[go: up one dir, main page]

WO2024227104A1 - Composés bifonctionnels pour dégrader le braf par l'intermédiaire d'une voie ubiquitine-protéosome - Google Patents

Composés bifonctionnels pour dégrader le braf par l'intermédiaire d'une voie ubiquitine-protéosome Download PDF

Info

Publication number
WO2024227104A1
WO2024227104A1 PCT/US2024/026679 US2024026679W WO2024227104A1 WO 2024227104 A1 WO2024227104 A1 WO 2024227104A1 US 2024026679 W US2024026679 W US 2024026679W WO 2024227104 A1 WO2024227104 A1 WO 2024227104A1
Authority
WO
WIPO (PCT)
Prior art keywords
fluorophenyl
piperidin
sulfonamide
pyridin
dioxopiperidin
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
PCT/US2024/026679
Other languages
English (en)
Inventor
Ge Peng
Jeffrey Wu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nurix Therapeutics Inc
Original Assignee
Nurix 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 Nurix Therapeutics Inc filed Critical Nurix Therapeutics Inc
Priority to AU2024260700A priority Critical patent/AU2024260700A1/en
Publication of WO2024227104A1 publication Critical patent/WO2024227104A1/fr
Priority to IL323616A priority patent/IL323616A/en
Priority to MX2025012819A priority patent/MX2025012819A/es
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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
    • C07D401/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • a compound of Formula (I) (I) wherein R 1 is alkyl, aryl, amino, alkylamino, dialkylamino, cycloalkyl, or heterocycloalkyl, each unsubstituted or substituted with one or more halogen or hydroxyl; R 1a is halogen; R 1b is hydrogen, haloalkyl, or halogen; R 2 is hydrogen, alkyl, cycloalkyl, haloalkyl, or -[Ar 1 -Z 1 ]n-Z 2 -Cy 1 -Z 3 -L-UBM; X 1 is carbon or nitrogen; X 2 is carbon or nitrogen; X 3 is sulfur, nitrogen, oxygen, or carbon; the bonds among X 1 , X 2 , and X 3 comprise single and double bonds, and the ring containing X 1 , X 2 , and X 3 is aromatic; X 4 is carbon or nitrogen; X 5 is hydrogen or -
  • R 1 is alkyl, aryl, amino, alkylamino, dialkylamino, cycloalkyl, or heterocycloalkyl, each unsubstituted or substituted with one or more halogen or hydroxyl;
  • R 1a is halogen;
  • R 1b is hydrogen or halogen;
  • R 2 is hydrogen, alkyl, cycloalkyl, haloalkyl, or -[Ar 1 -Z 1 ]n-Z 2 -Cy 1 -Z 3 -L-UBM;
  • X 1 is carbon or nitrogen;
  • X 2 is carbon or nitrogen;
  • X 3 is sulfur, nitrogen, oxygen, or carbon; the bonds among X 1 , X 2 , and X 3 comprise single and double bonds, and the ring containing X 1 , X 2 , and X 3 is aromatic;
  • X 4 is carbon or nitrogen;
  • X 5 is hydrogen or -NR 3 R 4 ;
  • R 3 is
  • R 1 is alkyl; R 1a is fluoro; R 2 is -[Ar 1 -Z 1 ] n -Z 2 -Cy 1 -Z 3 -L-UBM; Ar 1 is ; Z 1 is a bond; n is one; Z 2 and Z 3 are absent; and Cy 1 is an unsubstituted heterocycloalkylene.
  • X 4 is carbon and X 5 is hydrogen.
  • L 1 is -C(R 11 )2-.
  • R 11 hydrogen.
  • the compound of claim 15 wherein L 2 is Q 1 ; and L 3 and L 4 are absent. 17.
  • L 2 is absent, Q 1 , Q 2 , -C(R 11 ) 2 -, -C(O)-, or -O-.
  • L 3 is absent, Q 1 , or -CH2CH2CH2-; and L 4 is absent.
  • R 1 is -CH 2 CH 2 CH 3 .
  • UBM binds an E3 ubiquitin ligase.
  • UBM binds SCF ⁇ -TRCP, VHL, MDM2, IAP, or CRBN.
  • UBM binds VHL. 28.
  • UBM binds VHL and has the following chemical formula wherein designates attachment to L;
  • Z 4 is a bond, -CH 2 -, -C(O)-, -C(O)N(R 12 )-, or -N(R 12 )-, wherein R 12 is hydrogen or methyl;
  • X 6 is C-H or nitrogen;
  • R 8 is alkyl, alkenyl, alkylene, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - S(O)(R 13 ), or -S(O) 2 (R 13 ); wherein R 13 is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, aryl, heterocycle, or heteroaryl, wherein each alkyl, alkenyl, alkylene, alkynyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl is unsubstituted or substituted
  • UBM binds VHL and has the following chemical formula wherein designates attachment to L;
  • Z 5 is a bond, -CH2-, -C(O)-, -C(O)N(R 12 )-, -N(R 12 )-, or -O-, wherein R 12 is hydrogen or methyl;
  • A is phenyl or C 4 -heteroaryl;
  • X 7 is -CH 2 , -NR 12 , oxygen, or sulfur, wherein R 12 is hydrogen or methyl;
  • p is zero or one;
  • R 15 is unsubstituted or substituted C1-8 alkyl, -AA 1 -AA 2 -R 14 , wherein each AA 1 and AA 2 is an amino acid residue, and R 14 is hydrogen or methyl.
  • UBM binds VHL and has the following chemical formula wherein designates attachment to L;
  • Z 6 is a bond, -CH2-, -C(O)-, -C(O)N(R 12 )-, or N(R 12 ), wherein R 12 is hydrogen or methyl;
  • W is , , or wherein, designates attachment to X 8 , wherein designates attachment to X 9 , and wherein, designates attachment to Z 6 ;
  • X 8 is carbon or nitrogen;
  • X 9 is C–H or -CH2-;
  • R 16 is hydrogen, –OH, halogen, –NH2, -C1-3 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C1-3 alkoxy, -C 1 - 3 thioalkyl, -C 1 - 3 alkylamine, -C 6 - 10 aryl, cycloalkyl, heterocycloalkyl, or heteroaryl
  • UBM binds CRBN.
  • UBM binds CRBN and has the following chemical formula or wherein X 6 absent or NR 3 ; X 7 absent or -C(O)-; and X 8 is arylene or heteroarylene.
  • UBM binds CRBN and is selected from the group consisting of , , , , , , , , , , and wherein X 9 is absent or halogen; and m is one, two, three, or four. 34.
  • a compound of Formula (II) (II) wherein R 1 is alkyl, aryl, amino, alkylamino, dialkylamino, cycloalkyl, or heterocycloalkyl, each unsubstituted or substituted with one or more halogen or hydroxyl; R 1a is halogen; R 1b is hydrogen or halogen; R 2 is -[Ar 1 -Z 1 ]n-Z 2 -Cy 1 -Z 3 -L-UBM wherein Ar 1 is arylene or heteroarylene, each unsubstituted or substituted with one or more alkyl or one or more halogen; Z 1 is a bond or -CH2-; n is zero or one; Z 2 is absent, -C(O)-, -O-, C 1-10 alkylene, C 1-10 alkylene-C(Me)(Me)-, three- to six-membered cycloalkylene, three- to six-membered cyclo
  • UBM binds VHL and has the following chemical formula wherein designates attachment to L;
  • Z 4 is a bond, -CH2-, -C(O)-, -C(O)N(R 12 )-, or -N(R 12 )-, wherein R 12 is hydrogen or methyl;
  • X 6 is C-H or nitrogen;
  • R 8 is alkyl, alkenyl, alkylene, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, - S(O)(R 13 ), or -S(O)2(R 13 ); wherein R 13 is hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, aryl, heterocycle, or heteroaryl, wherein each alkyl, alkenyl, alkylene, alkynyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl is unsubstituted or substituted;
  • UBM binds VHL and has the following chemical formula wherein designates attachment to L;
  • Z 5 is a bond, -CH2-, -C(O)-, -C(O)N(R 12 )-, -N(R 12 )-, or -O-, wherein R 12 is hydrogen or methyl;
  • A is phenyl or C4-heteroaryl;
  • X 7 is -CH2, -NR 12 , oxygen, or sulfur, wherein R 12 is hydrogen or methyl;
  • p is zero or one;
  • R 15 is unsubstituted or substituted C1-8 alkyl, -AA 1 -AA 2 -R 14 , wherein each AA 1 and AA 2 is an amino acid residue, and R 14 is hydrogen or methyl.
  • UBM binds VHL and has the following chemical formula wherein designates attachment to L;
  • Z 6 is a bond, -CH 2- , -C(O)-, -C(O)N(R 12 )-, or N(R 12 ), wherein R 12 is hydrogen or methyl;
  • W is , , or wherein, designates attachment to X 8 , wherein designates attachment to X 9 , and wherein, designates attachment to Z 6 ;
  • X 8 is carbon or nitrogen;
  • X 9 is C–H or -CH2-;
  • R 16 is hydrogen, –OH, halogen, –NH 2 , -C 1 - 3 alkyl, -C 2 - 6 alkenyl, -C 2 - 6 alkynyl, -C 1 - 3 alkoxy, -C1-3 thioalkyl, -C1-3 alkylamine, -C6-10 aryl, cycloalkyl, heterocycloalkyl
  • L comprises at least one -Q 1 -; at least one -Q 2 -; at least one -Q 3 -; at least one -C(R 11 )2-; or at least one C1-8 alkylene-.
  • L is selected from the group consisting of a. -Q 1 -; b. -Q 1 -C(O)-Q 1 -; c. -C(R 11 ) 2 -Q 1 -; d. -Q 1 -C(R 11 ) 2 -Q 1 -; e. -C(R 11 )2-O-; f.
  • -Q 1 - is or wherein R 19 is hydrogen, hydroxyl, halogen, or unsubstituted alkyl, n 1 is one or two, n 2 is one or two, and n 3 is one or two.
  • -Q 1 - is selected from the group consisting of , , , and , wherein R 19 is hydrogen, hydroxyl, fluoro, or methyl.
  • -Q 2 - is , wherein n 4 is one or two, n 5 is one or two, and n 6 is one or two.
  • -C 1-8 alkylene- is selected from the group consisting of -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, - CH2CH2CH2CH2CH2-, -CH 2 CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -, and -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -. 64.
  • linker L is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,
  • R 1 is selected from the group consisting of propyl, ethylmethylamino, sec-butyl, , , , , , , , , , , and . 76.
  • R 1a is chloro or fluoro
  • R 1b is 8 .
  • p g formula X 7 absent or -C(O)-; and
  • X 8 is arylene or heteroarylene.
  • the compound of claim 81 wherein UBM binds CRBN and is selected from the consi of , , , , , , X 9 is absent or h l d m is one, two, 83.
  • the co y one of claims 1 or , compound is selected from the group consisting of (R)-N-(5-chloro-3-(1-(4-(4-((1-(5-(2,4-dioxotetrahydropyrimidin- 1(2H)-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-3-(pyridin-4-yl)-1H- pyrazol-4-yl)-2-fluorophenyl)-3-fluoropyrrolidine-1-sulfonamide; (R)-N-(5-chloro-3-(1-(4-(4- ((1-(5-((R)-2,6-d
  • a pharmaceutical composition comprising e compoun o any one of the previous claims and a pharmaceutically acceptable carrier, excipient, and/or diluent.
  • a method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound or composition of any one of the previous claims.
  • r is cancer.
  • the compound of Formula (I) is selected from the group consisting of (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane-l -sulfonamide
  • the compond of Formula (I) is selected from the group consisting of (R)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(3-(2-(4-(3-(2-(2,6-di oxopiperi din-3-yl)- 1,3- dioxoisoindolin-4-yl)propyl)piperazin-l-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)- 2-fluorophenyl)propane- 1 -sulfonamide, N-(3 -(5 -(2-aminopyrimidin-4-yl)-2-( 1 -(( 15,4r)-4-((6- ((5)-2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(lJ7)-yl)methyl)cyclohexane-l- carbon
  • the compound of Formula (I) is selected from the group consisting of (R)-4-(4-((6-((4-(2-(tert-butyl)-4-(2-fluoro-3-(propylsulfonamido)phenyl)thiazol-5- yl)pyrimidin-2-yl)amino)-2-azaspiro[3.3]heptan-2-yl)methyl)piperidin-l-yl)-7V-(2,6- di oxopiperi din-3 -yl)benzamide, 7V-(3-(2-(tert-butyl)-5-(2-((2-(2-((5)-l-(5-((5)-2,6- dioxopiperidin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)ethyl)-2-azaspiro[3.3]heptan-6- yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-
  • the compound of Formula (I) is selected from the group consisting of (5)-7V-(3-(l-(4-(4-((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, ( ?)-7V-(3-(l-(4-(4-(((l-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-4- yl)methyl)piperazin-l-yl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol-4-yl)-2-fluorophenyl)propane- 1 -sulfonamide, and (5)-7V-(3-(l
  • the compound of Formula (I) is selected from the group consisting of (R)-7V-(3-(l-(4-(4-(l-(4-(2,6-dioxopiperidin-3- yl )phenyl)pi peri di ne-4-carbonyl)piperazine-l -carbonyl )phenyl)-3-(pyri di n-4-yl)-U7-pyrazol - 4-yl)-2-fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(l-(4-(4-(((l-(4-(2,6-dioxopiperidin-3- yl)phenyl)piperidin-4-yl)methyl)piperazine-l-carbonyl)phenyl)-3-(pyridin-4-yl)-l/7-pyrazol- 4-yl)-2-fluorophenyl)propane-l -sulf
  • the compound of Formula (II) is selected from the group consisting of (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(5-(2,6-dioxopiperidin-3- yl)pyridin-2-yl)piperidine-4-carbonyl)piperidine-4-carbonyl)piperidin-4-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, (5)-7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-(l-(l-(5- (2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-methylpiperidine-4-carbonyl)piperidine-4- carbonyl)piperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)propane
  • the compound of Formula (II) is selected from the group consisting of (R)-N-(3-(5-(2- aminopyrimidin-4-yl)-2-(3 -(2-(4-(3 -(2-(2,6-dioxopiperi din-3 -yl)- 1 ,3 -dioxoi soindolin-4- yl)propyl)piperazin-l-yl)acetyl)-3-azaspiro[5.5]undecan-9-yl)thiazol-4-yl)-2- fluorophenyl)propane-l -sulfonamide, 7V-(3-(5-(2-aminopyrimidin-4-yl)-2-(l-((15',4r)-4-((6- ((5)-2,6-dioxopiperidin-3-yl)-3,4-dihydroisoquinolin-2(lJ7)-yl)methyl)cyclohexane
  • X 1 is carbon; X 2 is nitrogen, X 3 is nitrogen; X 4 is carbon; and X 5 is hydrogen.
  • R 1 is alkyl, dialkylamino, cycloalkyl, or heterocycloalkyl each unsubstituted or substituted with one or more halogen;
  • R la is halogen;
  • R lb is hydrogen, haloalkyl or halogen;
  • R 2 is -[Ar 1 -Z 1 ] n -Z 2 -Cy 1 - Z 3 -L-UBM;
  • Ar 1 is arylene or heteroarylene, each unsubstituted or substituted with one or more halogen;
  • Z 1 is a bond; n is one; Z 2 is absent; Cy 1 is absent or heterocycloalkylene, unsubstituted or substituted with one or more alkyl or one or more halogen;
  • Z 3 is absent or Ci-io alkylene;
  • R 1 is selected from the group consisting propyl. In one embodiment, R 1 is ethylmethylamino. In one embodiment, R 1 is ec-butyl. In one embodiment, R 1 is . In one embodiment, R 1 is one embodiment, R 1 is . In one embodiment, R 1 is embodiment,
  • R 1 is . In one embodiment, R 1 is . In one embodiment, [000109] In certain embodiments of Formula (I), R la is chloro or fluoro; and R lb is hydrogen, chloro, fluoro, or haloalkyl. In certain embodiments of Formula (I), Ar 1 is arylene or heteroarylene unsubstituted or substituted with one or two halogen. In certain embodiments of Formula (I), UBM binds an E3 ubiquitin ligase. In certain embodiments of Formula (I), UBM binds SCFP-TRCP, VHL, MDM2, IAP, or CRBN. In certain embodiments of Formula (I), UBM binds CRBN.
  • UBM binds CRBN and has the following chemical formula wherein X 6 absent or NR 3 ; X 7 absent or -C(O)-; and X 8 is arylene or heteroarylene.
  • UBM binds CRBN and is selected from the group consisting absent or halogen; and m is one, two, three, or four.
  • UBM binds CRBN wherein X 9 is absent or halogen; and m is one, two, three, or four.
  • UBM binds CRBN and is wherein X 9 is absent.
  • UBM binds wherein X 9 is halogen; and m is one.
  • UBM binds wherein X 9 is halogen; and m is two.
  • UBM binds wherein X 9 is halogen; and m is three. In one embodiment, UBM binds wherein X 9 is halogen; and m is four. In one embodiment, UBM binds one embodiment, UBM binds CRBN and is . In one embodiment, UBM binds CRBN and is . In one embodiment, UBM binds one embodiment, UBM binds , embodiment, UBM binds wherein X 9 is absent or halogen; and m is one, two, three, or four. In one embodiment, UBM binds wherein X 9 is absent. In one embodiment, UBM binds wherein
  • X 9 is halogen; and m is one.
  • UBM binds wherein X 9 is halogen; and m is two.
  • UBM binds CRBN and is wherein X 9 is halogen; and m is three.
  • UBM binds , , embodiment, UBM binds one embodiment, UBM binds CRBN ,
  • the compound is selected from the group consisting of (R)-7V-(5-chloro-3-(l-(4-(4-((l-(5-(2,4-dioxotetrahydropyrimidin-l(2J7)- yl)pyridin-2-yl)piperidin-4-yl )methyl)piperazin-l -yl)phenyl )-3-(pyridin-4-yl)-l //-pyrazol-4- yl)-2-fluorophenyl)-3 -fluoropyrrolidine- 1 -sulfonamide; (R)-N-(5 -chi oro-3 -( 1 -(4-(4-((l -(5-
  • L is a linker.
  • the linker can be any linker suitable for linking the right and left portions of a molecule or Formula herein. In certain embodiments, the linker does not interfere with the harness or hook functions of a molecule or Formula herein. In certain embodiments, the linker provides useful solubility, flexibility, and/or distance between the portions of a molecule or Formula herein.
  • L is a linker according to -L1L2L3L4L5L 6 -!?- or In certain embodiments, L is a linker according to -L1L2L 3 -L4 -L5-L; 6 - or -L6L5L4L 3 -!?-!?-. In certain embodiments, L is a linker according to In certain embodiments, L is a linker according to
  • L is a linker according to -L 1 -L 2 - L 3 - or -L 3 -L 2 -L 1 -. In certain embodiments, L is a linker according to -L 1 -L 2 - or -L 2 -L 1 -. In certain embodiments, L is a linker according to -L 1 -, -L 2 -, -L 3 -, -L 4 -, -L 5 -, -L 6 -, -L 7 -, or other combinations as would be appreciated by a person of skill in the art.
  • L is a linker according to -L 1 -L 3 -L 6 -, -L 7 -L 5 -L 1 -, or -L 1 -L 3 -L 6 -L 2 -.
  • Each group L x is described in detail below.
  • the linker L comprises at least one heterocyclic group.
  • the linker L comprises one heterocyclic group.
  • the linker L comprises two heterocyclic groups.
  • the linker L comprises three heterocyclic groups.
  • the linker L comprises at least one spiro bicyclic heterocycloalkylene group.
  • the linker L comprises one spiro bicyclic heterocycloalkylene group. In certain embodiments, the linker L comprises two spiro bicyclic heterocycloalkylene groups. In certain embodiments, the linker L comprises three spiro bicyclic heterocycloalkylene groups. In certain embodiments, the linker L comprises at least one heterocycloalkylene group and at least one spiro bicyclic heterocycloalkylene. The remaining groups of or within the linker are selected for chemical compatibility with adjacent groups, as will be recognized by those of skill in the art. [0001 12] In certain embodiments, L is a linker according to -L ⁇ L ⁇ L ⁇ lAlAlAL 7 -.
  • L is a linker according to -L 7 -L 6 -L 5 -L 4 -L 3 -L 2 -L 1 -.
  • -L 1 - is absent, -N(R 10 )-, -C(R 11 )2-, -C(O)-, -Ci-8 alkylene-, -C2-8 alkynylene-, -Ce-Cio aryl-, -heteroaryl-, -C4-C10 heteroaryl-, -Q 1 -, or -Q 2 -; each -L 2 -, -L 3 -, -L 4 -, and -L 5 - is independently, absent, -N(R 10 )-, -C(R n )2-, -C(O)-, -O-, -(CH2-CH2-O)I-8-, C1-8 alkylene-, -C2-8 alkyny
  • L comprises at least one -Q 1 -. In certain embodiments, L comprises one -Q 1 -. In certain embodiments, L comprises two -Q 1 -. In certain embodiments, L comprises three -Q 1 -. In certain embodiments, L comprises at least one -Q 2 -. In certain embodiments, L comprises one -Q 2 -. In certain embodiments, L comprises two -Q 2 -. In certain embodiments, L comprises three -Q 2 -. In certain embodiments, L comprises at least one -Q 1 - and at least one -Q 2 -. In certain embodiments, L comprises one -Q 1 - and one -Q 2 -.
  • each -Q 1 - is an unsubstituted or substituted three- to seven-membered heterocycloalkylene comprising at least one nitrogen; each -Q 2 - is a five- to thirteen-membered bicyclic heterocycloalkylene comprising at least one nitrogen, wherein the five- to thirteen-membered bicyclic heterocycloalkylene is optionally a spiro bicyclic heterocycloalkylene ring; each -Q 3 - is a three- to six-membered cycloalkylene; each R 10 is hydrogen or methyl; and each R 11 is independently, hydrogen, methyl, aryl, substituted aryl, or heteroaryl.
  • R 10 is hydrogen. In certain embodiments, R 10 is methyl. In certain embodiments, one R 11 is hydrogen. In certain embodiments, both R 11 are hydrogen. In certain embodiments, one R 11 is methyl. In certain embodiments, one R 11 is hydrogen and the other is methyl. In certain embodiments, both R 11 are methyl. In certain embodiments, one R 11 is aryl. In certain embodiments, one R 11 is hydrogen or methyl and the other is aryl. In certain embodiments, both R 11 are aryl. In certain embodiments, R 11 is a substituted aryl. In certain embodiments, one R 11 is heteroaryl. In certain embodiments, one R 11 is hydrogen or methyl and the other is heteroaryl. In certain embodiments, both R 11 are heteroaryl.
  • L comprises at least one -Q 1 - according t , wherein n 1 is one or two, and n 2 is one or two. [0001 15] In certain embodiments of Formula (I) or (II), L comprises at least one -Q 1 -.
  • L is selected from
  • X is oxygen or sulfur.
  • L comprises at least one
  • L comprises at least one - certain embodiments of
  • L comprises at least one embodiments of Formula (I) or Formula (II), L comprises at least one
  • L comprises at least one -Q 1 - as embodiments of Formula (I) or Formula (II), L comprises at least one certain embodiments of Formula (I) or Formula (II), L comprises at least one -Q 1 - as In certain embodiments of Formula (I) or Formula (II), L comprises at least one [0001 18] In certain embodiments of Formula (I) or Formula (II), L comprises at least one
  • n 3 is one or two.
  • L comprises at least one
  • L comprises at least one
  • n 4 is one or two
  • n 5 is one or two
  • n 6 is one or two.
  • L comprises at least one
  • L comprises at least one
  • n 8 is one or two.
  • L comprises at least one
  • L comprises at least one
  • L comprises at least one
  • L comprises at least one n 22 / ⁇ / ⁇ n 23
  • n 22 is zero to two; n 23 is zero to two, and n 24 is one or two, or wherein n 22 is two and each n 23 and n 24 is one; or n 22 is two and each n 23 and n 24 is two.
  • L comprises at least one
  • L comprises at least one
  • L comprises at least one
  • n 1 is one or two
  • n 2 is one or two.
  • L comprises at least one
  • L comprises at least one certain embodiments of Formula (I) or Formula (II), L comprises at least one comprises at least one
  • compositions that further comprise a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle.
  • this disclosure provides a pharmaceutical composition comprising one or more compounds described herein, and a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle.
  • this disclosure provides a pharmaceutical composition comprising an effective amount of one or more compounds of this disclosure, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle.
  • Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients, or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices.
  • compositions of this description provide a composition comprising one or more compounds herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • Pharmaceutical compositions of this description comprise a therapeutically effective amount of one or more compounds of Formula (I) or (II), wherein a “therapeutically effective amount” is an amount that is (a) effective to measurably degrade BRAF (or reduce the amount of BRAF) in a biological sample or in a patient; or (b) effective in treating and/or ameliorating a disease or disorder that is mediated by BRAF.
  • a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct/educt or derivative that upon administration to a patient in need is capable of providing, directly or indirectly, one or more compounds as otherwise described herein, or a metabolite, or residue thereof.
  • the term “pharmaceutically acceptable salt” refers to those salts that are, within the scope of sound medical practice or judgment, suitable for use in contact with cells, tissues, and/or the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts include salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid; or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid; or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pect
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium (NH 4 + ), and N + (CI- 4 alkyl) 4 salts. This description also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • compositions include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • a pharmaceutically acceptable carrier may contain inert ingredients that do not unduly inhibit the biological activity of the compounds described herein.
  • the pharmaceutically acceptable carriers should be biocompatible, for example, non-toxic, non-inflammatory, non- immunogenic, and/or devoid of other undesired reactions or side-effects upon administration to a subject. Standard pharmaceutical formulation techniques can be employed.
  • the pharmaceutically acceptable carrier, adjuvant, or vehicle includes any and all solvents, diluents, or other liquid vehicle, dispersion, or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as suited to the particular dosage form desired.
  • Remington s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions, and known techniques for the preparation thereof.
  • any conventional carrier medium is incompatible with the compounds described herein, such as by producing any undesirable biological effect, or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition
  • the use of such conventional carrier medium is contemplated to be within the scope of this description.
  • side effects encompasses unwanted and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Side effects are usually unwanted, but unwanted effects are not necessarily adverse or unbeneficial. An adverse effect from a therapy (e.g., prophylactic or therapeutic agent) might be harmful, uncomfortable, or risky.
  • Side effects include, but are not limited to, fever, chills, lethargy, gastrointestinal toxicities (including gastric and intestinal ulcerations and erosions), nausea, vomiting, neurotoxicities, nephrotoxicities or renal toxicities (including such conditions as papillary necrosis and chronic interstitial nephritis), hepatic toxicities (including elevated serum liver enzyme levels), myelotoxicities (including leukopenia, myelosuppression, thrombocytopenia, and anemia), dry mouth, metallic taste, prolongation of gestation, weakness, somnolence, pain (including muscle pain, bone pain, and headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms, akathisia, cardiovascular disturbances, and sexual dysfunction.
  • gastrointestinal toxicities including gastric and intestinal ulcerations and erosions
  • nausea vomiting
  • neurotoxicities including nephrotoxicities or renal toxicities (including such conditions as papillary necrosis and chronic interstitial nephritis)
  • Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as Tween 80, phosphates, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, methylcellulose, hydroxypropyl methylcellulose, wool fat, sugars such as lactose, glucose, and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose
  • the term “measurably degrade” means a measurable reduction in (a) BRAF activity, between a sample comprising one or more compounds of this description and BRAF versus an equivalent sample comprising BRAF in the absence of said compound(s); or (b) the concentration of BRAF in a sample over time.
  • compositions of this disclosure may be administered orally, parenterally, via inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir.
  • parenteral includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intraocular, intrahepatic, intralesional, and intracranial injection or infusion techniques.
  • Compositions can be administered orally, intraperitoneally, or intravenously.
  • Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives
  • injectables are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • oils such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans, and other emulsifying agents or bioavailability enhancers that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions, or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents, such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents may also be added.
  • compositions of this disclosure may be administered in the form of suppositories for rectal or vaginal administration.
  • suppositories for rectal or vaginal administration.
  • These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal or vaginal temperature and therefore will melt in the rectum or vaginal cavity to release the drug.
  • suitable non-irritating excipient that is solid at room temperature but liquid at rectal or vaginal temperature and therefore will melt in the rectum or vaginal cavity to release the drug.
  • Such materials include cocoa butter, polyethylene glycol, or a suppository wax that is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.
  • compositions of this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be via a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, and water.
  • the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.
  • the pharmaceutically acceptable compositions may be formulated, for example, as micronized suspensions in isotonic, pH adjusted sterile saline or other aqueous solution, or as solutions in isotonic, pH adjusted sterile saline or other aqueous solution, either with or without a preservative such as benzyl alkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • the pharmaceutically acceptable compositions of this disclosure may also be administered by nasal aerosol or inhalation.
  • compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions of this disclosure are administered orally.
  • the pharmaceutically acceptable compositions of this description may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions, or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents, such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents may also be added.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents the oral compositions
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the biologically active compound(s) described herein are mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents, for example, cetylene glycol, and
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art.
  • Solid dosage forms optionally may contain opacifying agents. These solid dosage forms can also be of a composition such that they release the active ingredient(s) only, for example, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active compounds herein can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, for example, tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition such that they release the active ingredient(s) only, for example, in a certain part of the intestinal tract, optionally in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • dosage unit form refers to a physically discrete unit of agent appropriate for the subject, cell, tissue, or patient to be treated. It will be understood, however, that the total daily usage of the compounds, and compositions of this disclosure will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular subject, cell, tissue, patient, or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound(s) employed; the specific composition(s) employed; the age, body weight, general health, sex, and diet of the subject, cell, tissue, and/or patient; the time of administration, route of administration, and rate of excretion of the specific compound(s) employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound(s) employed, and like factors well known in the medical arts.
  • compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the compound(s) or inhibitor(s) can be administered to a subject, cell, tissue, and/or patient receiving these compositions.
  • additional therapeutic agents which are normally administered to treat or prevent that condition, may also be present in the compositions of this disclosure.
  • additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition are known as “appropriate for the disease, or condition, being treated.”
  • the compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents.
  • each agent will be administered at a dose and/or on a time schedule determined for that agent.
  • the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different composition.
  • the particular combination to employ in a regimen will take into account compatibility of the compounds described herein with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved.
  • additional therapeutically active agents utilized in combination will be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
  • Additional therapeutically active agents include, but are not limited to, small organic molecules such as drug compounds (e.g., compounds approved by the Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.
  • drug compounds e.g., compounds approved by the Food and Drug Administration as provided in the Code of Federal Regulations (CFR)
  • CFR Code of Federal Regulations
  • the additional therapeutically active agent is a cancer agent (e.g., a biotherapeutic or chemo therapeutic cancer agent). In other embodiments, the additional therapeutically active agent is an anti-inflammatory agent.
  • the amount of additional therapeutic agent present in the compositions of this disclosure will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • bifunctional compounds described herein are useful for degrading BRAF in biological samples, or in patients via a ubiquitin proteolytic pathway.
  • an embodiment of this disclosure provides a method of treating a BRAF-mediated disease or disorder.
  • the term “BRAF-mediated disease or disorder” means any disease, disorder, or other deleterious condition in which BRAF is known to play a role.
  • an BRAF- mediated disease or disorder is a proliferative disorder or an autoimmune disorder. Examples of proliferative disorders include cancer.
  • kits for treating or preventing cancer in a subject in need thereof comprise the step of orally administering to the subject an amount of a bifunctional compounds(s) described herein capable of inducing proteolytic degradation of BRAF. In certain embodiments, the amount is effective to treat or prevent the cancer.
  • the cancer is any cancer described below.
  • the cancer comprises a solid tumor.
  • the cancer is a B cell malignancy.
  • the cancer is selected from the group consisting of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), transformed CLL or Richter’s transformation, small cell lymphoma, follicular lymphoma (FL), diffuse large B- cell lymphoma (DLBCL), non-Hodgkin lymphoma, mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom macroglobulinemia (WM), and central nervous system (CNS) lymphoma.
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • Richter transformed CLL or Richter’s transformation
  • small cell lymphoma FL
  • DLBCL diffuse large B- cell lymphoma
  • MCL mantle cell lymphoma
  • MZL marginal zone lymphoma
  • the cancer is chronic lymphocytic leukemia.
  • the cancer is small cell lymphoma.
  • the cancer is follicular lymphoma.
  • the cancer is diffuse large B-cell lymphoma.
  • the cancer is non-Hodgkin lymphoma.
  • the cancer is mantle cell lymphoma.
  • the cancer is marginal zone lymphoma.
  • the cancer is Waldenstrom macroglobulinemia.
  • the cancer is small lymphocytic lymphoma (SLL).
  • the cancer is CNS lymphoma.
  • the cancer is transformed CLL or Richter’s transformation.
  • the cancer is chronic lymphocytic leukemia (CLL).
  • kits for degrading BRAF in a subj ect in need thereof comprise the step of orally administering to the subject an amount of a bifunctional compound(s) described herein and capable of inducing proteolytic degradation of BRAF. In certain embodiments, the amount is effective to degrade BRAF in the subject.
  • the BRAF can be expressed in any cells or tissues of the subject.
  • kits for preventing B cell activation in a subject in need thereof comprise the step of orally administering to the subject an amount of a bifunctional compound(s) described herein and capable of inducing proteolytic degradation of BRAF. In certain embodiments, the amount is effective to prevent B cell activation.
  • the B cell expresses CD69. In certain embodiments, the B cell expresses CD86. In certain embodiments, the B cell expresses CD69 and CD86.
  • the bifunctional compound(s) described herein comprise a moiety capable of specifically binding BRAF and further comprise a moiety capable of recruiting a ubiquitin ligase to degrade the BRAF.
  • Particular compounds with each capability are described herein.
  • the compounds can be administered in any form, including pharmaceutically acceptable salts and pharmaceutical compositions.
  • the bifunctional compound(s) described herein can be administered in any dose deemed suitable by the practitioner of skill.
  • the dose is 0.1-1000 mg/kg. In certain embodiments, the dose is 0.1-900 mg/kg. In certain embodiments, the dose is 0.1-800 mg/kg. In certain embodiments, the dose is 0.1-700 mg/kg. In certain embodiments, the dose is 0.1-600 mg/kg. In certain embodiments, the dose is 0.1-500 mg/kg. In certain embodiments, the dose is 0.1-400 mg/kg. In certain embodiments, the dose is 0.1-300 mg/kg. In certain embodiments, the dose is 0.1-200 mg/kg. In certain embodiments, the dose is 0.1- 100 mg/kg.
  • the dose is selected from the group consisting of 100 mg/kg, 200 mg/kg, 300 mg/kg, 450 mg/kg, 600 mg/kg, 800 mg/kg, and 1000 mg/kg. In certain embodiments, the dose is about 25 mg/kg. In certain embodiments, the dose is about 50 mg/kg. In certain embodiments, the dose is about 75 mg/kg. In certain embodiments, the dose is about 100 mg/kg. In certain embodiments, the dose is about 150 mg/kg. In certain embodiments, the dose is about 200 mg/kg. In certain embodiments, the dose is about 250 mg/kg. In certain embodiments, the dose is about 300 mg/kg. In certain embodiments, the dose is about 400 mg/kg.
  • the dose is about 450 mg/kg. In certain embodiments, the dose is about 500 mg/kg. In certain embodiments, the dose is about 600 mg/kg. In certain embodiments, the dose is about 700 mg/kg. In certain embodiments, the dose is about 750 mg/kg. In certain embodiments, the dose is about 800 mg/kg. In certain embodiments, the dose is about 900 mg/kg. In certain embodiments, the dose is about 1000 mg/kg.
  • the dose can be administered on a schedule deemed suitable by the person of skill in the art.
  • the dose is administered once per day.
  • the dose is administered twice per day.
  • the dose is administered three times per day.
  • the dose is administered four times per day.
  • the dose is administered in divided doses.
  • the dose is administered in two divided doses per day.
  • the dose is administered in three divided doses per day.
  • the dose is administered in four divided doses per day.
  • the dose is administered daily for fourteen days. In certain embodiments, the dose is administered daily for thirteen days. In certain embodiments, the dose is administered daily for twelve days. In certain embodiments, the dose is administered daily for eleven days. In certain embodiments, the dose is administered daily for ten days. In certain embodiments, the dose is administered daily for nine days. In certain embodiments, the dose is administered daily for eight days. In certain embodiments, the dose is administered daily for seven days. In certain embodiments, the dose is administered daily for six days. In certain embodiments, the dose is administered daily for five days. In certain embodiments, the dose is administered daily for four days. In certain embodiments, the dose is administered daily for three days. In certain embodiments, the dose is administered daily for two days. In certain embodiments, the dose is administered for one day.
  • the doses can be administered on consecutive days or cyclicly, according to the judgment of the practitioner of skill. In certain embodiments, the doses are administered on consecutive days. In certain embodiments, the doses are administered with an interval between doses. In certain embodiments, the interval is one day. In certain embodiments, the interval is two days. In certain embodiments, the interval is three days. In certain embodiments, the interval is four days. In certain embodiments, the interval is five days. In certain embodiments, the interval is six days.
  • the dose is administered weekly. In certain embodiments, the dose is administered twice per week. In certain embodiments, the dose is administered three times per week.
  • the dose(s) are administered for a period of time with a first interval between dose(s), and then the dose(s) are re-administered for a period of time following the first interval between dose(s), wherein this dosing regimen can be repeated (i.e., cyclicly or cyclically, for example, after a second, third, etc. interval between subsequent administrations of dose(s)) according to the judgment of the practitioner of skill.
  • a first dose is administered for one week, followed by a first interval of one week without the first dose administration; then, a second dose is re-administered for another week, followed by a second interval of one week without the first or second dose administration, and so on cyclically.
  • Other perturbations for first, second, third, etc. dose(s) followed by perturbations for first, second, third, etc. interval(s), and combinations thereof, are contemplated herein as would be appreciated by the practitioner of skill and the need of the subject, cell, tissue, and/or patient.
  • a first dose is administered daily for one week, followed by a first interval of three weeks without the first daily dose administration; then, a second dose is re-administered biweekly for another week, followed by a second interval of four weeks without the first daily or second biweekly dose administration, and so on cyclically.
  • the compound can be administered by any route of administration deemed suitable by the practioner of skill.
  • the dose is administered orally.
  • Formulations and techniques for administration are described elsewhere herein.
  • cancer includes, but is not limited to, the following cancers: epidermoid Oral: buccal cavity, lip, tongue, mouth, pharynx, squamous cell carcinoma of the head and neck (HNSCC); Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small cell lung cancer (NSCLC); Gastrointestinal: gastric
  • the term “autoimmune disease” includes, but is not limited to, the following autoimmune diseases: uticaria, graft-versus-host disease (GVHD), acute graft-versus-host disease, pemphigus vulgaris, achalasia, Addison’s disease, Adult Still’s disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti- GBM/anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, axonal and neuronal neuropathy (AMAN), Balo disease, Behcet’s disease, benign mucosal pemphigoi
  • GVHD graft
  • the term “inflammatory disease” includes, but is not limited to, the following inflammatory diseases: encephalitis, myelitis, meningitis, arachnoiditis, neuritis, dacryoadenitis, scleritis, episcleritis, keratitis, retinitis, chorioretinitis, blepharitis, conjunctivitis, uveitis, otitisexterna, otitismedia, labyrinthitis, mastoiditis, endocarditis, myocarditis, pericarditis, vasculitis, arteritis, phlebitis, capillaritis, sinusitis, rhinitis, pharyngitis, laryngitis, tracheitis, bronchitis, bronchiolitis, pneumonitis, pleuritis, mediastinitis, stomatitis, gingivitis
  • articles of manufacture comprising any of the compounds or pharmaceutical compositions described herein.
  • the articles of manufacture include suitable containers or packaging materials for the compounds or pharmaceutical compositions.
  • suitable container include, but are not limited to, a bottle, a vial, a syringe, an intravenous bag, or a tube.
  • kits comprising any of the compounds or pharmaceutical compositions described herein.
  • the kits can contain the compounds or pharmaceutiucal compositions in suitable containers or packaging materials, including, but not limited to, a bottle, a vial, a syringe, an intravenous bag, or a tube.
  • the kits can comprise the compounds or pharmaceutiucal compositions for administration to a subject, cell, tissue, and/or individual in single-dose form or in multiple-dose form.
  • the kits can further comprise instructions or a label for administering the compounds or pharmaceutiucal compositions to a subject, cell, tissue, and/or individual according to any of the methods disclosed herein.
  • kits can further comprise equipment for administering the compounds or pharmaceutiucal compositions to a subject, cell, tissue, and/or individual, including, but not limited to, needles, syringes, tubing, or intravenous bags.
  • the kits can further comprise instructions for producing any of the compounds or pharmaceutiucal compositions disclosed herein.
  • articles of manufacture comprising any of the compounds or pharmaceutical compositions described herein.
  • the articles of manufacture include suitable containers or packaging materials for the compounds or pharmaceutical compositions.
  • the articles of manufacture include suitable containers or packaging materials for the compounds or pharmaceutical compositions. Examples of a suitable container include, but are not limited to, a bottle, a vial, a syringe, an intravenous bag, or a tube.
  • a suitable container include, but are not limited to, a bottle, a vial, a syringe, an intravenous bag, or a tube.
  • Preparatory HPLC purifications were conducted with a flow rate of 15 mL/min and detection by UV wavelength at 214 nm and 254 nm (Column: Jupiter ⁇ 10 pM Proteo 90 A, 250 x 21.2 mm A, solvent: acetonitrile/water, containing a modifier such as 0.1% trifluoroacetic acid).
  • Step-1 Synthesis of tert-butyl 7V-(2-carbamoyl-2.,2- dimethylethyl)carbamate (2)
  • Step-2 Synthesis o butyl /V-(2-carbamothioyl-2.,2- dimethylethyl)carbamate (3)
  • Step-3 Synthesis of tert-butyl A-]2-[5-(2-chloropyrimidin-4-yl)-4-(2- fluoro-3-][(prop-2-en-l-yloxy)carbonyl]amino ⁇ phenyl)-l.,3-thiazol-2-yl]-2- methylpropyBcarbamate (4)
  • Step-4 Synthesis of prop-2-en-l-yl 7V-]3-[2-(l-amino-2-methylpropan-2- yl)-5-(2-chloropyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluorophenvncarbaniate (5)
  • Step-5 Synthesis of prop-Z-en-l-yl 7V-]3-[5-(2-chloroDyrimidin-4-yl)-2-[2- methyl-l- 4-ylformamido)propan-2-yl]-l.,3-thiazol-4-yl]-2- fluorophenyBcarbamate (6)
  • Step-6 Synthesis of A-]2-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)-l.,3-thiazol-2-yl]-2-methylpropynoxane-4-carboxamide (7)
  • Step-7 Synthesis of 7V-(2-(5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfon:iniido)phenyl)thi:izol-2-yl)-2-niethylpropyl)tetr:ihvdro-2//-pyran-4- carboxamide (8)
  • Step-8 Synthesis of tert-butyl 7V-(4-14-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-2-[2-methyl-l-(oxan-4-ylformamido)propan-2-yl]-l.,3-thiazol-5- vnpyrimidin-2-yl)carbamate (9)
  • Step-9 Synthesis of ⁇ -!2-
  • Step-1 Synthesis of tert-butyl 4-(2-(4-(3-(((allyloxy)carbonyl)amino)-2- fluoroDhenyl)-5-(2-chloroDyrimidin-4-yl)thiazol-2-yl)DroDan-2-yl)Diperidine-l- carboxylate (3)
  • Step-2 Synthesis of tert-butyl 4-]2-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)-l.,3-thiazol-2-yl]propan-2-vnpiperidine-l-carboxylate (4)
  • Step-3 Synthesis of tert-butyl 4-]2-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro- 3-(propane-l-sulfonamido)phenyl]-l.,3-thiazol-2-yl]propan-2-vnpiperidine-l- carboxylate (5)
  • Step-4 Synthesis of tert-butyl 4-
  • Step-5 Synthesis of ⁇ -!3-
  • Step-1 Synthesis of tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- f[(DroD-2-en-l-yloxy)carbonyl]amino ⁇ phenyl)-l.,3-thiazol-2-yl]DiDeridine-l-carboxylate
  • Step-2 Synthesis of tert-butyl 4-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)-l.,3-thiazol-2-yl]piperidine-l-carboxylate (3)
  • Step-3 Synthesis of tert-butyl 4-(5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)piperidine-l-carboxylate (4)
  • Step-5 Synthesis of A-13-[5-(2-aminopyrimidin-4-yl)-2-(piperidin-4-yl)- l,3-thiazol-4-yl]-2-fluorophenvnpropane-l-sulfonamide hydrochloride
  • Step-1 Synthesis of tert-butyl 4-14-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-5-(pyrimidin-4-yl)-l.,3-thiazol-2-vnpiperidine-l-carboxylate (2)
  • Step-2 Synthesis of 7V-12-fluoro-3-[2-(piperidin-4-yl)-5-(pyrimidin-4-yl)- l,3-thiazol-4-yl]phenvnpropane-l-sulfonamide hydrochloride
  • Step-1 Synthesis o butyl 4-(4-carbamoylDhenyl)Diperidine-l- carboxylate (2)
  • Step-2 Synthesis of tert-butyl 4-(4-carbamothioylphenyl)piperidine-l- carboxylate (3)
  • Step-3 Synthesis of tert-butyl 4-]4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-
  • Step-4 Synthesis of tert-butyl 4-]4-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)- 1.,3-thiazol-2-yl] phenyl] piperidine- 1-carboxylate (6)
  • Step-5 Synthesis of tert-butyl 4-(4-(5-(2-chloropyrimidin-4-yl)-4-(2-fluoro- 3-(propylsulfonamido)phenyl)thiazol-2-yl)phenyl)piperidine-l-carboxylate (7)
  • Step-6 Synthesis of tert-butyl 4-[4-(5- [(tert- butoxycarbonyl)amino]pyrimidin-4-vn-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-
  • Step-7 Synthesis of 7V-13-[5-(2-aminoDyrimidin-4-yl)-2-[4-(DiDeridin-4- Yl)phenyl]-l.,3-thiazol-4-yl]-2-fluoroDhenynDroDane-l-sulfonamide
  • the crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 38% B in 8 min; Wave Length: 220/254 nm; Rti (min): 6.75 to afford A- ⁇ 3-[5-(2-aminopyrimidin-4-yl)-2-[4-(piperidin-4-yl)phenyl]-l,3- thiazol-4-yl]-2-fhiorophenyl ⁇ propane-l-sulfonamide (223.7 mg, 70.01%) as a yellow solid.
  • Step-1 Synthesis of tert-butyl 8-(2-fluoro-4-nitrophenyl)-3.,8- diazabicyclo[3.2.1]octane-3-carboxylate (2)
  • Step-2 Synthesis of tert-butyl 8-(4-amino-2-fluorophenyl)-3.,8- diazabicyclo[3.2.1]octane-3-carboxylate (3)
  • Step-3 Synthesis of tert-butyl 8-
  • Step-4 Synthesis of 4-[2-tert-butyl-4-(3-][ethyl(methyl)sulfamoyl]amino ⁇ - 2-fluorophenyl)-l.,3-thiazol-5-yl]-7V-(4-f3.,8-diazabicvclo[3.2.1]octan-8-vn-3- fluorophenyl)pyrimidin-2-amine; trifluoroacetic acid
  • Step-1 Synthesis of tert-butyl 4-carbamothioyl-4-methylDiDeridine-l- carboxylate (2)
  • Step-2 Synthesis of tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- f[(prop-2-en-l-yloxy)carbonyl]amino ⁇ phenyl)-l.,3-thiazol-2-yl]-4-methylpiperidine-l- carboxylate (4)
  • Step-3 Synthesis of tert-butyl 4-(4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)thiazol-2-yl)-4-methylpiperidine-l-carboxylate (5)
  • Step-4 Synthesis of tert-butyl 4-(5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)-4-methylpiperidine-l-carboxylate (6)
  • tert-butyl 4-[4-(3-amino-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)-l,3- thiazol-2-yl]-4-methylpiperidine-l-carboxylate (1.6 g, 3.17 mmol, 1 equiv) in DCM (20 mL) was added TEA (963.7 mg, 9.52 mmol, 3 equiv) and propane- 1 -sulfonyl chloride (679.0 mg, 4.76 mmol, 1.5 equiv) at 0 °C.
  • Step-5 Synthesis of tert-butyl 4-(5-!2-
  • Step-6 Synthesis of 7V-f3-[5-(2-aminopyrimidin-4-yl)-2-(4- methylpiperidin-4-yl)-l.,3-thiazol-4-yl]-2-fluorophenvnpropane-l-sulfonaniide
  • Step-1 Synthesis o butyl 7-carbamoyl-2-azasDiro[3.5]nonane-2- carboxylate (2) To a mixture of 2-(tert-butoxycarbonyl)-2-azaspiro[3.5]nonane-7-carboxylic acid (4 g, 14.85 mmol, 1 equiv) and HATU (8.47 g, 22.28 mmol, 1.5 equiv) in DMF (40 mL) was added NH4CI (3.97 g, 74.26 mmol, 5 equiv) and the mixture was stirred for 15 min. Then, DIEA (5.76 g, 44.55 mmol, 3 equiv) was added.
  • Step-2 Synthesis of tert-butyl 7-carbamothioyl-2-azaspiro[3.5]nonane-2- carboxylate (3)
  • Step-3 Synthesis of tert-butyl 7-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- l[(prop-2-en-l-yloxy)carbonyl]amino ⁇ phenyl)-l.,3-thiazol-2-yl]-2-azaspiro[3.5]nonane-2- carboxylate (4)
  • Step-4 Synthesis of tert-butyl 7-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)-l.,3-thiazol-2-yl]-2-azaspiro[3.5]nonane-2-carboxylate (5)
  • Step-5 Synthesis of tert-butyl 7-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3- (propane-l-sulfonamido)phenyl]-l.,3-thiazol-2-yl]-2-azaspiro[3.5]nonane-2-carboxylate (6)
  • Step-6 Synthesis of tert-butyl 7-(5- [(tert- butoxycarbonyl)amino]pyrimidin-4-vn-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- l,3-thiazol-2-yl)-2-azaspiro[3.5]nonane-2-carboxylate (7)
  • Step-7 Synthesis of 7V-]3-[5-(2-aminoDyrimidin-4-yl)-2-]2- azasDiro[3.5]nonan-7-yn-l.,3-thiazol-4-yl]-2-fluoroDhenynDroDane-l-sulfonamide; trifluoroacetic acid
  • Step-1 Synthesis of tert-butyl 9-carbamoyl-3-azaspiro[5.5]undecane-3- carboxylate (2)
  • Step-2 Synthesis of tert-butyl 9-carbamothioyl-3-azaspiro[5.5]undecane-3- carboxylate (3)
  • Step-3 Synthesis of tert-butyl 9-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- l[(prop-2-en-l-yloxy)carbonyl]amino ⁇ phenyl)-l.,3-thiazol-2-yl]-3- azaspiro[5.5]nndecane-3-carboxylate (4)
  • Step-4 Synthesis of tert-butyl 9-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)-l.,3-thiazol-2-yl]-3-azaspiro[5.5]undecane-3-carboxylate (5)
  • Step-5 Synthesis of tert-butyl 9-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3- (propane-l-snlfonamido)phenyl]-l.,3-thiazol-2-yl]-3-azaspiro[5.5]undecane-3- carboxylate (6)
  • Step-6 Synthesis of tert-butyl 9-(5-!2-
  • Step-7 Synthesis of 7V-]3-[5-(2-aminopyrimidin-4-yl)-2-f3- azaspiro[5.5]undecan-9-vn-l.,3-thiazol-4-yl]-2-fluorophenvnpropane-l-sulfonaniide
  • Step-1 Synthesis of tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- l[(prop-2-en-l-yloxy)carbonyl]amino ⁇ phenyl)-l.,3-thiazol-2-yl]piperidine-l-carboxylate
  • Step-2 Synthesis of tert-butyl 4-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)-l.,3-thiazol-2-yl]piperidine-l-carboxylate (3)
  • Step-3 Synthesis of tert-butyl 4-(5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)piperidine-l-carboxylate (4)
  • Step-5 Synthesis of A-13-[5-(2-aminopyrimidin-4-yl)-2-(piperidin-4-yl)- l,3-thiazol-4-yl]-2-fluorophenvnpropane-l-sulfonamide hydrochloride
  • Step-1 Synthesis of tert-butyl 3-]4-[4-(3-amino-2-fluorophenyl)-3- (pyridin-4-yl)pyrazol-l-yl]phenvnazetidine-l-carboxylate (2)
  • Step-2 Synthesis of tert-butyl 3-(4-]4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-vnphenyl)azetidine-l-carboxylate (3) To a mixture of tert-butyl 3- ⁇ 4-[4-(3-amino-2-fluorophenyl)-3-(pyridin-4-yl)pyrazol-l- yl]phenyl ⁇ azetidine-l-carboxylate (60 mg, 0.12 mmol, 1 equiv) and TEA (38 mg, 0.37 mmol, 3 equiv) in DCM (3 mL) was added propane- 1 -sulfonyl chloride (53 mg, 0.37 mmol, 3 equiv) at 0 °C.
  • Step-3 Synthesis of 7V-(3-fl-[4-(azetidin-3-yl)Dhenyl]-3-(Dyridin-4- yl)Dyrazol-4-yl ⁇ -2-fluoroDhenyl)DroDane-l-sulfonamide; trifluoroacetic acid
  • Step-1 Synthesis of tert-butyl 4-14-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-
  • Step-2 Synthesis of te -butyl 4-14-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)-l.,3-thiazol-2-yl]piperidine-l-carbonvnpiperidine-l-carboxylate (4)
  • the resulting mixture was stirred for 30 min at room temperature.
  • the reaction was quenched by the addition of saturated aqueous NaHCOs at 0 °C.
  • the resulting mixture was extracted with CH2Q2.
  • the combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step-3 Synthesis of tert-butyl 4-(4-(5-(2-chloropyrimidin-4-yl)-4-(2-fluoro- 3-(propylsulfonamido)phenyl)thiazol-2-yl)piperidine-l-carbonyl)piperidine-l- carboxylate (5)
  • Step-4 Synthesis of tert-butyl 4-[4-(5-
  • Step-5 Synthesis of A-]3-[5-(2-aminopyrimidin-4-yl)-2-[l-(piperidine-4- carbonyl)piperidin-4-yl]-l.,3-thiazol-4-yl]-2-fluorophenvnpropane-l-sulfonaniide hydrochloride
  • Step-2 Synthesis of tert-butyl 4-(5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-3- (propylsulfonamido)phenyl)thiazol-2-yl)piperidine-l-carboxylate (3)
  • Step-3 Synthesis of A-]3-[5-(2-chloropyrimidin-4-yl)-2-(piperidin-4-yl)- l,3-thiazol-4-yl]-2-fluorophenvnpropane-l-sulfonamide (4)
  • Step-4 Synthesis of tert-butyl 4-G4-[5-(2-chloroDyrimidin-4-yl)-4-[2- fluoro-3-(propane-l-sulfonamido)phenyl]-l.,3-thiazol-2-yl]piperidin-l- vnmethyl)piperidine-l-carboxylate (5)
  • Step-5 Synthesis of tert-butyl 4-f[4-(5- [(tert- butoxycarbonyl)amino]pyrimidin-4-vn-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]- l,3-thiazol-2-yl)piperidin-l-yl]methvnpiperidine-l-carboxylate (6)
  • Step-6 Synthesis of ⁇ -!3-
  • Step-1 Synthesis of prop-2-en-l-yl 7V-13-[2-tert-butyl-5-(2- chloroDyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluoroDhenyncarbamate(2)
  • Step-2 Synthesis of 3-
  • Step-3 Synthesis of ⁇ -!3-
  • Step-4 Synthesis of tert-butyl 4-14-[(4-12-tert-butyl-4-[2-fluoro-3- (propane-l-sulfonamido)phenyl]-l.,3-thiazol-5-vnpyriniidin-2-yl)aniino]pyrazol-l- vnpiperidine-l-carboxylate (6)
  • the final reaction mixture was irradiated with microwave radiation for 2 h at 120 °C.
  • the resulting mixture was extracted with EtOAc.
  • the combined organic layers were washed with water and dried over anhydrous Na 2 SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step-5 Synthesis of ⁇ -!3-
  • Step-1 Synthesis of tert-butyl 6-[(4-]2-tert-butyl-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l.,3-thiazol-5-ynDyrimidin-2-yl)amino]-3.,4-dihydro-IH- isoquinoline-2-carboxylate (3)
  • the final reaction mixture was irradiated with microwave radiation for 2 h at 120 °C under the nitrogen atmosphere.
  • the resulting mixture was extracted with EtOAc.
  • the combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure.
  • Step-2 Synthesis of A-(3-]2-tert-butyl-5-[2-(l.,2.,3.,4-tetrahvdroisoquinolin- 6-ylamino)pyrimidin-4-yl]-l.,3-thiazol-4-vn-2-fluorophenyl)propane-l-sulfonamide hydrochloride
  • Step-1 Synthesis of tert-butyl 4-13-[(4-12-tert-butyl-4-[2-fluoro-3-
  • the final reaction mixture was irradiated with microwave radiation for 2 h at 120 °C.
  • the resulting mixture was extracted with EtOAc.
  • the combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure.
  • Step-2 Synthesis of A z -f3-[2-tert-butyl-5-(2-f[3-(Diperidin-4- yl)Dhenyl]amino ⁇ Dyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluoroDhenyl ⁇ DroDane-l- sulfonamide hydrochloride
  • Step-1 Synthesis of tert-butyl 4-]3-[(4-]2-tert-butyl-4-[2-fluoro-3- (propane-l-sulfonamido)phenyl]-l.,3-thiazol-5-vnpyrimidin-2- yl)amino]phenoxy ⁇ piperidine-l-carboxylate (3)
  • the final reaction mixture was irradiated with microwave radiation for 2 h at 120 °C under nitrogen atmosphere.
  • the resulting mixture was extracted with EtOAc.
  • the combined organic layers were washed with water and dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under reduced pressure.
  • Step-2 Synthesis of 7V-]3-[2-tert-butyl-5-(2-H3-(piperidin-4- yloxy)phenyl]amino ⁇ pyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluorophenvnpropane-l- sulfonamide hydrochloride
  • Step-1 Synthesis of tert-butyl 3-(4-nitrophenyl)-2.,5-dihvdropyrrole-l- carboxylate (2)
  • Step-2 Synthesis of tert-butyl 3-(3-aminophenyl)pyrrolidine-l-carboxylate (3)
  • Step-3 Synthesis of tert-butyl 3-]3-[(4-]2-tert-butyl-4-[2-fluoro-3- (propane-l-sulfonamido)phenyl]-l.,3-thiazol-5-vnpyrimidin-2- yl)amino]phenvnpyrrolidine-l-carboxylate (5)
  • the final reaction mixture was irradiated with microwave radiation for 2 h at 120 °C.
  • the resulting mixture was extracted with EtOAc.
  • the combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure.
  • Step-4 Synthesis of ⁇ -!3-
  • Step-1 Synthesis of tert-butyl 4-[(4-nitropyrazol-l-yl)methyl]piperidine-l- carboxylate (2)
  • Step-2 Synthesis of tert-butyl 4-[(4-aminopyrazol-l-yl)methyl]piperidine- 1-carboxylate (3)
  • Step-3 Synthesis of tert-butyl 4-(]4-[(4-]2-tert-butyl-4-[2-fluoro-3- (propane-l-sulfonamido)phenyl]-l.,3-thiazol-5-vnpyrimidin-2-yl)amino]pyrazol-l- vnmethyl)piperidine-l-carboxylate (4)
  • the final reaction mixture was irradiated with microwave radiation for 2 h at 120 °C under nitrogen atmosphere.
  • the resulting mixture was extracted with EtOAc.
  • the combined organic layers were washed with water and dried over anhydrous ISfeSCU After filtration, the filtrate was concentrated under reduced pressure.
  • Step-4 Synthesis of A-]3-[2-tert-butyl-5-(2-][l-(piperidin-4- ylmethyl)pyrazol-4-yl]amino ⁇ pyrimidin-4-yl)-l.,3-thiazol-4-yl]-2-fluorophenyl ⁇ propane- 1-sulfonamide hydrochloride
  • Step-1 Synthesis of tert-butyl 4-[4-(4,4.,5.,5-tetramethyl-l.,3.,2- dioxaborolan-2-yl)phenyl] piperidine-l-carboxylate (2)
  • Step-2 Synthesis of tert-butyl 4-]4-[4-bromo-3-(pyridin-4-yl)pyrazol-l- yl]phenvnpiperidine-l-carboxylate (4)
  • Step-3 Synthesis of tert-butyl 4-]4-[4-(3-amino-2-fluorophenyl)-3- (pyridin-4-yl)pyrazol-l-yl]phenvnpiperidine-l-carboxylate (6)
  • Step-4 Synthesis of tert-butyl 4-(4-]4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-vnphenyl)piperidine-l-carboxylate (7)
  • Step-5 Synthesis of A-(2-fluoro-3-H-[4-(Diperidin-4-yl)Dhenyl]-3- (Dyridin-4-yl)Dyrazol-4- Dropane-l-sulfonamide hydrochloride
  • Step-1 Synthesis of tert-butyl 4-I4-[4-bromo-3-(pyridin-4-yl)pyrazol-l- yllphenyllpiperazine-l-carboxylate (2)
  • Step-2 Synthesis of tert-butyl 4-I4-[4-(3-amino-2-fluorophenyl)-3- (pyridin-4-yl)pyrazol-l-yl]phenvnpiperazine-l-carboxylate (3)
  • Step-3 Synthesis of tert-butyl 4-(4-I4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-3-(pyridin-4-yl)pyrazol-l-vnphenyl)piperazine-l-carboxylate (4)
  • Step-4 Synthesis of A-(2-fluoro-3-H-[4-(piperazin-l-yl)phenyl]-3- (pyridin-4-yl)pyrazol-4-vnphenyl)propane-l-sulfonamide
  • Step-1 Synthesis of prop-2-en-l-yl A-(3-12-[l-(2-chloroacetyl)piperidin-4- yl]-5-(2-chloropyrimidin-4-yl)-l.,3-thiazol-4-yn-2-fluorophenyl)carbamate (2)
  • Step-2 Synthesis of tert-butyl 7-(2-]4-[5-(2-chloroDyrimidin-4-yl)-4-(2- fluoro-3-[[(prop-2-en-l-yloxy)carbonyl]amino ⁇ phenyl)-l.,3-thiazol-2-yl]piperidin-l-vn- 2-oxoethyl)-2,7-diazaspiro [3.5] nonane-2-carboxylate (4)
  • Step-3 Synthesis of tert-butyl 7-(2-[4-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)-l,3-thiazol-2-yl]piperidin-l-vn-2-oxoethyl)-2,7- diazaspiro [3.5] nonane-2-carboxylate (5)
  • Step-4 Synthesis of tert-butyl 7-(2-]4-[5-(2-chloroDyrimidin-4-yl)-4-[2- fluoro-3-(propane-l-sulfonamido)phenyl]-l.,3-thiazol-2-yl]piperidin-l-vn-2-oxoethyl)- 2,7-diazaspiro [3.5] nonane-2-carboxylate (6)
  • Step-5 Synthesis of tert-butyl 7-[2-[4-(5-[2-[(tert- butoxycarbonyl)amino]pyrimidin-4-vn-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-
  • Step-6 Synthesis of A z -13-[5-(2-aminopyrimidin-4-yl)-2-[l-(2-12.,7- diazaspiro[3.5]nonan-7-vnacetyl)piperidin-4-yl]-l.,3-thiazol-4-yl]-2- fluoroDhenynpropane-l-sulfonamide hydrochloride
  • Step-1 Synthesis o butyl 4-14-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-5-(pyrimidin-4-yl)-l.,3-thiazol-2-vnpiperidine-l-carboxylate (2) To a mixture of tert-butyl 4-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-l,3-thiazol-2-yl]piperidine-l-carboxylate (700 mg, 1.174 mmol, 1 equiv) and NH4OAC (905.14 mg, 11.740 mmol, 10 equiv) in MeOH (10 mL) was added Pd/C (700 mg) at room temperature.
  • Step-2 Synthesis of 7V-f2-fluoro-3-[2-(DiDeridin-4-yl)-5-(Dyrimidin-4-yl)-
  • Step-1 Synthesis of 2-bromo-l-(2-fluoro-3-nitrophenyl)ethanone (2)
  • Step-2 Synthesis of tert-butyl 4-[4-(2-fluoro-3-nitrophenyl)-l.,3-thiazol-2- yl]piperidine-l-carboxylate (4)
  • Step-3 Synthesis of tert-butyl 4-[5-bromo-4-(2-fluoro-3-nitrophenyl)-l.,3- thiazol-2-yl]piperidine-l-carboxylate (5)
  • Step-4 Synthesis of tert-butyl 4-[4-(3-amino-2-fluorophenyl)-5-bromo-l.,3- thiazol-2-vHpiperidine-l-carboxylate (6)
  • Step-5 Synthesis of tert-butyl 4-(5-bromo-4-(2-fluoro-3-
  • Step-6 Synthesis of tert-butyl 4-]4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-5-(pyridin-4-yl)-l.,3-thiazol-2-vnpiperidine-l-carboxylate (9)
  • Step-7 Synthesis of A-]2-fluoro-3-[2-(piperidin-4-yl)-5-(pyridin-4-yl)-l.,3- thiazol-4-vHphenvnpropane-l-sulfonamide
  • the crude product (500 mg) was purified by Prep-HPLC with the following conditions Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: water (10 mmol/L NH4HCO3); Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 30% B in 10 min; Wave Length: 254 nm; Rn (min): 8.6 to afford N- ⁇ 2- fluoro-3 -[2-(piperidin-4-yl)-5-(pyridin-4-yl)- 1 ,3 -thiazol-4-yl]phenyl (propane- 1 -sulfonamide (324.8 mg, 65.77%) as a white solid.
  • Step-1 Synthesis of tert-butyl 4-(4-carbamoylDhenyl)Diperidine-l- carboxylate (2)
  • Step-2 Synthesis of te -butyl 4-(4-carbamothioylphenyl)piperidine-l- carboxylate (3)
  • Step-3 Synthesis of tert-butyl 4-]4-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro-
  • Step-4 Synthesis of tert-butyl 4-]4-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)- 1.,3-thiazol-2-yl] phenyl] piperidine- 1-carboxylate (6)
  • Step-5 Synthesis of tert-butyl 4-(4-(5-(2-chloropyrimidin-4-yl)-4-(2-fluoro- 3-(propylsulfonamido)phenyl)thiazol-2-yl)phenyl)piperidine-l-carboxylate (7)
  • Step-6 Synthesis of tert-butyl 4-[4-(5-12-[(tert- butoxycarbonyl)amino]pyrimidin-4-vn-4-[2-fluoro-3-(propane-l-sulfonamido)phenyl]-
  • Step-7 Synthesis of 7V-f3-[5-(2-aminoDyrimidin-4-yl)-2-[4-(DiDeridin-4- Yl)phenyl]-l.,3-thiazol-4-yl]-2-fluoroDhenynDroDane-l-sulfonamide
  • Step-2 Synthesis of A-(2-fluoro-3-]5-[2-(methylamino)pyrimidin-4-yl]-2- (piperidin-4-yl)-l.,3-thiazol-4-vnphenyl)propane-l-sulfonamide hydrochloride
  • Step-1 Synthesis of tert-butyl 4-14-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-5-(2-l -l-hvdroxypropan-2-yl]amino ⁇ pyrimidin-4-yl)-l.,3- thiazol-2-yl ⁇ piperidine-l-carboxylate (2)
  • Step-2 Synthesis of A-12-fluoro-3-[5-(2-ll(21?)-l-hvdroxypropan-2- yl]amino ⁇ pyrimidin-4-yl)-2-(piperidin-4-yl)-l.,3-thiazol-4-yl]phenvnpropane-l- sulfonamide hydrochloride
  • Step-1 Synthesis of prop-Z-en-l-yl 7V-13-[5-(2-chloropyrimidin-4-yl)-2- methyl-l.,3-thiazol-4-yl]-2-fluorophenyncarbamate (1)
  • Step-2 Synthesis of 3-[5-(2-chloropyrimidin-4-yl)-2-methyl-l.,3-thiazol-4- yl]-2-fluoroaniline (2)
  • Step-3 Synthesis of ⁇ -!3-
  • Step-4 Synthesis of tert-butyl 4-]4-[(4-]4-[2-fluoro-3-(propane-l- sulfonamido)phenyl]-2-methyl-l.,3-thiazol-5-vnpyriniidin-2- yl)amino]phenvnpiperidine-l-carboxylate (4)
  • Step-5 Synthesis of A-]2-fluoro-3-[2-methyl-5-(2-][4-(Diperidin-4- yl)Dhenyl]amino ⁇ Dyrimidin-4-yl)-l.,3-thiazol-4-yl]DhenynDroDane-l-sulfonamide hydrochloride
  • Step-1 Synthesis of tert-butyl 4-(2-carbamoylethyl)piperidine-l- carboxylate (2)
  • Step-2 Synthesis of tert-butyl 4-(2-carbamothioylethyl)piperidine-l- carboxylate (3) To a mixture of tert-butyl 4-(2-carbamoylethyl)piperidine-l -carboxylate (3.0 g, 11.703 mmol, 1 equiv) in THF (30 mL) was added Lawesson’s Reagent (2.36 g, 5.851 mmol, 0.5 equiv). The resulting mixture was stirred for at 50 °C overnight. The reaction was quenched by the addition of saturated aqueous sodium hyposulfite at 0 °C. The resulting mixture was extracted with EtOAc.
  • Step-3 Synthesis of tert-butyl 4-f2-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro- 3-f[(prop-2-en-l-yloxy)carbonyl]amino ⁇ phenyl)-l.,3-thiazol-2-yl]ethvnpiperidine-l- carboxylate (5)
  • Step-4 Synthesis of tert-butyl 4-f2-[4-(3-amino-2-fluorophenyl)-5-(2- chloropyrimidin-4-yl)-l.,3-thiazol-2-yl]ethvnpiperidine-l-carboxylate (6)
  • Step-5 Synthesis of tert-butyl 4-f2-[5-(2-chloropyrimidin-4-yl)-4-[2-fluoro- 3-(propane-l-sulfonamido)phenyl]-l.,3-thiazol-2-yl]ethvnpiperidine-l-carboxylate (7)
  • Step-6 Synthesis of tert-butyl 4-f2-[5-(2-chloropyrimidin-4-yl)-4-(2-fluoro- 3-f[(prop-2-en-l-yloxy)carbonyl]amino ⁇ phenyl)-l.,3-thiazol-2-yl]ethvnpiperidine-l- carboxylate (8)
  • Step-7 Synthesis of ⁇ -!3-

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des composés de formule (I) utiles pour la dégradation ex vivo, in vitro ou in vivo de BRAF par l'intermédiaire d'une voie protéolytique de l'ubiquitine. La présente invention concerne également des compositions pharmaceutiquement acceptables comprenant lesdits composés, ainsi que des procédés d'utilisation des compositions dans le traitement de maladies, d'affections et/ou de troubles divers. (I)
PCT/US2024/026679 2023-04-28 2024-04-26 Composés bifonctionnels pour dégrader le braf par l'intermédiaire d'une voie ubiquitine-protéosome Pending WO2024227104A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU2024260700A AU2024260700A1 (en) 2023-04-28 2024-04-26 Bifunctional compounds for degrading braf via ubiquitin proteosome pathway
IL323616A IL323616A (en) 2023-04-28 2025-09-28 Bifunctional compounds for degradation of BRAF in the ubiquitin-proteasome pathway
MX2025012819A MX2025012819A (es) 2023-04-28 2025-10-27 Compuestos bifuncionales para degradar braf a traves de la via del proteosoma de ubiquitina

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363462918P 2023-04-28 2023-04-28
US63/462,918 2023-04-28

Publications (1)

Publication Number Publication Date
WO2024227104A1 true WO2024227104A1 (fr) 2024-10-31

Family

ID=91376068

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/026679 Pending WO2024227104A1 (fr) 2023-04-28 2024-04-26 Composés bifonctionnels pour dégrader le braf par l'intermédiaire d'une voie ubiquitine-protéosome

Country Status (4)

Country Link
AU (1) AU2024260700A1 (fr)
IL (1) IL323616A (fr)
MX (1) MX2025012819A (fr)
WO (1) WO2024227104A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112812109A (zh) * 2019-11-18 2021-05-18 中国科学院微生物研究所 化合物DaP-01及其制备方法和应用
WO2022093742A1 (fr) * 2020-10-26 2022-05-05 Dana-Farber Cancer Institute, Inc. Composés pour la dégradation ciblée de protéines de kinases
WO2022235698A1 (fr) * 2021-05-03 2022-11-10 Nurix Therapeutics, Inc. Composés pour inhiber ou dégrader des protéines cibles, compositions les comprenant, leurs procédés de fabrication et leurs procédés d'utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112812109A (zh) * 2019-11-18 2021-05-18 中国科学院微生物研究所 化合物DaP-01及其制备方法和应用
WO2022093742A1 (fr) * 2020-10-26 2022-05-05 Dana-Farber Cancer Institute, Inc. Composés pour la dégradation ciblée de protéines de kinases
WO2022235698A1 (fr) * 2021-05-03 2022-11-10 Nurix Therapeutics, Inc. Composés pour inhiber ou dégrader des protéines cibles, compositions les comprenant, leurs procédés de fabrication et leurs procédés d'utilisation

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
"March's Advanced Organic Chemistry", 2001, JOHN WILEY & SONS
"Organic Chemistry", 1999, THOMAS SORRELL
"Scientific Tables, Geigy Pharmaceuticals", 1970, ARDSLEY, pages: 537
E. W. MARTIN: "Remington's Pharmaceutical Sciences", 1980, MACK PUBLISHING CO
FREIREICH ET AL., CANCER CHEMOTHER. REP, vol. 50, 1966, pages 219
MARINI ELISABETTA ET AL: "Investigation into the Use of Encorafenib to Develop Potential PROTACs Directed against BRAFV600E Protein", MOLECULES, vol. 27, no. 23, 1 December 2022 (2022-12-01), DE, pages 8513, XP093201391, ISSN: 1433-1373, DOI: 10.3390/molecules27238513 *
S. M. BERGE ET AL.: "describe pharmaceutically acceptable salts in detail in", J. PHARMACEUTICAL SCIENCES, vol. 66, 1977, pages 1 - 19
STEINEBACH CHRISTIAN ET AL: "A MedChem toolbox for cereblon-directed PROTACs", MEDCHEMCOMM, vol. 10, no. 6, 19 June 2019 (2019-06-19), United Kingdom, pages 1037 - 1041, XP055857543, ISSN: 2040-2503, DOI: 10.1039/C9MD00185A *
WUTSGREENE: "Greene's Protective Groups in Organic Synthesis", 2006, WILEY-INTERSCIENCE

Also Published As

Publication number Publication date
IL323616A (en) 2025-11-01
AU2024260700A1 (en) 2025-11-13
MX2025012819A (es) 2025-12-01

Similar Documents

Publication Publication Date Title
JP7741282B2 (ja) ユビキチンプロテオソーム経路を介してｂｔｋを分解するための二官能性化合物
JP7687970B2 (ja) Ｉｒａｋ分解剤およびその使用
KR20230143632A (ko) Irak 분해제 및 이의 용도
KR20220112273A (ko) 유비퀴틴 프로테오솜 경로를 통해 btk를 분해하기 위한 이작용성 화합물
WO2022235698A1 (fr) Composés pour inhiber ou dégrader des protéines cibles, compositions les comprenant, leurs procédés de fabrication et leurs procédés d'utilisation
JP2022516401A (ja) Ｉｒａｋ分解剤およびそれらの使用
TW201919640A (zh) 作為ｒｓｖ抑制劑的組合藥劑
CN107108561A (zh) 用作irak抑制剂的杂芳基化合物及其用途
MXPA01009871A (es) Aminopiridinas como inhibidores de la sorbitol deshidrogenasa.
US20240279202A1 (en) Compounds for inhibiting or degrading itk, compositions, comprising the same methods of their making and methods of their use
EP2809652B1 (fr) Dérivés d'isoquinoléine et de naphtyridine
AU2022349569A1 (en) Pyridine derivative and use thereof
CA3078579A1 (fr) Composes inhibiteurs de pyrimidine tbk/ikk.epsilon. et leurs utilisations
CA3235182A1 (fr) Composes bifonctionnels pour la degradation de l'itk par l'intermediaire d'une voie de l'ubiquitine proteosome
WO2024227104A1 (fr) Composés bifonctionnels pour dégrader le braf par l'intermédiaire d'une voie ubiquitine-protéosome
OA21863A (en) Indazole based compounds and associated methods of use.
HK40081936A (en) Bifunctional compounds for degrading btk via ubiquitin proteosome pathway
HK1242303B (zh) 用作irak抑制剂的杂芳基化合物及其用途

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: 24730823

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 323616

Country of ref document: IL

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112025021880

Country of ref document: BR

WWE Wipo information: entry into national phase

Ref document number: AU2024260700

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 2024260700

Country of ref document: AU

Date of ref document: 20240426

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2024730823

Country of ref document: EP