Morphic forms of mutant BRAF degraders and methods for their preparation

Abstract

Provided herein are advantageous isolated morphic forms of the mutant BRAF degrader (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 (Compound 1), and methods for preparing morphic forms of Compound 1 for therapeutic use. The present invention also provides improved methods for the synthesis of Compound 1, novel pharmaceutical compositions containing Compound 1, and novel uses of Compound 1.

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of Chinese Patent Application No. 202211627337.6, filed December 2, 2022, U.S. Provisional Patent Application No. 63 / 438,422, filed January 11, 2023, and U.S. Provisional Patent Application No. 63 / 599,450, filed November 15, 2023, the entire contents of each of which are incorporated herein by reference for all purposes.

[0002] The present invention provides advantageous isolated morphic forms of the mutant BRAF degrader (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 (Compound 1), and methods for preparing morphic forms of Compound 1 for therapeutic uses as further described herein. The present invention also provides improved methods for the synthesis of Compound 1 and its isotopic (e.g., deuterium) derivatives, novel pharmaceutical compositions comprising Compound 1, and novel uses of Compound 1. [Background technology]

[0003] BRAF is a serine / threonine protein kinase that is a member of the signaling protein kinase family. BRAF plays a key role in the mitogen-activated protein kinase (MAPK) signaling pathway and is mutated in approximately 8% of all human cancers, including melanoma (approximately 60%), colorectal adenocarcinoma (approximately 10%), and lung adenocarcinoma (approximately 5%). BRAF mutations have also been identified in thyroid cancer and other cancers. The most common BRAF mutation is V600E (class I), which occurs in half of malignant melanomas. This mutation hyperactivates ERK, causing it to act 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 RAF homodimerization or heterodimerization.

[0004] The BRAF protein exhibits 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 the BRAF V600E / K substitution, BRAF signaling becomes independent of homodimers and / or heterodimers. The kinase activity becomes hyperactivated as a monomeric protein and drives cell proliferation signals.

[0005] Several BRAF inhibitors, including vemurafenib, dabrafenib, and encorafenib, have been reported that can inhibit monomeric but not dimeric BRAF. However, resistance usually develops within a year, including RAS mutations, BRAF V600E amplification, and BRAF V600E intragenic deletions or splice variants. These inhibitors are also ineffective against non-V600BRAF mutants (class II and class III) that activate ERK by promoting RAF homodimerization or heterodimerization.

[0006] Despite the therapeutic utility of available BRAF inhibitors, the duration of antitumor responses to these agents can be limited by the emergence of drug resistance.

[0007] Examples of BRAF inhibitors are described in patent applications filed by Hoffman La Roche AG, including US Pat. No. 5,629,292, US Pat. No. 5,629,293, US Pat. No. 5,629,294, US Pat. No. 5,629,295 ... and US Pat. No. 5,629,295.

[0008] C4 Therapeutics Inc. has filed a patent application, U.S. Patent Application Publication No. 2007 / 012999, which describes BRAF-degrading compounds. Further, non-limiting examples of BRAF-degrading compounds include those described in U.S. Patent Application Publication No. 2007 / 0129999, ...

[0009] Despite these efforts, there remains a need for new therapeutic agents and approaches to treat BRAF-mediated cancers, particularly agents 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. 2022 / 129259 [Patent Document 4] International Publication No. 2022 / 129260 [Patent Document 5] International Publication No. 2022 / 258612 [Patent Document 6] International Publication No. 2022 / 258600 [Patent Document 7] International Publication No. 2022 / 261250 [Patent Document 8] International Publication No. 2018 / 119448 [Patent Document 9] International Publication No. 2019 / 199816 [Patent Document 10] International Publication No. 2020 / 051564 [Patent Document 11] International Publication No. 2021 / 255212 [Patent Document 12] International Publication No. 2022 / 047145 Summary of the Invention

[0011] Stable crystalline morphic forms of Compound 1 have been identified, including Compound 1 Form B and Compound 1 sodium salt Form F. [ka]

[0012] Morphic Form B is superior to other morphic forms of Compound 1 due to its high stability, scalability, and reproducibility. For example, when Form B of Compound 1 is tested for stability over a one-week period at 25°C / 92% relative humidity in an open container, 40°C / 75% RH in an open container, and 60°C in an airtight container, Form B of Compound 1 exhibits excellent chemical and physical stability without any change in purity, crystalline morphology, or crystallinity (see Example 15, bulk stability). When Form B of Compound 1 is tested in a moisture sorption and desorption experiment at 25°C (see Example 16), Form B of Compound 1 exhibits excellent stability, no change in crystallinity, and only slight hygroscopicity (1.6% water absorption at 95% RH). Form B of Compound 1 also exhibits excellent morphic stability under compression (2 MPa and 10 MPa, Example 17), dry milling, and wet granulation conditions (Examples 18 and 19). Wet granulation experiments in the presence of water or ethanol also show no change in crystallinity (Example 19). These advantageous and beneficial stability properties of Compound 1 Form B are useful properties that increase the shelf life of Compound 1 Form B and its pharmaceutical compositions, and allow for increased purity and reproducibility in manufacturing-scale preparations. The high stability of Compound 1 Form B under high humidity conditions is useful and beneficial for the development and manufacture of pharmaceutical compositions. These properties can also be used to adjust the delivery rate of Compound 1 for improved therapeutic efficacy.

[0013] Sodium salt Form F also exhibits good physicochemical properties, including good crystallinity, stoichiometry, a high dehydration temperature, and good counterion stability. When sodium salt Form F of Compound 1 is tested for stability over a one-week period at 25°C / 92% relative humidity in an open container, 40°C / 75% RH in an open container, and 60°C in an airtight container, sodium salt Form F of Compound 1 exhibits excellent morphological stability (no morphological change) (see Example 25). Form F exhibits only a slight decrease in chemical purity (1.2%) after one week of stress at 25°C / 92% RH and a slight decrease in crystallinity after one week of stress at 60°C in an airtight container. In moisture sorption and desorption experiments at 25°C (Example 27), sodium salt Form F of Compound 1 exhibits excellent stability, with no change in crystallinity. These advantageous and beneficial stability properties of Compound 1 sodium salt Form F are useful properties that increase the shelf life of Compound 1 sodium salt Form F and pharmaceutical compositions thereof, and allow for increased purity and reproducibility in manufacturing-scale preparations. These properties can also be used for the manufacture of pharmaceutical compositions containing Compound 1 sodium salt Form F, and for modulating the delivery rate of Compound 1 for improved therapeutic efficacy.

[0014] Compound 1 is a small molecule mutant BRAF degrader that degrades mutant BRAF, e.g., class I, class II, and / or class III mutant BRAF, via the ubiquitin proteasome pathway. Compound 1 binds to the ubiquitously expressed E3 ligase protein cereblon (CRBN) and alters the substrate specificity of the CRBN E3 ubiquitin ligase complex, resulting in the recruitment and ubiquitination of mutant BRAF, e.g., BRAF V600E. Compound 1 degrades class I mutant BRAF, e.g., V600E; class II mutant BRAF, e.g., G469A; class III mutant BRAF, e.g., G466V; and p61-BRAF. V600E For example, in A375 cells, Compound 1 effectively degrades BRAF splice variants. V600E It strongly decomposes (E max= 26% (i.e., 74% of the BRAF protein is degraded), DC at 24 hours 50 =14 nM) and inhibited ERK phosphorylation (IC 50 =11 nM) and inhibits cell growth (GI at 96 hours) 50 =94nM).

[0015] In another aspect, a novel advantageous pharmaceutical composition suitable for human administration is provided, comprising Compound 1 or a morphic form of Compound 1 according to the present invention. This advantageous pharmaceutical composition comprises Compound 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, and the pharmaceutical composition is a tablet comprising both intragranular particles and extragranular particles, the intragranular particles comprising Compound 1. In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients are spray-dried to form a spray-dried dispersion, which is then processed into intragranular particles. In certain embodiments, intragranular excipients added prior to the spray-drying step include solubility enhancers, such as hypromellose acetate succinate, and permeation enhancers, such as d-α-tocopherol polyethylene glycol succinate. In certain embodiments, one or more additional intragranular excipients are added to the spray-dried dispersion. In certain embodiments, intragranular excipients added to the spray-dried dispersion include, but are not limited to, fillers such as mannitol, mucoadhesives / disintegrants such as croscarmellose sodium, flow aids such as colloidal silicon dioxide, and binders / glidants such as microcrystalline cellulose. In certain embodiments, the spray-dried dispersion and intragranular excipients added after the spray-drying process are blended, milled, and optionally roller-compacted together into ribbons, optionally with the addition of a lubricant such as magnesium stearate, which is added as an additional intragranular excipient. In certain embodiments, the material or ribbons are then milled and blended with the extragranular excipients.

[0016] Non-limiting examples of extragranular excipients include, but are not limited to, binders / glidants such as microcrystalline cellulose, mucoadhesives / disintegrants such as croscarmellose sodium, and lubricants such as magnesium stearate. In certain embodiments, the addition of a disintegrant as an extragranular excipient will contribute to the effective disintegration of the tablet into small pieces. In certain embodiments, the presence of a disintegrant as both an extragranular excipient and an intragranular excipient will ensure more efficient disintegration of the tablet.

[0017] The pharmaceutical formulation comprising the intragranular and extragranular excipients has improved pharmaceutical properties, such as improved tablet disintegration, drug release, dissolution properties, and / or mechanical strength.

[0018] In certain embodiments, pharmaceutical compositions comprising Compound 1 are prepared from a morphic form described herein, e.g., Compound 1 Form B. In certain embodiments, Compound 1 Form B can be dissolved and then spray-dried to form a solid spray-dried dispersion containing one or more pharmaceutically acceptable excipients. In some aspects, the pharmaceutical composition comprises Compound 1, a solubility enhancer, a permeation enhancer, a filler, one or more binders and / or glidants, and one or more flow aids. Non-limiting examples of pharmaceutically acceptable excipients include hypromellose (e.g., hypromellose acetate succinate), vitamin E (e.g., d-α-tocopherol polyethylene glycol succinate), mannitol, cellulose (e.g., microcrystalline cellulose), croscarmellose sodium, silicon dioxide (e.g., untreated fumed colloid), and magnesium stearate. In certain embodiments, pharmaceutical compositions according to the present invention are formulated into a dosage unit form, such as an oral dosage unit form. In certain embodiments, pharmaceutical compositions according to the present invention are formulated in tablet dosage form.

[0019] In certain non-limiting embodiments, pharmaceutical compositions comprising Compound 1 include the following excipients:

[0020] TIFF2025541736000003.tif77170

[0021] Also provided are methods for preparing pharmaceutical compositions comprising Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1, according to the present invention. In certain non-limiting embodiments, the method for preparing a pharmaceutical composition comprising Compound 1 includes (i) a spray-drying step to provide a spray-dried intermediate (SDI) containing Compound 1 and pharmaceutically acceptable excipients, (ii) a granulation step to provide a granule containing Compound 1 and one or more pharmaceutically acceptable excipients, the granule having a desired bulk density of about 0.4 g / mL to 0.6 g / mL, e.g., about 0.48 g / mL to 0.54 g / mL, and (iii) a tableting step to provide a pharmaceutical composition comprising Compound 1 and pharmaceutically acceptable excipients in an oral dosage unit form.

[0022] Pharmaceutical compositions comprising Compound 1 of the present invention or a morphic form of Compound 1 can be used to treat mutant BRAF-mediated cancers, such as, but not limited to, 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 non-limiting embodiments, pharmaceutical compositions comprising Compound 1 of the present invention or a morphic form of Compound 1 are used to treat solid tumors mediated by V600X mutant BRAF. Additional non-limiting examples of disorders that can be treated include solid tumor malignancies with mutant BRAF drivers.

[0023] In certain embodiments, a pharmaceutical composition comprising Compound 1 of the present invention or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1, can be administered to treat cancers that have developed resistance to BRAF inhibitors.

[0024] The present invention also provides improved methods for preparing Compound 1 or a pharmaceutically acceptable salt thereof or an isotopic derivative thereof, such as a deuterated derivative, on a manufacturing scale.

[0025] In certain aspects, the manufacturing scale production of Compound 1 or a pharmaceutically acceptable salt thereof includes the reaction of Compound A with Compound B according to the following Reaction Scheme 1, which results in amide bond formation. In non-limiting embodiments, deuterium is placed at an atom that is α, β, or γ relative to the site of metabolism.

[0026] Scheme 1: [ka]

[0027] In certain embodiments, to facilitate amide bond formation between compound A and compound B, the carboxylic acid group in compound B is activated by converting the carboxylic acid hydroxyl to a more reactive group. In certain embodiments, activation of the carboxylic acid group in compound B is achieved by reacting compound B with a coupling agent that activates carboxylic acids. In certain embodiments, the coupling agent is TSTU (2-succinimido-1,1,3,3-tetramethyluronium tetrafluoroborate). TSTU acts as an efficient coupling agent by rapidly activating carboxylic acids to form N-succinimidyl active esters, which react with primary amines to form carboxamides. This reaction is amenable to scale-up, effective in the presence of water, and selective for amines in the presence of alcohol groups.

[0028] In certain embodiments, the reaction between Compound A and Compound B to give Compound 1 can be carried out using separate activation reagents that result in amide bond formation. In certain embodiments, the reaction between Compound A and Compound B is carried out using a combination of N-hydroxysuccinimide (NHS) and EDCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), or a combination of NHS and DCC (dicyclohexylcarbodiimide).

[0029] In certain embodiments, Compound A and / or Compound B have at least one desired isotopic substitution of an atom at an amount above the natural abundance of the isotope, i.e., enriched. In certain embodiments, isotopic derivatives of Compound A and / or Compound B are used in the synthesis described in Scheme 1. In certain non-limiting embodiments, Compound A and / or Compound B contain one deuterium atom or multiple deuterium atoms. In certain embodiments, Compound A has Formula A-d3 and Compound B has Formula B-d4. [ka]

[0030] In certain embodiments, compound A or an isotopic derivative thereof, such as a deuterated derivative, is compound C of the following formula: [ka] (In the formula, R X is hydrogen or an amine protecting group). In certain embodiments, the amine protecting group R X Non-limiting examples of include, but are not limited to, carbobenzyloxy (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (Fmoc), benzoyl (Bz), benzyl (Bn), carbamate, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), and tosyl (Ts). In certain embodiments, the amine protecting group R X is tert-butyloxycarbonyl (BOC).

[0031] The improved synthetic procedures described herein include methods for preparing chirally pure Compound C. Compound C is used in the synthesis of Compound A either as a mixture of (R)- and (S)-stereoisomers or as an individual (R)-stereoisomer. [ka]

[0032] In certain embodiments, the (R)-stereoisomer of compound C is prepared using transaminase-catalyzed reductive amination of the corresponding ketone precursor. [ka]

[0033] In this asymmetric synthesis reaction, for example, isopropylamine can function as the sacrificial amine source.

[0034] In other embodiments, the (R)-stereoisomer of Compound C is prepared from racemic Compound C by diastereomeric recrystallization of the salt formed between racemic Compound C and a chiral resolving acid, followed by release of the desired enantiomer with a base. In certain embodiments, the chiral resolving acid is pyroglutamic acid. In certain embodiments, the chiral resolving acid is D-mandelic acid, and the base used to recover the separated individual (R)- and (S)-enantiomers of Compound C from their diastereomeric salts with D-mandelic acid is a suitable inorganic base, such as sodium hydroxide, as illustrated in Scheme 2. In other embodiments, the base used to recover the separated enantiomers is an organic base.

[0035] Scheme 2: [ka]

[0036] In certain embodiments, compound (R)-C is used to prepare compound A or an isotopic derivative thereof as shown in Scheme 3.

[0037] These two processes allow the preparation of chirally pure materials without the need for expensive chiral chromatography. The improved processes also avoid the loss of large amounts of highly synthesized materials with undesired chirality. Thus, the throughput and scalability of synthetic sequences are significantly improved.

[0038] Scheme 3: [ka]

[0039] In certain embodiments, step 1 in Scheme 3 involves reacting 5-hydroxyanthranilic acid (2-amino-5-hydroxybenzoic acid) or an isotopic derivative thereof, e.g., a deuterated derivative, with compound (R)-C and a trialkyl orthoformate, CH(OAlk), e.g., triethyl orthoformate, CH(OEt), to produce compound D, or an isotopic derivative thereof, containing a quinazolin-4-one ring system. In certain embodiments, the isotopic derivative of 2-amino-5-hydroxybenzoic acid is 2-amino-3,4,6-trideuterio-5-hydroxybenzoic acid. In certain embodiments, step 2 in Scheme 3 involves a nucleophilic aromatic substitution reaction (S) between 2,3,6-trifluorobenzonitrile and the hydroxyl of the quinazolinone fragment in compound D in the presence of a base, e.g., an organic or inorganic base, e.g., potassium carbonate. N In certain embodiments, in step 3 of Scheme 3, compound E or an isotopic derivative thereof is substituted by a nucleophilic aromatic substitution (S N Ar) conditions in the presence of a base, for example, an organic base or an inorganic base, for example, cesium carbonate, with [ethyl(methyl)sulfamoyl]amine to obtain compound A or an isotopic derivative thereof without loss of enantiomeric purity (e.g., greater than 99% ee). In certain embodiments, at any step, a nitrogen atom in compound A or an isotopic derivative thereof, for example, a deuterated derivative, is protected by a nitrogen protecting group R X, a protecting group such as carbobenzyloxy (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (Fmoc), benzoyl (Bz), benzyl (Bn), carbamate, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), or tosyl (Ts) can be removed to release the free amino group in Compound A. In certain embodiments, the amino protecting group R X When is BOC, the deprotection reaction is carried out under acidic conditions such as, but not limited to, hydrochloric acid in aqueous medium and / or organic solvent, for example, hydrochloric acid in acetone or ethyl acetate.

[0040] This synthetic sequence can be carried out on a manufacturing scale to produce chirally pure isomers (eg, greater than 90%, 95%, or 99% enantiomeric purity).

[0041] In certain embodiments, compound B or an isotopically enriched derivative thereof, such as a deuterated derivative, is prepared according to the reaction sequence shown in Scheme 4.

[0042] Scheme 4: [ka]

[0043] In certain embodiments, the synthetic route to compound B or its isotopic derivative or salt according to the present invention comprises four steps, as shown in Scheme 4. In certain embodiments, the first step involves the removal of a protecting group R Y Compound F or its isotopic derivative having a carboxylic acid group optionally protected by nucleophilic aromatic substitution reaction (S Nand 2,4,5-trifluorobenzonitrile under Ar conditions to give compound G. In certain embodiments, the isotopic derivative of compound F is tert-butyl 2-(3,3,5,5-tetradeuterio-4-hydroxy-4-piperidyl)acetate. The carboxylic acid protecting group R Y Examples of tert-butyl ( t Examples of protecting groups include, but are not limited to, 2,4-dimethoxybenzyl (Bu), trityl (Trt), 2,4-dimethoxybenzyl (Dmb), 9-fluorenylmethyl (Fm), and benzyl (Bn). In certain embodiments, the carboxylic acid protecting group R Y is tert-butyl ( t Bu). In certain embodiments, the nucleophilic aromatic substitution reaction of step 1 is carried out in the presence of a base. In certain embodiments, the base is an organic base or an inorganic base, including but not limited to sodium carbonate, potassium carbonate, cesium carbonate, or N,N-diisopropylethylamine (DIEA, Hunig's base).

[0044] The resulting intermediate compound G is converted to compound H, which contains an aminoindazole ring system, by heating with methylhydrazine in a suitable solvent, such as an organic or inorganic solvent including water and NMP (N-methyl-2-pyrrolidone). In certain embodiments, in step 3 of Scheme 4, compound K is prepared from compound H in the reaction of compound H with acrylic acid (or a derivative thereof, such as an ester, e.g., a methyl ester or an ethyl ester) under Michael addition conditions. In certain embodiments, the Michael addition conditions include basic conditions or acidic conditions. In certain embodiments, the Michael addition conditions include the use of dilute aqueous hydrochloric acid as a medium for the Michael addition reaction. In certain embodiments, compound K is converted to compound B via the intermediate formation of urea compound L in a condensation reaction with a cyanate salt, followed by the optional addition of a protecting group R. Yis removed (deprotected) to give compound B according to the present invention (steps 4a and 4b in Scheme 4). In certain embodiments, the cyanate used in step 4a of Scheme 4 is sodium cyanate or potassium cyanate used in the presence of acetic acid. In certain embodiments, the cyclization and deprotection step 4b in Scheme 4 is carried out under acidic conditions, including but not limited to, the use of dilute hydrochloric acid.

[0045] The synthetic methods according to the present invention, as depicted and described with reference to Schemes 1-4, have several advantageous and beneficial aspects. Advantageous features of the improved methods for preparing compound 1 and / or its isotopic forms, e.g., deuterated derivatives, according to the present invention include high yield and / or high purity of compound 1. Isotopic forms, e.g., deuterated derivatives thereof, and synthetic intermediates, including chemical and chiral purity, are also provided. Advantageous features of the improved methods for preparing compound 1 according to the present invention also include high reliability, reproducibility, scalability, and / or atom efficiency.

[0046] Another advantageous and beneficial aspect of the improved synthetic method according to the present invention is the palladium-free synthesis of synthetic intermediates and Compound 1 and / or its isotopes, such as deuterated derivatives. The use of palladium-free conditions in the synthesis of intermediate compounds and precursors for the preparation of Compound 1 or its isotopes, such as deuterated derivatives, provided herein makes it possible to avoid contamination of the final drug substance with toxic and undesirable trace amounts of palladium, which can be difficult to remove due to palladium complex formation with intermediate compounds and precursors carried over to downstream and / or final steps of the synthesis, thus eliminating additional purification steps. Palladium is a known toxic heavy metal that can damage bone marrow, kidneys, or liver and should be avoided, if possible, in pharmaceutical compositions and drug substances. Avoiding the use of a palladium catalyst avoids the need for costly and time-consuming palladium removal.

[0047] Therefore, the palladium-free synthesis of compound 1 and its isotopes, such as deuterated derivatives, according to the present invention is advantageous for the subsequent use of compound 1, its morphic forms and derivatives as bulk substances and in pharmaceutical compositions.

[0048] In another aspect, methods are provided for treating mutant BRAF-mediated cancers that have metastasized to the brain or central nervous system (CNS), comprising administering an effective amount of Compound 1, or a pharmaceutically acceptable salt or morphic form thereof, to a patient in need of treatment. In certain embodiments, the cancer that has metastasized to the brain or CNS is colorectal cancer, melanoma, or non-small cell lung cancer. In certain embodiments of this aspect, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to a patient in need thereof. In other embodiments of this aspect, a morphic form of Compound 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition prepared from a morphic form of Compound 1, is administered to a patient in need thereof.

[0049] Compound 1 has a high level of blood-brain barrier permeability (see Figure 52A and Example 34). When tested in an intracranial melanoma model, Compound 1 dramatically reduced the bioluminescence signal compared to vehicle control or encorafenib-treated mice, indicating a reduction in tumor burden (see Figure 40). This significant reduction in bioluminescence signal, as an indicator of tumor burden growth, resulted in a significant prolongation of survival of mice bearing intracranial melanoma tumors compared to encorafenib (see Figure 41).

[0050] In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is used to treat mutant BRAF-mediated cancers that have metastasized to the brain or CNS, in which BRAF has 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, V600M, and V600N. Non-limiting examples of Class II mutations include G469A, G469V, G469L, G469R, L597Q, and K601E. Non-limiting examples of Class III mutations include G466A, G466E, G466R, G466V, S467L, G469E, N581I, D594E, D594G, and D594N. In certain embodiments, the BRAF mutation is a V600 mutation, e.g., V600E BRAF, which mediates cancers that metastasize to the brain or CNS.

[0051] In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof can treat mutant BRAF-mediated cancers that have metastasized to the brain or CNS, where 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.

[0052] In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is a compound that inhibits the BRAF gene, wherein the mutation is a splice variant, e.g., p61-BRAF. V600E In one embodiment, mutant BRAF-mediated cancers that have metastasized to the brain or CNS can be treated.

[0053] In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is used to treat mutant BRAF-mediated cancers that have metastasized to the brain or CNS, which cancers are mediated by two or more mutant proteins, such as BRAF. V600E / NRAS Q61K or BRAF V600E / NRAS Q61R Non-limiting examples of double mutant cancers include those mediated by BRAF mutations, e.g., BRAF V600E , and mutations in NRAS, MEK1, or phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), e.g., BRAF V600E / MAP2K1 P124S , BRAF V600E / PIK3CA H1047R or BRAFV 600E / PIK3CA P449T Examples include colorectal cancer mediated by

[0054] In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is used to treat mutant BRAF-mediated cancer that has metastasized to the brain or CNS, and the cancer is resistant to at least one BRAF inhibitor, for example, a cancer that is resistant to or has acquired resistance to a BRAF inhibitor selected from dabrafenib, vemurafenib, and encorafenib. In certain embodiments, the cancer that is resistant to treatment with a BRAF inhibitor has a homodimerization- or heterodimerization-promoting mutation in the RAF protein. For example, in certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is used to treat mutant BRAF-mediated cancer that has metastasized to the brain or CNS, and the cancer has one or more mutations that promote dimerization of the RAF protein. In certain embodiments, the cancer that has one or more dimerization-promoting mutations in the RAF protein is resistant to treatment with a BRAF inhibitor, for example, dabrafenib, vemurafenib, or encorafenib. In certain embodiments, the RAF protein dimer is a BRAF-BRAF homodimer, while in other embodiments, the RAF protein dimer is a heterodimer with another RAF protein (BRAF-RAF1 or BRAF-ARAF).

[0055] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat cancer that has metastasized to the brain or CNS, the cancer being BRAF V600E / NRAS Q61K or BRAF V600E / NRAS Q61R Escape mutations such as double mutant cancers may occur.

[0056] In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is used to treat melanoma that has metastasized to the brain or CNS, hi other embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is used to treat colorectal cancer or lung cancer that has metastasized to the brain or CNS.

[0057] In an alternative embodiment, the S-enantiomer or a mixture of enantiomers, or a pharmaceutically acceptable salt thereof, is used in place of Compound 1 in the treatments or pharmaceutical compositions described herein. [ka]

[0058] Other features and advantages of the present application will be apparent from the following detailed description.

[0059] Thus, the present invention includes at least the following features: (a) a morphic form of Compound 1 described herein; (b) Form B of Compound 1; (c) the sodium salt form F of Compound 1; (d) A pharmaceutical composition comprising a morphic form of Compound 1 according to any one of embodiments (a) to (c) and one or more pharmaceutically acceptable excipients. (e) A pharmaceutical composition prepared from a morphic form of Compound 1 according to any one of embodiments (a) to (c), e.g., morphic form B; (f) the pharmaceutical composition of (e), wherein the pharmaceutical composition is prepared from a spray-dried dispersion of Compound 1 and one or more pharmaceutically acceptable excipients; (g) a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, a solubility enhancer, a permeation enhancer, a filler, a binder / glidant, and / or a mucoadhesive / disintegrant; (h) a method for treating a BRAF-mediated disorder, comprising administering an effective amount of a morphic form or pharmaceutical composition of Compound 1 according to any one of embodiments (a)-(g); (i) Use of a morphic form or pharmaceutical composition of Compound 1 according to any one of embodiments (a) to (g) in the treatment of a disorder mediated by BRAF; (j) Use of a compound or pharmaceutical composition according to any one of embodiments (a) to (g) in the manufacture of a medicament for the treatment of a BRAF-mediated disorder. (k) a method for treating cancer, comprising administering an effective amount of a morphic form or pharmaceutical composition of Compound 1 according to any one of embodiments (a)-(g); (l) A morphic form or pharmaceutical composition of Compound 1 according to any one of embodiments (a) to (g) for use in the treatment of cancer; (m) Use of a morphic form or a pharmaceutical composition of compound 1 according to any one of embodiments (a) to (g) for the treatment of cancer. (n) Use of a morphic form or a pharmaceutical composition of Compound 1 according to any one of embodiments (a) to (g) in the manufacture of a medicament for the treatment of cancer. (o) a process for preparing Form B of Compound 1 as described herein; (p) a process for preparing the sodium salt form F of Compound 1 described herein; (q) a method for treating mutant BRAF-mediated cancer that has metastasized to the brain or CNS, comprising administering an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof; (r) the method of (q), wherein the mutant BRAF-mediated cancer is melanoma; (s) the use of Compound 1 or a pharmaceutically acceptable salt thereof in the treatment of mutant BRAF-mediated cancers that have metastasized to the brain or CNS; (t) use of Compound 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of mutant BRAF-mediated cancer that has metastasized to the brain or CNS; and (u) The use of (s) or (t), wherein the mutant BRAF-mediated cancer is melanoma. [Brief explanation of the drawings]

[0060] [Figure 1] 1 shows the XRPD pattern of Form B of Compound 1. The experiment was performed as described in Example 8 and Example 28. [Figure 2] 1 shows a DSC thermogram of Form B of Compound 1. The experiment was performed as described in Example 28. [Figure 3] 1 shows a TGA thermogram of Form B of Compound 1. The experiment was performed as described in Example 28. [Figure 4] 1 shows a DVS isotherm plot of Form B of Compound 1 at 25° C. The experiment was performed as described in Example 28. [Figure 5] Figure 1 shows the DVS mass change plot of Form B of Compound 1 at 25°C. The experiment was performed as described in Example 28. [Figure 6] 1 shows an XRPD overlay before and after DVS testing of Form B of Compound 1. The experiment was performed as described in Example 28. [Figure 7] 1 shows the XRPD pattern of Form A of Compound 1. The experiment was performed as described in Example 8 and Example 28. [Figure 8] 1 shows a DSC thermogram of Form A of Compound 1. The experiment was performed as described in Example 28. [Figure 9] 1 shows a TGA thermogram of Form A of Compound 1. The experiment was performed as described in Example 28. [Figure 10] 1 shows the XRPD pattern of Form C of Compound 1. The experiment was performed as described in Example 8 and Example 28. [Figure 11] 1 shows a DSC thermogram of Form C of Compound 1. The experiment was performed as described in Example 28. [Figure 12] 1 shows the TGA thermogram of Form C of Compound 1. The experiment was performed as described in Example 28. [Figure 13] 1 shows an overlay of XRPD patterns of a Form B sample of Compound 1 before compression, after compression under 2 MPa, and after compression under 10 MPa. The experiment was performed as described in Example 28. [Figure 14] 1 shows an overlay of XRPD patterns before and after 1, 2, and 5 minutes of dry-milling of a sample of Form B of Compound 1. The experiment was performed as described in Example 28. [Figure 15]1 shows an overlay of XRPD patterns of a Form B sample of Compound 1 before wet granulation and after wet granulation in the presence of water or ethanol. The experiment was performed as described in Example 28. [Figure 16] Figure 1 shows a comparison of the XRPD pattern of Form C of Compound 1, the XRPD pattern obtained after subjecting Form C of Compound 1 to approximately eight equilibration cycles in 2-methyltetrahydrofuran, and the XRPD pattern of Form B of Compound 1. As a result of equilibration, Form C was converted to the more stable Form B. The experiment was performed as described in Example 28. [Figure 17] 1 shows the XRPD pattern of the sodium salt Form F of Compound 1. The experiment was performed as described in Example 28. [Figure 18] 1 shows the DSC thermogram of the sodium salt form F of Compound 1. The experiment was performed as described in Example 28. [Figure 19] 1 shows the TGA thermogram of the sodium salt Form F of Compound 1. The experiment was performed as described in Example 28. [Figure 20] 1 shows a DVS isotherm plot at 25° C. of sodium salt Form F of Compound 1. The experiment was performed as described in Example 28. [Figure 21] 1 shows the DVS mass change plot of the sodium salt form F of Compound 1 at 25° C. The experiment was performed as described in Example 28. [Figure 22] Figure 1 shows an XRPD overlay before and after DVS testing of sodium salt Form F of Compound 1. The experiment was performed as described in Example 28. [Figure 23] 1 shows the XRPD pattern of sodium salt Form D of Compound 1. The experiment was performed as described in Example 28. [Figure 24] 1 shows a DSC thermogram of the sodium salt Form D of Compound 1. The experiment was performed as described in Example 28. [Figure 25]1 shows the TGA thermogram of sodium salt Form D of Compound 1. The experiment was performed as described in Example 28. [Figure 26] 1 shows the XRPD pattern of the sodium salt Form E of Compound 1. The experiment was performed as described in Example 28. [Figure 27] 1 shows a DSC thermogram of the sodium salt Form E of Compound 1. The experiment was performed as described in Example 28. [Figure 28] 1 shows the TGA thermogram of the sodium salt Form E of Compound 1. The experiment was performed as described in Example 28. [Figure 29] 1 shows the XRPD pattern of potassium salt Form G of Compound 1. The experiment was performed as described in Example 28. [Figure 30] 1 shows a DSC thermogram of potassium salt Form G of Compound 1. The experiment was performed as described in Example 28. [Figure 31] 1 shows the TGA thermogram of potassium salt Form G of Compound 1. The experiment was performed as described in Example 28. [Figure 32] 1 shows the XRPD pattern of potassium salt Form H of Compound 1. The experiment was performed as described in Example 28. [Figure 33] 1 shows a DSC thermogram of potassium salt Form H of Compound 1. The experiment was performed as described in Example 28. [Figure 34] 1 shows the TGA thermogram of potassium salt Form H of Compound 1. The experiment was performed as described in Example 28. [Figure 35] 1 shows a comparison of the XRPD pattern of sodium salt Form D of Compound 1 obtained upon slurry equilibration of Form A of Compound 1 with one equivalent of sodium hydroxide in methanol, the amorphous XRPD pattern obtained upon slurry equilibration of Form A of Compound 1 with one equivalent of sodium hydroxide in acetone or acetonitrile, and the XRPD pattern of Form A of Compound 1. The experiment was performed as described in Example 21. [Figure 36] FIG. 1 shows a comparison of the XRPD patterns of the sodium salt Form E (prepared in methanol) and Form F (prepared in acetone or acetonitrile) of Compound 1 obtained upon slurry equilibration of Form A of Compound 1 with one equivalent of sodium bicarbonate, NaHCO, with the XRPD patterns of Forms A and B. The experiment was performed as described in Example 21. [Figure 37] Figure 1 shows a comparison of the XRPD pattern of Form I of Compound 1 obtained by slurry equilibration of Form A in the presence of 1 equivalent of ammonia in methanol and acetonitrile with the XRPD pattern of Form A. The experiment was performed as described in Example 21. [Figure 38] Figure 1 shows the single crystal structure of (R)-8-(tert-butoxycarbonyl)-1-oxa-8-azaspiro[4.5]decane-3-aminium (R)-2-hydroxy-2-phenylacetate. The experiment was performed as described in Example 32. [Figure 39] 1 is a line graph showing the viability of BRAF V600E mutant human colorectal adenocarcinoma HT29 cells 72 hours after treatment with Compound 1. The X-axis is the concentration of Compound 1 (nM) and the Y-axis is cell viability (%). The experiment was performed as described in Example 33. [Figure 40] Figure 1 shows a line graph depicting the change in luciferase bioluminescence signal over time in the BRAF V600E mutant A375-luciferase intracranial model after administration of test compounds (vehicle, encorafenib (administered at 35 mg / kg), Compound 1 (administered at 10 mg / kg and 30 mg / kg)), where the luciferase bioluminescence signal represents tumor burden. The X-axis is the number of days after initiation of treatment, and the Y-axis is bioluminescence (photons / second) corresponding to the luciferase signal. Error bars represent the standard error of the mean (SEM). Experiments were performed as described in Example 34. [Figure 41]Figure 1 shows Kaplan-Meier survival curves showing survival in the BRAF V600E A375-luciferase intracranial tumor model after treatment with test compounds (vehicle, encorafenib (administered at 35 mg / kg), Compound 1 (administered at 10 mg / kg and 30 mg / kg)). The X-axis represents days after initiation of treatment, and the Y-axis represents survival probability. Experiments were performed as described in Example 34. [Figure 42] FIG. 1 shows a line graph depicting the plasma concentration of test compounds (encorafenib (administered at 35 mg / kg), Compound 1 (administered at 10 mg / kg and 30 mg / kg)) over time in the BRAF V600E mutant A375-luciferase intracranial model. The X-axis is time after treatment and the Y-axis is the compound concentration in plasma (ng / mL). Error bars represent the standard error of the mean (SEM). The experiment was performed as described in Example 34. [Figure 43] FIG. 1 shows a line graph depicting the brain concentration of test compounds (encorafenib (administered at 35 mg / kg), Compound 1 (administered at 10 mg / kg and 30 mg / kg)) over time in the BRAF V600E mutant A375-luciferase intracranial model. The X-axis is time after treatment and the Y-axis is plasma compound concentration (ng / g). Error bars represent the standard error of the mean (SEM). The experiment was performed as described in Example 34. [Figure 44] Figure 1 shows a line graph depicting BRAF V600E proteolysis in A375 CNS tumors following administration of test compounds (encorafenib administered at 35 mg / kg, Compound 1 administered at 10 mg / kg and 30 mg / kg) over time. The X-axis is time after treatment and the Y-axis is mutant BRAF levels (normalized). Error bars represent the standard error of the mean (SEM). The experiment was performed as described in Example 34. [Figure 45]FIG. 1 shows a line graph depicting the change in human colorectal adenocarcinoma (HT-29 CDX model of CRC) tumor size over time following administration of test compounds (10 μL / kg vehicle, 11 mg / kg cetuximab, 10 mg / kg Compound 1, 10 mg / kg Compound 1 + 11 mg / kg cetuximab, 35 mg / kg encorafenib, and 35 mg / kg encorafenib + 11 mg / kg cetuximab) over time. The X-axis is days after treatment and the Y-axis is tumor size (mm). Error bars represent the standard error of the mean (SEM). The experiment was performed as described in Example 35. [Figure 46]

[0023] Figure 1 shows a line graph depicting the change in tumor size in a BRAF V600E mutant NSCLC xenograft model (a PDX model of NSCLC) over time after administration of test compounds (vehicle control, 0.1 mg / kg trametinib, 100 mg / kg dabrafenib, 100 mg / kg dabrafenib + 0.1 mg / kg trametinib, 10 mg / kg Compound 1, and 10 mg / kg Compound 1 + 0.1 mg / kg trametinib) over time. On day 28, mice treated with Compound 1 with or without trametinib were discontinued and monitored for tumor growth until day 45. The X-axis represents days after treatment initiation, and the Y-axis represents tumor size (mm). Error bars represent the standard error of the mean (SEM). The experiment was performed as described in Example 36. [Figure 47]

[0023] Figure 1 shows a line graph depicting the change in tumor size in melanoma PDX models of BRAF inhibitor-resistant melanoma with acquired BRAF kinase domain duplication during treatment with the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib over time, following administration of test compounds over time (vehicle control, 0.1 mg / kg trametinib, 100 mg / kg dabrafenib + 0.1 mg / kg trametinib, 10 mg / kg Compound 1, and 10 mg / kg Compound 1 + 0.1 mg / kg trametinib). On day 21, mice treated with Compound 1 + trametinib discontinued treatment and were monitored for tumor growth until day 38. The X-axis represents days after treatment initiation, and the Y-axis represents tumor volume / size (mm). Experiments were performed as described in Example 37. [Figure 48] Figure 1 shows a line graph depicting the change in tumor size in the A2058 human melanoma cancer cell-derived xenograft CDX model of BRAF inhibitor-resistant melanoma harboring a BRAF V600E plus MEK1 P124S mutation over time, following administration of test compounds (10 μL / g vehicle control, 100 mg / kg dabrafenib, 35 mg / kg encorafenib, and 10 mg / kg Compound 1) over time. The X-axis is days after treatment, and the Y-axis is tumor volume / size (mm). Error bars represent the standard error of the mean (SEM). The experiment was performed as described in Example 38. [Figure 49] 1 is a line graph showing body weight changes after administration of test compounds in female BALB / c nude mice bearing A2058 melanoma xenografts with oncogenic mutations BRAF V600E and MEK1 P124S. The X-axis is the number of days after treatment, and the Y-axis is the group mean body weight (g). Data points represent the group mean body weight. Error bars represent the standard error of the mean (SEM). The experiment was performed as described in Example 39. [Figure 50]Figure 1 shows a line graph showing the % change in body weight (BW) over time in mice implanted with A2058 melanoma CDX. BW change was calculated based on the animal's weight on the first day of grouping. The X-axis is the number of days after treatment, and the Y-axis is the % change in body weight. Data points represent the group mean % change in BW. Error bars represent the standard error of the mean (SEM). The experiment was performed as described in Example 39. [Figure 51] Figure 1 shows a line graph showing tumor volume (mm3) after administration of test compounds in female BALB / c nude mice bearing A2058 xenografts. The X-axis is days after treatment, and the Y-axis is tumor size (mm). Data points represent group mean tumor volume. Error bars represent standard error of the mean (SEM). The experiment was performed as described in Example 39. [Figure 52A]

[0023] Figure 1 shows a bar graph depicting the concentration of Compound 1 over time in plasma and tumors collected from mice implanted with A2058 melanoma CDX at 1 hour, 6 hours, 12 hours, 24 hours, and 48 hours post-dose. The Y-axis is the concentration of Compound 1 (ng / g). Error bars represent the standard error of the mean (SEM). The experiment was performed as described in Example 39. [Figure 52B]

[0023] Figure 1 shows a bar graph depicting the concentration of encorafenib over time in plasma and tumors collected from mice implanted with A2058 melanoma CDX at 1 hour, 6 hours, 12 hours, 24 hours, and 48 hours after compound administration. The Y-axis is the concentration of encorafenib 1 (ng / g). Error bars represent the standard error of the mean (SEM). The experiment was performed as described in Example 39. [Figure 52C]

[0023] Figure 1 shows a bar graph depicting the concentration of dabrafenib over time in plasma and tumors collected from mice implanted with A2058 melanoma CDX, with levels at 6, 12, 24, and 48 hours post-dose. The Y-axis represents the concentration of dabrafenib (ng / g). Error bars represent the standard error of the mean (SEM). The experiment was performed as described in Example 39. [Figure 53A]1 is a bar graph showing Western blot analysis of p-ERK and ERK expression levels in A2058 tumors at 6 hours, 12 hours, 24 hours, and 48 hours after administration of a single dose of 10 mg / kg of Compound 1. Vehicle-induced expression levels at 6 hours after administration were used as a control. The experiment was performed as described in Example 39. [Figure 53B] 1 is a bar graph showing Western blot analysis of p-ERK and ERK expression levels in A2058 tumors at 6, 12, 24, and 48 hours after administration of 35 mg / kg encorafenib. Vehicle-induced expression levels at 6 hours post-administration were used as a control. The experiment was performed as described in Example 39. [Figure 53C] Figure 1 shows a bar graph depicting Western blot analysis of p-ERK and ERK expression levels in A2058 tumors at 6, 12, 24, and 48 hours after administration of 100 mg / kg dabrafenib. Vehicle-induced expression levels at 6 hours post-administration were used as a control. The experiment was performed as described in Example 39. [Figure 54A] 1 shows a bar graph showing Western blot analysis of BRAF (V600E) expression levels in A2058 tumors at 6 hours, 12 hours, 24 hours, and 48 hours after administration of 10 mg / kg of Compound 1. The expression level of vehicle at 6 hours after administration was used as a control. The experiment was carried out as described in Example 39. [Figure 54B] 1 is a bar graph showing Western blot analysis of BRAF(V600E) expression levels in A2058 tumors at 6, 12, 24, and 48 hours after administration of 35 mg / kg encorafenib. Vehicle-induced expression levels at 6 hours post-administration were used as a control. The experiment was performed as described in Example 39. [Figure 54C]1 is a bar graph showing Western blot analysis of BRAF(V600E) expression levels in A2058 tumors at 6, 12, 24, and 48 hours after administration of 100 mg / kg dabrafenib. Vehicle-induced expression levels at 6 hours post-administration were used as a control. The experiment was performed as described in Example 39. DETAILED DESCRIPTION OF THE INVENTION

[0061] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. As used herein, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice and testing of this application, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. References cited herein are not admitted to be prior art to this application. In case of conflict, the present specification, including definitions, will control. Additionally, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0062] Compounds are described using their proper names. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0063] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items. The term "or" means "and / or." The recitation of ranges of values, unless otherwise stated herein, is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and are independently combinable. All methods described herein can be performed in any suitable order unless otherwise stated herein or clearly contradicted by context. The use of examples or exemplary language (e.g., "such as") is intended merely to better describe the invention and does not purport to limit the scope of the invention unless otherwise stated in the claims.

[0064] The term "alkyl," alone or in combination, refers to a straight-chain, branched-chain, or cyclic alkyl group having 1 to 8 carbon atoms, particularly a straight-chain, branched-chain, or cyclic alkyl group having 1 to 6 carbon atoms, and more particularly a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms. Examples of straight-chain, branched, or cyclic C1-C6 alkyl are methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, cyclobutyl, isobutyl, tert-butyl, pentyl, cyclopentyl, isopentyl, hexyl, isohexyl, and cyclohexyl. In certain embodiments, "alkyl" is methyl. In certain embodiments, "alkyl" is ethyl.

[0065] The present invention includes the compounds described herein, which have at least one desired isotopic substitution of an atom, that is, enriched, in an amount exceeding the natural abundance of the isotope.Isotopes are atoms with the same atomic number but different mass numbers, that is, the same number of protons but different number of neutrons.When isotope substitution is used, it is common to replace at least one hydrogen with deuterium.

[0066] More generally, examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, and fluorine, e.g. 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 17 O. 18 O. 18 F, and 35 In one non-limiting embodiment, the isotopically labeled compounds are used in metabolic studies (e.g., 14 C), reaction kinetic studies (e.g. 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or radiation treatment of patients. Additionally, any hydrogen atoms present in the compounds of the present invention can be replaced by 18 It may be substituted with an F atom, which may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or examples and preparations described below, by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0067] General examples, without limitation, include isotopes of hydrogen, such as deuterium ( 2 H) and tritium ( 3 H) can be used anywhere in the depicted structures where the desired result is achieved. Alternatively, or additionally, isotopes of carbon, such as 13 C and 14 C can be used.

[0068] Isotopic substitution, e.g., deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is replaced with deuterium. In certain embodiments, the isotope is enriched to 90%, 95%, or 99% or more at any position of interest. In one non-limiting embodiment, deuterium is enriched to 90%, 95%, or 99% at the desired position.

[0069] In one non-limiting embodiment, substitution of a hydrogen atom with a deuterium atom can occur in any compound described herein. For example, an alkyl residue can be deuterated if any of the groups is methyl, ethyl, or methoxy, or contains these, e.g., by substitution (such as, in non-limiting embodiments, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, OCDH2, OCD2H, or OCD3). In certain other embodiments, when two substituents combine to form a ring, the unsubstituted carbon can be deuterated. This substitution can improve the properties of Compound 1; for example, deuterium substitution at a metabolic site can decrease the metabolic rate (e.g., kinetic isotope effect). Similarly, deuterium substitution near a metabolic site can also decrease the metabolic rate. In certain embodiments, deuterium is substituted at a metabolic site or the α, β, or γ position.

[0070] The compounds of the present invention can form solvates with solvents, including water. Thus, in one non-limiting embodiment, the present invention includes solvated forms of the compounds described herein. The term "solvate" refers to a molecular complex of a compound of the present invention (including its salts) with one or more solvent molecules. Non-limiting examples of solvents include water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex of a compound of the present invention with water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent may be isotopically substituted, for example, DO, acetone-d6, and DMSO-d6. Solvates may be in liquid or solid form.

[0071] "Dosage form" means a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injectables, suspensions, liquids, emulsions, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gels, mucosal, etc. "Dosage form" can also include implants, for example, implants inserted into a tumor or abnormal cell growth.

[0072] "Parenteral" administration of the compounds includes, for example, subcutaneous (sc), intravenous (iv), intramuscular (im), or intrasternal injection or infusion techniques.

[0073] The term "pharmaceutically acceptable salt" refers to a salt suitable for use in contact with human and animal tissues. Salts of the present compounds can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (e.g., hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg, or K), or by reacting the free base form of the compound with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where feasible. Salts of the present compounds may optionally further comprise a solvate of the compound or its salt.

[0074] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues. For example, conventional non-toxic base salts include those derived from inorganic bases such as sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium bicarbonate, and potassium carbonate. Further lists of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0075] The term "carrier" refers to a diluent, excipient, or vehicle in which an active agent is used or delivered.

[0076] The term "pharmaceutically acceptable excipient" refers to ingredients used in the manufacture of a dosage form and are suitably non-toxic, such as disintegrants, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants or lubricants used in formulating pharmaceutical products.

[0077] A "patient" or "host" or "subject" is a human or non-human animal in need of treatment for any of the disorders specifically described herein, e.g., disorders regulated by BRAF, particularly mutant BRAF. Typically, the host is a human. "Host" can alternatively refer to, for example, mammals, primates (e.g., humans), horses, dogs, cats, cows, sheep, goats, birds, etc.

[0078] A "therapeutically effective amount" means the amount of a compound that, when administered to a host in need thereof, is sufficient to treat a medical condition. A "therapeutically effective amount" will vary depending on the medical condition being treated, the severity of the disease being treated, the age and relative health of the host, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0079] Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description in range format is for convenience only and should not be construed as a limitation on the scope of the invention. The description of a range should be considered to specifically disclose all possible subranges and individual numerical values ​​within that range. For example, description of a range such as 1 to 6 should be considered to be a specific disclosure of each subrange of 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, e.g., 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the broadness of the range.

[0080] 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.

[0081] If one of the starting materials or compounds of the present invention 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 (e.g., as described in "Protective Groups in Organic Chemistry" by PGM Wuts, 5th Ed., 2007, Wiley, New York) can be introduced before the critical step by applying methods known in the literature. 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-butyl (tBu), tert-butoxycarbonyl (Boc), 9-fluorenylmethylcarbamate (Fmoc), 2-trimethylsilylethylcarbamate (Teoc), carbobenzyloxy (Cbz), and p-methoxybenzyloxycarbonyl (Moz).

[0082] The compounds of the present invention may contain 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, unless the context dictates otherwise.

[0083] The term "asymmetric carbon atom" refers to a carbon atom that has four different substituents. According to the Cahn-Ingold-Prelog rules, an asymmetric carbon atom can have either the "R" or "S" configuration.

[0084] 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, unless otherwise indicated in the context or in a drawing.

[0085] In embodiments in which chirally pure isomers (or optically pure enantiomers) are provided, chiral purity means that the compound contains greater than 90 mole % of the desired isomer, particularly greater than 95 mole % of the desired isomer, greater than 98 mole % of the desired isomer, or greater than 99 mole % of the desired isomer, said mole percentages being based on the total moles 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.

[0086] Morphic form of compound 1 A study of the morphic forms of Compound 1 was conducted on Compound 1 itself (free form) and salts of Compound 1 (salt forms). A total of three crystalline free forms of Compound 1 were identified as polymorphs, including Form A, a hydrate, and two anhydrates identified as Forms B and C. From the salt study, five salts and their polymorphs were identified, including sodium salt Form D of Compound 1, sodium salt Form E of Compound 1, sodium salt Form F of Compound 1, potassium salt Form G of Compound 1, and potassium salt Form H of Compound 1.

[0087] Morphic forms of free compound 1 The formation of morphic forms of compound 1 was investigated under various crystallization conditions. The conditions tested included equilibration, slow cooling, slow evaporation, precipitation by addition of antisolvent, and vapor diffusion.

[0088] Three crystalline forms of Compound 1 have been identified: Form A, the starting material, and two anhydrates, Form B and Form C.

[0089] Compound 1 Form A Form A is a low-crystalline form. Form A was obtained from IPA, MTBE, EtOH, IPAc, and toluene by equilibration at 25°C, from IPA, IPAc, toluene, DMSO / water (v:v=23:77), and DMSO / water (v:v=57:43) by temperature cycling, and from acetone by antisolvent addition experiments. After two weeks of equilibration, no improvement in crystallinity was observed. KF results indicate a water content of approximately 1.9 wt%. DSC shows a broad endothermic peak starting at approximately 13°C. Form A has a T of 167.9°C. onset It melts at 160°C with an enthalpy of 18 J / g. TGA shows a weight loss of about 2.7% at about 160°C. 1 No residual solvent is detected by 1 H NMR.

[0090] In certain embodiments, Form A is characterized by an XRPD pattern having one or more peaks within + / - 0.4°, 0.3°, or 0.2° 2θ of the peaks set forth in Peak List #1 (see Example 28 for a description of the XRPD method).

[0091] TIFF2025541736000013.tif36170

[0092] 1. In certain embodiments, Form A of Compound 1 is characterized by an XRPD pattern having at least three peaks selected from 15.3, 18.4, 24.9, and 25.3 + / - 0.4 degrees 2θ. In other embodiments, Form A of Compound 1 is characterized by an XRPD pattern having at least three peaks selected from 15.3, 18.4, 24.9, and 25.3 + / - 0.3 degrees 2θ. Alternatively, in other embodiments, Form A of Compound 1 is characterized by an XRPD pattern having at least three peaks selected from 15.3, 18.4, 24.9, and 25.3 + / - 0.2 degrees 2θ.

[0093] In certain embodiments, Form A is characterized by an onset of melting of about 167.9°C ± 10°C in a DCS thermogram and / or a melting enthalpy of about 18 J / g ± 10 J / g. In certain embodiments, Form A is characterized by a weight loss of about 2.7% at about 160.0°C ± 10°C as measured by TGA.

[0094] In certain embodiments, Form A is characterized by a solubility in DMSO of at least about 250 mg / mL when dissolved at about 25° C.±5° C., as described in Example 7.

[0095] Figure 7 shows the XRPD pattern of Compound 1 Form A. Figure 8 shows the DSC thermogram of Compound 1 Form A. Figure 9 shows the TGA thermogram of Compound 1 Form A.

[0096] Form B of Compound 1 Form B is anhydrous. Form B was obtained from the solvent system tested by equilibration. Form B has moderate crystallinity. DSC shows a T of 194.4°C. onset Form B exhibits a melting peak at about 170°C. Form B decomposes upon melting. TGA shows a weight loss of about 1.1% at about 170°C. 1No residual solvent is detected by H NMR. Form B can also be isolated from organic solvents such as methanol or acetonitrile and water mixtures with a water activity greater than about 0.9, so this anhydrate should also be stable in aqueous media.

[0097] Morphic Form B is superior to other morphic forms of Compound 1 due to its high stability, scalability, and reproducibility. For example, when Form B of Compound 1 is tested for stability over a one-week period at 25°C / 92% relative humidity in an open container, 40°C / 75% RH in an open container, and 60°C in an airtight container, Form B of Compound 1 exhibits excellent chemical and physical stability without any change in purity, crystalline morphology, and / or crystallinity. When Form B of Compound 1 is tested in a moisture sorption and desorption experiment at 25°C with a 40-0-95-0-40% RH cycle, Form B of Compound 1 exhibits excellent stability, no change in crystallinity, and only slight hygroscopicity (1.6% water absorption at 95% RH). Form B of Compound 1 also exhibits excellent morphic stability under compression (2 MPa and 10 MPa), dry milling, and wet granulation conditions. Wet granulation experiments in the presence of water or ethanol also show no change in crystallinity. Form B of Compound 1 also exhibits morphic form stability in aqueous media over a wide pH range spanning from 1.2 to 7.0.

[0098] In certain embodiments, Form B is characterized by an XRPD pattern having one or more peaks within + / - 0.4°, 0.3°, or 0.2° 2θ of the peaks set forth in Peak List #2 (see Example 28 for a description of the XRPD method).

[0099] TIFF2025541736000014.tif252170

[0100] 1. In certain embodiments, Form B of Compound 1 is characterized by an XRPD pattern having at least three peaks selected from 7.5, 8.8, 10.0, 10.5, 12.6, 14.7, 15.4, 16.4, 16.7, 18.6, 22.7, and 25.3 + / - 0.4 degrees 2θ.

[0101] Other embodiments include, but are not limited to:

[0102] 2. The morphic form of embodiment 1, wherein Form B of Compound 1 is characterized by an XRPD pattern having at least three peaks selected from 7.5, 8.8, 10.0, 10.5, 12.6, 14.7, 15.4, 16.4, 16.7, 18.6, 22.7, and 25.3 + / - 0.3 degrees 2θ.

[0103] 3. The morphic form of embodiment 1, wherein Form B of Compound 1 is characterized by an XRPD pattern having at least three peaks selected from 7.5, 8.8, 10.0, 10.5, 12.6, 14.7, 15.4, 16.4, 16.7, 18.6, 22.7, and 25.3 + / - 0.2 degrees 2θ.

[0104] 4. The morphic form of any one of embodiments 1 to 3, exhibiting at least four of the above-listed peaks.

[0105] 5. The morphic form of any one of embodiments 1 to 3, exhibiting at least five of the above-listed peaks.

[0106] 6. The morphic form of any one of embodiments 1 to 3, exhibiting at least six of the recited peaks.

[0107] 7. The morphic form of any one of embodiments 1-3, exhibiting at least seven of the recited peaks.

[0108] 8. The morphic form of any one of embodiments 1 to 3, exhibiting at least eight of the recited peaks.

[0109] 9. The morphic form of any one of embodiments 1-3, exhibiting at least nine of the recited peaks.

[0110] 10. The morphic form of any one of embodiments 1-3, exhibiting at least 10 of the recited peaks.

[0111] 11. The morphic form of any one of embodiments 1-10, wherein the XRPD comprises a peak at 16.4 + / - 0.2 degrees 2θ.

[0112] 12. The morphic form of any one of embodiments 1-11, wherein the XRPD comprises a peak at 10.0+ / -0.2 degrees 2θ.

[0113] 13. The morphic form of any one of embodiments 1-12, wherein the XRPD comprises a peak at 15.4 + / - 0.2 degrees 2θ.

[0114] 14. The morphic form of any one of embodiments 1-13, wherein the XRPD comprises a peak at 16.7+ / -0.2 degrees 2θ.

[0115] 15. The morphic form of any one of embodiments 1-14, wherein the XRPD comprises a peak at 8.8+ / -0.2 degrees 2θ.

[0116] 16. The morphic form of any one of embodiments 1-15, wherein the XRPD comprises a peak at 12.6+ / -0.2 degrees 2θ.

[0117] 17. The morphic form of any one of embodiments 1-16, wherein the XRPD comprises a peak at 14.7+ / -0.2 degrees 2θ.

[0118] 18. The morphic form of any one of embodiments 1-17, wherein the XRPD comprises a peak at 10.5+ / -0.2 degrees 2θ.

[0119] 19. The morphic form of any one of embodiments 1-18, wherein the XRPD comprises a peak at 25.3 + / - 0.2 degrees 2θ.

[0120] 20. The morphic form of any one of embodiments 1-19, wherein the XRPD comprises a peak at 22.7+ / -0.2 degrees 2θ.

[0121] In certain embodiments, Form B of Compound 1 is characterized by an onset of melting of about 194.4° C.±10° C. in a DCS thermogram and / or a melting enthalpy of about 71.3 J / g±10 J / g. In certain embodiments, Form B is characterized by a weight loss of about 1.1% at about 170.0° C.±10° C. as measured by TGA.

[0122] In certain embodiments, Form B of Compound 1 is characterized by a solubility of at least about 250 mg / mL in DMSO when dissolved at about 25° C.±5° C., as described in Example 7.

[0123] Figure 1 shows the XRPD pattern of Form B of Compound 1. Figure 2 shows the DSC thermogram of Form B of Compound 1. Figure 3 shows the TGA thermogram of Form B of Compound 1.

[0124] Form C of Compound 1 Form C is an anhydrate. Form C was obtained from ethyl acetate and 2-methyltetrahydrofuran (2-MeTHF) by equilibration at 25°C and from 2-MeTHF by temperature cycling. Form C has moderate crystallinity. DSC shows a broad endothermic peak at 25.9°C with a T of 185.3°C. onset Form C exhibits a melting peak at about 180°C. Form C decomposes upon melting. TGA shows a weight loss of about 2.2% at about 180°C. 1H NMR indicates about 2.7% by weight of ethyl acetate residues (0.2 equivalents by molar ratio). Form C is a metastable anhydrate. Form C, for example, converted to the anhydrate form B after about 8 temperature cycles.

[0125] In certain embodiments, Form C is characterized by an XRPD pattern having one or more peaks within + / - 0.4°, 0.3°, or 0.2° 2θ of the peaks set forth in Peak List #3 (see Example 28 for a description of the XRPD method).

[0126] TIFF2025541736000015.tif98170

[0127] 1. In certain embodiments, Form C of Compound 1 is characterized by an XRPD pattern having at least three peaks selected from 7.2, 13.4, 14.5, 14.9, 15.8, 16.5, 17.9, 18.4, 19.7, 20.6, 22.2, and 29.4 + / - 0.4 degrees 2θ.

[0128] 2. The morphic form of embodiment 1, wherein Form C of Compound 1 is characterized by an XRPD pattern having at least three peaks selected from 7.2, 13.4, 14.5, 14.9, 15.8, 16.5, 17.9, 18.4, 19.7, 20.6, 22.2, and 29.4 + / - 0.3 degrees 2θ.

[0129] 3. The morphic form of embodiment 1, wherein Form C of Compound 1 is characterized by an XRPD pattern having at least three peaks selected from 7.2, 13.4, 14.5, 14.9, 15.8, 16.5, 17.9, 18.4, 19.7, 20.6, 22.2, and 29.4 + / - 0.2 degrees 2θ.

[0130] Other embodiments include, but are not limited to:

[0131] 4. The morphic form of any one of embodiments 1 to 3, exhibiting at least four of the above-listed peaks.

[0132] 5. The morphic form of any one of embodiments 1 to 3, exhibiting at least five of the above-listed peaks.

[0133] 6. The morphic form of any one of embodiments 1 to 3, exhibiting at least six of the recited peaks.

[0134] 7. The morphic form of any one of embodiments 1-3, exhibiting at least seven of the recited peaks.

[0135] 8. The morphic form of any one of embodiments 1 to 3, exhibiting at least eight of the recited peaks.

[0136] 9. The morphic form of any one of embodiments 1-3, exhibiting at least nine of the recited peaks.

[0137] 10. The morphic form of any one of embodiments 1-3, exhibiting at least 10 of the recited peaks.

[0138] 11. The morphic form of any one of the preceding embodiments, wherein the XRPD comprises a peak at 20.6 + / - 0.2 degrees 2θ.

[0139] 12. The morphic form of any one of embodiments 1-11, wherein the XRPD comprises a peak at 18.4 + / - 0.2 degrees 2θ.

[0140] 13. The morphic form of any one of embodiments 1-12, wherein the XRPD comprises a peak at 15.8+ / -0.2 degrees 2θ.

[0141] 14. The morphic form of any one of embodiments 1-13, wherein the XRPD comprises a peak at 19.7+ / -0.2 degrees 2θ.

[0142] 15. The morphic form of any one of embodiments 1-14, wherein the XRPD comprises a peak at 17.9 + / - 0.2 degrees 2θ.

[0143] 16. The morphic form of any one of embodiments 1-15, wherein the XRPD comprises a peak at 14.9 + / - 0.2 degrees 2θ.

[0144] 17. The morphic form of any one of embodiments 1-16, wherein the XRPD comprises a peak at 14.5+ / -0.2 degrees 2θ.

[0145] 18. The morphic form of any one of embodiments 1-17, wherein the XRPD comprises a peak at 16.5+ / -0.2 degrees 2θ.

[0146] 19. The morphic form of any one of embodiments 1-18, wherein the XRPD comprises a peak at 22.2 + / - 0.2 degrees 2θ.

[0147] 20. The morphic form of any one of embodiments 1-19, wherein the XRPD comprises a peak at 13.4 + / - 0.2 degrees 2θ.

[0148] In certain embodiments, Form C is characterized by an onset of melting of about 185.3°C ± 10°C in a DCS thermogram and / or a melting enthalpy of about 33.9 J / g ± 10 J / g. In certain embodiments, Form C is characterized by a weight loss of about 2.2% at about 180.0°C ± 10°C as measured by TGA.

[0149] Figure 10 shows the XRPD pattern of Form C of Compound 1. Figure 11 shows the DSC thermogram of Form C of Compound 1. Figure 12 shows the TGA thermogram of Form C of Compound 1.

[0150] Salt morphic form of compound 1 The formation of the salt morphic form of Compound 1 was investigated under various crystallization conditions. The conditions tested included slurry equilibration, precipitation by addition of antisolvent, and reslurrying.

[0151] Five crystalline salt morphic forms of compound 1 have been identified: sodium salt form D, sodium salt form E, sodium salt form F, potassium salt form G, and potassium salt form H. Among these salt forms D-H, sodium salt form F exhibits favorable physicochemical properties, including good crystallinity, reasonable stoichiometry, high dehydration onset, and good counterion stability.

[0152] Sodium salt form F of compound 1 The sodium salt form F of Compound 1 is a hydrate. Sodium salt form F has a moderate degree of crystallinity. DSC shows dehydration peaks at 13.7°C, 64.7°C, and 116.5°C, with a T of 194.7°C. onset The melting point is 180°C. TGA shows a weight loss of about 4.8% at about 180°C. HPLC shows a chemical purity of 98.9%. IC and HPLC show a stoichiometry of 1:1.2 for the form and sodium salt. 1 No residual solvent is detected by H NMR. KF (Karl Fischer analysis) indicates that it contains about 4.6% water by weight (corresponding to 2.5 water molecules). This hydrate form is stable under vacuum drying at about 30°C.

[0153] Sodium salt Form F shows a loss of chemical purity of about 1% after photostability evaluation. Sodium salt Form F shows a slight loss of chemical purity (about 1.2%) after stress at 25°C / 92%RH. Sodium salt Form F also shows a slight loss of crystallinity after stressing at 60°C for 1 week in a closed container, which may be due to partial dehydration.

[0154] The hygroscopicity of sodium salt Form F was evaluated by dynamic vapor sorption (DVS) testing at 25° C. Sodium salt Form F is slightly hygroscopic below 80% RH. Thereafter, sodium salt Form F becomes hygroscopic, exhibiting a water absorption of 12.6% from 80% RH to 95% RH at 25° C. After the DVS testing, sodium salt Form F shows no morphological change and no decrease in crystallinity.

[0155] In certain embodiments, Form F is characterized by an XRPD pattern having one or more peaks within + / - 0.4°, 0.3°, or 0.2° 2θ of the peaks set forth in Peak List #4 (see Example 28 for a description of the XRPD method).

[0156] TIFF2025541736000016.tif213170

[0157] 1. In certain embodiments, sodium salt Form F of Compound 1 is characterized by an XRPD pattern having at least three peaks selected from 13.6, 15.0, 15.5, 16.0, 17.5, 18.3, 19.7, 20.3, 21.7, 24.0, 24.5, 30.3, 30.4, and 34.5 + / - 0.4 degrees 2θ.

[0158] 2. The morphic form of embodiment 1, wherein sodium salt Form F of Compound 1 is characterized by an XRPD pattern having at least three peaks selected from 13.6, 15.0, 15.5, 16.0, 17.5, 18.3, 19.7, 20.3, 21.7, 24.0, 24.5, 30.3, 30.4, and 34.5 + / - 0.3 degrees 2θ.

[0159] 3. The morphic form of embodiment 1, wherein sodium salt Form F of Compound 1 is characterized by an XRPD pattern having at least three peaks selected from 13.6, 15.0, 15.5, 16.0, 17.5, 18.3, 19.7, 20.3, 21.7, 24.0, 24.5, 30.3, 30.4, and 34.5 + / - 0.2 degrees 2θ.

[0160] Other embodiments include, but are not limited to:

[0161] 4. The morphic form of any one of embodiments 1 to 3, exhibiting at least four of the above-listed peaks.

[0162] 5. The morphic form of any one of embodiments 1 to 3, exhibiting at least five of the above-listed peaks.

[0163] 6. The morphic form of any one of embodiments 1 to 3, exhibiting at least six of the recited peaks.

[0164] 7. The morphic form of any one of embodiments 1-3, exhibiting at least seven of the recited peaks.

[0165] 8. The morphic form of any one of embodiments 1 to 3, exhibiting at least eight of the recited peaks.

[0166] 9. The morphic form of any one of embodiments 1-3, exhibiting at least nine of the recited peaks.

[0167] 10. The morphic form of any one of embodiments 1-3, exhibiting at least 10 of the recited peaks.

[0168] 11. The morphic form of any one of embodiments 1-10, wherein the XRPD comprises a peak at 19.7+ / -0.2 degrees 2θ.

[0169] 12. The morphic form of any one of embodiments 1-11, wherein the XRPD comprises a peak at 20.3 + / - 0.2 degrees 2θ.

[0170] 13. The morphic form of any one of embodiments 1-12, wherein the XRPD comprises a peak at 15.0+ / -0.2 degrees 2θ.

[0171] 14. The morphic form of any one of embodiments 1-13, wherein the XRPD comprises a peak at 21.7+ / -0.2 degrees 2θ.

[0172] 15. The morphic form of any one of embodiments 1-14, wherein the XRPD comprises a peak at 30.4 + / - 0.2 degrees 2θ.

[0173] 16. The morphic form of any one of embodiments 1-15, wherein the XRPD comprises a peak at 13.6 + / - 0.2 degrees 2θ.

[0174] 17. The morphic form of any one of embodiments 1-16, wherein the XRPD comprises a peak at 24.0+ / -0.2 degrees 2θ.

[0175] 18. The morphic form of any one of the preceding embodiments, wherein the XRPD comprises a peak at 18.3 + / - 0.2 degrees 2θ.

[0176] 19. The morphic form of any one of embodiments 1-18, wherein the XRPD comprises a peak at 24.5+ / -0.2 degrees 2θ.

[0177] 20. The morphic form of any one of embodiments 1-19, wherein the XRPD comprises a peak at 34.5+ / -0.2 degrees 2θ.

[0178] In certain embodiments, Form F is characterized by peaks at any one of 59.8°C ± 10°C, 132.5°C ± 10°C, and 197.7°C ± 10°C, and / or a melting enthalpy of about 26.4 J / g ± 10 J / g and 41.8 J / g ± 10 J / g, as measured by DSC. In certain embodiments, Form F is characterized by a weight loss of about 2.7% at about 100.0°C ± 10°C, and about 3.2% in the temperature range of about 100.0°C to 170.0°C ± 10°C, as measured by TGA.

[0179] Figure 17 shows the XRPD pattern of Compound 1 sodium salt Form F. Figure 18 shows the DSC thermogram of Compound 1 sodium salt Form F. Figure 19 shows the TGA thermogram of Compound 1 sodium salt Form F.

[0180] Sodium salt form D of compound 1 The sodium salt form D of Compound 1 is a hydrate with moderate crystallinity. DSC shows a dehydration peak at 4.5°C, a peak at 67.5°C, an endothermic peak at 117.9°C, and a T of 229.5°C. onset The compound exhibits a melting point of 100°C. TGA shows a weight loss of about 6.9% at about 150°C. HPLC shows a chemical purity of 97.4%. IC and HPLC confirm the Na content of the compound. + This indicates that the stoichiometric salt ratio to is 1:1. 1 No residual solvent is detected by 1 H NMR.

[0181] In certain embodiments, Form D is characterized by an XRPD pattern having one or more peaks within + / - 0.4°, 0.3°, or 0.2° 2θ of the peaks set forth in Peak List #5 (see Example 28 for a description of the XRPD method).

[0182] TIFF2025541736000017.tif98170

[0183] 1. In certain embodiments, sodium salt Form D of Compound 1 is characterized by an XRPD pattern having at least three peaks selected from 6.2, 7.7, 11.7, 12.5, 13.6, 15.3, 15.7, 17.5, 20.8, and 27.5 + / - 0.4 degrees 2θ.

[0184] 2. The morphic form of embodiment 1, wherein sodium salt Form D of Compound 1 is characterized by an XRPD pattern having at least three peaks selected from 6.2, 7.7, 11.7, 12.5, 13.6, 15.3, 15.7, 17.5, 20.8, and 27.5 + / - 0.3 degrees 2θ.

[0185] 3. The morphic form of embodiment 1, wherein sodium salt Form D of Compound 1 is characterized by an XRPD pattern having at least three peaks selected from 6.2, 7.7, 11.7, 12.5, 13.6, 15.3, 15.7, 17.5, 20.8, and 27.5 + / - 0.2 degrees 2θ.

[0186] Figure 23 shows the XRPD pattern of the sodium salt Form D of Compound 1. Figure 24 shows the DSC thermogram of the sodium salt Form D of Compound 1. Figure 25 shows the TGA thermogram of the sodium salt Form D of Compound 1.

[0187] Sodium salt form E of compound 1 Sodium salt Form E of Compound 1 is a hydrate. Sodium salt Form E has moderate crystallinity. DSC shows a dehydration peak at 5.6°C, a peak at 61.1°C, and a T of 228.7°C. onset The compound exhibits a melting point of about 10.8% at about 180°C. TGA shows a weight loss of about 10.8% at about 180°C. HPLC shows a chemical purity of about 98%. IC and HPLC confirmed the Na + This indicates that the stoichiometric salt ratio to is 1:1. 1 No residual solvent is detected by H NMR. The water content by KF analysis is 10.2 wt%.

[0188] In certain embodiments, Form E is characterized by an XRPD pattern having one or more peaks within + / - 0.4°, 0.3°, or 0.2° 2θ of the peaks set forth in Peak List #6 (see Example 28 for a description of the XRPD method).

[0189] TIFF2025541736000018.tif103170

[0190] 1. In certain embodiments, sodium salt Form E of Compound 1 is characterized by an XRPD pattern having at least three peaks selected from 5.8, 6.3, 7.8, 12.5, 13.9, 15.7, 17.8, 20.2, and 25.3 + / - 0.4 degrees 2θ.

[0191] 2. The morphic form of embodiment 1, wherein the sodium salt Form E of Compound 1 is characterized by an XRPD pattern having at least three peaks selected from 5.8, 6.3, 7.8, 12.5, 13.9, 15.7, 17.8, 20.2, and 25.3 + / - 0.3 degrees 2θ.

[0192] 3. The morphic form of embodiment 1, wherein the sodium salt Form E of Compound 1 is characterized by an XRPD pattern having at least three peaks selected from 5.8, 6.3, 7.8, 12.5, 13.9, 15.7, 17.8, 20.2, and 25.3 + / - 0.2 degrees 2θ.

[0193] Figure 26 shows the XRPD pattern of the sodium salt Form E of Compound 1. Figure 27 shows the DSC thermogram of the sodium salt Form E of Compound 1. Figure 28 shows the TGA thermogram of the sodium salt Form E of Compound 1.

[0194] Potassium salt form G of compound 1 The potassium salt form G of compound 1 is a solvate. The potassium salt form G has low crystallinity. DSC shows multiple thermal events (Figure 30). TGA shows a weight loss of about 4.5% at about 170°C and a weight loss of about 4.8% in the temperature range of about 170°C to 230°C. HPLC shows a chemical purity of about 99%. IC and HPLC confirmed the K + This indicates that the stoichiometric salt ratio to is 1:1. 1 H NMR indicates 2.5 wt % acetone residual solvent (0.42 equivalents by molar ratio).

[0195] Figure 29 shows the XRPD pattern of the potassium salt Form G of Compound 1. Figure 30 shows the DSC thermogram of the potassium salt Form G of Compound 1. Figure 31 shows the TGA thermogram of the potassium salt Form G of Compound 1.

[0196] Potassium salt form H of compound 1 The potassium salt form H of Compound 1 is a hydrate. The potassium salt form H has a moderate degree of crystallinity. DSC shows a dehydration peak at 4.2°C, a peak at 87.2°C, an endothermic peak at 123.0°C, and a T of 221.7°C. onset The compound exhibits a melting point of about 170°C. TGA shows a weight loss of about 6.6% at about 170°C. HPLC shows a chemical purity of about 99%. IC and HPLC confirm the K + This indicates that the stoichiometric salt ratio to is 1:1.2. 1 No residual solvent is detected by 1 H NMR.

[0197] Figure 32 shows the XRPD pattern of potassium salt Form H of Compound 1. Figure 33 shows the DSC thermogram of potassium salt Form H of Compound 1. Figure 34 shows the TGA thermogram of potassium salt Form H of Compound 1.

[0198] Additional Embodiments 1. A structure characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five 2θ values ​​selected from 7.5±0.2°, 8.8±0.2°, 10.0±0.2°, 10.5±0.2°, 12.6±0.2°, 14.7±0.2°, 15.4±0.2°, 16.4±0.2°, 16.7±0.2°, 18.6±0.2°, 22.7±0.2°, and 25.3±0.2°: [ka] The isolated crystalline form B of the compound of formula (I).

[0199] 2. The isolated crystalline form B of embodiment 1, wherein the XRPD pattern comprises at least six 2θ values ​​selected from 7.5±0.2°, 8.8±0.2°, 10.0±0.2°, 10.5±0.2°, 12.6±0.2°, 14.7±0.2°, 15.4±0.2°, 16.4±0.2°, 16.7±0.2°, 18.6±0.2°, 22.7±0.2°, and 25.3±0.2°.

[0200] 3. The isolated crystalline form B of embodiment 1, wherein the XRPD pattern comprises at least seven 2θ values ​​selected from 7.5±0.2°, 8.8±0.2°, 10.0±0.2°, 10.5±0.2°, 12.6±0.2°, 14.7±0.2°, 15.4±0.2°, 16.4±0.2°, 16.7±0.2°, 18.6±0.2°, 22.7±0.2°, and 25.3±0.2°.

[0201] 4. The isolated crystalline form B of embodiment 1, wherein the XRPD pattern comprises at least eight 2θ values ​​selected from 7.5±0.2°, 8.8±0.2°, 10.0±0.2°, 10.5±0.2°, 12.6±0.2°, 14.7±0.2°, 15.4±0.2°, 16.4±0.2°, 16.7±0.2°, 18.6±0.2°, 22.7±0.2°, and 25.3±0.2°.

[0202] 5. The isolated crystalline form B of embodiment 1, wherein the XRPD pattern comprises at least nine 2θ values ​​selected from 7.5±0.2°, 8.8±0.2°, 10.0±0.2°, 10.5±0.2°, 12.6±0.2°, 14.7±0.2°, 15.4±0.2°, 16.4±0.2°, 16.7±0.2°, 18.6±0.2°, 22.7±0.2°, and 25.3±0.2°.

[0203] 6. The isolated crystalline form B of embodiment 1, wherein the XRPD pattern comprises at least ten 2θ values ​​selected from 7.5±0.2°, 8.8±0.2°, 10.0±0.2°, 10.5±0.2°, 12.6±0.2°, 14.7±0.2°, 15.4±0.2°, 16.4±0.2°, 16.7±0.2°, 18.6±0.2°, 22.7±0.2°, and 25.3±0.2°.

[0204] 7. The isolated crystalline form B of embodiment 1, wherein the XRPD pattern comprises at least 11 2θ values ​​selected from 7.5±0.2°, 8.8±0.2°, 10.0±0.2°, 10.5±0.2°, 12.6±0.2°, 14.7±0.2°, 15.4±0.2°, 16.4±0.2°, 16.7±0.2°, 18.6±0.2°, 22.7±0.2°, and 25.3±0.2°.

[0205] 8. The isolated crystalline form B of any one of embodiments 1 to 7, wherein the XRPD pattern comprises at least three 2θ values ​​selected from 7.5±0.1°, 8.8±0.1°, 10.0±0.1°, 10.5±0.1°, 12.6±0.1°, 14.7±0.1°, 15.4±0.1°, 16.4±0.1°, 16.7±0.1°, 18.6±0.1°, 22.7±0.1°, and 25.3±0.1°.

[0206] 9. The isolated crystalline form B of any one of embodiments 1 to 8, wherein the XRPD pattern comprises a 2θ value of at least 16.4±0.2°.

[0207] 10. The isolated crystalline form B of any one of embodiments 1 to 9, wherein the XRPD pattern comprises 2θ values ​​of at least 10.0±0.2 degrees.

[0208] 11. The isolated crystalline form B of any one of embodiments 1 to 10, wherein the XRPD pattern comprises a 2θ value of at least 15.4±0.2°.

[0209] 12. The isolated crystalline form B of any one of embodiments 1 to 11, wherein the XRPD pattern comprises a 2θ value of at least 16.7±0.2°.

[0210] 13. The isolated crystalline form B of any one of embodiments 1 to 12, wherein the XRPD pattern comprises a 2θ value of at least 8.8±0.2°.

[0211] 14. The isolated crystalline form B of any one of embodiments 1 to 13, wherein the XRPD pattern comprises a 2θ value of at least 12.6±0.2°.

[0212] 15. The isolated crystalline form B of any one of embodiments 1 to 14, wherein the XRPD pattern comprises a 2θ value of at least 14.7±0.2°.

[0213] 16. The isolated crystalline form B of any one of embodiments 1 to 15, wherein the XRPD pattern comprises a 2θ value of at least 10.5±0.2°.

[0214] 17. The isolated crystalline form B of any one of embodiments 1 to 16, wherein the XRPD pattern comprises a 2θ value of at least 25.3±0.2°.

[0215] 18. The isolated crystalline form B of any one of embodiments 1 to 17, wherein the XRPD pattern comprises a 2θ value of at least 22.7±0.2°.

[0216] 19. The isolated crystalline form B of any one of embodiments 1 to 18, characterized by an XRPD pattern having the characteristic 2θ values ​​of FIG. 1.

[0217] 20. The isolated crystalline form B of any one of embodiments 1-19, having a differential scanning calorimetry (DSC) onset endotherm of about 194±20°C.

[0218] 21. The isolated crystalline form B of any one of embodiments 1-20, having a differential scanning calorimetry (DSC) onset endotherm temperature of about 194±10°C.

[0219] 22. A pharmaceutical composition comprising the isolated crystalline form B of any one of embodiments 1-21 in a pharmaceutically acceptable carrier.

[0220] 23. A pharmaceutical composition comprising Compound 1, a solubility enhancer, a permeation enhancer, a filler, a binder / glidant, and a mucoadhesive / disintegrant, wherein Compound 1 has the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0221] twenty four. a. the solubility enhancer is hypromellose acetate succinate; b. the permeation enhancer is vitamin E; c. the filler is mannitol; d. the binder / glidant is cellulose; e. the mucoadhesive is croscarmellose sodium; 24. The pharmaceutical composition of embodiment 23.

[0222] 25. A method for treating a mutant BRAF-mediated disorder, comprising administering to a patient in need thereof an effective amount of isolated crystalline form B described in any one of embodiments 1 to 21 or the pharmaceutical composition described in any one of embodiments 22 to 24.

[0223] 26. The method of embodiment 25, wherein the patient is a human.

[0224] 27. The method of embodiment 25 or 26, wherein the mutant BRAF-mediated disorder is cancer.

[0225] 28. The method of embodiment 27, wherein the mutant BRAF-mediated cancer is melanoma.

[0226] 29. The method of embodiment 27, wherein the mutant BRAF-mediated cancer is lung cancer.

[0227] 30. The method of embodiment 27, wherein the mutant BRAF-mediated cancer is non-small cell lung cancer.

[0228] 31. The method of embodiment 27, wherein the mutant BRAF-mediated cancer is colorectal cancer.

[0229] 32. The method of embodiment 27, wherein the mutant BRAF-mediated cancer is microsatellite-stable colorectal cancer.

[0230] 33. The method of embodiment 27, wherein the mutant BRAF-mediated cancer is thyroid cancer.

[0231] 34. The method of embodiment 27, wherein the mutant BRAF-mediated cancer is ovarian cancer.

[0232] 35. The method of embodiment 25, 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, undifferentiated pleomorphic xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, pancreatic cancer, clear cell sarcoma of the breast, salivary gland carcinoma, or microsatellite-stable colorectal cancer.

[0233] 36. The method of any one of embodiments 25-35, wherein the patient is also administered an additional active agent.

[0234] 37. The method of embodiment 36, wherein the additional active agent is a MEK inhibitor.

[0235] 38. The method of embodiment 37, wherein the MEK inhibitor is trametinib.

[0236] 39. The method of embodiment 36, wherein the additional active agent is an immune checkpoint inhibitor.

[0237] 40. The method of embodiment 39, wherein the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, ipilimumab, leratolimab, atezolizumab, avelumab, and durvalumab.

[0238] 41. The method of embodiment 36, wherein the additional active agent is cetuximab or panitumumab.

[0239] 42. Isolated crystalline form B according to any one of embodiments 1 to 21 or a pharmaceutical composition according to any one of embodiments 22 to 24 for the therapeutic treatment of a mutant BRAF-mediated disorder.

[0240] 43. The isolated crystalline form B of embodiment 42, wherein the mutant BRAF-mediated disorder is cancer.

[0241] 44. The isolated crystalline form B of embodiment 43, wherein the mutant BRAF-mediated cancer is melanoma.

[0242] 45. The isolated crystalline form B of embodiment 43, wherein the mutant BRAF-mediated cancer is lung cancer.

[0243] 46. ​​The isolated crystalline form B of embodiment 43, wherein the mutant BRAF-mediated cancer is non-small cell lung cancer.

[0244] 47. The isolated crystalline form B of embodiment 43, wherein the mutant BRAF-mediated cancer is colorectal cancer.

[0245] 48. The isolated crystalline form B of embodiment 43, wherein the mutant BRAF-mediated cancer is microsatellite-stable colorectal cancer.

[0246] 49. The isolated crystalline form B of embodiment 43, wherein the mutant BRAF-mediated cancer is thyroid cancer.

[0247] 50. The isolated crystalline form B of embodiment 43, wherein the mutant BRAF-mediated cancer is ovarian cancer.

[0248] 51. The isolated crystalline form B of embodiment 42, 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, undifferentiated pleomorphic xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, pancreatic cancer, clear cell sarcoma of the breast, salivary gland carcinoma, or microsatellite-stable colorectal cancer.

[0249] 52. Isolated crystalline form B according to any one of embodiments 1 to 21 or a pharmaceutical composition according to any one of embodiments 22 to 24, for use in the treatment of a mutant BRAF-mediated disorder.

[0250] 53. The isolated crystalline form B of embodiment 52, wherein the mutant BRAF-mediated disorder is cancer.

[0251] 54. The isolated crystalline form B of embodiment 53, wherein the mutant BRAF-mediated cancer is melanoma.

[0252] 55. The isolated crystalline form B of embodiment 53, wherein the mutant BRAF-mediated cancer is lung cancer.

[0253] 56. The isolated crystalline form B of embodiment 53, wherein the mutant BRAF-mediated cancer is non-small cell lung cancer.

[0254] 57. The isolated crystalline form B of embodiment 53, wherein the mutant BRAF-mediated cancer is colorectal cancer.

[0255] 58. The isolated crystalline form B of embodiment 53, wherein the mutant BRAF-mediated cancer is microsatellite-stable colorectal cancer.

[0256] 59. The isolated crystalline form B of embodiment 53, wherein the mutant BRAF-mediated cancer is thyroid cancer.

[0257] 60. The isolated crystalline form B of embodiment 53, wherein the mutant BRAF-mediated cancer is ovarian cancer.

[0258] 61. The isolated crystalline form B of embodiment 52, 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, undifferentiated pleomorphic xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, pancreatic cancer, clear cell sarcoma of the breast, salivary gland carcinoma, or microsatellite-stable colorectal cancer.

[0259] 62. Use of isolated crystalline form B according to any one of embodiments 1 to 21 or a pharmaceutical composition according to any one of embodiments 22 to 24 in the manufacture of a medicament for the treatment of a mutant BRAF-mediated disorder.

[0260] 63. The use described in embodiment 62, wherein the mutant BRAF-mediated disorder is cancer.

[0261] 64. The use described in embodiment 63, wherein the mutant BRAF-mediated cancer is melanoma.

[0262] 65. The use described in embodiment 63, wherein the mutant BRAF-mediated cancer is lung cancer.

[0263] 66. The use described in embodiment 63, wherein the mutant BRAF-mediated cancer is non-small cell lung cancer.

[0264] 67. The use described in embodiment 63, wherein the mutant BRAF-mediated cancer is colorectal cancer.

[0265] 68. The use described in embodiment 63, wherein the mutant BRAF-mediated cancer is microsatellite-stable colorectal cancer.

[0266] 69. The use described in embodiment 63, wherein the mutant BRAF-mediated cancer is thyroid cancer.

[0267] 70. The use described in embodiment 63, wherein the mutant BRAF-mediated cancer is ovarian cancer.

[0268] 71. The use of embodiment 62, 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, undifferentiated pleomorphic xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, pancreatic cancer, clear cell sarcoma of the breast, salivary gland carcinoma, or microsatellite-stable colorectal cancer.

[0269] 72. The isolated crystalline form B according to any one of embodiments 1 to 21, for use as a therapeutically active substance.

[0270] 73. Formula: [ka] A method for preparing a compound of the formula In the presence of isopropylamine or an isopropylamine salt and a first base, a compound of the formula: [ka] to obtain said compound of formula A-1, In the formula, R X is selected from the group consisting of hydrogen and an amino protecting group.

[0271] 74. The amino protecting group R X is tert-butyloxycarbonyl (BOC), the first base is sodium hydroxide or potassium hydroxide; 74. The method of embodiment 73, wherein the isopropylamine salt is isopropylamine hydrochloride.

[0272] 75. Formula: [ka] A method for preparing a compound of the formula The method comprises: (i) Formula: [ka] with a chiral acid to obtain a mixture of diastereomeric salts formed between said compound of formula A-3 and said chiral acid; (ii) crystallizing the mixture of diastereomeric salts prepared in step (i) from a first solvent to obtain a compound having the anion of the chiral acid and the formula: [ka] obtaining a separately isolated diastereomeric salt formed between the N-protected (R)-1-oxa-8-azaspiro[4.5]decane-3-aminium cation of (iii) treating the separately isolated diastereomeric salt containing the cation of formula A-4 isolated in step (ii) with a second base to release the compound of formula A-1; Including, In the formula, R X is selected from the group consisting of hydrogen and an amino protecting group.

[0273] 76. The amino protecting group R X is tert-butyloxycarbonyl (BOC), the chiral acid is (R)-mandelic acid; the first solvent is acetonitrile; 76. The method of embodiment 75, wherein the second base is sodium hydroxide or potassium hydroxide.

[0274] 77. Formula: [ka] A method for preparing a compound of the formula The method comprises converting 2-amino-5-hydroxybenzoic acid to a compound of the formula: [ka] in a second solvent in the presence of trialkyl orthoformate; The compound of formula A-1 is prepared by the method of any one of embodiments 73 to 76, R X is selected from the group consisting of hydrogen and an amino protecting group.

[0275] 78. The amino protecting group RX is tert-butyloxycarbonyl (BOC), the trialkyl orthoformate is triethyl orthoformate, 78. The method of embodiment 77, wherein the second solvent is n-butanol.

[0276] 79. Formula: [ka] A method for preparing a compound of the formula 2,3,6-Trifluorobenzonitrile can be reacted with 2,3,6-trifluorobenzonitrile to produce a compound of the formula: [ka] in a third solvent in the presence of a third base; During the ceremony, R X is selected from the group consisting of hydrogen and an amino protecting group; The compound of formula A-5 is prepared according to any of embodiments 77 and 78.

[0277] 80. the third base is potassium carbonate and the third solvent is acetonitrile; The amino protecting group R X 80. The method of embodiment 79, wherein is tert-butyloxycarbonyl (BOC).

[0278] 81. Formula: [ka] A method for preparing a compound of the formula (i) [Methyl(sulfamoyl)amino]ethane NHSON(Me)Et of the formula: [ka] in a fourth solvent in the presence of a fourth base to produce a compound of formula A-8: [ka] A process for obtaining a compound of the formula The compound of formula A-6 is prepared according to the method of embodiment 79 or 80, R X is selected from the group consisting of hydrogen and an amino protecting group; (ii)R X is the amino protecting group, then removing the amino protecting group attached to the piperidine nitrogen atom of the compound of formula A-8 in the presence of a first acid; A method comprising:

[0279] 82. the fourth base is cesium carbonate and the fourth solvent is N,N-dimethylacetamide; The amino protecting group R X is tert-butyloxycarbonyl (BOC), 82. The method of embodiment 81, wherein the first acid is hydrochloric acid.

[0280] 83. Formula: [ka] A method for preparing a compound of the formula 2,4,5-Trifluorobenzonitrile can be converted to the formula: [ka] in a fifth solvent in the presence of a fifth base; In the formula, R Y is hydrogen or a carboxylic acid protecting group.

[0281] 84. the fifth base is N,N-diisopropylethylamine and the fifth solvent is N,N-dimethylformamide; R Y However, tert-butyl ( t 84. The method of embodiment 83, wherein

[0282] 85. Formula: [ka] A method for preparing a compound of the formula Methylhydrazine can be converted to the formula: [ka] in the presence of a sixth solvent; The compound of formula B-1 is prepared according to the method of embodiment 83 or 84, In the formula, R Y is hydrogen or a carboxylic acid protecting group.

[0283] 86. the sixth solvent is N-methyl-2-pyrrolidone; R Y 86. The method of embodiment 85, wherein is tert-butyl.

[0284] 87. Formula: [ka] A method for preparing a compound of the formula Acrylic acid can be converted to the formula: [ka] in a seventh solvent, The compound of formula B-3 is prepared according to the method of embodiment 85 or 86, R Y is hydrogen or a carboxylic acid protecting group.

[0285] 88. the seventh solvent is an aqueous solution of hydrochloric acid; R Y 88. The method of embodiment 87, wherein is tert-butyl.

[0286] 89. Formula: [ka] A method for preparing a compound of the formula (i) First, a metal cyanate is reacted with the compound of formula: [ka] in the presence of a second acid to produce a compound of the formula: [ka] obtaining a reaction mixture containing a first intermediate compound of The compound of formula B-4 is prepared according to the method of embodiment 87 or 88, R Y is hydrogen or a carboxylic acid protecting group; (ii) The first intermediate compound of formula B-6 from step (i) is then cyclized, optionally in the presence of a third acid, to give a compound of formula: [ka] obtaining a second intermediate compound of (iii) Next, R Y is the carboxylic acid protecting group, then converting the carboxylic acid protecting group R from the second intermediate compound of formula B-7 by step (ii) Y in the presence of a fourth acid to obtain said compound of formula B-5; A method comprising:

[0287] 90. R Y is tert-butyl, the metal cyanate is sodium cyanate or potassium cyanate; the second acid is acetic acid; the third acid is hydrochloric acid or acetic acid; 90. The method of embodiment 89, wherein the fourth acid is hydrochloric acid.

[0288] 91. Formula: [ka] A method for preparing a compound of the formula The method comprises: (i) First, the formula: [ka] with a carboxylic acid hydroxyl activating reagent in the presence of a sixth base and an eighth solvent to produce a compound of the formula: [ka] obtaining a third intermediate compound of The carboxylic acid hydroxyl is converted to the more reactive group -OR Z is converted to The compound of formula B-5 is prepared according to the method of embodiment 89 or 90, (ii) Then, the formula: [ka] (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoro-phenoxy]-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane with the third intermediate compound of formula B-8 prepared in step (ii) in the presence of a seventh base and a ninth solvent to obtain the compound of formula 1, The compound of formula A-7 is prepared according to the method of embodiment 81 or 82, A method comprising:

[0289] 92. (i) the sixth base is N,N-diisopropylethylamine; the eighth solvent is acetonitrile; the carboxylic acid hydroxyl activating reagent is 2-succinimido-1,1,3,3-tetramethyluronium tetrafluoroborate, and R Z the group is 2,5-dioxopyrrolidin-1-yl, (ii) The method of embodiment 91, wherein the seventh base is triethylamine and the ninth solvent is N,N-dimethylformamide.

[0290] 93. A method of treating brain metastases or central nervous system (CNS) metastases of mutant BRAF-mediated cancer, comprising administering to a subject an effective amount of the structure: [ka] or a pharmaceutically acceptable salt thereof to a human patient in need of treatment.

[0291] 94. The method of embodiment 93, wherein the cancer has metastasized to the brain.

[0292] 95. The method of embodiment 93 or 94, wherein the cancer has metastasized to the CNS.

[0293] 96. The method of any one of embodiments 93 to 95, wherein the mutant BRAF-mediated cancer is melanoma.

[0294] 97. The method of any one of embodiments 93 to 95, wherein the mutant BRAF-mediated cancer is lung cancer.

[0295] 98. The method of any one of embodiments 93 to 95, wherein the mutant BRAF-mediated cancer is non-small cell lung cancer.

[0296] 99. The method of any one of embodiments 93 to 95, wherein the mutant BRAF-mediated cancer is colorectal cancer.

[0297] 100. The method of any one of embodiments 93 to 95, wherein the mutant BRAF-mediated cancer is microsatellite-stable colorectal cancer.

[0298] 101. The method of any one of embodiments 93 to 95, wherein the mutant BRAF-mediated cancer is thyroid cancer.

[0299] 102. The method of any one of embodiments 93 to 95, wherein the mutant BRAF-mediated cancer is ovarian cancer.

[0300] 103. The method of any one of embodiments 93-95, wherein the mutant BRAF-mediated cancer is cholangiocarcinoma, Erdheim-Chester disease, Langerhans histiocytosis, ganglioglioma, glioma, glioblastoma, hairy cell leukemia, metanephric adenoma, multiple myeloma, non-small cell lung cancer, ovarian cancer, pilocytic astrocytoma, undifferentiated pleomorphic xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, pancreatic cancer, clear cell sarcoma of the breast, salivary gland carcinoma, or microsatellite-stable colorectal carcinoma.

[0301] 104. The method of any one of embodiments 93-103, wherein the patient is also administered an additional active agent.

[0302] 105. The method of embodiment 104, wherein the additional active agent is a MEK inhibitor.

[0303] 106. The method of embodiment 105, wherein the MEK inhibitor is trametinib.

[0304] 107. The method of embodiment 104, wherein the additional active agent is an immune checkpoint inhibitor.

[0305] 108. The method of embodiment 107, wherein the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, ipilimumab, leratolimab, atezolizumab, avelumab, and durvalumab.

[0306] 109. The method of embodiment 104, wherein the additional active agent is cetuximab or panitumumab.

[0307] 110. The method of any one of embodiments 93 to 109, wherein the mutant BRAF has a V600 mutation.

[0308] 111. The method of embodiment 110, wherein the V600 mutation is V600E, V600K, V600R, V600D, V600M, or V600N.

[0309] 112. The method of embodiment 110, wherein the V600 mutation is V600E.

[0310] 113. The method of any one of embodiments 93 to 112, wherein the mutant BRAF has a mutation selected from G469A, G469V, G469L, G469R, L597Q, and K601E.

[0311] 114. The method of any one of embodiments 93 to 113, wherein the mutant BRAF has a mutation selected from G466A, G466E, G466R, G466V, S467L, G469E, N581I, D594E, D594G, and D594N.

[0312] 115. The method of any one of embodiments 93 to 114, wherein the mutant BRAF has a mutation selected from G464I, G464R, N581T, L584F, E586K, G593D, G596C, L597R, L597S, S605I, S607F, N684T, E26A, V130M, L745L, and D284E.

[0313] 116. The method of any one of embodiments 93 to 115, wherein the mutant BRAF has a splice mutation.

[0314] 117. The method of embodiment 116, wherein the splice mutation is a p61-BRAF V600 splice mutation.

[0315] 118. The method of any one of embodiments 93 to 117, wherein the mutant BRAF-mediated cancer has an NRAS, MEK1, or PI3K mutation.

[0316] 119. The method of embodiment 118, wherein the cancer has an NRAS mutation.

[0317] 120. The method of embodiment 119, wherein the NRAS mutation is Q61K.

[0318] 121. The method of embodiment 119, wherein the NRAS mutation is Q61R.

[0319] 122. The method of embodiment 118, wherein the cancer has a MEK1 mutation.

[0320] 123. The method of embodiment 118, wherein the cancer has a PI3K mutation.

[0321] 124. PI3K mutations include PIK3CA H1047R or PIK3CA P449T 124. The method of embodiment 123, wherein

[0322] 125. The method of any one of embodiments 93 to 123, wherein the mutant BRAF-mediated cancer has one or more mutations that promote homodimerization or heterodimerization of RAF proteins.

[0323] 126. The method of embodiment 125, wherein the one or more mutations promote homodimerization of the RAF protein.

[0324] 127. The method of embodiment 125, wherein the one or more mutations promote heterodimerization of RAF proteins.

[0325] Treating BRAF-mediated disorders Compound 1 is a small molecule that degrades mutant BRAF, such as class I, class II, and / or class III mutant BRAF, via the ubiquitin proteasome pathway. Compound 1 binds to the ubiquitously expressed E3 ligase protein cereblon (CRBN) and alters the substrate specificity of the CRBN E3 ubiquitin ligase complex, resulting in the recruitment and ubiquitination of mutant BRAF, such as BRAF V600E. Compound 1 effectively degrades class I mutant BRAF, such as V600E, class II mutant BRAF, such as G469A, and class III mutant BRAF, such as G466V.

[0326] Thus, a pharmaceutical composition comprising an effective amount of Compound 1 of the present invention or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1, 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, a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat solid tumors mediated by V600X mutant BRAF. Non-limiting examples of disorders that can be treated with a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form thereof, include melanoma, non-small cell lung cancer, thyroid cancer, colorectal cancer, and other solid tumor malignancies with mutant BRAF drivers.

[0327] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form thereof, can treat cancers that have developed resistance to BRAF inhibitors. For example, Compound 1 is effective in treating G466V mutant BRAF lung tumor cell lines. In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof is orally bioavailable.

[0328] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or its pharmaceutically acceptable salt or its morphic form is used to treat BRAF-mediated cancer in which BRAF is mutated from wild type. 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, V600M, and V600N. Non-limiting examples of class II mutations include G469A, G469V, G469L, G469R, L597Q, and K601E. Non-limiting examples of Class III mutations include G466A, G466E, G466R, G466V, S467L, G469E, N581I, D594E, D594G, and D594N.

[0329] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof treats a BRAF mutation-mediated disorder, wherein 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.

[0330] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof is administered to treat a patient in which the mutation is a splice variant, e.g., p61-BRAF V600E and treating BRAF mutation-mediated disorders.

[0331] Compound 1, a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof, or a pharmaceutical composition thereof, or a pharmaceutically acceptable salt of Compound 1 or a pharmaceutical composition thereof can be used to treat patients with any disorder mediated by mutant BRAF.

[0332] BRAF is a serine / threonine protein kinase that is a member of signal transduction protein kinases. BRAF V600X mutations, particularly 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, V600M, and V600N. In many of these indications, despite the therapeutic benefits provided by clinically available BRAF inhibitors, the duration of antitumor responses to these agents is limited by the development of drug resistance.

[0333] The BRAF protein exhibits 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 the BRAF V600X substitution, BRAF signaling becomes independent of homodimer and / or heterodimer formation. In this context, the kinase becomes hyperactivated as a monomeric protein and drives cell proliferation signals.

[0334] Because currently available inhibitors block only the activity of the monomeric form of BRAF and have no effect on BRAF homodimers or heterodimers, it is not surprising that many BRAF resistance mechanisms act by restoring signaling mediated by BRAF homodimerization and heterodimerization.

[0335] Targeted proteolysis induces target ubiquitination by recruiting E3 ligases, thereby promoting proteasome-mediated destruction of the target of interest. Degradation of BRAF by targeted degradation provides an advantage over conventional inhibition because it removes the scaffolding activity of BRAF V600E / K, specifically inducing BRAF protein elimination. This activity prevents dimerization-mediated mechanisms of resistance.

[0336] Inhibition of BRAF protein may be a strategy to not only target tumors that acquire resistance to available inhibitors but also delay the onset of resistance, providing a novel therapeutic opportunity in the treatment of BRAF V600X mutant tumors such as melanoma, colorectal cancer, and lung cancer.

[0337] Another aspect of the present invention provides a morphic form of Compound 1 or an isotopic derivative of Compound 1, a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition thereof, as described herein, for use in the manufacture of a medicament for treating or preventing cancer in a patient in need thereof, wherein BRAF inhibition is indicated for the treatment or prevention of cancer.

[0338] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or its morphic form is 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, V600M, and V600N. Non-limiting examples of Class II mutations include G469A, G469V, G469L, G469R, L597Q, and K601E. Non-limiting examples of Class III mutations include G466A, G466E, G466R, G466V, S467L, G469E, N581I, D594E, D594G, and D594N.

[0339] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof treats a BRAF mutation-mediated disorder, wherein 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.

[0340] In certain embodiments, the BRAF mutation is an exon 11 mutation.

[0341] In certain embodiments, the BRAF mutation is an exon 15 mutation.

[0342] In certain embodiments, the BRAF mutation is a G464 mutation.

[0343] In certain embodiments, the BRAF mutation is a G466 mutation.

[0344] In certain embodiments, the BRAF mutation is a G466R mutation.

[0345] In certain embodiments, the BRAF mutation is a G466E mutation.

[0346] In certain embodiments, the BRAF mutation is a G469 mutation.

[0347] In certain embodiments, the BRAF mutation is a G469E mutation.

[0348] In certain embodiments, the BRAF mutation is a D594 mutation.

[0349] In certain embodiments, the BRAF mutation is a D594A mutation.

[0350] In certain embodiments, the BRAF mutation is an L597 mutation.

[0351] In certain embodiments, the BRAF mutation is an L597R mutation.

[0352] In certain embodiments, the BRAF mutation is the L597S mutation.

[0353] In certain embodiments, the BRAF mutation is an L597Q mutation.

[0354] In certain embodiments, the BRAF mutation is a V600 mutation.

[0355] In certain embodiments, the BRAF mutation is a V600E mutation.

[0356] In certain embodiments, the BRAF mutation is a V600K mutation.

[0357] In certain embodiments, the BRAF mutation is a V600R mutation.

[0358] In certain embodiments, the BRAF mutation is a V600D mutation.

[0359] In certain embodiments, the BRAF mutation is a V600M mutation.

[0360] In certain embodiments, the BRAF mutation is a V600N mutation.

[0361] In certain embodiments, the BRAF mutation is a K601 mutation.

[0362] In certain embodiments, the BRAF mutation is a K601E mutation.

[0363] In certain embodiments, the BRAF mutation is a K601N mutation.

[0364] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof is administered to treat a patient in which the mutation is a splice variant, e.g., p61-BRAF V600E or a BRAF kinase domain duplication or a BRAF amplification.

[0365] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof is used to treat disorders mediated by two or more mutant proteins, such as BRAF. V600E / NRAS Q61K or BRAF V600E / NRAS Q61R Treating double mutant-mediated cancers.

[0366] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof is used to treat a cancer that is resistant to at least one BRAF inhibitor, for example, a cancer that is resistant to or has acquired resistance to a BRAF inhibitor selected from dabrafenib, vemurafenib, and encorafenib.

[0367] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof is used to treat BRAF V600E NRAS Q61K Cancers that have harbored escape mutations, such as double mutant cancers, are treated.

[0368] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof is used to treat melanoma.

[0369] 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.

[0370] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof is used to treat triple-negative breast cancer, for example, triple-negative breast cancer with a G464V BRAF mutation.

[0371] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof is used to treat lung cancer, for example, lung adenocarcinoma harboring a G466V BRAF mutation.

[0372] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof is used to treat melanoma harboring a V600 BRAF mutation.

[0373] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is provided for the treatment of cancer in which the mutation is a splice variant, e.g., p61-BRAF V600E and treating BRAF mutation-mediated disorders.

[0374] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat disorders mediated by two or more mutant proteins, such as BRAF. V600E / NRAS Q61K or BRAF V600E / NRAS Q61R Treating double mutant-mediated cancers.

[0375] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat BRAF V600E NRAS Q61K Cancers that have harbored escape mutations, such as double mutant cancers, are treated.

[0376] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat a cancer that is resistant to at least one BRAF inhibitor, for example, a cancer that is resistant to or has acquired resistance to a BRAF inhibitor selected from dabrafenib, vemurafenib, and encorafenib.

[0377] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat melanoma.

[0378] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat triple-negative breast cancer, for example, triple-negative breast cancer with a G464V BRAF mutation.

[0379] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat lung cancer, for example, lung adenocarcinoma harboring a G466V BRAF mutation.

[0380] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat melanoma harboring a V600 BRAF mutation.

[0381] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat cholangiocarcinoma.

[0382] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat Erdheim-Chester disease.

[0383] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat Langerhans histiocytosis.

[0384] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat ganglioglioma.

[0385] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat glioma.

[0386] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat GIST.

[0387] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat glioblastoma.

[0388] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat hairy cell leukemia.

[0389] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat multiple myeloma.

[0390] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat non-small cell lung cancer.

[0391] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat ovarian cancer.

[0392] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat pilocytic astrocytoma.

[0393] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat anaplastic pleomorphic xanthoastrocytoma.

[0394] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat astrocytoma.

[0395] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat thyroid cancer.

[0396] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat papillary thyroid carcinoma.

[0397] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat anaplastic thyroid cancer.

[0398] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat pancreatic cancer.

[0399] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat clear cell sarcoma of the breast.

[0400] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat salivary gland cancer.

[0401] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat colorectal cancer.

[0402] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is used to treat microsatellite-stable colorectal cancer.

[0403] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form thereof, is 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, undifferentiated 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.

[0404] In certain aspects, methods are provided for treating mutant BRAF-mediated cancers that have metastasized to the brain or central nervous system (CNS), comprising administering an effective amount of Compound 1, or a pharmaceutically acceptable salt or morphic form thereof, to a patient in need of treatment. In certain embodiments, the cancer that has metastasized to the brain or CNS is colorectal cancer, melanoma, non-small cell lung cancer, or other solid tumors that harbor BRAF V600E. In certain embodiments of this aspect, Compound 1 or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof. In other embodiments of this aspect, a morphic form of Compound 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition prepared from a morphic form of Compound 1, is administered to a patient in need thereof.

[0405] In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is used to treat mutant BRAF-mediated cancers that have metastasized to the brain or CNS, in which BRAF has 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, V600M, and V600N. Non-limiting examples of Class II mutations include G469A, G469V, G469L, G469R, L597Q, and K601E. Non-limiting examples of Class III mutations include G466A, G466E, G466R, G466V, S467L, G469E, N581I, D594E, D594G, and D594N. In certain embodiments, the BRAF mutation is a V600 mutation, e.g., V600E BRAF, which mediates cancer that metastasizes to the brain or CNS.

[0406] In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof can treat mutant BRAF-mediated cancers that have metastasized to the brain or CNS, where the mutation is not a Class I mutation, Class II mutation, 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.

[0407] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is an exon 11 mutation.

[0408] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is an exon 15 mutation.

[0409] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is a G464 mutation.

[0410] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is a G466 mutation.

[0411] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is a G466R mutation.

[0412] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is a G466E mutation.

[0413] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is a G469 mutation.

[0414] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is a G469E mutation.

[0415] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is a D594 mutation.

[0416] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is a D594A mutation.

[0417] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is an L597 mutation.

[0418] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is an L597R mutation.

[0419] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is the L597S mutation.

[0420] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is the L597Q mutation.

[0421] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is a V600 mutation.

[0422] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is a V600E mutation.

[0423] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is a V600K mutation.

[0424] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is a V600R mutation.

[0425] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is a V600D mutation.

[0426] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is a V600M mutation.

[0427] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is a V600N mutation.

[0428] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is a K601 mutation.

[0429] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is a K601E mutation.

[0430] In certain embodiments, the disorder is cancer that has metastasized to the brain or CNS and the BRAF mutation is a K601N mutation.

[0431] In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is a compound that inhibits the growth of a target gene, such as a BRAF gene, in which the mutation is a splice variant, e.g., p61-BRAF. V600E In one embodiment, mutant BRAF-mediated cancers that have metastasized to the brain or CNS can be treated.

[0432] In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is used to treat mutant BRAF-mediated cancers that have metastasized to the brain or CNS, where the cancer is mediated by two or more mutant proteins, e.g., BRAF V600E / NRAS Q61K or BRAF V600E / NRAS Q61R Non-limiting examples of double mutant cancers include those mediated by BRAF mutations, e.g., BRAF V600E , and mutations in NRAS, MEK1, or PI3K, e.g., BRAF V600E / PIK3CA H1047R or BRAF V600E / PIK3CA P449T Examples include colorectal cancer mediated by

[0433] In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is used to treat mutant BRAF-mediated cancers that have metastasized to the brain or CNS, and the cancer is resistant to at least one BRAF inhibitor, for example, a cancer that is resistant to or has acquired resistance to a BRAF inhibitor selected from dabrafenib, vemurafenib, and encorafenib. In certain embodiments, the cancer that is resistant to treatment with a BRAF inhibitor has a homodimerization- or heterodimerization-promoting mutation in the RAF protein. For example, in certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is used to treat mutant BRAF-mediated cancers that have metastasized to the brain or CNS, and the cancer has one or more mutations that promote the dimerization of the RAF protein. In certain embodiments, the cancer that has one or more dimerization-promoting mutations in the RAF protein is resistant to treatment with a BRAF inhibitor, for example, dabrafenib, vemurafenib, or encorafenib. In certain embodiments, the RAF protein dimer is a homodimer (BRAF-BRAF) or a heterodimer with another RAF protein (BRAF-RAF1 or BRAF-ARAF).

[0434] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat cancer that has metastasized to the brain or CNS, and the cancer is a BRAF V600E / NRAS Q61K or BRAF V600E / NRAS Q61R Escape mutations such as double mutant cancers have arisen.

[0435] In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is used to treat cancer that has metastasized to the brain or CNS, where the cancer has undergone amplification of a driver mutation.

[0436] In another embodiment, Compound 1 reduces phosphorylated ERK signaling, demonstrating inhibition of the EGFR-mediated MAPK pathway. In another embodiment, Compound 1 is used to treat BRAF V600X colorectal cancer (CRC). In certain embodiments, Compound 1 is used to treat BRAF-V600X non-small cell lung cancer (NSCLC). In certain embodiments, Compound 1 demonstrates activity against resistant tumor mutations, such as point mutations in MEK, PI3K, splice variants such as p61-BRAF-V600E, BRAF kinase domain duplications, and BRAF amplification.

[0437] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, can be used to treat V600-mutated colorectal cancer, for example, in certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, can be used to reduce tumor growth in a BRAF V600-mutated colorectal cancer model more than the combination of encorafenib and cetuximab.

[0438] In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is used to treat melanoma that has metastasized to the brain or CNS. In other embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is used to treat colorectal cancer that has metastasized to the brain or CNS.

[0439] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat melanoma that has metastasized to the brain or CNS.

[0440] In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is used to treat triple-negative breast cancer that has metastasized to the brain or CNS, for example, triple-negative breast cancer with a G464V BRAF mutation that has metastasized to the brain or CNS.

[0441] In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is used to treat lung cancer that has metastasized to the brain or CNS, for example, lung adenocarcinoma with a G466V BRAF mutation that has metastasized to the brain or CNS.

[0442] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat melanoma that has metastasized to the brain or CNS and has a V600 BRAF mutation.

[0443] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat cholangiocarcinoma that has metastasized to the brain or CNS.

[0444] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat Erdheim-Chester disease that has metastasized to the brain or CNS.

[0445] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat Langerhans histiocytosis that has metastasized to the brain or CNS.

[0446] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat ganglioglioma that has metastasized to the brain or CNS.

[0447] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat glioma that has metastasized to the brain or CNS.

[0448] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat GIST that has metastasized to the brain or CNS.

[0449] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat glioblastoma that has metastasized to the brain or CNS.

[0450] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat hairy cell leukemia that has metastasized to the brain or CNS.

[0451] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat multiple myeloma that has metastasized to the brain or CNS.

[0452] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat non-small cell lung cancer that has metastasized to the brain or CNS.

[0453] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat ovarian cancer that has metastasized to the brain or CNS.

[0454] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat pilocytic astrocytoma that has metastasized to the brain or CNS.

[0455] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat anaplastic pleomorphic xanthoastrocytoma that has metastasized to the brain or CNS.

[0456] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat astrocytoma that has metastasized to the brain or CNS.

[0457] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat thyroid cancer that has metastasized to the brain or CNS.

[0458] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat papillary thyroid carcinoma that has metastasized to the brain or CNS.

[0459] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat anaplastic thyroid cancer that has metastasized to the brain or CNS.

[0460] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat pancreatic cancer that has metastasized to the brain or CNS.

[0461] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat clear cell sarcoma of the breast that has metastasized to the brain or CNS.

[0462] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat salivary gland cancer that has metastasized to the brain or CNS.

[0463] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat colorectal cancer that has metastasized to the brain or CNS.

[0464] In certain embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used to treat microsatellite-stable colorectal cancer that has metastasized to the brain or CNS.

[0465] In certain embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is used to treat mutant BRAF-mediated cancers that have metastasized to the brain. In other embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is used to treat mutant BRAF-mediated cancers that have metastasized to the CNS.

[0466] Another aspect of the present invention provides a method for treating or preventing a proliferative disease, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising an effective amount of Compound 1, or a morphic form of Compound 1, or an enantiomer, diastereomer, or stereoisomer, or isotopic derivative of Compound 1, as described herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally a pharmaceutically acceptable carrier.

[0467] In certain embodiments, the disease or disorder is cancer or a proliferative disease.

[0468] In certain embodiments, the BRAF-mediated disorder is abnormal cell proliferation, including, but not limited to, solid cancer or hematological cancer.

[0469] In certain embodiments, the hematological cancer is 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, or 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.

[0470] Solid tumors that are sensitive to the inhibition or degradation of BRAF or mutant BRAF and therefore can be treated using the compounds described herein include lung cancer, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), inflammatory breast cancer, breast cancer, including 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), and glioma. brain cancer, including 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 tumor (PanNET), osteosarcoma, giant cell tumor of bone, thyroid cancer, bladder cancer, urothelial carcinoma, vulvar cancer, cervical cancer, endometrial cancer, mesothelioma, esophageal cancer, salivary gland cancer, gastric cancer, nasopharyngeal carcinoma, buccal cancers, 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).

[0471] In a further embodiment, the disease or disorder is a sarcoma of bone, muscle, tendon, cartilage, nerve, fat, or blood vessels.

[0472] In a further embodiment, the disease or disorder is soft tissue sarcoma, bone sarcoma, or osteosarcoma.

[0473] 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.

[0474] In certain embodiments, the disorder is a sarcoma of bone, muscle, tendon, cartilage, nerve, fat, or blood vessels.

[0475] In other embodiments, the disease or disorder is a cancer that is sensitive to the inhibition or degradation of BRAF or mutant BRAF, 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.

[0476] The term "cancer," as used herein, refers to cancers that can be treated with Compound 1, and refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas, etc., which diseases are sensitive to the inhibition or degradation of BRAF or mutant BRAF. For example, cancers include, but are not limited to, mesothelioma, leukemia, and lymphomas, such as cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, human T-cell lymphotropic virus (HTLV)-associated lymphomas, 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 myeloid 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 cancers (e.g., oral cancer, laryngeal cancer, nasopharyngeal cancer, and esophageal cancer), genitourinary tract cancers (e.g., prostate cancer, bladder cancer, kidney cancer, uterine cancer, ovarian cancer, 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, stomach cancer, brain tumors, tumors associated with Gorlin syndrome (such as medulloblastoma or meningioma), and liver cancer.

[0477] One aspect of the present application provides pharmaceutical compositions comprising an effective amount of Compound 1 or a morphic form of Compound 1, useful for treating diseases, disorders, and conditions characterized by excessive or abnormal cell proliferation that are sensitive to the inhibition or degradation of BRAF or mutant BRAF. 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, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, colorectal cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, and biliary tract cancer. cancers of the oral cavity (oral cancer), lip cancer, tongue cancer, oral cancer, pharynx cancer, small intestine cancer, colorectal cancer, large intestine cancer, rectal cancer, brain cancer and central nervous system cancer, chronic myeloid leukemia (CML), and leukemia. The term "cancer" includes, but is not limited to, cancers selected from the following: myeloma, lymphoma, or 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 pulmonary cancer.

[0478] Further exemplary forms of cancer include, but are not limited to, skeletal or smooth muscle cancer, gastric cancer, cancer of the small intestine, rectum carcinoma, cancer of the salivary glands, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0479] Additional cancers that can be treated by the present invention include colon cancer, familial adenomatous polyposis, and hereditary nonpolyposis colorectal cancer, or melanoma. Further cancers include, but are not limited to, labial carcinoma, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, thyroid cancer (medullary thyroid carcinoma and papillary thyroid carcinoma), 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 the various types of cancer disclosed herein.

[0480] In some embodiments, the pharmaceutical compositions or morphic forms described herein are useful for treating cancers sensitive to the inhibition or degradation of BRAF or mutant BRAF, 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 myeloid leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mastocytosis. In some embodiments, the morphic forms of compound 1 described herein are useful for treating hematopoietic disorders sensitive to the inhibition or degradation of BRAF or mutant BRAF, particularly acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute promyelocytic leukemia, and acute lymphocytic leukemia (ALL).

[0481] In certain embodiments, the pharmaceutical compositions or morphic forms described herein can be used in an effective amount to treat a host, e.g., a human, having a lymphoma, or a lymphocytic or myeloid proliferative disorder or abnormality. For example, a morphic form of Compound 1 described herein can be administered to a host suffering from Hodgkin's lymphoma or non-Hodgkin's lymphoma. For example, the host may be suffering from, 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 have 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; non-Hodgkin's lymphoma such as Langerhans cell histiocytosis or Waldenstrom's macroglobulinemia.

[0482] In other embodiments, the pharmaceutical compositions or morphic forms described herein can be used in an effective amount to treat a patient, e.g., a human, having Hodgkin lymphoma, including, 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.

[0483] The present application further encompasses the treatment or prevention of cell proliferative disorders, such as hyperplasia, dysplasia, and precancerous lesions, that are sensitive to the inhibition or degradation of BRAF or mutant BRAF. Dysplasia is the earliest form of precancerous lesion that can be recognized by a pathologist in a biopsy. The pharmaceutical compositions or morphic forms described herein can be administered to prevent such hyperplasia, dysplasia, or precancerous lesions from continuing to grow or becoming cancerous. Examples of precancerous lesions can occur in the skin, esophageal tissue, breast, and cervical intraepithelial tissue.

[0484] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or its morphic form is 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, V600M, and V600N. Non-limiting examples of Class II mutations include G469A, G469V, G469L, G469R, L597Q, and K601E. Non-limiting examples of Class III mutations include G466A, G466E, G466R, G466V, S467L, G469E, N581I, D594E, D594G, and D594N.

[0485] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof 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.

[0486] Another aspect of the present invention provides a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof for use in the manufacture of a medicament for treating or preventing a disease mediated by BRAF.

[0487] In certain embodiments, pharmaceutical compositions comprising an effective amount of Compound 1 or a morphic form thereof are useful for treating disorders involving abnormal cell proliferation, such as tumors or cancers, in which BRAF is an oncogenic protein or a signaling mediator of an abnormal cell proliferation pathway, and its degradation reduces abnormal cell growth.

[0488] Combination therapy A pharmaceutical composition comprising an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1, as described herein, can be used alone or in combination with another bioactive agent or second therapeutic agent, or administered simultaneously or sequentially, to treat a patient, such as a human, suffering from a mutant BRAF-mediated disorder, including, but not limited to, those described herein.

[0489] The terms "bioactive agent" or "additional active agent" are used to describe an agent other than Compound 1 or a pharmaceutically acceptable salt thereof or a morphic form of Compound 1 according to the present invention that can be used in combination or alternation with a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof or a morphic form of Compound 1 to achieve a desired outcome of therapy. In certain embodiments, the pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof or a morphic form of Compound 1 and the bioactive agent are combined in a manner such that they are active in vivo during an overlapping period, e.g., C max , T max In another embodiment, a pharmaceutical composition comprising effective amounts of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1, and a bioactive agent do not have overlapping pharmacokinetic parameters, but one has a therapeutic impact on the therapeutic effectiveness of the other, and are administered to a patient in need thereof.

[0490] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof is used in combination with a second active agent described herein to treat mutant BRAF-mediated cancers. Non-limiting examples of classes of molecules that can be used in combination with a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof include MEK inhibitors, immune checkpoint inhibitors, and EGFR antibodies. In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof is used in combination with trametinib to treat mutant BRAF-mediated cancers, such as melanoma or non-small cell lung cancer. In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof is used in combination with an immune checkpoint inhibitor to treat mutant BRAF-mediated cancers. In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof is used in combination with cetuximab or panitumumab to treat mutant BRAF-mediated cancers, such as colorectal cancer. In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof is 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.

[0491] In other aspects, a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof is used in combination with two or more additional active agents described herein to treat mutant BRAF-mediated cancers. In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a morphic form thereof is used in combination with a MEK inhibitor and an immune checkpoint inhibitor to treat melanoma or non-small cell lung cancer.

[0492] In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1 is used in combination with another BRAF inhibitor, such as sorafenib, vemurafenib (ZELBORAF™), dabrafenib (TAFINLAR™), or encorafenib (BRAFTOVI™).

[0493] 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 / BAY8697 66 / 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-4-iodophenyl)amino]-benzamide), TAK7 33 (I-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]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxylate ruboxamide), 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-2-yl)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.

[0494] In certain embodiments, the MEK inhibitor is trametinib.

[0495] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1, is used in combination with cetuximab or trametinib to treat colorectal cancer. In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1, is used in combination with cetuximab and BYL719 to treat colorectal cancer. In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1, is used in combination with cetuximab and irinotecan to treat colorectal cancer.

[0496] In certain embodiments, the bioactive agent is an SHP2 inhibitor. In certain embodiments, the SHP2 inhibitor is SHP099.

[0497] 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™)).

[0498] In certain embodiments, the RAF inhibitor is encorafenib.

[0499] In certain embodiments, the RAF inhibitor is vemurafenib.

[0500] In certain embodiments, the RAF inhibitor is dabrafenib.

[0501] 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.

[0502] 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).

[0503] 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.

[0504] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1, is administered in combination with osimertinib to a patient in need thereof.

[0505] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1, is administered in combination with rociletinib to a patient in need thereof.

[0506] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1, is administered in combination with avitinib to a patient in need thereof.

[0507] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1, is administered in combination with lazertinib to a patient in need thereof.

[0508] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1, is administered in combination with nazartinib to a patient in need thereof.

[0509] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1, is administered to a patient in need thereof in combination with an EGFR antibody, such as cetuximab, panitumumab, or necitumumab.

[0510] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1, is administered in combination with cetuximab to a patient in need thereof.

[0511] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1, is administered in combination with panitumumab to a patient in need thereof.

[0512] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1, is administered in combination with necitumumab to a patient in need thereof.

[0513] In certain embodiments, 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 molecules, peptides, nucleotides, or other inhibitors. In certain aspects, the immunomodulatory agent is an antibody, such as a monoclonal antibody.

[0514] 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).

[0515] In certain embodiments, the checkpoint inhibitor is selected from nivolumab (OPDIVO™), pembrolizumab (KEYTRUDA™), and PDL2 / lg fusion proteins such as pidilizumab / CT-011, MPDL3280A / RG7446, MEDI4736, MSB0010718C, BMS 936559, 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.

[0516] In yet another embodiment, Compound 1 or its pharmaceutically acceptable salt or morphic form of Compound 1 described herein can be administered in effective amounts in combination with or alternating with an effective amount of an estrogen inhibitor, including but not limited to a SERM (selective estrogen receptor modulator), a SERD (selective estrogen receptor degrader), a 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 in some cases, estrogenic effects during the progression of breast cancer, which 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.

[0517] 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 assigned to Olema Pharmaceuticals, and U.S. Patent Application Publication No. 2013 / 0178445, 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.

[0518] Additional non-limiting examples of anti-estrogen compounds include SERMs such as anordrin, bazedoxifene, broparestriol, 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.

[0519] 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 / 2020444. 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. 6,821,989;U.S. Patent Application Publication No. 2002 / 0128276;U.S. Patent No. 6,777,424;U.S. Patent Application Publication No. 2002 / 0016340;U.S. Patent No. 6,326,392;U.S. Patent No. 6,756,401;U.S. Patent Application Publication No. 2002 / 0013327 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; EP 0802184; 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.

[0520] In another embodiment, a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1, can be administered in an effective amount 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 full androgen receptor degrader, or another form of partial or full androgen antagonist, for the treatment of abnormal tissue of the male reproductive system, such as prostate cancer or testicular cancer. In certain embodiments, the prostate or testicular cancer is androgen-resistant.

[0521] Non-limiting examples of anti-androgen compounds are provided in WO 2011 / 156518 and U.S. Patent Nos. 8,455,534 and 8,299,112. Additional non-limiting examples of anti-androgen compounds include enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topirutamide, abiraterone acetate, and cimetidine.

[0522] In certain embodiments, the bioactive agent is an ALK inhibitor. Examples of ALK inhibitors include, but are not limited to, crizotinib (XALKORI™), alectinib (ALECENSA™), ceritinib, TAE684 (NVP-TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and AP26113.

[0523] In certain embodiments, the bioactive agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab.

[0524] In certain embodiments, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab (GAZYVA™), rituximab (RITUXAN™), ofatumumab, ibritumomab, tositumomab, and ocrelizumab.

[0525] In certain embodiments, the bioactive agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tasocitinib.

[0526] In certain embodiments, the bioactive agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclax, ABT-199 (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), and venetoclax (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl). [I-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3(trifluoromethyl)benzamide) (navitoclax), (fluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (Ovatoclax mesylate, (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole; methanesulfonic acid), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester), pogosin, ethyl 2- amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate, nilotinib-d3, TW-37 (N-[4-[[2-(1,1-dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide), apogossypolone (ApoG2), HA14-1, AT101, sabutoclax, gambogic acid, or G3139 (oblimersen).

[0527] In certain embodiments, the bioactive agent is a kinase inhibitor, hi certain embodiments, the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.

[0528] Examples of PI3 kinase inhibitors include wortmannin, demethoxyviridin, perifosine, idelalisib, pictilisib, palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (taselisib), (2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2-methylpropanamide), MLN-1117 ((2R)-1-phenoxy-2-butanyl hydrogen ionomer), and the like. (S)-Methylphosphonate; or methyl(oxo){[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium), BYL-719 ((2S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK2126458 (2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide), mido) (omipalisib), TGX-221 ((±)-7-methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidin-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 (I-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-9- (N-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-mohydroxypropan-1-one), TGR-1202 / RP5264, GS-9820 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-mohydroxypropan-1-one), GS-1101 (5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409 (N-(4-(N-(3-((3,5-Dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinaz), AS 252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione), CZ 24832 (5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), buparlisib (5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941 (2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl ]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14-(carboxymethyl) -8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecane-18-oate), PF-05212384 (N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-( 4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl]urea) (gedatrisib), LY3023414, BEZ235 (2-methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile) (dactolisib), XL-765 (N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), GSK1059615 (5-[[4-(4-pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidenedione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethyl) (ethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5h]isochromen-10-yl]acetate (also known as sonolisib), LY294002, AZD8186, PF-4989216, pilaralisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL Examples of such inhibitors include, but are not limited to, 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, and apitolisib (GDC-0980; RG7422).

[0529] Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (IMBRUVICA™) (1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), dianilinopyrimidine inhibitors such as AVL-101 and AVL-291 / 292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide) (Avila Therapeutics (see U.S. Patent Application Publication No. 2011 / 0117073, which is incorporated herein by reference in its entirety), dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide]), LFM-A13 (α-cyano-β -hydroxy-β-methyl-N-(2,5-dibromophenyl)propenamide), GDC-0834 ([RN-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide]), CGI-560 4-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide, CGI-1746 (4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide), CNX-774 (4-(4 -((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide), CTA056 (7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one), GDC-0834 (IN-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837 (IN-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1-acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyl quinolin-2(1H)-one) and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one), as well as other molecules capable of inhibiting BTK activity, such as the BTK inhibitors disclosed in Akinleye et al., Journal of Hematology & Oncology, 2013, 6:59, which is incorporated herein by reference in its entirety.

[0530] Syk inhibitors include cerdulatinib (4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), and fostamatinib ([6-({5-fluoro-2-[(3,4,5-trimethoxysilyl)phenyl]phenyl)amino)pyrimidine-5-carboxamide). phenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate), fostamatinib disodium salt (sodium (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate), BAY 61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamide HCl), RO9021 (6-[(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide), imatinib (GLEEVEC™; 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), staurosporine, GSK1 43 (2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide), PP2 (1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), PRT-060318 (2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT-062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112 (3,3'-((5-fluoropyrimidine-2,4-diyl)bis(azanediyl))diphenol), R348 (3-ethyl-4-methylpyridine), R406 (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one), piceatannol (3-hydroxyresveratrol), YM193306 (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in its entirety), Compound D (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in its entirety), PRT060318 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in its entirety), 3614-3643 (incorporated herein by reference in its entirety)), luteolin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643 (incorporated herein by reference in its entirety), apigenin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein by reference in its entirety)), quercetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein by reference in its entirety)), fisetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein by reference in its entirety)), 3614-3643 (incorporated herein by reference in its entirety), myricetin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein by reference in its entirety)), and morin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein by reference in its entirety)).

[0531] In certain embodiments, the bioactive agent is a c-MET inhibitor, such as crizotinib (XALKORI™, CRIZONIX™), tepotinib (XL880, EXEL-2880, GSK1363089, GSK089), or tivantinib (ARQ197).

[0532] In certain embodiments, the bioactive agent is an AKT inhibitor, including but not limited to, MK-2206, GSK690693, perifosine (KRX-0401), GDC-0068, triciribine, AZD5363, honokiol, PF-04691502, and miltefosine; an FLT-3 inhibitor, including but not limited to, P406, dovitinib, quizartinib (AC220), amuvatinib (MP-470), tanzutinib (MLN518), ENMD-2076, and KW-2449; or a combination thereof.

[0533] In certain embodiments, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogs, everolimus (AFINITOR™), temsirolimus, ridaforolimus, sirolimus, and deforolimus.

[0534] In certain embodiments, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, Reolysin and siG12D LODER.

[0535] In certain embodiments, the bioactive agent is an HSP inhibitor, including, but not limited to, geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG), and radicicol.

[0536] Additional biologically active compounds include, for example, everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, Aurora kinase inhibitors, PIK-1 modulators, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, Cdk inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, focal adhesion kinase inhibitors, MAP kinase (MEK) inhibitors, VEGF Trap antibody, pemetrexed, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IpdR1KRX-0402, lucanton, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, Talampanel, Atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole,DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258; 3-[5-(methylsulfonylpiperazinemethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megence acetate strolol, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, lapatinib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid acid), valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, GLEEVEC™, gemcitabine , hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine,Altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastatin, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene e), spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezomib, paclitaxel, paclitaxel without cremophor, docetaxel, epothilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte-colony stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony stimulating factor Stimulators, histrelin, peginterferon α-2a, interferon α-2a, peginterferon α-2b, interferon α-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab tiuxetan,androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof.

[0537] In certain embodiments, a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1, is administered in combination with ifosfamide.

[0538] In certain embodiments, the bioactive agent is imatinib mesylate (GLEEVEC™), dasatinib (SPRYCEL™), nilotinib (TASIGNA™), bosutinib (BOSULIF™), trastuzumab (HERCEPTIN™), trastuzumab-DM1, pertuzumab (PERJETA™), lapatinib (TYKERB™), gefitinib (IRESSA™), erlotinib (TARCEVA™), cetuximab (ERBITUX™), panitumumab (VECTIBIX™), vandetanib (CAPRELSA™), vemurafenib (ZELBORAF™), vorinostat (ZOL™), or rifampin (RI). In some embodiments, the anti-inflammatory drug is selected from, but not limited to, INZA™), romidepsin (ISTODAX™), bexarotene (TAGRETIN™), alitretinoin (PANRETIN™), tretinoin (VESANOID™), carfilzomib (KYPROLIS™), pralatrexate (FOLOTYN™), bevacizumab (AVASTIN™), ziv-aflibercept (ZALTRAP™), sorafenib (NEXAVAR™), sunitinib (SUTENT™), pazopanib (VOTRIENT™), regorafenib (STIVARGA™), and cabozantinib (COMETRIQ™).

[0539] In certain embodiments, the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic agent, an additional therapeutic agent, or an immunosuppressant.

[0540] Suitable chemotherapeutic bioactive agents include, but are not limited to, radioactive molecules, toxins, also referred to as cytotoxins or cytotoxic drugs, any agent detrimental to cell viability, and liposomes or other vesicles containing chemotherapeutic compounds. Common anti-cancer drugs include vincristine (ONCOVINE™) or liposomal vincristine (MARQIBO™), daunorubicin (daunomycin or CERUBIDINE™) or doxorubicin (adriamycin™), cytarabine (cytosine arabinoside, ara-C or CYTOSAR™), L-asparaginase (ELSPAR™) or PEG-L-asparaginase (pegaspargase or ONCASPAR™), etoposide, riboflavin ... These include cyclophosphamide (VP-16), teniposide (VUMON™), 6-mercaptopurine (6-MP or PURINETHOL™), methotrexate, cyclophosphamide (CYTOXAN™), prednisone, dexamethasone (DECADRON™), imatinib (GLEEVEC™), dasatinib (SPRYCEL™), nilotinib (TASIGNA™), bosutinib (BOSULIF™), and ponatinib (ICLUSIG™).

[0541] Examples of additional suitable chemotherapeutic agents include 1-dehydrotestosterone, 5-fluorouracil, dacarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, alkylating agents, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC), antimitotic agents, cis-dichlorodiamineplatinum(II) (DDP) (cisplatin), diaminodichloroplatinum, anthracyclines, antibiotics, antimetabolites, asparaginase, live BCG bacteria (BCG), live) (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, leucovorin calcium, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), chlorambucil, cisplatin, cladribine, colchicine, conjugated estrogens, cyclophosphamide, cyclothosphamide, cytarabine, cytochalasin B, cytoxan, dacarbazine, dactinomycin, dactinomycin (formerly actinomycin), daunorubicin HCl, daunorubicin citrate, denileukin diftitox, dexrazoxane, dibromomannitol, dihydroxy anthracin dione dione), docetaxel, dolasetron mesylate, doxorubicin HCl, dronabinol, Escherichia coli (E.coli) L-asparaginase, emetine, epoetin-α, Erwinia L-asparaginase, esterified estrogens, estradiol, estramustine sodium phosphate, ethidium bromide, ethinyl estradiol, etidronate, etoposide, citrovorum factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine HCl, glucocorticoids, goserelin acetate, gramicidin D, granisetron HCl, hydroxyurea, idarubicin HCl, ifosfamide, interferon α-2b, irinotecan HCl, letrozole, leucovorin calcium, leuprolide acetate, levamisole HCl, lidocaine, lomustine, maytansinoids Mechlorethamine HCl, medroxyprogesterone acetate, megestrol acetate, melphalan HCl, mercaptopurine, mesna, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron HCl, paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCl, primycin, porfimer sodium, procaine, procarbazine HCl, propranolol, rituximab, sargramostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone, tetracaine, thioepa chlorambucil chlorambucil), thioguanine, thiotepa, topotecan HCl, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

[0542] In some embodiments, a pharmaceutical composition containing an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof or a morphic form of Compound 1 is administered in combination with a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer). Examples of chemotherapeutic agents include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted ureas, methylhydrazine derivatives, adrenocortical suppressants, corticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin (LV), binutuzum, oxaliplatin, capecitabine, paclitaxel, and docetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine. ylamelamines); acetogenins (especially bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryostatins; kallistatins; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including the synthetic analogs KW-2189 and CB1-TM1); eluterobin; pancratistatin; sarcodictyin; spongistatins;Nitrogen mustards such as chlorambucil, chlornaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobuenbiquine, fenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; enediyne antibiotics (e.g., calicheamicins, particularly calicheamicin γ11 and calicheamicin ω11 (e.g., Agnew, Chem. Inti. Ed. Engl. 33:183-186)); (1994)); dynemicins, including dynemicin A; bisphosphonates, such as clodronate; esperamicin; and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN™ (morpholinodoxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolinodoxorubicin, and deoxydoxorubicin). doxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;Pyrimidine analogues such as ancitabine, obinutuzumab, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; anti-adrenals such as aminoglutethimide, mitotane, and trilostane; florinic acid Folic acid supplements such as aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; bestravcil; bisantrene; binutuzum; defofamine; demecolcine; diaziconazole; elfomithine; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidammol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK™ polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triazicon; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; obinutuzumab, e.g., TAXOL™ (paclitaxel;Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE™, a Cremophor-free albumin-modified nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, IL), and TAXOTERE™ docetaxel (Rhone-Poulenc Rorer, Antony, France); binutuzumab; GEMZAR™ gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE™ vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Two or more chemotherapeutic agents can be used in a cocktail administered in combination with a pharmaceutical composition containing an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1. Suitable dosing regimens for combination chemotherapy are known in the art. For example, combination dosing regimens are described in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999) and Douillard et al., Lancet 355(9209): 1041-1047 (2000).

[0543] Additional therapeutic agents that may be administered in combination with a pharmaceutical composition comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1, include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522), cilengitide, erlotinib, cetuximab, Panitumumab, gefitinib, trastuzumab, dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukine, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, HLL1, huN901-DM1, atiplimod, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir , nelfinavir mesylate, indinavir sulfate, belinstat, panobinostat, mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin, talmapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene, AZD 4547, rilotumumab, oxaliplatin (ELOXATIN™), PD0332991, ribociclib (LEE011), abemaciclib (LY2835219), HDM201, fulvestrant (FASLODEX™), exemestane (AROMASIN™), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (ALIMTA™), and ramucirumab (IMC-1121B).

[0544] In certain embodiments, the additional therapy is a monoclonal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Similar to antibodies naturally produced by B cells, these MAbs can "coat" the surface of cancer cells and induce their destruction by the immune system. For example, bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor microenvironment that promotes the development of tumor blood vessels. When VEGF binds to bevacizumab, it cannot interact with its cell receptor, preventing signaling that leads to the growth of new blood vessels. MAbs that bind to cell surface growth factor receptors prevent the target receptor from sending normal growth-promoting signals. They can also induce apoptosis and activate the immune system to destroy tumor cells.

[0545] In one embodiment of the invention, the bioactive agent is an immunosuppressant. The immunosuppressant may be a calcineurin inhibitor, such as cyclosporine or ascomycin, e.g., cyclosporine A (NEORAL™), FK506 (tacrolimus), pimecrolimus, an mTOR inhibitor, such as rapamycin or a derivative thereof, e.g., sirolimus (RAPAMUNE™), everolimus (CERTICAN™), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g., ridaforolimus, azathioprine, campath 1H, an S1P receptor modulator, e.g., fingolimod or an analog thereof, an anti-IL-8 antibody, mycophenolic acid or a salt thereof, e.g., the sodium salt or a prodrug thereof, e.g., mycophenolate mofetil (CELLCEPT™), OKT3 (ORTHOCLONE™), or a combination thereof. OKT3™), prednisone, ATGAM™, THYMOGLOBULIN™, brequinar sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, tresperimus, leflunomide (ARAVA™), CTLAI-Ig, anti-CD25, anti-IL2R, basiliximab (SIMULECT™), daclizumab (ZENAPAX™), mizoribine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, ELIDEL™), CTLA4Ig (abatacept), belatacept, LFA3Ig, etanercept (sold as ENBREL™ by Immunex), adalimumab (HUMIRA™), infliximab (REMICADE™), anti-LFA-1 antibody, natalizumab (ANTEGREN™), enlimomab, gavilimomab, anti-thymocyte immunoglobulin, siplizumab, alefacept, efalizumab, pentasa, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, aspirin and ibuprofen.

[0546] In some embodiments, the bioactive agent is a therapeutic agent that is a biologic, such as a cytokine (e.g., an interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In some embodiments, the biologic is an anti-angiogenesis agent, such as an anti-VEGF agent, e.g., bevacizumab (AVASTIN™). In some embodiments, the biologic is an immunoglobulin-based biologic, such as a monoclonal antibody (e.g., a humanized antibody, fully human antibody, Fc fusion protein, or functional fragment thereof), that agonizes a target, stimulates an anti-cancer response, or antagonizes an antigen important to cancer.Such agents include RITUXAN™ (rituximab), ZENAPAX™ (daclizumab), SIMULECT™ (basiliximab), SYNAGIS™ (palivizumab), REMICADE™ (infliximab), HERCEPTIN™ (trastuzumab), MYLOTARG™ (gemtuzumab ozogamicin), CAMPATH™ (alemtuzumab), and HERCEPTIN™ (trastuzumab). ), ZEVALIN™ (ibritumomab tiuxetan), HUMIRA™ (adalimumab), XOLAIR™ (omalizumab), BEXXAR™ (tositumomab-I-131), RAPTIVA™ (efalizumab), ERBITUX™ (cetuximab), AVASTIN™ (bevacizumab), TYSABRI™ (natalizumab), ACTEMRA™ ( tocilizumab), VECTIBIX™ (panitumumab), LUCENTIS™ (ranibizumab), SOURIS™ (eculizumab), CIMZIA™ (certolizumab pegol), SIMPONI™ (golimumab), ILARIS™ (canakinumab), STELARA™ (ustekinumab), ARZERRA™ (ofatumumab), PROLIA™ (denosine monophosphate), mab), NUMAX™ (motavizumab), ABTHRAX™ (raxibacumab), BENLYSTA™ (belimumab), YERVOY™ (ipilimumab), ADCETRIS™ (brentuximab vedotin), PERJETA™ (pertuzumab), KADCYLA™ (ado-trastuzumab emtansine), and GAZYVA™ (obinutuzumab). Antibody-drug conjugates are also included.

[0547] The combination therapy may also include a therapeutic agent that is a non-drug treatment. For example, in addition to radiation therapy, cryotherapy, thermotherapy, and / or surgical removal of tumor tissue, a pharmaceutical composition containing an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof or a morphic form of Compound 1 may be administered.

[0548] Pharmaceutical Composition Novel and advantageous pharmaceutical compositions are provided according to the present invention that are suitable for administration to humans, comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1. In certain embodiments, pharmaceutical compositions comprising Compound 1 or a pharmaceutically acceptable salt thereof are prepared from a morphic form described herein, such as Form B of Compound 1. For example, Form B of Compound 1 can be dissolved and then spray-dried to form a solid spray-dried dispersion containing one or more pharmaceutically acceptable excipients.

[0549] Pharmaceutically acceptable excipients suitable for use as carriers or diluents are known to those skilled in the art and can be used in a variety of formulations. See, for example, Remington's Pharmaceutical Sciences, 23rd Edition, A. Adejare, Editor, Academic Press (2020), Handbook of Pharmaceutical Excipients, 6th Edition, RC Rowe, PJ Sheskey, ME Quinn Editors, American Pharmaceutical Association, and Pharmaceutical Press (2009), and Handbook of Pharmaceutical Additives, 3rd Edition, compiled by Michael and Irene Ash, Synapse Information Resources (2007).

[0550] The pharmaceutical compositions can be formulated as any pharmaceutically useful form, such as a solid dosage form, liquid, aerosol, cream, gel, pill, injection or infusion solution, capsule, tablet, syrup, transdermal patch, subcutaneous patch, dry powder, inhalation formulation, in a medical device, suppository, buccal or sublingual formulation, parenteral formulation, or eye drops. Some dosage forms, such as tablets and capsules, are divided into suitably sized unit doses containing an appropriate amount of the active ingredient, for example, an effective amount to achieve a desired purpose.

[0551] Carriers include excipients and diluents and should be of sufficiently high purity and sufficiently low toxicity to be suitable for administration in effective amounts to patients being treated. Carriers may be inert or may have their own medicinal properties. The amount of carrier used in conjunction with Compound 1 or its pharmaceutically acceptable salt or morphic form of Compound 1 is sufficient to provide a practical amount of material for administration per unit dose of the compound.

[0552] The types of carriers include, but are not limited to, binders, buffers, coloring agents, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents.Some carriers may be classified into more than one type, for example, vegetable oils can be used as lubricants in some formulations and as diluents in other formulations.Exemplary pharmaceutically acceptable carriers include sugar, starch, cellulose, powdered tragacanth, malt, gelatin; talc, and vegetable oil.Any active agent that does not substantially interfere with the activity of Compound 1 may be included in the pharmaceutical composition.

[0553] An effective amount of Compound 1 or a pharmaceutically acceptable salt thereof or a morphic form of Compound 1 disclosed herein can be administered orally, topically, systemically, parenterally, by inhalation or spray, sublingually, by implant, for example, an implant inserted into a tumor or site of abnormal cell growth, transdermally, by buccal administration, rectally, as ophthalmic solution, as an injection, including intravenous, intra-aortal, intracranial, subdermal, intraperitoneal, subcutaneous, nasal, sublingual, or rectal, or by other means, in a dosage unit formulation containing a conventional pharmaceutically acceptable carrier.

[0554] In certain embodiments, pharmaceutical compositions prepared from or comprising Compound 1 of the present invention or a pharmaceutically acceptable salt thereof or a morphic form of Compound 1 are provided in solid, gel, or liquid dosage forms for oral delivery.

[0555] In certain embodiments, the pharmaceutical composition comprises Compound 1 or a pharmaceutically acceptable salt thereof, a dissolution enhancer, a permeation enhancer, a filler, one or more binders and / or glidants, and one or more flow aids. Non-limiting examples of pharmaceutically acceptable excipients include hypromellose (e.g., hypromellose acetate succinate), vitamin E (e.g., d-α-tocopheryl polyethylene glycol succinate), mannitol, cellulose (e.g., microcrystalline cellulose), croscarmellose sodium, silicon dioxide (e.g., untreated fumed colloid), and magnesium stearate. In certain embodiments, the pharmaceutical composition according to the present invention is formulated into a dosage unit form, such as an oral dosage unit form. In certain embodiments, the pharmaceutical composition according to the present invention is formulated into a tablet dosage form.

[0556] In certain embodiments, pharmaceutical compositions comprising Compound 1 or a pharmaceutically acceptable salt thereof include one or more of the following excipients:

[0557] TIFF2025541736000048.tif77170

[0558] In certain embodiments, there is also provided a method for preparing a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, or a morphic form of Compound 1, according to the present invention. In certain embodiments, the method for preparing a pharmaceutical composition comprising Compound 1 includes (i) a spray-drying step to provide a spray-dried intermediate (SRI) comprising Compound 1 and a pharmaceutically acceptable excipient, (ii) a granulation step to provide granules comprising Compound 1 and a pharmaceutically acceptable excipient, the granules having a desired bulk density of about 0.4 g / mL to 0.6 g / mL, for example, about 0.48 g / mL to 0.54 g / mL, and (iii) a tableting step to provide the pharmaceutical composition comprising Compound 1 and a pharmaceutically acceptable excipient in an oral dosage unit form.

[0559] In certain embodiments, the dosage strength of the pharmaceutical composition is at least about 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 440 mg, 480 mg, 520 mg, 560 mg, The dose is 600 mg, 640 mg, 680 mg, 720 mg, 760 mg, or 800 mg, which in non-limiting embodiments may be administered once weekly, twice weekly, three times weekly, four times weekly, five times weekly, six times weekly, once daily (QD), or twice daily (BID), optionally with treatment on days 1-7, 1-14, 1-21, or 1-28 of a 28-day treatment cycle. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof or a morphic form of Compound 1 of the present invention is provided as a soft-shell capsule or tablet for oral administration. In certain embodiments, the solid or gel dosage form has a dosage strength of at least about 10 mg, 20 mg, 40 mg, 80 mg, 140 mg, 240 mg, 360 mg, or 480 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 800 mg, which, in non-limiting aspects, can be administered once weekly, twice weekly, three times weekly, four times weekly, five times weekly, six times weekly, once daily (QD), or twice daily (BID), optionally with treatment occurring on days 1-7, 1-14, 1-21, or 1-28 of a 28-day treatment cycle.

[0560] In certain embodiments, the pharmaceutical composition is administered orally once or twice daily (BID) as needed.

[0561] Embodiments of the pharmaceutical composition include the following: 1. In certain embodiments, Compound 1 is provided in an effective amount in a pharmaceutical composition that includes at least three, four, or all of a solubility enhancer, a permeation enhancer, a filler, a binder / glidant, and / or a mucoadhesive / disintegrant. 2. The pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition is provided in tablet form. 3. The pharmaceutical composition of embodiment 1 or 2, wherein the pharmaceutical composition is prepared from a morphic form of Compound 1, for example, by dissolving Form B of Compound 1 and then spray drying. 4. The pharmaceutical composition of any one of embodiments 1 to 3, wherein the pharmaceutical composition further comprises a flow aid and a lubricant. 5. The pharmaceutical composition of any one of embodiments 1 to 4, wherein the pharmaceutical composition comprises about 5% to about 20% by weight of Compound 1. 6. The pharmaceutical composition of any one of embodiments 1 to 5, wherein the solubility enhancer is hypromellose or a hypromellose derivative. 7. The pharmaceutical composition of embodiment 6, wherein the hypromellose derivative is hypromellose acetate succinate. 8. The pharmaceutical composition of any one of embodiments 1 to 7, wherein the permeation enhancer is vitamin E or a vitamin E derivative. 9. The pharmaceutical composition of embodiment 8, wherein the vitamin E derivative is d-α-tocopheryl polyethylene glycol succinate. 10. The pharmaceutical composition of any one of embodiments 1-9, wherein the filler is mannitol. 11. The pharmaceutical composition of any one of embodiments 1-10, wherein the binder / glidant is cellulose. 12. The pharmaceutical composition according to embodiment 11, wherein the binder / glidant is microcrystalline cellulose. 13. The pharmaceutical composition of any one of embodiments 1-12, wherein the mucoadhesive / disintegrant is croscarmellose or a croscarmellose derivative. 14. The pharmaceutical composition of embodiment 13, wherein the croscarmellose derivative is croscarmellose sodium. 15. The pharmaceutical composition of any one of embodiments 4-14, wherein the flow aid is colloidal silicon dioxide. 16. The pharmaceutical composition of embodiment 15, wherein the colloidal silicon dioxide is untreated fumed colloidal silicon dioxide. 17. The pharmaceutical composition of any one of embodiments 4-16, wherein the lubricant is magnesium stearate. 18. The pharmaceutical composition according to any one of embodiments 1 to 17, wherein the pharmaceutical composition comprises from about 15% to about 55% by weight of the solubility enhancer. 19. The pharmaceutical composition of any one of embodiments 1-18, wherein the pharmaceutical composition comprises about 1% to about 10% by weight of the permeation enhancer. 20. The pharmaceutical composition of any one of embodiments 1-19, wherein the pharmaceutical composition comprises about 20% to about 40% by weight of a filler. 21. The pharmaceutical composition of any one of embodiments 1-20, wherein the pharmaceutical composition comprises from about 10% to about 30% by weight of a binder / glidant. 22. The pharmaceutical composition according to any one of embodiments 1-21, wherein the pharmaceutical composition comprises from about 0.5% to about 5% by weight of the mucoadhesive / disintegrant. 23. The pharmaceutical composition of any one of embodiments 1-22, wherein the pharmaceutical composition comprises about 10% by weight of Compound 1. 24. The pharmaceutical composition according to any one of embodiments 1 to 23, wherein the pharmaceutical composition comprises about 35% by weight of the solubility enhancer. 25. The pharmaceutical composition of any one of embodiments 1-24, wherein the pharmaceutical composition comprises about 5% by weight of the permeation enhancer. 26. The pharmaceutical composition according to any one of embodiments 1 to 25, wherein the pharmaceutical composition comprises about 28% by weight of a filler. 27. The pharmaceutical composition of any one of embodiments 1-26, wherein the pharmaceutical composition comprises about 20% by weight of a binder / glidant. 28. The pharmaceutical composition according to any one of embodiments 1-27, wherein the pharmaceutical composition comprises about 2% by weight of the mucoadhesive / disintegrant. 29. The pharmaceutical composition of any one of embodiments 4-28, wherein the pharmaceutical composition comprises about 0.5% by weight of a flow aid. 30. The pharmaceutical composition of any one of embodiments 4-29, wherein the pharmaceutical composition comprises about 0.6% by weight of a lubricant.

[0562] Pharmaceutical Compositions Comprising Morphic Forms of Compound 1 While the morphic forms of Compound 1 can be administered as the pure chemical, they are often administered to a host, typically a human, in need of treatment for any of the disorders described herein as a pharmaceutical composition comprising an effective amount of a morphic form of Compound 1. Accordingly, the present disclosure provides pharmaceutical compositions comprising an effective amount of a morphic form of Compound 1 together with at least one pharmaceutically acceptable carrier or excipient described herein. The pharmaceutical composition can include a morphic form of Compound 1 as the sole active agent, or in alternative embodiments, can include a morphic form of Compound 1 and at least one additional active agent.

[0563] In certain embodiments, the pharmaceutical composition is in a unit dosage form containing about 0.001 mg to about 1000 mg, about 0.01 mg to about 800 mg, about 1 mg to about 800 mg, or about 200 mg to about 600 mg of the morphic form of Compound 1, and optionally about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of an additional active agent. Examples include dosage forms having at least about 0.001 mg, about 0.005 mg, about 0.010 mg, about 0.10 mg, about 1 mg, about 5 mg, about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, or about 750 mg, or less than 0.001 mg, less than 0.005 mg, less than 0.010 mg, less than 0.10 mg, less than 1 mg, less than 5 mg, less than 10 mg, less than 25 mg, less than 50 mg, less than 100 mg, less than 200 mg, less than 250 mg, less than 300 mg, less than 400 mg, less than 500 mg, less than 600 mg, less than 700 mg, or less than 750 mg of a morphic form of Compound 1.

[0564] In certain embodiments, the pharmaceutical composition is in a dosage form containing about 50 mg of the morphic form of Compound 1. In certain embodiments, the pharmaceutical composition is in a dosage form containing about 100 mg of the morphic form of Compound 1. In certain embodiments, the pharmaceutical composition is in a dosage form containing about 150 mg of the morphic form of Compound 1. In certain embodiments, the pharmaceutical composition is in a dosage form containing about 200 mg of the morphic form of Compound 1. In certain embodiments, the pharmaceutical composition is in a dosage form containing about 250 mg of the morphic form of Compound 1. In certain embodiments, the pharmaceutical composition is in a dosage form containing about 300 mg of the morphic form of Compound 1. In certain embodiments, the pharmaceutical composition is in a dosage form containing about 400 mg of the morphic form of Compound 1. In certain embodiments, the pharmaceutical composition is in a dosage form containing about 500 mg of the morphic form of Compound 1. In certain embodiments, the pharmaceutical composition is in a dosage form containing about 600 mg of the morphic form of Compound 1. In certain embodiments, the pharmaceutical composition is in a dosage form containing about 700 mg of the morphic form of Compound 1. In certain embodiments, the pharmaceutical composition is in a dosage form containing about 800 mg of the morphic form of Compound 1.

[0565] In certain embodiments, a morphic form of Compound 1 is administered to a patient in need of a morphic form of Compound 1 once or twice daily.

[0566] In certain embodiments, pharmaceutical compositions according to the present invention comprise a morphic form of Compound 1 and a pharmaceutically acceptable excipient, including, but not limited to, hypromellose acetate succinate, vitamin E TPGS (d-α-tocopheryl polyethylene glycol succinate), mannitol, microcrystalline cellulose, croscarmellose sodium, untreated fumed colloidal silicon dioxide, and magnesium stearate.

[0567] Pharmaceutical compositions can be formulated for oral administration. These compositions can contain any amount of the morphic form of Compound 1 that achieves the desired results, for example, 0.1% to 99% by weight (wt.%) of the morphic form of Compound 1, typically at least about 5% by weight of the morphic form of Compound 1. In some embodiments, the morphic form of Compound 1 contains about 5% to about 30%, about 25% to about 50%, or about 5% to about 75% by weight of the morphic form of Compound 1. [Example]

[0568] general synthesis The compounds described herein can be prepared by methods known to those skilled in the art. As a non-limiting example, the disclosed compounds can be made using the following schemes:

[0569] Compounds of the present invention that have a stereocenter may be conveniently depicted without stereochemistry. Those skilled in the art will recognize that pure enantiomers and diastereomers can be prepared by methods known in the art. Examples of methods for obtaining optically active materials include at least the following:

[0570] i) Physical Separation of Crystals - a technique in which visible crystals of the individual enantiomers are manually separated. This technique can be used when crystals of the separate enantiomers exist, i.e. the material is a conglomerate, and the crystals are visually distinguishable.

[0571] ii) Simultaneous crystallization - a technique in which the individual enantiomers are crystallized separately from a solution of the racemate, which is only possible if the enantiomers are conglomerates in the solid state.

[0572] iii) Enzymatic resolution - a technique for partially or completely separating a racemate by virtue of the difference in the reaction rates of the enantiomers with an enzyme.

[0573] iv) Enzymatic Asymmetric Synthesis - a synthetic technique that uses an enzymatic reaction in at least one step of the synthesis to obtain an enantiomerically pure or enantiomerically enriched synthetic precursor of a desired enantiomer.

[0574] v) Chemical asymmetric synthesis - a synthetic technique in which a desired enantiomer is synthesized from non-chiral precursors under conditions that result in asymmetry (ie, chirality) in the product, which may be achieved by means of chiral catalysts or chiral auxiliaries.

[0575] vi) Diastereomeric separation - a technique in which a racemate is reacted with an enantiomerically pure reagent (chiral auxiliary) that converts the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization due to their more distinct structural differences, followed by removal of the chiral auxiliary to give the desired enantiomer.

[0576] vii) First and second order asymmetric transformation - a technique in which the diastereomers derived from the racemate are rapidly equilibrated to give rise to a preponderance in the dissolution of the diastereomer derived from the desired enantiomer, or the preferential crystallization of the diastereomer derived from the desired enantiomer disrupts the equilibrium, ultimately converting essentially all of the material from the desired enantiomer to the crystalline diastereomer, followed by liberation of the desired enantiomer from the diastereomer.

[0577] viii) Kinetic Resolution - This technique refers to achieving partial or complete resolution of a racemate (or further resolution of a partially resolved compound) by the unequal reaction rates of enantiomers with chiral, non-racemic reagents or catalysts under kinetic conditions.

[0578] ix) Enantiospecific synthesis from non-racemic precursors - a synthetic technique in which the desired enantiomer is obtained from non-chiral starting materials with little or no loss of stereochemical integrity during synthesis.

[0579] x) Chiral Liquid Chromatography - a technique in which the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their different interactions with a stationary phase (including by chiral HPLC). The stationary phase may be made of a chiral material, or the mobile phase may contain additional chiral material to effect the different interactions.

[0580] xi) Chiral gas chromatography - a technique in which the racemate is volatilized and the enantiomers are separated by their different interactions in a gaseous mobile phase by means of a column containing a fixed non-racemic chiral adsorbent phase.

[0581] xii) Extraction with chiral solvents- a technique in which enantiomers are separated by selective dissolution of one enantiomer in a particular chiral solvent.

[0582] xiii) Transport across chiral membranes - a technique in which a racemate is placed in contact with a thin membrane barrier. The barrier can separate two miscible fluids, one of which contains the racemate, and a driving force such as a concentration or pressure difference results in preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral properties of the membrane, which allows only one enantiomer of the racemate to pass through.

[0583] xiv) Simulated moving bed chromatography is used in certain embodiments. A wide variety of chiral stationary phases are commercially available.

[0584] "Nucleophilic aromatic substitution" (S N Ar) refers to a substitution reaction in which a nucleophile displaces a good leaving group on an aromatic ring, such as a halide (F, Cl, Br, I), tosylate, mesylate, or triflate. NExamples of nucleophiles in the Ar reaction include, but are not limited to, amines, including aromatic amines, alcohols, phenols, and aromatic compounds containing a hydroxyl group attached to the aromatic ring. The nucleophilic aromatic substitution can be carried out at low temperatures (below 0°C), room temperature (about 25°C), or elevated temperatures (about 30°C to 200°C). The reaction is carried out in a suitable solvent, including, but not limited to, DMSO, N,N-dimethylformamide, THF, N,N-dimethylacetamide, 1,4-dioxane, and acetonitrile. The reaction is carried out in the presence of a base, such as an inorganic or organic base, including, but not limited to, NaOH, KOH, Na2CO3, Na3PO4, Cs2CO3, Li2CO3, DIEA (N,N-diisopropylethylamine, or Hunig's base).

[0585] The synthesis of the compounds according to the present invention may include steps of protecting and deprotecting some reactive groups, such as amino groups and carboxyl and hydroxyl groups. Methods for protecting and deprotecting amino and hydroxyl groups and corresponding protecting groups are known to those skilled in the art and are described, for example, in Greene's Protective Groups in Organic Synthesis, 5th Edition, PGM Wuts, Wiley (2014).

[0586] Example 1: Synthesis of tert-butyl (R)-3-(6-(2-cyano-3,6-difluorophenoxy)-4-oxoquinazolin-3(4H)-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate - Route 1 (via transamination) [ka]

[0587] Step 1 can be carried out on a manufacturing scale to prepare large quantities of 1-2 for use in preparing compound 1. A non-limiting example of this scaled-up reaction and raw material inputs is provided below. [ka]

[0588] TIFF2025541736000051.tif254170

[0589] 1 H NMR (400 MHz, CDCl3), δ, ppm: 3.94 (m, 1H) 3.46 - 3.67 (m, 4H) 3.26 - 3.39 (m, 2H) 2.06 (m, 1H) 1.69 - 1.76 (m, 1H) 1.65 (m, 1H) 1.54 - 1.62 (m, 1H) 1.48 - 1.52 (m, 2H) 1.41 - 1.48 (m, 11H).

[0590] Step 2 can be carried out on a manufacturing scale to prepare large quantities of 1-4 for use in preparing compound 1. A non-limiting example of this scaled-up reaction and raw material inputs is provided below. [ka]

[0591] TIFF2025541736000053.tif39170

[0592] TIFF2025541736000054.tif143170

[0593] Step 3 can be carried out on a manufacturing scale to prepare large quantities of 1-6 for use in preparing compound 1. A non-limiting example of this scaled-up reaction and raw material inputs is provided below. [ka]

[0594] TIFF2025541736000056.tif44170

[0595] TIFF2025541736000057.tif106170

[0596] Step 4 can be carried out on a manufacturing scale to prepare large quantities of 1-7 for use in preparing compound 1. A non-limiting example of this scaled-up reaction and raw material inputs is provided below. [ka]

[0597] TIFF2025541736000059.tif43170

[0598] TIFF2025541736000060.tif129170

[0599] Example 2: Synthesis of tert-butyl (R)-3-(6-(2-cyano-3,6-difluorophenoxy)-4-oxoquinazolin-3(4H)-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate - Route 2 (via diastereomeric crystallization) [ka]

[0600] Step 1: Synthesis of tert-butyl 3-(hydroxyimino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (2-1). To a solution of tert-butyl 3-oxo-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1-1, 30 g, 117.50 mmol) in ethanol (450 mL), sodium acetate (14.46 g, 176.26 mmol) and hydroxylamine hydrochloride (12.25 g, 176.26 mmol) were added. The mixture was stirred at 70 °C for 1 hour. The reaction mixture was concentrated to remove EtOH and diluted with ethyl acetate (300 mL) and water (300 mL). The aqueous layer was extracted with ethyl acetate (2×150 mL) and the combined organic phases were washed with saturated sodium bicarbonate (aqueous 300 mL), water (300 mL), brine (300 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford tert-butyl 3-(hydroxyimino)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (2-1, 32 g, crude) as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 8.71 - 7.60 (m, 1H), 4.52 (s, 1H), 4.38 (s, 1H), 3.74 - 3.57 (m, 2H), 3.41 - 3.26 (m,2H), 2.58 (s, 1H), 2.50 (s, 1H), 1.77 - 1.66 (m, 2H), 1.65 - 1.54 (m, 2H), 1.46 (s, 9H).

[0601] Step 2: Synthesis of tert-butyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (2-2). To a solution of tert-butyl (3E)-3-hydroxyimino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (2-1, 32 g, 118.38 mmol) in ethanol (600 mL), Raney Ni (6.00 g, 70.03 mmol) and ammonium acetate (19.1 g, 247.79 mmol) were added. The mixture was stirred at 70 °C under a hydrogen atmosphere (15 psi) for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was dissolved in aqueous hydrochloric acid (1 M, 150 mL), and the resulting mixture was washed with methyl tert-butyl ether (2 × 150 mL). The pH was then adjusted to 12 by the addition of aqueous sodium hydroxide (4 M). The aqueous layer was extracted with dichloromethane (3 × 150 mL) and the combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated to give a pale yellow solid tert-butyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (2-2, 22.2 g, 86.60 mmol, 73.16% yield). 1 H NMR (400 MHz, CDCl3) δ 4.02 - 3.85 (m, 1H), 3.70 - 3.43 (m, 4H), 3.39 - 3.21 (m, 2H), 2.05 (br dd, J = 7.5, 12.7 Hz, 1H), 1.78 - 1.53 (m, 3H), 1.51 - 1.33 (m, 13H).

[0602] Step 3: Synthesis of (R)-8-(tert-butoxycarbonyl)-1-oxa-8-azaspiro[4.5]decane-3-aminium (R)-2-hydroxy-2-phenylacetate (2-4) (D-mandelate salt). To a mixture of tert-butyl 3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (2-2, 25 g, 97.53 mmol) in acetonitrile (350 mL), (2R)-2-hydroxy-2-phenylacetic acid (2-3, 7.42 g, 48.76 mmol) was added in small portions at 15 °C (ambient temperature). A precipitate formed, and the mixture was then stirred at 70 °C for 2 hours. After slowly cooling to 15 °C, the suspension was stirred at 15 °C for an additional 12 hours. The precipitate was filtered, washed with acetonitrile (100 mL), and dried under vacuum. (R)-8-(tert-butoxycarbonyl)-1-oxa-8-azaspiro[4.5]decane-3-aminium (R)-2-hydroxy-2-phenylacetate (2-4, 19.5 g) was obtained. 1 H NMR (400 MHz, methanol-d4) δ = 7.52 - 7.45 (m, 2H), 7.35 - 7.28 (m, 2H), 7.28 - 7.21 (m, 1H), 4.89 (br s, 1H), 4.01(dd, J = 5.4, 10.1 Hz, 1H), 3.91 - 3.79 (m, 2H), 3.65 (tdd, J = 4.5, 8.7, 13.1 Hz, 2H), 3.32 - 3.21 (m, 2H), 2.24 (dd, J = 8.0, 13.9Hz, 1H), 1.80 - 1.62 (m, 4H), 1.55 - 1.49 (m, 1H), 1.48 (s, 9H). 1H NMR (400 MHz, DMSO-d6) δ = 7.37 (d, J = 7.3 Hz, 2H), 7.28 - 7.21 (m, 2H), 7.20 - 7.13 (m, 1H), 4.57 (s, 1H), 3.86 (dd, J =6.0, 9.5 Hz, 2H), 3.71 (ddd, J = 5.6, 8.0, 10.9 Hz, 2H), 3.62 (dd, J = 4.9, 9.5 Hz, 2H), 3.42 (qd, J = 4.2, 13.1 Hz, 3H), 3.19 (br d, J = 10.3 Hz, 3H), 2.05 (dd, J = 8.1, 13.4 Hz, 1H), 1.66 - 1.54 (m, 3H), 1.54 - 1.45 (m, 1H), 1.45 - 1.40 (m, 1H), 1.39 (s, 9H).

[0603] Step 4: Synthesis of tert-butyl (3R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1-2). (R)-8-(tert-butoxycarbonyl)-1-oxa-8-azaspiro[4.5]decane-3-aminium (R)-2-hydroxy-2-phenylacetate 2-4 was suspended in water (200 mL) and neutralized with aqueous sodium hydroxide (2 M, 25 mL). The mixture was extracted with ethyl acetate (3 × 250 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl (3R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1-2, 10.3 g, 95.3% ee) as a white solid.

[0604] Repeating steps 3 and 4 can provide 1-2 with higher enantiomeric purity. To a mixture of tert-butyl (3R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1-2, 10.3 g, 39 mmol) in acetonitrile (350 mL), (2R)-2-hydroxy-2-phenylacetic acid (2-3, 5.76 g, 37.8 mmol) was added portionwise at 15 °C (ambient temperature). A precipitate formed, and the mixture was then stirred at 70 °C for 2 h. After slowly cooling to 15 °C, the suspension was stirred at 15 °C for an additional 12 h. The precipitate was filtered, washed with acetonitrile (40 mL), and dried under vacuum (3 g remained). The remaining D-mandelate salt was suspended in water (80 mL), neutralized with aqueous sodium hydroxide (2 M, 20 mL), and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with brine (50 mL × 3), dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl (3R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1-2, 6.5 g, 23.80 mmol, 99.5% ee) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 3.93 (dd, J = 5.8, 8.8 Hz, 1H), 3.72 - 3.43 (m, 4H), 3.41 - 3.23 (m, 2H), 2.05 (dd, J = 7.3, 12.6 Hz, 1H), 1.79 - 1.53 (m, 4H), 1.52 - 1.34 (m, 13H).

[0605] Stereochemistry determination of compounds 2-4 The mandelate salt 2-4 from Example 2 was determined by X-ray crystallography to be (R)-8-(tert-butoxycarbonyl)-1-oxa-8-azaspiro[4.5]decane-3-aminium (R)-2-hydroxy-2-phenylacetate (see Example 32 for single crystal X-ray crystallography structure determination). This intermediate 2-4 was then carried on to synthesize compound 1-7, which is also the R isomer based on the subsequent reaction mechanism.

[0606] The stereochemistry of compounds 1-7 obtained in Example 2 (Route 2) was then compared with that from Example 1 (Route 1) using chiral SFC and polarimetry.

[0607] Chiral SFC method: Column: CHIRALPAK (trademark) AD-3, 50 mm x inner diameter 4.6 mm, 3 μm; Mobile phase: phase A for CO2, phase B for MeOH (0.05% DEA); Gradient elution: 40% MeOH (0.05% DEA) in CO2; Flow rate: 3mL / min; Detector: PDA; Column temperature: 35°C; Back pressure: 100bar Retention time of 1-7 (path 2) = 1.70 min (late eluting peak). Retention time of 1-7 (path 1) = 1.69 min (late eluting peak). Retention times for racemate 1-7 (control) = 0.96 min (early eluting peak) and 1.77 min (late eluting peak). Specific rotation [α] of 1-7 (route 2) 25 D =-67.310°. Specific rotation [α] of 1-7 (route 1) 25 D =-71.501°.

[0608] Intermediate 1-7 from both Route 1 and Route 2 was the late eluting peak by chiral SFC (same method) and had the same negative sign for specific rotation, determining that compound 1-7 from Route 1 was the R isomer. This confirms that the absolute stereochemistry of compound 1 is R, as shown below. [ka]

[0609] Example 3: Synthesis of 2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidin-4-yl)acetic acid [ka]

[0610] Step 1 can be carried out on a manufacturing scale to prepare large quantities of 3-3 for use in preparing compound 1. A non-limiting example of this scaled-up reaction and raw material inputs is provided below. [ka]

[0611] TIFF2025541736000065.tif29170

[0612] TIFF2025541736000066.tif126170

[0613] Step 2 can be carried out on a manufacturing scale to prepare large quantities of 3-4 for use in preparing compound 1. A non-limiting example of this scaled-up reaction and raw material inputs is provided below. [ka]

[0614] TIFF2025541736000068.tif24170

[0615] TIFF2025541736000069.tif151170

[0616] Step 3 can be carried out on a manufacturing scale to prepare large quantities of 3-6 for use in preparing compound 1. A non-limiting example of this scaled-up reaction and raw material inputs is provided below. [ka]

[0617] TIFF2025541736000071.tif29170

[0618] TIFF2025541736000072.tif142170

[0619] Step 4 can be carried out on a manufacturing scale to prepare large quantities of 3-7 for use in preparing compound 1. A non-limiting example of this scaled-up reaction and raw material inputs is provided below. [ka]

[0620] TIFF2025541736000074.tif36170

[0621] TIFF2025541736000075.tif165170

[0622] Example 4 Synthesis of (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 (Compound 1) [ka]

[0623] Compound 1 was prepared in seven steps from three starting materials 4-1, 1-7, and 3-7, as shown in the scheme above. Starting material 4-1 was treated with sulfuryl chloride (SO2Cl2) in the presence of triethylamine (TEA) to give sulfamoyl chloride 4-2, which was reacted with ammonia in the presence of methanol (NH3 / MeOH) to generate sulfamide 4-3. 1-7 (>99% ee) was converted to 4-3 by nucleophilic aromatic substitution (S N Ar) afforded intermediate 4-4 without loss of its enantiomeric purity (>99% ee). Deprotection of the Boc group of 4-4 with HCl afforded intermediate 4-5 as the free base. Treatment of 3-7 with TSTU afforded its activated form 4-6. Formation of an amide bond between 4-5 and 4-6 in the presence of DIEA afforded compound 1 as an amorphous solid. Recrystallization of this amorphous compound 1 from a mixture of acetone and water afforded the parent compound of compound 1 as a crystalline solid with >99% ee.

[0624] The compound 1 was prepared in seven steps, the general process of which is described below.

[0625] Step 1: Starting material 4-1 was treated with sulfuryl chloride and triethylamine in dichloromethane at -10°C to 5°C to produce sulfamoyl chloride 4-2. After the reaction was completed, water was slowly added to the reaction mixture. The resulting organic layer was collected, washed with water, and concentrated in vacuo to give 4-2 as a dichloromethane solution.

[0626] Step 2: Sulfamoyl chloride 4-2 in dichloromethane was added to a methanolic solution of ammonia at -10°C to 0°C, and the reaction was warmed to 15°C to 25°C to produce sulfamide 4-3. After completion of the reaction, the reaction mixture was concentrated in vacuo and subjected to aqueous workup using ethyl acetate and water. After solvent exchange, 4-3 was isolated as a solution in dimethylacetamide.

[0627] Step 3: A mixture of starting material 1-7, sulfamide 4-3, and cesium carbonate in dimethylacetamide was stirred at 55-65°C to produce intermediate 4-4. After the reaction reached the target conversion, water was added to the reaction mixture at 20-30°C and filtered to remove residual solids. The resulting aqueous solution was washed with methyl tert-butyl ether, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer containing the product was filtered through a CUNO filter. The filtered solution was concentrated under vacuum to give 4-4 as an ethyl acetate solution with chiral purity (>99% ee) maintained.

[0628] Step 4: Intermediate 4-4 in ethyl acetate was treated with aqueous hydrochloric acid at 45°C to 55°C to give deprotected intermediate 4-5. After the reaction was complete, water was added to the reaction mixture, followed by the addition of 20% aqueous sodium carbonate solution to adjust the pH of the reaction mixture to approximately 9. The free base 4-5 was isolated as a solid by filtration.

[0629] Step 5: Starting material 3-7 was treated with N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate (TSTU) in the presence of diisopropylethylamine (DIEA) in acetonitrile, initially at -5°C to 5°C, followed by warming to 20°C to 30°C, to produce activated 4-6. After the reaction reached the target conversion, the resulting solid was collected by filtration. The filtered solid was washed with water, followed by acetonitrile. The washed solid was dried to give 4-6 as a white solid.

[0630] Step 6: A mixture of intermediates 4-5 and 4-6 in dimethylformamide was treated with triethylamine and stirred at 20-30°C to generate compound 1. After the reaction reached the target conversion, the reaction mixture was added to a second reactor containing water. The resulting solid was first collected by filtration and redissolved in dichloromethane. The dichloromethane layer containing the product was passed through a CUNO filter. The filtered solution was concentrated under vacuum. The concentrated material was triturated with a mixture of dimethylformamide and water to yield compound 1 as an amorphous solid.

[0631] Step 7: Amorphous Compound 1 was recrystallized from a mixture of acetone, water, and ethanol to obtain crystalline Compound 1 drug substance. First, amorphous Compound 1 was dissolved in a mixture of acetone and water at 48°C to 58°C, and then a small amount of crystalline Compound 1 was used as a seed and treated at 35°C to 45°C. After stirring for several hours, ethanol was slowly added to the mixture. The resulting mixture was cooled to -3°C to 3°C and stirred at that temperature for several hours. After filtration, washing with ethanol, and drying, Compound 1 drug substance was obtained as a crystalline solid. In certain embodiments, the crystalline solid of Compound 1 is Compound 1 Form B.

[0632] Step 1 can be carried out on a manufacturing scale to prepare large quantities of 4-2 for use in preparing compound 1. A non-limiting example of this scaled-up reaction is provided below. [ka]

[0633] TIFF2025541736000078.tif79170

[0634] Step 2 can be carried out on a manufacturing scale to prepare large quantities of 4-3 for use in preparing compound 1. A non-limiting example of this scaled-up reaction is provided below. [ka]

[0635] TIFF2025541736000080.tif130170

[0636] Step 3 can be carried out on a manufacturing scale to prepare large quantities of 4-4 for use in preparing compound 1. A non-limiting example of this scaled-up reaction is provided below. [ka]

[0637] TIFF2025541736000082.tif240170

[0638] Step 4 can be carried out on a manufacturing scale to prepare large quantities of 4-5 for use in preparing compound 1. A non-limiting example of this scaled-up reaction is provided below. [ka]

[0639] TIFF2025541736000084.tif89170

[0640] Step 5 can be carried out on a manufacturing scale to prepare large quantities of 4-6 for use in preparing compound 1. A non-limiting example of this scaled-up reaction is provided below. [ka]

[0641] TIFF2025541736000086.tif84170

[0642] 1 H NMR (400 MHz, DMSO-d6): δ ppm 1.70 - 2.01 (m, 4 H) 2.66-2.93 (m, 8 H) 2.99-3.22 (m, 4 H) 3.76-4.09 (m, 5 H) 4.96 (br s, 1 H) 7.13 (br d, J = 1.10 Hz, 1 H) 7.33 (br d, J = 11.49 Hz, 1 H) 10.54 (br s, 1 H).

[0643] Step 6 can be carried out on a manufacturing scale to prepare large quantities of Compound 1 (amorphous) for use in preparing Compound 1. A non-limiting example of this scaled-up reaction is provided below. [ka]

[0644] TIFF2025541736000088.tif139170

[0645] 1 H NMR (400 MHz, DMSO-d6): δ ppm 10.53 (s, 1H), 10.20 (br s, 1H), 8.36 (s, 1H), 7.95-7.75 (m, 2H), 7.70 (dd, J = 3.2, 8.8 Hz, 1H), 7.50 (dd, J = 4.4, 9.6 Hz, 1H), 7.41-7.26 (m, 2H), 7.11 (d, J = 7.2 Hz, 1H), 5.40-5.19 (m, 1H), 5.03 (br s, 1H), 4.18-4.08 (m, 2H), 3.94 (s, 3H), 3.89 (t, J = 6.7 Hz, 2H), 3.78 (br dd, J = 4.8, 12.8 Hz, 1H), 3.68-3.58 (m, 1H), 3.56-3.39 (m, 2H), 3.19-3.14 (m, 4H), 3.10-3.00 (m, 2H), 2.79 (s, 3H), 2.73 (t, J = 6.7 Hz, 2H), 2.57 (br s, 2H), 2.42-2.32 (m, 1H), 2.14-1.97 (m, 1H), 1.86-1.49 (m, 8H), 1.05 (t, J = 7.2 Hz, 3H).

[0646] Step 7 can be carried out on a manufacturing scale to prepare large quantities of crystalline Compound 1. A non-limiting example of this scaled-up reaction is provided below. [ka]

[0647] TIFF2025541736000090.tif111170

[0648] In certain aspects, step 7 is modified such that, for example, in certain embodiments, crystallization is carried out at a lower temperature, such as from about 0° C. to about 35° C., from about 20° C. to about 35° C., from about 0° C. to about 20° C., or from about 10° C. to about 30° C. In certain embodiments, the temperature is about 0° C., about 5° C., about 10° C., about 15° C., about 20° C., about 25° C., or about 30° C.

[0649] In certain embodiments, crystallization is carried out at a low stirring speed, such as about 50 rpm to about 300 rpm, about 150 rpm to about 300 rpm, or about 200 rpm to about 300 rpm. In certain embodiments, the stirring is at about 50 rpm, about 60 rpm, about 70 rpm, about 80 rpm, about 90 rpm, about 100 rpm, about 110 rpm, about 120 rpm, about 130 rpm, about 140 rpm, about 150 rpm, about 160 rpm, about 170 rpm, about 180 rpm, about 190 rpm, about 200 rpm, about 210 rpm, about 220 rpm, about 230 rpm, about 240 rpm, about 250 rpm, about 260 rpm, about 270 rpm, about 280 rpm, about 290 rpm, or about 300 rpm.

[0650] In certain embodiments, the crystallization is carried out for a period of more than 10 hours, e.g., about 10 to about 30 hours, about 15 to about 30 hours, about 20 to about 30 hours, about 10 to about 25 hours, or about 15 to about 25 hours. In certain embodiments, the crystallization time is about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 25 hours, about 26 hours, about 27 hours, about 28 hours, about 29 hours, about 30 hours, about 31 hours, about 32 hours, about 33 hours, about 34 hours, or about 35 hours.

[0651] Example 5: Synthesis of (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoro-phenoxy]-4-oxo-quinazolin-3-yl]-8-[2-[3,3,5,5-tetradeuterio-1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol-6-yl]-4-hydroxy-4-piperidyl]acetyl]-1-oxa-8-azaspiro[4.5]decane [ka]

[0652] Step 1: To a solution of 1-benzylpiperidin-4-one (10 g, 52.84 mmol, 9.80 mL, 1 equiv.) in CDCl (50 mL) and DO (50 mL), 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine (1.40 g, 10.06 mmol, 0.19 equiv.) was added. The mixture was stirred in a sealed tube at 15 °C for 16 h. The reaction mixture was adjusted to pH 7 by adding aqueous HCl (1 M), and the separated organic phase was washed with water (20 mL) and brine (20 mL), dried over NaSO, filtered, and concentrated to give compound 1-benzyl-3,3,5,5-tetradeuterio-piperidin-4-one (9.8 g, crude) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ = 7.53–7.14 (m, 5H), 3.64 (s, 2H), 2.75 (s, 4H).

[0653] Step 2: To a solution of LDA (2 M, 30.11 mL, 1.2 equiv) was added a solution of tert-butyl acetate (7.00 g, 60.22 mmol, 8.08 mL, 1.2 equiv) in THF (75 mL) at −65° C., the mixture was stirred at −60° C. for 0.5 h, and then a solution of 1-benzyl-3,3,5,5-tetradeuterio-piperidin-4-one (9.7 g, 50.19 mmol, 1.76 mL, 1 equiv) in THF (10 mL) was added at −60° C. The mixture was stirred at −60° C. for 1.5 h, and then the mixture was stirred at 10° C. for 0.5 h. The reaction mixture was poured into saturated NH4Cl (100 mL) and extracted with EtOAc (100 mL x 2), and the combined organic phase was washed with water (100 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated to give compound tert-butyl 2-(1-benzyl-3,3,5,5-tetradeuterio-4-hydroxy-4-piperidyl)acetate (17 g, crude) as a yellow solid. LCMS m / z (ESI): 310.2 [M + H] + . 1 H NMR (400 MHz, chloroform-d) δ = 7.28 - 7.14 (m, 5H), 3.53 (s, 1H), 3.45 (s, 2H), 2.49 (br d, J = 11.4 Hz, 2H), 2.34 (br d, J = 11.4 Hz, 2H), 2.30 (s, 2H), 1.39 (s, 9H).

[0654] Step 3: To a solution of tert-butyl 2-(1-benzyl-3,3,5,5-tetradeuterio-4-hydroxy-4-piperidyl)acetate (17 g, 54.94 mmol, 1 equiv.) in EtOH (170 mL), Pd(OH)2 / C (3.40 g, 20% purity) and HCOOH (5.28 g, 109.88 mmol, 2 equiv.) were added. The mixture was stirred at 50 °C for 2 h. The reaction mixture was filtered and concentrated. The residue was triturated with petroleum / EtOAc (10 / 1, 5V) at 25 °C for 2 h, the suspension was filtered, and the filter cake was collected. Compound tert-butyl 2-(3,3,5,5-tetradeuterio-4-hydroxy-4-piperidyl)acetate (10 g, crude) was obtained as a yellow solid.1 H NMR (400 MHz, chloroform-d) δ = 3.02 (br d, J = 12.4 Hz, 2H), 2.82 (d, J = 12.4 Hz, 2H), 2.38 (s, 2H), 1.47 (s, 9H).

[0655] Step 4: To a solution of tert-butyl 2-(3,3,5,5-tetradeuterio-4-hydroxy-4-piperidyl)acetate (10 g, 45.60 mmol, 1 equiv.) in DMF (40 mL), DIEA (11.79 g, 91.19 mmol, 15.88 mL, 2 equiv.) and 2,4,5-trifluorobenzonitrile (6.80 g, 43.32 mmol, 0.95 equiv.) were added. The mixture was stirred at 70° C. for 1 hour. The reaction mixture was cooled to 25° C. and poured into water (250 mL). The resulting mixture was stirred at 25° C. for 2 hours, filtered, and the filter cake was collected. The compound tert-butyl 2-[1-(4-cyano-2,5-difluoro-phenyl)-3,3,5,5-tetradeuterio-4-hydroxy-4-piperidyl]acetate (12 g, crude) was obtained as a yellow solid. LCMS m / z (ESI): 357.1 [M + H] + . 1 H NMR (400 MHz, chloroform-d) δ = 7.17 (dd, J = 6.0, 12.4 Hz, 1H), 6.66 (dd, J = 7.0, 11.0 Hz, 1H), 3.87 (s, 1H), 3.46–3.35 (m, 2H), 3.31–3.22 (m, 2H), 2.43 (s, 2H), 1.49 (s, 9H).

[0656] Step 5: To a solution of tert-butyl 2-[1-(4-cyano-2,5-difluoro-phenyl)-3,3,5,5-tetradeuterio-4-hydroxy-4-piperidyl]acetate (12 g, 33.67 mmol, 1 equiv.) in NMP (100 mL) was slowly added methylhydrazine (19.43 g, 168.70 mmol, 22.21 mL, 40% purity, 5.0 equiv.) at 55 °C. The mixture was stirred at 90 °C for 16 h. The reaction mixture was quenched by the addition of aqueous citric acid, and the pH was adjusted to 6-7 at 25 °C. Water was then added, and the mixture was brought to 600 mL. The resulting mixture was stirred at 20 °C for 2 h, filtered, and the filter cake was collected. The compound tert-butyl 2-[1-(3-amino-5-fluoro-1-methyl-indazol-6-yl)-3,3,5,5-tetradeuterio-4-hydroxy-4-piperidyl]acetate (11 g, crude) was obtained as a yellow solid. LCMS m / z (ESI): 383.2 [M + H] + . 1 H NMR (400 MHz, chloroform-d) δ = 7.12 (d, J = 11.8 Hz, 1H), 6.73–6.65 (m, 1H), 3.81 (s, 1H), 3.79 (s, 3H), 3.27–3.22 (m, 2H), 3.18–3.09 (m, 2H), 2.46 (s, 2H), 1.50 (s, 9H).

[0657] Step 6: To a solution of tert-butyl 2-[1-(3-amino-5-fluoro-1-methyl-indazol-6-yl)-3,3,5,5-tetradeuterio-4-hydroxy-4-piperidyl]acetate (11 g, 28.76 mmol, 1 eq.) in dioxane (110 mL), acrylic acid (6.22 g, 86.28 mmol, 5.92 mL, 3 eq.) was added. The mixture was stirred at 100 °C for 30 h. The reaction mixture was diluted with water (300 mL) and extracted with 2-MeTHF / MeOH (5 / 1, 200 × 3). The organic phase was washed with brine (200 mL), dried over Na SO , filtered, and concentrated. The residue was triturated with petroleum ether / EtOAc (1 / 1, 110 mL) at 20 °C for 2 h and then filtered. The filter cake was collected and further triturated with i-PrOH / i-PrOAc (5 / 1, 10V) at 50°C for 2 hours. The mixed suspension was filtered at 50°C. The compound 3-[[6-[4-(2-tert-butoxy-2-oxo-ethyl)-3,3,5,5-tetradeuterio-4-hydroxy-1-piperidyl]-5-fluoro-1-methyl-indazol-3-yl]amino]propanoic acid (5.2 g, 10.53 mmol, yield 36.60%, purity 92%) was obtained as a white solid. LCMS m / z (ESI): 455.3 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 7.36 (d, J = 12.6 Hz, 1H), 6.86 (d, J = 7.0 Hz, 1H), 3.70 (s, 3H), 3.40 (br t, J = 6.8 Hz, 2H), 3.13 - 3.05 (m, 2H), 3.02 - 2.95 (m, 2H), 2.56 (t, J = 6.8 Hz, 2H), 2.37 (s, 2H), 1.42 (s, 9H).

[0658] Step 7: To a solution of 3-[[6-[4-(2-tert-butoxy-2-oxo-ethyl)-3,3,5,5-tetradeuterio-4-hydroxy-1-piperidyl]-5-fluoro-1-methyl-indazol-3-yl]amino]propanoic acid (5.2 g, 11.44 mmol, 1 equiv.) in AcOH (50 mL) was added sodium cyanate (1.49 g, 22.88 mmol, 2 equiv.). The mixture was stirred at 60° C. for 12 hours, then HCl (2 M, 52.00 mL, 9.09 equiv.) was added and the mixture was stirred at 60° C. for 16 hours. Saturated NaCO and NaHCO were added to the reaction mixture to adjust the pH to about 5, and the mixture was stirred at 15° C. for 2 hours. A solid precipitated and was filtered. The filter cake was collected and triturated with water (10V) at 100° C. for 16 hours, then filtered. The compound 2-[3,3,5,5-tetradeuterio-1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol-6-yl]-4-hydroxy-4-piperidyl]acetic acid (2.4 g, 5.64 mmol, 49.30% yield, 99.5% purity) was obtained as a gray solid. LCMS m / z (ESI): 424.1 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 10.53 (s, 1H), 7.33 (br d, J = 12.8 Hz, 1H), 7.12 (br d, J = 6.8 Hz, 1H), 4.03 - 3.81 (m, 5H), 3.15 (br d, J = 11.6 Hz, 2H), 3.04 (br d, J = 11.6 Hz, 2H), 2.74 (br t, J = 6.4 Hz, 2H), 2.43 (s, 2H).

[0659] Step 8: To a solution of 2-[3,3,5,5-tetradeuterio-1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol-6-yl]-4-hydroxy-4-piperidyl]acetic acid (2.4 g, 5.67 mmol, 1 equiv.) in ACN (24 mL) was added TSTU (3.41 g, 11.34 mmol, 2 equiv.) and DIEA (1.47 g, 11.34 mmol, 1.97 mL, 2 equiv.) at 15° C. The mixture was stirred at 15° C. for 2 hours. The reaction mixture was filtered, and the filter cake was washed with MeCN (10 mL), water (10 mL), and MeCN (10 mL). The compound (2,5-dioxopyrrolidin-1-yl) 2-[3,3,5,5-tetradeuterio-1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol-6-yl]-4-hydroxy-4-piperidyl]acetate (2.4 g, crude) was obtained as a white solid. LCMS m / z (ESI): 521.2 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 10.54 (s, 1H), 7.33 (br d, J = 12.8 Hz, 1H), 7.14 (br d, J = 7.0 Hz, 1H), 4.94 (s, 1H), 4.01 - 3.78 (m, 5H), 3.18 (br d, J = 11.6 Hz, 2H), 3.04 (br d, J = 11.6 Hz, 2H), 2.83 (br d, J = 9.0 Hz, 6H), 2.73 (br t, J = 6.4 Hz, 2H).

[0660] Step 9: To a solution of (2,5-dioxopyrrolidin-1-yl)2-[3,3,5,5-tetradeuterio-1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol-6-yl]-4-hydroxy-4-piperidyl]acetate (1 g, 1.92 mmol, 1 equiv.) in DMF (10 mL) was added (3 R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoro-phenoxy]-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane (1.07 g, 1.92 mmol, 1 equiv.) and TEA (97.20 mg, 960.61 μmol, 133.71 μL, 0.5 equiv.) were added. The mixture was stirred at 25° C. for 18 h. The reaction mixture was slowly added to water (80 mL), then the pH was adjusted to 6 with aqueous HCl (1 M) and filtered. The filter cake was collected and triturated with i-PrOH / i-PrOAc (5 / 1, 20 mL) at 25° C. for 2 h, followed by further trituration with MeOH (14 mL) at 25° C. for 12 h. The compound (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoro-phenoxy]-4-oxo-quinazolin-3-yl]-8-[2-[3,3,5,5-tetradeuterio-1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol-6-yl]-4-hydroxy-4-piperidyl]acetyl]-1-oxa-8-azaspiro[4.5]decane (1.4 g, 1.43 mmol, 74.69% yield, 98.6% purity) was obtained as a gray solid. LCMS m / z (ESI): 962.5 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ = 10.52 (s, 1H), 10.18 (br s, 1H), 8.35 (s, 1H), 7.92 - 7.75 (m, 2H), 7.69 (dd, J = 2.8, 9.0 Hz, 1H), 7.49 (br dd. 2H), 4.01 - 3.83 (m, 5H), 3.82 - 3.71 (m, 1H), 3.68 - 3.58 (m, 1H), 3.51 (br d, J = 7.4 Hz, 1H), 3.46 - 3.38 (m, 1H), 3.20 - 3.10 (m, 4H), 3.04 (br d, J = 11.6 Hz, 2H), 2.84 - 2.69 (m, 5H), 2.56 (br s, 2H), 2.41 - 2.34 (m, 1H), 2.14 - 2.00 (m, 1H), 1.84 - 1.48 (m, 4H), 1.05 (t, J = 7.0 Hz, 3H).

[0661] Example 6: Synthesis of (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoro-phenoxy]-5,7,8-trideuterio-4-oxo-quinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol-6-yl]-4-hydroxy-4-piperidyl]acetyl]-1-oxa-8-azaspiro[4.5]decane [ka]

[0662] Step 1: To a solution of 1,2,3,4,5-pentadeuterio-6-nitro-benzene (25 g, 195.10 mmol, 4.17 mL, 1 equiv) in HSO (140 mL, 98% purity) was added TCCA (15.42 g, 66.33 mmol, 0.34 equiv) and the mixture was stirred at 80 °C for 3 h. The reaction mixture was cooled to room temperature, poured into ice-water (200 mL), and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with water (2 × 40 mL), brine (2 × 40 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO™, 220 g SepaFlash™ silica flash column, eluent 0% ethyl acetate / petroleum ether, gradient: 50 mL / min) to give 1-chloro-2,3,4,6-tetradeuterio-5-nitro-benzene (32 g, crude) as a light brown oil. HPLC Rt=2.386 min. 2 H NMR (400 MHz, DMSO) δ = 8.72-8.21 (m, 2H).

[0663] Step 2: To a solution of 1-chloro-2,3,4,6-tetradeuterio-5-nitrobenzene (37 g, 228.99 mmol, 7.19 mL, 1 equiv) and NH4Cl in MeOH (480 mL) and HO (80 mL), Fe (76.73 g, 1.37 mol, 6 equiv) (97.99 g, 1.83 mol, 8 equiv) was added portionwise, and the mixture was stirred at 80 °C for 1 h. The mixture was filtered through Celite, and the filter cake was washed with MeOH (4 × 50 mL) and EtOAc (4 × 50 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was diluted with HO (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by reverse-phase HPLC (0.1% FA condition; HO / ACN = 1 / 0 → 1 / 1) to give 3-chloro-2,4,5,6-tetradeuterio-aniline (17.8 g, 132.56 mmol, 57.89% yield, 98% purity) as a light brown oil. LCMS m / z (ESI): 132.0 [M + H] + .1 H NMR (400 MHz, DMSO-d6) δ = 5.36 (s, 2H). 2 H NMR (400 MHz, DMSO) δ = 7.53 (s, 1H), 7.12-7.04 (m, 3H).

[0664] Step 3: A solution of NaNO (9.23 g, 133.74 mmol, 1.1 equiv) in HO (48 mL) was added to a solution of 3-chloro-2,4,5,6-tetradeuterio-aniline (16 g, 121.58 mmol, 1 equiv) in HSO (258.51 g, 843.44 mmol, 140.50 mL, 32% purity) at 0 °C, and the mixture was stirred at 0 °C for 1 h. Then, a solution of KI (30.27 g, 182.38 mmol, 1.5 equiv) in HO (80 mL) was added at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. HO (50 mL) was added at 0 °C, and the resulting mixture was extracted with EtOAc (80 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (SepaFlash™ silica flash column; eluent: petroleum ether) to give 1-chloro-2,3,4,6-tetradeuterio-5-iodo-benzene (20 g, 78.77 mmol, 64.79% yield, 95.5% purity) as a light brown oil. 2 H NMR (400 MHz, DMSO) δ = 7.71 (s, 1H), 7.58 (s, 1H), 7.31 (s, 1H), 7.702 (s, 1H).

[0665] Step 4: To a solution of 1-chloro-2,3,4,6-tetradeuterio-5-iodo-benzene (19 g, 78.36 mmol, 518.13 μL, 1 equiv.) in THF (190 mL) was added n-BuLi (2.5 M, 34.48 mL, 1.1 equiv.) at −65° C., and the mixture was stirred at −65° C. for 1 h. The reaction mixture was poured into a large amount of dry ice and stirred at −65° C. for 1 h. The mixture was then quenched with saturated NH4Cl (50 mL), basified to pH = 11, and extracted with MBTE (3 × 40 mL). The aqueous phase was adjusted to pH 4 with aqueous HCl and extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (2×40 mL) and dried in vacuo to give 3-chloro-2,4,5,6-tetradeuterio-benzoic acid (9.5 g, 57.26 mmol, 73.08% yield, 96.8% purity) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 13.46 (s, 1H). 2 H NMR (400 MHz, DMSO) δ = 8.44 -8.08 (m, 4H).

[0666] Step 5: To a solution of 3-chloro-2,4,5,6-tetradeuterio-benzoic acid (8.6 g, 53.55 mmol, 103.63 μL, 1 equiv) in HSO (15 mL, 98% purity) was added a mixture of HNO (7.60 g, 82.06 mmol, 5.43 mL, 68%, 1.53 equiv) and HSO (10.72 g, 107.10 mmol, 5.83 mL, 98%, 2 equiv) at 25 °C. The resulting mixture was stirred at 25 °C for 2 h and then at 40 °C for 1 h. The mixture was poured into ice / HO (180 mL) and extracted with DCM (3 × 200 mL). The organic layer was washed with 0.1% aqueous HCl (160 mL), dried over NaSO, and evaporated to give 3-chloro-2,4,5-trideuterio-6-nitro-benzoic acid (10.2 g, 43.5 mmol, 79.68% yield, 87.3% purity) as a pale yellow solid. LCMS m / z (ESI): 203.0 [M - H] - . 2 H NMR (400 MHz, DMSO) δ = 8.84 -8.70 (m, 3H).

[0667] Step 6: A mixture of 3-chloro-2,4,5-trideuterio-6-nitro-benzoic acid (8 g, 39.10 mmol, 103.63 μL, 1 equiv.) and NaOH (12.51 g, 312.83 mmol, 8 equiv.) in DO (156.4 mL) was stirred at 100 °C (internal temperature) for 20 h. The mixture was cooled to room temperature, acidified with 6 N HCl, and extracted with EtOAc (80 mL × 3). The combined organic layers were dried over NaSO and evaporated to dryness. The crude product was triturated with EtOAc / Tol (1 / 10, 10 V) at 25 °C for 12 h to give 2,4,5-trideuterio-3-hydroxy-6-nitro-benzoic acid (6.1 g, 30.48 mmol, 77.94% yield, 93% purity) as a pale yellow solid. LCMS m / z (ESI): 185.1 [M + H] - . 1 H NMR (400 MHz, DMSO-d6) δ = 14.30 - 13.13 (m, 1H), 11.91 - 10.84 (m, 1H). 2 H NMR (400 MHz, DMSO) δ = 8.80 - 8.29 (m, 1H), 7.72 - 7.31 (m, 2H).

[0668] Step 7: To a solution of 2,4,5-trideuterio-3-hydroxy-6-nitrobenzoic acid (2 g, 10.74 mmol, 1 equivalent) in CD3OD (20 mL) was added Pd / C (0.4 g, 10% purity). The mixture was stirred at 25° C. under a D2 (15 psi) atmosphere for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to give compound 2-amino-3,4,6-trideuterio-5-hydroxybenzoic acid (1.2 g, crude) as a black solid. 1 H NMR (400 MHz, DMSO-d6) δ = 8.60 (s, 1H), 8.50 - 7.76 (m, 2H).

[0669] Step 8: To a solution of 2-amino-3,4,6-trideuterio-5-hydroxybenzoic acid (1.2 g, 7.68 mmol, 1 equiv.) in n-BuOH (12 mL) was added tert-butyl (3R)-3-amino-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.97 g, 7.68 mmol, 1 equiv.) in n-BuOH (12 mL) at 120 °C. The mixture was stirred at 125 °C for 15 minutes, and then diethoxymethoxyethane (2.73 g, 18.44 mmol, 3.07 mL, 2.4 equiv.) was added. The mixture was stirred at 125 °C for 16 hours. The reaction mixture was diluted with water (50 mL), EtOAc (50 mL), and then filtered. The filtrate was washed with aqueous HCl (1M, 20 mL), aqueous NaHCO (20 mL), water (20 mL), and brine (20 mL), dried over NaSO, filtered, and concentrated. The residue was triturated with petroleum / EtOAc (3 / 1, 15 mL) at 20 °C for 2 hours, then filtered, and the filter cake was collected. The compound tert-butyl (3R)-3-(5,7,8-trideuterio-6-hydroxy-4-oxo-quinazolin-3-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.5 g, 3.40 mmol, 44.30% yield, 91.8% purity) was obtained as a brown solid. LCMS m / z (ESI): 405.1 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 10.49 - 9.97 (m, 1H), 8.19 (s, 1H), 5.34 (br s, 1H), 4.10 (br d, J = 5.0 Hz, 2H), 3.42 (br s, 2H), 2.37 (br dd, J = 9.0, 13.0 Hz, 1H), 1.98 (br dd, J = 5.2, 13.4 Hz, 1H), 1.73 - 1.61 (m, 3H), 1.54 (br d, J = 7.8 Hz, 1H), 1.39 (br s, 9H).

[0670] Step 9: To a solution of 2,3,6-trifluorobenzonitrile (704.22 mg, 4.08 mmol, 91% purity, 1.1 equiv.) in ACN (15 mL) was added CsCO (3.02 g, 9.27 mmol, 2.5 equiv.) and tert-butyl (3R)-3-(5,7,8-trideuterio-6-hydroxy-4-oxo-quinazolin-3-yl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.5 g, 3.71 mmol, 1 equiv.). The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated and then diluted with EtOAc (20 mL) and water (20 mL). The organic phase was washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the compound tert-butyl (3R)-3-[6-(2-cyano-3,6-difluoro-phenoxy)-5,7,8-trideuterio-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.4 g, crude) as a brown foam solid. LCMS m / z (ESI): 542.3 [M + H] + . 1 H NMR (400 MHz, chloroform-d) δ = 8.33 (s, 1H), 7.46 (dt, J = 5.0, 9.4 Hz, 1H), 7.12 (ddd, J = 3.6, 7.6, 9.2 Hz, 1H), 5.50 (dt, J = 4.0, 9.0 Hz, 1H), 4.27 - 4.10 (m, 2H), 3.66 (br s, 2H), 3.45 - 3.16 (m, 2H), 2.48 (dd, J = 8.9, 14.0 Hz, 1H), 1.89 (dd, J = 4.2, 14.0 Hz, 1H), 1.83 - 1.69 (m, 3H), 1.60 - 1.51 (m, 1H), 1.46 (s, 9H).

[0671] Step 10: To a solution of [methyl(sulfamoyl)amino]ethane (535.85 mg, 3.88 mmol, 1.5 equiv.) in DMAc (12 mL), CsCO (2.53 g, 7.76 mmol, 3 equiv.) and tert-butyl (3R)-3-[6-(2-cyano-3,6-difluoro-phenoxy)-5,7,8-trideuterio-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.4 g, 2.59 mmol, 1 equiv.) were added. The mixture was stirred at 65 °C in a sealed tube for 16 h. The reaction mixture was poured into water (60 mL) and washed with MTBE (20 mL × 3). The aqueous phase was adjusted to pH 6-7 with HCl (aq., 1 M) and extracted with EtOAc (20 mL × 2). The organic phase was washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated to give the compound tert-butyl (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoro-phenoxy]-5,7,8-trideuterio-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.1 g, 1.47 mmol, 56.76% yield, 88% purity) as a brown foam solid. LCMS m / z (ESI): 660.3 [M + H] + . 1 H NMR (400 MHz, chloroform-d) δ = 8.32 (s, 1H), 7.58 - 7.50 (m, 1H), 7.45 - 7.34 (m, 1H), 5.48 (br dd, J = 4.6, 8.6 Hz, 1H), 4.22 - 4.04 (m, 2H), 3.64 (br s, 2H), 3.39 - 3.23 (m, 4H), 3.00 (s, 3H), 2.46 (dd, J = 8.8, 14.0 Hz, 1H), 1.86 (dd, J = 4.2, 14.0 Hz, 1H), 1.81 - 1.66 (m, 3H), 1.59 - 1.49 (m, 1H), 1.44 (s, 9H), 1.20 - 1.11 (m, 3H).

[0672] Step 11: To a solution of tert-butyl (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoro-phenoxy]-5,7,8-trideuterio-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (1.1 g, 1.67 mmol, 1 equiv.) in acetone (6 mL) was added HCl (12 M, 486.30 μL, 3.5 equiv.). The mixture was stirred at 50 °C for 3 h. The reaction mixture was concentrated. The residue was diluted with water (3 mL) and EtOAc (3 mL), and then the pH was adjusted to 7-8 with aqueous NaHCO3, resulting in the precipitation of a large amount of solid. The mixture was stirred at 25 °C for 1 h, filtered, and the filter cake was collected. The compound (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoro-phenoxy]-5,7,8-trideuterio-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane (0.63 g, 1.07 mmol, 64.14% yield, 95% purity) was obtained as a gray solid. LCMS m / z (ESI): 560.3 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.29 (s, 1H), 7.34 - 7.13 (m, 2H), 5.28 (br s, 1H), 4.27 - 4.01 (m, 2H), 3.09 (br d, J = 1.2 Hz, 4H), 2.96 (q, J = 7.0 Hz, 2H), 2.53 (s, 3H), 2.43 - 2.32 (m, 1H), 2.13 (br d, J = 8.8 Hz, 1H), 2.01 - 1.68 (m, 4H), 1.01 (br t, J = 7.0 Hz, 3H).

[0673] Step 12: To a solution of (2,5-dioxopyrrolidin-1-yl)2-[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol-6-yl]-4-hydroxy-4-piperidyl]acetate (273.49 mg, 519.99 μmol, 98.2% purity, 1 equiv.) in DMF (3 mL) was added (3R)-3-[6-[2- Cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoro-phenoxy]-5,7,8-trideuterio-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane (0.3 g, 519.99 μmol, 97% purity, 1 equivalent) and TEA (26.31 mg, 259.99 μmol, 36.19 μL, 0.5 equivalent) were added. The mixture was stirred at 25° C. for 16 hours. The reaction mixture was slowly added to water (20 mL), and the pH was adjusted to 6 with aqueous HCl (1 M). The mixture was stirred at 20° C. for 0.5 hours and filtered. The filter cake was triturated with i-PrOH / i-PrOAc (5 / 1, 3 mL) at 25 ° C. for 2 hours, filtered, and further triturated with MeOH (3 mL) at 25 ° C. for 2 hours, filtered, to give the compound (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoro-phenoxy]-5,7,8-trideuterio-4-oxo-quinazolin-3-yl]-8-[2-[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-5-fluoro-1-methyl-indazol-6-yl]-4-hydroxy-4-piperidyl]acetyl]-1-oxa-8-azaspiro[4.5]decane (250 mg, 242.71 μmol, 46.68% yield, 93.3% purity) as a gray solid. LCMS m / z (ESI): 961.5 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ = 10.52 (br s, 1H), 10.18 (br d, J = 0.9 Hz, 1H), 8.35 (br s, 1H), 7.85 (br t, J = 9.1 Hz, 1H), 7.49 (br d, J = 5.6 Hz, 1H), 7.40 - 7.24 (m, 1H), 7.11 (br d, J = 6.0 Hz, 1H), 5.29 (br s, 1H), 5.03 (br s, 1H), 4.14 (br s, 2H), 4.02 - 3.83 (m, 5H), 3.78 (br d, J = 4.8 Hz, 1H), 3.62 (br d, J = 3.6 Hz, 1H), 3.56 - 3.44 (m, 2H), 3.16 (br d, J = 6.4 Hz, 4H), 3.07 (br d, J = 10.0 Hz, 2H), 2.86 - 2.67 (m, 5H), 2.56 (br s, 2H), 2.37 (br s, 1H), 2.07 (br dd, J = 5.4, 6.8 Hz, 1H), 1.88 - 1.46 (m, 8H), 1.05 (br t, J = 6.4 Hz, 3H).

[0674] Evaluation of the free morphic form of compound 1 The following procedures were used to characterize the free morphic form of compound 1.

[0675] Example 7: Approximate Solubility at 25°C and 50°C Approximately 5 mg of Compound 1 Form A was weighed into a 2 mL glass vial. A 20 μL aliquot of each solvent was added to dissolve the drug substance at 25° C. Approximately 10 mg of Compound 1 Form A was weighed into a 2 mL glass vial. A 20 μL aliquot of each solvent was added to dissolve the drug substance at 50° C. Vortexing and sonication were applied to facilitate dissolution. The maximum amount of each solvent added was 1 mL. Approximate solubility was determined visually.

[0676] Approximately 5 mg of Compound 1 Form B was weighed into a 2 mL glass vial. A 20 μL aliquot of each solvent was added to dissolve the drug substance at 25° C. Approximately 10 mg of Compound 1 Form B was weighed into a 2 mL glass vial. A 20 μL aliquot of each solvent was added to dissolve the drug substance at 50° C. Vortexing and sonication were applied to facilitate dissolution. The maximum amount of each solvent added was 1 mL. Approximate solubility was determined visually.

[0677] The results are summarized in Table 1.

[0678] TIFF2025541736000093.tif112170

[0679] Example 8: Equilibration with solvent at 25°C for 4 weeks Approximately 50 mg of Compound 1 free form A was equilibrated in 0.1 mL to 1 mL of solvent at 25°C for 4 weeks using a stir bar on a magnetic stir plate at a speed of 300 rpm. The resulting suspension was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm. The solids (wet cake) were examined by XRPD. The results are summarized in Tables 2 and 3.

[0680] TIFF2025541736000094.tif128170

[0681] TIFF2025541736000095.tif205170

[0682] FIG. 1 shows the XRPD pattern of Compound 1 Form B, FIG. 7 shows the XRPD pattern of Compound 1 Form A, and FIG. 10 shows the XRPD pattern of Compound 1 Form C.

[0683] Example 9: Equilibration under temperature cycling Approximately 50 mg of Compound 1 Form A was equilibrated in 0.1 mL to 1 mL of solvent under temperature cycling from 5°C to 40°C at a heating / cooling rate of 0.1°C / min for 16 cycles. Equilibration was performed using a stir bar on a magnetic stir plate at a speed of 300 rpm. The resulting suspension was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm. The solids (wet cake) were examined by XRPD. The results are summarized in Tables 4 and 5.

[0684] TIFF2025541736000096.tif149170

[0685] TIFF2025541736000097.tif207170

[0686] Example 10: Crystallization at room temperature by slow evaporation Approximately 30 mg of Compound 1 Form A was dissolved in 0.2 mL to 10 mL of solvent. The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clear solution was allowed to slowly evaporate under ambient conditions (approximately 20°C to 25°C, 40% RH to 80% RH). The solid residue was examined by XRPD. The results are summarized in Table 6.

[0687] TIFF2025541736000098.tif74170

[0688] Example 11: Crystallization from a hot saturated solution by slow cooling Approximately 50 mg of Compound 1 Form A was dissolved in a minimal amount of selected solvent at 50°C. The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clear solution was cooled to 5°C at 0.1°C / min. The precipitate-free sample at 5°C was further cooled to -20°C. The precipitate was collected by centrifugal filtration at 14000 rpm through a 0.45 μm nylon membrane filter. The solid (wet cake) was examined by XRPD.

[0689] To confirm whether Form B of Compound 1 could be obtained from the clear solution, cooling was also attempted to prepare crystalline Form B. Approximately 50 mg of Form A of Compound 1 was dissolved in a minimal amount of ACN or acetone at 50°C. The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clear solution was cooled to 5°C at 0.1°C / min. Approximately 2 mg of seeds were added to the clear solution cooled to approximately 24°C. The resulting suspension was cooled to 5°C at 0.1°C / min and held at 5°C for approximately 12 hours. The precipitate was collected by centrifugal filtration at 14,000 rpm through a 0.45 μm nylon membrane filter. The solids (wet cake) were examined by XRPD. The results indicated that crystalline Form B could be obtained directly from the clear acetone solution by adding Form B crystal seeds and cooling. The results are summarized in Table 7.

[0690] TIFF2025541736000099.tif149170

[0691] Example 12: Crystallization by addition of antisolvent Approximately 50 mg of Compound 1 Form A was dissolved in a minimal amount of a selected good solvent at ambient temperature (approximately 20°C to 25°C). The resulting solution was filtered through a 0.45 μm syringe membrane filter. One to four volumes of a poor solvent were slowly added to the clear solution until a large amount of solid precipitated. The precipitate was collected by centrifugal filtration at 14,000 rpm through a 0.45 μm nylon membrane filter. The solid (wet cake) was examined by XRPD. The results are summarized in Table 8.

[0692] TIFF2025541736000100.tif134170

[0693] Example 13: Crystallization by vapor diffusion method Approximately 50 mg of Compound 1 Form A was dissolved in a minimal amount of selected solvent at ambient temperature (approximately 20°C to 25°C). The resulting solution was filtered through a 0.45 μm syringe membrane filter. The clear solution was transferred to an 8 mL open glass vial. These open 8 mL vials were then transferred to 40 mL glass vials. Antisolvent was added to the 40 mL vials. These 40 mL vials were then tightly capped and placed at ambient conditions for up to 21 days. The precipitate was collected by centrifugal filtration at 14,000 rpm through a 0.45 μm nylon membrane filter. The solids (wet cake) were examined by XRPD. The results are summarized in Table 9.

[0694] TIFF2025541736000101.tif61170

[0695] Example 14: Crystallization by Heat-Cool DSC The polymorphic behavior of Form A of Compound 1 was investigated by two different heating-cooling DSC cycles. A Tzero pan and a Tzero airtight lid with a pinhole were used for this experiment. No new crystalline forms were obtained by heating-cooling DSC. The results are summarized in Table 10.

[0696] TIFF2025541736000102.tif69170

[0697] Example 15: Bulk Stability Form B of Compound 1 was subjected to one week of stress at 25°C / 92% RH in an open container, 40°C / 75% RH in an open container, and 60°C in a closed container. The stressed samples were characterized by XRPD and HPLC and examined for color change. The results are summarized in Table 11.

[0698] TIFF2025541736000103.tif135170

[0699] Example 16: Moisture sorption and desorption experiments The moisture sorption and desorption behavior of Form B of Compound 1 was investigated by DVS at 25°C, 40-0-95-0-40% RH, dm / dt 0.002, a minimum equilibration time of 60 minutes, and a maximum equilibration time of 360 minutes. After the DVS test, XRPD was measured to determine the morphological change. The results are summarized in Table 12.

[0700] TIFF2025541736000104.tif140170

[0701] Example 17: Compression simulation experiment Approximately 20 mg of Compound 1 Form B was compressed at 2 MPa and 10 MPa for 5 minutes using a hydraulic press. Potential morphological changes and crystallinity were assessed by XRPD. The results are summarized in Table 13.

[0702] TIFF2025541736000105.tif41170

[0703] Example 18: Dry milling simulation experiment Approximately 20 mg of Compound 1 Form B was manually ground with a mortar and pestle for 1 minute, 2 minutes, and 5 minutes. Potential morphological changes and crystallinity were assessed by XRPD. The results are summarized in Table 14.

[0704] TIFF2025541736000106.tif33170

[0705] Example 19: Wet granulation simulation experiment Water or ethanol was added dropwise to approximately 20 mg of Compound 1 Form B until the sample was sufficiently wetted. The wet sample was gently ground using a mortar and pestle. The granulated sample was allowed to dry at ambient conditions for 10 minutes. Potential morphological changes and crystallinity were assessed by XRPD. The results are summarized in Table 15.

[0706] TIFF2025541736000107.tif27170

[0707] Example 20: Preparation of Form B of Compound 1 Form B was prepared by the following procedure.

[0708] Experiment 1. Approximately 500 mg of Compound 1 Form A was weighed into a 20 mL glass vial. Then, 3 mL of ACN / HO (v:v=96:4) was added to the vial with stirring at 40° C. for approximately 5 minutes to obtain a suspension.

[0709] Approximately 2 mg of Form B seeds were added to the above suspension.

[0710] The suspension was equilibrated under temperature cycling from 5°C to 40°C at a heating / cooling rate of 0.1°C / min for approximately 9 cycles.

[0711] The solid was collected by suction filtration and dried under vacuum at 35° C. for approximately 1 hour.

[0712] 400 mg of Form B was obtained as an off-white solid in 80% yield.

[0713] Experiment 2: Approximately 300 mg of Compound 1 Form A was weighed into a 20 mL glass vial. Then, 3 mL of ACN / HO (v:v=96:4) was added to the vial with stirring at 40° C. for approximately 5 minutes to obtain a sticky substance (Sticky substance).

[0714] Approximately 5 mg of Form B seeds were added to the above sticky material. After 7 hours, it turned into a suspension (sticky material to suspension).

[0715] Equilibration was carried out using a stir bar on a magnetic stir plate at a speed of 300 rpm under a temperature cycle of 5°C to 40°C at a heating / cooling rate of 0.1°C / min for approximately 8 cycles (suspension).

[0716] The solid was collected by suction filtration and then dried under vacuum at 30° C. for approximately 4 hours.

[0717] 174 mg of Form B was obtained as an off-white solid in 58% yield.

[0718] In other aspects, Form B of Compound 1 is obtained using the methods described herein by varying the temperature, stirring rate, or crystallization time. For example, in certain embodiments, Form B of Compound 1 is formed without temperature cycling, and instead is crystallized from solution with stirring at a temperature of about 0°C to about 50°C, about 20°C to about 35°C, about 0°C to about 20°C, or about 10°C to about 30°C. In certain embodiments, the temperature is about 0°C, about 5°C, about 10°C, about 15°C, about 20°C, about 25°C, about 30°C, about 35°C, about 40°C, about 45°C, or about 50°C.

[0719] In certain embodiments, the methods described herein are modified to have a slow stirring speed, such as stirring at about 50 rpm to about 300 rpm, stirring at about 150 rpm to about 300 rpm, or stirring at about 200 rpm to about 300 rpm. In certain embodiments, the stirring is at about 50 rpm, about 60 rpm, about 70 rpm, about 80 rpm, about 90 rpm, about 100 rpm, about 110 rpm, about 120 rpm, about 130 rpm, about 140 rpm, about 150 rpm, about 160 rpm, about 170 rpm, about 180 rpm, about 190 rpm, about 200 rpm, about 210 rpm, about 220 rpm, about 230 rpm, about 240 rpm, about 250 rpm, about 260 rpm, about 270 rpm, about 280 rpm, about 290 rpm, or about 300 rpm.

[0720] In certain embodiments, the methods described herein are modified to have a long crystallization period, e.g., a crystallization time of about 10 hours to about 30 hours, a crystallization time of about 15 hours to about 30 hours, a crystallization time of about 20 hours to about 30 hours, a crystallization time of about 10 hours to about 25 hours, or a crystallization time of about 15 hours to about 25 hours. In certain embodiments, the crystallization time is about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, about 25 hours, about 26 hours, about 27 hours, about 28 hours, about 29 hours, about 30 hours, about 31 hours, about 32 hours, about 33 hours, about 34 hours, or about 35 hours. In other embodiments, the crystallization time is greater than about 30 hours.

[0721] In certain embodiments, a temperature or temperature range without temperature cycling, a slow stirring rate, and an extended crystallization time is used to prepare Form B of Compound 1. In certain embodiments, a temperature cycle, a slow stirring rate, and an extended crystallization time is used to prepare Form B of Compound 1.

[0722] Evaluation of the morphic forms of salts of compound 1 Example 21: Slurry Equilibration Approximately 30 mg of Compound 1 Form A and 0.5 or 1 equivalent of base were added to a solvent in a 2 mL glass vial. In experiments using NaHCO3, Ca(OH)2, and Mg(OH)2, 5% by volume of water was added to improve the solubility of the counterion in the tested solvent. The resulting mixture was stirred at 25°C for at least 48 hours.

[0723] The resulting suspension was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm. After drying under vacuum at 25° C. for 2 hours, the solids were analyzed by XRPD. The results are summarized in Table 16.

[0724] TIFF2025541736000108.tif180170

[0725] FIG. 23 shows the XRPD pattern of sodium salt form D of Compound 1, FIG. 26 shows the XRPD pattern of sodium salt form E of Compound 1, FIG. 17 shows the XRPD pattern of sodium salt form F of Compound 1, FIG. 29 shows the XRPD pattern of potassium salt form G of Compound 1, and FIG. 32 shows the XRPD pattern of potassium salt form H of Compound 1.

[0726] Example 22: Addition of antisolvent The clear solution obtained from the slurry equilibration was processed by the addition of anti-solvent (Table 17).

[0727] TIFF2025541736000109.tif20170

[0728] Example 23: Reslurry The sticky material or clear solution obtained from the slurry equilibration was treated with slow evaporation under ambient conditions and addition of MTBE, toluene, and ethyl acetate (EA) (Table 18).

[0729] TIFF2025541736000110.tif33170

[0730] The salt forms identified in the study (Table 16) were analyzed by XRPD, DCS, TGA, KF, HPLC, and 1 Further characterization was performed by 1 H NMR / IC (Table 19).

[0731] TIFF2025541736000111.tif228170

[0732] Example 24: Preparation of Sodium Salt Form F of Compound 1 Sodium salt Form F was prepared by the following procedure.

[0733] Approximately 500 mg of Compound 1 Form A and 47 mg of NaHCO (approximately 1.0 equivalent) were weighed into a 20 mL glass vial. Then, 8 mL of ACN and 100 μL of water were added to the vial while stirring at 400 rpm at 25° C. for approximately 1 minute to obtain a suspension (Suspension).

[0734] Approximately 2 mg of sodium salt form F seeds was added to the above suspension (Suspension).

[0735] The suspension turned into a sticky substance after about 5 minutes (suspension to sticky substance).

[0736] The sticky substance turned into a suspension after equilibrating at 25°C for about 6 hours (sticky substance to suspension).

[0737] The solid was collected by suction filtration after equilibrating at 25°C for about 9 days and then vacuum dried at 30°C for about 3 hours.

[0738] Approximately 419 mg of sodium salt Form F was obtained as an off-white solid in 76% yield. The chemical and physical properties of sodium salt Form F of Compound 1 are summarized in Table 20.

[0739] TIFF2025541736000112.tif66170

[0740] Example 25: Bulk Stability of Sodium Salt Form F of Compound 1 Sodium salt Form F was subjected to one week at 25°C / 92% RH in an open container, 40°C / 75% RH in an open container, and 60°C in a closed container. Post-stress samples were characterized by XRPD and HPLC and examined for color change. The results are summarized in Table 21.

[0741] TIFF2025541736000113.tif114170

[0742] Example 26: Solubility of Compound 1 Form B and Compound 1 S...

Claims

1. 2. The structure of claim 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five 2θ values ​​selected from: 7.5±0.2°, 8.8±0.2°, 10.0±0.2°, 10.5±0.2°, 12.6±0.2°, 14.7±0.2°, 15.4±0.2°, 16.4±0.2°, 16.7±0.2°, 18.6±0.2°, 22.7±0.2°, and 25.3±0.2°. 【Chemistry 1】 1. Isolated crystalline form B of the compound of formula (I).

2. 2. The isolated crystalline form B of claim 1, wherein the XRPD pattern comprises at least six 2θ values ​​selected from 7.5±0.2°, 8.8±0.2°, 10.0±0.2°, 10.5±0.2°, 12.6±0.2°, 14.7±0.2°, 15.4±0.2°, 16.4±0.2°, 16.7±0.2°, 18.6±0.2°, 22.7±0.2°, and 25.3±0.2°.

3. 2. The isolated crystalline form B of claim 1, wherein the XRPD pattern comprises at least seven 2θ values ​​selected from 7.5±0.2°, 8.8±0.2°, 10.0±0.2°, 10.5±0.2°, 12.6±0.2°, 14.7±0.2°, 15.4±0.2°, 16.4±0.2°, 16.7±0.2°, 18.6±0.2°, 22.7±0.2°, and 25.3±0.2°.

4. 2. The isolated crystalline form B of claim 1, wherein the XRPD pattern comprises at least eight 2θ values ​​selected from 7.5±0.2°, 8.8±0.2°, 10.0±0.2°, 10.5±0.2°, 12.6±0.2°, 14.7±0.2°, 15.4±0.2°, 16.4±0.2°, 16.7±0.2°, 18.6±0.2°, 22.7±0.2°, and 25.3±0.2°.

5. 2. The isolated crystalline form B of claim 1, wherein the XRPD pattern comprises at least nine 2θ values ​​selected from 7.5±0.2°, 8.8±0.2°, 10.0±0.2°, 10.5±0.2°, 12.6±0.2°, 14.7±0.2°, 15.4±0.2°, 16.4±0.2°, 16.7±0.2°, 18.6±0.2°, 22.7±0.2°, and 25.3±0.2°.

6. 2. The isolated crystalline form B of claim 1, wherein the XRPD pattern comprises at least ten 2θ values ​​selected from 7.5±0.2°, 8.8±0.2°, 10.0±0.2°, 10.5±0.2°, 12.6±0.2°, 14.7±0.2°, 15.4±0.2°, 16.4±0.2°, 16.7±0.2°, 18.6±0.2°, 22.7±0.2°, and 25.3±0.2°.

7. 2. The isolated crystalline form B of claim 1, wherein the XRPD pattern comprises at least 11 2θ values ​​selected from 7.5±0.2°, 8.8±0.2°, 10.0±0.2°, 10.5±0.2°, 12.6±0.2°, 14.7±0.2°, 15.4±0.2°, 16.4±0.2°, 16.7±0.2°, 18.6±0.2°, 22.7±0.2°, and 25.3±0.2°.

8. 8. The isolated crystalline form B of any one of claims 1 to 7, wherein the XRPD pattern comprises at least three 2θ values ​​selected from 7.5±0.1°, 8.8±0.1°, 10.0±0.1°, 10.5±0.1°, 12.6±0.1°, 14.7±0.1°, 15.4±0.1°, 16.4±0.1°, 16.7±0.1°, 18.6±0.1°, 22.7±0.1°, and 25.3±0.1°.

9. 9. The isolated crystalline form B of any one of claims 1 to 8, wherein the XRPD pattern comprises a 2θ value of at least 16.4±0.2°.

10. 10. The isolated crystalline form B of any one of claims 1 to 9, wherein the XRPD pattern comprises 2θ values ​​of at least 10.0±0.2 degrees.

11. 11. The isolated crystalline form B of any one of claims 1 to 10, wherein the XRPD pattern comprises a 2θ value of at least 15.4±0.2 degrees.

12. 12. The isolated crystalline form B of any one of claims 1 to 11, wherein the XRPD pattern comprises a 2θ value of at least 16.7±0.2 degrees.

13. 13. The isolated crystalline form B of any one of claims 1 to 12, wherein the XRPD pattern comprises a 2θ value of at least 8.8±0.2 degrees.

14. 14. The isolated crystalline form B of any one of claims 1 to 13, wherein the XRPD pattern comprises a 2θ value of at least 12.6±0.2 degrees.

15. 15. The isolated crystalline form B of any one of claims 1 to 14, wherein the XRPD pattern comprises a 2θ value of at least 14.7±0.2 degrees.

16. 16. The isolated crystalline form B of any one of claims 1 to 15, wherein the XRPD pattern comprises a 2θ value of at least 10.5±0.2 degrees.

17. 17. The isolated crystalline form B of any one of claims 1 to 16, wherein the XRPD pattern comprises a 2θ value of at least 25.3±0.2 degrees.

18. 18. The isolated crystalline form B of any one of claims 1 to 17, wherein the XRPD pattern comprises a 2θ value of at least 22.7±0.2 degrees.

19. 19. The isolated crystalline form B of any one of claims 1 to 18, characterized by an XRPD pattern having the characteristic 2θ values ​​of Figure 1.

20. 20. The isolated crystalline form B of any one of claims 1 to 19, having a differential scanning calorimetry (DSC) onset endotherm temperature of about 194±20°C.

21. 21. The isolated crystalline form B of any one of claims 1 to 20, having a differential scanning calorimetry (DSC) onset endotherm temperature of about 194±10°C.

22. A pharmaceutical composition comprising the isolated crystalline form B of any one of claims 1 to 21 in a pharmaceutically acceptable carrier.

23. 1. A pharmaceutical composition comprising Compound 1, a solubility enhancer, a permeation enhancer, a filler, a binder / glidant, and a mucoadhesive / disintegrant, wherein Compound 1 has the structure: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof.

24. a. the solubility enhancer is hypromellose acetate succinate; b. the permeation enhancer is vitamin E; c. the filler is mannitol; d. the binder / glidant is cellulose; e. the mucoadhesive is croscarmellose sodium; 24. The pharmaceutical composition of claim 23.

25. 26. A method of treating a mutant BRAF-mediated disorder, comprising administering to a patient in need thereof an effective amount of isolated crystalline form B of any one of claims 1 to 21 or a pharmaceutical composition of any one of claims 22 to 24.

26. 26. The method of claim 25, wherein the patient is a human.

27. 27. The method of claim 25 or 26, wherein the mutant BRAF-mediated disorder is cancer.

28. 28. The method of claim 27, wherein the mutant BRAF-mediated cancer is melanoma.

29. 28. The method of claim 27, wherein the mutant BRAF-mediated cancer is lung cancer.

30. 28. The method of claim 27, wherein the mutant BRAF-mediated cancer is non-small cell lung cancer.

31. 28. The method of claim 27, wherein the mutant BRAF-mediated cancer is colorectal cancer.

32. 28. The method of claim 27, wherein the mutant BRAF-mediated cancer is microsatellite-stable colorectal cancer.

33. 28. The method of claim 27, wherein the mutant BRAF-mediated cancer is thyroid cancer.

34. 28. The method of claim 27, wherein the mutant BRAF-mediated cancer is ovarian cancer.

35. 26. The method of claim 25, 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, undifferentiated pleomorphic xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, pancreatic cancer, clear cell sarcoma of the breast, salivary gland carcinoma, or microsatellite-stable colorectal cancer.

36. The method of any one of claims 25 to 35, wherein the patient is also administered an additional active agent.

37. 37. The method of claim 36, wherein the additional active agent is a MEK inhibitor.

38. 38. The method of claim 37, wherein the MEK inhibitor is trametinib.

39. 37. The method of claim 36, wherein the additional active agent is an immune checkpoint inhibitor.

40. 40. The method of claim 39, wherein the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, ipilimumab, leratolimab, atezolizumab, avelumab, and durvalumab.

41. 37. The method of claim 36, wherein the additional active agent is cetuximab or panitumumab.

42. The isolated crystalline form B of any one of claims 1 to 21 or the pharmaceutical composition of any one of claims 22 to 24 for the therapeutic treatment of mutant BRAF-mediated disorders.

43. 43. The isolated crystalline form B of claim 42, wherein the mutant BRAF-mediated disorder is cancer.

44. 44. The isolated crystalline form B of claim 43, wherein the mutant BRAF-mediated cancer is melanoma.

45. 44. The isolated crystalline form B of claim 43, wherein the mutant BRAF-mediated cancer is lung cancer.

46. 44. The isolated crystalline form B of claim 43, wherein the mutant BRAF-mediated cancer is non-small cell lung cancer.

47. 44. The isolated crystalline form B of claim 43, wherein the mutant BRAF-mediated cancer is colorectal cancer.

48. 44. The isolated crystalline form B of claim 43, wherein the mutant BRAF-mediated cancer is microsatellite-stable colorectal cancer.

49. 44. The isolated crystalline form B of claim 43, wherein the mutant BRAF-mediated cancer is thyroid cancer.

50. 44. The isolated crystalline form B of claim 43, wherein the mutant BRAF-mediated cancer is ovarian cancer.

51. 43. The isolated crystalline form B of claim 42, 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, undifferentiated pleomorphic xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, pancreatic cancer, clear cell sarcoma of the breast, salivary gland carcinoma, or microsatellite-stable colorectal cancer.

52. The isolated crystalline form B of any one of claims 1 to 21 or the pharmaceutical composition of any one of claims 22 to 24 for use in the treatment of a mutant BRAF-mediated disorder.

53. 53. The isolated crystalline form B of claim 52, wherein the mutant BRAF-mediated disorder is cancer.

54. 54. The isolated crystalline form B of claim 53, wherein the mutant BRAF-mediated cancer is melanoma.

55. 54. The isolated crystalline form B of claim 53, wherein the mutant BRAF-mediated cancer is lung cancer.

56. 54. The isolated crystalline form B of claim 53, wherein the mutant BRAF-mediated cancer is non-small cell lung cancer.

57. 54. The isolated crystalline form B of claim 53, wherein the mutant BRAF-mediated cancer is colorectal cancer.

58. 54. The isolated crystalline form B of claim 53, wherein the mutant BRAF-mediated cancer is microsatellite-stable colorectal cancer.

59. 54. The isolated crystalline form B of claim 53, wherein the mutant BRAF-mediated cancer is thyroid cancer.

60. 54. The isolated crystalline form B of claim 53, wherein the mutant BRAF-mediated cancer is ovarian cancer.

61. 53. The isolated crystalline form B of claim 52, 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, undifferentiated pleomorphic xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, pancreatic cancer, clear cell sarcoma of the breast, salivary gland carcinoma, or microsatellite-stable colorectal cancer.

62. Use of the isolated crystalline form B of any one of claims 1 to 21 or the pharmaceutical composition of any one of claims 22 to 24 in the manufacture of a medicament for the treatment of a mutant BRAF-mediated disorder.

63. 63. The use of claim 62, wherein the mutant BRAF-mediated disorder is cancer.

64. 64. The use of claim 63, wherein the mutant BRAF-mediated cancer is melanoma.

65. 64. The use of claim 63, wherein the mutant BRAF-mediated cancer is lung cancer.

66. 64. The use of claim 63, wherein the mutant BRAF-mediated cancer is non-small cell lung cancer.

67. 64. The use of claim 63, wherein the mutant BRAF-mediated cancer is colorectal cancer.

68. 64. The use of claim 63, wherein the mutant BRAF-mediated cancer is microsatellite-stable colorectal cancer.

69. 64. The use of claim 63, wherein the mutant BRAF-mediated cancer is thyroid cancer.

70. 64. The use of claim 63, wherein the mutant BRAF-mediated cancer is ovarian cancer.

71. 63. The use of claim 62, 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, undifferentiated pleomorphic xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, pancreatic cancer, clear cell sarcoma of the breast, salivary gland carcinoma, or microsatellite-stable colorectal cancer.

72. The isolated crystalline form B according to any one of claims 1 to 21 for use as a therapeutically active substance.

73. formula: 【Transformation 3】 A method for preparing a compound of the formula In the presence of isopropylamine or an isopropylamine salt and a first base, a compound of the formula: 【Chemistry 4】 to obtain said compound of formula A-1, In the formula, R Ｘ is selected from the group consisting of hydrogen and an amino protecting group.

74. The amino protecting group R Ｘ is tert-butyloxycarbonyl (BOC), the first base is sodium hydroxide or potassium hydroxide; 74. The method of claim 73, wherein the isopropylamine salt is isopropylamine hydrochloride.

75. formula: 【Transformation 5】 A method for preparing a compound of the formula The method comprises: (i) Formula: 【Transformation 6】 with a chiral acid to obtain a mixture of diastereomeric salts formed between said compound of formula A-3 and said chiral acid; (ii) crystallizing the mixture of diastereomeric salts prepared in step (i) from a first solvent to obtain a compound having the anion of the chiral acid and the formula: 【Transformation 7】 obtaining a separately isolated diastereomeric salt formed between the N-protected (R)-1-oxa-8-azaspiro[4.5]decane-3-aminium cation of (iii) treating the separately isolated diastereomeric salt containing the cation of formula A-4 isolated in step (ii) with a second base to release the compound of formula A-1; Including, In the formula, R Ｘ is selected from the group consisting of hydrogen and an amino protecting group.

76. The amino protecting group R Ｘ is tert-butyloxycarbonyl (BOC), the chiral acid is (R)-mandelic acid; the first solvent is acetonitrile; 76. The method of claim 75, wherein the second base is sodium hydroxide or potassium hydroxide.

77. formula: 【Transformation 8】 A method for preparing a compound of the formula The method comprises converting 2-amino-5-hydroxybenzoic acid to a compound of the formula: 【Chemistry 9】 in the presence of trialkyl orthoformate in a second solvent; The compound of formula A-1 is prepared by the method of any one of claims 73 to 76, R Ｘ is selected from the group consisting of hydrogen and an amino protecting group.

78. The amino protecting group R Ｘ is tert-butyloxycarbonyl (BOC), the trialkyl orthoformate is triethyl orthoformate, 78. The method of claim 77, wherein the second solvent is n-butanol.

79. formula: 【Chemistry 10】 A method for preparing a compound of the formula 2,3,6-trifluorobenzonitrile can be converted to a compound of the formula: 【Chemistry 11】 in a third solvent in the presence of a third base; During the ceremony, R Ｘ is selected from the group consisting of hydrogen and an amino protecting group; 79. The method of claim 77 or 78, wherein the compound of formula A-5 is prepared according to the method of claim 77 or 78.

80. the third base is potassium carbonate and the third solvent is acetonitrile; The amino protecting group R Ｘ 80. The method of claim 79, wherein is tert-butyloxycarbonyl (BOC).

81. formula: 【Chemistry 12】 A method for preparing a compound of the formula (i) [methyl(sulfamoyl)amino]ethane NH ２ SO ２ N(Me)Et can be converted to a compound of the formula: 【Chemistry 13】 in a fourth solvent in the presence of a fourth base to obtain a compound of formula A-8: 【Chemistry 14】 A process for obtaining a compound of the formula The compound of formula A-6 is prepared according to the method of claim 79 or 80, R Ｘ is selected from the group consisting of hydrogen and an amino protecting group; (ii) R Ｘ is the amino protecting group, then removing the amino protecting group attached to the piperidine nitrogen atom of the compound of formula A-8 in the presence of a first acid; A method comprising:

82. the fourth base is cesium carbonate and the fourth solvent is N,N-dimethylacetamide; The amino protecting group R Ｘ is tert-butyloxycarbonyl (BOC), 82. The method of claim 81, wherein the first acid is hydrochloric acid.

83. formula: 【Chemistry 15】 A method for preparing a compound of the formula 2,4,5-trifluorobenzonitrile can be converted to a compound of the formula: 【Chemistry 16】 in a fifth solvent in the presence of a fifth base; In the formula, R Ｙ is hydrogen or a carboxylic acid protecting group.

84. the fifth base is N,N-diisopropylethylamine, and the fifth solvent is N,N-dimethylformamide; R Ｙ is tert-butyl ( ｔ Bu).

85. formula: 【Chemistry 17】 A method for preparing a compound of the formula Methylhydrazine can be converted to the formula: [Chemistry 18] in the presence of a sixth solvent; The compound of formula B-1 is prepared according to the method of claim 83 or 84, In the formula, R Ｙ is hydrogen or a carboxylic acid protecting group.

86. the sixth solvent is N-methyl-2-pyrrolidone; R Ｙ 86. The method of claim 85, wherein is tert-butyl.

87. formula: 【Chemistry 19】 A method for preparing a compound of the formula Acrylic acid can be converted to the formula: 【Chemistry 20】 in a seventh solvent, The compound of formula B-3 is prepared according to the method of claim 85 or 86, R Ｙ is hydrogen or a carboxylic acid protecting group.

88. the seventh solvent is an aqueous solution of hydrochloric acid; R Ｙ 88. The method of claim 87, wherein is tert-butyl.

89. formula: 【Chemistry 21】 A method for preparing a compound of the formula (i) First, a metal cyanate is reacted with a compound of the formula: 【Chemistry 22】 in the presence of a second acid to produce a compound of the formula: 【Chemistry 23】 obtaining a reaction mixture containing a first intermediate compound of The compound of formula B-4 is prepared according to the method of claim 87 or 88, R Ｙ is hydrogen or a carboxylic acid protecting group; (ii) said first intermediate compound of formula B-6 from step (i) is then cyclized, optionally in the presence of a third acid, to give a compound of formula: 【Chemistry 24】 obtaining a second intermediate compound of (iii) Next, R Ｙ is the carboxylic acid protecting group, the carboxylic acid protecting group R Ｙ in the presence of a fourth acid to obtain said compound of formula B-5; A method comprising:

90. R Ｙ is tert-butyl, the metal cyanate is sodium cyanate or potassium cyanate; the second acid is acetic acid; the third acid is hydrochloric acid or acetic acid; 90. The method of claim 89, wherein the fourth acid is hydrochloric acid.

91. formula: 【Chemistry 25】 A method for preparing a compound of the formula The method comprises: (i) First, a compound of the formula: 【Chemistry 26】 with a carboxylic acid hydroxyl activating reagent in the presence of a sixth base and an eighth solvent to produce a compound of the formula: 【Chemistry 27】 obtaining a third intermediate compound of The carboxylic acid hydroxyl is converted to the more reactive group -OR Ｚ is converted to The compound of formula B-5 is prepared according to the method of claim 89 or 90, (ii) Then, the formula: 【Chemistry 28】 reacting (3R)-3-[6-[2-cyano-3-[[ethyl(methyl)sulfamoyl]amino]-6-fluoro-phenoxy]-4-oxo-quinazolin-3-yl]-1-oxa-8-azaspiro[4.5]decane of formula B-1 with the third intermediate compound of formula B-8 prepared in step (ii) in the presence of a seventh base and a ninth solvent to obtain the compound of formula 1; The compound of formula A-7 is prepared according to the method of claim 81 or 82, A method comprising:

92. (i) the sixth base is N,N-diisopropylethylamine; the eighth solvent is acetonitrile; the carboxylic acid hydroxyl activating reagent is 2-succinimido-1,1,3,3-tetramethyluronium tetrafluoroborate, and Ｚ The group is 2,5-dioxopyrrolidin-1-yl, 92. The method of claim 91, wherein (ii) the seventh base is triethylamine and the ninth solvent is N,N-dimethylformamide.

93. 1. A method for treating mutant BRAF-mediated cancer brain or central nervous system (CNS) metastases, comprising administering an effective amount of a compound of the structure: 【Chemistry 29】 or a pharmaceutically acceptable salt thereof to a human patient in need of treatment.

94. 94. The method of claim 93, wherein the cancer has metastasized to the brain.

95. 95. The method of claim 93 or 94, wherein the cancer has metastasized to the CNS.

96. 96. The method of any one of claims 93 to 95, wherein the mutant BRAF-mediated cancer is melanoma.

97. 96. The method of any one of claims 93 to 95, wherein the mutant BRAF-mediated cancer is lung cancer.

98. 96. The method of any one of claims 93 to 95, wherein the mutant BRAF-mediated cancer is non-small cell lung cancer.

99. 96. The method of any one of claims 93 to 95, wherein the mutant BRAF-mediated cancer is colorectal cancer.

100. 96. The method of any one of claims 93 to 95, wherein the mutant BRAF-mediated cancer is microsatellite-stable colorectal cancer.

101. 96. The method of any one of claims 93 to 95, wherein the mutant BRAF-mediated cancer is thyroid cancer.

102. 96. The method of any one of claims 93 to 95, wherein the mutant BRAF-mediated cancer is ovarian cancer.

103. 96. The method of any one of claims 93-95, wherein the mutant BRAF-mediated cancer is cholangiocarcinoma, Erdheim-Chester disease, Langerhans histiocytosis, ganglioglioma, glioma, glioblastoma, hairy cell leukemia, metanephric adenoma, multiple myeloma, non-small cell lung carcinoma, ovarian carcinoma, pilocytic astrocytoma, undifferentiated 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.

104. 104. The method of any one of claims 93 to 103, wherein the patient is also administered an additional active agent.

105. 105. The method of claim 104, wherein the additional active agent is a MEK inhibitor.

106. 106. The method of claim 105, wherein the MEK inhibitor is trametinib.

107. 105. The method of claim 104, wherein the additional active agent is an immune checkpoint inhibitor.

108. 108. The method of claim 107, wherein the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, ipilimumab, leratolimab, atezolizumab, avelumab, and durvalumab.

109. 105. The method of claim 104, wherein the additional active agent is cetuximab or panitumumab.

110. 110. The method of any one of claims 93 to 109, wherein the mutant BRAF has a V600 mutation.

111. 111. The method of claim 110, wherein the V600 mutation is V600E, V600K, V600R, V600D, V600M, or V600N.

112. 111. The method of claim 110, wherein the V600 mutation is V600E.

113. 113. The method of any one of claims 93 to 112, wherein the mutant BRAF has a mutation selected from G469A, G469V, G469L, G469R, L597Q, and K601E.

114. 114. The method of any one of claims 93 to 113, wherein the mutant BRAF has a mutation selected from G466A, G466E, G466R, G466V, S467L, G469E, N581I, D594E, D594G, and D594N.

115. 115. The method of any one of claims 93 to 114, wherein the mutant BRAF has a mutation selected from G464I, G464R, N581T, L584F, E586K, G593D, G596C, L597R, L597S, S605I, S607F, N684T, E26A, V130M, L745L, and D284E.

116. 116. The method of any one of claims 93 to 115, wherein the mutant BRAF has a splice mutation.

117. 117. The method of claim 116, wherein the splice mutation is a p61-BRAF V600 splice mutation.

118. 118. The method of any one of claims 93 to 117, wherein the mutant BRAF-mediated cancer has an NRAS, MEK1, or PI3K mutation.

119. 119. The method of claim 118, wherein the cancer has an NRAS mutation.

120. 120. The method of claim 119, wherein the NRAS mutation is Q61K.

121. 120. The method of claim 119, wherein the NRAS mutation is Q61R.

122. 119. The method of claim 118, wherein the cancer has a MEK1 mutation.

123. 119. The method of claim 118, wherein the cancer has a PI3K mutation.

124. PI3K mutation is PIK3CA Ｈ１０４７Ｒ or PIK3CA Ｐ４４９Ｔ The method of claim 123, wherein

125. 125. The method of any one of claims 93 to 124, wherein the mutant BRAF-mediated cancer has one or more mutations that promote homodimerization or heterodimerization of RAF proteins.

126. 126. The method of claim 125, wherein the one or more mutations promote homodimerization of the RAF protein.

127. 126. The method of claim 125, wherein the one or more mutations promote heterodimerization of RAF proteins.

128. 1. A compound for use in the manufacture of a medicament for treating brain or central nervous system (CNS) metastases of mutant BRAF-mediated cancer, comprising the structure: 【Transformation 30】 or a pharmaceutically acceptable salt thereof.

129. 129. The compound of claim 128 for treating brain metastases.

130. 129. The compound of claim 128 for treating CNS metastases.

131. 131. The compound of any one of claims 128 to 130, wherein the mutant BRAF-mediated cancer is melanoma.

132. 131. The compound of any one of claims 128 to 130, wherein the mutant BRAF-mediated cancer is lung cancer.

133. 131. The compound of any one of claims 128 to 130, wherein the mutant BRAF-mediated cancer is non-small cell lung cancer.

134. 131. The compound of any one of claims 128 to 130, wherein the mutant BRAF-mediated cancer is colorectal cancer.

135. 131. The compound of any one of claims 128 to 130, wherein the mutant BRAF-mediated cancer is microsatellite-stable colorectal cancer.

136. 131. The compound of any one of claims 128 to 130, wherein the mutant BRAF-mediated cancer is thyroid cancer.

137. The compound of any one of claims 128 to 130, wherein the mutant BRAF-mediated cancer is ovarian cancer.

138. 131. The compound of any one of claims 128-130, wherein the mutant BRAF-mediated cancer is cholangiocarcinoma, Erdheim-Chester disease, Langerhans histiocytosis, ganglioglioma, glioma, glioblastoma, hairy cell leukemia, metanephric adenoma, multiple myeloma, non-small cell lung cancer, ovarian cancer, pilocytic astrocytoma, undifferentiated pleomorphic xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, pancreatic cancer, clear cell sarcoma of the breast, salivary gland carcinoma, or microsatellite-stable colorectal cancer.

139. 131. The compound of any one of claims 128 to 130, wherein the patient is also administered an additional active agent.

140. 140. The compound of claim 139, wherein the additional active agent is a MEK inhibitor.

141. 141. The compound of claim 140, wherein the MEK inhibitor is trametinib.

142. 140. The compound of claim 139, wherein the additional active agent is an immune checkpoint inhibitor.

143. 143. The compound of claim 142, wherein the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, ipilimumab, leratolimab, atezolizumab, avelumab, and durvalumab.

144. 140. The compound of claim 139, wherein the additional active agent is cetuximab or panitumumab.

145. 145. The compound of any one of claims 128 to 144, wherein the mutant BRAF has a V600 mutation.

146. 146. The compound of claim 145, wherein the V600 mutation is V600E, V600K, V600R, V600D, V600M, or V600N.

147. 146. The compound of claim 145, wherein the V600 mutation is V600E.

148. 148. The compound of any one of claims 128 to 147, wherein the mutant BRAF has a mutation selected from G469A, G469V, G469L, G469R, L597Q, and K601E.

149. 149. The compound of any one of claims 128-148, wherein the mutant BRAF has a mutation selected from G466A, G466E, G466R, G466V, S467L, G469E, N581I, D594E, D594G, and D594N.

150. 150. The compound of any one of claims 128 to 149, wherein the mutant BRAF has a mutation selected from G464I, G464R, N581T, L584F, E586K, G593D, G596C, L597R, L597S, S605I, S607F, N684T, E26A, V130M, L745L, and D284E.

151. The compound of any one of claims 128 to 150, wherein the mutant BRAF has a splice mutation.

152. 152. The compound of claim 151, wherein the splice mutation is a p61-BRAF V600 splice mutation.

153. 153. The compound of any one of claims 128-152, wherein the mutant BRAF-mediated cancer has an NRAS, MEK1, or PI3K mutation.

154. The compound of claim 153, wherein the cancer has an NRAS mutation.

155. 155. The compound of claim 154, wherein the NRAS mutation is Q61K.

156. 155. The compound of claim 154, wherein the NRAS mutation is Q61R.

157. 154. The compound of claim 153, wherein the cancer has a MEK1 mutation.

158. 154. The compound of claim 153, wherein the cancer has a PI3K mutation.

159. PI3K mutation is PIK3CA Ｈ１０４７Ｒ or PIK3CA Ｐ４４９Ｔ 159. The compound of claim 158, wherein:

160. 160. The compound of any one of claims 128-159, wherein the mutant BRAF-mediated cancer has one or more mutations that promote homodimerization or heterodimerization of RAF proteins.

161. 161. The compound of claim 160, wherein the one or more mutations promote homodimerization of the RAF protein.

162. 161. The compound of claim 160, wherein the one or more mutations promote heterodimerization of RAF proteins.

163. 1. Use of a compound in the manufacture of a medicament for treating brain or central nervous system (CNS) metastases of a mutant BRAF-mediated cancer, said compound having the structure: 【Chemistry 31】 or a pharmaceutically acceptable salt thereof.

164. 1. Use of a compound in the treatment of brain or central nervous system (CNS) metastases of mutant BRAF-mediated cancer, said compound having the structure: 【Chemistry 32】 or a pharmaceutically acceptable salt thereof.

165. 165. The use of claim 163 or 164, wherein the cancer has metastasized to the brain.

166. 166. The use of any one of claims 163 to 165, wherein the cancer has metastasized to the CNS.

167. 167. The use of any one of claims 163 to 166, wherein the mutant BRAF-mediated cancer is melanoma.

168. 167. The use of any one of claims 163 to 166, wherein the mutant BRAF-mediated cancer is lung cancer.

169. 167. The use of any one of claims 163 to 166, wherein the mutant BRAF-mediated cancer is non-small cell lung cancer.

170. 167. The use of any one of claims 163 to 166, wherein the mutant BRAF-mediated cancer is colorectal cancer.

171. 167. The use of any one of claims 163 to 166, wherein the mutant BRAF-mediated cancer is microsatellite-stable colorectal cancer.

172. 167. The use of any one of claims 163 to 166, wherein the mutant BRAF-mediated cancer is thyroid cancer.

173. 167. The use of any one of claims 163 to 166, wherein the mutant BRAF-mediated cancer is ovarian cancer.

174. 167. The use of any one of claims 163 to 166, wherein the mutant BRAF-mediated cancer is cholangiocarcinoma, Erdheim-Chester disease, Langerhans histiocytosis, ganglioglioma, glioma, glioblastoma, hairy cell leukemia, metanephric adenoma, multiple myeloma, non-small cell lung cancer, ovarian cancer, pilocytic astrocytoma, undifferentiated pleomorphic xanthoastrocytoma, astrocytoma, papillary thyroid carcinoma, anaplastic thyroid carcinoma, pancreatic cancer, clear cell sarcoma of the breast, salivary gland carcinoma, or microsatellite-stable colorectal cancer.

175. 175. The use of any one of claims 163 to 174, wherein the patient is also administered an additional active agent.

176. 176. The use of claim 175, wherein the additional active agent is a MEK inhibitor.

177. 177. The use of claim 176, wherein the MEK inhibitor is trametinib.

178. 176. The use of claim 175, wherein the additional active agent is an immune checkpoint inhibitor.

179. 179. The use of claim 178, wherein the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, cemiplimab, ipilimumab, leratolimab, atezolizumab, avelumab, and durvalumab.

180. 176. The use of claim 175, wherein the additional active agent is cetuximab or panitumumab.

181. 181. The use of any one of claims 163 to 180, wherein the mutant BRAF has a V600 mutation.

182. 182. The use of claim 181, wherein the V600 mutation is V600E, V600K, V600R, V600D, V600M, or V600N.

183. The use described in claim 181, wherein the V600 mutation is V600E.

184. 184. The use of any one of claims 163 to 183, wherein the mutant BRAF has a mutation selected from G469A, G469V, G469L, G469R, L597Q, and K601E.

185. 185. The use of any one of claims 163 to 184, wherein the mutant BRAF has a mutation selected from G466A, G466E, G466R, G466V, S467L, G469E, N581I, D594E, D594G, and D594N.

186. 186. The use of any one of claims 163 to 185, wherein the mutant BRAF has a mutation selected from G464I, G464R, N581T, L584F, E586K, G593D, G596C, L597R, L597S, S605I, S607F, N684T, E26A, V130M, L745L, and D284E.

187. 187. The use of any one of claims 163 to 186, wherein the mutant BRAF has a splice mutation.

188. 188. The use of claim 187, wherein the splice mutation is a p61-BRAF V600 splice mutation.

189. 189. The use of any one of claims 163 to 188, wherein the mutant BRAF-mediated cancer has an NRAS, MEK1, or PI3K mutation.

190. 190. The use of claim 189, wherein the cancer has an NRAS mutation.

191. The use of claim 190, wherein the NRAS mutation is Q61K.

192. The use of claim 190, wherein the NRAS mutation is Q61R.

193. 190. The use of claim 189, wherein the cancer has a MEK1 mutation.

194. 190. The use of claim 189, wherein the cancer has a PI3K mutation.

195. PI3K mutation is PIK3CA Ｈ１０４７Ｒ or PIK3CA Ｐ４４９Ｔ The use of claim 194, wherein

196. 196. The use of any one of claims 163 to 195, wherein the mutant BRAF-mediated cancer has one or more mutations that promote homodimerization or heterodimerization of RAF proteins.

197. 197. The use of claim 196, wherein the one or more mutations promote homodimerization of the RAF protein.

198. 197. The use of claim 196, wherein the one or more mutations promote heterodimerization of RAF proteins.

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