Compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides

Patent metadata

Field	Value
Publication number	US-10723717-B2
Application number	US-201715853166-A
Country	US
Kind code	B2
Filing date	Dec 22, 2017
Priority date	Dec 23, 2016
Publication date	Jul 28, 2020
Grant date	Jul 28, 2020

Abstract

The present disclosure relates to bifunctional compounds, which find utility as modulators of Rapidly Accelerated Fibrosarcoma (RAF, such as c-RAF, A-RAF and/or B-RAF; the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein, or the constitutive activation of the target protein, are treated or prevented with compounds and compositions of the present disclosure.

First claim

What is claimed is:

1. A bifunctional compound having the chemical structure:
ULM-L-PTM,

or a pharmaceutically acceptable salt, enantiomer, or stereoisomer thereof,
wherein:
(a) the ULM is a Von Hippel-Lindau (VHL) E3 ubiquitin binding moiety (VLM) with a chemical structure represented by:

wherein:
X 1 , X 2 are each independently selected from the group of a bond, O, NR Y3 , CR Y3 R Y4 , C═O, C═S, SO, and SO 2 ;
R Y3 , R Y4 are each independently selected from the group of H, linear or branched C 1-6 alkyl optionally substituted by 1 or more halo, C 1-6 alkoxyl optionally substituted by 0-3 R P groups;
R P is 0, 1, 2, or 3 groups, each independently selected from H, halo, —OH, C 1-3 alkyl, and C═O;
W 3 is selected from the group consisting of an optionally substituted -T-N(R 1a R 1b )X 3 , optionally substituted -T-N(R 1a R 1b ), optionally substituted -T-Aryl, an optionally substituted -T-Heteroaryl, an optionally substituted -T-Heterocycle, an optionally substituted —NR 1 -T-Aryl, an optionally substituted —NR 1 -T-Heteroaryl, and an optionally substituted -NR 1 -T-Heterocycle;
X 3 of Formula ULM-a is C═O, R 1 , R 1a , and R 1b ;
R 1 , R 1a , R 1b are each independently selected from the group consisting of H, linear or branched C 1 -C 6 alkyl group optionally substituted by 1 or more halo or —OH groups, R Y3 C═O, R Y3 C═S, R Y3 SO, R Y3 SO 2 , N(R Y3 R Y4 )C═O, N(R Y3 R Y4 )C═S, N(R Y3 R Y4 )SO, and N(R Y3 R Y4 )SO 2 ;
T is selected from the group of an optionally substituted alkyl, —(CH 2 ) n — group, wherein each one of the methylene groups is optionally substituted with one or two substituents selected from the group of halogen, methyl, a linear or branched C 1 -C 6 alkyl group optionally substituted by 1 or more halogen or —OH groups or an amino acid side chain optionally substituted; and
n is 0 to 6,
W 4 is

R 14a , R 14b are each independently selected from the group of H, haloalkyl, or optionally substituted alkyl;
W 5 is selected from the group of a phenyl or a 5-10 membered heteroaryl,
R 15 is selected from the group of H, halogen, CN, OH, NO 2 , N R 14a R 14b , OR 14a , CONR 14a R 14b , NR 14a COR 14b , SO 2 NR 14a R 14b , NR 14a SO 2 R 14b , optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloheteroalkyl;
o is an integer from 0-4;
R 16 is independently selected from the group of halo, optionally substituted alkyl, optionally substituted haloalkyl, hydroxy, or optionally substituted haloalkoxy; and
indicates the site of attachment of the VLM to the linker (L);

(b) the L is a chemical linking group connecting the ULM and the PTM and that has a chemical structural unit represented by the formula:
-(A L ) q -,
wherein:
(A L ) q is a group which is connected to a ULM or PTM moiety;
q is an integer greater than or equal to 1;
each A L is independently selected from the group consisting of CR L1 R L2 , O, S, SO, SO 2 , NR L3 , SO 2 NR L3 , SONR L3 , CONR L3 , NR L3 CONR L4 , NR L3 SO 2 NR L4 , CO, CR L1 ═CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 P(O)OR L1 , NR L3 C(═NCN)NR L4 , NR L3 C(═NCN), NR L3 C(═CNO 2 )NR L4 , C 3-11 cycloalkyl optionally substituted with 0-6 R L1 and/or R L2 groups, C 3-11 heterocyclyl optionally substituted with 0-6 R L1 and/or R L2 groups, aryl optionally substituted with 0-6 R L1 and/or R L2 groups, heteroaryl optionally substituted with 0-6 R L1 and/or R L2 groups, where R L1 or R L2 , each independently are optionally linked to other groups to form cycloalkyl and/or heterocyclyl moiety, optionally substituted with 0-4 R L5 groups; and
R L1 , R L2 , R L3 , R L4 and R L5 are, each independently, H, halo, C 1-8 alkyl, OC 1-8 alkyl, SC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 , C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclyl, OC 1-8 cycloalkyl, SC 1-8 cycloalkyl, NHC 1-8 cycloalkyl, N(C 1-8 cycloalkyl) 2 , N(C 1-8 cycloalkyl)(C 1-8 alkyl), OH, NH 2 , SH, SO 2 C 1-8 alkyl, P(O)(OC 1-8 alkyl)(C 1-8 alkyl), P(O)(OC 1-8 alkyl) 2 , CC—C 1-8 alkyl, CCH, CH═CH(C 1-8 alkyl), C(C 1-8 alkyl)═CH(C 1-8 alkyl), C(C 1-8 alkyl)═C(C 1-8 alkyl) 2 , Si(OH) 3 , Si(C 1-8 alkyl) 3 , Si(OH)(C 1-8 alkyl) 2 , COC 1-8 alkyl, CO 2 H, halogen, CN, CF 3 , CHF 2 , CH 2 F, NO 2 , SF 5 , SO 2 NHC 1-8 alkyl, SO 2 N(C 1-8 alkyl) 2 , SONHC 1-8 alkyl, SON(C 1-8 alkyl) 2 , CONHC 1-8 alkyl, CON(C 1-8 alkyl) 2 , N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl) 2 , NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl) 2 , NHCONH 2 , N(C 1-8 alkyl)SO 2 NH(C 1-8 alkyl), N(C 1-8 alkyl) SO 2 N(C 1-8 alkyl) 2 , NH SO 2 NH(C 1-8 alkyl), NH SO 2 N(C 1-8 alkyl) 2 , NH SO 2 NH 2 ; and

(c) the PTM is a small molecule comprising a rapidly accelerated fibrosarcoma (RAF) protein targeting moiety represented by chemical structure PTM-IIa or PTM-IIb:

wherein:
X PTM1 , X PTM2 , X PTM3 , X PTM4 , X PTM5 , and X PTM6 are independently selected from CH or N;
R PTM5a is selected from the group consisting of: H, optionally substituted amide, optionally substituted amine,

—NHC(O)R PTM5 ;
R PTM5 is selected from the group consisting of

R PTM6a and R PTM6b are each independently selected from hydrogen, halogen, or optionally substituted linear or branched C 1 -C 6 alkyl;
R PTM6 is either of the following groups: absent, hydrogen, halogen, aryl, methyl, ethyl, OCH 3 , NHCH 3 or M1-CH 2 —CH 2 -M 2 , wherein M1 is CH 2 , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle,
R PTM7 is absent, hydrogen, halogen, aryl, methyl, ethyl, OCH 3 , NHCH 3 or M1-CH 2 —CH 2 -M2, wherein M1 is CH 2 , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle,
R PTM8 , R PTM9 or R PTM10 are independently selected from the group consisting of absent, hydrogen, halogen, aryl, heteroaryl, alkyl, cycloalkyl, heterocycle, methyl, ethyl, OCH 3 , NHCH 3 or M1-CH 2 —CH 2 -M2, wherein M1 is CH 2 , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle; and
R PTM11 is absent, hydrogen, halogen, methyl, ethyl, OCH 3 , NHCH 3 or M1-CH 2 —CH 2 -M2, wherein M1 is CH 2 , O and NH, and M2 is hydrogen, alkyl, cyclic alkyl, aryl or heterocycle,
wherein at least one of R PTM8 , R PTM9 or R PTM10 is modified to be covalently joined to the linker (L).

2. The bifunctional compound according to claim 1 , wherein when R PTM9 is the covalently joined position, R PTM7 and R PTM8 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R PTM7 and R PTM8 are attached.

3. The bifunctional compound according to claim 1 , wherein when R PTM8 is the covalently joined position, R PTM9 and R PTM10 are connected together via a covalent bond in a way to form a bicyclic group with the ring to which R PTM9 and R PTM10 are attached.

4. The bifunctional compound according to claim 1 , wherein when R PTM10 is the covalently joined position,

Assignees

• Arvinas Inc
• Univ Yale
• Arvinas Operations Inc

Inventors

• Crew Andrew P
• Hornberger Keith R
• Wang Jing
• Dong Hanqing
• Qian Yimin
• Crews Craig M
• Jaime-Figueroa Saul

Classifications

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K47/55

  the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug · CPC title

• A61K47/555

  pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title