WO2022040377A1 - Procédés de préparation de dérivés de quinazoline - Google Patents

Procédés de préparation de dérivés de quinazoline Download PDF

Info

Publication number
WO2022040377A1
WO2022040377A1 PCT/US2021/046606 US2021046606W WO2022040377A1 WO 2022040377 A1 WO2022040377 A1 WO 2022040377A1 US 2021046606 W US2021046606 W US 2021046606W WO 2022040377 A1 WO2022040377 A1 WO 2022040377A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
salt
alkyl
formula
iii
Prior art date
Application number
PCT/US2021/046606
Other languages
English (en)
Inventor
Hua Miao
Danmei Dai
Kui YUAN
Jiatao YU
Wu-Yan Zhang
Original Assignee
Black Diamond Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Black Diamond Therapeutics, Inc. filed Critical Black Diamond Therapeutics, Inc.
Publication of WO2022040377A1 publication Critical patent/WO2022040377A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom

Definitions

  • ErbB inhibitors are a known treatment for a number of cancers. However, not every patient is responsive satisfactorily to this treatment. Thus, there is a long-felt need in the art for new therapies that are able to address the variable responsiveness of cancer patients to known therapies.
  • the present disclosure provides compositions and methods for preventing or treating cancer in patients with these oncogenic mutations without the variable responsiveness observed when patients having these ErbB mutants are treated using the existing standard of care.
  • the present disclosure provides a method of preparing a compound of Formula (VII): or a salt thereof, comprising steps (v-1) and (v-2):
  • the compound of Formula (V) or the salt thereof is prepared by a process comprising one or more steps of (i), (ii), (iii), or (iv):
  • the present disclosure provides a method of preparing Compound No. 7: (Compound No. 7) or a salt thereof, comprising comprising steps (v-1) and (v-2):
  • the Compound No. 5 or the salt thereof is prepared by a process comprising one or more steps of (i), (ii), (iii), or (iv):
  • the method further comprises one or more steps of (i), (ii), (iii), or (iv).
  • the present disclosure provides a compound being prepared by a method described herein.
  • the present disclosure provides a pharmaceutical composition comprising a compound described herein, and one or more pharmaceutically acceptable carriers or excipients.
  • a pharmaceutical composition comprising a compound being prepared by a method described herein, and one or more pharmaceutically acceptable carriers or excipients.
  • a method of preventing or treating a disease or disorder in a subject comprising administering to the subject a pharmaceutically effective amount of a compound described herein.
  • the present disclosure provides a method of preparing a compound of Formula (VII): or a salt thereof, comprising steps (v-1) and (v-2):
  • the compound of Formula (V) or the salt thereof is prepared by a process comprising one or more steps of (i), (ii), (iii), or (iv)
  • the present disclosure provides a method of preparing Compound No.
  • the Compound No. 5 or the salt thereof is prepared by a process comprising one or more steps of (i), (ii), (iii), or (iv):
  • the method further comprises one or more steps of (i), (ii), (iii), or (iv).
  • step (v-1) comprises forming a compound of Formula (VI): or a salt thereof.
  • step (v-1) comprises forming Compound No. 6: (Compound No. 6) or a salt thereof.
  • the acid in step (v-1), is an organic acid or an inorganic acid.
  • the acid is an organic acid.
  • the acid in step (v-1), is inorganic acid.
  • the acid is methanesulfonic acid (MsOH), trifluoroacetic acid (TfOH), toluenesulfonic acid, benezenesulfonic acid, hydrochloric acid (HC1), hydrobromic acid (HBr), or sulfuric acid (H2SO4),
  • the acid is methanesulfonic acid (MsOH) or trifluoroacetic acid (TfOH).
  • the acid is methanesulfonic acid (MsOH).
  • step (v-1) the contacting is performed in the presence of a solvent.
  • the solvent comprises an organic solvent, an inorganic solvent, or a combination thereof.
  • the solvent comprises N-methyl-2-pyrrolidone (NMP), dimethylformamide (DMF), tetrahydrofuran (THF), water, or any combination thereof.
  • NMP N-methyl-2-pyrrolidone
  • DMF dimethylformamide
  • THF tetrahydrofuran
  • the solvent comprises an organic solvent.
  • the solvent comprises N-methyl-2-pyrrolidone (NMP), dimethylformamide (DMF), or tetrahydrofuran (THF).
  • NMP N-methyl-2-pyrrolidone
  • DMF dimethylformamide
  • THF tetrahydrofuran
  • the solvent comprises N-methyl-2-pyrrolidone (NMP).
  • the solvent comprises an organic solvent and an inorganic solvent.
  • the solvent comprises tetrahydrofuran (THF) and water.
  • step (v-1) comprises one or more of the following steps:
  • (v-1-1) providing a first mixture comprising a compound of Formula (V) or the salt thereof (e.g., Compound No. 5) in the solvent (e.g., NMP);
  • step (v-1 -2) adding the acid (MsOH) to the first mixture at a temperature ranging from about -5 °C ro about 5 °C.
  • step (v-1 -2) adding the acid (MsOH) to the first mixture at a temperature of about about 20 ⁇ 10 °C, about 20 ⁇ 5 °C, about 20 ⁇ 2 °C, about 20 ⁇ l °C (e.g., about 20 °C).
  • step (v-1-4) comprises stirring the third mixture at a temperature ranging from about -5 °C ro about 5 °C.
  • step (v-1-4) comprises stirring the third mixture at a temperature of about about 20 ⁇ 10 °C, about 20 ⁇ 5 °C, about 20 ⁇ 2 °C, about 20 ⁇ l °C (e.g., about 20 °C).
  • step (v-1-4) comprises stirring the third mixture for about 60 ⁇ 30 minutes, about 60 ⁇ 15 minutes, about 60 ⁇ 10 minutes, or about 60 ⁇ 5 minutes (e.g., about 60 minutes).
  • step (v-1) comprises detecting the presence of the compound of Formula (VI) or the salt thereof (e.g., Compound No. 6).
  • step (v-1) does not comprise detecting the presence of the compound of Formula (VI) or the salt thereof (e.g., Compound No. 6).
  • step (v-1) comprises isolating the compound of Formula (VI) or the salt thereof (e.g., Compound No. 6).
  • step (v-1) does not comprise isolating the compound of Formula (VI) or the salt thereof (e.g., Compound No. 6).
  • step (v-1) comprises purifying the compound of Formula (VI) or the salt thereof (e.g., Compound No. 6).
  • step (v-1) does not comprise purifying the compound of Formula (VI) or the salt thereof (e.g., Compound No. 6).
  • the base in step (v-2), is an organic base or an inorganic base.
  • the base is an organic base.
  • the base in step (v-2), is an inorganic base.
  • the base in step (v-2), is N,N-diisopropylethylamine (DIPEA), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N,N,N,N-tetramethyl guanidine (TMG), sodium hydroxide (NaOH), lithium hydroxide (LiOH), potassium hydroxide (KOH), or potassium carbonate (K2CO3).
  • DIPEA N,N-diisopropylethylamine
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • TMG N,N,N,N-tetramethyl guanidine
  • NaOH sodium hydroxide
  • LiOH lithium hydroxide
  • KOH potassium hydroxide
  • K2CO3 potassium carbonate
  • the base is a N,N-diisopropylethylamine (DIPEA).
  • DIPEA N,N-diisopropylethylamine
  • the solvent comprises NMP; and in step (v-2), the base is DIPEA, DBU, or TMG.
  • step (v-1) the solvent comprises NMP; and in step (v-2), the base is DIPEA.
  • the solvent comprises THF and water; and in step (v-2), the base is NaOH, LiOH, KOH, or K2CO3.
  • the solvent comprises THF and water; and in step (v-2), the base is NaOH or LiOH.
  • step (v-2) comprises adding the base (e.g., DIPEA) to the mixture formed in step (v-1).
  • the base e.g., DIPEA
  • step (v-2) comprises adding the base (e.g., DIPEA) to the compound of Formula (VI) or the salt thereof (e.g., Compound No. 6).
  • base e.g., DIPEA
  • step (v-2) comprises adding the base (e.g., DIPEA) to the compound of Formula (VI) or the salt thereof (e.g., Compound No. 6).
  • step (v-2) comprises adding the base (e.g., DIPEA) to the isolated compound of Formula (VI) or the salt thereof (e.g., Compound No. 6).
  • base e.g., DIPEA
  • step (v-2) comprises adding the base (e.g., DIPEA) to the isolated compound of Formula (VI) or the salt thereof (e.g., Compound No. 6).
  • step (v-2) comprises adding the base (e.g., DIPEA) to the purified compound of Formula (VI) or the salt thereof (e.g., Compound No. 6).
  • base e.g., DIPEA
  • step (v-2) comprises adding the base (e.g., DIPEA) to the purified compound of Formula (VI) or the salt thereof (e.g., Compound No. 6).
  • step (v-2) comprises one or more of the following steps:
  • step (v-2-1) adding the base (e.g., DIPEA) to the mixture formed in step (v-1), thereby forming a first mixture; or
  • the base e.g., DIPEA
  • step (v-2-2) comprises heating the first mixture at about 70 ⁇ 20 °C, about 70 ⁇ 15 °C, about 70 ⁇ 10 °C, about 70 ⁇ 5 °C, about 70 ⁇ 2 °C, about 70 ⁇ l °C, (e.g., about 70 °C).
  • step (v-2-2) comprises heating the first mixture for about about 13 ⁇ 5 hours, about 13 ⁇ 2 hours, about 13 ⁇ 1 hours, about 13 ⁇ 0.5 hours, about 13 ⁇ 0.2 hours, about 13 ⁇ 0.1 hours (e.g., about 13 hours).
  • step (v-2) further comprises one or more of the following steps: (v-2-3) adding water to the heated second mixture, thereby forming a third mixture; (v-2-4) stirring the third mixture;
  • step (v-2-4) comprises stirring the third mixture at about 25 ⁇ 10 °C, about 25 ⁇ 5 °C, about 25 ⁇ 2 °C, about 25 ⁇ 1 °C, (e.g., about 25 °C).
  • step (v-2-4) comprises stirring the third mixture for about 16 ⁇ 5 hours, about 16 ⁇ 2 hours, about 16 ⁇ 1 hours, about 16 ⁇ 0.5 hours, about 16 ⁇ 0.2 hours, about 16 ⁇ 0.1 hours (e.g., about 16 hours).
  • step (v-2-5) further comprises washing the filtered third mixture with water.
  • step (v-2-6) comprises mixing the filtered third mixture with dimethyl sulfoxide (DMSO) at about 75 ⁇ 20 °C, about 75 ⁇ 15 °C, about 75 ⁇ 10 °C, about 75 ⁇ 5 °C, about 75 ⁇ 2 °C, about 75 ⁇ 1 °C, (e.g., about 75 °C).
  • DMSO dimethyl sulfoxide
  • step (v-2-8) comprises stirring the fifth mixture at about 75 ⁇ 20 °C, about 75 ⁇ 15 °C, about 75 ⁇ 10 °C, about 75 ⁇ 5 °C, about 75 ⁇ 2 °C, about 75 ⁇ 1 °C, (e.g., about 75 °C).
  • step (v-2-8) comprises stirring the fifth mixture for about 2 ⁇ 1 hours, about 2 ⁇ 0.5 hours, about 2 ⁇ 0.2 hours, about 2 ⁇ 0.1 hours (e.g., about 2 hours).
  • step (v-2-9) comprises adding water to the fifth mixture at about 75 ⁇ 20 °C, about 75 ⁇ 15 °C, about 75 ⁇ 10 °C, about 75 ⁇ 5 °C, about 75 ⁇ 2 °C, about 75 ⁇ 1 °C, (e.g., about 75 °C).
  • step (v-2-10) comprises cooling the sixth mixture at about about 25 ⁇ 10 °C, about 25 ⁇ 5 °C, about 25 ⁇ 2 °C, about 25 ⁇ 1 °C, (e.g., about 25 °C).
  • step (v-2-10) further comprises stirring the colled sixth mixture for about 2 ⁇ 1 hours, about 2 ⁇ 0.5 hours, about 2 ⁇ 0.2 hours, about 2 ⁇ 0.1 hours (e.g., about 2 hours).
  • step (v-2-11) further comprises washing the isolated compound of Formula (VII) or the salt thereof (e.g., Compound No. 7) with water.
  • step (v-2-11) further comprises drying the isolated compound of Formula (VII) or the salt thereof (e.g., Compound No. 7).
  • steps (v-1) and (v-2), taken together produces the compound of Formula (VII) or the salt thereof (e.g., Compound No. 7) with a yield of about 80% or higher, about 85% or higher, about 86% or higher, about 87% or higher, about 88% or higher, about 89% or higher, about 90% or higher, about 91% or higher, about 92% or higher, about 93% or higher, about 94% or higher, about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, or about 99% or higher.
  • a yield of about 80% or higher, about 85% or higher, about 86% or higher, about 87% or higher, about 88% or higher, about 89% or higher, about 90% or higher, about 91% or higher, about 92% or higher, about 93% or higher, about 94% or higher, about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, or about 99% or higher.
  • steps (v-1) and (v-2), taken together produces the compound of Formula (VII) or the salt thereof (e.g., Compound No. 7) with a purity of about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 99% or higher, about 99.1% or higher, about 99.2% or higher, about 99.3% or higher, about 99.4% or higher, about 99.5% or higher, about 99.6% or higher, about 99.7% or higher, about 99.8% or higher, or about 99.9% or higher.
  • steps (v-1) and (v-2), taken together, produces the compound of Formula (VII) or the salt thereof (e.g., Compound No. 7) with:
  • Step (b) a purity of about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 99% or higher, about 99.1% or higher, about 99.2% or higher, about 99.3% or higher, about 99.4% or higher, about 99.5% or higher, about 99.6% or higher, about 99.7% or higher, about 99.8% or higher, or about 99.9% or higher.
  • the chlorinating agent is thionyl chloride (SOCh).
  • step (i) comprises contacting Compound No. 1 or a salt thereof with the chlorinating agent (e.g., SOCh) in the presence of a catalyst.
  • the chlorinating agent e.g., SOCh
  • the catalyst is dimethylformamide (DMF).
  • step (i) comprises one or more of the following steps:
  • step (i-2) comprises heating the first mixture at a temperature ranging from about 70°C to about 95 °C.
  • step (i) further comprises:
  • step (i-3) is repeated for one or more times.
  • step (i) comprises detecting the presence of Compound No. 2.
  • step (i) does not comprise detecting the presence of Compound No. 2.
  • step (i) comprises isolating Compound No. 2.
  • step (i) does not comprise isolating Compound No. 2.
  • step (i) comprises purifying Compound No. 2.
  • step (i) does not comprise purifying Compound No. 2.
  • step (ii) comprises contacting Compound No. 2 or the salt thereof with Compound No. 2A or a salt thereof in the presence of a solvent.
  • the solvent comprises an organic solvent.
  • the solvent conmprises N-methyl-2-pyrrolidone (NMP), acetonitrile (MeCN), or a combination thereof.
  • step (ii) the solvent conmprises N-methyl-2-pyrrolidone (NMP).
  • step (ii) comprises one or more of the following steps:
  • step (ii-1) adding the mixture of step (i) to a first mixture comprising a compound of Formula (II-A) or a salt thereof (e.g., Compound No. 2A) and the solvent (e.g., NMP), thereby forming a second mixture; or
  • step (ii-1) comprises adding the mixture of step (i) to a first mixture comprising a compound of Formula (II-A) or a salt thereof (e.g., Compound No. 2A) and the solvent (e.g., NMP) at about 25 ⁇ 10 °C, about 25 ⁇ 5 °C, about 25 ⁇ 2 °C, about 25 ⁇ 1 °C, (e.g., about 25 °C).
  • a compound of Formula (II-A) or a salt thereof e.g., Compound No. 2A
  • the solvent e.g., NMP
  • step (ii-2) comprises stirring the second mixture for about 2 ⁇ 1 hours, about 2 ⁇ 0.5 hours, about 2 ⁇ 0.2 hours, about 2 ⁇ 0.1 hours (e.g., about 2 hours).
  • step (ii) further comprises one or more of the following steps:
  • the base is triethylamine (EtsN).
  • step (ii-3) comprises adding a solution of the base (e.g., EtsN) in water to the second mixture at a temperature below about 40 °C.
  • a solution of the base e.g., EtsN
  • step (ii-4) comprises stirring the third mixture at about 25 ⁇ 10 °C, about 25 ⁇ 5 °C, about 25 ⁇ 2 °C, about 25 ⁇ 1 °C, (e.g., about 25 °C).
  • step (ii-4) comprises stirring the third mixture overnight.
  • step (ii-5) further comprises washing the filtered third mixture with water and tetrahydrofuran (THF).
  • step (ii-6) comprises adding tetrahydrofuran (THF) to the filtered third mixture at about 45 ⁇ 10 °C, about 45 ⁇ 5 °C, about 45 ⁇ 2 °C, about 45 ⁇ 1 °C, (e.g., about 45 °C).
  • step (ii-7) further comprises washing the isolated compound of Formula (III) or a salt thereof (e.g., Compound No. 3).
  • step (ii-7) further comprises drying the isolated compound of Formula (III) or a salt thereof (e.g., Compound No. 3).
  • step (ii-7) further comprises drying the isolated compound of Formula (III) or a salt thereof (e.g., Compound No. 3) at a temperature below about 50 °C.
  • steps (i) and (ii), taken together produces the compound of Formula (III) or the salt thereof (e.g., Compound No. 3) with a yield of about 60% or higher, about 65% or higher, about 70% or higher, about 75% or higher, about 76% or higher, about 77% or higher, about 78% or higher, about 79% or higher, about 80% or higher, about 81% or higher, about 82% or higher, about 83% or higher, about 84% or higher, about 85% or higher, about 90% or higher, or about 95% or higher.
  • steps (i) and (ii), taken together produces the compound of Formula (III) or the salt thereof (e.g., Compound No. 3) with a purity of about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 99% or higher, about 99.1% or higher, about 99.2% or higher, about 99.3% or higher, about 99.4% or higher, about 99.5% or higher, about 99.6% or higher, about 99.7% or higher, about 99.8% or higher, or about 99.9% or higher.
  • steps (i) and (ii), taken together produces the compound of Formula (III) or the salt thereof (e.g., Compound No. 3) with:
  • the modifying agent in step (iii), is Compound No. 3 A: (Compound No. 3 A) or a salt thereof.
  • step (iii) contacting the compound of Formula (III) or the salt thereof (e.g., Compound No. 3) with the modifying agent (e.g., Compound No. 3A) in the presence of a base.
  • the compound of Formula (III) or the salt thereof e.g., Compound No. 3
  • the modifying agent e.g., Compound No. 3A
  • the base is a potassium salt.
  • the base is potassium tert-butoxide (t-BuOK).
  • the base e.g., t-BuOK
  • the compound of Formula (III) or the salt thereof e.g., Compound No. 3
  • the base e.g., t-BuOK
  • the compound of Formula (III) or the salt thereof e.g., Compound No. 3
  • step (iii) contacting the compound of Formula (III) or the salt thereof (e.g., Compound No. 3) with the modifying agent (e.g., Compound No. 3A) in the presence of a solvent.
  • the compound of Formula (III) or the salt thereof e.g., Compound No. 3
  • the modifying agent e.g., Compound No. 3A
  • the solvent comprises tetrahydrofuran (THF), dimethylformamide (DMF), or a combination thereof.
  • step (iii) comprises filtering the compound of Formula (IV) or the salt thereof (e.g., Compound No. 4) in the presence of acetic acid (AcOH), methanol (MeOH), or a combination thereof.
  • step (iii) comprises one or more of the following steps:
  • step (iii-2) adding the base (e.g., t-BuOK) to the first mixture at about 25 ⁇ 10 °C, about 25 ⁇ 5 °C, about 25 ⁇ 2 °C, about 25 ⁇ 1 °C, (e.g., about 25 °C).
  • base e.g., t-BuOK
  • step (iii-3) comprises stirring the second mixture for about 2 ⁇ 1 hours, about 2 ⁇ 0.5 hours, about 2 ⁇ 0.2 hours, about 2 ⁇ 0.1 hours (e.g., about 2 hours). [0126] In some embodiments, step (iii) further comprises one or more of the following steps:
  • step (iii-4) the acid is acetic acid (AcOH).
  • step (iii-6) comprises stirring the fourth mixture at about 10 ⁇ 5 °C, about 10 ⁇ 2 °C, about 10 ⁇ l °C, (e.g., about 10 °C).
  • step (iii-6) comprises stirring the fourth mixture for about 16 ⁇ 5 hours, about 16 ⁇ 2 hours, about 16 ⁇ 1 hours, about 16 ⁇ 0.5 hours, about 16 ⁇ 0.2 hours, about 16 ⁇ 0.1 hours (e.g., about 16 hours).
  • step (iii-7) further comprises washing the isolated compound of Formula (IV) or the salt thereof (e.g., Compound No. 4) with methanol.
  • step (iii-7) further comprises drying the isolated compound of Formula (IV) or the salt thereof (e.g., Compound No. 4).
  • step (iii-7) further comprises drying the isolated compound of Formula (IV) or the salt thereof (e.g., Compound No. 4) at about 50 ⁇ 10 °C, about 50 ⁇ 5 °C, about 50 ⁇ 2 °C, about 50 ⁇ l °C, (e.g., about 50 °C).
  • step (iii) produces the compound of Formula (IV) or the salt thereof (e.g., Compound No. 4) with a yield of about 60% or higher, about 65% or higher, about 70% or higher, about 75% or higher, about 80% or higher, about 85% or higher, about 86 or higher, about 87 or higher, about 88 or higher, about 89 or higher, about 90% or higher, about 91 or higher, about 92 or higher, about 93 or higher, about 94 or higher, or about 95% or higher.
  • step (iii) produces the compound of Formula (IV) or the salt thereof (e.g., Compound No. 4) with a purity of about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 99% or higher, about 99.1% or higher, about 99.2% or higher, about 99.3% or higher, about 99.4% or higher, about 99.5% or higher, about 99.6% or higher, about 99.7% or higher, about 99.8% or higher, or about 99.9% or higher.
  • step (iii) produces the compound of Formula (IV) or the salt thereof (e.g., Compound No. 4) with:
  • the hydrogenating agent is hydrogen (H2).
  • step (iv) comprises contacting the compound of formula (IV) or the salt thereof (e.g., Compound No. 4) with the hydrogenating agent in the presence of a catalyst.
  • the catalyst comprises platinum.
  • the catalyst in step (iv), is a platinum and vanadium on carbon (Pt/V/C).
  • step (iv) comprises contacting the compound of formula (IV) or the salt thereof (e.g., Compound No. 4) with the hydrogenating agent in the presence of the catalyst under a condition substantially free of oxygen.
  • step (iv) comprises contacting the compound of formula (IV) or the salt thereof (e.g., Compound No. 4) with the hydrogenating agent in the presence of a solvent.
  • the solvent comprises an organic solvent.
  • the solvent comprises tetrahydrofuran (THF), methanol (MeOH), or a combination thereof.
  • the catalyst e.g., Pt/V/C
  • the catalyst is present at a loading of about 18% or less, about 17% or less, about 16% or less, about 15% or less, about 14% or less, about 13% or less, about 12% or less, about 11% or less, about 10% or less, about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less (e.g., about 5%).
  • step (iv) comprises one or more of the following steps:
  • the hydrogen (H2) is present at a pressure of about 70 ⁇ 30 psi, about 70 ⁇ 20 psi, about 70 ⁇ 15 psi, about 70 ⁇ 10 psi, about 70 ⁇ 9 psi, about 70 ⁇ 8 psi, about 70 ⁇ 7 psi, about 70 ⁇ 6 psi, about 70 ⁇ 5 psi, about 70 ⁇ 4 psi, about 70 ⁇ 3 psi, about 70 ⁇ 2 psi, or about 70 ⁇ l psi (e.g., about 70 psi).
  • step (iv-2) comprises stirring the first mixture in the presence of hydrogen (H2) at about 50 ⁇ 10 °C, about 50 ⁇ 5 °C, about 50 ⁇ 2 °C, about 50 ⁇ l °C, (e.g., about 50 °C).
  • step (iv-2) comprises stirring the first mixture in the presence of hydrogen (H2) for about 24 ⁇ 5 hours, about 24 ⁇ 2 hours, about 24 ⁇ 1 hours, about 24 ⁇ 0.5 hours, about 24 ⁇ 0.2 hours, about 24 ⁇ 0.1 hours (e.g., about 24 hours).
  • step (iv) further comprises one or more of the following steps:
  • step (iv-4) the filtering removes at least a portion of the catalyst.
  • step (iv-4) further comprises washing the filtered cake with tetrahydrofuran (THF) and water, and collecting the filtrate from the washing.
  • THF tetrahydrofuran
  • step (iv-4) further comprises washing the filtered cake with water, and collecting the filtrate from the washing.
  • step (iv-6) comprises stirring the concentrated second mixture at about 20 ⁇ 10 °C, about 20 ⁇ 5 °C, about 20 ⁇ 2 °C, about 20 ⁇ l °C, (e.g., about 20 °C).
  • step (iv-6) comprises stirring the concentrated second mixture for about 3 ⁇ 1 hours, about 3 ⁇ 0.5 hours, about 3 ⁇ 0.2 hours, about 3 ⁇ 0.1 hours (e.g., about 3 hours).
  • step (iv-7) further comprises washing the isolated compound of formula (V) or the salt thereof (e.g., Compound No. 5) with water.
  • step (iv-7) further comprises drying the isolated compound of formula (V) or the salt thereof (e.g., Compound No. 5).
  • step (iv-7) further comprises drying the isolated compound of formula (V) or the salt thereof (e.g., Compound No. 5) at about 50 ⁇ 10 °C, about 50 ⁇ 5 °C, about 50 ⁇ 2 °C, about 50 ⁇ l °C, (e.g., about 50 °C).
  • step (iv-7) further comprises drying the isolated compound of formula (V) or the salt thereof (e.g., Compound No. 5) at about 50 ⁇ 10 °C, about 50 ⁇ 5 °C, about 50 ⁇ 2 °C, about 50 ⁇ l °C, (e.g., about 50 °C).
  • step (iv) produces the compound of Formula (V) or the salt thereof (e.g., Compound No. 5) with a yield of about 60% or higher, about 65% or higher, about 70% or higher, about 75% or higher, about 80% or higher, about 85% or higher, about 86 or higher, about 87 or higher, about 88 or higher, about 89 or higher, about 90% or higher, about 91 or higher, about 92 or higher, about 93 or higher, about 94 or higher, or about 95% or higher.
  • step (iv) produces the compound of Formula (V) or the salt thereof (e.g., Compound No. 5) with a purity of about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 99% or higher, about 99.1% or higher, about 99.2% or higher, about 99.3% or higher, about 99.4% or higher, about 99.5% or higher, about 99.6% or higher, about 99.7% or higher, about 99.8% or higher, or about 99.9% or higher.
  • Compound No. 5 Compound No. 5
  • step (iv) produces the compound of Formula (V) or the salt thereof (e.g., Compound No. 5) with a purity of about 95% or higher, about 96% or higher, about 97% or higher, about 98% or higher, about 99% or higher, about 99.1% or higher, about 99.2% or higher, about 99.3% or higher, about 99.4% or higher, about 99.5% or higher, about 99.6% or higher, about 99.7% or higher
  • step (iv) produces the compound of Formula (V) or the salt thereof (e.g., Compound No. 5) with:
  • Y is -Y2-L-Z
  • L is absent, C1-C4 alkyl
  • Z is -(NR 4 R 5 ), wherein R 4 and R 5 each are independently H, Ci-Ce alkyl, cyclopropyl, cylobutyl, 3 to 6-membered heterocycloalkyl; or Z is -(NR 6 R 7 ), or -(CHR 6 R 7 ), wherein R 6 and R 7 , together with the atom to which they are attached to, form 3 to 6-membered heteroaryl or 3 to 9-membered heterocycloalkyl, wherein the 3 to 9-membered heterocycloalkyl optionally substituted with one or more C1-C4 alkyl, halogen, -OR’, or -NR’R”, wherein R’ and R” each are independently H or C1-C4 alkyl;
  • L 1 is absent or C1-C3 alkyl optionally substituted with one or more halogen
  • Ar is Ce aryl or 6-membered heteroaryl, wherein the Ce aryl or 6-membered heteroaryl is optionally substituted with one or more halogen, Ci-Ce alkyl, Ci-Ce alkoxy, -CF3, or -OCF3.
  • the compound of Formula (VII) or the salt thereof is a compound described in PCT Appl’n Pub. No. WO/2020/068873 (incorporated by referenced).
  • Y is -Y2-L-Z
  • L is absent, C1-C4 alkyl, , , or
  • Z is -(NR 4 R 5 ), wherein R 4 and R 5 each are independently H, Ci-Ce alkyl, cyclopropyl, cylobutyl, 3 to 6-membered heterocycloalkyl; or Z is -(NR 6 R 7 ), or -(CHR 6 R 7 ), wherein R 6 and R 7 , together with the atom to which they are attached to, form 3 to 6-membered heteroaryl or 3 to 9-membered heterocycloalkyl, wherein the 3 to 9-membered heterocycloalkyl optionally substituted with one or more C1-C4 alkyl, halogen, -OR’, or -NR’R”, wherein R’ and R” each are independently H or C1-C4 alkyl;
  • Ar 1 is Ce aryl or 6-membered heteroaryl, wherein the Ce aryl or 6-membered heteroaryl is optionally substituted with one or more halogen, Ci-Ce alkyl, or Ci-Ce alkoxy;
  • X 1 is -O-, -CH2-, -NH-, or -S-;
  • L 1 is absent or Ci-Ce alkyl optionally substituted with one or more halogen
  • Ar 2 is Ce aryl or 6-membered heteroaryl, wherein the Ce aryl or 6-membered heteroaryl is optionally substituted with one or more halogen, Ci-Ce alkyl, Ci-Ce alkoxy, -CF3, or -OCF3.
  • Y 2 is -O-.
  • L is C1-C4 alkyl.
  • L is ethyl
  • Z is -(NR 6 R 7 ), wherein R 6 and R 7 , together with the atom to which they are attached to, form 3 to 9-membered heterocycloalkyl.
  • Z is morpholinyl
  • Ar 1 is Ce aryl optionally substituted with one or more halogen.
  • Ar 1 is phenyl optionally substituted with one or more Cl.
  • X 1 is -O-.
  • L 1 is Ci-Ce alkyl.
  • L 1 is methyl
  • Ar 2 is 6-membered heteroaryl.
  • Ar 2 is pyridinyl
  • Y is -Y2-L-Z
  • Y 2 is -O-
  • L is C1-C4 alkyl (e.g., L is ethyl);
  • Z is -(NR 6 R 7 ), wherein R 6 and R 7 , together with the atom to which they are attached to, form 3 to 9-membered heterocycloalkyl;
  • Ar 1 is Ce aryl optionally substituted with one or more halogen
  • X 1 is -O-
  • L 1 is Ci-Ce alkyl (e.g., L 1 is methyl);
  • Ar 2 is 6-membered heteroaryl (e.g., pyridinyl).
  • the compound of Formula (VII) or the salt thereof is Compound No. 7 or a salt thereof.
  • the compound of Formula (VII) or the salt thereof is a compound described in PCT Appl’n Pub. No. WO/2020/068867 (incorporated by referenced).
  • Y is z ;
  • Z is 3- to 12-membered heterocycloalkyl optionally substituted with one or more R z ; each R z independently is halogen, CN, -OH, -NH2, -O-(Ci-Ce alkyl), -NH(Ci-Ce alkyl), - N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, Ce-Cio aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the -O-(Ci-Ce alkyl), - NH(Ci-Ce alkyl), -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, Ce-Cio aryl,
  • X is Ce-Cio aryl optionally substituted with one or more R A1 ; each R A1 independently is halogen, CN, -OH, -NH2, -OR Ala , -O-(Ci-Ce alkyl), -NH(Ci- Ce alkyl), -N(Ci-Ce alkyl)2, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, Ce-Cio aryl, 3- to 10-membered heterocycloalkyl, or 5- to 10-membered heteroaryl; wherein the -O-(Ci- C 6 alkyl), -NH(CI-C 6 alkyl), -N(CI-C 6 alkyl) 2 , Ci-C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, Ce-Cio ary
  • the compound of Formula (VII) or the salt thereof is a compound described in PCT Appl’n No. PCT/US2020/046425 (incorporated by referenced).
  • the combination further comprises an acid (e.g., MsOH).
  • an acid e.g., MsOH.
  • the present disclosure provides a combination comprising a compound of Formula (VI) or a salt thereof (e.g., Compound No. 6) and a base (e.g., DIPEA).
  • a compound of Formula (VI) or a salt thereof e.g., Compound No. 6
  • a base e.g., DIPEA
  • the present disclosure provides a combination comprising Compound No. 2 or a salt thereof, a compound of Formula (II-A) or a salt thereof (e.g., Compound No. 2A), and a solvent (e.g., NMP).
  • a solvent e.g., NMP
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound described herein and one or more pharmaceutically acceptable carriers or excipients.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound being prepared by a method described herein (e.g., Compound No. 7) and one or more pharmaceutically acceptable carriers or excipients.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions.
  • the compounds of present disclosure can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.
  • the formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle.
  • the aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient.
  • Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity/suspending agent, buffer, and pH modifying agent, and a mixture thereof.
  • any suitable solubility enhancing agent can be used.
  • a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-P- cyclodextrin, methyl-P-cyclodextrin, randomly methylated-P-cyclodextrin, ethylated-P- cyclodextrin, triacetyl-P-cyclodextrin, peracetylated-P-cyclodextrin, carboxymethyl-P- cyclodextrin, hydroxyethyl-P-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-P- cyclodextrin, glucosyl-P-cyclodextrin, sulfated P-cyclodextrin (S-P-CD), maltosyl-P- cyclodextrin, P-cyclodextrin sulfobuty
  • Any suitable chelating agent can be used.
  • a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.
  • any suitable preservative can be used.
  • a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.
  • quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine
  • the aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure).
  • the tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.
  • the aqueous vehicle may also contain a viscosity/suspending agent.
  • Suitable viscosity/suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.
  • the formulation may contain a pH modifying agent.
  • the pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid.
  • the aqueous vehicle may also contain a buffering agent to stabilise the pH.
  • the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and s-aminocaproic acid, and mixtures thereof.
  • the formulation may further comprise a wetting agent.
  • wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.
  • Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier.
  • compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavouring agent such as peppermint, methyl salicylate, orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent
  • a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.
  • compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or
  • compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended foral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent an inflammasome related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat an inflammasome related condition referred to herein, slow its progression and/or reduce the symptoms associated with the condition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
  • the present disclosure is directed to a method of inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR), comprising administering the subject in need thereof a therapeutically effective amount of a compound being prepared by a method described herein.
  • an oncogenic variant of an ErbB receptor e.g., an oncogenic variant of an EGFR
  • the present disclosure is directed to a method of preventing or treating cancer, comprising administering the subject in need thereof a therapeutically effective amount of a compound being prepared by a method described herein.
  • the present disclosure is directed to a compound being prepared by a method described herein for use in the inhibition of an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR).
  • an oncogenic variant of an ErbB receptor e.g., an oncogenic variant of an EGFR
  • the present disclosure is directed to a compound being prepared by a method described herein for use in the prevention or treatment of cancer.
  • the present disclosure is directed to use of a compound being prepared by a method described in the manufacture of a medicament for inhibiting an oncogenic variant of an ErbB receptor (e.g., an oncogenic variant of an EGFR).
  • an oncogenic variant of an ErbB receptor e.g., an oncogenic variant of an EGFR
  • cancer is a solid tumor.
  • the cancer is a bladder cancer, a breast cancer, a cervical cancer, a colorectal cancer, an endometrial cancer, a gastric cancer, a glioblastoma (GBM), a head and neck cancer, a lung cancer, a non-small cell lung cancer (NSCLC), or any subtype thereof.
  • the cancer is glioblastoma (GBM) or any subtype thereof.
  • the cancer is glioblastoma.
  • the cancer expresses an oncogenic variant of an epidermal growth factor receptor (EGFR)
  • EGFR epidermal growth factor receptor
  • the oncogenic variant of an EGFR is an allosteric variant of EGFR.
  • the oncogenic variant of an EGFR is an allosteric variant of EGFR.
  • the oncogenic variant of an EGFR comprises an EGFR variant III (EGFR-Viii) mutation.
  • the oncogenic variant of an EGFR is an allosteric variant of EGFR
  • the oncogenic variant of an EGFR comprises EGFR-Vii, EGFR-Vvi, EGFR-R222C, EGFR-R252C, EGFR-R252P, EGFR-R256Y, EGFR-T263P, EGFR-Y270C, EGFR-A289T, EGFR-A289V, EGFR-A289D, EGFR-H304Y, EGFR-G331R, EGFR-P596S, EGFR-P596L, EGFR-P596R, EGFR-G598V, EGFR-G598A, EGFR-G614D, EGFR-C620Y, EGFR-C614W, EGFR-C628F, EGFR-C628Y, EGFR-C636Y, EGFR-G
  • the cancer expresses one or more of: (a) a wild type human epidermal growth factor receptor 2 (HER2) receptor or (b) an oncogenic variant of a HER-2 receptor.
  • HER2 human epidermal growth factor receptor 2
  • the oncogenic variant of the HER-2 receptor is an allosteric variant of the HER-2 receptor.
  • the oncogenic variant of a HER2 receptor comprises HER2-A16, HER2-C311R, HER2-S310F, p95-HER2-M611 or any combination thereof.
  • the oncogenic variant of the HER-4 receptor is an allosteric variant of the HER4 receptor.
  • the oncogenic variant of a HER4 receptor comprises deletion of exon 16 (HER4-A16).
  • the term “about” refers to a range covering any normal fluctuations appreciated by one of ordinary skill in the relevant art. In some embodiments, the term “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).
  • the term “contact” or “contacting” refers an action causing two or more reactants to be in a proximity, e.g., such that the two or more reactants chemically react. In some embodiments, the contacting comprising mixing the two or more reactants. In some embodiments, the contacting is under a reaction condition suitable for forming the desired reaction product from the two or more reactants.
  • alkyl As used herein, “alkyl”, “Ci, C 2 , C 3 , C 4 , C 5 or C 6 alkyl” or “Ci-C 6 alkyl” is intended to include Ci, C 2 , C3, C 4 , C5 or Ce straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C 4 , C5 or Ce branched saturated aliphatic hydrocarbon groups.
  • Ci-C 6 alkyl is intended to include Ci, C2, C3, C 4 , C5 or Ce alkyl groups.
  • alkyl examples include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl or n-hexyl.
  • a straight chain or branched alkyl has six or fewer carbon atoms e.g., Ci-Ce for straight chain, C3- Ce for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.
  • cycloalkyl refers to a saturated or unsaturated nonaromatic hydrocarbon mono- or multi-ring (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-Cs).
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl.
  • heterocycloalkyl refers to a saturated or unsaturated nonaromatic 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g. t 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, unless specified otherwise.
  • heteroatoms such as O, N, S, P, or Se
  • heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2- oxa-5-azabicyclo[2.2.
  • aryl includes groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure.
  • aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In some embodiments, an aryl is phenyl.
  • heteroaryl is intended to include a stable 5-, 6-, or 7- membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g. , 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur.
  • the nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined).
  • heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.
  • aryl and heteroaryl include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodi oxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.
  • the term “subject” is interchangeable with the term “subject in need thereof,” both of which refer to a subject having a disease or having an increased risk of developing the disease.
  • a “subject” includes a mammal.
  • the mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig.
  • the subject can also be a bird or fowl.
  • the mammal is a human.
  • treating describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder.
  • the term “treat” can also include treatment of a cell in vitro or an animal model.
  • preventing or “prevent” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder.
  • the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a formulation that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
  • salt or “pharmaceutically acceptable salt” refers to a derivative of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric,
  • salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l -carboxylic acid, 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like.
  • the present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • the ratio of the compound to the cation or anion of the salt can be 1 : 1, or any ratio other than 1 : 1, e.g., 3: 1, 2: 1, 1 :2, or 1 :3.
  • all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs
  • the mixture was divided into two portions (2/5 and 3/5). [0247] For the 3/5 portion, water (2.7 L) was added to the reaction mixture. The resulting surry was stirred at ⁇ 25 °C for 16 h and filtered. The filter cake was washed with water (720 mL). The filter cake was dissolved in DMSO (1820 mL) at ⁇ 75 °C. To the solution water (223 mL) was added. The mixture was stirred at ⁇ 75 °C for 2 h at which time solid formed. Additional water (1333 mL) was added slowly at ⁇ 75 °C. The mixture was slowly cooled to ⁇ 25 °C and then stirred for 2h and fitered.

Abstract

La présente divulgation concerne des procédés de préparation de composés de formule (VII) et de sels de ceux-ci, et concerne des composés et des combinaisons utiles pour la préparation. La présente divulgation concerne également des composés préparés au moyen des procédés et leurs utilisations.
PCT/US2021/046606 2020-08-20 2021-08-19 Procédés de préparation de dérivés de quinazoline WO2022040377A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063068192P 2020-08-20 2020-08-20
US63/068,192 2020-08-20

Publications (1)

Publication Number Publication Date
WO2022040377A1 true WO2022040377A1 (fr) 2022-02-24

Family

ID=77711476

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2021/046606 WO2022040377A1 (fr) 2020-08-20 2021-08-19 Procédés de préparation de dérivés de quinazoline

Country Status (1)

Country Link
WO (1) WO2022040377A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008020711A1 (fr) * 2006-08-16 2008-02-21 Chong Kun Dang Pharmaceutical Corp. Dérivé de quinazoline comme inhibiteur de phosphodiesterase et procédé d'élaboration correspondant
WO2020068873A1 (fr) 2018-09-25 2020-04-02 Black Diamond Therapeutics, Inc. Compositions d'inhibiteur de tyrosine kinase, procédés de fabrication et procédés d'utilisation
WO2020068867A1 (fr) 2018-09-25 2020-04-02 Black Diamond Therapeutics, Inc. Dérivés de quinazoline utilisés en tant qu'inhibiteur de tyrosine kinase, compositions, leurs procédés de préparation et leur utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008020711A1 (fr) * 2006-08-16 2008-02-21 Chong Kun Dang Pharmaceutical Corp. Dérivé de quinazoline comme inhibiteur de phosphodiesterase et procédé d'élaboration correspondant
WO2020068873A1 (fr) 2018-09-25 2020-04-02 Black Diamond Therapeutics, Inc. Compositions d'inhibiteur de tyrosine kinase, procédés de fabrication et procédés d'utilisation
WO2020068867A1 (fr) 2018-09-25 2020-04-02 Black Diamond Therapeutics, Inc. Dérivés de quinazoline utilisés en tant qu'inhibiteur de tyrosine kinase, compositions, leurs procédés de préparation et leur utilisation

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CARMI CATERINA ET AL: "S1 Supporting Information Irreversible Inhibition of the Epidermal Growth Factor Receptor by 3-Aminopropanamides", J. MED. CHEM. 2012, 55, 5, SUPPLEMENTARY INFORMATION, 26 January 2012 (2012-01-26), pages S1 - S11, XP055851669, Retrieved from the Internet <URL:https://pubs.acs.org/doi/10.1021/jm201507x#> [retrieved on 20211015] *
CATERINA CARMI ET AL: "Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 5, 17 February 2012 (2012-02-17), US, pages 2251 - 2264, XP055623654, ISSN: 0022-2623, DOI: 10.1021/jm201507x *
YIN DONGSHENG M ET AL: "Supporting Information Studying the Conformation of a Receptor Tyrosine Kinase in Solution by Inhibitor-Based Spin Labeling", ANGEWANDTE CHEMIE INT ED, 2017, 56, 8417-8421, 1 January 2017 (2017-01-01), pages 1 - 24, XP055851114, Retrieved from the Internet <URL:https://onlinelibrary.wiley.com/doi/epdf/10.1002/anie.201703154> [retrieved on 20211013] *
YIN DONGSHENG M. ET AL: "Studying the Conformation of a Receptor Tyrosine Kinase in Solution by Inhibitor-Based Spin Labeling", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, vol. 56, no. 29, 19 June 2017 (2017-06-19), DE, pages 8417 - 8421, XP055851111, ISSN: 1433-7851, Retrieved from the Internet <URL:https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1002%2Fanie.201703154> DOI: 10.1002/anie.201703154 *

Similar Documents

Publication Publication Date Title
AU2021201784B2 (en) Plinabulin compositions
JP7291243B2 (ja) Ｒｅｔ阻害剤としてのピラゾロピリジン系化合物及びその使用
ES2746207T3 (es) Derivado cristalino de 6,7-insaturado-7-carbamoilmorfinano y método de producción del mismo
US7148231B2 (en) [6,7-Bis(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)amine hydrochloride polymorph
AU2013271768A1 (en) Solid forms of an antiviral compound
KR20100137517A (ko) 4-아미노-5-플루오로-3-[5-(4-메틸피페라진-1-일)-1ｈ-벤즈이미다졸-2-일]퀴놀린-2(1ｈ)-온 락트산 염의 결정질 형태 및 2가지 용매화물 형태
WO2017167180A1 (fr) Sel d&#39;acide pamoïque de vortioxétine et sa forme cristalline
US10550101B2 (en) Crystalline forms of mesylate salt of pyridinyl amino pyrimidine derivative, preparation methods therefor, and applications thereof
US20210040103A1 (en) Gabaa positive allosteric modulator compounds, methods of making, and uses thereof
JP2014040426A (ja) ［５−（４，６−ジメチル−１ｈ−ベンゾイミダゾール−２−イル）−４−メチル−ピリミジン−２−イル］−［３−（１−メチル−ピペリジン−４−イル）−プロピル］−アミンの結晶性ヘミタートレート
AU2013301156B2 (en) Process for the preparation of pemetrexed and lysin salt thereof
KR20220097388A (ko) 헤테로시클릭 아미드계 화합물, 이의 약학적으로 허용 가능한 염 및 이의 제조 방법 및 용도
KR20240056531A (ko) 염소화된 테트랄린 화합물 및 약제학적 조성물
WO2022117111A1 (fr) Sel de composé pyrrolopyrimidine, forme cristalline de celui-ci et utilisation associée
US10654876B2 (en) TH-302 solid forms and methods related thereto
WO2022040377A1 (fr) Procédés de préparation de dérivés de quinazoline
US9006253B2 (en) Crystal of 2-(3,4-dichlorobenzyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-D]pyrimidine-6-carboxylic acid
JP2021505596A (ja) フェニルプロピオンアミド誘導体の塩およびその製造方法
EP3398946A1 (fr) Sel de dérivé de morpholine et sa forme cristalline, et procédé de préparation, composition pharmaceutique et utilisation de ce dernier
CN113816965B (zh) 一种具有ido抑制活性的化合物及其制备方法
KR20210040228A (ko) 항히스타민 화합물, 이들의 약학 조성물 및 의약 용도
RU2020140818A (ru) Фармацевтические соли производных пиримидина и способ лечения заболеваний
JP2023528394A (ja) 大環状ｊａｋ阻害剤およびその適用
WO2020027723A1 (fr) Composés bicycliques utilisés en tant que modulateurs de kinase, procédés et utilisations de ceux-ci
KR20110101488A (ko) 올란자핀 지나포에이트염 및 이의 용도

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21769278

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21769278

Country of ref document: EP

Kind code of ref document: A1