WO2021255213A1

WO2021255213A1 - Heterobifunctional compounds as degraders of braf

Info

Publication number: WO2021255213A1
Application number: PCT/EP2021/066526
Authority: WO
Inventors: Cosimo Dolente; David Stephen HEWINGS; Daniel Hunziker; Bernd Kuhn; Piergiorgio Francesco Tommaso PETTAZZONI; Fabienne Ricklin; Claus Riemer; Juergen Wichmann
Original assignee: F. Hoffmann-La Roche Ag; Hoffmann-La Roche Inc.; C4 Therapeutics, Inc.
Priority date: 2020-06-19
Filing date: 2021-06-18
Publication date: 2021-12-23

Abstract

Present invention provides compounds that cause specifically the degradation of BRAF. The present compounds are useful for the treatment of various cancers.

Description

HETEROBIFUNCTIONAL COMPOUNDS AS DEGRADERS OF BRAF

Field of the Invention

Present invention provides compounds that cause specifically the degradation of BRAF, via the ubiquitination of the BRAF protein and subsequent proteasomal degradation. The present compounds are useful for the treatment of various cancers.

Background of the Invention

BRAF V600E/K mutations are often observed in a variety of human tumors including Melanoma, Tyroid cancer, Colorectal cancer, Lung Cancer and others. Despite the evident therapeutic benefits exerted by available BRAF inhibitors in the clinic in many of these indications, the duration of the antitumor response to these drugs is limited by the acquisition of drug resistance.

The BRAF protein presents a peculiar mechanism for signaling propagation that require protein homo (BRAF -BRAF) or hetero-dimerization with other RAF proteins (BRAF -RAF 1 or BRAF-ARAF). When BRAF is mutated, as observed in oncological indications with BRAF V600E/K substitution, BRAF signaling become independent from the generation of homo and/or heterodimers. In this context, the kinase became hyperactivated as monomeric protein and drive cellular proliferative signals.

Because currently available inhibitors only block BRAF activity in its monomeric form while are inffective on BRAF homo or heterodimer, it is not surprising that many BRAFi- resistance inducing mechanisms act by restoring RAF homo and heterodimerisation mediated signaling.

Targeted protein degradation is an emerging mode of action, which induce target ubiquitination by recruiting a specific E3 ligase thus promoting proteasome-mediated disruption of the engaged target.

The degradation of BRAF trough targeted degradation offers evident advantage over conventional inhibition since allows eliminating scaffolding activities of BRAF V600E/K and particularly, by inducing BRAF protein extinction, it can prevent and exert activity on dimerization-mediated mechanisms of resistance.

In agreement with these evidences, literature reports demonstrated that BRAF protein abrogation could represent a strategy to delay the onset of resistance acquisition as well potentially targeting tumors that acquired resistance to available inhibitors offering novel therapeutic opportunities in the treatment of BRAF V600E/K mutated tumors like melanoma, colorecal cancer, lung cancer.

Summary of the Invention

Present invention provides compounds that cause specifically the degradation of BRAF presenting the mutation V600E via the targeted ubiquitination of the BRAF protein and subsequent proteasomal degradation. The present compounds bind to the ubiquitously expressed E3 ligase protein cereblon (CRBN) on one hand and alter the substrate specificity of the CRBN E3 ubiquitin ligase complex, resulting in the recruitment and ubiquitination of BRAF V600E. The present compounds are also effective binders of WT BRAF, RAFl and ARAF, however effective targeted degradation is triggered by these compounds only for BRAF V600E.

Present invention provides compounds of formula I or II, or a pharmaceutically acceptable salt thereof,

wherein the substituents and variables are as described below and in the claims, or a pharmaceutically acceptable salt thereof. The present compounds are useful for the therapeutic and/or prophylactic treatment of cancer.

Detailed Description of the Invention

The present invention provides a compound of formula I or II and their pharmaceutically acceptable salts thereof, the preparation of the above mentioned compounds, medicaments containing them and their manufacture as well as the use of the above mentioned compounds in the therapeutic and/or prophylactic treatment of cancer.

The following definitions of the general terms used in the present description apply irrespectively of whether the terms in question appear alone or in combination with other groups.

Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms “a”, “an,” and “the” include plural referents unless the context clearly dictates otherwise.

The term "Ci-₆-alkyl", alone or in combination with other groups, stands for a hydrocarbon radical which may be linear or branched, with single or multiple branching, wherein the alkyl group in general comprises 1 to 6 carbon atoms, for example, methyl (Me), ethyl (Et), propyl, isopropyl (i-propyl), n-butyl, i-butyl (isobutyl), 2-butyl (sec-butyl), t-butyl (/tvV-butyl), isopentyl, 2-ethyl-propyl (2 -methyl -propyl), 1,2-dimethyl -propyl and the like. Specific groups are methyl and ethyl.

The term “C3-8-cycloalkyl” denotes a monovalent saturated monocyclic or bicyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means a ring system consisting of two saturated carbocycles having one or two carbon atoms in common. Examples of monocyclic C3-8- cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. Example of bicyclic C3-8-cycloalkyl is spiro[3.3]heptanyl. Particular monocyclic C3-8-cycloalkyl groups are cyclopropyl, cyclobutanyl. More particular monocyclic C3-8-cycloalkyl group is cyclopropyl.

The term "halogen", alone or in combination with other groups, denotes chloro (Cl), iodo (I), fluoro (F) and bromo (Br). Specific group is F.

The term “heterocycloalkyl” denotes a monovalent saturated or partly unsaturated mono- or bicyclic ring system of 4 to 9 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon which is optionally substituted with oxo. Bicyclic means consisting of two cycles having one or two ring atoms in common. The heterocycloalkyl is preferably a monovalent saturated or partly unsaturated monocyclic ring system of 4 to 6 ring atoms, comprising 1 or 2 ring heteroatoms selected from N, O and S (4- to 6- membered heterocycloalkyl). Examples for monocyclic saturated heterocycloalkyl are 4,5-dihydro-oxazolyl, oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-4-yl, 3-oxo- morpholin-6-yl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, l,l-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples for bicyclic saturated heterocycloalkyl are oxabicyclo[2.2.1]heptanyl, oxaspiro[3.3]heptanyl, 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8- oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or 3- thia-9-aza-bicyclo[3.3.1]nonyl. Examples for partly unsaturated heterocycloalkyl are dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl or dihydropyranyl. Heterocyclyl is preferably azetidinyl, morpholinyl, pyrrolidinyl, piperazinyl, oxetanyl, 2-oxo- pyrrolidin-4-yl, or 3-oxo- morpholin-6-yl. Particular heterocycloalkyl is pyrrolidinyl.

The term “pharmaceutically acceptable” denotes an attribute of a material which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and is acceptable for veterinary as well as human pharmaceutical use.

The term "a pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and animals. Examples of suitable salts with inorganic and organic acids are, but are not limited to acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methane-sulfonic acid, nitric acid, phosphoric acid, p- toluenesulphonic acid, succinic acid, sulfuric acid (sulphuric acid), tartaric acid, trifluoroacetic acid and the like. Particular acids are formic acid, trifluoroacetic acid and hydrochloric acid.

The terms “pharmaceutically acceptable auxiliary substance” refer to carriers and auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation.

The term "pharmaceutical composition" encompasses a product comprising specified ingredients in pre-determined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts. Particularly it encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. “Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The “therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.

The term “as defined herein” and “as described herein” when referring to a variable incorporates by reference the broad definition of the variable as well as particularly, more particularly and most particularly definitions, if any.

The terms “treating”, “contacting” and “reacting” when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product. It should be appreciated that the reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.

The term “pharmaceutically acceptable excipient” denotes any ingredient having no therapeutic activity and being non-toxic such as disintegrators, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants or lubricants used in formulating pharmaceutical products.

The term "pharmaceutical composition" encompasses a product comprising specified ingredients in pre-determined amounts or proportions, as well as any product that results, directly or indirectly, from combining specified ingredients in specified amounts. Particularly it encompasses a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.

The term “inhibitor” denotes a compound which competes with, reduces or prevents the binding of a particular ligand to particular receptor or which reduces or prevents the function of a particular protein.

“Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The “therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors. The term “aromatic” denotes the conventional idea of aromaticity as defined in the literature, in particular in IUPAC.

Whenever a chiral carbon is present in a chemical structure, it is intended that all stereoisomers associated with that chiral carbon are encompassed by the structure as pure stereoisomers as well as mixtures thereof. The invention also provides pharmaceutical compositions, methods of using, and methods of preparing the aforementioned compounds.

All separate embodiments may be combined.

El: One embodiment of the invention relates to a compound of formula I or II, or a pharmaceutically acceptable salt thereof,

A¹ is selected from i) -NR²-, and ii) -CHR³-;

R¹ is selected from i) H, ii) Ci-₆-alkyl, and iii) C_3-8-cycloalkyl; R² is selected from i) H, ii) Ci-₆-alkyl, and iii) C_3-8-cycloalkyl; or R¹ and R² together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by R¹⁴, R¹⁵ and R¹⁶;

R³ is selected from i) H, ii) Ci-₆-alkyl, and iii) C_3-8-cycloalkyl; or R¹ and R³ together with the carbon atom to which they are attached form a cycloalkyl optionally substituted by R¹⁴, R¹⁵ and R¹⁶;

R¹⁴, R¹⁵ and R¹⁶ are independently selected from i) H, ii) halogen, iii) Ci-₆-alkyl, and iv) C_3-8-cycloalkyl;

R⁷ and R⁸ are independently selected from i) H, and ii) halogen;

A² and A³ are independently selected from i) -CH-, and ii) -N-;

X is selected from i) a bound, ii) -NR⁴-, and iii) -0-;

R⁴ is selected from i) H, and ii) Ci-₆-alkyl;

A⁴ is selected from i) -C(O)-, and ii) -CH2-;

A is selected from i) -(CFh)p-; and ii) the ring systems A, B, C, D, E and F;

p is selected from i) 3, and ii) 5; m is selected from i) 0, ii) 1, iii) 2;

B is selected from the ring systems G and H;

n is selected from i) 0, and ii) 1;

R⁵ and R⁶ are independently selected from i) H, and ii) Ci-₆-alkyl; or R⁵ and R⁶ together form -CH2-.

E2: A certain embodiment of the invention relates to the compound of formula I or II as described herein, or a pharmaceutically acceptable salt thereof, wherein A¹ is selected from i) -NR²-, and ii) -CHR³-;

R¹ is selected from i) Ci-₆-alkyl, and ii) C_3-8-cycloalkyl;

R² is Ci-₆-alkyl; or R¹ and R² together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by R¹⁴, R¹⁵ and R¹⁶;

R³ is Ci-₆-alkyl;

R⁷ and R⁸ are halogen;

A² and A³ are independently selected from i) -CH-, and ii) -N-;

X is selected from i) a bound, ii) -NR⁴-, and iii) -0-;

R⁴ is H;

A⁴ is selected from i) -C(O)-, and ii) -CH2-;

A is selected from i) -(CFh)p-; and ii) the ring systems A, B, C, D, E and F;

p is selected from i) 3, and ii) 5; m is selected from i) 0, ii) 1, iii) 2;

B is selected from the ring systems G and H;

n is selected from i) 0, and ii) 1;

R⁵ and R⁶ are H; or R⁵ and R⁶ together form -CH2-.

E3 : A certain embodiment of the invention relates to the compound of formula I or II as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I). E4: A certain embodiment of the invention relates to the compound of formula I or II as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (II).

E5: A certain embodiment of the invention relates to the compound of formula I or II as described herein, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from i) Ci-6-alkyl, and ii) C3-8-cycloalkyl.

E6: A certain embodiment of the invention relates to the compound of formula I or II as described herein, or a pharmaceutically acceptable salt thereof, wherein R² is Ci-₆-alkyl.

E7: A certain embodiment of the invention relates to the compound of formula I or II as described herein, or a pharmaceutically acceptable salt thereof, wherein R¹ and R² together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by R¹⁴, R¹⁵ and R¹⁶.

E8: A certain embodiment of the invention relates to the compound of formula I or II as described herein, or a pharmaceutically acceptable salt thereof, wherein R¹ and R² together with the nitrogen atom to which they are attached form an unsubstituted heterocycloalkyl.

E9: A certain embodiment of the invention relates to the compound of formula I or II as described herein, or a pharmaceutically acceptable salt thereof, wherein the heterocycloalkyl formed by R¹ and R² together with the nitrogen atom to which they are attached is a pyrrolidinyl.

E10: A certain embodiment of the invention relates to the compound of formula I or II as described herein, or a pharmaceutically acceptable salt thereof, wherein R³ is Ci-₆-alkyl.

El l: A certain embodiment of the invention relates to the compound of formula I or II as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁷ and R⁸ are halogen.

E12: A certain embodiment of the invention relates to the compound of formula I or II as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁴ is H.

E13: A certain embodiment of the invention relates to the compound of formula I or II as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁵ and R⁶ are H.

E14: A certain embodiment of the invention relates to the compound of formula I or II as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁵ and R⁶ together form -CEh-. El 5: A certain embodiment of the invention relates to the compound of formula I or II as described herein, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

5-[4-[[4-[4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl]amino]butanoyl]piperazin-l-yl]methyl]phenyl]-3-[3-

[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-lH-pyrrolo[2,3-b]pyridine;

5-[4-[[4-[3-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-4- piperidyl]propanoyl]piperazin-l-yl]methyl]phenyl]-3-[3-

5-[4-[[4-[2-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-4- piperidyl]acetyl]piperazin-l-yl]methyl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-

2,6-difluoro-benzoyl]-lH-pyrrolo[2,3-b]pyridine;

3 -[3 -[[ethyl (methyl )sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-[[rac-( l R,5S)-8-[4-

[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]butanoyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methyl]phenyl]-lH-pyrrolo[2,3-b]pyridine;

5-[6-[[4-[4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl]amino]butanoyl]piperazin-l-yl]methyl]-3-pyridyl]-3-[3-

5-[2-[4-[3-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-4- piperidyl]propanoyl]piperazin-l-yl]pyrimidin-5-yl]-3-[3-

5-[2-[4-[4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl]amino]butanoyl]piperazin-l-yl]pyrimidin-5-yl]-3-[3-

N-[3-[5-[4-[[4-[4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl]amino]butanoyl]piperazin-l-yl]methyl]phenyl]-lH-pyrrolo[2,3-b]pyridine-3- carbonyl]-2,4-difluoro-phenyl]pyrrolidine-l -sulfonamide formic acid;

3-[3-[[cyclopropyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-[[4-[4-[[2- (2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]butanoyl]piperazin-l- yl]methyl]phenyl]-lH-pyrrolo[2,3-b]pyridine formic acid; 5-[6-[4-[3-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-4- piperidyl]propanoyl]piperazin-l-yl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-

2,6-difluoro-benzoyl]-lH-pyrrolo[2,3-b]pyridine;

5-[6-[4-[4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl]amino]butanoyl]piperazin-l-yl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-

2,6-difluoro-benzoyl]-lH-pyrrolo[2,3-b]pyridine;

5-[6-[4-[4-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]oxypiperidine-l- carbonyl]piperazin-l-yl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6- difluoro-b enzoyl ] - 1 H-pyrrol o [2, 3 -b ] pyri dine;

5-[6-[4-[4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl]amino]cyclohexanecarbonyl]piperazin-l-yl]-3-pyridyl]-3-[3-

5-[4-[[4-[3-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl]amino]cyclobutanecarbonyl]piperazin-l-yl]methyl]phenyl]-3-[3-

5-[6-[[4-[3-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl]amino]cyclobutanecarbonyl]piperazin-l-yl]methyl]-3-pyridyl]-3-[3-

5-[6-[4-[3-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl]amino]cyclobutanecarbonyl]piperazin-l-yl]-3-pyridyl]-3-[3-

5-[6-[4-[2-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]pyrrolidin-3- yl]acetyl]piperazin-l-yl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6- difluoro-b enzoyl ] - 1 H-pyrrol o [2, 3 -b ] pyri dine;

5-[6-[4-[3-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]azetidin-3- yl]propanoyl]piperazin-l-yl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6- difluoro-b enzoyl ] - 1 H-pyrrol o [2, 3 -b ] pyri dine;

5-[6-[4-[4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxybutanoyl]piperazin-l- yl]-3 -pyri dyl]-3 -[3 -[[ethyl (methyl )sulfamoyl]ami no] -2,6-difluoro-benzoyl]-l H- pyrrolo[2,3 -bjpyridine; 5-[6-[4-[2-[4-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]oxy-l- piperidyl]acetyl]piperazin-l-yl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6- difluoro-b enzoyl ] - 1 H-pyrrol o [2, 3 -b ] pyri dine;

5-[6-[4-[4-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]piperidine-l- carbonyl]piperazin-l-yl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6- difluoro-b enzoyl ] - 1 H-pyrrol o [2, 3 -b ] pyri dine;

N-[3-[5-[6-[4-[3-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl]amino]cyclobutanecarbonyl]piperazin-l-yl]-3-pyridyl]-lH-pyrrolo[2,3-b]pyridine-3- carbonyl]-2,4-difluoro-phenyl]butane-2-sulfonamide;

5-[2-[4-[4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxybutanoyl]piperazin-l- yljpyri mi din-5-yl]-3 -[3 -[[ethyl (methyl )sulfamoyl]ami no] -2,6-difluoro-benzoyl]-l H- pyrrolo[2,3 -bjpyridine;

5-[4-[[4-[l-[2-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-4- piperidyl]acetyl]-4-piperidyl]piperazin-l-yl]methyl]phenyl]-3-[3-

5-[4-[[4-[l-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]piperidine-4- carbonyl]-4-piperidyl]piperazin-l-yl]methyl]phenyl]-3-[3-

5-[4-[[4-[l-[2-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]-4- piperidyl]acetyl]-4-piperidyl]piperazin-l-yl]methyl]phenyl]-3-[3-

5-[4-[4-[3-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-4- piperidyl]propanoyl]piperazin-l-yl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6- difluoro-b enzoyl ] - 1 H-pyrrol o [2, 3 -b ] pyri dine;

5-[4-[4-[3-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl]amino]cyclobutanecarbonyl]piperazin-l-yl]phenyl]-3-[3-

5-[4-[4-[4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxybutanoyl]piperazin-l- yl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-lH- pyrrolo[2, 3 -bjpyridine; and 5-[4-[[4-[l-[6-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]hexanoyl]- 4-piperidyl]piperazin-l-yl]methyl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6- difluoro-b enzoyl ] - 1 H-pyrrol o [2, 3 -b ] pyri dine .

E16: A certain embodiment of the invention relates to the compound of formula I or II as described herein, or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance.

El 7: A certain embodiment of the invention relates to a pharmaceutical composition comprising the compound of formula I or II as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary substance.

El 8: A certain embodiment of the invention relates to the use of compound of formula I or II as described herein, or a pharmaceutically acceptable salt thereof, for the therapeutic and/or prophylactic treatment of cancer, in particular melanoma, colorecal cancer and lung cancer.

E19: A certain embodiment of the invention relates to the compound of formula I or II as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prophilaxyis of cancer, in particular melanoma, colorecal cancer and lung cancer.

E20: A certain embodiment of the invention relates to the compound of formula I or II as described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of cancer, in particular melanoma, colorecal cancer and lung cancer.

E21 : A certain embodiment of the invention relates to a method for the therapeutic and/or prophylactic treatment of cancer, in particular melanoma, colorecal cancer and lung cancer, by administering the compound of formula I or II as described herein, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

E22: The invention includes all substituents in its corresponding deuterated form, wherever applicable, of the compounds of formula I or II.

E23: The invention includes all optical isomers, i.e. diastereoisomers, diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and/or tautomers as well as their solvates, wherever applicable, of the compounds of formula I or II.

The compounds of formula I or II may contain one or more asymmetric centers and can therefore occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within this invention. The present invention is meant to encompass all such isomeric forms of these compounds. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.

In the embodiments, where optically pure enantiomers are provided, optically pure enantiomer means that the compound contains > 90 % of the desired isomer by weight, particularly > 95 % of the desired isomer by weight, or more particularly > 99 % of the desired isomer by weight, said weight percent based upon the total weight of the isomer(s) of the compound. Chirally pure or chirally enriched compounds may be prepared by chirally selective synthesis or by separation of enantiomers. The separation of enantiomers may be carried out on the final product or alternatively on a suitable intermediate.

Compounds of formula (I) and (II) can be prepared according to the following processes. As described in the following general schemes 1 to 6 and using method known to the person silled in the art.

Scheme 1 : general scheme A

Degraders of formula (I) and (II) can be prepared by amide coupling of an CRBN intermediate of formula (III) or (V) with BRAF intermediate of formula (IV) in a solvent such as N,N- dimethylformamide, a base such as Huenig’s Base and a coupling reagent such as HATU.

Scheme 2: general scheme B Degraders of formula (I) or (II) can be prepared by treatment of CRBN intermediate of formula (VI) or (VII) with triphosgene in a solvent such as dichloromethane and a base such as Huenig’s Base. The carbamoyl intermediate is trapped in situ with an BRAF intermediate of formula (IV) in a solvent such as dichloromethane or N,N-dimethylformamide and a base such as Huenig’s Base.

Scheme 3 : general scheme C

CRBN intermediates of formula (VI) and (VII) can be prepared by thermal condensation of a fluoro-derivative of formula (VIII) with amino-acids of formula (IX) or (X) in a solvent such as DMSO or NMP and a base such as Huenig’s Base or triethylamine. Amino-acids of formula xxx and xxx are either commercially available or can be prepared by methods known in the art

(VI) or (VII) Scheme 4: general scheme D

CRBN intermediates of formula (VI) or (VII) can be obtained by alkylation of an compound of formula (XI) with an alkyl halogenide such as tert-butyl bromoacetate in a solvent such as N,N- dimethylformamide and a base such as Huenig’s Base.

Scheme 5: general scheme E

CRBN intermediates of formula (VI) or (VII) can be prepared by thermal condensation of an alkylated phenol derivative of formula (XII) with amino-glutarimide in a solvent such as acetonitrile and a base such as potassium carbonate. Phenol derivatives of formula (XII) are either commercially available or can be prepared by methods known in the art.

Scheme 6: general scheme F

Treatment of a protected intermediate of formula (XIII) with a sulfamoyl- or sulfonyl-chloride intermediate of formula (XIV) in a solvent such as pyridine at 80 °C gives rise to Bromo intermediates of formula (XV). Cross coupling of an intermediate of formula (XV) with a boronic acid ester of formula xxx in the presence of a palladium catalyst, e.g. formed in situ from palladium acetate and triphenylphosphine, and an inorganic base such as potassium carbonate gives an intermediate of formula (IV). ROUTE 1

(XIV)

Generally speaking, the sequence of steps used to synthesize the compounds of formula I or

II can also be modified in certain cases.

Isolation and purification of the compounds Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the preparations and examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used. Racemic mixtures of chiral compounds of formula I or II can be separated using chiral HPLC. Racemic mixtures of chiral synthetic intermediates may also be separated using chiral HPLC.

Salts of compounds of formula

In cases where the compounds of formula I or II are basic they may be converted to a corresponding acid addition salt. The conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. A specific salt is the fumarate. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid added in a similar solvent. The temperature is maintained between 0 °C and 50 °C. The resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent.

Insofar as their preparation is not described in the examples, the compounds of formula I or II as well as all intermediate products can be prepared according to analogous methods or according to the methods set forth herein. Starting materials are commercially available, known in the art or can be prepared by methods known in the art or in analogy thereto.

It will be appreciated that the compounds of general formula I or II in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.

Pharmacological Tests

The compounds of formula I or II and their pharmaceutically acceptable salts possess valuable pharmacological properties. The compounds were investigated in accordance with the test given hereinafter.

Materials DMEM no-phenol red medium supplemented with L-glutamine was purchased from (Coming). Fetal bovine serum (FBS) was purchased from Gibco (Grand Island, NY, USA). Nano- Glo® HiBiT Lytic Assay Buffer & Reagents were purchased from Promega (Madison, WI, USA). A375 (harboring BRAF homozygous V600E mutation) was purchased from ATCC. A375.10 cell line was generated from A375 cell line from ATCC by knocking-in a HiBiT tag at the N-terminal of BRAF^V600E protein via CRISPR technology. Cell culture flasks and 384-well black flat-bottom polystyrene TC-treated microplates were acquired from Corning (Corning, NY, USA).

HiBiT Cellular BRAF^V600E Degradation Assay

Prior to the assay, the A375.10 cell line is maintained in DMEM no-phenol red medium supplemented with 10% fetal bovine serum (FBS). Following compound treatment, BRAF^V600E degradation was determined based on quantification of HiBiT luminescence signal by lysing the cells followed by addition of Nano-Glo® HiBiT Lytic Assay Reagents. The luminescence signal detected correlates with the total BRAF^V600E protein level in cells. Briefly, test compounds were added to the 384-well plate from a top concentration of 10 mM with 11 half log dilutions of compound, plated in duplicate. Then, 30 uL of a suspension of A375.10 cell lines was dispensed into columns 1-24 of the 384-well plates at a cell density of 7500 cells per well. The plates were kept at 37 °C with 5% C02 for the duration of the assay (6 or 24 hr). After the desired incubation time with compound, 30 uL of Nano-Glo® HiBiT Lytic Buffer containing LgBiT protein (diluted 1:100) and luminescence substrate (diluted 1:50) were added to the cells in columns 1-23 of the assay plate. The plate was the incubated for 30 min on the bench at room temperature. Finally, HiBiT luminescence signal was acquired on EnVision™ Multilabel Reader (PerkinElmer, Santa Clara, CA, USA).

Quantification of luminescence responses measured in the presence of compound were normalized to a high signal/no degradation control (untreated cells + lytic detection reagent) and a low signal/full degradation control (untreated cells, no lytic detection reagent). Data were analyzed with a 4-parameter logistic fit to generate sigmoidal dose-response curves. The DC50 is the concentration of compound at which exactly 50% of the total cellular BRAF^V600E has been degraded. The Emax, or maximum effect of each compound, represents the amount of residual protein remaining in the cell following compound treatment.

Table 1: DC50 value

Pharmaceutical Compositions

The compounds of formula I or II and the pharmaceutically acceptable salts can be used as therapeutically active substances, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

The compounds of formula I or II and the pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, com starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatin capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can, moreover, contain pharmaceutically acceptable auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

Medicaments containing a compound of formula I or II or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also provided by the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I or II and/or pharmaceutically acceptable salts thereof and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.

The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or II or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated. The following examples illustrate the present invention without limiting it, but serve merely as representative thereof. The pharmaceutical preparations conveniently contain about 1-500 mg, particularly 1-100 mg, of a compound of formula I or II. Examples of compositions according to the invention are:

Example A Tablets of the following composition are manufactured in the usual manner:

Table 2: possible tablet composition Manufacturing Procedure

1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.

2. Dry the granules at 50°C. 3. Pass the granules through suitable milling equipment.

4. Add ingredient 5 and mix for three minutes; compress on a suitable press.

Example B-l Capsules of the following composition are manufactured:

Table 3: possible capsule ingredient composition Manufacturing Procedure

1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add ingredients 4 and 5 and mix for 3 minutes.

3. Fill into a suitable capsule.

The compound of formula I or II, lactose and corn starch are firstly mixed in a mixer and then in a comminuting machine. The mixture is returned to the mixer; the talc is added thereto and mixed thoroughly. The mixture is filled by machine into suitable capsules, e.g. hard gelatin capsules.

Example B-2

Soft Gelatin Capsules of the following composition are manufactured:

Table 4: possible soft gelatin capsule ingredient composition

Table 5: possible soft gelatin capsule composition Manufacturing Procedure

The compound of formula I or II is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are treated according to the usual procedures.

Example C

Suppositories of the following composition are manufactured:

Table 6: possible suppository composition Manufacturing Procedure The suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to

45°C. Thereupon, the finely powdered compound of formula I or II is added thereto and stirred until it has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to cool; the suppositories are then removed from the moulds and packed individually in wax paper or metal foil. Example D

Injection solutions of the following composition are manufactured:

Table 7: possible injection solution composition Manufacturing Procedure

The compound of formula I or II is dissolved in a mixture of Polyethylene Glycol 400 and water for injection (part). The pH is adjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

Example E

Sachets of the following composition are manufactured:

Table 8: possible sachet composition Manufacturing Procedure

The compound of formula I or II is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granulate is mixed with magnesium stearate and the flavoring additives and filled into sachets. Experimental Part

The following examples are provided for illustration of the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof.

Bromo-Intermediates

General procedure I: Treatment of anilines with sulfamoyl chlorides / sulfonyl chlorides

A mixture of (3-(3-amino-2,6-difluorobenzoyl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-l-yl)(2,6- dichlorophenyl)methanone CAS1501153-67-8 (1 eq) and an appropriately selected sulfamoyl chloride (3-4 eq) in pyridine (0.3 M) is stirred at 85 °C for 15-24 h. After cooling to room temperature the reaction mixture is partitioned between an organic solvent such as ethyl acetate or dichloromethane and 0.5M aqueous hydrogen chloride solution. The layers are separated. The aqueous layer is extracted with one or two portions of organic solvent. The combined organic layers are washed with one portion of 0.5 M aqueous hydrogen chloride solution, two 50-ml portions of 1 M sodium carbonate solution and one 50-ml portion of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification is done by flash-chromatography.

Bromo-Intermediate 1

5-Bromo-l-(2,6-dichlorobenzoyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro- benzoyl]pyrrolo[2,3-b]pyridine

The title compound was obtained as off-white solid in 52% with a purity of 85% by UV according to the general procedure V from (3-(3-amino-2,6-difluorobenzoyl)-5-bromo-lH-pyrrolo[2,3- b]pyridin-l-yl)(2,6-dichlorophenyl)methanone and ethyl(methyl)sulfamoyl chloride. MS m/e: 646.9 ([M+H+]⁺). Bromo-Intermediate 2

N-[3-[5-Bromo-l -(2, 6-di chi orobenzoyl)pyrrolo[2, 3 -b]pyridine-3 -carbonyl ]-2,4-difluoro- phenyl ] pyrroli dine- 1 - sulfonami de

The title compound was obtained as off-white solid in 92 % with a purity of 80% by UV, according to the general procedure V from (3-(3-amino-2,6-difluorobenzoyl)-5-bromo-lH-pyrrolo[2,3- b]pyridin-l-yl)(2,6-dichlorophenyl)methanone and cyclopentysulfamoyl chloride. MS m/e: 659.1 ([M+H+]⁺). Bromo-Intermediate 3

(3R)-N-[3-[5-Bromo-l-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4- difluoro-phenyl]-3-fluoro-pyrrolidine-l-sulfonamide

The title compound was obtained as brown solid in 47 % with a purity of 77% by UV, according to the general procedure V from (3-(3-amino-2,6-difluorobenzoyl)-5-bromo-lH-pyrrolo[2,3- b]pyri din- l-yl)(2, 6-di chi orophenyl)methanone and (R)-3-fluoropyrrolidine-l-sulfamoyl chloride. MS m/e: 675, 677 ([M+H+]⁺).

Bromo-Intermediate 4 RS-N-[3-[5-Bromo-l-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro- phenyl]butane-2-sulfonamide

To a solution of (3-(3-amino-2,6-difluorobenzoyl)-5-bromo-lH-pyrrolo[2,3-b]pyridin-l-yl)(2,6- dichlorophenyl)methanone (1 g, 1.9 mmol, Eq: 1) and pyridine (904 mg, 924 mΐ, 11.4 mmol, Eq: 6) in tetrahydrofuran (9.52 ml) was added butane-2-sulfonyl chloride (895 mg, 5.71 mmol, Eq:

3) at RT. The reaction mixture was heated at 65 °C for 3 d. The reaction mixture was partitioned between ethyl acetate (50 ml) and 0.5 M aqueous hydrogen chloride solution (30 ml). The layers were separated. The aqueous layer was extracted with one 50-ml portion of ethyl acetate. The combined organic layers were washed with one 30-ml portion of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography to give the title compound (0.425 g, 35%) as off-white solid, MS m/e: 646.1 ([M+H+]⁺).

BRAE Intermediates

General procedure II: a) Suzuki cross coupling, b) 2,6-dichlorobenzoyl deprotection, c)

N-BOC deprotection a) To a mixture of an appropriately selected sulfamoyl intermediate (1 eq) or sulfonamide intermediate (1 eq), a boronic acid which is either commercially available or prepared by methods known in the art (1.5 eq) and potassium carbonate (3 eq) in 1, 2-dimethoxy ethane / water (4:1, 0.1- 0.2 M), which has been purged with argon, are consecutively added triphenylphosphine (0.1 eq) and palladium(II)acetate (0.05 eq). The mixture is stirred at reflux for 3-20 h. After cooling to room temperature the reaction mixture is partitioned between an organic solvent such as ethyl acetate or dichloromethane and 1M sodium bicarbonate solution. The layers are separated. The aqueous layer is extracted with one or two portions of organic solvent. The combined organic layers are washed with one portion of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by flash-chromatography gives the desired intermediate 1001. b) To a solution of an intermediate 1001 in methanol (0.1-0.3 M) is added potassium carbonate (3-5 eq). The mixture is stirred at reflux for 30-60 minutes. After cooling to room temperature the reaction mixture is filtrated over Decalite. The filtrate is concentrated in vacuo. Purification by flash-chromatography gives an intermediate 1002. c) A solution of an intermediate 1002 (1 eq) in dichloromethane (0.1 M) and trifluoroacetic acid (20 eq) is stirred at room temperature for 6-20 h. Alternatively an intermediate of formula xxx is stirred at room temperature in a solvent such as ethyl acetate or tetrahydrofuran (0.1-0.2M) and 4M hydrogen chloride solution in 1,4-dioxane (10 eq) for 20-72 h. The precipitate is filtrated and washed with ethyl acetate to give the an intermediate of formula xxx as hydrochloride salt. Optionally the free base can be obtained by partitioning the hydrochloride or trifluoroacetic acid salt between 1 M aqueous sodium carbonate solution and an organic solvent, e.g. ethyl acetate or dichloromethane. The layers are separated and the aqueous layer is extracted with two portions of the organic solvent. The combined organic layers are dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the free base of the desired BRAF intermediate.

BRAF Intermediate 1

3-[3-[[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(6-piperazin-l-yl-3- pyri dyl)- 1 H-pyrrol o [2, 3 -b ] pyri dine

The title compound was obtained as light yellow solid according to the general procedure VII after two deprotection steps, from 5-bromo-l-(2,6-dichlorobenzoyl)-3-[3-

[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]pyrrolo[2,3-b]pyridine and (6-(4-(tert- butoxycarbonyl)piperazin- l-yl)pyri din-3 -yl)boronic acid. MS m/e: 556 ([M+H+]⁺).

BRAF Intermediate 2

3-[3-[[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-(piperazin-l- ylmethyl)phenyl]-lH-pyrrolo[2,3-b]pyridine

The title compound was obtained as light brown solid according to the general procedure VII after two deprotection steps, from 5-bromo-l-(2,6-dichlorobenzoyl)-3-[3-

[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]pyrrolo[2,3-b]pyridine and tert-butyl 4- [[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazine-l-carboxylate. MS m/e: 569 ([M+H+]⁺).

BRAF Intermediate 3

3-[3-[[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-piperazin-l- ylpyrimidin-5-yl)-lH-pyrrolo[2,3-b]pyridine

The title compound was obtained as off-white solid according to the general procedure VII after two deprotection steps, from 5-bromo-l-(2,6-dichlorobenzoyl)-3-[3-

[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]pyrrolo[2,3-b]pyridine and (2-(4-(tert- butoxycarbonyl)piperazin-l-yl)pyrimidin-5-yl)boronic acid. MS m/e: 557 ([M+H+]⁺).

BRAF Intermediate 4

3-[3-[[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[6-(piperazin-l- ylmethyl)-3-pyridyl]-lH-pyrrolo[2,3-b]pyridine

[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]pyrrolo[2,3-b]pyridine and (6-((4-(tert- butoxycarbonyl)piperazin- l-yl)methyl)pyri din-3 -yl)boronic acid. MS m/e: 570 ([M+H+]⁺).

BRAF Intermediate 5

3-[3-[[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(4-piperazin-l-ylphenyl)- lH-pyrrolo[2,3-b]pyridine

The title compound was obtained as light solid according to the general procedure VII after two deprotection steps, from 5-bromo-l-(2,6-dichlorobenzoyl)-3-[3-

[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]pyrrolo[2,3-b]pyridine and (4-(4-(tert- butoxycarbonyl)piperazin-l-yl)phenyl)boronic acid. MS m/e: 555 ([M+H+]⁺).

BRAF Intermediate 6

3-[3-[[cyclopropyl(methyl)sulfamoyl]amino]-2_,6-difluoro-benzoyl]-5-[4-(piperazin-l - ylmethyl)phenyl]-lH-pyrrolo[2,3-b]pyridine

a) tert-butyl4-[[4-[3-(3-amino-2,6-difluoro-benzoyl)-l-(2,6-dichlorobenzoyl)pyrrolo[2,3- b]pyridin-5-yl]phenyl]methyl]piperazine-l-carboxylate

A mixture of compound tert-butyl4-[[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl]methyl]piperazine-l-carboxylate (2.433 g ,6.05 mmol), and (3 -amino-2, 6-difluoro- phenyl)-[5-bromo-l-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridin-3-yl]methanone (3.176 g, 6.05 mmol), l,r-bis(diphenylphosphino)ferrocene-palladium(II)di chloride dichloromethane complex (494.0 mg, 0.610 mmol) and potassium carbonate (1.673 g, 12.11 mmol) in 1,4-dioxane (50 mL) was stirred at 100⁰ C for 15 hours under N2. The mixture was filtered through celite, the filtrate was concentrated in vacuo to give a residue, which was purified by column chromatography on silica to afford tert-butyl4-[[4-[3-(3-amino-2,6-difluoro-benzoyl) -l-(2,6- dichlorobenzoyl)pyrrolo[2,3-b]pyridin-5-yl]phenyl]methyl]piperazine-l-carboxylate (3120 mg, 71.6% yield) as yellow solid, MS m/e: 720.4 ([M+H+]⁺). b) tert-butyl4-[[4-[3-[3-[[cyclopropyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-l-(2,6- dichlorobenzoyl)pyrrolo[2,3-b]pyridin-5-yl]phenyl]methyl]piperazine-l-carboxylate

To a solution of compound tert-butyl4-[[4-[3-(3-amino-2,6-difluoro-benzoyl)-l-(2,6- dichlorobenzoyl)pyrrolo[2,3-b]pyridin-5-yl]phenyl]methyl]piperazine-l-carboxylate (1500.0 mg, 2.08 mmol, 1 eq) in DCM (75 mL) was added Triethylamine (0.87 mL, 6.24 mmol, 3 eq) and sulfuryl chloride (365.24 mg, 2.71 mmol, 1.3 eq) at -30 °C. After 2 h, N- methylcyclopropanamine (222.07 mg, 3.12 mmol, 1.5 eq) was added to the reaction, the reaction was stirred at -30°C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column on silica and concentrated under reduced pressure to give a mixture (1.3 g) as a yellow solid. The above material was purified by prep- HPLC to give tert-butyl 4-[[4-[3-[3-[[cyclopropyl(methyl)sulfamoyl]amino]-2,6-difluoro- benzoyl]-l-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridin-5-yl]phenyl]methyl]piperazine-l- carboxylate (760 mg, 0.890 mmol, 37.2% yield) as a brown oil. MS m/e: 853.1 ([M+H+]⁺). c) 3-[3-[[cyclopropyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-(piperazin-l- ylmethyl)phenyl]-lH-pyrrolo[2,3-b]pyridine hydrochloride

According to the general procedure VII starting from tert-butyl 4-[[4-[3-[3- [[cyclopropyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-l-(2,6- dichlorobenzoyl)pyrrolo[2,3-b]pyridin-5-yl]phenyl]methyl]piperazine-l-carboxylate (750.0 mg, 0.760 mmol) and using only the two deprotection steps, the title compound was obtained as white solid (360 mg, 0.580 mmol, 94% yield) MS m/e: 581.1 ([M+H+]⁺).

BRAF Intermediate 7

N-[2,4-difluoro-3-[5-[4-(piperazin-l-ylmethyl)phenyl]-lH-pyrrolo[2,3-b]pyridine-3- carbonyl]phenyl]pyrrolidine-l -sulfonamide

Using to the above procedure described for BRAF Intermediate 6 starting from tert-butyl4-[[4- [3-(3-amino-2,6-difluoro-benzoyl)-l-(2,6-dichlorobenzoyl)pyrrolo[2,3-b]pyridin-5- yl]phenyl]methyl]piperazine-l-carboxylate, sulfuryl chloride and pyrrolidine, the title compound was obtained as white solid (800 mg, 70%, purity 98 %), MS m/e: 581.1 ([M+H+]⁺).

BRAF Intermediate 8

3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-[[rac-(lS,5R)-3,8- diazabicyclo[3.2.1]octan-3-yl]methyl]phenyl]-lH-pyrrolo[2,3-b]pyridine

a) tert-Butyl 3-[[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]methyl]-3,8- diazabicyclo[3.2.1 ]octane-8-carboxylate In a 25ml sealed tube, 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (500 mg, 1.68 mmol, Eq: 1), K2C03 (465 mg, 3.37 mmol, Eq: 2) and tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (357 mg, 1.68 mmol, Eq: 1, CAS 149771-44-8) were combined with DMF (8.03 ml) to give a white suspension. The reaction mixture was heated to 23 °C and stirred for 20 h under argon. The crude reaction mixture was concentrated in vacuo, then diluted with AcOEt (10 ml) and 5 ml water, applicated over Chem Elut Cartridge (lOg), eluted with AcOEt (100 ml). The crude reaction mixture was concentrated in vacuo and dried under vacuo over night. A white solid (716 mg; yield 99%; UV purity 83%) was used without further purification for the next step. LCMS (ESI+) : 429.2 (M+H) b) tert-Butyl 3-[[4-[3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-lH- pyrrolo[2,3-b]pyridin-5-yl]phenyl]methyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

In a 20 mL sealed tube, tert-butyl 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (362 mg, 845 pmol, Eq: 2), 5-bromo-3-[3- [[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-lH-pyrrolo[2,3-b]pyridine (200 mg, 423 pmol, Eq: 1) and potassium carbonate (175 mg, 1.27 mmol, Eq: 3) were combined with Dioxane (3 ml) and water (0.3 ml) to give a brown suspension under argon. XPHOS PD G2 (66.5 mg, 84.5 pmol, Eq: 0.2) and XPHOS (40.3 mg, 84.5 pmol, Eq: 0.2) were added. The reaction mixture was heated to 130 °C and stirred for 2 h. The reaction mixture was diluted with AcOEt (10 ml) and water (5 ml), applicated over Chem Elut Cartridge (lOg), eluted with AcOEt (100 ml) and concentrated in vacuo. The crude material was purified by flash chromatography to give brown residue (220 mg; yield 74%; UV purity 68%). LCMS (ESI+) : 695.4 (M+H)

c) 5-[4-(3,8-diazabicyclo[3.2.1]octan-3-ylmethyl)phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-

2.6-difluoro-benzoyl]-lH-pyrrolo[2,3-b]pyridine;2,2,2-trifluoroacetic acid

In a 25 mL round-bottomed flask, tert-butyl 3-(4-(3-(3-((N-ethyl-N-methylsulfamoyl)amino)-

2.6-difluorobenzoyl)-lH-pyrrolo[2,3-b]pyridin-5-yl)benzyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (220 mg, 317 pmol, Eq: 1) was combined with DCM (10 ml) to give a yellow solution. TFA (1.48 g, 1 ml, 13 mmol, Eq: 41) was added. The reaction mixture was heated to 23 °C and stirred for 20 h. The crude reaction mixture was concentrated in vacuo. The crude material was triturated with EtOAc and heptane to give K1 176 mg (78% yield; UV purity 100%) as white solid. LCMS (ESI+) : 595.2 (M+H)

BRAF Intermediate 9

3 -[3 -[[ethyl (methyl )sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-[[4-(4-pi peri dyl)piperazin-l - yl ] methyl ] phenyl ] - 1 H-pyrrol o [2, 3 -b ] pyri dine

a) tert-butyl 4-[4-[[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]methyl]piperazin-l- yl]piperidine-l-carboxylate

In a 250 mL round-bottomed flask, 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzaldehyde (862 mg, 3.71 mmol, Eq: 1), tert-butyl 4-(piperazin-l-yl)piperidine-l-carboxylate (lg, 3.71 mmol, Eq: 1) and acetic acid (223 mg, 213 mΐ, 3.71 mmol, Eq: 1) were combined with DCM (35ml) to give a light yellow solution. The reaction mixture was stirred for 15min at RT. Sodium triacetoxyborohydride (1.02 g, 4.83 mmol, Eq: 1.3) was added. The reaction mixture was stirred over night at RT, then diluted with AcOEt (10 ml) and water (5 ml), applicated over Chem Elut Cartridge (lOg), eluted with AcOEt (100 ml). The crude reaction mixture was concentrated in vacuo to give 3.5 g (83%, purity 43%) as white gum used for the next step without purification. b) tert-butyl 4-[4-[[4-[l-(2,6-dichlorobenzoyl)-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6- difluoro-benzoyl]pyrrolo[2,3-b]pyridin-5-yl]phenyl]methyl]piperazin-l-yl]piperidine-l- carboxylate

In a 20 mL tube, tert-butyl 4-(4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzyl)piperazin-l-yl)piperidine-l-carboxylate (2.39 g, 2.11 mmol, Eq: 2), 5-bromo-3-[3- [[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-lH-pyrrolo[2,3-b]pyridine (500 mg, 1.06 mmol, Eq: 1) and potassium carbonate (292 mg, 2.11 mmol, Eq: 2) were combined with Dioxane (7.5 ml) and water (2ml) to give a light yellow suspension. Chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-l,r-biphenyl)[2-(2'-amino-l,r- biphenyl)]palladium(II) (XPHOS PD G2) (166 mg, 211 pmol, Eq: 0.2) and 2- ( dicyclohexylphosphino)-2',4',6'- triisopropylbiphenyl (XPHOS) (101 mg, 211 pmol, Eq: 0.2) were added under argon. The reaction mixture was heated to 130 °C and stirred for 1.5h, and then concentrated in vacuo. The reaction mixture was diluted with AcOEt (10 ml) and water (5 ml), applicated over Chem Elut Cartridge (lOg), eluted with AcOEt (100 ml) and the volatiles were removed. The above material was purified by flash chromatography to give 488mg (61%, purity 87%) of a orange oil. LCMS (ESI+) : 752.6 (M+H). c) 3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-[[4-(4-piperidyl)piperazin- l-yl]methyl]phenyl]-lH-pyrrolo[2,3-b]pyridine; 2,2,2-trifluoroacetic acid

In a 150 mL round-bottomed flask, tert-butyl 4-(4-(4-(3-(3-((N-ethyl-N- methylsulfamoyl)amino)-2,6-difluorobenzoyl)-lH-pyrrolo[2,3-b]pyridin-5-yl)benzyl)piperazin- l-yl)piperidine-l-carboxylate (488mg, 649 pmol, Eq: 1) and TFA (740 mg, 500 pi, 6.49 mmol, Eq: 10) were combined with DCM (5 ml) to give a orange suspension. The reaction was stirred for 1.5hr at RT. The reaction mixture was concentrated in vacuo to give 593 mg light brown solid. Recrystallization from EtOAc and heptane afforded a light brown solid. K1 362 mg 73% purity 97% LCMS (ESI+) : 652.6 (M+H)

BRAF Intermediate 10

N-[2,4-difluoro-3-[5-(6-piperazin-l-yl-3-pyridyl)-lH-pyrrolo[2,3-b]pyridine-3- carbonyl]phenyl]butane-2-sulfonamide

The title compound was obtained as off-white solid according to the general procedure VII after two deprotection steps, from N-(3-(5-bromo-l-(2,6-dichlorobenzoyl)-lH-pyrrolo[2,3-b]pyridine- 3-carbonyl)-2,4-difluorophenyl)butane-2-sulfonamide and (6-(4-(tert-butoxycarbonyl)piperazin- l-yl)pyri din-3 -yl)boronic acid. MS m/e: 555 ([M+H+]⁺). CRBN Intermediates

CRBN Intermediate 1

2-[l-[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindol-4-yl]piperidin-4-yl]acetic acid

A mixture of 2-(4-piperidyl)acetic acid hydrochloride (2341.26 mg, 13.03 mmol, 1.2 eq) 2 -(2, 6- dioxo-3-piperidyl)-4-fluoro-isoindoline-l,3-dione (3000.0 mg, 10.86 mmol, 1 eq) N,N- Diisopropylethylamine (5.68 mL, 32.58 mmol, 3 eq) in DMSO (50 mL) was stirred at 100 °C for 16 h. The reaction mixture was poured into water(500mL), and then the mixture was extracted with EtOAc (200.0 mL x 3). The combined organic layers were washed with brine (250.0 mL), dried (Na2S04) and concentrated to give a residue. The residue was dissolved in ACN(30mL) and stirred for 5 min, then a yellow solid was precipitated, filtered and the filter cake was dried under high vacuum to afford2-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-4- piperidyljacetic acid (2300 mg, 5.76 mmol, 52% yield, purity 98% ) as a yellow solid, MS m/e : 400.1 ([M+H+]⁺).

CRBN Intermediate 2

2-[l-[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindol-4-yl]pyrrolidin-3-yl]acetic acid

A mixture of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-l,3-dione (CAS 835616-60-9) (0.3 g, 1.09 mmol, Eq: 1), 2-(pyrrolidin-3-yl)acetic acid hydrochloride (234 mg, 1.41 mmol, Eq: 1.3) and N,N-diisopropylethylamine (421 mg, 569 mΐ, 3.26 mmol, Eq: 3) in N-methyl-2-pyrrolidinone (2.17 ml) was heated at 150 °C and stirred for 1 h. The reaction mixture was partitioned between ethyl acetate (30 ml) and 0.1 M aqueous hydrogen chloride solution (30 ml). The layers were separated. The aqueous layer was extracted with two 30-ml portions of ethyl acetate. The combined organic layers were washed with one 30-ml portion of 0.1 M aqueous hydrogen chloride solution and one 20-ml portion of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated in ethyl acetate (5-ml). The precipitate was collected by filtration, washed with cold ethyl acetate and dried in vacuo to give the title compound (0.395 g, 94 %; purity 100%) as yellow solid. MS m/e : 386.1 ([M+H+]⁺)

CRBN Intermediate 3

3-[l-[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindol-4-yl]piperidin-4-yl]propanoic acid

Using a procedure analogous to that described in example CRBN intermediate 1 starting from 2- (2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-l,3-dione and 3-(4-piperidyl)propanoic acid hydrochloride, the title compound was obtained as yellow solid (2.30 g, 50%, purity 97%), MS m/e : 414.1 ([M+H+]⁺).

CRBN Intermediate 4 4-[[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindol-4-yl]amino]cyclohexane-l-carboxylic acid

To a solution of trans-4-aminocyclohexanecarboxylic acid (0.5 g, 3.49 mmol, 1 eq) in NMP (4 mL) was added 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-l,3-dione (0.96 g, 3.49 mmol, 1 eq) and TEA (1059.46 mg, 10.47 mmol, 3 eq), and the reaction mixture was stirred at 150 °C for 1 h at microwave. Purification by HPLC-prep (HC1) afford 4-[[2-(2,6-dioxo-3-piperidyl)-l,3- dioxo-isoindolin-4-yl]amino]cyclohexanecarboxylic acid (0.480 g, 1.2 mmol, 34 % yield) as yellow solid, MS m/e : 400 ([M+H]⁺ ).

CRBN Intermediate 5 3-[[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindol-4-yl]amino]cyclobutane-l-carboxylic acid

The title compound was obtained as a yellow solid (0.21 g, 52%), MS m/e : 372 ([M+H+]⁺), using an analogous procedure to the one used for example CRBN intermediate 2 starting from 2-(2,6- dioxo-3-piperidyl)-4-fluoro-isoindoline-l,3-dione and (lR,3R)-3-aminocyclobutane-l-carboxylic acid hydrochloride.

CRBN Intermediate 6

2-[4-[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindol-5-yl]oxypiperidin-l-yl]acetic acid

a) tert-Butyl 2-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)oxy)piperidin-l- yl)acetate

To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yloxy)isoindoline-l,3-dione CAS2222116-10-9-(93 mg, 260 pmol, Eq: 1) and tert-butyl 2-bromoacetate (45.7 mg, 34.6 mΐ,

234 pmol, Eq: 0.9) in N,N-dimethylformamide (2.6 ml) was added DIPEA (101 mg, 136 pi, 781 pmol, Eq: 3). The reaction mixture was heated at 60 °C for 15 h. The reaction mixture was partitioned between ethyl acetate (15 ml) and 1 M sodium bicarbonate solution (10 ml). The layers were separated. The aqueous layer was extracted with 1 10-ml portions of ethyl acetate. The combined organic layers were washed with 3 10-ml portion of water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give off-white solid (125 mg, 100%, purity 100%), MS m/e : 472 ([M+2]⁺). b) 2-[4-[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindol-5-yl]oxypiperidin-l-yl]acetic acid

To a solution of tert-butyl 2-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)oxy)piperidin-l-yl)acetate (125 mg, 265 pmol, Eq: 1) in dichloromethane (2.65 ml) was added trifluoroacetic acid (605 mg, 408 pi, 5.3 mmol, Eq: 20). The reaction mixture was stirred at rt for 30 hours, then concentrated in vacuo. Kugelrohr distillation was used to remove excess of DMF from previous step. The title compound was obtained as white powder (110 mg, 98%, purity 98%), MS m/e : 416 ([M+H+]⁺).

CRBN Intermediate 7

3-[l-[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindol-4-yl]azetidin-3-yl]propanoic acid

The title compound was obtained as a yellow solid (0.25 g, 25%), MS m/e : 386 ([M+H+]⁺), using an analogous procedure to the one used for example CRBN intermediate 2 starting from 2-(2,6- dioxo-3-piperidyl)-4-fluoro-isoindoline-l,3-dione and 3-(azetidin-3-yl)propanoic acid hydrochloride.

CRBN Intermediate 8 l-[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindol-5-yl]piperidine-4-carboxylic acid

The title compound was obtained as light green solid (2.93 g, 67%, purity 95%), MS m/e : 386.0 ([M+H+]⁺), using a procedure analogous to that described in example CRBN intermediate 1 starting from 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-l,3-dione and isonipecotic acid.

CRBN Intermediate 9 2-[l-[2-(2,6-Dioxopiperidin-3-yl)-l,3-dioxoisoindol-5-yl]piperidin-4-yl]acetic acid

Using a procedure analogous to that described in example CRBN intermediate 1 starting from 2- (2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-l,3-dione and 2-(4-piperidyl)acetic acid hydrochloride, the title compound was obtained as yellow solid (2.12 g, 47%, purity 97%), MS m/e : 400.3 ([M+H+]⁺).

CRBN Intermediate 10

4-[[2-(2,6-dioxopiperidin-3-yl)- l -oxo-3//-isoindol-4-yl]oxy]butanoic acid

a) Methyl 4-(4-tert-butoxy-4-oxo-butoxy)-2-methyl-benzoate

In a round-bottom flask, methyl 3-hydroxy-2-methylbenzoate (2.0 g, 12.04 mmol, 1 eq) was dissolved in DMF (10 mL) and K₂CO₃ (3.32 g, 24.07 mmol, 2 eq) were added to the stirred solution. Then t-butyl 4-bromobutanoate (3.22 g, 14.44 mmol, 1.2 eq) was added dropwise. The resulting mixture was stirred at 60 °C for 12 h. The reaction mixture was purified by prep-HPLC (ACID) to afford methyl 3-(4-tert-butoxy-4-oxo-butoxy)-2- methyl -benzoate (3 g, 9.73 mmol, 80 % yield, purity >95%) as white solid. b) Methyl 2-(bromomethyl)-3-(4-tert-butoxy-4-oxo-butoxy)benzoate

A mixture of methyl 4-(4-tert-butoxy-4-oxo-butoxy)-2-m ethyl -benzoate (3.7 g, 12 mmol, 1 eq), N-bromosuccinimide (2.35 g, 13.2 mmol, 1.1 eq) and 2,2'-azobis(2- methylpropionitrile) (0.2 g, 1.2 mmol, 0.100 eq) in carbon tetrachloride (200 mL) was stirred at 80 °C for 4 h under N2 atmosphere. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to give methyl 2-(bromomethyl)-4-(4-tert-butoxy-4-oxo-butoxy)benzoate (4.65 g) as a light yellow oil. c) tert-Butyl 4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxybutanoate

To a solution of methyl 2-(bromomethyl)-3-(4-tert-butoxy-4-oxo-butoxy)benzoate (4.0 g, 10.33 mmol, 1 eq) in ACN (70 mL) was added K₂CO₃ (11.49 g, 82.63 mmol, 8 eq) and 3-aminopiperidine-2,6-dione hydrochloride (1.7 g, 10.33 mmol, 1 eq), and the reaction mixture was stirred at 80 °C for 12 h. Purification by Prep-HPLC(acid) afford tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxybutanoate (1 g, 2.48 mmol, 24% yield, purity 63%) as light yellow solid. d) 4-[2-(2,6-Dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxybutanoic acid

To a solution of tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4- yljoxybutanoate (1.0 g, 2.48 mmol, 1 eq) in DCM (15 mL) was added TFA (5.0 mL, 2.48 mmol, 1 eq), and the reaction mixture was stirred at 25 °C for 12 h. Purification by prep- HPLC(TFA) afford 4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxybutanoic acid (0.270 g, 0.780 mmol, 30 % yield, purity 95%) as light yellow solid, MS m/e : 347 ([M+H+]⁺).

GENERAL COUPLING PROCEDURE General procedure III: Amide coupling

To a mixture of an appropriately selected acid CRBN intermediate (1 eq) in a solvent such as N,N-dimethylformamide or N-methylpyrrolidone (0.1-0.3 M) is added a coupling reagent such as HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; 1 eq). The reaction mixture is stirred at room temperature for 30 minutes. An appropriately selected BRAF intermediate is added and stirring is continued for 1-24 h. The reaction mixture is partitioned between an organic solvent such as ethyl acetate or dichloromethane/methanol (19:1) and 1M sodium bicarbonate solution. The layers are separated. The aqueous layer is extracted with one or two portions of organic solvent. The combined organic layers are washed with one portion of brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by flash-chromatography with dichloromethane / methanol or by preparative HPLC give the desired degrader.

General procedure IV: Urea formation

To a solution of an appropriately selected CRBN intermediate (1 eq) in a solvent mixture consisting of tetrahydrofuran and dichloromethane (1:1 to 5:1, 0.003 M) is added N-N- diisopropylethyl amine (5 eq) and bis(trichloromethyl)carbonate (0.4 eq) at room temperature. After lh, an appropriately selected BRAF intermediate (1 eq) is added to the reaction. The reaction mixture is heated to 60-70 °C and stirring is continued for 2-12 h. The solvent mixture is evaporated and the residue is purified by preparative HPLC to give the desired degrader. Example 1

5-[4-[[4-[4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]butanoyl]piperazin-l- yl]methyl]phenyl]-3 -[3 -[[ethyl (methyl )sulfamoyl]amino]-2,6-difluoro-benzoyl]-l //-pyrrol o[2, 3- b] pyri dine

According to general procedure III starting from 4-[[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]amino]butanoic acid (CAS 2225940-47-4) and 3-[3- [[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-(piperazin-l-ylmethyl)phenyl]-lH- pyrrolo[2,3-b]pyridine (BRAF Intermediate 2), the title compound was obtained as yellow solid, MS m/e: 910.3 ([M+H+ j ).

Example 2

5-[4-[[4-[3-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-4- piperidyl]propanoyl]piperazin-l-yl]methyl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6- difluoro-b enzoyl ] - 1 H-py rrol o [2, 3 -b ] pyri dine According to general procedure III starting from 3-[l-[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]piperidin-4-yl]propanoic acid (CRBN Intermediate 3) and 3-[3- [[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-(piperazin-l-ylmethyl)phenyl]-lH- pyrrolo[2,3-b]pyridine (BRAF Intermediate 2), the title compound was obtained as white solid, MS m/e: 964.4 ([M+H+ j ).

Example 3

5-[4-[[4-[2-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-4- piperidyl]acetyl]piperazin-l-yl]methyl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6- difluoro-b enzoyl ] - 1 H-py rrol o [2, 3 -b ] pyri dine

According to general procedure III starting from 2-[l-[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]piperidin-4-yl]acetic acid (CRBN Intermediate 1) and 3-[3- [[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-(piperazin-l-ylmethyl)phenyl]-lH- pyrrolo[2,3-b]pyridine (BRAF Intermediate 2), the title compoundwas obtained as yellow solid, MS m/e: 950.4 (/M H / ).

Example 4

3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-[[rac-(lR,5S)-8-[4-[[2-(2,6- dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]butanoyl]-3,8-diazabicyclo[3.2.1]octan-3- yl ] methyl ] phenyl ] - 1 //-pyrrol o [2, 3 -b ] pyri dine According to general procedure III starting from 4-[[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]amino]butanoic acid (CAS 2225940-47-4) and 3-[3- [[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-[[rac-(lS,5R)-3,8- diazabicyclo[3.2.1]octan-3-yl]methyl]phenyl]-lH-pyrrolo[2,3-b]pyridine (BRAF Intermediate 8), the title compound was obtained as yellow solid (10 mg, 19%), MS m/e: 936.4 ([M+H+]⁺).

Example 5

5-[6-[[4-[4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]butanoyl]piperazin-l- yl]methyl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-l//- pyrrolo[2,3-b]pyridine

According to general procedure III starting from 4-[[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]amino]butanoic acid (CAS 2225940-47-4) and 3-[3-

[[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[6-(piperazin-l-ylmethyl)-3-pyridyl]- lH-pyrrolo[2,3-b]pyridine (BRAF Intermediate 4), the title compound was obtained as white solid, MS m/e: 456 (/M 2 H / ).

Example 6

5-[2-[4-[3-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-4- piperidyl]propanoyl]piperazin-l-yl]pyrimidin-5-yl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6- difluoro-benzoyl]- l//-pyrrolo[2,3-b]pyridine

According to general procedure III starting from 3-[l-[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]piperidin-4-yl]propanoic acid (CRBN Intermediate 3) and 3-[3- [[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-piperazin-l-ylpyrimidin-5-yl)-lH- pyrrolo[2,3-b]pyridine (BRAF Intermediate 3), the title compound was obtained as white solid, MS m/e: 953 ([M+H+ j ).

Example 7

5-[2-[4-[4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]butanoyl]piperazin-l- yl]pyrimidin-5-yl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-lH-pyrrolo[2,3- b] pyridine

According to general procedure III starting from 4-[[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]amino]butanoic acid (CAS 2225940-47-4) and 3-[3- [[Ethyl (methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-piperazin-l-ylpyrimidin-5-yl)-lH- pyrrolo[2,3-b]pyridine (BRAF Intermediate 3), the title compoundwas obtained as yellow solid, MS m/e: 898 (/M H / ).

Example 8

N-[3-[5-[4-[[4-[4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl]amino]butanoyl]piperazin-l -yl]methyl]phenyl] - l//-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4- difluoro-phenyl]pyrrolidine-l -sulfonamide formic acid According to general procedure III starting from 4-[[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]amino]butanoic acid (CAS 2225940-47-4) and N-[2,4-difluoro-3-[5-[4- (piperazin-l-ylmethyl)phenyl]-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]pynOlidine-l- sulfonamide (BRAF Intermediate 7), the title compoundwas obtained as yellow solid (55 mg, 28% yield), MS m/e: 922.0 (/M H / ).

Example 9

3-[3-[[cyclopropyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-[[4-[4-[[2-(2,6-dioxo-3- piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]butanoyl]piperazin-l-yl]methyl]phenyl]-l/7- pyrrolo[2,3-b]pyridine formic acid

According to general procedure III starting from 4-[[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]amino]butanoic acid (CAS 2225940-47-4) and 3-[3- [[cyclopropyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-(piperazin-l- ylmethyl)phenyl]-lH-pyrrolo[2,3-b]pyridine (BRAF Intermediate 6), the title compoundwas obtained as yellow solid (20.8 mg, 25% yield), MS m/e: 922.0 (/M H j ).

Example 10

5-[6-[4-[3-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-4- piperidyl]propanoyl]piperazin-l-yl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6- difluoro-benzoyl]-l//-pyrrolo[2,3-b]pyridine According to general procedure III starting from 3-[l-[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]piperidin-4-yl]propanoic acid (CRBN Intermediate 3) and 3-[3- [[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(6-piperazin-l-yl-3-pyridyl)-lH- pyrrolo[2,3-b]pyridine (BRAF Intermediate 1), the title compound was obtained as yellow solid, MS m/e: 951.4 ([M+H+ j ).

Example 11

5-[6-[4-[4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]butanoyl]piperazin-l-yl]- 3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-l //-pyrrol o[2, 3- b] pyridine

According to general procedure III starting from 4-[[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]amino]butanoic acid (CAS 2225940-47-4) and 3-[3- [[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(6-piperazin-l-yl-3-pyridyl)-lH- pyrrolo[2,3-b]pyridine (BRAF Intermediate 1 ), the title compoundwas obtained as white solid, MS m/e: 897.3 (/M H / ).

Example 12

5-[6-[4-[4-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]oxypiperidine-l- carbonyl]piperazin-l-yl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro- benzoyl]-l /-pyrrolo[2,3-b]pyridine According to general procedure IV starting from 2-(2,6-Dioxo-3-piperidyl)-5- (4piperidyloxy)isoindoline-l,3-dione (CRBN Intermediate 6) and 3-[3- [[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(6-piperazin-l-yl-3-pyridyl)-lH- pyrrolo[2,3-b]pyridine (BRAF Intermediate 1 ), the title compoundwas obtained as white solid, MS m/e: 939.5 (/M H / ).

Example 13

5-[6-[4-[4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl]amino]cyclohexanecarbonyl]piperazin-l-yl]-3-pyridyl]-3-[3- [[ethyl (methyl )sulfamoyl]amino]-2,6-difluoro-benzoyl]-l //-pyrrol o[2,3-b]pyri dine

According to general procedure III starting from 4-[[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]amino]cyclohexane-l -carboxylic acid (CRBN Intermediate 4) and 3-[3- [[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(6-piperazin-l-yl-3-pyridyl)-lH- pyrrolo[2,3-b]pyridine (BRAF Intermediate 1 ), the title compound was obtained as white solid, MS m/e: 937.6 (/M H / ).

Example 14

[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-l /-pyrrolo[2,3-b]pyridine

According to general procedure III starting from 3-[[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]amino]cyclobutane-l-carboxylic acid (CRBN Intermediate 5) and 3-[3- [[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-(piperazin-l-ylmethyl)phenyl]-lH- pyrrolo[2,3-b]pyridine (BRAF Intermediate 2), the title compoundwas obtained as white solid, MS m/e: 922 ([M+H+ j ).

Example 15

[[ethyl (methyl )sulfamoyl]amino]-2,6-difluoro-benzoyl]-l //-pyrrol o[2,3-b]pyri dine

According to general procedure III starting from 3-[[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]amino]cyclobutane-l-carboxylic acid (CRBN Intermediate 5) and 3-[3- [[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[6-(piperazin-l-ylmethyl)-3-pyridyl]- lH-pyrrolo[2,3-b]pyridine (BRAF Intermediate 4), the title compound was obtained as yellow solid, MS m/e: 923 (/M H / ). Example 16

5-[6-[4-[3-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl]amino]cyclobutanecarbonyl]piperazin-l-yl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]- 2,6-difluoro-benzoyl]-l//-pyrrolo[2,3-b]pyridine

According to general procedure III starting from 3-[[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]amino]cyclobutane-l-carboxylic acid (CRBN Intermediate 5) and 3-[3- [[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(6-piperazin-l-yl-3-pyridyl)-lH- pyrrolo[2,3-b]pyridine (BRAF Intermediate 1 ), the title compoundwas obtained as white solid, MS m/e: 455 (/M 2 H / ).

Example 17

5-[6-[4-[2-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]pyrrolidin-3- yl]acetyl]piperazin-l-yl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro- benzoyl]-l//-pyrrolo[2,3-b]pyridine According to general procedure III starting from 2-[l-[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]pyrrolidin-3-yl]acetic acid (CRBN Intermediate 2) and 3-[3- [[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(6-piperazin-l-yl-3-pyridyl)-lH- pyrrolo[2,3-b]pyridine (BRAF Intermediate 1 ), the title compound was obtained as yellow solid, MS m/e: 923 (/M H / ).

Example 18

5-[6-[4-[3-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]azetidin-3- yl]propanoyl]piperazin-l-yl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro- benzoyl] -l//-pyrrolo[2,3-b]pyri dine

According to general procedure III starting from 3-[l-[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]azetidin-3-yl]propanoic acid (CRBN Intermediate 7) and 3-[3- [[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(6-piperazin-l-yl-3-pyridyl)-lH- pyrrolo[2,3-b]pyridine (BRAF Intermediate 1 ), the title compoundwas obtained as yellow solid, MS m/e: 923 (/M H / ).

Example 19

5-[6-[4-[4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxybutanoyl]piperazin-l-yl]-3- pyridyl] -3 -[3 -[[ethyl (methyl )sulfamoyl]amino]-2,6-difluoro-benzoyl]-l /-pyrrol o[2,3-b]pyri dine According to general procedure III starting from 4-[[2-(2,6-dioxopiperidin-3-yl)-l-oxo-3 /- isoindol-4-yl]oxy]butanoic acid (CRBN Intermediate 10) and 3-[3-

[[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(6-piperazin-l-yl-3-pyridyl)-lH- pyrrolo[2,3-b]pyridine (BRAF Intermediate l), the title compoundwas obtained as white solid, MS m/e: 884.6 (/M H / ).

Example 20

5-[6-[4-[2-[4-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]oxy-l- piperidyl]acetyl]piperazin-l-yl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro- benzoyl]-l /-pyrrolo[2,3-b]pyridine

According to general procedure III starting from 2-[4-[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-5-yl]oxypiperidin-l-yl]acetic acid (CRBN Intermediate 6) and 3-[3- [[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(6-piperazin-l-yl-3-pyridyl)-lH- pyrrolo[2,3-b]pyridine (BRAF Intermediate 1 ), the title compound was obtained as white solid, MS m/e: Ml (/M 2 H / ). Example 21

5-[6-[4-[4-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]piperidine-l-carbonyl]piperazin- 1 -yl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]- l//-pyrrolo[2,3- b] pyridine

According to general procedure IV starting from 2-(2,6-Dioxopiperidin-3-yl)-5-piperidin-4- ylisoindole-l,3-dione (CAS 2229718-43-6) and 3-[3-[[Ethyl(methyl)sulfamoyl]amino]-2,6- difluoro-benzoyl]-5-(6-piperazin-l-yl-3-pyridyl)-lH-pyrrolo[2,3-b]pyridine (BRAF Intermediate 1), the title compound was obtained as white solid, MS m/e: 462 ([ /2+H+ / ).

Example 22

/V-[3-[5-[6-[4-[3-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl]amino]cyclobutanecarbonyl]piperazin- 1 -yl]-3-pyridyl]- l//-pyrrolo[2,3-b]pyridine-3- carbonyl]-2,4-difluoro-phenyl]butane-2-sulfonamide

According to general procedure III starting from 3-[[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]amino]cyclobutane-l-carboxylic acid (CRBN Intermediate 5) and N-[2,4- difluoro-3-[5-(6-piperazin-l-yl-3-pyridyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl]butane- 2-sulfonamide (BRAF Intermediate 10), the title compound was obtained as yellow solid, MS m/e: 455 ([M/2+H+]⁺). Example 23

5-[2-[4-[4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxybutanoyl]piperazin-l- yljpyri mi din-5-yl]-3 -[3 -[[ethyl (methyl )sulfamoyl]amino]-2,6-dif1uoro-benzoyl]- l //-pyrrol o[2, 3- b] pyridine

According to general procedure III starting from 4-[[2-(2,6-dioxopiperidin-3-yl)-l-oxo-3 /- isoindol-4-yl]oxy]butanoic acid (CRBN Intermediate 10) and 3-[3- [[Ethyl (methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(2-piperazin-l-ylpyrimidin-5-yl)-lH- pyrrolo[2,3-b]pyridine (BRAF Intermediate 3), the title compoundwas obtained as white solid, MS m/e: 885.6 ([M+H+J⁺f

Example 24

5-[4-[[4-[l-[2-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-4-piperidyl]acetyl]-4- piperidyl]piperazin-l-yl]methyl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro- benzoyl]-! //-pyrrolo[2,3-b]pyri dine According to general procedure III starting from 2-[l-[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]piperidin-4-yl]acetic acid (CRBN Intermediate 1) and 3-[3- [[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-[[4-(4-piperidyl)piperazin-l- yl]methyl]phenyl]-lH-pyrrolo[2,3-b]pyridine (BRAF Intermediate 9), the title compound was obtained as yellow solid, MS m/e: 1033.9 f/M H I ). Example 25

5-[4-[[4-[l-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]piperidine-4-carbonyl]-4- piperidyl]piperazin-l-yl]methyl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro- benzoyl]- l//-pyrrolo[2,3-b]pyridine

According to general procedure III starting from l-[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-5-yl]piperidine-4-carboxylic acid (CRBN Intermediate 8) and 3-[3- [[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-[[4-(4-piperidyl)piperazin-l- yl]methyl]phenyl]-lH-pyrrolo[2,3-b]pyridine (BRAF Intermediate 9), the title compound was obtained as yellow solid, MS m/e: 1019.9 (jM H / ).

Example 26

5-[4-[[4-[l-[2-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]-4-piperidyl]acetyl]-4- piperidyl]piperazin-l-yl]methyl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro- benzoyl]-l//-pyrrolo[2,3-b]pyridine According to general procedure III starting from 2-[l-[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-5-yl]piperidin-4-yl]acetic acid (CRBN Intermediate 9) and 3-[3- [[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-[[4-(4-piperidyl)piperazin-l- yl]methyl]phenyl]-lH-pyrrolo[2,3-b]pyridine (BRAF Intermediate 9), the title compound was obtained as white solid, MS m/e: 1033.9 ([M+H+]⁺).

Example 27

5-[4-[4-[3-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-4- piperidyl]propanoyl]piperazin-l-yl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro- benzoyl] -l//-pyrrolo[2,3-b]pyri dine

According to general procedure III starting from 3-[l-[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]piperidin-4-yl]propanoic acid (CRBN Intermediate 3) and 3-[3- [[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(4-piperazin-l-ylphenyl)-lH- pyrrolo[2,3-b]pyridine (BRAF Intermediate 5), the title compound was obtained as yellow solid, MS m/e: 950.8 (/M H / ).

Example 28

5-[4-[4-[3-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl]amino]cyclobutanecarbonyl]piperazin-l-yl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-

2,6-difluoro-benzoyl]-l /-pyrrolo[2,3-b]pyridine

According to general procedure III starting from 3-[[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]amino]cyclobutane-l-carboxylic acid (CRBN Intermediate 5) and 3-[3- [[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(4-piperazin-l-ylphenyl)-lH- pyrrolo[2,3-b]pyridine (BRAF Intermediate 5), the title compoundwas obtained as white solid, MS m/e: 908.7 ([M+H+ j ).

Example 29

5-[4-[4-[4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxybutanoyl]piperazin-l-yl]phenyl]- 3 -[3 -[[ethyl (methyl )sulfamoyl]ami no] -2,6-difluoro-benzoyl]-l //-pyrrol o[2,3-b]pyri dine According to general procedure III starting from 4-[[2-(2,6-dioxopiperidin-3-yl)-l -oxo-3//- isoindol-4-yl]oxy]butanoic acid (CRBN Intermediate 10) and 3-[3- [[Ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-(4-piperazin-l-ylphenyl)-lH- pyrrolo[2,3-b]pyridine (BRAF Intermediate 5), the title compoundwas obtained as white solid, MS m/e: 883.7 ([M+H+ j ).

5-[4-[[4-[l-[6-[[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindol-4-yl]amino]hexanoyl]piperidin-4- yl]piperazin-l-yl]methyl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluorobenzoyl]- 1 //-pyrrol o[2, 3 -bjpyridine

5-[4-[[4-[l-[6-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]hexanoyl]-4- piperidyl]piperazin-l-yl]methyl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro- benzoyl]-l /-pyrrolo[2,3-b]pyridine

According to general procedure III starting from 6-[[2-(2,6-Dioxopiperidin-3-yl)-l,3- dioxoisoindol-4-yl]amino]hexanoic acid (CAS 2225940-49-6) and 3-[3- [[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-[[4-(4-piperidyl)piperazin-l- yl]methyl]phenyl]-lH-pyrrolo[2,3-b]pyridine (BRAF Intermediate 9), the title compoundwas obtained as yellow solid, MS m/e: 1021.9 ([M+H+ / ).

Claims

1. A compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof,

A¹ is selected from i) -NR²-, and ii) -CHR³-;

R¹ is selected from i) H, ii) Ci-6-alkyl, and iii) C_3-8-cycloalkyl; R² is selected from i) H, ii) Ci-6-alkyl, and iii) C_3-8-cycloalkyl; or R¹ and R² together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by R¹⁴, R¹⁵ and R¹⁶;

R⁷ and R⁸ are independently selected from i) H, and ii) halogen;

A² and A³ are independently selected from i) -CH-, and ii) -N-;

X is selected from i) a bound, ii) -NR⁴-, and iii) -0-;

R⁴ is selected from i) H, and ii) Ci-6-alkyl;

A⁴ is selected from i) -C(O)-, and ii) -CH2-; A is selected from i) -(CFh)p-; and ii) the ring systems A, B, C, D, E and F;

p is selected from i) 3, and ii) 5; m is selected from i) 0, ii) 1, iii) 2;

B is selected from the ring systems G and H;

n is selected from i) 0, and ii) 1;

R⁵ and R⁶ are independently selected from i) H, and i) Ci-₆-alkyl; or R⁵ and R⁶ together form -CH2-.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A¹ is selected from i) -NR²-, and ii) -CHR³-;

R¹ is selected from i) Ci-₆-alkyl, and ii) C3-8-cycloalkyl;

R² is Ci-₆-alkyl; or R¹ and R² together with the nitrogen atom to which they are attached form an unsubstituted heterocycloalkyl;

R³ is Ci-₆-alkyl;

R⁷ and R⁸ are halogen;

A² and A³ are independently selected from i) -CH-, and ii) -N-;

X is selected from i) a bound, ii) -NR⁴-, and iii) -0-;

R⁴ is H;

A⁴ is selected from i) -C(O)-, and ii) -CH2-;

A is selected from i) -(CFh)p-; and ii) the ring systems A, B, C, D, E and F;

p is selected from i) 3, and ii) 5; m is selected from i) 0, ii) 1, iii) 2;

B is selected from the ring systems G and H;

n is selected from i) 0, and ii) 1;

R⁵ and R⁶ are H; or R⁵ and R⁶ together form -CH2-.

3. A compound according to claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I).

4. A compound according to claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (II).

5. A compound according to anyone of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from i) Ci-₆-alkyl, and ii) C3-8-cycloalkyl.

6. A compound according to anyone of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R² is Ci-₆-alkyl.

7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R¹ and R² together with the nitrogen atom to which they are attached form a heterocycloalkyl optionally substituted by R¹⁴, R¹⁵ and R¹⁶.

8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R¹ and R² together with the nitrogen atom to which they are attached form anunsub stituted heterocycloalkyl .

9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein the heterocycloalkyl formed by R¹ and R² together with the nitrogen atom to which they are attached is a pyrrolidinyl.

10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R³ is Ci-₆-alkyl.

11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R⁷ and R⁸ are halogen.

12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R⁴ is H.

13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R⁵ and R⁶ are H.

14. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R⁵ and R⁶ together form -CH2-.

15. A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, selected from 5-[4-[[4-[4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]butanoyl]piperazin- l-yl]methyl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-lH- pyrrol o [2, 3 -b ] pyri dine ;

5-[4-[[4-[3-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-4- piperidyl]propanoyl]piperazin-l-yl]methyl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-

2,6-difluoro-benzoyl]-lH-pyrrolo[2,3-b]pyridine;

5-[4-[[4-[2-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-4- piperidyl]acetyl]piperazin-l-yl]methyl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6- difluoro-benzoyl]-lH-pyrrolo[2,3-b]pyridine;

3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-[[rac-(lR,5S)-8-[4-[[2-

(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]butanoyl]-3,8- diazabicyclo[3.2.1]octan-3-yl]methyl]phenyl]-lH-pyrrolo[2,3-b]pyridine;

5-[6-[[4-[4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]butanoyl]piperazin- l-yl]methyl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-lH- pyrrolo[2,3-b]pyridine;

5-[2-[4-[3-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-4- piperidyl]propanoyl]piperazin-l-yl]pyrimidin-5-yl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-

2,6-difluoro-benzoyl]-lH-pyrrolo[2,3-b]pyridine;

5-[2-[4-[4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]butanoyl]piperazin- 1 -yl]pyri mi din-5-yl]-3 -[3 -[[ethyl (methyl )sulfamoyl]amino]-2,6-difluoro-benzoyl]-l H- pyrrolo[2,3-b]pyridine;

N-[3-[5-[4-[[4-[4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4- yl]amino]butanoyl]piperazin-l-yl]methyl]phenyl]-lH-pyrrolo[2,3-b]pyridine-3-carbonyl]- 2,4-difluoro-phenyl]pyrrolidine-l -sulfonamide formic acid;

3-[3-[[cyclopropyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-5-[4-[[4-[4-[[2-(2,6- dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]butanoyl]piperazin-l-yl]methyl]phenyl]- lH-pyrrolo[2,3-b]pyridine formic acid;

5-[6-[4-[3-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-4- piperidyl]propanoyl]piperazin-l-yl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6- difluoro-benzoyl]-lH-pynOlo[2,3-b]pyridine; 5-[6-[4-[4-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]butanoyl]piperazin- l-yl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-lH- pyrrolo[2,3-b]pyridine;

5-[6-[4-[4-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]oxypiperidine-l- carbonyl]piperazin-l-yl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro- benzoyl]-lH-pyrrolo[2,3-b]pyridine;

5-[6-[4-[2-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]pyrrolidin-3- yl]acetyl]piperazin-l-yl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro- benzoyl]-lH-pyrrolo[2,3-b]pyridine;

5-[6-[4-[3-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]azetidin-3- yl]propanoyl]piperazin-l-yl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro- benzoyl]-lH-pyrrolo[2,3-b]pyridine;

5-[6-[4-[4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxybutanoyl]piperazin-l-yl]-3- pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-lH-pyrrolo[2,3- bjpyridine;

5-[6-[4-[2-[4-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]oxy-l- piperidyl]acetyl]piperazin-l-yl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6- difluoro-benzoyl]-lH-pyrrolo[2,3-b]pyridine; 5-[6-[4-[4-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]piperidine-l- carbonyl]piperazin-l-yl]-3-pyridyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro- benzoyl]-lH-pyrrolo[2,3-b]pyridine;

5-[2-[4-[4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxybutanoyl]piperazin-l- yl]pyrimidin-5-yl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-lH- pyrrolo[2,3-b]pyridine;

5-[4-[[4-[l-[2-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-4-piperidyl]acetyl]-4- piperidyl]piperazin-l-yl]methyl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro- benzoyl]-lH-pyrrolo[2,3-b]pyridine;

5-[4-[[4-[l-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]piperidine-4-carbonyl]-4- piperidyl]piperazin-l-yl]methyl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro- benzoyl]-lH-pyrrolo[2,3-b]pyridine;

5-[4-[[4-[l-[2-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-5-yl]-4-piperidyl]acetyl]-4- piperidyl]piperazin-l-yl]methyl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro- benzoyl]-lH-pyrrolo[2,3-b]pyridine;

5-[4-[4-[3-[l-[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]-4- piperidyl]propanoyl]piperazin-l-yl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6- difluoro-benzoyl]-lH-pyrrolo[2,3-b]pyridine;

5-[4-[4-[4-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-4-yl]oxybutanoyl]piperazin-l- yl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro-benzoyl]-lH-pyrrolo[2,3- bjpyridine; and

5-[4-[[4-[l-[6-[[2-(2,6-dioxo-3-piperidyl)-l,3-dioxo-isoindolin-4-yl]amino]hexanoyl]-4- piperidyl]piperazin-l-yl]methyl]phenyl]-3-[3-[[ethyl(methyl)sulfamoyl]amino]-2,6-difluoro- b enzoyl] - 1 H-pyrrolo [2, 3 -b ] pyri dine .

16. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

18. The use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for the therapeutic and/or prophylactic treatment of cancer.

19. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prophylaxis of cancer.

20. The use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the therapeutic and/or prophylactic treatment of cancer.

21. A method for the therapeutic and/or prophylactic treatment of cancer, which method comprises administering an effective amount of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.

22. The invention as hereinbefore described.