Therapeutic drugs that degrade mutant BRAF

Abstract

The present invention provides compounds, or pharma- ceutically acceptable salts thereof, and pharmaceutical compositions thereof, that can be administered to a host, such as a human in need thereof, for the treatment of disorders, such as cancer, mediated by mutant BRAF, which effectively degrade class I, class II, and class III mutant BRAF proteins.

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of European Patent Application No. 21178145.5, European Patent Application No. 21178150.5, and European Patent Application No. 21178152.1, filed June 8, 2021, respectively, and U.S. Provisional Application No. 63 / 277,973, filed November 10, 2021, the entireties of which are incorporated by reference herein for all purposes.

[0002] The present invention provides compounds and their pharma- ceutically acceptable salts, uses, compositions, and manufactures that degrade mutant BRAF, such as class I, class II, and / or class III mutant BRAF. The compounds of the present invention can be administered to a host, such as a human in need thereof, for therapeutic and / or prophylactic treatment of disorders, such as cancer, mediated by mutant BRAF. [Background technology]

[0003] BRAF is a serine / threonine protein kinase that is a member of the signal transduction protein kinases. BRAF plays an important role in the MAPK signal transduction pathway and is mutated in approximately 8% of all human cancers, including melanoma (about 60%), thyroid cancer (about 60%), and lung adenocarcinoma (about 10%). BRAF mutations have also been observed in thyroid cancer, colorectal cancer, lung cancer, etc. The most common mutation in BRAF is V600E (class I), which occurs in half of malignant melanomas. This mutation hyperactivates ERK, which transmits signals as a RAF inhibitor-sensitive monomer. Other common activating mutations include class II mutations such as G469A and class III mutations such as G466V. Class II and class III mutations activate ERK by promoting homodimerization or heterodimerization of RAF.

[0004] Despite the therapeutic utility of available BRAF inhibitors, the duration of antitumor responses to these agents can be limited by the acquisition of drug resistance.

[0005] BRAF proteins exhibit a mechanism of signaling propagation that requires protein homodimerization (BRAF-BRAF) or heterodimerization with other RAF proteins (BRAF-RAF1 or BRAF-ARAF). When BRAF is mutated, as observed in oncological indications with BRAF V600E / K substitutions, BRAF signaling becomes independent of homodimers and / or heterodimers. The kinase activity becomes hyperactivated as a monomeric protein and drives cell proliferation signals.

[0006] Several BRAF inhibitors, including vemurafenib, dabrafenib, and encorafenib, have been reported that can inhibit monomeric but not dimeric BRAF, but resistance usually appears within a year, including RAS mutations, BRAFV600E amplification, and BRAFV600E intragenic deletions or splice variants. These inhibitors are also ineffective against non-V600BRAF mutants (class II and class III) that activate ERK by promoting homodimerization or heterodimerization of RAF.

[0007] Examples of BRAF inhibitors are described in US Pat. No. 5,399,623 and US Pat. No. 5,499,623.

[0008] Non-limiting examples of BRAF-degrading compounds include those described in US Pat. Nos. 5,993,323, 5,103,432, 5,103,545, and 5,103,626.

[0009] Despite these efforts, there remains a need for new therapeutic agents to treat BRAF-mediated cancers, particularly those that treat mutant BRAF-mediated cancers. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Publication No. 2021 / 116055 [Patent Document 2] International Publication No. 2021 / 116050 [Patent Document 3] International Publication No. 2018 / 119448 [Patent Document 4] International Publication No. 2019 / 199816 [Patent Document 5] International Publication No. 2020 / 051564 [Patent Document 6] International Publication No. 2022 / 047145 Summary of the Invention

[0011] The present invention provides compounds and their pharma- ceutically acceptable salts, uses, compositions, and manufactures that degrade mutant BRAF, e.g., class I, class II, and / or class III mutant BRAF, via the ubiquitin proteasome pathway. The compounds presented herein degrade wild-type BRAF poorly. These compounds bind to the ubiquitously expressed E3 ligase protein cereblon (CRBN) and alter the substrate specificity of the CRBN E3 ubiquitin ligase complex, resulting in the recruitment and ubiquitination of mutant BRAF, e.g., BRAF V600E. The compounds of the present invention are also binders of wild-type BRAF, RAF1, and ARAF, but they also degrade class I mutant BRAF, e.g., V600E, class II mutant BRAF, e.g., G469A, class III mutant BRAF, e.g., G466V mutant, and p61-BRAF. V600E More effective targeted degradation is induced against mutant BRAF, such as splice variants thereof (see Example 231).

[0012] By degrading mutant BRAF, the compounds of the present invention can be used to treat mutant BRAF-mediated cancers, such as melanoma, lung cancer, including non-small cell lung cancer, colorectal cancer, including microsatellite-stable colorectal cancer, thyroid cancer, including anaplastic thyroid cancer, or ovarian cancer.In certain embodiments, the compounds of the present invention are used to treat solid tumors mediated by V600X mutant BRAF.Additional non-limiting examples of disorders 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 drivers.

[0013] In certain embodiments, compounds of the invention, such as compound 157, have about 10-fold, 100-fold, or even greater than 1000-fold selectivity for degradation of mutant BRAF over wild-type BRAF, KRAS, and / or CRAF (see Example 234). For example, in A375 cells, compound 157 inhibits BRAF V600E Strongly decomposes (E max = 26% (i.e., 74% of the BRAF protein is degraded) in DCs at 24 hours. 50 =14 nM), inhibiting ERK phosphorylation (IC 50 =11 nM) and inhibited cell growth (GI at 96 hours) 50 =94 nM) while having no effect in the mutant KRAS-driven cell line HCT-116 (see Example 235 and Example 236). In A375 xenografts, oral delivery of compound 157 was more efficacious than clinically relevant doses of encorafenib, resulting in highly significant tumor regression when administered BID at 10 mg / kg (see Example 241).

[0014] [ka] Compound 157 / Example 157

[0015] The compounds of the invention can be used to treat difficult-to-treat double-mutant cancers with one mutation in BRAF. For example, compound 157 inhibits the BRAF inhibitor-resistant engineered A375-BRAF V600E / NRAS Q61K Compound 157 was much more effective than encorafenib in degrading BRAF in a double mutant model (see Example 231 and Example 241). In this model, administration of the single agent compound 157 in vivo caused potent tumor growth inhibition and, in combination with the MEK inhibitor trametinib, produced tumor regression. The combination of encorafenib and trametinib showed no activity in the same model. In certain embodiments, the compounds of the present invention can be used to degrade class I, class II, class III BRAF mutants and their splice variants. For example, compound 157 was used to degrade G469A (class II), G466V (class III), and p61-BRAF using heterologous expression in HEK293T cells. V600E Additional BRAF mutant proteins, including splice variants, can be degraded.

[0016] In certain embodiments, the compounds of the present invention can treat cancers that have developed resistance to BRAF inhibitors. For example, compound 157 is effective in treating G466V mutant BRAF lung tumor cell lines in which encorafenib has no activity (see Example 231). In certain embodiments, the compounds of the present invention, such as compound 157, are orally bioavailable.

[0017] In certain embodiments, a compound of formula I or formula II, such as compound 157: [ka] or a pharma- ceutically acceptable salt thereof is provided.

[0018] In other embodiments, the compound of formula III, formula IV, formula V, or formula VI: [ka] (In the formula, A 1 -NR 2 -and-CHR 2 '- selected from, R 1 is selected from hydrogen, alkyl, and cycloalkyl; R 2 is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with R 2 ' is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 ', together with the carbon atom to which they are attached, represent one or two R 3 forming an optionally substituted cycloalkyl with Each R 3 is independently selected from hydrogen, halogen (e.g., F), alkyl, cycloalkyl, and alkoxy; R 4 is selected from hydrogen, alkyl, cyano, and halogen (e.g., F); R 5 is selected from hydrogen, alkyl, cyano, and halogen (e.g., F); A 2 is selected from -O-, -NH-, and -(C=O)-; A 22 is selected from -O- and -NH-; W 1 is selected from -N- and -CH-; W 2 -N- and -CR 26 - selected from R 6is selected from hydrogen, halogen (e.g., F), hydroxy, amino, dialkylamino, alkoxy, alkyl, and alkoxyalkyl; R 26 is selected from hydrogen, halogen, hydroxy, amino, alkoxy, and alkyl; A 3 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -CH 2 -, -CH 2 -CH(CH 3 )-CH 2 -, -CH 2 -CH 2 -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - selected from A 23 represents a bond, -O-, and -CH 2 - selected from A is selected from a bond, pyrimidinyl, pyridinyl, pyrazolyl, and 3-azabicyclo[3.1.0]hexyl; A30 is a bond, -CH 2 -, pyrimidinyl, pyridinyl, pyrazolyl, and 3-azabicyclo[3.1.0]hexyl; B is phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 1 , 1-dioxo-1λ6-thia-8-azaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-methyl-1,8-diazaspiro[4.5]decyl, 1,8-diazaspiro[4.5]decyl, and 8-azaspiro[4.5]decyl, where B is optionally substituted with 1 or 2 substituents independently selected from halogen, alkyl, and alkoxy; B2 is selected from phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, and 8-azaspiro[4.5]decyl, where B2 is optionally substituted with 1 or 2 substituents independently selected from halogen, alkyl, and alkoxy; B3 is selected from phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 1,1-dioxo-1λ6-thia-8-azaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-methyl-1,8-diazaspiro[4.5]decyl, 1,8-diazaspiro[4.5]decyl, and 8-azaspiro[4.5]decyl; n is 0 or 1, A 4 is a bond, -CH 2 -,-(SO2 )-CH 2 -, -CH(CH 2 -OH)-, -NH-, and -O-; A 14 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CH(CH 2 -OH)-, -NH-, -O-, cycloalkyl, and alkylamino; C is selected from azepanyl, azetidinyl, cycloalkyl, piperazinyl, and piperidinyl, where C is optionally substituted with 1 or 2 substituents independently selected from halogen (e.g., F), hydroxy, alkyl, and alkoxy; D is [ka] is selected from R 7 is selected from hydrogen, alkyl, cyano, halogen (e.g., F), and alkoxy; R 8 is selected from hydrogen, alkyl, cyano, halogen (e.g., F), and alkoxy; R 9 is selected from hydrogen, alkyl, cyano, halogen (e.g., F), and alkoxy; R 17 is selected from hydrogen, alkyl, cyano, hydroxy, cycloalkyl, halogen, and alkoxy; R 18 is selected from hydrogen, alkyl, cyano, hydroxy, cycloalkyl, halogen, and alkoxy; R 19 is selected from hydrogen, alkyl, cyano, hydroxy, cycloalkyl, halogen, and alkoxy; A 5 is -CH- or -N-, A 15 is selected from a bond, -O-, and -NH-; A 6 is -CH- or -N-, and The linker is a divalent chemical group), or a pharma- ceutically acceptable salt thereof.

[0019] In certain embodiments, the linker is [ka] (In the formula, X 1 and X 2 is independently, in each occurrence, a bond, a heterocycle, NR 2 , C(R 2 ) 2 , O, C(O), and S; R 20 , R 21 , R 22 , R 23 , and R 24 is independently, at each occurrence, a bond, an alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO 2 -, -S(O)-, -C(S)-, -C(O)NR 2 -, -NR 2 C(O)-, -O-, -S-, -NR 2 -, -C(R 40 R 40 )-, -P(O)(OR 36 )O-, -P(O)(OR 36 )-, bicyclic, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic, glycolic, and carbocyclic, each of which is selected from the group consisting of a divalent moiety selected from R 40 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 36 is independently selected at each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic; and R 40is independently, in each occurrence, hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azido, amino, cyano, -NH (aliphatic with alkyl), -N (aliphatic with alkyl), 2 , -NHSO 2 (aliphatic containing alkyl), -N(aliphatic containing alkyl)SO 2 Alkyl, -NHSO 2 (aryl, heteroaryl, or heterocycle), -N(alkyl)SO 2 (aryl, heteroaryl, or heterocycle), -NHSO 2 Alkenyl, -N(alkyl)SO 2 Alkenyl, -NHSO 2 Alkynyl, -N(alkyl)SO 2 alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, and cycloalkyl).

[0020] In certain embodiments, the linker is [ka] It is.

[0021] Non-limiting examples of compounds of Formula I and Formula II include: [ka] or a pharma- ceutically acceptable salt thereof.

[0022] The present invention provides compounds that specifically degrade mutant BRAF, such as BRAF exhibiting the mutation V600E, through targeted ubiquitination and subsequent proteasomal degradation of the BRAF protein. The compounds bind to the ubiquitously expressed E3 ligase protein cereblon (CRBN) and alter the substrate specificity of the CRBN E3 ubiquitin ligase complex, resulting in the recruitment and ubiquitination of mutant BRAF, such as BRAF V600E. Although the compounds are also effective binders of wild-type BRAF, RAF1, and ARAF, effective targeted degradation of mutant BRAF, such as BRAF V600E, is induced by these compounds.

[0023] In certain embodiments, the compounds of the present invention are used to treat BRAF-mediated cancers in which BRAF is mutated from wild type. There are many possible BRAF mutations. In certain 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.

[0024] In certain embodiments, the compounds of the invention treat BRAF mutation-mediated disorders where the mutation is not a class I, class II, or class 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.

[0025] In certain embodiments, the compounds of the present invention are directed to compounds in which the mutation is a splice variant, e.g., p61-BRAF V600E The present invention relates to a BRAF mutation-mediated disorder.

[0026] In certain embodiments, the compounds of the present invention can be used to treat disorders mediated by two or more mutant proteins, such as BRAF. V600E / NRAS Q61K Treating double mutant mediated cancers.

[0027] In certain embodiments, the compounds of the invention are used to treat cancers that are resistant to at least one BRAF inhibitor, such as cancers that are resistant or have acquired resistance to a BRAF inhibitor selected from dabrafenib, trametinib, vemurafenib, and encorafenib.

[0028] In certain embodiments, the compounds described herein can be used to treat BRAF V600E / NRAS Q61K Cancers that have harbored escape mutations, such as double mutant cancers, are treated.

[0029] In certain embodiments, the compounds described herein are used to treat melanoma.

[0030] In certain embodiments, the selected compounds of the present invention provide improved efficacy and / or safety profile compared to at least one known BRAF inhibitor. For example, the degraders of the present invention have the efficacy of the protein-binding portion of the inhibitor alone combined with the catalytic degradation activity of cereblon-activated proteasomal degradation. This results in rapid activity against mutant BRAF-mediated cancers due to the active portion being able to quickly "return to action" and repeat catalytic function. In this way, BRAF is rapidly destroyed as is done by covalent suicide inhibitors, but the active drug is not destroyed at the same time.

[0031] In certain embodiments, the degrader compounds of the invention have one or more advantages over the use of enzyme inhibitors alone in the treatment of BRAF-mediated disorders.

[0032] In certain embodiments, fewer moles of a compound described herein are required to treat a BRAF-mediated disorder than moles of the BRAF-targeted ligand moiety alone.

[0033] In certain embodiments, the compounds of the invention exhibit at least one less side effect in treating a BRAF-mediated disorder than the BRAF-targeted ligand moiety alone.

[0034] Another aspect of the invention provides a compound as described herein, or an enantiomer, diastereomer or stereoisomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in the manufacture of a medicament for inhibiting or preventing a disorder mediated by BRAF, or modulating or reducing the amount of BRAF.

[0035] Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer or stereoisomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing a disease mediated by BRAF.

[0036] In certain embodiments, select compounds described herein are useful for the treatment of disorders involving abnormal cell proliferation, such as tumors or cancer, where BRAF is an oncoprotein or signaling mediator of an abnormal cell proliferation pathway, and its degradation reduces the abnormal cell growth.

[0037] In certain embodiments, the compounds of the invention have at least one desired isotopic substitution of an atom at an amount greater than the natural abundance of that isotope, ie, are enriched.

[0038] In certain embodiments, the compounds of the present invention contain one deuterium atom or multiple deuterium atoms.

[0039] In certain embodiments, the compounds of the present invention are useful for the therapeutic and / or prophylactic treatment of cancer.

[0040] In certain embodiments, the compounds of the present invention are used in combination with the second active agent described herein to treat mutant BRAF-mediated cancer.Non-limiting examples of classes of molecules that can be used in combination with the compounds of the present invention include MEK inhibitors, immune checkpoint inhibitors, and EGFR antibodies.In certain embodiments, the compounds of the present invention are used in combination with trametinib to treat mutant BRAF-mediated cancer, such as melanoma or non-small cell lung cancer.In certain embodiments, the compounds of the present invention are used in combination with immune checkpoint inhibitors to treat mutant BRAF-mediated cancer.In certain embodiments, the compounds of the present invention are used in combination with cetuximab or panitumumab to treat mutant BRAF-mediated cancer, such as colorectal cancer. In certain embodiments, compounds of the invention are used in combination with nivolumab, pembrolizumab, cemiplimab, ipilimumab, leratolimab, atezolizumab, avelumab, or durvalumab to treat mutant BRAF-mediated cancers, such as colorectal cancer, melanoma, or non-small cell lung cancer.

[0041] In other aspects, the compounds of the invention are used in combination with two or more additional active agents described herein to treat mutant BRAF-mediated cancers. In certain embodiments, the compounds described herein are used in combination with a MEK inhibitor and an immune checkpoint inhibitor to treat melanoma or non-small cell lung cancer.

[0042] Other features and advantages of the present application will become apparent from the following detailed description.

[0043] Thus, the present invention includes at least the following features: (a) a compound of formula I, II, III, IV, V, or VI, or a pharma- ceutically acceptable salt or isotopic derivative thereof (including deuterated derivatives); (b) a method of treating mutant BRAF-mediated disorders, such as abnormal cell proliferation, including cancer, comprising administering to a patient in need of treatment an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI, as described herein, or a pharma- ceutically acceptable salt thereof; (c) A compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI, or a pharma- ceutically acceptable salt or isotopic derivative thereof (including deuterated derivatives), for use in the treatment of a disorder mediated by mutant BRAF, e.g., abnormal cell proliferation such as a tumor or cancer; (d) the use of an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI, or a pharma- ceutically acceptable salt thereof, in the treatment of a patient, typically a human, in need of treatment, suffering from a mutant BRAF-mediated disorder, e.g., abnormal cell proliferation, such as a tumor or cancer; (e) use of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI, or a pharma- ceutically acceptable salt or isotopic derivative thereof (including deuterated derivatives), in the manufacture of a medicament for the treatment of a mutant BRAF-mediated disorder, e.g., abnormal cell proliferation such as a tumor or cancer; (f) the use of an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI, or a pharma- ceutically acceptable salt thereof, in the treatment of a patient, typically a human, in need of treatment suffering from a mutant BRAF-mediated disorder, e.g., abnormal cell proliferation such as a tumor or cancer; (g) a pharmaceutical composition comprising an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI, or a pharma- ceutically acceptable salt, isotopic derivative thereof, and optionally a pharma- ceutically acceptable carrier or diluent, to treat a patient; (h) a compound of formula I, II, III, IV, V, or VI as described herein, as a mixture of enantiomers or diastereomers (where applicable), including racemates; (i) a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI as described herein in an enantiomerically- or diastereomerically-enriched (where applicable) form (i.e., greater than about 85%, greater than about 90%, greater than about 95%, greater than about 97%, or greater than about 99% pure), including an isolated enantiomer or diastereomer; and (j) A method for preparing a therapeutic product comprising an effective amount of a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI described herein, or a pharma- ceutically acceptable salt thereof.

[0044] BRIEF DESCRIPTION OF THE DRAWINGS As used in the figures, both compound 157 and example 157 are [ka] Refers to...

[0045] Compound 157 was referred to as Compound 14 / Example 14 in U.S. Provisional Application No. 63 / 277,973 and European Patent Application No. 21178150.5. [Brief description of the drawings]

[0046] [Figure 1] Figure 1 shows a line graph showing HiBiT-BRAFV600E protein levels after 24 hours of treatment with compound 157. Compound 157 has a DC50 of about 100nM and an Emax of about 25% degradation with a concomitant loss of phospho-ERK (pERK), confirming blockade of the MAPK pathway with an IC50<5nM. The y-axis is the remaining protein measured in %. The x-axis is the concentration of compound 157 measured in nanomolar concentrations. The experimental procedure is shown in Example 229 and Example 230. [Diagram 2] FIG. 1 shows a line graph showing stable GSPT1 protein levels after treatment with various concentrations of Compound 157. The y-axis is the remaining protein measured in %. The x-axis is the concentration of Compound 157 measured in nanomolar concentrations. The experimental procedure is shown in Example 229. [Diagram 3] FIG. 1 shows a line graph showing stable SALL4 protein levels after treatment with various concentrations of Compound 157. The y-axis is the remaining protein measured in %. The x-axis is the concentration of Compound 157 measured in nanomolar concentrations. The experimental procedure is shown in Example 229. [Figure 4] Figure 1 shows a Western blot showing BRAF V600E levels in A375 cells in response to the degrader compound 157 while being loaded with inhibitors or competitors related to the function of proteasome-dependent molecules. (- / +) indicates the presence of compound 157 in the sample. When treated with DMSO alone, BRAF V600E is at normal levels, but after 24 hours of exposure to compound 157, BRAF V600E levels are significantly reduced. This degradation is blocked by adding excess targeting ligand, preventing the degrader from binding to BRAF V600E. This degradation is also blocked when cells are pretreated with a compound (IMID) specific for a binding site on cereblon. Taken together, this suggests that to degrade BRAF V600E, the degrader must bind to both BRAF and CRBN simultaneously. Furthermore, treatment of cells with a combination of the neddylation inhibitor MLN4962 or the proteasome inhibitor bortezomib and compound 157 blocked degradation, indicating that this loss of BRAF V600E by compound 157 is dependent on neddylation and the proteasome system. The experimental procedure is shown in Example 231. [Diagram 5] FIG. 2 shows a line graph depicting ternary complex formation between BRAF V600E and cereblon with various concentrations of compound 157 or compound 157NMe. The y-axis is the percentage of ternary complex. The x-axis is the concentration of compound 157 measured in nanomolar concentrations. Compound 157NMe is an analog of compound 157 that has minimal or no interaction with cereblon and is therefore not a functional degrader. The experimental procedure is shown in Example 232. [Figure 6]FIG. 1 shows a TREEspot™ interaction map showing the relative amount of 10 nM compound 157 binding to several proteins. Kinases that show binding to compound 157 are highlighted with black circles. Circle size reflects % inhibition. Experimental procedure is shown in Example 233. [Figure 7] FIG. 1 shows a TREEspot™ interaction map showing the relative amount of 1000 nM compound 157 binding to several proteins. Kinases that show binding to compound 157 are highlighted with black circles. Circle size reflects % inhibition. Experimental procedure is shown in Example 233. [Figure 8] Scatter plots showing data from cell lysates analyzed by multiplex quantitative proteomics of A375 cells or JURKAT cells treated with 300 nM compound 157 for 24 hours (see below for experimental method). For each experiment, data was analyzed by comparing samples treated with compound 157 (biological replicates) with control samples treated with 300 nM dabrafenib (A375 cells) or DMSO (JURKAT cells), and the fold change in relative abundance is shown in the resulting scatter plot. Log2 fold change is shown on the x-axis, and negative Log10 adjusted p-value (T-test of compound 157 vs. DMSO control adjusted by Benjamini-Hochberg correction) is shown on the y-axis. Horizontal dashed lines indicate statistical significance (p-value ≦0.001), and vertical lines indicate fold change cutoff of ≧2. Experimental procedures are shown in Example 234. [Figure 9]Figure 1 shows a Western blot showing BRAF V600E and pERK levels in A375 cells in response to degrader compound 157 and null degrader compound 157NMe. BRAF V600E levels are dose-dependently reduced with compound 157 until the hook at 1 μM characteristic of bifunctional degraders is reached. MAPK signaling, as read by ERK phosphorylation, is significantly depressed after treatment with compound 157. Compound 157NMe is an analog of compound 157 with minimal binding to cereblon and is therefore not a functional degrader. As expected, BRAF V600E levels remain unchanged and the loss of ERK phosphorylation is not as pronounced as with functional degraders. The effect on ERK phosphorylation seen with null degraders is due to the inhibitory contribution of the ligand-targeting side of bifunctional degraders. The experimental procedure is shown in Example 231. [Figure 10] Figure 2 shows a line graph of cell confluence of A375 cells cultured with compound 157 and compound 157NMe by live cell imaging over 7 days. DMSO treated cells grow rapidly with expected doubling time, reaching 100% confluence around day 5. When treated with BRAF degrader compound 157, cells are significantly stunted, barely reaching 20% ​​confluence by the end of the 7-day experiment. Cells treated with cerebron null compound 157NMe grow at normal rate initially, but are inhibited to approximately 70% confluence. The changes between the two compounds support the contribution of BRAF V600E degradation to the inhibition of cell growth, compared to comparable BRAF V600E inhibition alone. The experimental procedure is shown in Example 231. [Figure 11]Figure 13 shows a line graph of cell confluence of A375 cells cultured with compound 157 and compound 157NMe by live cell imaging at day 5. The contribution of BRAF V600E degradation to inhibition of cell growth is further supported by observing cell growth by concentration at a fixed time point (day 5) compared to comparable BRAF V600E inhibition alone at cell growth (note that the degrader is shifted to the right from its cerebron null counterpart). The experimental procedure is shown in Example 231. [Figure 12] Figure 2 shows a Western blot showing wild-type BRAF and pERK levels in HCT-116 cells with endogenous wild-type BRAF in response to degrader compound 157. As expected, wild-type BRAF levels and ERK phosphorylation are minimally affected. The experimental procedure is shown in Example 231. [Figure 13] Figure 2 shows a growth time course experiment showing HCT-116 wild-type BRAF cells after treatment with compound 157 or a pan-RAF inhibitor. This cell line is dependent on RAF signaling, and it has been documented that treatment with a pan-RAF inhibitor significantly impedes cell growth. Since the curve for treated cells overlaps exactly with DMSO-treated cells, compound 157 does not affect cell growth, supporting the hypothesis that the phenotypic results of compound 157 are specific to mutant BRAF. The experimental procedure is shown in Example 236. [Figure 14]Figure 2 shows a line graph depicting the in vivo efficacy of compound 157 and encorafenib in treating female BALB / c nude mice bearing A375 tumors. Mice were treated by oral gavage (PO) with vehicle control, encorafenib (35 mg / kg), or compound 157 (0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, or 10 mg / kg) once daily (QD), twice daily (BID), or three times daily (TID) as indicated. Efficacy data are presented as mean ± SEM. Dashed lines represent progression without treatment. The x-axis is time measured in days and the y-axis is A375 tumor volume measured in mm3. Experimental procedures are shown in Example 238. [Figure 15] Figure 2 shows a line graph showing the weight change of compound 157 and encorafenib in the treatment of female BALB / c nude mice bearing A375 tumors. Mice were treated once daily (QD), twice daily (BID), or three times daily (TID) by oral gavage (PO) with vehicle control, encorafenib (35 mg / kg), or compound 157 (0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, or 10 mg / kg) as indicated. Efficacy data are presented as mean ± SEM. Dashed lines represent progression without treatment. The x-axis is time measured in days and the y-axis is weight change in percent. Experimental procedures are shown in Example 238. [Figure 16] Figure 2 shows a line graph showing the in vivo pharmacokinetic activity of Compound 157 in plasma after a single oral (PO) dose of 0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg. Plasma and tumor were collected at the indicated time points and injected into an LC / MS / MS system for quantitative analysis. The concentrations of Compound 157 in plasma (ng / ml) and Compound 157 in tumor (ng / g) are expressed as mean ± SEM. The experimental procedure is shown in Example 239. [Figure 17]Figure 2 shows a line graph showing the in vivo pharmacokinetic activity of compound 157 in A375 xenograft tumors after a single oral (PO) dose of 0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg. Plasma and tumor were collected at the indicated time points and injected into an LC / MS / MS system for quantitative analysis. The concentrations of compound 157 in plasma (ng / ml) and in tumor (ng / g) are expressed as mean ± SEM. The experimental procedure is shown in Example 239. [Figure 18] Figure 2 shows a line graph showing the relative protein expression of B-RAF in A375 xenograft tumors. BALB / c nude mice were injected with A375 tumor cells in the right flank. Compound 157 was administered as a single oral (PO) dose at 0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg, A375 tumors were harvested at the indicated time points, and protein expression of B-RAF was measured by Western blot. The x-axis is time measured in hours after single dose administration, and the y-axis is the percentage of protein relative to vehicle-treated tumors. Data are expressed as mean ± SEM. The experimental procedure is shown in Example 239. [Figure 19] Figure 2 shows a line graph showing the relative protein expression of phospho-ERK in A375 xenograft tumors. BALB / c nude mice were injected with A375 tumor cells into the right flank. Compound 157 was administered as a single oral (PO) dose at 0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg, A375 tumors were harvested at the indicated time points, and protein expression of pERK was measured by Western blot. The x-axis is time measured in hours after single dose administration, and the y-axis is the percentage of protein relative to vehicle-treated tumors. Data are expressed as mean ± SEM. The experimental procedure is shown in Example 239. [Figure 20]Western blot of A375 cells expressing oncogenic NRASQ61K mutants treated with compound 157 or encorafenib in a 5-point dose response with or without 1 nM trametinib for 24 hours. NRASQ61K expression in addition to BRAF V600E represents a resistance mechanism seen in patients, and is a greater challenge to overcome with suppression of MAPK signaling. Compound 157, a degrader, alone can suppress MAPK signaling as readout by ERK phosphorylation. In combination with MEK inhibitor trametinib, ERK activation is completely suppressed by 10 nM compound 157. In comparison, BRAF V600E inhibitor encorafenib fails to significantly suppress ERK phosphorylation levels with or without trametinib. This data indicates that compound 157 may be advantageous in controlling MAPK signaling in the resistant environment of BRAF V600E. The experimental procedure is shown in Example 231. [Figure 21] Figure 2 shows a line graph of cell growth over time for A375 cells expressing oncogenic NRASQ61K mutation. Cells treated with DMSO alone show normal doubling time. When treated with compound 157, a BRAF V600E degrader, cell growth is inhibited and cells cannot achieve more than 50% confluency. When treated with its matched pair compound 157NMe, which has minimal or no binding to cereblon, cell growth is not inhibited. Encorafenib does not inhibit cell growth in resistant model cell lines. Experimental procedures are shown in Example 235. [Figure 22]FIG. 1 shows a line graph depicting the effect of various concentrations of compound on tumors in female BALBc / nude mice bearing xenografts of the A375 NRASQ61K mutant melanoma cell line. Mice were administered vehicle, trametinib (MEK inhibitor (MEKi) 0.1 mg / kg twice daily (BID)), encorafenib (35 mg / kg once daily (QD) + MEKi), compound 157 (1 mg / kg, 3 mg / kg, 10 mg / kg, or 30 mg / kg BID), or the same dose of compound 157 in combination with MEKi at 0.1 mg / kg (BID) by oral gavage. Compound 157 was efficacious as a single agent at doses of 10 mg / kg (BID) and 30 mg / kg (BID) and caused regressions when administered in combination with MEKi at 0.1 mg / kg (BID). Efficacy data are expressed as mean tumor volume ± SEM. All doses were well tolerated, with no group experiencing a mean weight loss of more than 4.5% throughout the study. The experimental procedure is shown in Example 241. [Figure 23] Figure 2 shows Western blot that supports the decomposition ability of compound 157 except BRAF V600E. HEK-293T (ATCC, CRL-3216) cells are engineered to express BRAF V600E, wild type, p61 splice variant, class II mutant G469A and class III mutant G466V using lentivirus. Compound 157 can decompose all mutants except wild type BRAF. The experimental procedure is shown in Example 231. [Figure 24] Figure 2 shows the Western blot of cell line H1666 (ATCC, CRL-5885) that endogenously expresses class III mutation G466V. H1666 cells were treated with compound 157 for 24 hours. Treatment of H1666 cells with compound 157 causes a 53% decrease in BRAF signal, including any wild-type BRAF that may be present because the cells are heterozygous for the mutation, and compound 157 does not degrade wild-type BRAF. There is also a decrease in phosphorylated ERK signal, indicating the inhibition of MAPK pathway. The experimental procedure is shown in Example 231. [Diagram 25] Figure 1 shows a line graph supporting cell growth over time in H1666 cells endogenously expressing the class III BRAF mutation G466V. Cells treated with DMSO alone show normal doubling times. When treated with the BRAF degrader compound 157, cell growth is inhibited and cells are unable to achieve more than 30% confluency over 7 days. When treated with the matched pair compound 157NMe, which has minimal or no binding to cereblon, cell growth is not significantly inhibited. Furthermore, encorafenib does not inhibit cell growth in BRAF class III mutant cell lines. The most significant disruption to cell growth was the combination of compound 157 with the MEK inhibitor trametinib at a dose of 1 nM. Cells were unable to expand and proliferation was severely impaired. The experimental procedure is shown in Example 242. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] In certain embodiments, the present invention provides a compound represented by formula I: [ka] wherein the substituents and variables are as described herein, or a pharma- ceutically acceptable salt thereof.

[0048] In certain embodiments, the compound of formula I has formula IA: [ka] (In the formula, A 2 is -O-, n is 1, and R 4 is cyano and R 5 is fluoro, and the remaining substituents and variables are as described herein, or a pharma- ceutically acceptable salt thereof.

[0049] In certain embodiments, the compound of formula IB has the formula IB: [ka] (In the formula, A 2 is -NH-, n is 1, and R 4 is cyano and R 5 is fluoro, and the remaining substituents and variables are as described herein, or a pharma- ceutically acceptable salt thereof.

[0050] In certain embodiments, the compound of formula I has the formula IC: [ka] (In the formula, A 2 is -O-, and A 3 is a bond, A is a bond, n is 0, and A 4 is a bond, and R 4 is cyano and R 5 is fluoro, and the remaining substituents and variables are as described herein, or a pharma- ceutically acceptable salt thereof.

[0051] In certain embodiments, the compound of formula I has formula ID: [ka] (In the formula, A 2 is -(C=O)-, and A 3 is a bond, A is a bond, and the remaining substituents and variables are as described herein, or a pharma- ceutically acceptable salt thereof.

[0052] The compounds are useful for the therapeutic and / or prophylactic treatment of cancer.

[0053] The present invention provides compounds of formula I, II, III, IV, V, or VI, or pharma- ceutically acceptable salts thereof, the preparation of said compounds, medicaments containing them and their manufacture, and the use of said compounds in the therapeutic and / or prophylactic treatment of cancer.

[0054] Academic terminology The following definitions of general terms used herein apply regardless of whether the subject term appears by itself or in combination with other terms.

[0055] Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions set forth below. It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0056] The term "alkyl", alone or in combination, means a straight or branched chain alkyl group having 1 to 8 carbon atoms, in particular a straight or branched chain alkyl group having 1 to 6 carbon atoms, and more particularly a straight or branched chain alkyl group having 1 to 4 carbon atoms. 1 ~C 8 Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, the isomeric pentyls, isomeric hexyls, isomeric heptyls, and isomeric octyls, in particular methyl, ethyl, propyl, butyl, and pentyl. 1 ~C 6 Examples of alkyl are methyl, ethyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. Methyl and ethyl are specific examples of "alkyl."

[0057] The term "cyano", alone or in combination with other groups, refers to the group -C≡N.

[0058] The term "halogen" or "halo" refers to fluorine, chlorine, bromine or iodine, particularly fluorine, chlorine or bromine, more particularly fluorine. The term "halo", in combination with another group, refers to the substitution of said group with at least one halogen, particularly 1 to 5 halogens, particularly 1 to 4 halogens, i.e. 1, 2, 3 or 4 halogens.

[0059] The term "haloalkyl", alone or in combination with other groups, refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced by the same or different halogen atom. Examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl. Particular haloalkyl groups include fluoroethyl and difluoroethyl.

[0060] The terms "hydroxyl" and "hydroxy", alone or in combination, refer to an --OH group.

[0061] The term "amino", alone or in combination, refers to a primary amino group (-NH 2 ), a secondary amino group (-NH-), or a tertiary amino group (-N-).

[0062] The term "carbonyl", alone or in combination, means the -(C=O)- group.

[0063] The term "alkylamino" is an alkyl group linked to an -NH- group. The term "dialkylamino" means two alkyl groups linked to an -N- atom.

[0064] The terms "alkoxy" or "alkyloxy", alone or in combination, mean a radical of the formula alkyl-O-, where the term "alkyl" has the meaning given above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy. A particular example of "alkoxy" is methoxy.

[0065] The term "cycloalkyl", alone or in combination with other groups, refers to a monovalent monocyclic or bicyclic saturated hydrocarbon radical of 3 to 8 ring carbon atoms, especially 3 to 6 ring carbon atoms. Bicyclic means a ring system consisting of two saturated carbocyclic rings having one or two carbon atoms in common. Examples of monocyclic "cycloalkyl" are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An example of a bicyclic "cycloalkyl" is spiro[3.3]heptanyl. More specific examples of monocyclic "cycloalkyl" are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0066] The term "heterocycloalkyl", alone or in combination with other groups, refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 4 to 10 ring atoms containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon optionally substituted with oxo. Bicyclic means consisting of two rings having 1 or 2 ring atoms in common. Heterocycloalkyl is preferably a monovalent saturated or partially unsaturated monocyclic ring system of 4 to 7 ring atoms containing 1 or 2 ring heteroatoms selected from N, O, and S (4- to 7-membered heterocycloalkyl). Examples of monocyclic saturated heterocycloalkyls include 4,5-dihydro-oxazolyl, oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-4-yl, 3-oxo-morpholin-6-yl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, 1,4-diazacycloheptyl, diazepanyl, homopiperazinyl, and oxazepanyl. Examples of bicyclic saturated heterocycloalkyls include 3-azabicyclo[3.1.0]hexyl, oxabicyclo[2.2.1]heptanyl, oxaspiro[3.3]heptanyl, 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 7-azaspiro[3.5]nonyl, 9-aza-bicyclo[3.3.1]nonyl, 3-aza-bicyclo[3.2.1]cyclopentyl, 4-aza-bicyclo[3.2.1]cyclopentyl, 5-aza-bicyclo[3.2.1]cyclopentyl, 6-aza-bicyclo[3.2.1]cyclopentyl, 7-azaspiro[3.5]nonyl, 8-aza-bicyclo[3.2.1]cyclopentyl, 9-aza-bicyclo[3.3.1]cyclopentyl, 10-aza-bicyclo[3.2.1]cyclopentyl, 11-aza-bicyclo[3.2.1]cyclopentyl, 12-aza-bicyclo[3.2.1]cyclopentyl, 13-aza-bicyclo[3.2.1]cyclopentyl, 14-aza-bicyclo[3.2.1]cyclopentyl, 15-aza-bicyclo[3.2.1]cyclopentyl, 16-aza-bicyclo[3.2.1]cyclopentyl, 17-aza-bicyclo[3.2.1]cyclopentyl, 18-aza-bicyclo[3.2.1]cyclopentyl, 19-aza-bicyclo[3.3.1]cyclopentyl, 20-aza-bicyclo[3.2.1]cyclopentyl, 21-aza-bicyclo[3.2.1]cyclopentyl, 2 -oxa-9-aza-bicyclo[3.3.1]nonyl, 3-thia-9-aza-bicyclo[3.3.1]nonyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 1-oxa-8-azaspiro[4.5]decyl, 8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, and 3-azaspiro[5.5]undecyl. Examples of partially unsaturated heterocycloalkyl include dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, and dihydropyranyl.Particular examples of "heterocycloalkyl" are azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, and 3-azabicyclo[3.1.0]hexyl.

[0067] The term "sulfonyl", alone or in combination with other groups, refers to the group -SO 2 -It is.

[0068] The term "pharmaceutical acceptable" refers to the attributes of materials useful in making pharmaceutical compositions that are generally safe, non-toxic, not biologically or otherwise undesirable, and acceptable for medical use in humans as well as animals.

[0069] The term "pharmaceutically acceptable salt" refers to a salt suitable for use in contact with human and animal tissue. Examples of suitable salts with inorganic and organic acids include, but are not limited to, salts of 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 (sulphuric acid), tartaric acid, trifluoroacetic acid, etc. Particular acids are formic acid, trifluoroacetic acid, and hydrochloric acid.

[0070] The term "pharmaceutically acceptable auxiliary substances" refers to carriers and auxiliary substances, such as diluents or excipients that are compatible with the other ingredients of the formulation.

[0071] The term "pharmaceutical composition" encompasses not only products containing specified ingredients in predetermined amounts or ratios, but also any product that is obtained directly or indirectly by combining the specified ingredients in the specified amounts. In particular, the term encompasses not only products containing one or more active ingredients and any carrier, including inactive ingredients, but also any product that is obtained directly or indirectly by combination, complexation or aggregation of any two or more ingredients, or dissociation of one or more ingredients, or any other type of reaction or interaction of one or more ingredients.

[0072] "Therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a medical condition, is sufficient to effect such treatment for the medical condition. A "therapeutically effective amount" will vary depending on the compound, the condition being treated, the severity or disease being treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0073] The terms "as defined herein" and "as described herein" when referring to a variable moiety incorporate by reference the broad definition of the variable moiety, as well as the definitions of "in particular," "more particularly," and "most particularly," if any.

[0074] The terms "treating," "contacting," and "reacting," when referring to a chemical reaction, mean the addition or mixing of two or more reagents under appropriate conditions to produce a specified and / or desired product. It is understood that a reaction that produces a specified and / or desired product does not necessarily result directly from the combination of the two reagents initially added; i.e., there may be one or more intermediates that are produced in the mixture that ultimately results in the formation of the specified and / or desired product.

[0075] The term "pharmaceutical acceptable excipient" refers to any ingredient that has no therapeutic activity and is non-toxic, such as a disintegrant, binder, filler, solvent, buffer, isotonicity agent, stabilizer, antioxidant, surfactant, or lubricant, used in the formulation of a pharmaceutical product.

[0076] The term "inhibitor" refers to a compound that competes with, reduces or prevents the binding of a particular ligand to a particular receptor, or reduces or prevents the function of a particular protein.

[0077] If one of the starting materials or compounds of formula I, II, III, IV, V, or VI contains one or more functional groups that are not stable or reactive under the reaction conditions of one or more reaction steps, suitable protecting groups (for example, as described in "Protective Groups in Organic Chemistry", TW Greene and PGM Wuts, 3rd Ed., 1999, Wiley, New York) can be introduced before the critical step applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butoxycarbonyl (Boc), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethylcarbamate (Teoc), carbobenzyloxy (Cbz), and p-methoxybenzyloxycarbonyl (Moz).

[0078] The compounds of formula I, formula II, formula III, formula IV, formula V, and formula VI may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, such as racemates, mixtures of diastereoisomers, diastereoisomeric racemates, or mixtures of diastereoisomeric racemates.

[0079] The term "asymmetric carbon atom" means a carbon atom that has four different substituents. According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can have the "R" or "S" configuration.

[0080] Whenever a chiral carbon is present in a chemical structure, all stereoisomers associated with that chiral carbon are intended to be encompassed by that structure, both as pure stereoisomers and mixtures thereof.

[0081] The compounds of the present invention can exist as tautomers, i.e., structural isomers that interconvert, particularly in solution, with the compounds of Formula I, II, III, IV, V, or VI depicted herein. Compounds of Formula I, II, III, IV, V, or VI are intended to encompass all tautomeric forms thereof that exist.

[0082] The compounds of the present invention can exist as solvates. The compounds of Formula I, II, III, IV, V, or VI are intended to encompass all solvates thereof which may exist.

[0083] The present invention provides pharmaceutical compositions, methods of using and methods of making the above compounds.

[0084] The compounds of the present invention may have one or more asymmetric centers and therefore may occur as racemates, enantiomeric mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may exist depending on the nature of the various substituents on the molecule. Each such asymmetric center independently gives rise to two optical isomers, and all possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are intended to be included in the present invention. The present invention is intended to encompass all such isomeric forms of these compounds. The independent syntheses of these diastereomers or their chromatographic separations can be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry can be determined by x-ray crystallography of crystalline products or crystalline intermediates that are derivatized, if necessary, with a reagent having an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds can be separated and the individual enantiomers isolated. Resolution can be carried out by methods known in the art, for example by coupling a racemic mixture of a compound to an enantiomerically pure compound to form a diastereomeric mixture, and then separating the individual diastereomers by standard methods such as fractional crystallization or chromatography.

[0085] In embodiments in which optically pure enantiomers are provided, optically pure enantiomer means that the compound contains more than 90% by weight of the desired isomer, particularly more than 95% by weight or more particularly more than 99% by weight of the desired isomer, the weight percentage being based on the total weight of the isomer(s) of the compound. Chirally pure or chirally enriched compounds can be prepared by chirally selective synthesis or by separation of enantiomers. Separation of enantiomers can be carried out on the final product or alternatively on a suitable intermediate.

[0086] Formula I and Formula II Embodiments In certain embodiments, the compound of formula I is [ka] or a pharma- ceutically acceptable salt thereof.

[0087] In certain embodiments, the compound of formula II is [ka] or a pharma- ceutically acceptable salt thereof.

[0088] In certain embodiments, the compounds of the present invention are [ka] or a pharma- ceutically acceptable salt thereof.

[0089] In certain embodiments, the compounds of the present invention are [ka] or a pharma- ceutically acceptable salt thereof.

[0090] In certain embodiments, the compounds of the present invention are [ka] TIFF2024523839000020.tif230170TIFF2024523839000021.tif222170 or a pharma- ceutically acceptable salt thereof.

[0091] In certain embodiments, the compounds of the present invention are [ka] TIFF2024523839000023.tif227170TIFF2024523839000024.tif147170 or a pharma- ceutically acceptable salt thereof.

[0092] In certain embodiments, the compounds of the present invention are [ka] TIFF2024523839000026.tif238170 or a pharma- ceutically acceptable salt thereof.

[0093] In certain embodiments, the compounds of the present invention are [ka] TIFF2024523839000028.tif117170 or a pharma- ceutically acceptable salt thereof.

[0094] In certain embodiments, the compounds of the present invention are [ka] TIFF2024523839000030.tif213170TIFF2024523839000031.tif249170 or a pharma- ceutically acceptable salt thereof.

[0095] In certain embodiments, the compounds of the present invention are [ka] TIFF2024523839000033.tif107170 or a pharma- ceutically acceptable salt thereof.

[0096] In certain embodiments, the compound of formula I: [ka] (In the formula, A1 -NR 2 -and-CHR 2 '- selected from, R 1 is selected from hydrogen, alkyl, and cycloalkyl; R 2 is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with R 2 ' is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 ', together with the carbon atom to which they are attached, represent one or two R 3 forming an optionally substituted cycloalkyl with Each R 3 is independently selected from hydrogen, halogen, alkyl, cycloalkyl, and alkoxy; R 4 is selected from hydrogen, alkyl, cyano, and halogen; R 5 is selected from hydrogen, alkyl, cyano, and halogen; A 2 is selected from -O-, -NH-, and -(C=O)-; R 6 is selected from hydrogen, halogen, hydroxy, amino, dialkylamino, alkoxy, alkyl, and alkoxyalkyl; A 3 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -CH 2 -, -CH 2 -CH(CH3 )-CH 2 -, -CH 2 -CH 2 -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - selected from A is selected from a bond, pyrimidinyl, pyridinyl, pyrazolyl, and 3-azabicyclo[3.1.0]hexyl; B is phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 1 , 1-dioxo-1λ6-thia-8-azaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-methyl-1,8-diazaspiro[4.5]decyl, 1,8-diazaspiro[4.5]decyl, and 8-azaspiro[4.5]decyl, where B is optionally substituted with 1 or 2 substituents independently selected from halogen, alkyl, and alkoxy; n is 0 or 1, A 4 is a bond, -CH 2 -,-(SO 2 )-CH 2 -, -CH(CH 2 -OH)-, -NH-, and -O-; C is selected from azepanyl, azetidinyl, cycloalkyl, piperazinyl, and piperidinyl, where C is optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, alkyl, and alkoxy; R 7 is selected from hydrogen, alkyl, cyano, halogen, and alkoxy; R 8 is selected from hydrogen, alkyl, cyano, halogen, and alkoxy; R 9 is selected from hydrogen, alkyl, cyano, halogen, and alkoxy; A 5 is -CH- or -N-, or a pharma- ceutically acceptable salt thereof.

[0097] One embodiment of the present invention comprises: A 1 But -NR 2 -and-CHR 2 '- selected from, R 1 is selected from hydrogen, alkyl, and cycloalkyl; R 2 is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with R 2 ' is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 ', together with the carbon atom to which they are attached, form one or two R 3 forming an optionally substituted cycloalkyl with Each R 3 is independently selected from hydrogen, halogen, alkyl, cycloalkyl, and alkoxy; R 4 is selected from hydrogen, alkyl, cyano, and halogen; R 5 is selected from hydrogen, alkyl, cyano, and halogen; A 2 is selected from -O-, -NH-, and -(C=O)-; R 6is selected from hydrogen, halogen, hydroxy, amino, dialkylamino, alkoxy, alkyl, and alkoxyalkyl; A 3 is a bond, -CH 2 -, -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 - selected from A is selected from a bond, pyrimidinyl, pyridinyl, pyrazolyl, and 3-azabicyclo[3.1.0]hexyl; B is selected from phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 1,1-dioxo-1λ6-thia-8-azaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-methyl-1,8-diazaspiro[4.5]decyl, 1,8-diazaspiro[4.5]decyl, and 8-azaspiro[4.5]decyl; n is 0 or 1; A 4 is a bond, -CH 2 -,-(SO 2 )-CH 2 -, -CH(CH 2 -OH)-, -NH-, and -O-; C is selected from azetidinyl, cycloalkyl, piperazinyl, halopiperidinyl, hydroxypiperidinyl, and piperidinyl; R 7 is selected from hydrogen, alkyl, cyano, halogen, and alkoxy; R 8 is selected from hydrogen, alkyl, cyano, halogen, and alkoxy; R 9 is selected from hydrogen, alkyl, cyano, halogen, and alkoxy; and A 5is -CH- or -N-, or a pharma- ceutically acceptable salt thereof.

[0098] One embodiment of the present invention comprises: A 1 But -NR 2 -and-CHR 2 '- selected from, R 1 is alkyl, R 2 is selected from alkyl and cycloalkyl; Or R 1 and R 2 together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with R 2 ' is alkyl, Or R 1 and R 2 ' together with the carbon atom to which they are attached form a cycloalkyl, and each R 3 is independently selected from halogen and alkoxy.

[0099] One embodiment of the present invention comprises: A 1 But -NR 2 -and-CHR 2 '- selected from, R 1 is methyl, R 2 is selected from ethyl, tert-butyl and cyclopropyl; Or R 1 and R 2 together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with R 2 ' is methyl, Or R 1 and R 2' together with the carbon atom to which they are attached form a cycloalkyl, and each R 3 is independently selected from fluoro and methoxy.

[0100] The present invention further provides: R 1 is methyl, or a pharma- ceutically acceptable salt thereof; R 2 is selected from ethyl, tert-butyl, and cyclopropyl, or a pharma- ceutically acceptable salt thereof; A 1 Ga-NR 2 or a pharma- ceutically acceptable salt thereof; A 1 -CHR 2 '-, or a pharma- ceutically acceptable salt thereof; R 1 and R 2 and the heterocycloalkyl formed by R 1 , taken together with the nitrogen atom to which they are attached, is selected from pyrrolidinyl, piperidinyl, azetidinyl, and 3-azabicyclo[3.1.0]hexyl, and the heterocycloalkyl is selected from one or two R 2 , each occurrence independently selected from fluoro and methoxy. 3 or a pharma- ceutically acceptable salt thereof, R 1 and R 2 ' together with the carbon atom to which they are attached, the cycloalkyl formed is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; or a pharma- ceutically acceptable salt thereof; Each R 3 is independently selected from fluoro and methoxy, or a pharma- ceutically acceptable salt thereof; R 4 is cyano, or a pharma- ceutically acceptable salt thereof; R 4is fluoro, or a pharma- ceutically acceptable salt thereof; R 5 is halogen, or a pharma- ceutically acceptable salt thereof; R 5 is fluoro, or a pharma- ceutically acceptable salt thereof; A 2 is selected from -O- and -NH-, or a pharma- ceutically acceptable salt thereof; A 2 is -O-, or a pharma- ceutically acceptable salt thereof; A 2 is -NH-, or a pharma- ceutically acceptable salt thereof; R 6 is selected from hydrogen, halogen, hydroxy, amino, alkoxy, and dialkylamino, or a pharma- ceutically acceptable salt thereof; R 6 is selected from hydrogen, fluoro, chloro, hydroxy, amino, methoxy, and dimethylamino, or a pharma- ceutically acceptable salt thereof; A 3 is a bond, -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 or a pharma- ceutically acceptable salt thereof, A 3 is a bond, or a pharma- ceutically acceptable salt thereof; A compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein A is selected from a bond and pyrimidinyl; A compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein A is a bond; A compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein A is pyrimidinyl; A compound of formula I, wherein B is selected from piperidinyl, piperazinyl, 1-oxa-8-azaspiro[4.5]decyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 1,1-dioxo-1λ6-thia-8-azaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-methyl-1,8-diazaspiro[4.5]decyl, and 8-azaspiro[4.5]decyl, or a pharma- ceutically acceptable salt thereof; A compound of formula I, wherein B is selected from piperidin-4-yl, piperazin-1-yl, 1-oxa-8-azaspiro[4.5]decyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 1,1-dioxo-1λ6-thia-8-azaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-methyl-1,8-diazaspiro[4.5]decyl, and 8-azaspiro[4.5]decyl, or a pharma- ceutically acceptable salt thereof; A compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein B is selected from 1-oxa-8-azaspiro[4.5]decyl and 8-azaspiro[4.5]decyl; B is 8-azaspiro[4.5]decyl; or a pharma- ceutically acceptable salt thereof; A 4 is a bond, -CH 2 , - and -(SO 2 )-CH 2 or a pharma- ceutically acceptable salt thereof, A 4 Ga-CH 2 or a pharma- ceutically acceptable salt thereof; A compound of formula I, wherein C is selected from azetidinyl, cyclohexyl, piperazinyl, difluoropiperidinyl, hydroxypiperidinyl, piperidinyl phosphate, and piperidinyl, or a pharma- ceutically acceptable salt thereof; A compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein C is selected from azetidinyl, cyclohexyl, piperazinyl, difluoropiperidinyl, hydroxypiperidinyl, and piperidinyl; A compound of formula I, wherein C is selected from azetidin-1-yl, cyclohexyl, piperazin-1-yl, 3,3-difluoropiperidin-1-yl, 4-hydroxypiperidin-4-yl, piperidin-1-yl, and piperidin-4-yl, or a pharma- ceutically acceptable salt thereof; A compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein C is selected from hydroxypiperidinyl and piperidinyl; A compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein C is selected from hydroxypiperidin-4-yl, piperidin-1-yl, and piperidin-4-yl; R 7 is alkyl, or a pharma- ceutically acceptable salt thereof; R 7 is methyl, or a pharma- ceutically acceptable salt thereof; R 8 is selected from hydrogen and halogen, or a pharma- ceutically acceptable salt thereof; R 8 is selected from hydrogen and fluoro, or a pharma- ceutically acceptable salt thereof; R 9 is selected from hydrogen and halogen, or a pharma- ceutically acceptable salt thereof; R 9 is selected from hydrogen and fluoro, or a pharma- ceutically acceptable salt thereof; A 5 is -NH-, or a pharma- ceutically acceptable salt thereof; A 5 is -CH-, or a pharma- ceutically acceptable salt thereof; A compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein n is 1; and A compound of formula I, or a pharma- ceutically acceptable salt thereof, wherein n is 0.

[0101] The present invention further comprises: 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[1-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]piperidin-4-yl]ethyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[3-[1-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]piperidin-4-yl]propyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[1-[1-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]piperidin-4-yl]pyrazol-4-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[7-[2-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-7-azaspiro[3.5]nonan-2-yl]-4-oxoquinazoline, 3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[7-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-7-azaspiro[3.5]nonan-2-yl]-4-oxoquinazoline, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 9-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-3-[2-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-3-azaspiro[5.5]undecane, 9-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-3-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-3-azaspiro[5.5]undecane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 9-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-3-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-3-azaspiro[5.5]undecane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]-3,3-difluoropiperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]-3,3-difluoropiperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]piperazin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 9-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-3-[2-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]piperazin-1-yl]acetyl]-3-azaspiro[5.5]undecane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]piperazin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-N-[2-cyano-3-[3-[(3R)-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-fluoropyrrolidine-1-sulfonamide, 6-[2-chloro-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, N-[2-cyano-3-[3-[(3R)-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopentanesulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]propane-2-sulfonamide, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]cyclohexyl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]cyclohexyl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[3-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]azetidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-7-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-7-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-5-fluoro-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxypyrrolidine-1-sulfonamide, (3S)—N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxypyrrolidine-1-sulfonamide, (3R)-N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxypyrrolidine-1-sulfonamide, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoroanilino]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-5-(dimethylamino)-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]piperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-5-methoxy-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[5-amino-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoroanilino]-5-fluoro-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[5-chloro-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoroanilino]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-5-hydroxy-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]piperidine-1-sulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclohexanesulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]propane-2-sulfonamide, (3R)-N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-fluoropyrrolidine-1-sulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopentanesulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopropanesulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxyazetidine-1-sulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-azabicyclo[3.1.0]hexane-3-sulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]pyrrolidine-1-sulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]azetidine-1-sulfonamide, (3R)-3-[6-[2-cyano-3-[[cyclopropyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclobutanesulfonamide, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3R)-8-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]piperidin-1-yl]-1-oxaspiro[4.5]decan-3-yl]-4-oxoquinazoline, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-fluoropiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoroanilino]-5-fluoro-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]piperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[(4R)-4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-3,3-difluoropiperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[(4S)-4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-3,3-difluoropiperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-8-[2-[1-[5-chloro-3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1,1-dioxo-1λ6-thia-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3R)-8-[[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]methylsulfonyl]-1-oxaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1,8-diazaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-methyl-1,8-diazaspiro[4.5]decan-3-yl]-4-oxoquinazoline, (3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-3-[6-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluorobenzoyl]-4-oxoquinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[3-[[tert-butyl(methyl)sulfamoyl]amino]-2-cyano-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]cyclohexyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]cyclohexyl]-1-oxa-8-azaspiro[4.5]decane, and (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-propan-2-ylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, or a pharma- ceutically acceptable salt thereof.

[0102] The present invention further comprises: (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxypyrrolidine-1-sulfonamide, (3R)-N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxypyrrolidine-1-sulfonamide, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]piperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoroanilino]-5-fluoro-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]piperidine-1-sulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclohexanesulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]propane-2-sulfonamide, (3R)-N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-fluoropyrrolidine-1-sulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopentanesulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopropanesulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]pyrrolidine-1-sulfonamide, (3R)-3-[6-[2-cyano-3-[[cyclopropyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, and N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclobutanesulfonamide, or a pharma- ceutically acceptable salt thereof.

[0103] The present invention further comprises: A compound of formula I or a pharma- ceutically acceptable salt thereof for use as a therapeutically active substance, A pharmaceutical composition comprising a compound of formula I or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier; The use of a compound of formula I or a pharma- ceutically acceptable salt thereof for the therapeutic and / or prophylactic treatment of cancer, A compound of formula I or a pharma- ceutically acceptable salt thereof for use in the treatment and / or prevention of cancer. Use of a compound of formula I or a pharma- ceutically acceptable salt thereof for the preparation of a medicament for the therapeutic and / or prophylactic treatment of cancer, A method for the therapeutic and / or prophylactic treatment of cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula I or a pharma- ceutically acceptable salt thereof; Provide 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 is targeted therapy naive, and In some embodiments, the cancer is selected from melanoma, colorectal cancer, and lung cancer, particularly non-small cell lung cancer.

[0104] In certain embodiments, the compounds of the present invention are [ka] or a pharma- ceutically acceptable salt thereof.

[0105] In certain embodiments, the compounds of the present invention are [ka] or a pharma- ceutically acceptable salt thereof.

[0106] Additional Embodiments of Formula I 1. Formula I: [ka] (In the formula, A 1 -NR 2 -and-CHR 2 '- selected from, R 1 is selected from hydrogen, alkyl, and cycloalkyl; R 2 is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with R 2 ' is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 ', together with the carbon atom to which they are attached, represent one or two R 3 forming an optionally substituted cycloalkyl with Each R 3 is independently selected from hydrogen, halogen, alkyl, cycloalkyl, and alkoxy; R 4 is selected from hydrogen, alkyl, cyano, and halogen; R 5 is selected from hydrogen, alkyl, cyano, and halogen; A 2 is selected from -O-, -NH-, and -(C=O)-; R 6 is selected from hydrogen, halogen, hydroxy, amino, dialkylamino, alkoxy, alkyl, and alkoxyalkyl; A 3 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CH2 -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -CH 2 -, -CH 2 -CH(CH 3 )-CH 2 -, -CH 2 -CH 2 -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - selected from A is selected from a bond, pyrimidinyl, pyridinyl, pyrazolyl, and 3-azabicyclo[3.1.0]hexyl; B is phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 1 , 1-dioxo-1λ6-thia-8-azaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-methyl-1,8-diazaspiro[4.5]decyl, 1,8-diazaspiro[4.5]decyl, and 8-azaspiro[4.5]decyl, where B is optionally substituted with 1 or 2 substituents independently selected from halogen, alkyl, and alkoxy; n is 0 or 1, A 4 is a bond, -CH 2 -,-(SO 2 )-CH 2 -, -CH(CH 2 -OH)-, -NH-, and -O-; C is selected from azepanyl, azetidinyl, cycloalkyl, piperazinyl, and piperidinyl, where C is optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, alkyl, and alkoxy; R 7 is selected from hydrogen, alkyl, cyano, halogen, and alkoxy; R 8 is selected from hydrogen, alkyl, cyano, halogen, and alkoxy; R 9 is selected from hydrogen, alkyl, cyano, halogen, and alkoxy; A 5 is -CH- or -N-, or a pharma- ceutically acceptable salt thereof.

[0107] 2.A 1 But -NR 2 -and-CHR 2 '- selected from, R 1 is selected from hydrogen, alkyl, and cycloalkyl; R 2 is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with R 2 ' is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 ', together with the carbon atom to which they are attached, form one or two R 3 forming an optionally substituted cycloalkyl with Each R 3 is independently selected from hydrogen, halogen, alkyl, cycloalkyl, and alkoxy; R 4 is selected from hydrogen, alkyl, cyano, and halogen; R 5 is selected from hydrogen, alkyl, cyano, and halogen; A 2 is selected from -O-, -NH-, and -(C=O)-; R 6 is selected from hydrogen, halogen, hydroxy, amino, dialkylamino, alkoxy, alkyl, and alkoxyalkyl; A 3 is a bond, -CH 2 -, -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 - selected from A is selected from a bond, pyrimidinyl, pyridinyl, pyrazolyl, and 3-azabicyclo[3.1.0]hexyl; B is selected from phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 1,1-dioxo-1λ6-thia-8-azaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-methyl-1,8-diazaspiro[4.5]decyl, 1,8-diazaspiro[4.5]decyl, and 8-azaspiro[4.5]decyl; n is 0 or 1; A 4 is a bond, -CH 2 -,-(SO 2 )-CH 2 -, -CH(CH 2 -OH)-, -NH-, and -O-; C is selected from azetidinyl, cycloalkyl, piperazinyl, halopiperidinyl, hydroxypiperidinyl, and piperidinyl; R 7 is selected from hydrogen, alkyl, cyano, halogen, and alkoxy; R 8is selected from hydrogen, alkyl, cyano, halogen, and alkoxy; R 9 is selected from hydrogen, alkyl, cyano, halogen, and alkoxy; and A 5 is -CH- or -N-; or a pharma- ceutically acceptable salt thereof.

[0108] 3.A 1 But -NR 2 -and-CHR 2 '- selected from, R 1 is alkyl, R 2 is selected from alkyl and cycloalkyl; Or R 1 and R 2 together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with R 2 ' is alkyl, Or R 1 and R 2 ' together with the carbon atom to which they are attached form a cycloalkyl, and each R 3 The compound of embodiment 1 or 2, wherein is independently selected from halogen and alkoxy.

[0109] 4.A 1 But -NR 2 -and-CHR 2 '- selected from, R 1 is methyl, R 2 is selected from ethyl, tert-butyl and cyclopropyl; Or R 1 and R 2 together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with R 2' is methyl, Or R 1 and R 2 ' together with the carbon atom to which they are attached form a cycloalkyl, and each R 3 The compound of any one of embodiments 1-3, wherein is independently selected from fluoro and methoxy.

[0110] 5.R 1 The compound of any one of embodiments 1-4, wherein is methyl.

[0111] 6.R 2 The compound of any one of embodiments 1-5, wherein is selected from ethyl, tert-butyl, and cyclopropyl.

[0112] 7.A 1 Ga-NR 2 -.

[0113] 8.A 1 -CHR 2 The compound of any one of embodiments 1-6, wherein R is 1'-.

[0114] 9.R 1 and R 2 and the heterocycloalkyl formed by R 1 , taken together with the nitrogen atom to which they are attached, is selected from pyrrolidinyl, piperidinyl, azetidinyl, and 3-azabicyclo[3.1.0]hexyl, and the heterocycloalkyl is selected from one or two R 2 , each occurrence independently selected from fluoro and methoxy. 3 The compound of any one of embodiments 1-8, optionally substituted with:

[0115] 10.R 1 and R 2 Compounds according to any one of embodiments 1-9, wherein cycloalkyl, formed by ' taken together with the carbon atom to which they are attached, is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0116] 11.Each R 3 The compound of any one of embodiments 1-10, wherein is independently selected from fluoro and methoxy.

[0117] 12.R 4 The compound of any one of embodiments 1-11, wherein is cyano.

[0118] 13.R 5 The compound of any one of embodiments 1-12, wherein is halogen.

[0119] 14.R 5 The compound of any one of embodiments 1-13, wherein is fluoro.

[0120] 15.A 2 The compound of any one of embodiments 1-14, wherein is selected from -O- and -NH-.

[0121] 16.A 2 The compound of any one of embodiments 1-15, wherein is -O-.

[0122] 17.R 6 The compound of any one of embodiments 1-16, wherein is selected from hydrogen, halogen, hydroxy, amino, alkoxy, and dialkylamino.

[0123] 18.R 6 The compound of any one of embodiments 1-17, wherein is selected from hydrogen, fluoro, chloro, hydroxy, amino, methoxy, and dimethylamino.

[0124] 19.A 3 is a bond, -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 -,

[0125] 20.A 3 The compound of any one of embodiments 1-19, wherein is a bond.

[0126] 21. A compound according to any one of embodiments 1-20, wherein A is selected from a bond and pyrimidinyl.

[0127] 22. The compound according to any one of embodiments 1-21, wherein A is a bond.

[0128] 23. The compound according to any one of embodiments 1 to 22, wherein B is selected from piperidinyl, piperazinyl, 1-oxa-8-azaspiro[4.5]decyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 1,1-dioxo-1λ6-thia-8-azaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-methyl-1,8-diazaspiro[4.5]decyl, and 8-azaspiro[4.5]decyl.

[0129] 24. The compound according to any one of embodiments 1-23, wherein B is selected from 1-oxa-8-azaspiro[4.5]decyl and 8-azaspiro[4.5]decyl.

[0130] 25.A 4 is a bond, -CH 2 , - and -(SO 2 )-CH 2 -,

[0131] 26.A 4 Ga-CH 2 -.

[0132] 27. The compound according to any one of the preceding embodiments, wherein C is selected from azetidinyl, cyclohexyl, piperazinyl, difluoropiperidinyl, hydroxypiperidinyl, and piperidinyl.

[0133] 28. A compound according to any one of embodiments 1-27, wherein C is selected from hydroxypiperidinyl and piperidinyl.

[0134] 29.R 7 The compound of any one of embodiments 1-28, wherein is alkyl.

[0135] 30.R 7 The compound of any one of embodiments 1-29, wherein is methyl.

[0136] 31.R 8 The compound of any one of embodiments 1-30, wherein is selected from hydrogen and halogen.

[0137] 32.R 8 The compound according to any one of embodiments 1-31, wherein is selected from hydrogen and fluoro.

[0138] 33.R 9 The compound of any one of embodiments 1-32, wherein is selected from hydrogen and halogen.

[0139] 34.R 9 The compound of any one of embodiments 1-33, wherein is selected from hydrogen and fluoro.

[0140] 35.A 5 The compound of any one of embodiments 1-34, wherein is -NH-.

[0141] 36.A 5 The compound of any one of embodiments 1-34, wherein is -CH-.

[0142] 37. The compound according to any one of the preceding embodiments, wherein n is 1.

[0143] 38. 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[1-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]piperidin-4-yl]ethyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[3-[1-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]piperidin-4-yl]propyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[1-[1-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]piperidin-4-yl]pyrazol-4-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[7-[2-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-7-azaspiro[3.5]nonan-2-yl]-4-oxoquinazoline, 3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[7-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-7-azaspiro[3.5]nonan-2-yl]-4-oxoquinazoline, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 9-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-3-[2-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-3-azaspiro[5.5]undecane, 9-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-3-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-3-azaspiro[5.5]undecane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 9-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-3-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-3-azaspiro[5.5]undecane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]-3,3-difluoropiperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]-3,3-difluoropiperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]piperazin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 9-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-3-[2-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]piperazin-1-yl]acetyl]-3-azaspiro[5.5]undecane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]piperazin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-N-[2-cyano-3-[3-[(3R)-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-fluoropyrrolidine-1-sulfonamide, 6-[2-chloro-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, N-[2-cyano-3-[3-[(3R)-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopentanesulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]propane-2-sulfonamide, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]cyclohexyl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]cyclohexyl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[3-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]azetidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-7-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-7-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-5-fluoro-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxypyrrolidine-1-sulfonamide, (3S)—N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxypyrrolidine-1-sulfonamide, (3R)-N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxypyrrolidine-1-sulfonamide, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoroanilino]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-5-(dimethylamino)-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]piperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-5-methoxy-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[5-amino-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoroanilino]-5-fluoro-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[5-chloro-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoroanilino]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-5-hydroxy-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]piperidine-1-sulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclohexanesulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]propane-2-sulfonamide, (3R)-N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-fluoropyrrolidine-1-sulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopentanesulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopropanesulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxyazetidine-1-sulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-azabicyclo[3.1.0]hexane-3-sulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]pyrrolidine-1-sulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]azetidine-1-sulfonamide, (3R)-3-[6-[2-cyano-3-[[cyclopropyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclobutanesulfonamide, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3R)-8-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]piperidin-1-yl]-1-oxaspiro[4.5]decan-3-yl]-4-oxoquinazoline, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-fluoropiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoroanilino]-5-fluoro-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]piperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[(4R)-4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-3,3-difluoropiperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[(4S)-4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-3,3-difluoropiperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-8-[2-[1-[5-chloro-3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1,1-dioxo-1λ6-thia-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3R)-8-[[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]methylsulfonyl]-1-oxaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1,8-diazaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-methyl-1,8-diazaspiro[4.5]decan-3-yl]-4-oxoquinazoline, (3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-3-[6-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluorobenzoyl]-4-oxoquinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[3-[[tert-butyl(methyl)sulfamoyl]amino]-2-cyano-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]cyclohexyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]cyclohexyl]-1-oxa-8-azaspiro[4.5]decane, and (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-propan-2-ylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, or a pharma- ceutically acceptable salt thereof.

[0144] 39. (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[3-(2,6-dioxopiperidin-3-yl)-1-methylindazol-6-yl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxypyrrolidine-1-sulfonamide, (3R)-N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxypyrrolidine-1-sulfonamide, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]piperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoroanilino]-5-fluoro-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]piperidine-1-sulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclohexanesulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]propane-2-sulfonamide, (3R)-N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-fluoropyrrolidine-1-sulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopentanesulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopropanesulfonamide, N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]pyrrolidine-1-sulfonamide, (3R)-3-[6-[2-cyano-3-[[cyclopropyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, and N-[2-cyano-3-[3-[(3R)-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclobutanesulfonamide, or a pharma- ceutically acceptable salt thereof.

[0145] 40. A compound according to any one of embodiments 1-39 or a pharma- ceutically acceptable salt thereof for use as a therapeutically active substance.

[0146] 41. A pharmaceutical composition comprising a compound according to any one of embodiments 1-39 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0147] 42. Use of a compound according to any one of embodiments 1 to 39 or a pharma- ceutically acceptable salt thereof for the therapeutic and / or prophylactic treatment of cancer.

[0148] 43. A compound according to any of embodiments 1-39 or a pharma- ceutically acceptable salt thereof for use in the treatment and / or prevention of cancer.

[0149] 44. Use of a compound according to any one of embodiments 1 to 39 or a pharma- ceutically acceptable salt thereof for the preparation of a medicament for the therapeutic and / or prophylactic treatment of cancer.

[0150] 45. A method for the therapeutic and / or prophylactic treatment of cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of embodiments 1-39 or a pharma- ceutically acceptable salt thereof.

[0151] 46. ​​The invention described herein.

[0152] Formula III and Formula IV Embodiments In certain embodiments, the compound of formula III has formula III-A: [ka] (In the formula, A 2 is -O-, n is 1, and R 4is cyano, and the remaining substituents and variables are as described herein, or a pharma- ceutically acceptable salt thereof.

[0153] In certain embodiments, the compound of formula III has formula III-B: [ka] (In the formula, A 2 is -NH-, n is 1, and R 4 is cyano and R 5 is fluoro, and the remaining substituents and variables are as described herein, or a pharma- ceutically acceptable salt thereof.

[0154] In certain embodiments, the compound of formula III has formula III-C: [ka] (In the formula, A 1 Ha-NR 2 - and A 2 is -O-, n is 1, and A 14 Ha-CH 2 - and A 15 is -NH-, and A 6 is -CH-, and the remaining substituents and variables are as described herein, or a pharma- ceutically acceptable salt thereof.

[0155] In certain embodiments, the compound of formula IV is [ka] or a pharma- ceutically acceptable salt thereof.

[0156] In certain embodiments, the compound of formula III: [ka] (In the formula, A 1 -NR 2-and-CHR 2 '- selected from, R 1 is selected from hydrogen, alkyl, and cycloalkyl; R 2 is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with R 2 ' is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 ', together with the carbon atom to which they are attached, represent one or two R 3 forming an optionally substituted cycloalkyl with Each R 3 is independently selected from hydrogen, halogen, alkyl, cycloalkyl, and alkoxy; R 4 is selected from hydrogen, alkyl, cyano, and halogen; R 5 is selected from hydrogen, alkyl, cyano, and halogen; A 2 is selected from -O-, -NH-, and -(C=O)-; R 6 is selected from hydrogen, halogen, hydroxy, amino, dialkylamino, alkoxy, alkyl, and alkoxyalkyl; A 3 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -CH 2 -, -CH 2 -CH(CH 3 )-CH 2 -, -CH2 -CH 2 -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - selected from A is selected from a bond, pyrimidinyl, pyridinyl, pyrazolyl, and 3-azabicyclo[3.1.0]hexyl; B2 is selected from phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, and 8-azaspiro[4.5]decyl, where B2 is optionally substituted with 1 or 2 substituents independently selected from halogen, alkyl, and alkoxy; n is 0 or 1, A 14 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CH(CH 2 -OH)-, -NH-, -O-, cycloalkyl, and alkylamino; C is selected from azepanyl, azetidinyl, cycloalkyl, piperazinyl, and piperidinyl, where C is optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, alkyl, and alkoxy; R 17 is selected from hydrogen, alkyl, cyano, hydroxy, cycloalkyl, halogen, and alkoxy; R 18 is selected from hydrogen, alkyl, cyano, hydroxy, cycloalkyl, halogen, and alkoxy; R 19is selected from hydrogen, alkyl, cyano, hydroxy, cycloalkyl, halogen, and alkoxy; A 15 is selected from a bond, -O-, and -NH-; and A 6 is -CH- or -N-, or a pharma- ceutically acceptable salt thereof.

[0157] In certain aspects, the present invention provides a method for producing a composition comprising: A 1 Ga-NR 2 -and-CHR 2 '- selected from, R 1 is selected from hydrogen, alkyl, and cycloalkyl; R 2 is selected from alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with R 2 ' is selected from alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 ', together with the carbon atom to which they are attached, form one or two R 3 forming an optionally substituted cycloalkyl with Each R 3 is independently selected from hydrogen, halogen, and alkoxy; R 4 is selected from hydrogen, alkyl, cyano, and halogen; R 5 is selected from hydrogen, alkyl, cyano, and halogen; A 2 is selected from -O-, -NH-, and -(C=O)-; R 6 is selected from hydrogen, halogen, hydroxy, amino, dialkylamino, alkoxy, alkyl, and alkoxyalkyl; A 3 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -CH 2 -, -CH 2 -CH(CH 3 )-CH 2 -, -CH 2 -CH 2 -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - selected from A is selected from a bond, pyrimidinyl, pyridinyl, pyrazolyl, and 3-azabicyclo[3.1.0]hexyl; B2 is selected from phenyl, piperidinyl, piperazinyl, halopiperidinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, and 8-azaspiro[4.5]decyl; n is 0 or 1; A 14 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CH(CH 2 -OH)-, -NH-, -O-, cycloalkyl, and alkylamino; C is selected from azepanyl, azetidinyl, cycloalkyl, halopiperidinyl, hydroxypiperidinyl, alkoxypiperidinyl, piperazinyl, and piperidinyl; R 17 is selected from hydrogen, halogen, and alkoxy; R 18 is selected from hydrogen, halogen, and alkoxy; R 19 is selected from hydrogen, halogen, and alkoxy; A 15 is selected from a bond, -O-, and -NH-; and A 6 is -CH- or -N-, or a pharma- ceutically acceptable salt thereof.

[0158] In another embodiment of the present invention, A 1 Ga-NR 2 -and-CHR 2 '- selected from, R 1 is alkyl, R 2 is selected from alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with R 2 ' is alkyl, Or R 1 and R 2 ' together with the carbon atom to which they are attached form a cycloalkyl, Each R 3 is independently selected from halogen and alkoxy.

[0159] One embodiment of the present invention comprises: A 1 Ga-NR 2 -and-CHR 2 '- selected from, R 1 is methyl, R 2is selected from ethyl, fluoroethyl, difluoroethyl, and cyclopropyl; Or R 1 and R 2 together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with R 2 ' is alkyl, Or R 1 and R 2 ' together with the carbon atom to which they are attached form a cycloalkyl, and each R 3 is independently selected from fluoro and methoxy.

[0160] Further embodiments of the present invention provide: R 1 is methyl, or a pharma- ceutically acceptable salt thereof; R 2 is selected from ethyl, fluoroethyl, difluoroethyl, and cyclopropyl, or a pharma- ceutically acceptable salt thereof; A 1 Ga-NR 2 or a pharma- ceutically acceptable salt thereof; A 1 -CHR 2 '-, or a pharma- ceutically acceptable salt thereof; R 1 and R 2 and the heterocycloalkyl formed by R 1 , taken together with the nitrogen atom to which they are attached, is selected from pyrrolidinyl, piperidinyl, azetidinyl, and 3-azabicyclo[3.1.0]hexyl, and the heterocycloalkyl is selected from one or two R 2 , each occurrence independently selected from fluoro and methoxy. 3 or a pharma- ceutically acceptable salt thereof, R 1 and R 2' together with the carbon atom to which they are attached, the cycloalkyl formed is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; or a pharma- ceutically acceptable salt thereof; Each R 3 is independently selected from fluoro and methoxy, or a pharma- ceutically acceptable salt thereof; R 4 is cyano, or a pharma- ceutically acceptable salt thereof; R 5 is selected from cyano and halogen, or a pharma- ceutically acceptable salt thereof; R 5 is selected from cyano and fluoro, or a pharma- ceutically acceptable salt thereof; R 5 is selected from hydrogen and halogen, or a pharma- ceutically acceptable salt thereof; R 5 is selected from hydrogen and fluoro, or a pharma- ceutically acceptable salt thereof; R 5 is halogen, or a pharma- ceutically acceptable salt thereof; R 5 is fluoro, or a pharma- ceutically acceptable salt thereof; R 5 is cyano, or a pharma- ceutically acceptable salt thereof; A 2 is selected from -O- and -NH-, or a pharma- ceutically acceptable salt thereof; A 2 is -O-, or a pharma- ceutically acceptable salt thereof; R 6 is selected from hydrogen, fluoro, chloro, bromo, hydroxy, amino, methoxy, methyl, and methoxymethyl, or a pharma- ceutically acceptable salt thereof; R 6 is hydrogen, or a pharma- ceutically acceptable salt thereof; A3 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -CH 2 -, -CH 2 -CH(CH 3 )-CH 2 - and -CH 2 -CH 2 -CH(CH 3 )-, or a pharma- ceutically acceptable salt thereof; A 3 is a bond, or a pharma- ceutically acceptable salt thereof; A compound of formula III, or a pharma- ceutically acceptable salt thereof, wherein A is selected from a bond, pyridinyl, and pyrimidinyl; A compound of formula III, wherein B2 is selected from phenyl, piperidin-4-yl, 4-fluoro-piperidin-4-yl, piperazin-1-yl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, and 8-azaspiro[4.5]decyl, or a pharma- ceutically acceptable salt thereof; A compound of formula III, or a pharma- ceutically acceptable salt thereof, wherein B2 is selected from phenyl, piperidinyl, piperazinyl, 1-oxa-8-azaspiro[4.5]decyl, 7-azaspiro[3.5]nonyl, and 8-azaspiro[4.5]decyl; A compound of formula III, wherein B2 is selected from phenyl, piperidin-4-yl, piperazin-1-yl, 1-oxa-8-azaspiro[4.5]decyl, 7-azaspiro[3.5]nonyl, and 8-azaspiro[4.5]decyl, or a pharma- ceutically acceptable salt thereof; A compound of formula III, or a pharma- ceutically acceptable salt thereof, wherein B2 is selected from piperazinyl and 1-oxa-8-azaspiro[4.5]decyl; A compound of formula III, or a pharma- ceutically acceptable salt thereof, wherein B2 is selected from piperazin-1-yl and 1-oxa-8-azaspiro[4.5]decyl; A 14 Ga-CH 2 or a pharma- ceutically acceptable salt thereof; A compound of formula III, wherein C is selected from azepan-1-yl, azetidin-1-yl, cycloalkyl, piperazin-1-yl, piperazin-1-yl, piperidin-4-yl, 4-hydroxypiperidin-4-yl, 3,3-difluoropiperidin-1-yl, and 3-methoxypiperidin-1-yl, or a pharma- ceutically acceptable salt thereof; A compound of formula III, or a pharma- ceutically acceptable salt thereof, wherein C is selected from difluoropiperidinyl, hydroxypiperidinyl, methoxypiperidinyl, piperazinyl, and piperidinyl; A compound of formula III, or a pharma- ceutically acceptable salt thereof, wherein C is selected from difluoropiperidinyl, hydroxypiperidinyl, methoxypiperidinyl, piperazinyl, and piperidinyl; C is piperidin-1-yl; or a pharma- ceutically acceptable salt thereof; R 17 is selected from hydrogen, fluoro, and methoxy, or a pharma- ceutically acceptable salt thereof; R 17 is fluoro, or a pharma- ceutically acceptable salt thereof; R 18 is selected from hydrogen and fluoro, or a pharma- ceutically acceptable salt thereof; R 18 is hydrogen, or a pharma- ceutically acceptable salt thereof; R 19 is selected from hydrogen, fluoro, and methoxy, or a pharma- ceutically acceptable salt thereof; R 19is hydrogen, or a pharma- ceutically acceptable salt thereof; A 15 is -NH-, or a pharma- ceutically acceptable salt thereof; A 15 is -CH-, or a pharma- ceutically acceptable salt thereof; A compound of formula III, or a pharma- ceutically acceptable salt thereof, wherein n is 1; and A compound of formula III, or a pharma- ceutically acceptable salt thereof, wherein n is 0.

[0161] In one embodiment, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]ethyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[1-[2-[4-[4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]ethyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-3-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]ethyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[3-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]phenyl]piperidin-1-yl]acetyl]piperidin-4-yl]propyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[3-[1-[2-[4-[4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]propyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[3-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]propyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[3-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]phenyl]piperidin-1-yl]-2-oxoethyl]piperidin-4-yl]propyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]ethyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]phenyl]piperidin-1-yl]acetyl]piperazin-1-yl]ethyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[4-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]butan-2-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[3-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]butyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[3-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-4-methylpiperidin-4-yl]propyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-4-fluoropiperidin-4-yl]ethyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[3-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]-2-methylpropyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[3-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-4-fluoropiperidin-4-yl]propyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[1-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]pyrazol-4-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[1-[1-[2-[4-[4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]pyrazol-4-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[1-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]phenyl]piperidin-1-yl]acetyl]piperidin-4-yl]pyrazol-4-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[1-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-3-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]pyrazol-4-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[1-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2,6-difluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]pyrazol-4-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[1-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]phenyl]piperidin-1-yl]-2-oxoethyl]piperidin-4-yl]pyrazol-4-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[7-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-7-azaspiro[3.5]nonan-2-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[7-[2-[1-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]-4-hydroxypiperidin-4-yl]acetyl]-7-azaspiro[3.5]nonan-2-yl]-4-oxoquinazoline, 3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[3-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-3-azabicyclo[3.1.0]hexan-6-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]phenoxy]-3-[7-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-7-azaspiro[3.5]nonan-2-yl]-4-oxoquinazoline, 3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 4-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-9-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-9-azaspiro[5.5]undecane, 9-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-3-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-3-azaspiro[5.5]undecane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[[7-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-7-azaspiro[3.5]nonan-2-yl]methyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-2-azaspiro[4.5]decan-8-yl]-4-oxoquinazoline, (3S)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 4-[6-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-N-[1-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-4-yl]benzamide, 3-[[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]methyl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-N-[1-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-4-yl]-7-azaspiro[3.5]nonane-7-carboxamide, 3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-N-[1-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-4-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxamide, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[7-[3-[3-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]azetidin-1-yl]cyclobutanecarbonyl]-7-azaspiro[3.5]nonan-2-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3R)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3R)-8-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3R)-8-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperazin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, (3R)-N-[2-cyano-3-[3-[(3R)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-fluoropyrrolidine-1-sulfonamide, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperazin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-5-fluoro-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-5-fluoro-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-3-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-3-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl]piperazin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, N-[2-cyano-3-[3-[(3R)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopentanesulfonamide, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-5-methyl-4-oxoquinazoline, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]-3,3-difluoropiperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-5-methyl-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl]piperazin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, N-[2-cyano-3-[3-[(3R)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]propane-2-sulfonamide, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2,5-difluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2,3-difluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2,3-difluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl]-3,3-difluoropiperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl]-3,3-difluoropiperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2,5-difluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 3-[5-bromo-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 5-bromo-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 5-chloro-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 3-[5-chloro-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-5-fluoro-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[5-bromo-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3S)-3-[5-bromo-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluoro-5-methoxyphenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]azepan-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[5-chloro-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3S)-3-[5-chloro-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 5-chloro-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 5-chloro-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3R)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 3-[5-amino-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoroanilino]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]cyclohexyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[6-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyridin-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-5-fluoro-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[6-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluoro-6-methoxyphenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyridin-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluoro-5-methoxyphenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluoro-6-methoxyphenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[6-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluoro-5-methoxyphenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyridin-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]-3-hydroxypropanoyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[6-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyridin-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[6-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyridin-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, (3R)—N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxypyrrolidine-1-sulfonamide, (3R)-N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxypyrrolidine-1-sulfonamide, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[(2S)-2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]-3-hydroxypropanoyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-5-methoxy-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-5-methoxy-4-oxoquinazoline, 5-amino-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 5-amino-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[(3R,4R)-4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]-3-methoxypiperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[(3S,4S)-4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]-3-methoxypiperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclohexanesulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]piperidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]pyrrolidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopentanesulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopentanesulfonamide, (3S)—N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxypyrrolidine-1-sulfonamide, (3S)-N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxypyrrolidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]propane-2-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]piperidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopropanesulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopropanesulfonamide, (3R)—N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-fluoropyrrolidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxyazetidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]propane-2-sulfonamide, 6-[2-cyano-3-[[2,2-difluoroethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-6-fluoro-3-[[2-fluoroethyl(methyl)sulfamoyl]amino]phenoxy]-3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-6-fluoro-3-[[2-fluoroethyl(methyl)sulfamoyl]amino]phenoxy]-3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[2,2-difluoroethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3,3-difluoropyrrolidine-1-sulfonamide, (3R)-N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-fluoropyrrolidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]azetidine-1-sulfonamide, 6-[2-cyano-3-[[cyclopropyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[cyclopropyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, (1S,5R)-N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-azabicyclo[3.1.0]hexane-3-sulfonamide, (3R,4R)—N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3,4-difluoropyrrolidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]azetidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclobutanesulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclobutanesulfonamide, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-5-(methoxymethyl)-4-oxoquinazoline, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]cyclohexyl]-1-oxa-8-azaspiro[4.5]decane, N-[3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-2,4-difluorophenyl]cyclopentanesulfonamide, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-5-(methoxymethyl)-4-oxoquinazoline, 3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-6-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluorophenoxy]-4-oxoquinazoline, 3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-6-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluorophenoxy]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-5-hydroxy-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-5-hydroxy-4-oxoquinazoline, 3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-6-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluorobenzoyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]ethyl]-4-oxo-quinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]ethyl]-4-oxo-quinazoline, N-[2-cyano-3-[3-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]ethyl]-4-oxo-quinazolin-6-yl]oxy-4-fluoro-phenyl]cyclopentanesulfonamide, 6-[3-[[tert-butyl(methyl)sulfamoyl]amino]-2-cyano-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, and 6-[3-[[tert-butyl(methyl)sulfamoyl]amino]-2-cyano-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, or a pharma- ceutically acceptable salt thereof.

[0162] One embodiment of the present invention comprises: (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, (3R)-N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxypyrrolidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]pyrrolidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopentanesulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]propane-2-sulfonamide, and N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopropanesulfonamide, or a pharma- ceutically acceptable salt thereof.

[0163] The present invention further comprises: A compound of formula III or a pharma- ceutically acceptable salt thereof for use as a therapeutically active substance, a pharmaceutical composition comprising a compound of formula III or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier; Use of a compound of formula III or a pharma- ceutically acceptable salt thereof for the therapeutic and / or prophylactic treatment of cancer, A compound of formula III or a pharma- ceutically acceptable salt thereof for use in the treatment and / or prevention of cancer: Use of a compound of formula III or a pharma- ceutically acceptable salt thereof for the preparation of a medicament for the therapeutic and / or prophylactic treatment of cancer, A method for the therapeutic and / or prophylactic treatment of cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula III or a pharma- ceutically acceptable salt thereof; In regards to 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 is targeted therapy naive, and In some embodiments, the cancer is selected from melanoma, colorectal cancer, and lung cancer, particularly non-small cell lung cancer.

[0164] Additional Embodiments of Formula III 1.Formula III: [ka] (In the formula, A 1 -NR 2 -and-CHR 2 '- selected from, R 1 is selected from hydrogen, alkyl, and cycloalkyl; R 2 is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with R 2 ' is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 ', together with the carbon atom to which they are attached, represent one or two R 3 forming an optionally substituted cycloalkyl with Each R 3 is independently selected from hydrogen, halogen, alkyl, cycloalkyl, and alkoxy; R 4 is selected from hydrogen, alkyl, cyano, and halogen; R 5 is selected from hydrogen, alkyl, cyano, and halogen; A 2 is selected from -O-, -NH-, and -(C=O)-; R 6 is selected from hydrogen, halogen, hydroxy, amino, dialkylamino, alkoxy, alkyl, and alkoxyalkyl; A 3 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -CH 2 -, -CH 2 -CH(CH 3 )-CH 2 -, -CH 2 -CH 2 -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - selected from A is selected from a bond, pyrimidinyl, pyridinyl, pyrazolyl, and 3-azabicyclo[3.1.0]hexyl; B2 is selected from phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, and 8-azaspiro[4.5]decyl, where B2 is optionally substituted with 1 or 2 substituents independently selected from halogen, alkyl, and alkoxy; n is 0 or 1, A 14 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CH(CH 2 -OH)-, -NH-, -O-, cycloalkyl, and alkylamino; C is selected from azepanyl, azetidinyl, cycloalkyl, piperazinyl, and piperidinyl, where C is optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, alkyl, and alkoxy; R 17 is selected from hydrogen, alkyl, cyano, hydroxy, cycloalkyl, halogen, and alkoxy; R 18 is selected from hydrogen, alkyl, cyano, hydroxy, cycloalkyl, halogen, and alkoxy; R 19 is selected from hydrogen, alkyl, cyano, hydroxy, cycloalkyl, halogen, and alkoxy; A 15 is selected from a bond, -O-, and -NH-; and A 6 is -CH- or -N-, or a pharma- ceutically acceptable salt thereof.

[0165] 2.A 1 Ga-NR 2 -and-CHR 2 '- selected from, R 1 is selected from hydrogen, alkyl, and cycloalkyl; R 2 is selected from alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with R 2 ' is selected from alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 ', together with the carbon atom to which they are attached, form one or two R 3 forming an optionally substituted cycloalkyl with Each R 3is independently selected from hydrogen, halogen, and alkoxy; R 4 is selected from hydrogen, alkyl, cyano, and halogen; R 5 is selected from hydrogen, alkyl, cyano, and halogen; A 2 is selected from -O-, -NH-, and -(C=O)-; R 6 is selected from hydrogen, halogen, hydroxy, amino, dialkylamino, alkoxy, alkyl, and alkoxyalkyl; A 3 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -CH 2 -, -CH 2 -CH(CH 3 )-CH 2 -, -CH 2 -CH 2 -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - selected from A is selected from a bond, pyrimidinyl, pyridinyl, pyrazolyl, and 3-azabicyclo[3.1.0]hexyl; B2 is selected from phenyl, piperidinyl, piperazinyl, halopiperidinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, and 8-azaspiro[4.5]decyl; n is 0 or 1, A 14 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CH(CH 2 -OH)-, -NH-, -O-, cycloalkyl, and alkylamino; C is selected from azepanyl, azetidinyl, cycloalkyl, halopiperidinyl, hydroxypiperidinyl, alkoxypiperidinyl, piperazinyl, and piperidinyl; R 17 is selected from hydrogen, halogen, and alkoxy; R 18 is selected from hydrogen, halogen, and alkoxy; R 19 is selected from hydrogen, halogen, and alkoxy; A 15 is selected from a bond, -O-, and -NH-; and A 6 is -CH- or -N-, or a pharma- ceutically acceptable salt thereof.

[0166] 3.A 1 Ga-NR 2 -and-CHR 2 '- selected from, R 1 is alkyl, R 2 is selected from alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with R 2 ' is alkyl, Or R 1 and R 2 ' together with the carbon atom to which they are attached form a cycloalkyl, and each R 3 The compound of embodiment 1 or 2, wherein is independently selected from halogen and alkoxy.

[0167] 4.A 1 Ga-NR 2 -and-CHR 2 '- selected from, R 1 is methyl, R 2 is selected from ethyl, fluoroethyl, difluoroethyl, and cyclopropyl; Or R 1 and R 2 together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with R 2 ' is alkyl, Or R 1 and R 2 ' together with the carbon atom to which they are attached form a cycloalkyl, and each R 3 The compound of any one of embodiments 1-3, wherein is independently selected from fluoro and methoxy.

[0168] 5.R 1 The compound of any one of embodiments 1-4, wherein is methyl.

[0169] 6.R 2 The compound of any one of embodiments 1-5, wherein is selected from ethyl, fluoroethyl, difluoroethyl, and cyclopropyl.

[0170] 7.A1 Ga-NR 2 -.

[0171] 8.A 1 -CHR 2 The compound of any one of embodiments 1-6, wherein R is 1'-.

[0172] 9.R 1 R 2 and the heterocycloalkyl formed by R 1 , taken together with the nitrogen atom to which they are attached, is selected from pyrrolidinyl, piperidinyl, azetidinyl, and 3-azabicyclo[3.1.0]hexyl, and the heterocycloalkyl is selected from one or two R 2 , each occurrence independently selected from fluoro and methoxy. 3 The compound of any one of embodiments 1-8, optionally substituted with:

[0173] 10.R 1 and R 2 Compounds according to any one of embodiments 1-9, wherein cycloalkyl, formed by ' taken together with the carbon atom to which they are attached, is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0174] 11.Each R 3 The compound of any one of embodiments 1-10, wherein is independently selected from fluoro and methoxy.

[0175] 12.R 4 The compound of any one of embodiments 1-11, wherein is cyano.

[0176] 13.R 5 The compound of any one of embodiments 1-12, wherein is selected from hydrogen and halogen.

[0177] 14.R 5 The compound of any one of embodiments 1-13, wherein is selected from hydrogen and fluoro.

[0178] 15.A 2 The compound of any one of embodiments 1-14, wherein is selected from -O- and -NH-.

[0179] 16.A 2 The compound of any one of embodiments 1-15, wherein is -O-.

[0180] 17.R 6 The compound of any one of embodiments 1-16, wherein is selected from hydrogen, fluoro, chloro, bromo, hydroxy, amino, methoxy, methyl, and methoxymethyl.

[0181] 18.R 6 The compound of any one of embodiments 1-17, wherein is hydrogen.

[0182] 19.A 3 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -CH 2 -, -CH 2 -CH(CH 3 )-CH 2 - and -CH 2 -CH 2 -CH(CH 3 19. The compound according to any one of embodiments 1-18, wherein the compound is selected from:

[0183] 20.A 3 The compound of any one of embodiments 1-19, wherein is a bond.

[0184] 21. A compound according to any one of embodiments 1-20, wherein A is selected from a bond, piperidinyl and piperidyl.

[0185] 22. The compound according to any one of embodiments 1-21, wherein B2 is selected from phenyl, piperidinyl, piperazinyl, 1-oxa-8-azaspiro[4.5]decyl, 7-azaspiro[3.5]nonyl, and 8-azaspiro[4.5]decyl.

[0186] 23. The compound according to any one of embodiments 1-22, wherein B2 is selected from piperazinyl and 1-oxa-8-azaspiro[4.5]decyl.

[0187] 24.A 14 Ga-CH 2 -.

[0188] 25. The compound according to any one of embodiments 1-24, wherein C is selected from difluoropiperidinyl, hydroxypiperidinyl, methoxypiperidinyl, piperazinyl, and piperidinyl.

[0189] 26. A compound according to any one of embodiments 1-25, wherein C is piperidinyl.

[0190] 27.R 17 The compound of any one of embodiments 1-26, wherein is selected from hydrogen, fluoro, and methoxy.

[0191] 28.R 18 The compound according to any one of embodiments 1-27, wherein is selected from hydrogen and fluoro.

[0192] 29.R 19 The compound of any one of embodiments 1-28, wherein is selected from hydrogen, fluoro, and methoxy.

[0193] 30.A 15 The compound of any one of embodiments 1-29, wherein is -NH-.

[0194] 31.A 15 The compound of any one of embodiments 1-29, wherein is -CH-.

[0195] 32. The compound according to any one of the preceding embodiments, wherein n is 1.

[0196] 33. 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]ethyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[1-[2-[4-[4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]ethyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-3-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]ethyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[3-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]phenyl]piperidin-1-yl]acetyl]piperidin-4-yl]propyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[3-[1-[2-[4-[4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]propyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[3-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]propyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[3-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]phenyl]piperidin-1-yl]-2-oxoethyl]piperidin-4-yl]propyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]ethyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]phenyl]piperidin-1-yl]acetyl]piperazin-1-yl]ethyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[4-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]butan-2-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[3-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]butyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[3-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-4-methylpiperidin-4-yl]propyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-4-fluoropiperidin-4-yl]ethyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[3-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]-2-methylpropyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[3-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-4-fluoropiperidin-4-yl]propyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[1-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]pyrazol-4-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[1-[1-[2-[4-[4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]pyrazol-4-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[1-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]phenyl]piperidin-1-yl]acetyl]piperidin-4-yl]pyrazol-4-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[1-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-3-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]pyrazol-4-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[1-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2,6-difluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]pyrazol-4-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[1-[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]phenyl]piperidin-1-yl]-2-oxoethyl]piperidin-4-yl]pyrazol-4-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[7-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-7-azaspiro[3.5]nonan-2-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[7-[2-[1-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]-4-hydroxypiperidin-4-yl]acetyl]-7-azaspiro[3.5]nonan-2-yl]-4-oxoquinazoline, 3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[3-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-3-azabicyclo[3.1.0]hexan-6-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]phenoxy]-3-[7-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-7-azaspiro[3.5]nonan-2-yl]-4-oxoquinazoline, 3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 4-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-9-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-9-azaspiro[5.5]undecane, 9-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-3-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-3-azaspiro[5.5]undecane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[[7-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-7-azaspiro[3.5]nonan-2-yl]methyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-2-azaspiro[4.5]decan-8-yl]-4-oxoquinazoline, (3S)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 4-[6-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-3-azabicyclo[3.1.0]hexan-3-yl]-N-[1-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-4-yl]benzamide, 3-[[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]methyl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 2-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-N-[1-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-4-yl]-7-azaspiro[3.5]nonane-7-carboxamide, 3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-N-[1-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-4-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxamide, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[7-[3-[3-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]azetidin-1-yl]cyclobutanecarbonyl]-7-azaspiro[3.5]nonan-2-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3R)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3R)-8-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3R)-8-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[1-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperazin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, (3R)-N-[2-cyano-3-[3-[(3R)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-fluoropyrrolidine-1-sulfonamide, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperazin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-5-fluoro-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-5-fluoro-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-3-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-3-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl]piperazin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, N-[2-cyano-3-[3-[(3R)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopentanesulfonamide, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-5-methyl-4-oxoquinazoline, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]-3,3-difluoropiperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-5-methyl-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl]piperazin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, N-[2-cyano-3-[3-[(3R)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]propane-2-sulfonamide, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2,5-difluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2,3-difluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2,3-difluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl]-3,3-difluoropiperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl]-3,3-difluoropiperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2,5-difluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 3-[5-bromo-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 5-bromo-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 5-chloro-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 3-[5-chloro-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-5-fluoro-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[5-bromo-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3S)-3-[5-bromo-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluoro-5-methoxyphenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]azepan-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[5-chloro-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3S)-3-[5-chloro-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 5-chloro-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3S)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 5-chloro-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[(3R)-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]-4-oxoquinazoline, 3-[5-amino-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoroanilino]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]cyclohexyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[6-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyridin-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-5-fluoro-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[6-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluoro-6-methoxyphenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyridin-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluoro-5-methoxyphenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluoro-6-methoxyphenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[6-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluoro-5-methoxyphenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyridin-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]-3-hydroxypropanoyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[6-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyridin-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[6-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyridin-3-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, (3R)—N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxypyrrolidine-1-sulfonamide, (3R)-N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxypyrrolidine-1-sulfonamide, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[(2S)-2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]-3-hydroxypropanoyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-5-methoxy-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-5-methoxy-4-oxoquinazoline, 5-amino-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 5-amino-6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[(3R,4R)-4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]-3-methoxypiperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[(3S,4S)-4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]-3-methoxypiperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclohexanesulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]piperidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]pyrrolidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopentanesulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopentanesulfonamide, (3S)—N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxypyrrolidine-1-sulfonamide, (3S)-N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxypyrrolidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]propane-2-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]piperidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopropanesulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopropanesulfonamide, (3R)—N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-fluoropyrrolidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxyazetidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]propane-2-sulfonamide, 6-[2-cyano-3-[[2,2-difluoroethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-6-fluoro-3-[[2-fluoroethyl(methyl)sulfamoyl]amino]phenoxy]-3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-6-fluoro-3-[[2-fluoroethyl(methyl)sulfamoyl]amino]phenoxy]-3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[2,2-difluoroethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3,3-difluoropyrrolidine-1-sulfonamide, (3R)-N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-fluoropyrrolidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]azetidine-1-sulfonamide, 6-[2-cyano-3-[[cyclopropyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 6-[2-cyano-3-[[cyclopropyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, (1S,5R)-N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-azabicyclo[3.1.0]hexane-3-sulfonamide, (3R,4R)—N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3,4-difluoropyrrolidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]azetidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclobutanesulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclobutanesulfonamide, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-5-(methoxymethyl)-4-oxoquinazoline, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]cyclohexyl]-1-oxa-8-azaspiro[4.5]decane, N-[3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-2,4-difluorophenyl]cyclopentanesulfonamide, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-5-(methoxymethyl)-4-oxoquinazoline, 3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-6-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluorophenoxy]-4-oxoquinazoline, 3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-6-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluorophenoxy]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-5-hydroxy-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-5-hydroxy-4-oxoquinazoline, 3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-6-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluorobenzoyl]-4-oxoquinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]ethyl]-4-oxo-quinazoline, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]-2-oxo-ethyl]-4-piperidyl]ethyl]-4-oxo-quinazoline, N-[2-cyano-3-[3-[2-[1-[2-[4-[4-[(2,6-dioxo-3-piperidyl)amino]phenyl]-1-piperidyl]acetyl]-4-piperidyl]ethyl]-4-oxo-quinazolin-6-yl]oxy-4-fluoro-phenyl]cyclopentanesulfonamide, 6-[3-[[tert-butyl(methyl)sulfamoyl]amino]-2-cyano-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, and 6-[3-[[tert-butyl(methyl)sulfamoyl]amino]-2-cyano-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, 33. The compound according to any one of embodiments 1 to 32, selected from: or a pharma- ceutically acceptable salt thereof.

[0197] 34. (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-oxoquinazolin-3-yl]-8-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-3-[2-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazoline, (3R)-N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3R)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]-3-methoxypyrrolidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]pyrrolidine-1-sulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopentanesulfonamide, N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]propane-2-sulfonamide, and N-[2-cyano-3-[3-[2-[4-[2-[4-[4-[[(3S)-2,6-dioxopiperidin-3-yl]amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperazin-1-yl]pyrimidin-5-yl]-4-oxoquinazolin-6-yl]oxy-4-fluorophenyl]cyclopropanesulfonamide, 34. The compound according to any one of embodiments 1 to 33, selected from: or a pharma- ceutically acceptable salt thereof.

[0198] 35. A compound according to any one of embodiments 1-34 or a pharma- ceutically acceptable salt thereof for use as a therapeutically active substance.

[0199] 36. A pharmaceutical composition comprising a compound according to any one of embodiments 1-34 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0200] 37. Use of a compound according to any one of embodiments 1 to 34 or a pharma- ceutically acceptable salt thereof for the therapeutic and / or prophylactic treatment of cancer.

[0201] 38. A compound according to any one of embodiments 1-34 or a pharma- ceutically acceptable salt thereof for use in the treatment and / or prevention of cancer.

[0202] 39. Use of a compound according to any one of embodiments 1 to 34 or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic and / or prophylactic treatment of cancer.

[0203] 40. A method for the therapeutic and / or prophylactic treatment of cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of embodiments 1 to 34 or a pharma- ceutically acceptable salt thereof.

[0204] Formula V and Formula VI Embodiments In certain embodiments, the compound of formula V has the formula VA: [ka] wherein the substituents and variables are as described herein, or a pharma- ceutically acceptable salt thereof.

[0205] In certain embodiments, the compound of formula V has formula VB: [ka] wherein the substituents and variables are as described herein, or a pharma- ceutically acceptable salt thereof.

[0206] In certain embodiments, the compound of formula V has the formula VC: [ka] wherein the substituents and variables are as described herein, or a pharma- ceutically acceptable salt thereof.

[0207] In certain embodiments, the compound of formula V has formula VD: [ka] wherein the substituents and variables are as described herein, or a pharma- ceutically acceptable salt thereof.

[0208] In certain embodiments, the compound of formula V has the formula VE: [ka] wherein the substituents and variables are as described herein, or a pharma- ceutically acceptable salt thereof.

[0209] In certain embodiments, the compound of formula V has formula VF: [ka] wherein the substituents and variables are as described herein, or a pharma- ceutically acceptable salt thereof.

[0210] In certain embodiments, the compound of formula VI is [ka] or a pharma- ceutically acceptable salt thereof.

[0211] Formula V: [ka] (In the formula, A 1 -NR 2 -and-CHR 2 '- selected from, R 1 is selected from hydrogen, alkyl, and cycloalkyl; R 2 is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with R 2 ' is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 ', together with the carbon atom to which they are attached, represent one or two R 3 forming an optionally substituted cycloalkyl with Each R 3 is independently selected from hydrogen, halogen, alkyl, cycloalkyl, and alkoxy; R 4 is selected from hydrogen, alkyl, cyano, and halogen; R 5 is selected from hydrogen, alkyl, cyano, and halogen; A 22 is selected from -O- and -NH-; W 1 is selected from -N- and -CH-; W 2 -N- and -CR 26 - selected from R 26 is selected from hydrogen, halogen, hydroxy, amino, alkoxy, and alkyl; A 23 represents a bond, -O-, and -CH 2 - selected from A30 is a bond, -CH 2 -, pyrimidinyl, pyridinyl, pyrazolyl, and 3-azabicyclo[3.1.0]hexyl; B3 is selected from phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 1,1-dioxo-1λ6-thia-8-azaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-methyl-1,8-diazaspiro[4.5]decyl, 1,8-diazaspiro[4.5]decyl, and 8-azaspiro[4.5]decyl; A 24 is a bond, -CH 2 -, -NH-, and -O-; C is selected from azepanyl, azetidinyl, cycloalkyl, piperazinyl, and piperidinyl, where C is optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, alkyl, and alkoxy; and D is [ka] or a pharma- ceutically acceptable salt thereof.

[0212] One embodiment of the present invention comprises: A 1 Ga-NR 2 - and R 1 is selected from hydrogen, alkyl, and cycloalkyl; R 2 is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with Each R 3 is independently selected from halogen and alkoxy; R 4 is selected from hydrogen, alkyl, cyano, and halogen; R 5 is selected from hydrogen, alkyl, cyano, and halogen; A 22 is selected from -O- and -NH-; W 1 is selected from -N- and -CH-; W 2 -N- and -CR 26 - selected from R 26 is selected from hydrogen, halogen, hydroxy, amino, alkoxy, and alkyl; A 23 is a bond, -O-, and -CH 2 - selected from A30 is a bond, -CH 2 -, pyrimidinyl, pyridinyl, pyrazolyl, and 3-azabicyclo[3.1.0]hexyl; B3 is selected from phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 1,1-dioxo-1λ6-thia-8-azaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-methyl-1,8-diazaspiro[4.5]decyl, 1,8-diazaspiro[4.5]decyl, and 8-azaspiro[4.5]decyl; A 24 is bond, -CH 2 -, -NH-, and -O-; C is selected from hydroxypiperidinyl and piperidinyl; and D, [ka] or a pharma- ceutically acceptable salt thereof.

[0213] One embodiment of the present invention comprises: A 1 Ga-NR 2 - and R 1 is alkyl, and R 2 is alkyl.

[0214] One embodiment of the present invention comprises: A 1 Ga-NR 2 - and R 1 is methyl, and R 2 is selected from ethyl, tert-butyl, and cyclopropyl.

[0215] The present invention further relates to: R 1 is methyl, or a pharma- ceutically acceptable salt thereof; R 2 is ethyl, or a pharma- ceutically acceptable salt thereof; A 1 Ga-NR 2 or a pharma- ceutically acceptable salt thereof; R 1 and R 2 and the heterocycloalkyl formed by R 1 , taken together with the nitrogen atom to which they are attached, is selected from pyrrolidinyl, piperidinyl, azetidinyl, and 3-azabicyclo[3.1.0]hexyl, and the heterocycloalkyl is selected from one or two R 2 , each occurrence independently selected from fluoro and methoxy. 3 or a pharma- ceutically acceptable salt thereof, R 1 and R 2 ' together with the carbon atom to which they are attached, the cycloalkyl formed is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; or a pharma- ceutically acceptable salt thereof; Each R 3 is independently selected from fluoro and methoxy, or a pharma- ceutically acceptable salt thereof; R 4 is cyano, or a pharma- ceutically acceptable salt thereof; R 5 is halogen, or a pharma- ceutically acceptable salt thereof; R 5 is fluoro, or a pharma- ceutically acceptable salt thereof; A 22 is -O-, or a pharma- ceutically acceptable salt thereof; W 1 is -CH-, or a pharma- ceutically acceptable salt thereof; W2 is -N-, or a pharma- ceutically acceptable salt thereof; W 2 -CR 26 or a pharma- ceutically acceptable salt thereof; R 26 is selected from hydrogen and alkoxy, or a pharma- ceutically acceptable salt thereof; R 26 is selected from hydrogen and methoxy, or a pharma- ceutically acceptable salt thereof; A 23 is selected from a bond and -O-, or a pharma- ceutically acceptable salt thereof; A 23 is a bond, or a pharma- ceutically acceptable salt thereof; A30 is a bond, -CH 2 -, and pyrazolyl, or a pharma- ceutically acceptable salt thereof; A compound of formula V, or a pharma- ceutically acceptable salt thereof, wherein A30 is a bond; A30 is -CH 2 or a pharma- ceutically acceptable salt thereof; A compound of formula V, or a pharma- ceutically acceptable salt thereof, wherein A30 is pyrazolyl; A compound of formula V, wherein B3 is selected from piperidinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 2,8-diazaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, and 8-azaspiro[4.5]decyl, or a pharma- ceutically acceptable salt thereof; B3 is 1-oxa-8-azaspiro[4.5]decyl; or a pharma- ceutically acceptable salt thereof; A 24 Ga-CH 2 or a pharma- ceutically acceptable salt thereof; The compound of formula V, wherein C is selected from hydroxypiperidinyl and piperidinyl. D, [ka] or a pharma- ceutically acceptable salt thereof; and D, [ka] or a pharma- ceutically acceptable salt thereof.

[0216] The present invention further comprises: 7-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-2-[4-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1,4-diazepan-1-yl]pyrazol-1-yl]quinoxaline, 7-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-2-[[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]methoxy]quinoxaline, 7-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-2-[[(1R,5S)-3-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-3-azabicyclo[3.1.0]hexan-6-yl]methoxy]quinoxaline, 3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]quinolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 7-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-2-[8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-2,8-diazaspiro[4.5]decan-2-yl]quinoxaline, 7-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-2-[8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]quinoxaline, 3-[7-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]quinoxalin-2-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3S)-3-[7-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]quinoxalin-2-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[7-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]quinoxalin-2-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3S)-3-[7-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]quinoxalin-2-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3S)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-methoxyquinolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-methoxyquinolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, and (3S)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]cinnolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, or a pharma- ceutically acceptable salt thereof.

[0217] The present invention further comprises: A compound of formula V or a pharma- ceutically acceptable salt thereof for use as a therapeutically active substance, A pharmaceutical composition comprising a compound of formula V or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier. Use of a compound of formula V or a pharma- ceutically acceptable salt thereof for the therapeutic and / or prophylactic treatment of cancer, A compound of formula V or a pharma- ceutically acceptable salt thereof for use in the treatment and / or prevention of cancer: Use of a compound of formula V or a pharma- ceutically acceptable salt thereof for the preparation of a medicament for the therapeutic and / or prophylactic treatment of cancer, A method for the therapeutic and / or prophylactic treatment of cancer, comprising administering to a patient in need thereof an effective amount of a compound of formula V or a pharma- ceutically 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 is targeted therapy naive, and In some embodiments, the cancer is selected from melanoma, colorectal cancer, and lung cancer, particularly non-small cell lung cancer.

[0218] Additional Embodiments of Formula V 1.Formula V: [ka] (In the formula, A 1 -NR 2 -and-CHR 2 '- selected from, R 1 is selected from hydrogen, alkyl, and cycloalkyl; R 2 is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with R 2 ' is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 ', together with the carbon atom to which they are attached, represent one or two R 3 forming an optionally substituted cycloalkyl with Each R 3 is independently selected from hydrogen, halogen, alkyl, cycloalkyl, and alkoxy; R 4is selected from hydrogen, alkyl, cyano, and halogen; R 5 is selected from hydrogen, alkyl, cyano, and halogen; A 22 is selected from -O- and -NH-; W 1 is selected from -N- and -CH-; W 2 -N- and -CR 26 - selected from R 26 is selected from hydrogen, halogen, hydroxy, amino, alkoxy, and alkyl; A 23 represents a bond, -O-, and -CH 2 - selected from A30 is a bond, -CH 2 -, pyrimidinyl, pyridinyl, pyrazolyl, and 3-azabicyclo[3.1.0]hexyl; B3 is selected from phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 1,1-dioxo-1λ6-thia-8-azaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-methyl-1,8-diazaspiro[4.5]decyl, 1,8-diazaspiro[4.5]decyl, and 8-azaspiro[4.5]decyl; A 24 is a bond, -CH 2 -, -NH-, and -O-; C is selected from azepanyl, azetidinyl, cycloalkyl, piperazinyl, and piperidinyl, where C is optionally substituted with 1 or 2 substituents independently selected from halogen, hydroxy, alkyl, and alkoxy; and D is [ka] or a pharma- ceutically acceptable salt thereof.

[0219] 2.A 1 Ga-NR 2 - and R 1 is selected from hydrogen, alkyl, and cycloalkyl; R 2 is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with Each R 3 is independently selected from halogen and alkoxy; R 4 is selected from hydrogen, alkyl, cyano, and halogen; R 5 is selected from hydrogen, alkyl, cyano, and halogen; A 22 is selected from -O- and -NH-; W 1 is selected from -N- and -CH-; W 2 -N- and -CR 26 - selected from R 26 is selected from hydrogen, halogen, hydroxy, amino, alkoxy, and alkyl; A 23 is a bond, -O-, and -CH 2 - selected from A30 is a bond, -CH 2 -, pyrimidinyl, pyridinyl, pyrazolyl, and 3-azabicyclo[3.1.0]hexyl; B3 is selected from phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 1,1-dioxo-1λ6-thia-8-azaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-methyl-1,8-diazaspiro[4.5]decyl, 1,8-diazaspiro[4.5]decyl, and 8-azaspiro[4.5]decyl; A 24 is bond, -CH 2 -, -NH-, and -O-; C is selected from hydroxypiperidinyl and piperidinyl; and D, [ka] or a pharma- ceutically acceptable salt thereof.

[0220] 3.A 1 Ga-NR 2 - and R 1 is alkyl, and R 2 The compound of embodiment 1 or 2, wherein is alkyl.

[0221] 4.A 1 Ga-NR 2 - and R 1 is methyl, and R 2 The compound of any one of embodiments 1-3, wherein is ethyl.

[0222] 5.R 4 The compound of any one of embodiments 1-4, wherein is cyano.

[0223] 6.R 5The compound of any one of embodiments 1-5, wherein is halogen.

[0224] 7.R 5 The compound of any one of embodiments 1-6, wherein is fluoro.

[0225] 8.A 22 The compound of any one of embodiments 1-7, wherein is -O-.

[0226] 9.W 1 The compound of any one of embodiments 1-8, wherein is -CH-.

[0227] 10. W 2 The compound of any one of embodiments 1-9, wherein is -N-.

[0228] 11.W 2 -CR 26 -.

[0229] 12.R 26 The compound of any one of embodiments 1-11, wherein is selected from hydrogen and alkoxy.

[0230] 13.R 26 The compound of any one of embodiments 1-12, wherein is selected from hydrogen and methoxy.

[0231] 14.A 23 The compound of any one of embodiments 1-13, wherein is selected from a bond and -O-.

[0232] 15.A 23 The compound of any one of embodiments 1-14, wherein is a bond.

[0233] 16. A30 is a bond, -CH 2 -, and pyrazolyl.

[0234] 17. The compound according to any one of embodiments 1-16, wherein A30 is a bond.

[0235] 18. The compound according to any one of embodiments 1-17, wherein B3 is selected from piperidinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 2,8-diazaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, and 8-azaspiro[4.5]decyl.

[0236] 19.A 24 Ga-CH 2 -.

[0237] 20. The compound according to any one of embodiments 1-19, wherein C is selected from hydroxypiperidinyl and piperidinyl.

[0238] 21.D is [ka] 21. The compound of any one of embodiments 1-20, wherein

[0239] 22.D is [ka] 21. The compound of any one of embodiments 1-20, wherein

[0240] 23. 7-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-2-[4-[4-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1,4-diazepan-1-yl]pyrazol-1-yl]quinoxaline, 7-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-2-[[1-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]piperidin-4-yl]methoxy]quinoxaline, 7-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-2-[[(1R,5S)-3-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-3-azabicyclo[3.1.0]hexan-6-yl]methoxy]quinoxaline, 3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]quinolin-3-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 7-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-2-[8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-2,8-diazaspiro[4.5]decan-2-yl]quinoxaline, 7-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-2-[8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-8-azaspiro[4.5]decan-3-yl]quinoxaline, 3-[7-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]quinoxalin-2-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3S)-3-[7-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]quinoxalin-2-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[7-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]quinoxalin-2-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3S)-3-[7-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]quinoxalin-2-yl]-8-[2-[4-[4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl]piperidin-1-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3S)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-methoxyquinolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]-4-methoxyquinolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, and (3S)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluorophenoxy]cinnolin-3-yl]-8-[2-[1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-5-fluoro-1-methylindazol-6-yl]-4-hydroxypiperidin-4-yl]acetyl]-1-oxa-8-azaspiro[4.5]decane, 23. The compound according to any one of embodiments 1 to 22, selected from: or a pharma- ceutically acceptable salt thereof.

[0241] 24. A compound according to any one of embodiments 1 to 23 or a pharma- ceutically acceptable salt thereof for use as a therapeutically active substance.

[0242] 25. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 23 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0243] 26. Use of a compound according to any one of embodiments 1 to 23 or a pharma- ceutically acceptable salt thereof for the therapeutic and / or prophylactic treatment of cancer.

[0244] 27. A compound according to any one of embodiments 1-23 or a pharma- ceutically acceptable salt thereof for use in the treatment and / or prevention of cancer.

[0245] 28. Use of a compound according to any one of embodiments 1 to 23 or a pharma- ceutically acceptable salt thereof for the preparation of a medicament for the therapeutic and / or prophylactic treatment of cancer.

[0246] 29. A method for the therapeutic and / or prophylactic treatment of cancer, comprising administering to a patient in need thereof an effective amount of a compound according to any one of embodiments 1 to 23 or a pharma- ceutically acceptable salt thereof.

[0247] Embodiments of Formula I, Formula II, Formula III, Formula IV, Formula V, and Formula VI 1. Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI: [ka] (In the formula, A 1 -NR 2 -and-CHR 2 '- selected from, R 1 is selected from hydrogen, alkyl, and cycloalkyl; R 2 is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 together with the nitrogen atom to which they are attached, one or two R 3 forming an optionally substituted heterocycloalkyl with R 2 ' is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl; Or R 1 and R 2 ', together with the carbon atom to which they are attached, represent one or two R 3 forming an optionally substituted cycloalkyl with Each R 3 is independently selected from hydrogen, halogen, alkyl, cycloalkyl, and alkoxy; R 4 is selected from hydrogen, alkyl, cyano, and halogen; R 5 is selected from hydrogen, alkyl, cyano, and halogen; A 2 is selected from -O-, -NH-, and -(C=O)-; A 22 is selected from -O- and -NH-; W 1 is selected from -N- and -CH-; W 2 -N- and -CR 26 - selected from R 6is selected from hydrogen, halogen, hydroxy, amino, dialkylamino, alkoxy, alkyl, and alkoxyalkyl; R 26 is selected from hydrogen, halogen, hydroxy, amino, alkoxy, and alkyl; A 3 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -CH 2 -, -CH 2 -CH(CH 3 )-CH 2 -, -CH 2 -CH 2 -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - selected from A 23 represents a bond, -O-, and -CH 2 - selected from A is selected from a bond, pyrimidinyl, pyridinyl, pyrazolyl, and 3-azabicyclo[3.1.0]hexyl; A30 is a bond, -CH 2 -, pyrimidinyl, pyridinyl, pyrazolyl, and 3-azabicyclo[3.1.0]hexyl; B is phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 1 , 1-dioxo-1λ6-thia-8-azaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-methyl-1,8-diazaspiro[4.5]decyl, 1,8-diazaspiro[4.5]decyl, and 8-azaspiro[4.5]decyl, where B is optionally substituted with 1 or 2 substituents independently selected from halogen, alkyl, and alkoxy; B2 is selected from phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, and 8-azaspiro[4.5]decyl, where B2 is optionally substituted with 1 or 2 substituents independently selected from halogen, alkyl, and alkoxy; B3 is selected from phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 1,1-dioxo-1λ6-thia-8-azaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-methyl-1,8-diazaspiro[4.5]decyl, 1,8-diazaspiro[4.5]decyl, and 8-azaspiro[4.5]decyl; n is 0 or 1, A 4 is a bond, -CH 2 -,-(SO2 )-CH 2 -, -CH(CH 2 -OH)-, -NH-, and -O-; A 14 is a bond, -CH 2 -, -CH 2 -CH 2 -, -CH(CH 2 -OH)-, -NH-, -O-, cycloalkyl, and alkylamino; C is selected from azepanyl, azetidinyl, cycloalkyl, piperazinyl, and piperidinyl, where C is optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl, and alkoxy; D is [ka] is selected from R 7 is selected from hydrogen, alkyl, cyano, halogen, and alkoxy; R 8 is selected from hydrogen, alkyl, cyano, halogen, and alkoxy; R 9 is selected from hydrogen, alkyl, cyano, halogen, and alkoxy; R 17 is selected from hydrogen, alkyl, cyano, hydroxy, cycloalkyl, halogen, and alkoxy; R 18 is selected from hydrogen, alkyl, cyano, hydroxy, cycloalkyl, halogen, and alkoxy; R 19 is selected from hydrogen, alkyl, cyano, hydroxy, cycloalkyl, halogen, and alkoxy; A 5 is -CH- or -N-, A 15 is selected from a bond, -O-, and -NH-; A 6 is -CH- or -N-, and The linker is a divalent chemical group, or a pharma- ceutically acceptable salt thereof.

[0248] 2. The compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0249] 3.A 4 The compound of embodiment 1 or 2, wherein is a bond.

[0250] 4.A 4 The compound of embodiment 1 or 2, wherein is -NH-.

[0251] 5.A 4 The compound of embodiment 1 or 2, wherein is -O-.

[0252] 6.A 5 The compound of any one of embodiments 1-5, wherein is -CH-.

[0253] 7.A 5 The compound of any one of embodiments 1-5, wherein is -N-.

[0254] 8.R 7 The compound of any one of embodiments 1-7, wherein is hydrogen.

[0255] 9.R 7 The compound of any one of embodiments 1-7, wherein is alkyl.

[0256] 10.R 7 The compound of any one of embodiments 1-7, wherein is methyl.

[0257] 11.R 8 The compound of any one of embodiments 1-10, wherein is hydrogen.

[0258] 12.R8 The compound of any one of embodiments 1-10, wherein is alkyl.

[0259] 13.R 8 The compound of any one of embodiments 1-10, wherein is halogen.

[0260] 14.R 9 The compound of any one of embodiments 1-13, wherein is hydrogen.

[0261] 15.R 9 The compound of any one of embodiments 1-13, wherein is alkyl.

[0262] 16.R 9 The compound of any one of embodiments 1-13, wherein is halogen.

[0263] 17.R 9 The compound of any one of embodiments 1-13, wherein is fluorine.

[0264] 18.B is [ka] The compound of any one of embodiments 1-17, wherein

[0265] 19.B is [ka] The compound of any one of embodiments 1-17, wherein

[0266] 20. The compound according to any one of embodiments 1-17, wherein B is phenyl, piperidinyl, or piperazinyl, optionally substituted with one or two substituents independently selected from halogen, alkyl, and alkoxy.

[0267] 21. The compound according to any one of embodiments 1-17, wherein B is phenyl, piperidinyl, or piperazinyl.

[0268] 22. The compound of any one of embodiments 1-17, wherein B is 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 1,1-dioxo-1λ6-thia-8-azaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-methyl-1,8-diazaspiro[4.5]decyl, 1,8-diazaspiro[4.5]decyl, or 8-azaspiro[4.5]decyl.

[0269] 23. The compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0270] 24.A 6 The compound of embodiment 1 or 23, wherein is -CH-.

[0271] 25.A 6 The compound of embodiment 1 or 23, wherein is -N-.

[0272] 26.A 14 The compound of any one of embodiments 23-25, wherein is a bond.

[0273] 27.A 14 -CH 2 -, -CH 2 -CH 2 - or -CH(CH 2 26. The compound of any one of embodiments 23-25, wherein R is H.

[0274] 28.A 14 The compound of any one of embodiments 23-25, wherein is -NH-.

[0275] 29.A 14 The compound of any one of embodiments 23-25, wherein is -O-.

[0276] 30.A 14 The compound of any one of embodiments 23-25, wherein is cycloalkyl.

[0277] 31.A 14 The compound of any one of embodiments 23-25, wherein is alkylamino.

[0278] 32.R 17 The compound of any one of embodiments 23-31, wherein is hydrogen.

[0279] 33.R 17 The compound of any one of embodiments 23-31, wherein is alkyl.

[0280] 34.R 17 The compound of any one of embodiments 23-31, wherein is halogen.

[0281] 35.R 17 The compound of any one of embodiments 23-31, wherein is fluorine.

[0282] 36.R 18 The compound of any one of embodiments 23-35, wherein is hydrogen.

[0283] 37.R 18 The compound of any one of embodiments 23-35, wherein is alkyl.

[0284] 38.R 18 The compound of any one of embodiments 23-35, wherein is halogen.

[0285] 39.R 18 The compound of any one of embodiments 23-35, wherein is fluorine.

[0286] 40.R 19 The compound of any one of embodiments 23-39, wherein is hydrogen.

[0287] 41.R 19 The compound of any one of embodiments 23-39, wherein is alkyl.

[0288] 42.R 19 The compound of any one of embodiments 23-39, wherein is halogen.

[0289] 43.R 19 The compound of any one of embodiments 23-39, wherein is fluorine.

[0290] 44.A 2 The compound of any one of embodiments 1-43, wherein is -O-.

[0291] 45.A 2 The compound of any one of embodiments 1-43, wherein is -NH-.

[0292] 46.A 2 The compound of any one of embodiments 1-43, wherein is -(C=O)-.

[0293] 47.A 3 The compound of any one of embodiments 1-46, wherein is a bond.

[0294] 48.A 3 -CH 2 -.

[0295] 49.A 3 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -CH 2 -, -CH2 -CH(CH 3 )-CH 2 -, -CH 2 -CH 2 -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -CH 2 - or -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -.

[0296] 50. The compound according to any one of embodiments 1-49, wherein n is 0.

[0297] 51. The compound according to any one of embodiments 1-49, wherein n is 1.

[0298] 52.R 6 The compound of any one of embodiments 1-51, wherein is hydrogen.

[0299] 53.R 6 The compound of any one of embodiments 1-51, wherein is halogen.

[0300] 54.R 6 The compound of any one of embodiments 1-51, wherein is amino or dialkylamino.

[0301] 55.R 6 The compound of any one of embodiments 1-51, wherein is hydroxy or alkoxy.

[0302] 56. The compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0303] 57.D is [ka] 57. The compound of embodiment 56, wherein

[0304] 58.D is [ka] 57. The compound of embodiment 56, wherein

[0305] 59.W 1 The compound of any one of embodiments 56-58, wherein is -N-.

[0306] 60.W 1 The compound of any one of embodiments 56-58, wherein is -CH-.

[0307] 61.W 2 The compound of any one of embodiments 56-60, wherein is -N-.

[0308] 62.W 2 -CR 26 -

[0309] 63.R 26 The compound of any one of embodiments 56-62, wherein is hydrogen.

[0310] 64.R 26 The compound of any one of embodiments 56-62, wherein is halogen.

[0311] 65.A 23 The compound of any one of embodiments 56-64, wherein is a bond.

[0312] 66.A 23 The compound of any one of embodiments 56-64, wherein is -O-.

[0313] 67.A 23-CH 2 -

[0314] 68. The compound according to any one of embodiments 56-67, wherein A30 is a bond.

[0315] 69.A30 is -CH 2 -.

[0316] 70. A compound according to any one of embodiments 56-67, wherein A30 is pyrimidinyl or pyridinyl.

[0317] 71. A compound according to any one of embodiments 56-67, wherein A30 is pyrazolyl.

[0318] 72. The compound according to any one of embodiments 56-67, wherein A30 is 3-azabicyclo[3.1.0]hexyl.

[0319] 73. The compound according to any one of embodiments 56-72, wherein B3 is phenyl.

[0320] 74. A compound according to any one of embodiments 56-72, wherein B3 is piperidinyl or piperazinyl.

[0321] 75. The compound according to any one of embodiments 56-72, wherein B3 is 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 1,1-dioxo-1λ6-thia-8-azaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-methyl-1,8-diazaspiro[4.5]decyl, 1,8-diazaspiro[4.5]decyl, or 8-azaspiro[4.5]decyl.

[0322] 76.A 22 The compound of any one of embodiments 56-75, wherein is -O-.

[0323] 77.A 22 The compound of any one of embodiments 56-75, wherein is -NH-.

[0324] 78. The compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0325] 79.A 5 is -CH-.

[0326] 80.A 5 The compound of embodiment 78, wherein is -N-.

[0327] 81.R 7 The compound of any one of embodiments 78-80, wherein is hydrogen.

[0328] 82.R 7 The compound of any one of embodiments 78-80, wherein is alkyl.

[0329] 83.R 7 The compound of any one of embodiments 78-80, wherein is methyl.

[0330] 84.R 8 The compound of any one of embodiments 78-83, wherein is hydrogen.

[0331] 85.R 8 The compound of any one of embodiments 78-83, wherein is alkyl.

[0332] 86.R 8The compound of any one of embodiments 78-83, wherein is halogen.

[0333] 87.R 9 The compound of any one of embodiments 78-86, wherein is hydrogen.

[0334] 88.R 9 The compound of any one of embodiments 78-86, wherein is alkyl.

[0335] 89.R 9 The compound of any one of embodiments 78-86, wherein is halogen.

[0336] 90.R 9 The compound of any one of embodiments 78-86, wherein is fluorine.

[0337] 91. The compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0338] 92.A 6 is -CH-.

[0339] 93.A 6 The compound of embodiment 91, wherein is -N-.

[0340] 94.R 17 The compound of any one of embodiments 91-93, wherein is hydrogen.

[0341] 95.R 17 The compound of any one of embodiments 91-93, wherein is alkyl.

[0342] 96.R 17 The compound of any one of embodiments 91-93, wherein is halogen.

[0343] 97.R 17 The compound of any one of embodiments 91-93, wherein is fluorine.

[0344] 98.R 18 The compound of any one of embodiments 91-97, wherein is hydrogen.

[0345] 99.R 18 The compound of any one of embodiments 91-97, wherein is alkyl.

[0346] 100.R 18 The compound of any one of embodiments 91-97, wherein is halogen.

[0347] 101.R 18 The compound of any one of embodiments 91-97, wherein is fluorine.

[0348] 102.R 19 The compound of any one of embodiments 91-101, wherein is hydrogen.

[0349] 103.R 19 The compound of any one of embodiments 91-101, wherein is alkyl.

[0350] 104.R 19 The compound of any one of embodiments 91-101, wherein is halogen.

[0351] 105.R 19 The compound of any one of embodiments 91-101, wherein is fluorine.

[0352] 106.A 2 The compound of any one of embodiments 78-105, wherein is -O-.

[0353] 107.A 2 The compound of any one of embodiments 78-105, wherein is -NH-.

[0354] 108.A 2 The compound of any one of embodiments 78-105, wherein is -(C=O)-.

[0355] 109. The compound according to any one of embodiments 78-108, wherein n is 0.

[0356] 110. The compound according to any one of embodiments 78-108, wherein n is 1.

[0357] 111.R 6 The compound of any one of embodiments 78-110, wherein is hydrogen.

[0358] 112.R 6 The compound of any one of embodiments 78-110, wherein is halogen.

[0359] 113.R 6 The compound of any one of embodiments 78-110, wherein is amino or dialkylamino.

[0360] 114.R 6 The compound of any one of embodiments 78-110, wherein is hydroxy or alkoxy.

[0361] 115. The compound has the formula: [ka] or a pharma- ceutically acceptable salt thereof.

[0362] 116.D is [ka] The compound of embodiment 115, wherein

[0363] 117.D is [ka] The compound of embodiment 115, wherein

[0364] 118.W 1 The compound of any one of embodiments 115-117, wherein is -N-.

[0365] 119.W 1 The compound of any one of embodiments 115-117, wherein is -CH-.

[0366] 120.W 2 The compound of any one of embodiments 115-119, wherein is -N-.

[0367] 121.W 2 -CR 26 -.

[0368] 122.R 26 The compound of any one of embodiments 115-121, wherein is hydrogen.

[0369] 123.R 26 The compound of any one of embodiments 115-121, wherein is halogen.

[0370] 124.A 22 The compound of any one of embodiments 115-123, wherein is -O-.

[0371] 125.A 22 The compound of any one of embodiments 115-123, wherein is -NH-.

[0372] 126. Linker: [ka] (In the formula, X 1 and X 2 is independently, in each occurrence, a bond, a heterocycle, NR 2 , C(R 2) 2 , O, C(O), and S; R 20 , R 21 , R 22 , R 23 , and R 24 is independently, at each occurrence, a bond, an alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO 2 -, -S(O)-, -C(S)-, -C(O)NR 2 -, -NR 2 C(O)-, -O-, -S-, -NR 2 -, -C(R 40 R 40 )-, -P(O)(OR 36 )O-, -P(O)(OR 36 )-, bicyclic, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocyclic, aliphatic, heteroaliphatic, heteroaryl, lactic, glycolic, and carbocyclic, each of which is selected from the group consisting of a divalent moiety selected from R 40 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 36 is independently selected at each occurrence from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocyclic, aliphatic, and heteroaliphatic; and R 40 is independently, in each occurrence, hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azido, amino, cyano, -NH (aliphatic with alkyl), -N (aliphatic with alkyl), 2 , -NHSO 2 (aliphatic containing alkyl), -N(aliphatic containing alkyl)SO 2 Alkyl, -NHSO 2 (aryl, heteroaryl, or heterocycle), -N(alkyl)SO 2 (aryl, heteroaryl, or heterocycle), -NHSO 2 Alkenyl, -N(alkyl)SO 2 Alkenyl, -NHSO 2Alkynyl, -N(alkyl)SO 2 The compound of any one of embodiments 78-125, wherein the aryl group is selected from the group consisting of alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocyclic, and cycloalkyl.

[0373] 127. The linker has the formula: [ka] The compound of embodiment 126, wherein the linker is

[0374] 128.X 1 The compound according to any one of embodiments 126 and 127, wherein is a bond.

[0375] 129.X 1 The compound according to any one of embodiments 126 and 127, wherein is a heterocycle.

[0376] 130.X 1 is NR 2 The compound according to any one of embodiments 126 and 127, wherein

[0377] 131.X 1 The compound according to any one of embodiments 126 and 127, wherein is C(O).

[0378] 132.X 2 The compound of any one of embodiments 126-131, wherein is a bond.

[0379] 133.X 2 The compound of any one of embodiments 126-131, wherein is a heterocycle.

[0380] 134.X 2 is NR 2 The compound of any one of embodiments 126-131, wherein

[0381] 135.X 2The compound of any one of embodiments 126-131, wherein is C(O).

[0382] 136.R 20 The compound of any one of embodiments 126-135, wherein is a bond.

[0383] 137.R 20 is CH 2 The compound of any one of embodiments 126-135, wherein

[0384] 138.R 20 The compound of any one of embodiments 126-135, wherein is a heterocycle.

[0385] 139.R 20 The compound of any one of embodiments 126-135, wherein is aryl.

[0386] 140.R 20 The compound according to any one of embodiments 126-135, wherein is phenyl.

[0387] 141.R 20 The compound of any one of embodiments 126-135, wherein is bicyclic.

[0388] 142.R 21 The compound of any one of embodiments 126-141, wherein is a bond.

[0389] 143.R 21 is CH 2 The compound of any one of embodiments 126-141, wherein

[0390] 144.R 21 The compound of any one of embodiments 126-141, wherein is a heterocycle.

[0391] 145.R 21 The compound of any one of embodiments 126-141, wherein is aryl.

[0392] 146.R 21 The compound of any one of embodiments 126-141, wherein

[0393] 147.R 21 The compound of any one of embodiments 126-141, wherein is bicyclic.

[0394] 148. The linker has the formula: [ka] The compound of embodiment 126, wherein the linker is

[0395] 149.R 22 The compound of any one of embodiments 126-148, wherein is a bond.

[0396] 150.R 22 is CH 2 The compound of any one of embodiments 126-148, wherein

[0397] 151.R 22 The compound of any one of embodiments 126-148, wherein is a heterocycle.

[0398] 152.R 22 The compound of any one of embodiments 126-148, wherein is aryl.

[0399] 153.R 22 The compound according to any one of embodiments 126-148, wherein is phenyl.

[0400] 154.R 22 The compound of any one of embodiments 126-148, wherein is bicyclic.

[0401] 155.R 23 The compound of any one of embodiments 126-154, wherein is a bond.

[0402] 156.R 23 is CH 2 The compound of any one of embodiments 126-154, wherein

[0403] 157.R 23 The compound of any one of embodiments 126-154, wherein is a heterocycle.

[0404] 158.R 23 The compound of any one of embodiments 126-154, wherein is aryl.

[0405] 159.R 23 The compound according to any one of embodiments 126-154, wherein is phenyl.

[0406] 160.R 23 The compound of any one of embodiments 126-154, wherein is bicyclic.

[0407] 161.R 24 The compound of any one of embodiments 126-160, wherein is a bond.

[0408] 162.R 24 is CH 2 The compound of any one of embodiments 126-160, wherein

[0409] 163.R 24 The compound of any one of embodiments 126-160, wherein is a heterocycle.

[0410] 164.R 24 The compound of any one of embodiments 126-160, wherein is aryl.

[0411] 165.R 24 The compound according to any one of embodiments 126-160, wherein is phenyl.

[0412] 166.R 24 The compound of any one of embodiments 126-160, wherein is bicyclic.

[0413] 167.R 24 The compound of any one of embodiments 126-160, wherein is C(O).

[0414] 168.A 1 -NR 2 -.

[0415] 169.A 1 -CHR 2’ -.

[0416] 170.A 1 The compound of any one of embodiments 1-167, wherein is -NH-.

[0417] 171.A 1 -NCH 3 -.

[0418] 172.A 1 -CH 2 -.

[0419] 173.R 1 The compound of any one of embodiments 1-172, wherein is hydrogen.

[0420] 174.R 1 The compound of any one of embodiments 1-172, wherein is alkyl.

[0421] 175.R 1 The compound of any one of embodiments 1-172, wherein is methyl.

[0422] 176.R 1 The compound of any one of embodiments 1-172, wherein is ethyl.

[0423] 177.R 4 The compound of any one of embodiments 1-176, wherein is hydrogen.

[0424] 178.R 4 The compound of any one of embodiments 1-176, wherein is cyano.

[0425] 179.R 4 The compound of any one of embodiments 1-176, wherein is halogen.

[0426] 180.R 5 The compound of any one of embodiments 1-179, wherein is hydrogen.

[0427] 181.R 5 The compound of any one of embodiments 1-179, wherein is halogen.

[0428] 182.R 5 The compound of any one of embodiments 1-179, wherein is fluorine.

[0429] 183.C is [ka] The compound of any one of embodiments 1-182, wherein

[0430] 184. A compound according to any one of embodiments 1-182, wherein C is azepanyl.

[0431] 185. A compound according to any one of the preceding embodiments, wherein C is azetidinyl.

[0432] 186. The compound according to any one of the preceding embodiments, wherein C is piperazinyl.

[0433] 187. The compound according to any one of the embodiments 1-182, wherein C is cycloalkyl optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl, and alkoxy.

[0434] 188. A compound according to any one of embodiments 1-182, wherein C is piperidinyl optionally substituted with 1 or 2 substituents independently selected from hydroxy, alkyl, and alkoxy.

[0435] 189. [ka] A compound selected from TIFF2024523839000080.tif237170TIFF2024523839000081.tif168170, or a pharma- ceutically acceptable salt thereof.

[0436] 190. The compound has the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0437] 191. The compound has the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0438] 192. The compound has the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0439] 193. The compound has the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0440] 194. The compound has the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0441] 195. The compound has the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0442] 196. The compound has the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0443] 197. The compound has the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0444] 198. The compound has the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0445] 199. The compound has the structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0446] 200. A pharmaceutical composition comprising a compound according to any one of embodiments 1-199 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0447] 201. A method for treating a mutant BRAF-mediated disorder, comprising administering to a patient in need of treatment an effective amount of a compound according to any one of embodiments 1 to 199 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 200.

[0448] 202. The method of embodiment 201, wherein the patient is a human.

[0449] 203. The method of embodiment 201 or 202, wherein the mutant BRAF-mediated disorder is cancer.

[0450] 204. The method of embodiment 203, wherein the mutant BRAF-mediated cancer is melanoma.

[0451] 205. The method of embodiment 203, wherein the mutant BRAF-mediated cancer is lung cancer.

[0452] 206. The method of embodiment 203, wherein the mutant BRAF-mediated cancer is non-small cell lung cancer.

[0453] 207. The method of embodiment 203, wherein the mutant BRAF-mediated cancer is colorectal cancer.

[0454] 208. The method of embodiment 203, wherein the mutant BRAF-mediated cancer is microsatellite-stable colorectal cancer.

[0455] 209. The method of embodiment 203, wherein the mutant BRAF-mediated cancer is thyroid cancer.

[0456] 210. The method of embodiment 203, wherein the mutant BRAF-mediated cancer is ovarian cancer.

[0457] 211. The method of embodiment 201, wherein the mutant BRAF mediated disorder is cholangiocarcinoma, Erdheim-Chester disease, Langerhans histiocytosis, ganglioglioma, glioma, glioblastoma, hairy cell leukemia, multiple myeloma, non-small cell lung cancer, ovarian cancer, pilocytic astrocytoma, anaplastic pleomorphic xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, pancreatic carcinoma, clear cell sarcoma of the breast, salivary gland carcinoma, or microsatellite-stable colorectal carcinoma.

[0458] 212. The method of any one of embodiments 201-211, wherein the patient is also administered an additional active agent.

[0459] 213. The method of embodiment 212, wherein the additional active agent is a MEK inhibitor.

[0460] 214. The method of embodiment 213, wherein the MEK inhibitor is trametinib.

[0461] 215. The method of embodiment 212, wherein the additional active agent is an immune checkpoint inhibitor.

[0462] 216. The method of embodiment 215, wherein the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, ipilimumab, leratolimab, atezolizumab, avelumab, and durvalumab.

[0463] 217. The method of embodiment 212, wherein the additional active agent is cetuximab or panitumumab.

[0464] 218. A compound according to any one of embodiments 1 to 199 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 200, for the therapeutic treatment of mutant BRAF-mediated disorders.

[0465] 219. The compound according to embodiment 218, wherein the mutant BRAF-mediated disorder is cancer.

[0466] 220. The compound according to embodiment 219, wherein the mutant BRAF-mediated cancer is melanoma.

[0467] 221. The compound according to embodiment 219, wherein the mutant BRAF-mediated cancer is lung cancer.

[0468] 222. The compound according to embodiment 219, wherein the mutant BRAF-mediated cancer is non-small cell lung cancer.

[0469] 223. The compound according to embodiment 219, wherein the mutant BRAF-mediated cancer is colorectal cancer.

[0470] 224. The compound according to embodiment 219, wherein the mutant BRAF-mediated cancer is microsatellite-stable colorectal cancer.

[0471] 225. The compound according to embodiment 219, wherein the mutant BRAF-mediated cancer is thyroid cancer.

[0472] 226. The compound according to embodiment 219, wherein the mutant BRAF-mediated cancer is ovarian cancer.

[0473] 227. The compound of embodiment 218, wherein the mutant BRAF mediated disorder is cholangiocarcinoma, Erdheim-Chester disease, Langerhans histiocytosis, ganglioglioma, glioma, glioblastoma, hairy cell leukemia, multiple myeloma, non-small cell lung cancer, ovarian cancer, pilocytic astrocytoma, anaplastic pleomorphic xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, pancreatic carcinoma, clear cell sarcoma of the breast, salivary gland carcinoma, or microsatellite-stable colorectal carcinoma.

[0474] 228. A compound according to any one of embodiments 1 to 199 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 200, for use in the treatment of a mutant BRAF-mediated disorder.

[0475] 229. The compound according to embodiment 228, wherein the mutant BRAF-mediated disorder is cancer.

[0476] 230. The compound according to embodiment 229, wherein the mutant BRAF-mediated cancer is melanoma.

[0477] 231. The compound according to embodiment 229, wherein the mutant BRAF-mediated cancer is lung cancer.

[0478] 232. The compound according to embodiment 229, wherein the mutant BRAF-mediated cancer is non-small cell lung cancer.

[0479] 233. The compound according to embodiment 229, wherein the mutant BRAF-mediated cancer is colorectal cancer.

[0480] 234. The compound according to embodiment 229, wherein the mutant BRAF-mediated cancer is microsatellite-stable colorectal cancer.

[0481] 235. The compound according to embodiment 229, wherein the mutant BRAF-mediated cancer is thyroid cancer.

[0482] 236. The compound according to embodiment 229, wherein the mutant BRAF-mediated cancer is ovarian cancer.

[0483] 237. The compound according to embodiment 228, wherein the mutant BRAF mediated disorder is cholangiocarcinoma, Erdheim-Chester disease, Langerhans histiocytosis, ganglioglioma, glioma, glioblastoma, hairy cell leukemia, multiple myeloma, non-small cell lung cancer, ovarian cancer, pilocytic astrocytoma, anaplastic pleomorphic xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, pancreatic carcinoma, clear cell sarcoma of the breast, salivary gland carcinoma, or microsatellite-stable colorectal carcinoma.

[0484] 238. Use of a compound according to any one of embodiments 1 to 199 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 200, in the manufacture of a medicament for the treatment of a mutant BRAF-mediated disorder.

[0485] 239. The use according to embodiment 238, wherein the mutant BRAF-mediated disorder is cancer.

[0486] 240. The use according to embodiment 239, wherein the mutant BRAF-mediated cancer is melanoma.

[0487] 241. The use according to embodiment 239, wherein the mutant BRAF-mediated cancer is lung cancer.

[0488] 242. The use according to embodiment 239, wherein the mutant BRAF-mediated cancer is non-small cell lung cancer.

[0489] 243. The use according to embodiment 239, wherein the mutant BRAF-mediated cancer is colorectal cancer.

[0490] 244. The use according to embodiment 239, wherein the mutant BRAF-mediated cancer is microsatellite-stable colorectal cancer.

[0491] 245. The use according to embodiment 239, wherein the mutant BRAF-mediated cancer is thyroid cancer.

[0492] 246. The use according to embodiment 239, wherein the mutant BRAF-mediated cancer is ovarian cancer.

[0493] 247. The use according to embodiment 238, wherein the mutant BRAF mediated disorder is cholangiocarcinoma, Erdheim-Chester disease, Langerhans histiocytosis, ganglioglioma, glioma, glioblastoma, hairy cell leukemia, multiple myeloma, non-small cell lung cancer, ovarian cancer, pilocytic astrocytoma, anaplastic pleomorphic xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, pancreatic carcinoma, clear cell sarcoma of the breast, salivary gland carcinoma, or microsatellite-stable colorectal carcinoma.

[0494] 248. A compound according to any one of embodiments 1-199 or a pharma- ceutically acceptable salt thereof for use as a therapeutically active substance.

[0495] Treatment method An effective amount of a compound of the invention, or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, can be used to treat a patient suffering from any disorder mediated by mutant BRAF.

[0496] BRAF is a serine / threonine protein kinase that is a member of signal transduction protein kinases. BRAF V600X mutations, especially BRAF V600E / K mutations, are frequently observed in various human tumors, including melanoma, thyroid cancer, colorectal cancer, lung cancer, etc. Non-limiting examples of V600X mutations include V600E, V600K, V600R, V600D, and V600N. Despite the therapeutic utility exerted by BRAF inhibitors available in the clinic in many of these indications, the duration of antitumor response to these agents is limited by the acquisition of drug resistance.

[0497] BRAF proteins exhibit a signaling propagation mechanism that requires protein homodimerization (BRAF-BRAF) or heterodimerization with other RAF proteins (BRAF-RAF1 or BRAF-ARAF). When BRAF is mutated, as observed in oncological indications with BRAF V600X substitution, BRAF signaling is no longer dependent on the formation of homodimers and / or heterodimers. In this context, the kinase is overactivated as a monomeric protein and drives cell proliferation signals.

[0498] Because currently available inhibitors only block BRAF activity in its monomeric form and are not effective against BRAF homodimers or heterodimers, it is not surprising that many BRAF resistance-inducing mechanisms function by restoring RAF homodimerization- and heterodimerization-mediated signaling.

[0499] Targeted proteolysis induces ubiquitination of targets by recruiting E3 ligases, thus facilitating proteasome-mediated destruction of bound targets. Degradation of BRAF by targeted degradation offers advantages over conventional inhibition, as it eliminates the scaffolding activity of BRAF V600E / K and specifically induces the removal of BRAF protein. This activity prevents dimerization-mediated resistance mechanisms.

[0500] Consistent with this theory, reports in the literature have demonstrated that ablation of the BRAF protein may not only be a strategy to delay the onset of resistance, but also has the potential to target tumors that have acquired resistance to available inhibitors. This observation provides novel therapeutic opportunities in the treatment of BRAF V600X mutant tumors, such as melanoma, colorectal cancer, and lung cancer.

[0501] Another aspect of the present invention provides a compound as described herein, or an enantiomer, diastereomer, or stereoisomer, or a pharma- ceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing cancer in a patient in need of such treatment or prevention, where such treatment or prevention requires BRAF inhibition.

[0502] In certain embodiments, the compounds of the present invention are used to treat BRAF-mediated cancers in which BRAF is mutated from wild type.There are many possibilities for BRAF mutation.In certain 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.

[0503] In certain embodiments, the compounds of the invention treat BRAF mutation-mediated disorders in which the mutation is not a class I mutation, a class II mutation, or a class 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.

[0504] In certain embodiments, the BRAF mutation is an exon 11 mutation.

[0505] In certain embodiments, the BRAF mutation is an exon 15 mutation.

[0506] In certain embodiments, the BRAF mutation is a G464 mutation.

[0507] In certain embodiments, the BRAF mutation is a G466 mutation.

[0508] In certain embodiments, the BRAF mutation is a G466R mutation.

[0509] In certain embodiments, the BRAF mutation is a G466E mutation.

[0510] In certain embodiments, the BRAF mutation is a G469 mutation.

[0511] In certain embodiments, the BRAF mutation is a G469E mutation.

[0512] In certain embodiments, the BRAF mutation is a D594 mutation.

[0513] In certain embodiments, the BRAF mutation is a D594A mutation.

[0514] In certain embodiments, the BRAF mutation is an L597 mutation.

[0515] In certain embodiments, the BRAF mutation is a L597R mutation.

[0516] In certain embodiments, the BRAF mutation is a L597S mutation.

[0517] In certain embodiments, the BRAF mutation is an L597Q mutation.

[0518] In certain embodiments, the BRAF mutation is a V600 mutation.

[0519] In certain embodiments, the BRAF mutation is a V600E mutation.

[0520] In certain embodiments, the BRAF mutation is a V600K mutation.

[0521] In certain embodiments, the BRAF mutation is a V600R mutation.

[0522] In certain embodiments, the BRAF mutation is a V600D mutation.

[0523] In certain embodiments, the BRAF mutation is a K601 mutation.

[0524] In certain embodiments, the BRAF mutation is a K601E mutation.

[0525] In certain embodiments, the BRAF mutation is a K601N mutation.

[0526] In certain embodiments, the compounds of the present invention are directed to compounds in which the mutation is a splice variant, e.g., p61-BRAF V600E The present invention relates to a BRAF mutation-mediated disorder.

[0527] In certain embodiments, compounds of the invention are used to treat disorders mediated by two or more mutant proteins, such as BRAF. V600E / NRAS Q61K Treating double mutant mediated cancers.

[0528] In certain embodiments, the compounds of the invention are used to treat cancers that are resistant to at least one BRAF inhibitor, such as cancers that are resistant or have acquired resistance to a BRAF inhibitor selected from dabrafenib, trametinib, vemurafenib, and encorafenib.

[0529] In certain embodiments, compounds of the invention can be used to treat BRAF V600E NRAS Q61K Cancers that have harbored escape mutations, such as double mutant cancers, are treated.

[0530] In certain embodiments, the compounds of the present invention are used to treat melanoma.

[0531] Non-limiting examples of melanoma include non-acral cutaneous melanoma, acral melanoma, mucosal melanoma, uveal melanoma, and leptomeningeal melanoma, each of which can be primary or metastatic.

[0532] In certain embodiments, the compounds of the invention are used to treat triple negative breast cancer, for example, triple negative breast cancer with a G464V BRAF mutation.

[0533] In certain embodiments, the compounds of the invention are used to treat lung cancer, for example, lung adenocarcinoma that has a G466V BRAF mutation.

[0534] In certain embodiments, the compounds of the invention are used to treat melanomas that harbor V600 BRAF mutations.

[0535] In certain embodiments, compound 157 is used to treat BRAF-mediated cancers in which BRAF is mutated from wild type. There are many possibilities for BRAF mutation. In certain 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.

[0536] In certain embodiments, compound 157 treats a BRAF mutation-mediated disorder in which the mutation is not a class I mutation, a class II mutation, or a class 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.

[0537] In certain embodiments, compound 157 is a compound that inhibits the BRAF mutation, e.g., a splice variant, such as p61-BRAF. V600E The present invention relates to a BRAF mutation-mediated disorder.

[0538] In certain embodiments, compound 157 is used to treat disorders mediated by two or more mutant proteins, such as BRAF. V600E / NRAS Q61K Treating double mutant mediated cancers.

[0539] In certain embodiments, compound 157 is used to treat a cancer that is resistant to at least one BRAF inhibitor, such as a cancer that is resistant or has acquired resistance to a BRAF inhibitor selected from dabrafenib, trametinib, vemurafenib, and encorafenib.

[0540] In certain embodiments, compound 157 is used to treat BRAF V600E NRAS Q61K Cancers that have harbored escape mutations, such as double mutant cancers, are treated.

[0541] In certain embodiments, compound 157 is used to treat melanoma.

[0542] In certain embodiments, compound 157 is used to treat triple-negative breast cancer, for example, triple-negative breast cancer with a G464V BRAF mutation.

[0543] In certain embodiments, compound 157 is used to treat lung cancer, such as lung adenocarcinoma with a G466V BRAF mutation.

[0544] In certain embodiments, compound 157 is used to treat melanoma that has a V600 BRAF mutation.

[0545] In certain embodiments, compound 157 is used to treat cholangiocarcinoma.

[0546] In certain embodiments, compound 157 is used to treat Erdheim-Chester disease.

[0547] In certain embodiments, compound 157 is used to treat Langerhans histiocytosis.

[0548] In certain embodiments, compound 157 is used to treat ganglioglioma.

[0549] In certain embodiments, compound 157 is used to treat glioma.

[0550] In certain embodiments, compound 157 is used to treat GIST.

[0551] In certain embodiments, compound 157 is used to treat glioblastoma.

[0552] In certain embodiments, compound 157 is used to treat hairy cell leukemia.

[0553] In certain embodiments, compound 157 is used to treat multiple myeloma.

[0554] In certain embodiments, compound 157 is used to treat non-small cell lung cancer.

[0555] In certain embodiments, compound 157 is used to treat ovarian cancer.

[0556] In certain embodiments, compound 157 is used to treat pilocytic astrocytoma.

[0557] In certain embodiments, compound 157 is used to treat anaplastic pleomorphic xanthoastrocytoma.

[0558] In certain embodiments, compound 157 is used to treat astrocytoma.

[0559] In certain embodiments, compound 157 is used to treat thyroid cancer.

[0560] In certain embodiments, compound 157 is used to treat papillary thyroid carcinoma.

[0561] In certain embodiments, compound 157 is used to treat anaplastic thyroid cancer.

[0562] In certain embodiments, compound 157 is used to treat pancreatic cancer.

[0563] In certain embodiments, compound 157 is used to treat breast clear cell sarcoma.

[0564] In certain embodiments, compound 157 is used to treat salivary gland cancer.

[0565] In certain embodiments, compound 157 is used to treat colorectal cancer.

[0566] In certain embodiments, compound 157 is used to treat microsatellite-stable colorectal cancer.

[0567] In certain embodiments, the compounds of the invention are used to treat a disorder selected from cholangiocarcinoma, Erdheim-Chester disease, Langerhans histiocytosis, ganglioglioma, glioma, GIST, glioblastoma, hairy cell leukemia, multiple myeloma, lung cancer, non-small cell lung cancer, ovarian cancer, pilocytic astrocytoma, anaplastic pleomorphic xanthoastrocytoma, astrocytoma, thyroid cancer, papillary thyroid carcinoma, anaplastic thyroid carcinoma, pancreatic cancer, clear cell sarcoma of the breast, salivary gland cancer, colorectal cancer, and microsatellite-stable colorectal cancer.

[0568] Another aspect of the present invention provides a method of treating or preventing a proliferative disease comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a compound as described herein, or an enantiomer, diastereomer or stereoisomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, and optionally a pharma- ceutically acceptable carrier.

[0569] In certain embodiments, the disease or disorder is cancer or a proliferative disease.

[0570] In certain embodiments, the BRAF-mediated disorder is abnormal cell proliferation, including, but not limited to, solid cancer or hematological cancer.

[0571] In certain embodiments, the hematological cancer is selected from the group consisting of 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 megakaryocytic leukemia, promyelocytic leukemia, mixed lineage leukemia, and / or mixed lineage leukemia. Leukemia (MLL), erythroleukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, Myc and B-cell leukemia (BCL)2 and / or BCL6 rearrangements / overexpression (double-hit and triple-hit lymphomas), myelodysplastic / myeloproliferative neoplasms, mantle cell lymphoma including bortezomib-resistant mantle cell lymphoma.

[0572] Solid tumors that may be treated using the compounds described herein include 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 carcinoma, liver cancer, kidney cancer, prostate cancer, including castration resistant prostate cancer (CRPC); brain cancer, including glioma, glioblastoma, neuroblastoma, and medulloblastoma, including MYC amplified medulloblastoma; colorectal cancer, Wilms' tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, head and neck cancer, melanoma, squamous cell carcinoma, ovarian cancer, pancreatic cancer, including pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors (PanNETs); osteosarcoma, giant cell tumor of bone, thyroid cancer, bladder cancer, urothelial cancer, vulvar cancer, cervical cancer, endometrial cancer, mesothelioma, esophageal cancer, salivary gland cancer, gastric cancer, nasopharyngeal cancer, buccal cancer, and the like. These include, but are not limited to, epithelial cancer, oral cancer, GIST (gastrointestinal stromal tumor), NUT midline carcinoma, testicular cancer, squamous cell carcinoma, hepatocellular carcinoma (HCC), MYCN-driven solid tumors, and NUT midline carcinoma (NMC).

[0573] In further embodiments, the disease or disorder is a sarcoma of bone, muscle, tendon, cartilage, nerve, fat, or blood vessels.

[0574] In further embodiments, the disease or disorder is soft tissue sarcoma, bone sarcoma or osteosarcoma.

[0575] In further embodiments, the disease or disorder is angiosarcoma, fibrosarcoma, liposarcoma, leiomyosarcoma, Kaposi's sarcoma, osteosarcoma, gastrointestinal stromal tumor, synovial sarcoma, pleomorphic sarcoma, chondrosarcoma, Ewing's sarcoma, reticulum cell sarcoma, angiosarcoma, botryoid sarcoma, rhabdomyosarcoma, or embryonal rhabdomyosarcoma.

[0576] In certain embodiments, the disorder is a sarcoma of bone, muscle, tendon, cartilage, nerve, fat, or blood vessels.

[0577] In other embodiments, pharmaceutical compositions comprising a compound described herein and an additional therapeutic agent are administered simultaneously or sequentially.

[0578] In other embodiments, the disease or disorder is cancer, hi further embodiments, the 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, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, squamous cell carcinoma of the head and neck, leukemia, lymphoma, myeloma, solid tumor, hematological cancer or solid tumor.

[0579] One aspect of the present application provides compounds useful for treating diseases, disorders, and conditions characterized by excessive or abnormal cell proliferation. Such diseases include, but are not limited to, proliferative or hyperproliferative diseases. Examples of proliferative and hyperproliferative diseases 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, pharyngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epithelioid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, colorectal cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, bone marrow disorders, lymphatic disorders, Hodgkin's disease, hairy cell carcinoma, buccal cavity and pharyngeal cancer (oral cancer), lip cancer, tongue cancer, oral cancer, pharyngeal cancer, small intestine cancer, colorectum cancer, colon 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 a cancer selected from gastric cancer, renal 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.

[0580] The term "cancer" refers to any cancer caused by the proliferation of malignant new cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas, etc. For example, cancers include, but are not limited to, mesothelioma, leukemias, 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 myelogenous leukemia, acute myelogenous leukemia, lymphoma, and multiple myeloma, non-Hodgkin's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), or hepatocellular carcinoma. Further examples include myelodysplastic syndromes, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft tissue sarcomas, common adult solid tumors such as head and neck cancer (e.g., oral, laryngeal, nasopharyngeal, and esophageal cancer), genitourinary tract cancer (e.g., prostate, bladder, kidney, uterine, ovarian, testicular cancer), lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), breast cancer, pancreatic cancer, melanoma and other skin cancers, gastric cancer, brain tumors, tumors associated with Gorlin's syndrome (such as medulloblastoma or meningioma), and liver cancer.

[0581] Further exemplary forms of cancer include, but are not limited to, skeletal or smooth muscle cancer, gastric cancer, small intestine cancer, rectal cancer, salivary gland cancer, endometrial cancer, adrenal gland cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0582] Further cancers that the compounds described herein may be useful in preventing, treating, and studying are, for example, colon cancer, familial adenomatous polyposis, and hereditary nonpolyposis colorectal cancer, or melanoma. Further, cancers include, but are not limited to, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, thyroid cancer (medullary and papillary thyroid cancer), kidney cancer, renal parenchymal cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumor, gallbladder cancer, bronchial carcinoma, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma. In one aspect of the present application, the present application provides the use of one or more compounds described herein in the manufacture of a medicament for the treatment of cancer, including, but not limited to, various types of cancer disclosed herein.

[0583] In some embodiments, the compounds of the present application are useful for treating cancer, such as colorectal cancer, thyroid cancer, breast cancer, and lung cancer, as well as myeloproliferative disorders, such as polycythemia vera, thrombocytopenia, myeloid metaplasia with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mastocytosis. In some embodiments, the compounds described herein are useful for treating hematopoietic disorders, particularly acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute promyelocytic leukemia, and acute lymphocytic leukemia (ALL).

[0584] In certain embodiments, the compounds described herein, or their corresponding pharma- ceutically acceptable salts, or isotopic derivatives, can be used in an effective amount to treat a host, e.g., a human, having lymphoma, or a lymphocytic or myeloid proliferation disorder or abnormality. For example, the compounds described herein can be administered to a host suffering from Hodgkin's lymphoma or non-Hodgkin's lymphoma. For example, the host can be, but is not limited to, AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK-cell lymphoma; Burkitt's lymphoma; Burkitt-like lymphoma (small non-cleaved cell lymphoma); small cleaved cell diffuse lymphoma (DSCCL); chronic lymphocytic leukemia / small lymphocytic lymphoma; cutaneous T-cell lymphoma; diffuse large B-cell lymphoma; enteropathic type The patient may be suffering from a non-Hodgkin's lymphoma such as T-cell lymphoma; follicular lymphoma; hepatosplenic gamma-delta T-cell lymphoma; lymphoblastic lymphoma; mantle cell lymphoma; marginal zone lymphoma; nasal T-cell lymphoma; childhood lymphoma; peripheral T-cell lymphoma; primary central nervous system lymphoma; T-cell leukemia; transformed lymphoma; therapy-related T-cell lymphoma; Langerhans cell histiocytosis or Waldenstrom's macroglobulinemia.

[0585] In another embodiment, the compounds described herein, or their corresponding pharma- ceutically acceptable salts, or isotopic derivatives, can be used in an effective amount to treat a patient, e.g., a human, having Hodgkin lymphoma, such as, but not limited to, nodular sclerosing classical Hodgkin lymphoma (CHL), mixed cellularity CHL, lymphopenic CHL, lymphocyte-rich CHL, lymphocyte-predominant Hodgkin lymphoma, or nodular lymphocyte-predominant HL.

[0586] The present application further encompasses the treatment or prevention of cell proliferation disorders such as hyperplasia, dysplasia, and precancerous lesions. Metaplasia is the earliest form of precancerous lesion that can be recognized by a pathologist in a biopsy. The compounds can be administered to prevent the hyperplasia, dysplasia, or precancerous lesion from continuing to grow or becoming cancerous. Examples of precancerous lesions can occur in the skin, esophageal tissue, breast, and cervical intraepithelial tissue.

[0587] In accordance with the above, the present application further provides a method of preventing or treating any of the above diseases or disorders in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound as described herein, or an enantiomer, diastereomer or stereoisomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof. For any of the above uses, the dosage required will vary depending on the method of administration, the particular condition to be treated, and the effect desired.

[0588] Combination therapy The disclosed compounds described herein, or pharma- ceutically acceptable salts thereof, or pharmaceutical compositions can be used alone or in combination with another compound of the invention or another bioactive agent or second therapeutic agent in an effective amount to treat a patient, such as a human, suffering from a mutant BRAF-mediated disorder, including, but not limited to, those described herein.

[0589] The term "bioactive agent" or "additional active agent" is used to describe an agent other than the selected compound according to the present invention that can be used in combination or alternation with the compound of the present invention to achieve the desired outcome of therapy. In certain embodiments, the compound of the present invention and the bioactive agent are administered such that they are active in vivo during the overlapping period, e.g., Cmax, Tmax, AUC or another pharmacokinetic parameter overlapping period. In another embodiment, the compound of the present invention and the bioactive agent are administered to a patient in need thereof, which do not have overlapping pharmacokinetic parameters, but one has a therapeutic effect on the therapeutic efficacy of the other.

[0590] In some embodiments, selected compounds provided herein, or a pharma- ceutically acceptable salt thereof, are used in combination with another BRAF inhibitor, such as sorafenib, vemurafenib (ZELBORAF™), dabrafenib (TAFINLAR™), or encorafenib (BRAFTOVI™).

[0591] In certain embodiments, the bioactive agent is a MEK inhibitor. MEK inhibitors are known, such as trametinib / GSK1120212 (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), XL-518 / GDC-0973 (1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol), refametinib / BAY869766 / RDEA119 (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 TAK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-benzamide), ]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655 / CH4987655(3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2yl)methyl)benzamide) or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX02189, BIX02188, binimetinib, SL-327, TAK-733, PD318088.

[0592] In certain embodiments, the MEK inhibitor is trametinib.

[0593] In certain embodiments, compounds of the invention are used in combination with cetuximab or trametinib to treat colorectal cancer. In certain embodiments, compounds of the invention are used in combination with cetuximab and BYL719 to treat colorectal cancer. In certain embodiments, compounds of the invention are used in combination with cetuximab and irinotecan to treat colorectal cancer.

[0594] In certain embodiments, compound 157 is used in combination with cetuximab or trametinib to treat colorectal cancer. In certain embodiments, compound 157 is used in combination with cetuximab and BYL719 to treat colorectal cancer. In certain embodiments, compound 157 is used in combination with cetuximab and irinotecan to treat colorectal cancer.

[0595] In certain embodiments, the bioactive agent is an SHP2 inhibitor. In certain embodiments, the SHP2 inhibitor is SHP099.

[0596] In certain 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-methylpyridine-2-carboxamide; 4-methylbenzenesulfonate), AZ62 8 (3-(2-cyanopropan-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-bromoardisine (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-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, AZ628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120 and GX818 (encorafenib (BRAFTOVI™)).

[0597] In certain embodiments, the RAF inhibitor is encorafenib.

[0598] In certain embodiments, the RAF inhibitor is vemurafenib.

[0599] In certain embodiments, the RAF inhibitor is dabrafenib.

[0600] In certain 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™), afatinib (GLOTRIF™, GIOTRIFF™, AFANIX™), lazertinib, or nazartinib.

[0601] Additional examples of EGFR inhibitors include rociletinib (CO-1686), olmutinib (OLITA™), nacotinib (ASP8273), nazartinib (EGF816), PF-06747775, icotinib (BPI-2009), neratinib (HKI-272; PB272), avitinib (AC0010), EAI045, taloxotinib (TH-4000; PR-610), These include PF-06459988 (Pfizer), tesevatinib (XL647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, dacomitinib (PF-00299804; Pfizer), brigatinib (ALUNBRIG™), lorlatinib, and PF-06747775 (PF7775).

[0602] In certain embodiments, the bioactive agent is a first generation EGFR inhibitor, such as erlotinib, gefitinib, or lapatinib. In certain embodiments, the bioactive agent is a second generation EGFR inhibitor, such as afatinib and / or dacomitinib. In certain embodiments, the bioactive agent is a third generation EGFR inhibitor, such as osimertinib.

[0603] In certain embodiments, compounds of the invention are administered in combination with osimertinib to a patient in need thereof.

[0604] In certain embodiments, compounds of the invention are administered in combination with rociletinib to a patient in need thereof.

[0605] In certain embodiments, compounds of the invention are administered in combination with avitinib to a patient in need thereof.

[0606] In certain embodiments, compounds of the invention are administered in combination with lazertinib to a patient in need thereof.

[0607] In certain embodiments, compounds of the invention are administered in combination with nazartinib to a patient in need thereof.

[0608] In certain embodiments, the compounds of the invention are administered to a patient in need thereof in combination with an EGFR antibody, such as cetuximab, panitumumab, or necitumumab.

[0609] In certain embodiments, compounds of the invention are administered to a patient in need thereof in combination with cetuximab.

[0610] In certain embodiments, compounds of the invention are administered in combination with panitumumab to a patient in need thereof.

[0611] In certain embodiments, compounds of the invention are administered in combination with necitumumab to a patient in need thereof.

[0612] In one aspect of this embodiment, the bioactive agent is an immunomodulatory agent, including, but not limited to, checkpoint inhibitors, including, by way of non-limiting example, PD-1 inhibitors, PD-L1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, small molecule, peptide, nucleotide, or other inhibitors. In certain embodiments, the immunomodulatory agent is an antibody, such as a monoclonal antibody.

[0613] Examples of PD-1 inhibitors that block the interaction between PD-1 and PD-L1 by binding to the PD-1 receptor and inhibit immunosuppression include nivolumab (OPDIVO™), pembrolizumab (KEYTRUDA™), pidilizumab, 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.). Examples of PD-L1 inhibitors that block the interaction between PD-1 and PD-L1 by binding to the PD-L1 receptor and inhibit immunosuppression include atezolizumab (TECENTRIQ™), durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab Co. Ltd.) and BMS-936559 (Bristol-Myers Squibb). Examples of 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 (GlaxoSmithKline plc).

[0614] In certain embodiments, the checkpoint inhibitor is selected from nivolumab (OPDIVO™), pembrolizumab (KEYTRUDA™), and pidilizumab / CT-011, MPDL3280A / RG7446, MEDI4736, MSB0010718C, BMS 936559, PDL2 / lg fusion proteins such as AMP 224, or inhibitors of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof.

[0615] In yet another embodiment, one or more of the active compounds described herein can be administered in effective amounts in combination or alternation with an effective amount of an estrogen inhibitor, including but not limited to SERM (selective estrogen receptor modulator), SERD (selective estrogen receptor degrader), complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist or agonist, for the treatment of abnormal tissues of the female reproductive system, such as breast cancer, ovarian cancer, endometrial cancer or uterine cancer.Partial antiestrogen such as raloxifene and tamoxifen retain some estrogenic effects, including estrogenic stimulation of uterine growth, and even estrogenic effects during the progression of breast cancer that may actually stimulate tumor growth.In contrast, fulvestrant, a complete antiestrogen, does not have estrogenic effects on the uterus and is effective in tamoxifen-resistant tumors.

[0616] Non-limiting examples of anti-estrogen compounds are provided in WO 2014 / 19176 assigned to Astra Zeneca, WO 2013 / 090921, WO 2014 / 203129, WO 2014 / 203132, and U.S. Patent Application Publication No. 2013 / 0178445 assigned to Olema Pharmaceuticals, as well as U.S. Patent Nos. 9,078,871, 8,853,423, and 8,703,810, and U.S. Patent Application Publication Nos. 2015 / 0005286, WO 2014 / 205136, and WO 2014 / 205138.

[0617] Additional non-limiting examples of anti-estrogen compounds include SERMs such as anordrin, bazedoxifene, broparestrol, chlorotrianisene, clomiphene citrate, cyclophenyl, 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, chlormadinone acetate, cyproterone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, and spironolactone.

[0618] Other estrogen ligands that can be used in accordance with the present invention are described in U.S. Pat. Nos. 4,418,068; 5,478,847; 5,393,763; and 5,457,117, WO 2011 / 156518, U.S. Pat. Nos. 8,455,534 and 8,299,112, U.S. Pat. Nos. 9,078,871; 8,853,423; 8,703,810; U.S. Patent Application Publication No. 2015 / 0005286; and WO 2014 / 201636. 05138, U.S. Patent Application Publication No. 2016 / 0175289, U.S. Patent Application Publication No. 2015 / 0258080, WO 2014 / 191726, WO 2012 / 084711; WO 2002 / 013802; WO 2002 / 004418; WO 2002 / 003992; WO 2002 / 003991; WO 2002 / 003990; WO 2002 / 003989; WO 2002 / 003988 ;WO 2002 / 003986;WO 2002 / 003977;WO 2002 / 003976;WO 2002 / 003975;WO 2006 / 078834;U.S. Patent No. 6821989;U.S. Patent Application Publication No. 2002 / 0128276;U.S. Patent No. 6777424;U.S. Patent Application Publication No. 2002 / 0016340;U.S. Patent No. 6326392;U.S. Patent No. 6756401;U.S. Patent Application Publication No. 2002 / 0013327 No.; U.S. Patent No. 6,512,002; U.S. Patent No. 6,632,834; U.S. Patent Application Publication No. 2001 / 0056099; U.S. Patent No. 6,583,170; U.S. Patent No. 6,479,535; WO 1999 / 024027; U.S. Patent No. 6,005,102; European Patent No. 0802,184; U.S. Patent No. 5,998,402; U.S. Patent No. 5,780,497, U.S. Patent No. 5,880,137, WO 2012 / 048058 and WO 2007 / 087684.

[0619] In another embodiment, the active compounds described herein can be administered in effective amounts in combination or alternation with an effective amount of an androgen (such as testosterone) inhibitor, including but not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist, for the treatment of abnormal tissues of the male reproductive system, such as prostate or testicular cancer. In certain embodiments, the prostate or testicular cancer is androgen resistant.

[0620] Non-limiting examples of anti-androgenic compounds are provided in WO 2011 / 156518 and U.S. Patent Nos. 8,455,534 and 8,299,112. Additional non-limiting examp...

Claims

1. Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI: 【Chemical 1】 (wherein, A １ is selected from -NR ２ - and -CHR ２ '- and is selected from R １ is selected from hydrogen, alkyl, and cycloalkyl, R ２ is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl, or, R １ and R ２ together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted with one or two R ３ groups, R ２ ' is selected from hydrogen, alkyl, cycloalkyl, and haloalkyl, or R １ and R ２ ’ together with the carbon atom to which they are attached form a cycloalkyl optionally substituted with one or two R ３ groups, Each R ３ is independently selected from hydrogen, halogen, alkyl, cycloalkyl, and alkoxy, R ４ is selected from hydrogen, alkyl, cyano, and halogen, R ５ is selected from hydrogen, alkyl, cyano, and halogen, A ２ is selected from -O-, -NH-, and -(C=O)-, A ２２ is selected from -O- and -NH-, A ２４ is selected from a bond, -CH ２ -, -NH-, and -O-; W １ is selected from -N- and -CH-, W ２ is selected from -N- and -CR ２６ -, and R ６ is selected from hydrogen, halogen, hydroxy, amino, dialkylamino, alkoxy, alkyl, and alkoxyalkyl, R ２６ is selected from hydrogen, halogen, hydroxy, amino, alkoxy, and alkyl, A ３ is selected from bonding, -CH ２ -, -CH ２ -CH ２ -, -CH ２ -CH ２ -CH ２ -, -CH(CH ３ )-CH ２ -CH ２ -, -CH ２ -CH(CH ３ )-CH ２ -, -CH ２ -CH ２ -CH(CH ３ )-, -CH ２ -CH ２ -CH ２ -CH ２ -, and -CH ２ -CH ２ -CH ２ -CH ２ -CH ２ -CH - and is selected from A ２３ is selected from a bond, -O-, and -CH ２ -. A is selected from bond, pyrimidinyl, pyridinyl, pyrazolyl, and 3-azabicyclo[3.1.0]hexyl, A30 is selected from bonding, -CH ２ -, pyrimidinyl, pyridinyl, pyrazolyl, and 3-azabicyclo[3.1.0]hexyl, B is selected from phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 1,1-dioxo-1λ6-thia-8-azaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-methyl-1,8-diazaspiro[4.5]decyl, 1,8-diazaspiro[4.5]decyl, and 8-azaspiro[4.5]decyl, and here, B is optionally substituted with one or two substituents independently selected from halogen, alkyl, and alkoxy, B2 is selected from phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, and 8-azaspiro[4.5]decyl, and here, B2 is optionally substituted with one or two substituents independently selected from halogen, alkyl, and alkoxy, B3 is selected from phenyl, piperidinyl, piperazinyl, 1,4-diazacycloheptyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-9-azaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, 2-azaspiro[4.5]decyl, 3-azabicyclo[3.1.0]hexyl, 3-azaspiro[5.5]undecyl, 7-azaspiro[3.5]nonyl, 1,1-dioxo-1λ6-thia-8-azaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-methyl-1,8-diazaspiro[4.5]decyl, 1,8-diazaspiro[4.5]decyl, and 8-azaspiro[4.5]decyl, n is 0 or 1, A ４ is selected from bonding, -CH ２ -, -(SO ２ )-CH ２ -, -CH(CH ２ OH)-, -NH-, and -O-, and A １４ is selected from a bond, -CH ２ -, -CH ２ -CH ２ -, -CH(CH ２ OH)-, -NH-, -O-, cycloalkyl, and alkylamino, C is selected from azepanyl, azetidinyl, cycloalkyl, piperazinyl, and piperidinyl, where C is optionally substituted with one or two substituents independently selected from hydroxy, alkyl, and alkoxy, D is, 【Chemical 2】 selected from, R ７ is selected from hydrogen, alkyl, cyano, halogen, and alkoxy, R ８ is selected from hydrogen, alkyl, cyano, halogen, and alkoxy, R ９ is selected from hydrogen, alkyl, cyano, halogen, and alkoxy, R １７ is selected from hydrogen, alkyl, cyano, hydroxy, cycloalkyl, halogen, and alkoxy, R １８ is selected from hydrogen, alkyl, cyano, hydroxy, cycloalkyl, halogen, and alkoxy, R １９ is selected from hydrogen, alkyl, cyano, hydroxy, cycloalkyl, halogen, and alkoxy, A ５ is -CH- or -N-, A １５ is selected from a bond, -O-, and -NH- A ６ is -CH- or -N-, The linker is of the formula: [Chemical Formula 3] (wherein, X1 and X2 are independently, in each case, selected from a bond, a heterocycle, NR2, C(R2)2, O, C(O), and S, R20, R21, R22, R23, and R24 are independently, in each case, selected from the group consisting of a bond, alkyl, -C(O)-, -C(O)O-, -OC(O)-, -SO2-, -S(O)-, -C(S)-, -C(O)NR2-, -NR2C(O)-, -O-, -S-, -NR2-, -C(R40R40)-, -P(O)(OR36)O-, -P(O)(OR36)-, bicyclic, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl, lactic acid, glycolic acid, and a divalent moiety selected from the group consisting of carbocycles, each being optionally substituted with one, two, three, or four substituents independently selected from R40, R36 is independently, in each case, selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, aliphatic, and heteroaliphatic, and R40 is independently, in each case, selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, -NH(alkyl), -N(alkyl)2, -NHSO2(alkyl), -N(alkyl)SO2alkyl, -NHSO2(aryl, heteroaryl, or heterocycle), -N(alkyl)SO2(aryl, heteroaryl, or heterocycle), -NHSO2alkenyl, -N(alkyl)SO2alkenyl, -NHSO2alkynyl, -N(alkyl)SO2alkynyl, haloalkyl, aliphatic, heteroaliphatic, aryl, heteroaryl, heterocycle, and cycloalkyl) is a divalent chemical group) a compound or a pharmaceutically acceptable salt thereof.

2. The compound is of the formula: 【Chemical Formula 4】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is the compound.

3. A ４ is -CH ２ -, the compound according to claim 2 or a pharmaceutically acceptable salt thereof.

4. A ５ is the compound according to claim 2 or a pharmaceutically acceptable salt thereof, which is -N-.

5. R ７ The compound or a pharmaceutically acceptable salt thereof according to claim 4, wherein R is alkyl.

6. R ７ is methyl, the compound according to claim 4 or a pharmaceutically acceptable salt thereof.

7. R ８ is hydrogen, the compound according to claim 6, or a pharmaceutically acceptable salt thereof.

8. R ９ is a halogen, the compound according to claim 7 or a pharmaceutically acceptable salt thereof.

9. R ９ is fluorine, the compound according to claim 7 or a pharmaceutically acceptable salt thereof.

10. B is 【Chemical Formula 5】 The compound according to claim 9 or a pharmaceutically acceptable salt thereof, which is.

11. B is [Chemical Formula 6] The compound according to claim 9 or a pharmaceutically acceptable salt thereof, which is.

12. The said compound is of the formula: [Chemical Formula 7] The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is the compound.

13. A ６ The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein A is -CH-.

14. A ６ is the compound according to claim 12, or a pharmaceutically acceptable salt thereof, which is -N-.

15. A ２ is a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, which is -O-.

16. A ３ is a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, which is a bond.

17. n is 1, the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

18. R ６ is hydrogen, the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

19. The said compound is of the formula: 【Chemical 8】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is the compound.

20. The said compound is of the formula: 【Chemical Formula 9】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is the compound.

21. A ５ is the compound or a pharmaceutically acceptable salt thereof according to claim 20, which is -N-.

22. R ７ The compound according to claim 21, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

23. R ７ The compound according to claim 21, or a pharmaceutically acceptable salt thereof, wherein R is methyl.

24. R ８ is hydrogen, the compound according to claim 23, or a pharmaceutically acceptable salt thereof.

25. R ９ is a compound according to claim 24 which is a halogen or a pharmaceutically acceptable salt thereof.

26. R ９ is fluorine, the compound according to claim 24 or a pharmaceutically acceptable salt thereof.

27. The said compound is of the formula: 【Chemical Formula 10】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is the compound.

28. A ６ The compound according to claim 27, or a pharmaceutically acceptable salt thereof, wherein A is -CH-.

29. A ６ The compound according to claim 27, or a pharmaceutically acceptable salt thereof, wherein A is -N-.

30. A ２ is a compound or a pharmaceutically acceptable salt thereof according to any one of claims 20 to 29, which is -O-.

31. R ６ is hydrogen, the compound according to claim 30 or a pharmaceutically acceptable salt thereof.

32. The said compound is of the formula: 【Chemical 11】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is the compound.

33. D is 【Chemical 12】 The compound according to claim 19 or 32 or a pharmaceutically acceptable salt thereof, which is.

34. D is 【Chemical 13】 The compound according to claim 19 or 32 or a pharmaceutically acceptable salt thereof, which is.

35. A ２２ is a compound according to any one of claims 19 or 32 which is -O-, or a pharmaceutically acceptable salt thereof.

36. The linker is of the formula: 【Chemical Formula 14】 The linker, the compound according to any one of claims 1, 27 and 32 or a pharmaceutically acceptable salt thereof, which is.

37. X １ is a compound according to claim 36 or a pharmaceutically acceptable salt thereof, which is a bond.

38. X １ is the compound according to claim 36 or a pharmaceutically acceptable salt thereof, which is a complex ring.

39. X ２ is a compound according to claim 36 or a pharmaceutically acceptable salt thereof, which is a bond.

40. X ２ is the compound according to claim 36 or a pharmaceutically acceptable salt thereof, which is a complex ring.

41. R ２０ is a compound or a pharmaceutically acceptable salt thereof according to any one of claims 36, which is a bond.

42. R ２０ is CH ２ and is the compound according to claim 36 or a pharmaceutically acceptable salt thereof.

43. R ２０ is a compound according to claim 36 or a pharmaceutically acceptable salt thereof, which is a complex ring.

44. R ２０ is a bicyclic compound according to claim 36 or a pharmaceutically acceptable salt thereof.

45. R ２１ is a compound according to claim 36 or a pharmaceutically acceptable salt thereof, which is a bond.

46. R ２１ is CH ２ and is the compound according to claim 36 or a pharmaceutically acceptable salt thereof.

47. R ２１ is a compound according to claim 36 which is a complex ring or a pharmaceutically acceptable salt thereof.

48. R ２１ is a bicyclic compound according to claim 36 or a pharmaceutically acceptable salt thereof.

49. The linker is of the formula: 【Chemical Formula 15】 The linker, the compound according to claim 36 or a pharmaceutically acceptable salt thereof, which is.

50. R ２２ is a compound according to claim 49 which is a conjugate or a pharmaceutically acceptable salt thereof.

51. R ２２ is CH ２ and is the compound according to claim 49 or a pharmaceutically acceptable salt thereof.

52. R ２２ is the compound according to claim 49 which is a heterocyclic ring or a pharmaceutically acceptable salt thereof.

53. R ２２ is a bicyclic compound according to claim 49 or a pharmaceutically acceptable salt thereof.

54. R ２３ is a compound according to claim 49 which is a conjugate, or a pharmaceutically acceptable salt thereof.

55. R ２３ is CH ２ and is the compound according to claim 49 or a pharmaceutically acceptable salt thereof.

56. R ２３ is the compound according to claim 49 which is a complex ring or a pharmaceutically acceptable salt thereof.

57. R ２３ is a bicyclic compound or a pharmaceutically acceptable salt thereof according to claim 49.

58. R ２４ is a compound according to claim 49 which is a conjugate or a pharmaceutically acceptable salt thereof.

59. R ２４ is CH ２ and is the compound according to claim 49 or a pharmaceutically acceptable salt thereof.

60. R ２４ is a compound according to claim 49 which is a complex ring or a pharmaceutically acceptable salt thereof.

61. R ２４ is a bicyclic compound according to claim 49 or a pharmaceutically acceptable salt thereof.

62. A １ is —NR ２ —, a compound according to claim 36 or a pharmaceutically acceptable salt thereof.

63. A １ is - NCH ３ - and is the compound according to claim 36 or a pharmaceutically acceptable salt thereof.

64. R １ The compound according to claim 36, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

65. R １ The compound according to claim 36, or a pharmaceutically acceptable salt thereof, wherein R is ethyl.

66. R ４ is cyano, the compound according to claim 36 or a pharmaceutically acceptable salt thereof.

67. R ５ is a halogen, the compound according to claim 36 or a pharmaceutically acceptable salt thereof.

68. R ５ is fluorine, the compound according to claim 36 or a pharmaceutically acceptable salt thereof.

69. C is 【Chemical 16】 The compound according to any one of claims 1 to 14 and 19, or a pharmaceutically acceptable salt thereof.

70. 【Fig. 17】 【Chem.】 【Chem.】 A compound selected from, or a pharmaceutically acceptable salt thereof.

71. The compound has the structure: 【Chemical Formula 18】 The compound according to claim 1, which is a compound of or a pharmaceutically acceptable salt thereof.

72. A pharmaceutical composition for treating mutant BRAF-mediated disorders in a patient in need of treatment, comprising the compound according to any one of claims 1 to 71, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

73. The pharmaceutical composition according to claim 72, wherein the mutant BRAF-mediated disorder is cancer.

74. The pharmaceutical composition according to claim 73, wherein the mutant BRAF-mediated cancer is melanoma.

75. The pharmaceutical composition according to claim 73, wherein the mutant BRAF-mediated cancer is lung cancer.

76. The pharmaceutical composition according to claim 73, wherein the mutant BRAF-mediated cancer is non-small cell lung cancer.

77. The pharmaceutical composition according to claim 73, wherein the mutant BRAF-mediated cancer is colorectal cancer.

78. The pharmaceutical composition according to claim 73, wherein the mutant BRAF-mediated cancer is microsatellite stable colorectal cancer.

79. The pharmaceutical composition according to claim 73, wherein the mutant BRAF-mediated cancer is thyroid cancer.

80. The pharmaceutical composition according to claim 73, wherein the mutant BRAF-mediated cancer is ovarian cancer.

81. The mutant BRAF-mediated disorder is cholangiocarcinoma, Erdheim-Chester disease, Langerhans cell histiocytosis, ganglioglioma, glioma, glioblastoma, hairy cell leukemia, multiple myeloma, non-small cell lung cancer, ovarian cancer, pilocytic astrocytoma, anaplastic pleomorphic xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, pancreatic cancer, clear cell sarcoma of the chest, salivary gland carcinoma, or microsatellite stable colorectal cancer, the compound according to claim 72.

82. The method according to any one of claims 72 to 81, wherein the patient receives an additional active agent.

83. The method according to claim 82, wherein the additional active agent is a MEK inhibitor.

84. The method according to claim 83, wherein the MEK inhibitor is trametinib.

85. The method according to claim 82, wherein the additional active agent is an immune checkpoint inhibitor.

86. The method according to claim 85, wherein the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, semiprimab, ipilimumab, relatlimab, atezolizumab, avelumab, and durvalumab.

87. The method according to claim 82, wherein the additional active agent is cetuximab or panitumumab.

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