10% methanol / dichloromethane as eluent to give morpholine-4-sulfonamide (3.3 g, 17.15 mmol, 57% yield) as a grayish-white solid.1 H NMR (400 MHz, DMSO-) d 6 ): δ 6.83 (s, 2H), 3.65 (t, J = 4.80 Hz, 4H), 2.92(t, J = 4.80 Hz, 4H)

[1144] Step 3:

[1145] At room temperature, to contain (3 R )-3-[6-(2-cyano-3,6-difluoro-phenoxy)-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (4,300 mg, 543.97 μmol) in N,N - Morpholine-4-sulfonamide (3, 190.33 mg, 1.09 mmol) and Cs₂CO₃ (531.71 mg, 1.63 mmol) were added to a 40 mL pressure flask containing a well-stirred solution of dimethylformamide (6 mL). The reaction mixture was stirred at 60 °C for 16 hours. After the reaction was complete, the mixture was quenched with water (5 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with water (10 mL) and saturated NaCl solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude residue. This residue was purified by rapid column chromatography (25 g silica gel 230-400 mesh) using 0-100% ethyl acetate / hexane as eluent to obtain a grayish-white solid (3... R 3-[6-[2-cyano-6-fluoro-3-(N-morpholinylsulfonylamino)phenoxy]-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (5,240 mg, 298.87 μmol, 55% yield). UPLC-MS (ES+): m / z 629.5 [M- t Bu+H] + .

[1146] Step 4:

[1147] At 0℃, to contain (3 R1,4-dioxane (336.23 μmol, 3 mL) containing 4 M HCl was added to a 50 mL single-necked round-bottom flask containing a well-stirred solution of tert-butyl decane-8-carboxylate (5,270 mg, 336.23 μmol) in dichloromethane (6 mL). The resulting reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and co-distilled with toluene (10 mL) to give a grayish-white solid. N -[2-cyano-4-fluoro-3-[3-[(3 R )-1-oxa-8-azaspiro[4.5]dec-3-yl]-4-oxo-quinazolin-6-yl]oxy-phenyl]morpholine-4-sulfonamide (A-3, 220 mg, 314.09 μmol, 93% yield, HCl salt). UPLC-MS (ES+): m / z 585.2[M+H] + .

[1148] Synthesizing A4: Synthesis N -[2-cyano-4-fluoro-3-[3-[(3 R )-1-oxa-8-azaspiro[4.5]dec-3-yl]-4-oxo-quinazolin-6-yl]oxy-phenyl]tetrahydropyran-4-sulfonamide (A-4): Step 1:

[1149] Under a nitrogen atmosphere, a 25% ammonia solution (1.08 mmol, 2 mL) was added to a well-stirred solution of tetrahydropyran-4-sulfonyl chloride (1,200 mg, 1.08 mmol) in acetone (5 mL) at room temperature, and the mixture was stirred for 3 hours at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude residue, which was purified by rapid silica gel (230-400 mesh) column using 0-100% ethyl acetate / hexane as eluent to give tetrahydropyran-4-sulfonamide (2,165 mg, 898.85 μmol, 83% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO-) d 6): δ 6.75 (bs, 2H), 3.94 (dd, J= 4.00, 11.20 Hz, 2H), 3.35-3.29(m, 2H), 3.10-3.02(m,1H), 1.91-1.87(m, 2H), 1.66-1.55(m, 2H).

[1150] Step 2:

[1151] At room temperature, to contain (3 R )-3-[6-(2-cyano-3,6-difluoro-phenoxy)-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (3,350 mg, 649.90 μmol) in N,N - Cs₂CO₃ (529.38 mg, 1.62 mmol) and tetrahydropyran-4-sulfonamide (2, 161.06 mg, 974.86 μmol) were added to a 20 mL pressure flask containing a well-stirred solution of dimethylformamide (5 mL). The resulting reaction mixture was stirred at 65 °C for 16 hours. After the reaction was complete, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with water (50 mL) and saturated NaCl solution (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a crude residue. This residue was purified by rapid column chromatography (25 g, 230-400 mesh silica gel) using 0-100% ethyl acetate / hexane as eluent to obtain a grayish-white solid (3... R 3-[6-[2-cyano-6-fluoro-3-(tetrahydropyran-4-ylsulfonylamino)phenoxy]-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (4,230 mg, 329.55 μmol, 51% yield). UPLC-MS: m / z 682.0[M+H] + .

[1152] Step 3:

[1153] At 0°C, under a nitrogen atmosphere, 1,4-dioxane (4.0 M, 1.00 mL) containing HCl was added dropwise to a solution containing (3... R3-[6-[2-cyano-6-fluoro-3-(tetrahydropyran-4-ylsulfonylamino)phenoxy]-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (4,230 mg, 329.65 mmol) was added to a 25 mL single-necked round-bottom flask containing 5 mL of dichloromethane, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to give a crude product, which was co-distilled with hexane (2 × 10 mL). The crude product was ground with methyl tert-butyl ether (2 × 5 mL) and dried under reduced pressure to give a grayish-white solid. N -[2-cyano-4-fluoro-3-[3-[(3R)-1-oxa-8-azaspiro[4.5]dec-3-yl]-4-oxo-quinazolin-6-yl]oxy-phenyl]tetrahydropyran-4-sulfonamide (A-4, 200 mg, 317.02 μmol, 10% yield, HCl salt). UPLC-MS (ES+): m / z 584.4[M+H] + .

[1154] Synthesizing A5: Synthesis N -[2-cyano-4-fluoro-3-[3-[(3 R )-1-oxa-8-azaspiro[4.5]dec-3-yl]-4-oxo-quinazolin-6-yl]oxy-phenyl]-3-azabicyclo[3.1.0]hexane-3-sulfonamide (A-5): Step 1:

[1155] At 0 °C, add to a 100 mL double-necked round-bottom flask containing a well-stirred solution of 3-azabicyclo[3.1.0]hexane (2a, 1.0 g, 12.03 mmol) in dichloromethane (20 mL). N,N - Diisopropylethylamine (18.04 mmol, 3.14 mL) and thioyl chloride (30.07 mmol, 2.44 mL). The resulting reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was quenched with water (20 mL) at 0 °C and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with 1.5 N HCl solution (2 × 10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 3-azabicyclo[3.1.0]hexane-3-sulfonyl chloride (2b, 1.6 g, 8.81 mmol, 73% yield) as a pale yellow semi-solid. 1H NMR (400MHz, DMSO-) d 6): δ 1.83-1.68(m, 4H), 0.85-0.72(m, 2H), 0.49-0.32(m, 2H).

[1156] Step 2:

[1157] At 0 °C, a well-stirred methanol solution (7 M, 16 mL) containing 7 M ammonia was added to a 100 mL double-necked round-bottom flask containing a thoroughly stirred solution of 3-azabicyclo[3.1.0]hexane-3-sulfonyl chloride (2b, 1.6 g, 8.81 mmol) in methanol (20 mL), and the resulting reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was quenched with water (50 mL) at 0 °C and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with NaHCO3 solution (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue, which was ground with hexane (10 mL) and dried under reduced pressure to give 3-azabicyclo[3.1.0]hexane-3-sulfonamide (2, 0.700 g, 4.27 mmol, 49% yield) as a yellow solid. UPLC-MS (ES+): m / z 163.0 [M+H] + .

[1158] Step 3:

[1159] At room temperature, under a nitrogen atmosphere, to a substance containing (3 R )-3-[6-(2-cyano-3,6-difluoro-phenoxy)-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (1, 0.300 g, 557.06 μmol) and 3-azabicyclo[3.1.0]hexane-3-sulfonamide (2, 361.44 mg, 2.23 mmol) in N,N - Cs₂CO₃ (544.50 mg, 1.67 mmol) was added to a 40 mL pressure glass flask containing a well-stirred solution of dimethylformamide (5 mL). The resulting reaction mixture was stirred at 70 °C for 16 hours. After the reaction was complete, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with saturated NaCl (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue. This residue was purified by rapid column chromatography (25 g, 230-400 mesh silica gel) using 0-100% ethyl acetate / hexane as eluent to give a grayish-white solid (3... R3-[6-[3-(3-azabicyclo[3.1.0]hex-3-ylsulfonylamino)-2-cyano-6-fluoro-phenoxy]-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (3, 0.3 g, 409.85 μmol, 74% yield). UPLC-MS (ES+): m / z 681.5 [M+H] + .

[1160] Step 4:

[1161] At 0°C, under a nitrogen atmosphere, to a substance containing (3 R A solution of tert-butyl 3-[6-[3-(3-azabicyclo[3.1.0]hex-3-ylsulfonylamino)-2-cyano-6-fluoro-phenoxy]-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (3, 440.69 μmol, 1.2 mL) in dichloromethane (5 mL) was thoroughly stirred and then added to a 50 mL single-necked round-bottom flask containing dioxane (440.69 μmol, 1.2 mL). The resulting reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to give a brown liquid gel. N -[2-cyano-4-fluoro-3-[3-[(3 R )-1-oxa-8-azaspiro[4.5]dec-3-yl]-4-oxo-quinazolin-6-yl]oxy-phenyl]-3-azabicyclo[3.1.0]hexane-3-sulfonamide (A-5, 0.280 g, 435.59 μmol, 99% yield, HCl salt). UPLC-MS(ES+): m / z 581.2[M+H] + .

[1162] Synthesizing A6: Synthesis N -[2-cyano-4-fluoro-3-[3-[(3 R )-1-oxa-8-azaspiro[4.5]dec-3-yl]-4-oxo-quinazolin-6-yl]oxy-phenyl]-3-methoxy-azacyclobutane-1-sulfonamide (A-6): Step 1:

[1163] At -30°C, under a nitrogen atmosphere, add to a 100 mL double-necked round-bottom flask containing a well-stirred solution of 3-methoxyazacyclobutane (1.3 g, 24.28 mmol, HCl salt) in anhydrous dichloromethane (30 mL). N,N - Diisopropylethylamine (48.55 mmol, 8.46 mL) was followed by dropwise addition of thioyl chloride (48.55 mmol, 3.94 mL). After addition, the reaction mixture was stirred at -30 °C for 2 hours. After the reaction was complete, the mixture was quenched with cold water (50 mL) and extracted with dichloromethane (2 × 60 mL). The combined organic layers were washed with water (50 mL) and saturated NaCl solution (50 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give 3-methoxyazinobutane-1-sulfonyl chloride (2, 2.7 g, 14.53 mmol, 60% yield) as a colorless liquid. UPLC-MS (ES+): m / z 129.5 [M+- t Bu] + .

[1164] Step 2:

[1165] At 0 °C, a methanol solution containing 7 N ammonia (247.71 mg, 14.55 mmol) was added to a well-stirred solution of 3-methoxyazacyclobutane-1-sulfonyl chloride (2, 2.7 g, 14.55 mmol) in methanol (30 mL) in a 250 mL double-necked round-bottom flask, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give a crude product, which was then ground with hexane (2 × 10 mL) and concentrated under reduced pressure to give 3-methoxyazacyclobutane-1-sulfonamide (3, 2.3 g, 13.84 mmol, 95% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO-) d 6): δ 6.95(s, 2H), 4.09(m, 1H), 3.83-3.79(m, 2H), 3.59-3.56(m, 2H), 3.20(s, 3H).

[1166] Step 3:

[1167] At room temperature, to contain (3) R )-3-[6-(2-cyano-3,6-difluoro-phenoxy)-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (4,500 mg, 928.43 μmol) in N,N - 3-Methoxyazacyclobutane-1-sulfonamide (3,231.46 mg, 1.39 mmol) and Cs₂CO₃ (907.51 mg, 2.79 mmol) were added to a well-stirred solution of dimethylformamide (10 mL) in a 40 mL pressure flask, and the mixture was stirred at 70 °C for 16 hours. After the reaction was complete, the mixture was diluted with water (30 mL) and filtered through a Buchner funnel to remove fluorescent impurities. The filtrate was extracted with ethyl acetate (2 × 50 mL), and the combined organic layers were washed with cold water (2 × 20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a brown, gelatinous liquid (3... R 3-[6-[2-cyano-6-fluoro-3-[(3-methoxyazacyclobut-1-yl)sulfonylamino]phenoxy]-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (5,450 mg, 542.12 μmol, 58% yield). UPLC-MS (ES+): m / z 685.2[M+H] + .

[1168] Step 4:

[1169] Under a nitrogen atmosphere and at 0°C, trifluoroacetic acid (26.14 mmol, 2.0 mL) was slowly added to a volume containing (3... R 3-[6-[2-cyano-6-fluoro-3-[(3-methoxyaziridine-1-yl)sulfonylamino]phenoxy]-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (5,450 mg, 542.12 μmol) was added to a well-stirred 25 mL single-necked round-bottom flask containing anhydrous dichloromethane (5 mL). The resulting reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, ground with methyl tert-butyl ether (2 × 2 mL) to remove nonpolar impurities, and dried under reduced pressure to give a grayish-white solid. N -[2-cyano-4-fluoro-3-[3-[(3 R )-1-oxa-8-azaspiro[4.5]dec-3-yl]-4-oxo-quinazolin-6-yl]oxy-phenyl]-3-methoxy-azacyclobutane-1-sulfonamide (A-6, 420 mg, 535.40 μmol, 99% yield, TFA salt). UPLC-MS (ES+): m / z 585.1[M+H] +

[1170] Synthesize A7: SynthesizeN -[2-cyano-4-fluoro-3-[3-[(3 R )-1-oxa-8-azaspiro[4.5]dec-3-yl]-4-oxo-quinazolin-6-yl]oxy-phenyl]-2-azaspiro[3.3]heptane-2-sulfonamide (A-7): Step 1:

[1171] At -30°C, thioyl chloride (185.27 mmol, 15.02 mL) was added to a 250 mL double-necked round-bottom flask containing a well-stirred solution of 2-azaspiro[3.3]heptane (hemioxalate) (1.3 g, 30.88 mmol) in dichloromethane (30.00 mL). N,N - Diisopropylethylamine (92.63 mmol, 16.13 mL) was added and stirred for 2 hours under the same reaction conditions. After the reaction was complete, the reaction mixture was quenched by adding water dropwise (50 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with 1.5 N HCl solution (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give crude 2-azaspiro[3.3]heptane-2-sulfonyl chloride (2, 2.4 g, 12.14 mmol, 39% yield) as a light brown liquid. 1 H NMR (400 MHz, DMSO-) d 6 ): δ 4.19-4.02(m, 4H), 2.31-2.09(m, 4H), 1.81-1.73(m, 2H).

[1172] Step 2:

[1173] At 0 °C, methanol (7 M, 15.77 mL) containing 7 M ammonia was added to a 100 mL sealed tube containing a well-stirred solution of 2-azaspiro[3.3]heptane-2-sulfonyl chloride (2, 2.4 g, 12.27 mmol) in methanol (30 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, diluted with water (50 mL), and extracted with ethyl acetate (3 × 50 mL). The organic layer was washed with NaHCO3 solution (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was washed with n-hexane (3 × 25 mL) to give 2-azaspiro[3.3]heptane-2-sulfonamide (3, 1.2 g, 6.74 mmol, 55% yield) as a brown solid. 1 H NMR (400 MHz, DMSO-) d 6 ): δ 6.81(s, 2H),3.76(s, 4H), 2.09(t, J = 8.00 Hz, 4H), 1.82-1.75(m, 2H).

[1174] Step 3:

[1175] At room temperature, to contain (3 R )-3-[6-(2-cyano-3,6-difluoro-phenoxy)-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (4, 100 mg, 181.97 μmol) in N,N - Cs₂CO₃ (177.87 mg, 545.92 μmol) and 2-azaspiro[3.3]heptane-2-sulfonamide (3, 64.79 mg, 363.95 μmol) were added to a 20 mL pressure flask containing a well-stirred solution of diisopropylethylamine (3 mL), and the reaction mixture was stirred at 70 °C for 16 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (10 mL), washed with water (10 mL) and saturated NaCl solution (10 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain a crude residue. This residue was purified by rapid silica gel (230-400 mesh) column chromatography using 0-100% ethyl acetate / hexane to obtain a grayish-white solid (3... R3-[6-[3-(2-azaspiro[3.3]hept-2-ylsulfonylamino)-2-cyano-6-fluoro-phenoxy]-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (5, 90 mg, 80.31 μmol, 44% yield). UPLC-MS (ES+): m / z 695.3 [M+H] + .

[1176] Step 4:

[1177] At 0℃, to contain (3 R 3-[6-[3-(2-azaspiro[3.3]hept-2-ylsulfonylamino)-2-cyano-6-fluoro-phenoxy]-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (5, 90 mg, 85.50 μmol) was added to a 25 mL double-necked round-bottom flask containing a stirred solution of dichloromethane (2 mL). Trifluoroacetic acid (1.71 mmol, 130.85 μL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a crude residue, which was washed with methyl tert-butyl ether (2 × 5 mL) and dried under reduced pressure to obtain a grayish-white solid. N -[2-cyano-4-fluoro-3-[3-[(3 R )-1-oxa-8-azaspiro[4.5]dec-3-yl]-4-oxo-quinazolin-6-yl]oxy-phenyl]-2-azaspiro[3.3]heptane-2-sulfonamide (A-7, 90 mg, 68.58 μmol, 80% yield, TFA salt). UPLC-MS(ES+): m / z 595.2 [M+H] + .

[1178] Synthesizing A8: Synthesis N -[2-cyano-4-fluoro-3-[3-[(3 R )-1-oxa-8-azaspiro[4.5]dec-3-yl]-4-oxo-quinazolin-6-yl]oxy-phenyl]-5-azaspiro[2.4]heptane-5-sulfonamide (A-8): Step 1:

[1179] At -30°C, add to a 100 mL double-necked round-bottom flask a stirred solution containing 5-azaspiro[2,4]heptane (1, 1.0 g, 7.48 mmol, HCl salt) in anhydrous dichloromethane (15 mL). N,N - Diisopropylethylamine (11.23 mmol, 1.96 mL) was followed by dropwise addition of a solution prepared in anhydrous dichloromethane (2 mL) with thioyl chloride (7.48 mmol, 606.67 μL). After addition, the reaction mixture was stirred at -30°C to -50°C for 2 hours. After the reaction was complete, the reaction mixture was diluted with cold water (20 mL) and extracted with dichloromethane (2 × 30 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a crude residue, which was purified by rapid silica gel (60-120 mesh) column using 0-100% ethyl acetate / hexane to give a colorless liquid 5-azaspiro[2.4]heptane-5-sulfonyl chloride (2,690 mg, 3.53 mmol, 47% yield). 1 H NMR (400 MHz, DMSO-) d 6 ): δ 3.61(t, J = 6.80 Hz, 2H), 3.39(m, 2H), 1.92(t, J = 7.20 Hz, 2H), 0.73-0.69(m, 2H), 0.66-0.63(m, 2H).

[1180] Step 2:

[1181] At 0 °C, methanol (7 M, 10.08 mL) containing 7 ...

Claims

1. A compound of the following formula: (I)、 (II)、 (III)、 (IV)、 (V)、 (WE), (VII)、 (VIII)、 (IX)、 (X)、 (XI)、 (XII)、 (XIII)、 (XIV)、 (XV)、 (XVI)、 (XVII)、 (XVIII)、 (XIX)、 (XX)、 (XXI)、 (XXII)、 (XXIII)、 (XXIV)、 (XXV)、 (XXVI)、 (XXVII)、 (XXVIII)、 (XXIX)、 (XXX)、 (XXXI), or (XXXII), Or its pharmaceutically acceptable salt; in: ring It is a spiroheterocyclic group or piperidine-1,4-diyl group containing one or two nitrogen atoms and no other heteroatoms, wherein the ring Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; ring It is a spiroheterocyclic group containing one nitrogen atom and one oxygen atom and no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; ring It is a bridging heterocyclic group or spirocyclic group containing one or two nitrogen atoms and no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; ring It is a cycloalkyl group or a heterocyclic group containing one or two nitrogen atoms and one or two oxygen atoms and no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; ring It is a spiroheterocyclic group containing one oxygen atom and zero or one nitrogen atom, and containing no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; ring It is a cycloalkyl group, wherein the ring is cycloalkyl. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; ring It is a spiroheterocyclic group containing one or two nitrogen atoms and zero or one oxygen atom, and containing no other heteroatoms, wherein the ring... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; ring It is a cycloalkyl group, 3,3-difluoro-piperidine-1,4-diyl, piperazine-1,4-diyl, or a spiroheterocyclic group containing one or two nitrogen atoms and one or two oxygen atoms and without other heteroatoms, wherein the cycloalkyl group, piperazine-1,4-diyl, or spiroheterocyclic group is optionally substituted by one or two independent substituents selected from halogen, alkyl, and alkoxy groups; ring It is a cycloalkyl, piperidine-1,4-diyl, spiroheterocyclic group containing one or two nitrogen atoms and without other heteroatoms, wherein the cycloalkyl group is... Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; ring It is a cycloalkyl group substituted with 1, 2 or 3 substituents, which are independently selected from alkyl, alkoxy, F, Cl, Br and OH; ring It is a cycloalkyl, spirocycloalkyl, or heterocyclic group containing one or two nitrogen atoms and no other heteroatoms, wherein the cycloalkyl group is a cycloalkyl group. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; ring It is a cycloalkyl, spirocycloalkyl, or heterocyclic group containing one or two nitrogen atoms and no other heteroatoms, wherein the cycloalkyl group is a cycloalkyl group. Optionally substituted with one or two independent substituents selected from halogens, alkyl groups, and alkoxy groups; ring It is a heterocyclic group, which is optionally substituted by one or two independent substituents selected from halogens, alkyl groups, OH groups and alkoxy groups; A 1 Selected from -NR 2 -and-CHR 2' -; R 1 Selected from hydrogen and alkyl groups; R 2 Selected from hydrogen, alkyl, and haloalkyl; Or R 1 and R 2 Together with the nitrogen atom to which it is attached, it forms an optional structure via one or two R atoms. 3 Substituted heterocyclic alkyl groups; R 2' Selected from hydrogen, alkyl, and haloalkyl; Or R 1 and R 2' Together with the carbon atoms it is attached to, it forms an optional structure via one or two R atoms. 3 Substituted cycloalkyl groups; Each R 3 Independently selected from hydrogen, halogen, alkyl, and alkoxy groups; R 4 Selected from hydrogen, alkyl, cyano, and halogen; R 5 Selected from hydrogen, alkyl, cyano, and halogen; A 2 Selected from -O-, -NH- and -(C=O)-; R 6 Selected from hydrogen, halogen, hydroxyl, amino, dialkylamino, alkoxy, alkyl, and alkoxyalkyl; R 7 Selected from hydrogen and alkyl groups; R 8 Selected from hydrogen, alkyl, cyano, halogen, and alkoxy groups; R 9 Selected from hydrogen, alkyl, cyano, halogen, and alkoxy groups; R 17 Selected from hydrogen, alkyl, cyano, hydroxyl, halogen, and alkoxy groups; R 18 Selected from hydrogen, alkyl, cyano, hydroxyl, halogen, and alkoxy groups; R 19 Selected from hydrogen, alkyl, cyano, hydroxyl, halogen, and alkoxy groups; A 5 It can be -CH- or -N-; A 15 Selected from the bond, -O- and -NH-, where when A 15 When it is O or NH, A 6 Let CH be the case where A is the case where CH is ... 15 When A is the key 6 For N or CH; A 6 It can be -CH- or -N-; R 60 It is isopropyl, pyrrolidine-1-yl substituted with F or Ome, or cyclopropyl; q is 0 or 1; r is 0, 1, or 2; p is 0, 1, or 2; and w is 1 or 2.

2. The compound of claim 1, wherein the compound has the formula... (I)， Or its pharmaceutically acceptable salt.

3. The compound of claim 1, wherein the compound has the formula... (VIII), Or its pharmaceutically acceptable salt.

4. The compound of claim 1, wherein the compound has the formula... (XIII), Or its pharmaceutically acceptable salt.

5. The compound of claim 1, wherein the compound has the formula... (XVI), Or its pharmaceutically acceptable salt.

6. The compound of claim 1, wherein the compound has the formula... (XV), Or its pharmaceutically acceptable salt.

7. The compound of claim 1, wherein the compound has the formula... (XIV), Or its pharmaceutically acceptable salt.

8. The compound according to any one of claims 1 to 7, wherein the ring for .

9. The compound according to any one of claims 1 to 7, wherein the ring for .

10. The compound of claim 1, wherein the compound has the formula... (II), Or its pharmaceutically acceptable salt.

11. The compound of claim 1, wherein the compound has the formula... (XI), Or its pharmaceutically acceptable salt.

12. The compound of claim 10 or 11, wherein the ring... for , , or .

13. The compound of claim 10 or 11, wherein the ring... for , or .

14. The compound of claim 1, wherein the compound has the formula... (III), Or its pharmaceutically acceptable salt.

15. The compound of claim 1, wherein the compound has the formula... (IV), Or its pharmaceutically acceptable salt.

16. The compound of claim 1, wherein the compound has the formula... (XII), Or its pharmaceutically acceptable salt.

17. The compound of any one of claims 14 to 16, wherein the ring for .

18. The compound of claim 1, wherein the compound has the formula... (V)， Or its pharmaceutically acceptable salt.

19. The compound of claim 1, wherein the compound has the formula... (WE), Or its pharmaceutically acceptable salt.

20. The compound of claim 1, wherein the compound has the formula... (VII), Or its pharmaceutically acceptable salt.

21. The compound of claim 1, wherein the compound has the formula... (IX), Or its pharmaceutically acceptable salt.

22. The compound of claim 1, wherein the compound has the formula... (X)， Or its pharmaceutically acceptable salt.

23. The compound according to any one of claims 1 to 22, wherein A 5 It is -CH-.

24. The compound according to any one of claims 1 to 22, wherein A 5 It is -N-.

25. The compound according to any one of claims 1 to 24, wherein R 7 It is CH3.

26. The compound according to any one of claims 1 to 24, wherein R 7 For H.

27. The compound according to any one of claims 1 to 26, wherein R 8 It is CH3.

28. The compound according to any one of claims 1 to 26, wherein R 8 For H.

29. The compound according to any one of claims 1 to 26, wherein R 8 It is F.

30. The compound according to any one of claims 1 to 26, wherein R 8 For CN.

31. The compound according to any one of claims 1 to 26, wherein R 8 It is OCH3.

32. The compound according to any one of claims 1 to 31, wherein R 9 It is CH3.

33. The compound according to any one of claims 1 to 31, wherein R 9 For H.

34. The compound according to any one of claims 1 to 31, wherein R 9 It is F.

35. The compound according to any one of claims 1 to 31, wherein R 9 For CN.

36. The compound according to any one of claims 1 to 31, wherein R 9 It is OCH3.

37. The compound of claim 1, wherein the compound has the formula... (XVII), Or its pharmaceutically acceptable salt.

38. The compound of claim 1, wherein the compound has the formula... (XXIV), Or its pharmaceutically acceptable salt.

39. The compound of claim 1, wherein the compound has the formula... (XXIX), Or its pharmaceutically acceptable salt.

40. The compound of claim 1, wherein the compound has the formula... (XXX), Or its pharmaceutically acceptable salt.

41. The compound of claim 1, wherein the compound has the formula... (XXXI), Or its pharmaceutically acceptable salt.

42. The compound of claim 1, wherein the compound has the formula... (XXXII), Or its pharmaceutically acceptable salt.

43. The compound according to any one of claims 37 to 42, wherein the ring for .

44. The compound according to any one of claims 37 to 42, wherein the ring for .

45. The compound of claim 1, wherein the compound has the formula... (XVIII), Or its pharmaceutically acceptable salt.

46. ​​The compound of claim 1, wherein the compound has the formula... (XXVII), Or its pharmaceutically acceptable salt.

47. The compound of claim 45 or 46, wherein the ring... for , , or .

48. The compound of claim 45 or 46, wherein the ring for , or .

49. The compound of claim 1, wherein the compound has the formula... (XIX), Or its pharmaceutically acceptable salt.

50. The compound of claim 1, wherein the compound has the formula... (XX), Or its pharmaceutically acceptable salt.

51. The compound of claim 1, wherein the compound has the formula... (XXVIII), Or its pharmaceutically acceptable salt.

52. The compound according to any one of claims 49 to 51, wherein the ring for .

53. The compound of claim 1, wherein the compound has the formula... (XXI), Or its pharmaceutically acceptable salt.

54. The compound of claim 1, wherein the compound has the formula... (XXII), Or its pharmaceutically acceptable salt.

55. The compound of claim 1, wherein the compound has the formula... (XXIII), Or its pharmaceutically acceptable salt.

56. The compound of claim 1, wherein the compound has the formula... (XXV), Or its pharmaceutically acceptable salt.

57. The compound of claim 1, wherein the compound has the formula... (XXVI), Or its pharmaceutically acceptable salt.

58. The compound according to any one of claims 37 to 57, wherein A 6 For CH and A 15 It is -N-.

59. The compound according to any one of claims 37 to 57, wherein A 6 For CH and A 15 It is -O-.

60. The compound according to any one of claims 37 to 57, wherein A 6 For CH and A 15 For key.

61. The compound according to any one of claims 37 to 57, wherein A 6 For N and A 15 For key.

62. The compound according to any one of claims 37 to 61, wherein R 17 For H.

63. The compound according to any one of claims 37 to 61, wherein R 17 It is CH3.

64. The compound according to any one of claims 37 to 61, wherein R 17 It is a cyano group.

65. The compound according to any one of claims 37 to 61, wherein R 17 It is a hydroxyl group.

66. The compound according to any one of claims 37 to 61, wherein R 17 It is cyclopropyl.

67. The compound according to any one of claims 37 to 61, wherein R 17 It is F.

68. The compound according to any one of claims 37 to 61, wherein R 17 It is OCH3.

69. The compound according to any one of claims 37 to 68, wherein R 18 For H.

70. The compound according to any one of claims 37 to 68, wherein R 18 It is CH3.

71. The compound according to any one of claims 37 to 68, wherein R 18 It is a cyano group.

72. The compound according to any one of claims 37 to 68, wherein R 18 It is a hydroxyl group.

73. The compound according to any one of claims 37 to 68, wherein R 18 It is cyclopropyl.

74. The compound according to any one of claims 37 to 68, wherein R 18 It is F.

75. The compound according to any one of claims 37 to 68, wherein R 18 It is OCH3.

76. The compound according to any one of claims 37 to 75, wherein R 19 For H.

77. The compound according to any one of claims 37 to 75, wherein R 19 It is CH3.

78. The compound according to any one of claims 37 to 75, wherein R 19 It is a cyano group.

79. The compound according to any one of claims 37 to 75, wherein R 19 It is a hydroxyl group.

80. The compound according to any one of claims 37 to 75, wherein R 19 It is cyclopropyl.

81. The compound according to any one of claims 37 to 75, wherein R 19 It is F.

82. The compound according to any one of claims 37 to 75, wherein R 19 It is OCH3.

83. A compound described in Table 1.

84. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 83 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

85. A method of treating a BRAF mutant-mediated condition, comprising administering to a human patient in need an effective amount of the compound of any one of claims 1 to 83 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 84.

86. The method of claim 85, wherein the BRAF-mediated condition is cancer.

87. The method of claim 86, wherein the BRAF-mediated cancer of the mutant is melanoma.

88. The method of claim 86, wherein the BRAF-mediated cancer is lung cancer.

89. The method of claim 86, wherein the BRAF-mediated cancer is non-small cell lung cancer.

90. The method of claim 86, wherein the BRAF mutant-mediated cancer is colorectal cancer.

91. The method of claim 86, wherein the BRAF mutant-mediated cancer is microsatellite stable colorectal cancer.

92. The method of claim 86, wherein the BRAF-mediated cancer is thyroid cancer.

93. The method of claim 86, wherein the BRAF-mediated cancer is ovarian cancer.

94. The method of claim 85, wherein the mutant BRAF-mediated disease is cholangiocarcinoma, Eldheim-Chester disease, Langerhans cell histiocytosis, ganglioglioma, glioma, glioblastoma, hairy cell leukemia, metanephrotic adenoma, multiple myeloma, non-small cell lung cancer, ovarian cancer, pilomyxoid astrocytoma, anaplastic pleomorphic xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, pancreatic cancer, clear cell sarcoma of the chest, salivary gland cancer, or microsatellite stable colorectal cancer.

95. The method of any one of claims 85 to 94, wherein the patient also receives an additional active agent.

96. The method of claim 95, wherein the additional active agent is a MEK inhibitor.

97. The method of claim 96, wherein the MEK inhibitor is trametinib.

98. The method of claim 95, wherein the additional active agent is an immune checkpoint inhibitor.

99. The method of claim 98, wherein the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, cimiprilumab, ipilimumab, renalalimab, atezolizumab, avelumab, and duvalumab.

100. The method of claim 95, wherein the additional active agent is cetuximab or panitumumab.

101. The method of any one of claims 85 to 100, wherein the mutant BRAF has the V600 mutation.

102. The method of claim 101, wherein the V600 mutation is V600E, V600K, V600R, V600D, or V600N.

103. The method of claim 101, wherein the V600 mutation is V600E.

104. The method of any one of claims 85 to 103, wherein the mutant BRAF has a mutation selected from G469A, G469V, G469L, G469R, L597Q and K601E.

105. The method of any one of claims 85 to 104, wherein the mutant BRAF has a mutation selected from G466A, G466E, G466R, G466V, S467L, G469E, N581I, D594E, D594G, and D594N.

106. The method of any one of claims 85 to 105, wherein the mutant BRAF has a mutation selected from G464I, G464R, N581T, L584F, E586K, G593D, G596C, L597R, L597S, S605I, S607F, N684T, E26A, V130M, L745L, and D284E.

107. The method of any one of claims 85 to 106, wherein the mutant BRAF has a splicing mutation.

108. The method of claim 107, wherein the splicing mutation is a p61-BRAF splicing mutation.

109. The method of any one of claims 85 to 108, wherein the BRAF-mediated disease of the mutant is cancer and the cancer also has an NRAS, MEK1 or PI3K mutation.

110. The method of claim 109, wherein the cancer has an NRAS mutation.

111. The method of claim 110, wherein the NRAS mutation is Q61K.

112. The method of claim 110, wherein the NRAS mutation is Q61R.

113. The method of claim 109, wherein the cancer has a MEK1 mutation.

114. The method of claim 109, wherein the cancer has a PI3K mutation.

115. The method of claim 114, wherein the PI3K mutation is changed to PIK3CA. H1047R Or PIK3CA P449T .

116. The method of any one of claims 85 to 115, wherein the mutant BRAF-mediated condition is cancer and one or more mutations promote homodimerization or heterodimerization of the RAF protein.

117. The method of claim 116, wherein the one or more mutations promote homodimerization of the RAF protein.

118. The method of claim 116, wherein the one or more mutations promote heterodimerization of the RAF protein.

119. The method of any one of claims 85 to 115, wherein the BRAF-mediated disease is cancer that has metastasized to the brain or CNS.

120. The method of any one of claims 85 to 115, wherein the BRAF-mediated condition is cancer that has metastasized to the brain.

121. The method of any one of claims 85 to 115, wherein the BRAF-mediated disease of the mutant is cancer that has metastasized to the CNS.

122. The compound or a pharmaceutically acceptable salt thereof, or a combination thereof, as claimed in any one of claims 1 to 83, for the treatment of BRAF-mediated disease in human patients.

123. The compound of claim 122, wherein the BRAF-mediated condition of the mutant is cancer.

124. The compound of claim 123, wherein the BRAF-mediated cancer of the mutant is melanoma.

125. The compound of claim 123, wherein the BRAF-mediated cancer of the mutant is lung cancer.

126. The compound of claim 123, wherein the BRAF mutant-mediated cancer is non-small cell lung cancer.

127. The compound of claim 123, wherein the BRAF mutant-mediated cancer is colorectal cancer.

128. The compound of claim 123, wherein the BRAF mutant-mediated cancer is microsatellite stable colorectal cancer.

129. The compound of claim 123, wherein the BRAF-mediated cancer of the mutant is thyroid cancer.

130. The compound of claim 123, wherein the BRAF-mediated cancer of the mutant is ovarian cancer.

131. The compound of claim 122, wherein the mutant BRAF-mediated disease is cholangiocarcinoma, Eldheim-Chester disease, Langerhans cell histiocytosis, ganglioglioma, glioma, glioblastoma, hairy cell leukemia, metanephrotic adenoma, multiple myeloma, non-small cell lung cancer, ovarian cancer, pilomyxoid astrocytoma, anaplastic pleomorphic xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, pancreatic cancer, clear cell sarcoma of the chest, salivary gland cancer, or microsatellite stable colorectal cancer.

132. The compound of any one of claims 122 to 131, wherein the patient also receives an additional active agent.

133. The compound of claim 132, wherein the additional active agent is a MEK inhibitor.

134. The compound of claim 133, wherein the MEK inhibitor is trametinib.

135. The compound of claim 132, wherein the additional active agent is an immune checkpoint inhibitor.

136. The compound of claim 135, wherein the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, simiprelimab, ipilimumab, renalalimab, atezolizumab, avelumab, and durvalumab.

137. The compound of claim 132, wherein the additional active agent is cetuximab or panitumumab.

138. The compound of any one of claims 122 to 137, wherein the mutant BRAF has a V600 mutation.

139. The compound of claim 138, wherein the V600 mutation is V600E, V600K, V600R, V600D or V600N.

140. The compound of claim 138, wherein the V600 is mutated to V600E.

141. The compound of any one of claims 122 to 140, wherein the mutant BRAF has a mutation selected from G469A, G469V, G469L, G469R, L597Q and K601E.

142. The compound of any one of claims 122 to 141, wherein the mutant BRAF has a mutation selected from G466A, G466E, G466R, G466V, S467L, G469E, N581I, D594E, D594G and D594N.

143. The compound of any one of claims 122 to 142, wherein the mutant BRAF has a mutation selected from G464I, G464R, N581T, L584F, E586K, G593D, G596C, L597R, L597S, S605I, S607F, N684T, E26A, V130M, L745L and D284E.

144. The compound of any one of claims 122 to 143, wherein the mutant BRAF has a splicing mutation.

145. The compound of claim 144, wherein the splicing mutation is a p61-BRAF splicing mutation.

146. The compound of any one of claims 122 to 145, wherein the mutant BRAF-mediated condition is cancer and the cancer also has an NRAS, MEK1, or PI3K mutation.

147. The compound of claim 146, wherein the cancer has an NRAS mutation.

148. The compound of claim 147, wherein the NRAS mutation is Q61K.

149. The compound of claim 147, wherein the NRAS mutation is Q61R.

150. The compound of claim 146, wherein the cancer has a MEK1 mutation.

151. The compound of claim 146, wherein the cancer has a PI3K mutation.

152. The compound of claim 151, wherein the PI3K mutation is PIK3CA. H1047R Or PIK3CA P449T .

153. The compound of any one of claims 122 to 152, wherein the mutant BRAF-mediated condition is cancer and one or more mutations promote homodimerization or heterodimerization of the RAF protein.

154. The compound of claim 153, wherein the one or more mutations promote homodimerization of the RAF protein.

155. The compound of claim 153, wherein the one or more mutations promote heterodimerization of the RAF protein.

156. The compound of any one of claims 122 to 152, wherein the BRAF-mediated disease of the mutant is cancer that has metastasized to the brain or CNS.

157. The compound of any one of claims 122 to 152, wherein the BRAF-mediated condition of the mutant is cancer that has metastasized to the brain.

158. The compound of any one of claims 122 to 152, wherein the BRAF-mediated disease of the mutant is cancer that has metastasized to the CNS.

159. Use of any compound of claims 1 to 83 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in human patients for the treatment of BRAF-mediated disease by mutants.

160. Use of any compound or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as claimed in any one of claims 1 to 83, in the preparation of a medicament for treating mutant BRAF-mediated conditions in human patients.

161. The use as described in claim 159 or 160, wherein the BRAF-mediated condition of the mutant is cancer.

162. The use as described in claim 161, wherein the BRAF-mediated cancer of the mutant is melanoma.

163. The use as described in claim 161, wherein the BRAF-mediated cancer of the mutant is lung cancer.

164. The use as described in claim 161, wherein the BRAF-mediated cancer of the mutant is non-small cell lung cancer.

165. The use as described in claim 161, wherein the BRAF-mediated cancer of the mutant is colorectal cancer.

166. The use as described in claim 161, wherein the BRAF-mediated cancer of the mutant is microsatellite stable colorectal cancer.

167. The use as described in claim 161, wherein the BRAF-mediated cancer of the mutant is thyroid cancer.

168. The use as described in claim 161, wherein the BRAF-mediated cancer of the mutant is ovarian cancer.

169. The use as described in claim 159 or 160, wherein the mutant BRAF-mediated disease is cholangiocarcinoma, Eldheim-Chester disease, Langerhans cell histiocytosis, ganglioglioma, glioma, glioblastoma, hairy cell leukemia, metanephrotic adenoma, multiple myeloma, non-small cell lung cancer, ovarian cancer, pilomyxoid astrocytoma, anaplastic pleomorphic xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, undifferentiated thyroid carcinoma, pancreatic cancer, clear cell sarcoma of the chest, salivary gland cancer, or microsatellite stable colorectal cancer.

170. The use as described in any one of claims 159 to 169, wherein the patient also receives an additional active agent.

171. The use as described in claim 170, wherein the additional active agent is a MEK inhibitor.

172. The use as described in claim 171, wherein the MEK inhibitor is trametinib.

173. The use as described in claim 170, wherein the additional active agent is an immune checkpoint inhibitor.

174. The use as described in claim 173, wherein the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, cimiprilumab, ipilimumab, renalalimab, atezolizumab, avelumab, and duvalumab.

175. The use as described in claim 170, wherein the additional active agent is cetuximab or panitumumab.

176. The use as claimed in any one of claims 159 to 175, wherein the mutant BRAF has the V600 mutation.

177. The use as described in claim 176, wherein the V600 mutation is V600E, V600K, V600R, V600D, or V600N.

178. The use as described in claim 176, wherein the V600 mutation is V600E.

179. The use as claimed in any one of claims 159 to 178, wherein the mutant BRAF has a mutation selected from G469A, G469V, G469L, G469R, L597Q and K601E.

180. The use as claimed in any one of claims 159 to 179, wherein the mutant BRAF has a mutation selected from G466A, G466E, G466R, G466V, S467L, G469E, N581I, D594E, D594G, and D594N.

181. The use as claimed in any one of claims 159 to 180, wherein the mutant BRAF has a mutation selected from G464I, G464R, N581T, L584F, E586K, G593D, G596C, L597R, L597S, S605I, S607F, N684T, E26A, V130M, L745L and D284E.

182. The use as described in any one of claims 159 to 181, wherein the mutant BRAF has a splicing mutation.

183. The use as described in claim 182, wherein the splicing mutation is a p61-BRAF splicing mutation.

184. The use as claimed in any one of claims 159 to 183, wherein the BRAF-mediated condition of the mutant is cancer and the cancer also has an NRAS, MEK1, or PI3K mutation.

185. The use as described in claim 184, wherein the cancer has an NRAS mutation.

186. The use as described in claim 185, wherein the NRAS mutation is Q61K.

187. The use as described in claim 185, wherein the NRAS mutation is Q61R.

188. The use as described in claim 184, wherein the cancer has a MEK1 mutation.

189. The use as described in claim 184, wherein the cancer has a PI3K mutation.

190. The use as described in claim 189, wherein the PI3K mutation is PIK3CA. H1047R Or PIK3CA P449T .

191. The use as claimed in any one of claims 159 to 190, wherein the mutant BRAF-mediated condition is cancer and one or more mutations promote homodimerization or heterodimerization of the RAF protein.

192. The use as described in claim 191, wherein the one or more mutations promote homodimerization of the RAF protein.

193. The use as described in claim 191, wherein the one or more mutations promote heterodimerization of the RAF protein.

194. The use as described in any one of claims 159 to 190, wherein the BRAF-mediated condition of the mutant is cancer that has metastasized to the brain or CNS.

195. The use as described in any one of claims 159 to 190, wherein the BRAF-mediated condition of the mutant is cancer that has metastasized to the brain.

196. The use as described in any one of claims 159 to 190, wherein the BRAF-mediated disease of the mutant is cancer that has metastasized to the CNS.

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