WO2017046036A1

WO2017046036A1 - Compounds for the modulation of rip2 kinase activity

Info

Publication number: WO2017046036A1
Application number: PCT/EP2016/071466
Authority: WO
Inventors: John David Harling; Christopher E. Neipp; Israil Pendrak; Ian Edward David Smith; Lamont Roscoe Terrell; Mark Youngman
Original assignee: Glaxosmithkline Intellectual Property Development Limited
Priority date: 2015-09-14
Filing date: 2016-09-12
Publication date: 2017-03-23
Also published as: GB201516243D0

Abstract

The present invention relates to compounds, compositions, combinations and medicaments containing said compounds and processes for their preparation. The invention also relates to the use of said compounds, combinations, compositions and medicaments, for example as inhibitors of the activity of RIP2 kinase, including degrading RIP2 kinase, the treatment of diseases and conditions mediated by the RIP2 kinase, in particular for the treatment of inflammatory diseases or conditions.

Description

COMPOUNDS FOR THE MODULATION OF RIP2 KINASE ACTIVITY

Field of the Invention

The present invention relates to compounds, compositions, combinations and medicaments containing said compounds and processes for their preparation. The invention also relates to the use of said compounds, combinations, compositions and medicaments, for example as inhibitors of the activity of RIP2 kinase, including degrading RIP2 kinase, the treatment of diseases and conditions mediated by RIP2 kinase, in particular for the treatment of inflammatory diseases or conditions

Background of the Invention

Receptor interacting protein-2 (RIP2) kinase, which is also referred to as CARD3, RICK, CARDIAK, or RIPK2, is a TKL family serine/threonine protein kinase involved in innate immune signaling. RIP2 kinase is composed of an N-terminal kinase domain and a C- terminal caspase-recruitment domain (CARD) linked via an intermediate (IM) region ((1998) J Biol. Chem. 273, 12296-12300; (1998) Current Biology 8,885-889; and (1998) J Biol Chem. 273, 16968-16975). The CARD domain of RIP2 kinase mediates interaction with other CARD-containing proteins, such as NODI and NOD2 ((2000) J Biol Chem. 275, 27823-27831 and (2001) EMBO reports 2,736-742). NODI and NOD2 are cytoplasmic receptors which play a key role in innate immune surveillance. They recognize both gram positive and gram negative bacterial pathogens and are activated by specific peptidoglycan motifs, diaminopimelic acid (i.e., DAP) and muramyl dipeptide (MDP), respectively ((2007) J Immunol 178, 2380-2386).

Following activation, RIP2 kinase associates with NODI or NOD2 and appears to function principally as a molecular scaffold to bring together other kinases (TAKI, ΙΚΚα/β/γ) involved in N F-KB and mitogen-activated protein kinase activation ((2006) Nature Reviews Immunology 6, 9-20). RIP2 kinase undergoes a K63-linked polyubiquitination on lysine-209 which facilitates TAKI recruitment ((2008) EMBO Journal 27,373-383). This post-translational modification is required for signaling as mutation of this residue prevents NOD 1/2 mediated NF-kB activation. RIP2 kinase also undergoes autophosphorylation on serine-176, and possibly other residues ((2006) Cellular Signalling 18,2223-2229). Studies using kinase dead mutants (K47A) and non-selective small molecule inhibitors have demonstrated that RIP2 kinase activity is important for regulating the stability of RIP2 kinase expression and signaling ((2007) Biochem J 404, 179-190 and (2009) J Bioi. Chem. 284, 19183-19188).

Dysregulation of RIP2-dependent signaling has been linked to auto inflammatory diseases. Gain-of-function mutations in the NACHT -domain of NOD2 cause Blau Syndrome, early- onset sarcoidosis, a pediatric granulomateous disease characterized by uveitis, dermatitis, and arthritis ((2001) Nature Genetics 29,19-20; (2005) Journal of Rheumatology 32,373-375; (2005) Current Rheumatology Reports 7, 427-433; (2005) Blood 105, 1195- 1197; (2005) European Journal of Human Genetics 13, 742-747; (2006) American Journal of Ophthalmology 142, 1089-1092; (2006) Arthritis & Rheumatism 54, 3337-3344; (2009) Arthritis & Rheumatism 60, 1797-1803; and (2010) Rheumatology 49, 194-196). Mutations in the LRR-domain ofNOD2 have been strongly linked to susceptibility to Crohn's Disease ((2002) Am. J Hum. Genet. 70,845-857; (2004) European Journal of Human Genetics 12, 206- 212; (2008) Mucosal Immunology (2008) 1 (Suppll), S5-S9. 1, S5-S9; (2008) Inflammatory Bowel Diseases 14,295-302; (2008) Experimental Dermatology 17, 1057- 1058; (2008) British Medical Bulletin 87, 17-30; (2009) Inflammatory Bowel Diseases 15, 1145 - 1154 and (2009) Microbes and Infection 11, 912-918). Mutations in NODI have been associated with asthma ((2005) Hum. Mol. Genet. 14,935-941) and early-onset and extra-intestinal inflammatory bowel disease ((2005) Hum. Mol. Genet. 14, 1245-1250). Genetic and functional studies have also suggested a role for RIP2-dependent signaling in a variety of other granulomateous disorders, such as sarcoidosis ((2009) Journal of Clinical Immunology 29, 78-89 and (2006) Sarcoidosis Vasculitis and Diffuse Lung Diseases 23, 23-29) and Wegner's Granulomatosis ((2009) Diagnostic Pathology 4,23).

A potent, selective, small molecule inhibitor of RIP2 kinase activity would block RIP2- dependent pro-inflammatory signaling and thereby provide a therapeutic benefit in auto inflammatory diseases characterized by increased and/or dysregulated RIP2 kinase activity.

It would be desirable to investigate other approaches to antagonise RIP2 kinase. One approach would be to develop selective RIP2 kinases down regulators or degraders that reduce RIP2 expression at either the transcript or protein level.

Several methods are available for the manipulation of protein levels. The selective degradation of target proteins using small molecules is a new approach to the treatment of various diseases. Proteolysis Targeting Chimeric molecules (Protacs) are bifunctional compounds which can simultaneously bind a target protein and an E3 ubiquitin ligase thereby bringing the ligase and target in close proximity. These bifunctional compounds allow the efficient ubiquitin transfer from the ligase complex to the target protein which is subsequently recognized by the proteasome and degraded. This degradation of the target protein provides treatment of diseases or conditions modulated through the target protein by effectively lowering the level of said target protein in the cells of the patient. An advantage of Protacs is that a broad range of pharmacological activities is possible, consistent with the degradation/inhibition of targeted proteins from virtually any class or family.

E3 ubiquitin ligases (of which hundreds are known in humans) confer substrate specificity for ubiquitination and therefore are more attractive therapeutic targets than general proteasome inhibitors due to their specificity for certain protein substrates. The development of ligands for E3 ligases has proven challenging. One suitable E3 ubiquitin ligase is the von Hippel-Lindau tumour suppressor (VHL), see for example WO2013/106643.

It would be desirable to have a small molecule which can simultaneously bind RIP2 kinase and an E3 ubiquitin ligase and which promotes ubiquitination of RIP2 Kinase and leads to its degradation by the proteasome. One suitable E3 ubiquitin ligase is the von Hippel-Lindau tumour suppressor (VHL), see for example WO2013/106643.

It would be desirable to identify further ubiquitin ligase binding molecules to incorporate into PROTAC molecules. Cereblon is a protein in humans encoded by the CRBN gene. It forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDBl), which complex ubiquinates a number of other proteins.

The present inventors have identified E3 ubiquitin ligase cereblon binding compounds which when incorporated into PROTACs targeting RIP2 kinase are capable of promoting target degradation.

Summary of the Invention

In one aspect of the present invention there are provided novel heterobifunctional compounds (Protacs) useful for the targeted degradation of proteins and other polypeptides which on the one end binds to the cereblon and on the other end to the target protein (RIP2 kinase). By bringing the target protein in close proximity to the E3-Ligase, these compounds form a ternary complex leading to polyubiquitination of the target protein inducing its degradation.

The present invention provides a PROTAC compound which modulates RIP2 kinase activity including degradation thereof which comprise RIP2 kinase inhibitors having the following substructure:

wherein X represents N or -CH.

RIP 2 inhibitors with this substructure are disclosed in WO2014/128622, WO20140/43437, WO 2013/025958, WO 2012/122011, WO 2012/021580 and WO 2011140442. These applications describe suitable substitutions on equivalent positions to Z, R¹ and R² in the RIP2 binding portion depicted. In a first aspect the present invention provides a PROTAC compound which modulates RIP2 kinase activity which is a compound of formula (I):

ubiquitin ligase cereblon binding moiety

(I)

wherein

X represents N or CH;

Linker is a linking group comprising a length of 4-16 atoms in shortest length,

R¹ is H, -S0₂(Ci-C₄)alkyl, -CO(C C₄)alkyl, or (C C₄)alkyl; R² is - SR^a, -SOR^a, -S0₂R^a, -S0₂NH₂, or -S0₂NR^bR^c,

wherein R^a is (Ci-C₆)alkyl, halo(Ci-C₆)alkyl, (C₃-C₇)cycloalkyl, 4-7 membered heterocycloalkyi, aryl, or heteroaryl, wherein:

said (Ci-C₆)alkyl is optionally substituted by one or two groups each independently selected from the group consisting of cyano, hydroxyl, (Ci-C₆)alkoxy,

(Ci-C₆)alkoxy(C₂-C₆)alkoxy, -C0₂H, -C0₂(Ci-C₄)alkyl, -S0₂(Ci-C₄)alkyl, (C₃-C₇)cycloalkyl, phenyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl, 4-7 membered heterocycloalkyi and (phenyl)(Ci-C₄ alkyl)amino-, wherein said (C₃-C₇)cycloalkyl, phenyl,

(phenyl)(Ci-C₄ alkyl)amino-, 5-6 membered heteroaryl, 9-10 membered heteroaryl or 4-7 membered heterocycloalkyi is optionally substituted by 1-3 groups each independently selected from the group consisting of halogen, -CF₃, hydroxyl, amino, ((Ci-C₄)alkyl)amino-, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino-, (Ci-C₄)alkyl, phenyl(Ci-C₄)alkyl-, hydroxy(Ci-C₄)alkyl and (Ci-C₄)alkoxy,

said (C₃-C₇)cycloalkyl or 4-7 membered heterocycloalkyi is optionally substituted by 1-3 groups each independently selected from the group consisting of halogen, -CF₃, hydroxyl, amino, ((Ci-C₄)alkyl)amino-, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino-, (Ci-C₄)alkyl, phenyl(Ci-C₄)alkyl-, hydroxy(Ci-C₄)alkyl-, oxo and (Ci-C₄)alkoxy, and

said aryl or heteroaryl is optionally substituted by 1-3 groups each independently selected from the group consisting of halogen, -CF₃, hydroxyl, amino, ((Ci-C₄)alkyl)amino-, ((Ci-C₄)alkyl)((Ci-C₄)alkyl)amino-, (Ci-C₄)alkyl, phenyl(Ci-C₄)alkyl-, hydroxy(Ci-C₄)alkyl- and (Ci-C₄)alkoxy;

R^b is (Ci-C₆)alkyl or 4-7 membered heterocycloalkyi, wherein:

said (Ci-C₆)alkyl is optionally substituted by one or two groups each independently selected from the group consisting of hydroxyl, (Ci-C₆)alkoxy, (Ci-C₆)alkoxy(C₂-C₆)alkoxy, -C0₂H, -C0₂(Ci-C₄)alkyl, (Ci-C₄ alkyl)amino-, (Ci-C₄ alkyl)(Ci-C₄ alkyl)amino-, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyi, wherein said 5-6 membered heteroaryl or 4-7 membered heterocycloalkyi is optionally substituted by 1-3 groups each independently selected from the group consisting of halogen, (Ci-C₄)alkyl, hydroxy(Ci-C₄)alkyl and (Ci-C₄)alkoxy,

said 4-7 membered heterocycloalkyi is optionally substituted by 1-3 groups each independently selected from the group consisting of hydroxyl, amino, (Ci-C₄)alkyl,

(Ci-C₄)alkoxycarbonyl-, hydroxy(Ci-C₄)alkyl-, oxo and (Ci-C₄)alkoxy, and

R^c is H, (Ci-C₄)alkoxy or (Ci-C₆)alkyl;

or R^b and R^c taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocycloalkyi group, optionally containing one or two additional ring heteroatoms each independently selected from nitrogen and oxygen, wherein said 3-7 membered heterocycloalkyi is optionally substituted by 1-3 groups each independently selected from the group consisting of (Ci-C₄)alkyl, hydroxy, -C0₂H and -CO(Ci-C₄)alkyl; Z is phenyl or aryl(Ci-C₄)alkyl-, wherein in the phenyl group or the aryl moiety of the aryl(Ci-C₄)alkyl- group is substituted by R⁴, R⁵, R⁶ and R⁷, wherein:

R⁴ is H, halogen, cyano, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, (Ci-C₄)alkoxy, phenoxy, phenyl(Ci-C₄)alkoxy, hydroxyl, hydroxy(Ci-C₄)alkyl-, or aminocarbonyl, wherein the phenyl moiety of said phenoxy or phenyl(Ci-C₄)alkoxy- is optionally substituted by 1-3 substituents each independently selected from the group consisting of halogen, -CF₃, (Ci-C₄)alkyl and

(Ci-C₄)alkoxy; and each of R⁵, R⁶ and R⁷is independently selected from the group consisting of H, hydroxyl, halogen, -CF₃, hydroxy(Ci-C₄)alkyl, (Ci-C₄)alkyl and (Ci-C₄)alkoxy; or

Z is phenyl or pyridyl, substituted by R⁸, R⁹ and R¹⁰, wherein:

R⁸ and R⁹ are located on adjacent atoms and taken together with the atoms to which they are attached form a 5-membered ring containing 1, 2 or 3 heteroatoms each independently selected from N, 0 and S, which 5-membered ring is substituted by R¹¹; wherein one of R¹⁰ or R¹¹ is H, halogen, cyano, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl,

(Ci-C₄)alkoxy, phenoxy, phenyl(Ci-C₄)alkoxy, hydroxyl, hydroxy(Ci-C₄)alkyl-, or

aminocarbonyl, where the phenyl moiety of said phenoxy or phenyl(Ci-C₄)alkoxy is optionally substituted by 1-3 substituents each independently selected from the group consisting of halogen, -CF₃, (Ci-C₄)alkyl and (Ci-C₄)alkoxy; and

the other of R¹⁰ or R¹¹ is H, hydroxyl, halogen, -CF₃, hydroxy(Ci-C₄)alkyl, (Ci-C₄)alkyl or (Ci-C₄)alkoxy; or

pyrazolyl, having the form

R is H, methyl or hydroxymethyl;

R¹³ is methyl, trifluoromethyl or hydroxymethyl;

R¹⁴ is H, OH, or (Ci-C₃)alkyl; ^or

R¹² and R¹³, taken together with the atoms to which they are attached, form a 6-membered ring substituted by R¹⁵ and R¹⁶, wherein the 6-membered ring optionally contains 1 nitrogen atom;

wherein R¹⁵ and R¹⁶ are each independently selected from the group consisting of H, halogen, cyano, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, (Ci-C₄)alkoxy, phenoxy, phenyl(Ci-C₄)alkoxy, hydroxyl, hydroxy(Ci-C₄)alkyl-, and aminocarbonyl, wherein the phenyl moiety of said phenoxy or phenyl(Ci-C₄)alkoxy is optionally substituted by 1-3 substituents each independently selected from the group consisting of halogen, -CF₃, (Ci-C₄)alkyl and

(Ci-C₄)alkoxy; or a pharmaceutically acceptable salt thereof. In a further aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

In a further aspect there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of diseases conditions mediated by RIP2 Kinase.

In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

In a further aspect of the present invention, there is provided a method of treating diseases and conditions mediated by the RIP2 Kinase in a subject comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In a further aspect of the present invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating diseases and conditions mediated by the RIP2 Kinase.

In a further aspect there is provided a combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof and at least one further therapeutic agent.

In a further aspect there is provided a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one further therapeutic agent for use in therapy.

In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one further therapeutic agent and one or more pharmaceutically acceptable excipients.

In a further aspect of the invention there is provided a combination comprising compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one further therapeutic agent for use in treating diseases and conditions mediated by the RIP2 Kinase.

In a further aspect there is provided a method of treating diseases and conditions mediated by the RIP2 Kinase comprising administering to a human in need thereof a therapeutically effective amount of a combination comprising compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one further therapeutic agent.

In a further aspect there is provided the use of a combination comprising compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one further therapeutic agent in the manufacture of a medicament for treating diseases and conditions mediated by RIP2 Kinase.

In a further aspect there is provided a method of degrading RIP2 kinase comprising administering to a human in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof

Detailed description of the Invention

As used herein, "a compound of the invention" includes all solvates, complexes, polymorphs, isotope labelled derivatives, stereoisomers and optical isomers of the compounds of formula (I) and salts thereof.

As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The compounds of the invention may exist in solid or liquid form. In solid form, compound of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon the temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order ('glass transition'). The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order ('melting point').

The compound of formula (I) may exist in solvated and unsolvated forms. As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. The skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed for crystalline compounds wherein solvent molecules are incorporated into the crystalline lattice during crystallization. The incorporated solvent molecules may be water molecules or non-aqueous such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate molecules. Crystalline lattice incorporated with water molecules are typically referred to as "hydrates". Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The present invention includes all such solvates.

The compounds of the invention may have the ability to crystallize in more than one form, a characteristic, which is known as polymorphism, and it is understood that such polymorphic forms ("polymorphs") are within the scope of the invention. Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility and melting point.

It is also noted that the compounds of formula (I) may form tautomers. It is understood that all tautomers and mixtures of tautomers of the compounds of the present invention are included within the scope of the compounds of the present invention.

The compound of Formula (I) is a PROTAC targeting RIP Kinase wherein the RIP2 kinase inhibitor is linked via a linker to a cereblon binder.

In one embodiment, the present invention provides a PROTAC targeting RIP2 kinase which is a compound of Formula (II) (III) (IV) or (V):



(IV)

In particular, the definitions of R¹, Z, X and R² in the RIP2 inhibitor moiety in the compounds of formula (II) (V)are as defined in formula (I) above.

The linker is as defined for formula (I) above.

In one aspect the compound of formula 1 is a Protac targeting RIP2 kinase wherein the RIP 2 kinase binder is :

wherein the wavy bond denotes the attachment point of the linker.

In further aspect of the invention the Cereblon binding moiety is a compound thalidomide (7), pomalidomide (8) and lenalidomide (9):

In one embodiment the cereblon binding moiety is

wherein the wavy bond denotes the attachment point of the linker.

In a further as ect of the invention, compounds of Formula (I) are of formula (VI) and (VII):

(VI)

(VII) pharmaceutically acceptable salts thereof.

In one aspect of the invention in compounds of Formula (I)- (VII), the linker group is a straight chain alkylene group of 4-16 carbon atoms wherein one or more carbon atoms are replaced by a group each independently selected from

-0-, -NH-, -N(CH₃)-, CO

In one aspect of the present invention, in compounds of Formula (I)- (VII), the linker (in the direction RIP2 binder - cereblon binder) is selected from the following:

-O(CH₂)₅-₁₀CO- ,

-0(CH₂ CH₂0)₂-5 CH₂ CO- ' -0(CH₂CH₂0)₂-₅-,

-OCCH^-s-^-L²

wherein L¹ is:

L² is:

-(CH₂CH₂0)i-4-CH₂CO- , -(CH₂)i-ioCO- ,

-(CH₂CH₂0)i-4-(CH₂)_1-5-

Particular linkers include the following

-0(CH₂CH₂0)₄ CH₂CO- -0(CH₂CH₂0)₃ CH₂CO-

OCH₂CH₂CH₂ CH2CH2OCH2CH2CH2

-0(CH₂CH₂0)₅

Particular compounds are:

14-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-N-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-3,6,9,12-tetraoxatetradecan-l-amide

_(S)-2-(4-(3-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)propyl)piperazin-l-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)pyrimidin 5-carboxamide dihydrochloride

2-(4-(3-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)propyl)piperazin-l-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl) pyrimidine- -carboxamide

_(S)-3-(4-(3-(2-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino) quinazolin-7-yl)oxy)methyl)piperidin-l-yl)ethoxy)propyl)-l-oxoisoindolin-2-yl)piperidine-2,6- dione

jS)-3-(4-(8-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)methyl)piperidin-l-yl)octyl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione

jS)-3-(4-(10-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin^ 7- l)oxy)methyl)piperidin-l-yl)decyl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione

jS)-3-(4-(6-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin- 7-yl)oxy)ethyl)piperidin-l-yl)hexyl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione

jS)-3-(4-(8-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin- 7- l)oxy)ethyl)piperidin-l-yl)octyl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione

_(S)-3-(4-(10-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)ethyl)piperidin-l-yl)decyl)-l-oxoisoindolin-2-yl)piperidine-2,6- dione

_(S)-3-(4-(3-(2-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-l-yl)ethoxy)propyl)-l-oxoisoindolin-2- l)piperidine-2,6-dione

_(S)-3-(4-(3-(2-(4-(3-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-l-yl)ethoxy)propyl)-l-oxoisoindolin-2- l)piperidine-2,6-dione

(S)-3-(4-(3-(2-(4-(2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7- yl)oxy)ethyl)piperazin-l-yl)ethoxy)prop-l-yn-l-yl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione)

2-(2-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)ethyl)piperazin-l-yl)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)acetamide

3-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- l)oxy)ethyl)piperazin-l-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)propanamide

2-(2-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)methyl)piperidin-l-yl)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)acetamide

3-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)methyl)piperidin-l-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)propanamide

4-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)ethyl)piperazin-l-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)butanamide

2-(2-(4-(3-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)propyl)piperazin-l-yl)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)acetamide

2-(2-(2-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)ethyl)piperazin-l-yl)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- l)acetamide

2-(2-(2-(4-(3-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)propyl)piperazin-l-yl)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin 4- yl)acetamide

2-(2-(2-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)methyl)piperidin-l-yl)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin- 4-yl)acetamide

ll-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-N-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)undecanamide

ll-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)-N-(2- -dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)undecanamide

ll-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)methyl)piperidin-l-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)undecanamide

2-(2-(2-(2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7- yl)oxy)ethoxy)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)acetamide

and pharmaceutically acceptable salts thereof

The compounds of Formula (I) may be in the form of a salt.

Typically, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention. For a review on suitable salts see Berge et a I, J. Pharm. Sci. 1977, 66, 1-19.

Suitable pharmaceutically acceptable salts can include acid addition salts.

A pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2-naphthalenesulfonic), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration. A pharmaceutically acceptable acid addition salt of a compound of formula (I) can comprise or be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g. 2-naphthalenesulfonate) salt.

Other non-pharmaceutically acceptable salts, e.g. trifluoroacetates, may be used, for example in the isolation of compounds of the invention, and are included within the scope of this invention.

The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the compounds of formula (I).

While it is possible that, for use in therapy, the compound of the invention may be administered as the raw chemical, it is possible to present the compound of the invention as the active ingredient as a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Accordingly, the invention further provides pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically acceptable excipients. The excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical composition including the agent, or pharmaceutically acceptable salts thereof, with one or more pharmaceutically acceptable excipients. The pharmaceutical composition can be for use in the treatment and/or prophylaxis of any of the conditions described herein.

Generally, the compound of the invention is administered in a pharmaceutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound -administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. Administration of the active ingredient may range from continuous (e.g. intravenous drip), one or several doses per day to a regimen which is less than daily dosing by any appropriate route. Compounds may be admisistered in immediate release or controlled release.

Pharmaceutical compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.

Preferred unit dosage compositions are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Such unit doses may therefore be administered once or more than once a day. Such pharmaceutical compositions may be prepared by any of the methods well known in the pharmacy art.

Pharmaceutical compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, inhaled, intranasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).

Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in- oil liquid emulsions.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert excipient such as ethanol, glycerol, water and the like. Powders are prepared by reducing the compound to a suitable fine size and mixing with a similarly prepared pharmaceutical excipient such as an edible carbohydrate, as, for example, starch or mannitol. Flavouring, preservative, dispersing and colouring agent can also be present.

Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Excipients including glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary,excipients including suitable binders, glidants, lubricants, sweetening agents, flavours, disintegrating agents and colouring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages. Oral fluids such as solution, suspensions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.

Where appropriate, dosage unit compositions for oral administration can be microencapsulated. The composition can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like. The compounds of the invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. Pharmaceutical compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.

Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, for example mouth and skin, the compositions are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water- miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent. Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.

Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or as enemas.

Dosage forms for nasal or inhaled administration may conveniently be formulated as aerosols, solutions, suspensions drops, gels or dry powders. Compositions for intranasal administration include aqueous compositions administered to the nose by drops or by pressurised pump. Suitable compositions contain water as the diluent or carrier for this purpose. Compositions for administration to the lung or nose may contain one or more excipients, for example one or more suspending agents, one or more preservatives, one or more surfactants, one or more tonicity adjusting agents, one or more co-solvents, and may include components to control the pH of the composition, for example a buffer system. Further, the compositions may contain other excipients such as antioxidants, for example sodium metabisulphite, and taste-masking agents. Compositions may also be administered to the nose or other regions of the respiratory tract by nebulisation.

Intranasal compositions may permit the compound(s) of formula (I) pharmaceutically acceptable salt(s) thereof to be delivered to all areas of the nasal cavities (the target tissue) and further, may permit the compound(s) of formula (I) pharmaceutically acceptable salt(s) thereof to remain in contact with the target tissue for longer periods of time. A suitable dosing regime for intranasal compositions would be for the patient to inhale slowly through the nose subsequent to the nasal cavity being cleared. During inhalation the composition would be administered to one nostril while the other is manually compressed. This procedure would then be repeated for the other nostril. Typically, one or two sprays per nostril would be administered by the above procedure one, two, or three times each day, ideally once daily. Of particular interest are intranasal compositions suitable for once-daily administration. The suspending agent(s), if included, will typically be present in an amount of from 0.1 to 5% (w/w), such as from 1.5% to 2.4% (w/w), based on the total weight of the composition. Examples of pharmaceutically acceptable suspending agents include, but are not limited to, Avicef (microcrystalline cellulose and carboxymethylcellulose sodium), carboxymethylcellulose sodium, veegum, tragacanth, bentonite, methylcellulose, xanthan gum, carbopol and polyethylene glycols.

Compositions for administration to the lung or nose may contain one or more excipients may be protected from microbial or fungal contamination and growth by inclusion of one or more preservatives. Examples of pharmaceutically acceptable anti-microbial agents or preservatives include, but are not limited to, quaternary ammonium compounds (for example benzalkonium chloride, benzethonium chloride, cetrimide, cetylpyridinium chloride, lauralkonium chloride and myristyl picolinium chloride), mercurial agents (for example phenylmercuric nitrate, phenylmercuric acetate and thimerosal), alcoholic agents (for example chlorobutanol, phenylethyl alcohol and benzyl alcohol), antibacterial esters (for example esters of para-hydroxybenzoic acid), chelating agents such as disodium edetate (EDTA) and other anti-microbial agents such as chlorhexidine, chlorocresol, sorbic acid and its salts (such as potassium sorbate) and polymyxin. Examples of pharmaceutically acceptable anti-fungal agents or preservatives include, but are not limited to, sodium benzoate, sorbic acid, sodium propionate, methylparaben, ethylparaben, propylparaben and butylparaben. The preservative(s), if included, may be present in an amount of from 0.001 to 1% (w/w), such as from 0.015% to 0.5% (w/w) based on the total weight of the composition.

Compositions (for example wherein at least one compound is in suspension) may include one or more surfactants which functions to facilitate dissolution of the medicament particles in the aqueous phase of the composition. For example, the amount of surfactant used is an amount which will not cause foaming during mixing. Examples of pharmaceutically acceptable surfactants include fatty alcohols, esters and ethers, such as polyoxyethylene (20) sorbitan monooleate (Polysorbate 80), macrogol ethers, and poloxamers. The surfactant may be present in an amount of between about 0.01 to 10% (w/w), such as from 0.01 to 0.75% (w/w), for example about 0.5% (w/w), based on the total weight of the composition. One or more tonicity-adjusting agent(s) may be included to achieve tonicity with body fluids e.g. fluids of the nasal cavity, resulting in reduced levels of irritancy. Examples of pharmaceutically acceptable tonicity-adjusting agents include, but are not limited to, sodium chloride, dextrose, xylitol, calcium chloride, glucose, glycerine and sorbitol. A tonicity-adjusting agent, if present, may be included in an amount of from 0.1 to 10% (w/w), such as from 4.5 to 5.5% (w/w), for example about 5.0% (w/w), based on the total weight of the composition.

The compositions of the invention may be buffered by the addition of suitable buffering agents such as sodium citrate, citric acid, trometamol, phosphates such as disodium phosphate (for example the dodecahydrate, heptahydrate, dihydrate and anhydrous forms), or sodium phosphate and mixtures thereof.

A buffering agent, if present, may be included in an amount of from 0.1 to 5% (w/w), for example 1 to 3% (w/w) based on the total weight of the composition.

Examples of taste-masking agents include sucralose, sucrose, saccharin or a salt thereof, fructose, dextrose, glycerol, corn syrup, aspartame, acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, thaumatin, neotame, mannitol, menthol, eucalyptus oil, camphor, a natural flavouring agent, an artificial flavouring agent, and combinations thereof.

One or more co-solvent(s) may be included to aid solubility of the medicament compound(s) and/or other excipients. Examples of pharmaceutically acceptable co-solvents include, but are not limited to, propylene glycol, dipropylene glycol, ethylene glycol, glycerol, ethanol, polyethylene glycols (for example PEG300 or PEG400), and methanol. In one embodiment, the co-solvent is propylene glycol. Co-solvent(s), if present, may be included in an amount of from 0.05 to 30% (w/w), such as from 1 to 25% (w/w), for example from 1 to 10% (w/w) based on the total weight of the composition.

Compositions for inhaled administration include aqueous, organic or aqueous/organic mixtures, dry powder or crystalline compositions administered to the respiratory tract by pressurised pump or inhaler, for example, reservoir dry powder inhalers, unit-dose dry powder inhalers, pre-metered multi-dose dry powder inhalers, nasal inhalers or pressurised aerosol inhalers, nebulisers or insufflators. Suitable compositions contain water as the diluent or carrier for this purpose and may be provided with conventional excipients such as buffering agents, tonicity modifying agents and the like. Aqueous compositions may also be administered to the nose and other regions of the respiratory tract by nebulisation. Such compositions may be aqueous solutions or suspensions or aerosols delivered from pressurised packs, such as a metered dose inhaler, with the use of a suitable liquefied propellant.

Compositions for administration topically to the nose (for example, for the treatment of rhinitis) or to the lung, include pressurised aerosol compositions and aqueous compositions delivered to the nasal cavities by pressurised pump. Compositions which are non- pressurised and are suitable for administration topically to the nasal cavity are of particular interest. Suitable compositions contain water as the diluent or carrier for this purpose. Aqueous compositions for administration to the lung or nose may be provided with conventional excipients such as buffering agents, tonicity-modifying agents and the like. Aqueous compositions may also be administered to the nose by nebulisation.

A fluid dispenser may typically be used to deliver a fluid composition to the nasal cavities. The fluid composition may be aqueous or non-aqueous, but typically aqueous. Such a fluid dispenser may have a dispensing nozzle or dispensing orifice through which a metered dose of the fluid composition is dispensed upon the application of a user-applied force to a pump mechanism of the fluid dispenser. Such fluid dispensers are generally provided with a reservoir of multiple metered doses of the fluid composition, the doses being dispensable upon sequential pump actuations. The dispensing nozzle or orifice may be configured for insertion into the nostrils of the user for spray dispensing of the fluid composition into the nasal cavity. A fluid dispenser of the aforementioned type is described and illustrated in International Patent Application publication number WO 2005/044354 (Glaxo Group Limited). The dispenser has a housing which houses a fluid-discharge device having a compression pump mounted on a container for containing a fluid composition. The housing has at least one finger-operable side lever which is movable inwardly with respect to the housing to move the container upwardly in the housing by means of a cam to cause the pump to compress and pump a metered dose of the composition out of a pump stem through a nasal nozzle of the housing. In one embodiment, the fluid dispenser is of the general type illustrated in Figures 30-40 of WO 2005/044354.

Aqueous compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof may also be delivered by a pump as disclosed in International Patent Application publication number WO2007/138084 (Glaxo Group Limited), for example as disclosed with reference to Figures 22-46 thereof, or as disclosed in United Kingdom patent application number GB0723418.0 (Glaxo Group Limited), for example as disclosed with reference to Figures 7-32 thereof. The pump may be actuated by an actuator as disclosed in Figures 1-6 of GB0723418.0.

Dry powder compositions for topical delivery to the lung by inhalation may, for example, be presented in capsules and cartridges of for example gelatine, or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator. Powder blend compositions generally contain a powder mix for inhalation of the compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable powder base (carrier/diluent/excipient substance) such as mono-, di-, or polysaccharides (for example lactose or starch). Dry powder compositions may also include, in addition to the drug and carrier, a further excipient (for example a ternary agent such as a sugar ester for example cellobiose octaacetate, calcium stearate, or magnesium stearate.

In one embodiment, a composition suitable for inhaled administration may be incorporated into a plurality of sealed dose containers provided on medicament pack(s) mounted inside a suitable inhalation device. The containers may be rupturable, peelable, or otherwise openable one-at-a-time and the doses of the dry powder composition administered by inhalation on a mouthpiece of the inhalation device, as known in the art. The medicament pack may take a number of different forms, for instance a disk-shape or an elongate strip. Representative inhalation devices are the DISKHALER™ and DISKUS™ devices, marketed by GlaxoSmithKline.

A dry powder inhalable composition may also be provided as a bulk reservoir in an inhalation device, the device then being provided with a metering mechanism for metering a dose of the composition from the reservoir to an inhalation channel where the metered dose is able to be inhaled by a patient inhaling at a mouthpiece of the device. Exemplary marketed devices of this type are TURBUHALER™ (AstraZeneca), TWISTHALER™ (Schering) and CLICKHALER™ (Innovata.)

A further delivery method for a dry powder inhalable composition is for metered doses of the composition to be provided in capsules (one dose per capsule) which are then loaded into an inhalation device, typically by the patient on demand. The device has means to rupture, pierce or otherwise open the capsule so that the dose is able to be entrained into the patient's lung when they inhale at the device mouthpiece. As marketed examples of such devices there may be mentioned ROTAHALER™ (GlaxoSmithKline) and HANDIHALER™ (Boehringer Ingelheim.)

Pressurised aerosol compositions suitable for inhalation can be either a suspension or a solution and may contain a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable propellant such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes, especially 1,1,1,2- tetrafluoroethane, 1,1,1,2,3, 3, 3-heptafluoro-n-propane or a mixture thereof. The aerosol composition may optionally contain additional composition excipients well known in the art such as surfactants e.g. oleic acid, lecithin or an oligolactic acid or derivative thereof e.g. as described in WO 94/21229 and WO 98/34596 (Minnesota Mining and Manufacturing Company) and co-solvents e.g. ethanol. Pressurised compositions will generally be retained in a canister (e.g. an aluminium canister) closed with a valve (e.g. a metering valve) and fitted into an actuator provided with a mouthpiece.

Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical compositions adapted for parental administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

It should be understood that in addition to the ingredients particularly mentioned above, the compositions may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.

Antisense or RNA interference molecules may be administered to the mammal in need thereof. Alternatively, constructs including the same may be administered. Such molecules and constructs can be used to interfere with the expression of the protein of interest, e.g., histone demethylase and as such, modify histone demethylation. Typically delivery is by means known in the art.

Antisense or RNA interference molecules can be delivered in vitro to cells or in vivo, e.g., to tumors of a mammal. Nodes of delivery can be used without limitations, including: intravenous, intramuscular, intraperitoneal, intra-arterial, local delivery during surgery, endoscopic, subcutaneous, and per os. Vectors can be selected for desirable properties for any particular application. Vectors can be viral or plasmid. Adenoviral vectors are useful in this regard. Tissue-specific, cell-type specific, or otherwise regulatable promoters can be used to control the transcription of the inhibitory polynucleotide molecules. Non-viral carriers such as liposomes or nanospheres can also be used. The compounds of formula (I) and pharmaceutically acceptable salts thereof may also be formulated with vaccines as adjuvants to modulate their activity. Such compositions may contain antibody(ies) or antibody fragment(s) or an antigenic component including but not limited to protein, DNA, live or dead bacteria and/or viruses or virus-like particles, together with one or more components with adjuvant activity including but not limited to aluminium salts, oil and water emulsions, heat shock proteins, lipid A preparations and derivatives, glycolipids, other TLR agonists such as CpG DNA or similar agents, cytokines such as GM-CSF or IL-12 or similar agents.

A therapeutically effective amount of the agent will depend upon a number of factors including, for example, the age and weight of the subject, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian. In particular, the subject to be treated is a mammal, particularly a human. The agent may be administered in a daily dose. This amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same.

Suitably, the amount of the compound of the invention administered according to the present invention will be an amount selected from O.Olmg to lg per day (calculated as the free or unsalted compound).

The compounds of formula (I) and pharmaceutically acceptable salts thereof may be employed alone or in combination with other therapeutic agents. The compounds of formula (I) and pharmaceutically acceptable salts thereof and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order, by any convenient route in separate or combined pharmaceutical compositions.

The amounts of the compound(s) of formula (I) or pharmaceutically acceptable salt(s) thereof and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired com bined therapeutic effect. The compounds of the present invention and further therapeutic agent(s) may be em ployed in combination by administration simultaneously in a unitary pharmaceutical composition including both compounds. Alternatively, the combination may be administered separately in separate pharmaceutical compositions, each including one of the compounds in a sequential manner wherein, for example, the compound of the invention is administered first and the other second and visa versa. Such sequential administration may be close in time (e.g. simultaneously) or remote in time. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and the other compound may be administered orally. Suitably, both compounds are administered orally.

The combinations may be presented as a combination kit. By the term "combination kit" "or kit of parts" as used herein is meant the pharmaceutical composition or compositions that are used to administer the combination according to the invention. When both compounds are administered simultaneously, the combination kit can contain both compounds in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions. When the compounds are not administered simultaneously, the combination kit will contain each compound in separate pharmaceutical compositions either in a single package or in separate pharmaceutical compositions in separate packages.

The combination kit ca n also be provided by instruction, such as dosage and administration instructions. Such dosage and administration instructions ca n be of the kind that are provided to a doctor, for example by a drug product label, or they ca n be of the kind that are provided by a doctor, such as instructions to a patient.

When the combination is administered separately in a sequential manner wherein one is administered first and the other second or vice versa, such sequential administration may be close in time or remote in time. For example, administration of the other agent several minutes to several dozen minutes after the administration of the first agent, and administration of the other agent several hours to several days after the administration of the first agent are included, wherein the lapse of time is not limited, For example, one agent may be administered once a day, and the other agent may be administered 2 or 3 times a day, or one agent may be administered once a week, and the other agent may be administered once a day and the like.

It will be clear to a person skilled in the art that, where appropriate, the other therapeutic ingredients(s) may be used in the form of salts, for example as alkali metal or amine salts or as acid addition salts, or prodrugs, or as esters, for example lower alkyl esters, or as solvates, for example hydrates, to optimise the activity and/or stability and/or physical characteristics, such as solubility, of the therapeutic ingredient. It will be clear also that, where appropriate, the therapeutic ingredients may be used in optically pure form.

When combined in the same composition it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the composition and may be formulated for administration. When formulated separately they may be provided in any convenient composition, conveniently, in such a manner as known for such compounds in the art.

When the compound of formula (I) is used in combination with a second therapeutic agent active against the same disease, condition or disorder ,the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.

In one embodiment the mammal in the methods and uses of the present invention is a human.

The compounds of the invention may be particularly useful for treatment of RIP2 kinase-mediated diseases or disorders, particularly, uveitis, interleukin-1 converting enzyme (ICE, also known as Caspase-1) associated fever syndrome, dermatitis, acute lung injury, type 2 diabetes mellitus, arthritis (specifically rheumatoid arthritis), inflammatory bowel disorders (such as ulcerative colitis and Crohn's disease), early-onset and extra-intestinal inflammatory bowel disease, prevention of ischemia reperfusion injury in solid organs (specifically kidney) in response ischemia induced by cardiac surgery, organ transplant, sepsis and other insults, liver diseases (non-alcohol steatohepatitis, alcohol steatohepatitis, and autoimmune hepatitis), allergic diseases (such as asthma), transplant reactions (such as graft versus host disease), autoimmune diseases (such as systemic lupus erythematosus, and multiple sclerosis), and granulomateous disorders (such as sarcoidosis, Blau syndrome, early-onset sarcoidosis, Wegner's granulomatosis, and interstitial pulmonary disease).

The compounds of this invention may be particularly useful in the treatment of uveitis, ICE fever, Blau Syndrome, early-onset sarcoidosis, ulcerative colitis, Crohn's disease, Wegener's granulamatosis and sarcoidosis.

Treatment of RIP2 kinase-mediated diseases or disorders, or more broadly, treatment of immune mediated diseases including, but not limited to, allergic diseases, autoimmune diseases, prevention of transplant rejection and the like, may be achieved using a compound of this invention as a monotherapy, or in dual or multiple combination therapy, particularly for the treatment of refractory cases, such as in combination with other anti-inflammatory and/or anti-TNF agents, which may be administered in

therapeutically effective amounts as is known in the art.

For example, the compounds of this invention may be administered in combination with corticosteroids and/or anti-TNF agents to treat Blau syndrome, early-onset sarcoidosis; or in combination with anti-TNF biologies or other anti-inflammatory biologies to treat Crohn's Disease; or in combination with 5-ASA (mesalamine) or sulfasalazine to treat ulcerative colitis; or in combination with low-dose corticosteroids and/or methotrexate to treat Wegener's granulamatosis or sarcoidosis or interstitial pulmonary disease; or in combination with a biologic (e.g. anti-TNF, anti-IL-6, etc.) to treat rheumatoid arthritis; or in combination with anti-IL6 and/or methotrexate to treat ICE fever. Examples of suitable anti-inflammatory agents include corticosteroids, particularly low-dose corticosteroids (such as prednisone) and anti-inflammatory biologies (such as anti- IL6R mAb and anti-CD20 mAb. Examples of suitable anti-TNF agents include anti-TNF biologies etanecerpt adalimumab), infliximab) and golimumab.

This invention also provides a compound of Formula (I), or a salt thereof, particularly a pharmaceutically acceptable salt thereof, for use in therapy. This invention specifically provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as an active therapeutic substance in the treatment of a RIP2 kinase-mediated disease or disorder, for example the diseases and disorders recited herein; more specifically, for use in the treatment of a disease mediated by inhibition of RIP2 kinase.

The invention also provides for the use of a compound of Formula (I), or a salt thereof, particularly a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a RIP2 kinase-mediated disease or disorder, for example the diseases and disorders recited herein.

In a further aspect there is provided a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one further therapeutic agent useful in the treatment of a disease mediated by inhibition of RIP2 kinase

In a further aspect there is provided a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one further therapeutic agent useful in the treatment of a disease mediated by inhibition of RIP2 kinase for use in therapy.

In a further aspect there is provided a combination comprising a compound of formula (I) or pharmaceutically acceptable salt thereof and at least one one further therapeutic agent useful in the treatment of allergic disease, inflammation or autoimmune disease, for use in the treatment a disease mediated by inhibition of RIP2 kinase.

In a further aspect there is provided the use of a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one one further therapeutic agent useful in the treatment of allergic disease, inflammation or autoimmune diseasein the manufacture of a medicament for the treatment of a disease mediated by inhibition of RIP2 kinase In a further aspect there is provided a method of treating allergic disease, inflammation or autoimmune disease comprising administering to a human in need thereof a therapeutically effective amount of a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one further therapeutic agent useful in the treatment of a disease mediated by inhibition of RIP2 kinase.

In a further aspect there is provided a pharmaceutical composition comprising a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one further therapeutic agent useful in the treatment of a disease mediated by inhibition of RIP2 kinase and one or more of pharmaceutically acceptable excipients.

General Synthetic Methods

Compounds of general formula (I) may be prepared by methods known in the art of organic synthesis. In all of the methods, it is well understood that protecting groups for sensitive or reactive groups may be employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1999) Protective Groups in Organic Synthesis, 3^rd edition, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of Formula (I).

Methods for preparing RIP2 inhibitors included in the present invention can be found in WO 2014/128622, WO 2014/043437, WO 2013/025958, WO 2012/122011, WO 2012/021580 and WO 2011/140442. Experimental

Abbreviations:

DCM: dichloromethane.

DIAD: diisopropyl azodicarboxylate

D I P E A: N,N-diisopropylethylamine.

DMF: N,N-dimethylformamide.

h: hour.

H/ArL/:2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate. HPLC: high-performance liquid chromatography.

LCMS: liquid chromatography-mass spectrometry

Min: minutes.

NMR: Nuclear magnetic resonance.

RT: retention time.

tBu: tert-butoxide.

TFA: trifluoroacetic acid.

THF: tetrahydrofuran.

LCMS Method A:

The analysis was conducted on an Acquity UPLC BEH C18 column (50mm x 2.1mm internal diameter 1.7μιτι packing diameter) at 40°C.

The solvents employed were:

A = 0.1% v/v solution of formic acid in water.

B = 0.1% v/v solution of formic acid in acetonitrile.

The gradient employed was as follows: Time Flow Rate

% A % B

(minutes) (mL/min)

0 1 97 3

1.5 1 0 100

1.9 1 0 100

2.0 1 97 3

The UV detection was an averaged signal from wavelength of 210nm to 350nm and mass spectra were recorded on a mass spectrometer using alternate-scan positive and negative mode electrospray ionization.

LCMS Method B:

The analysis was conducted on an Acquity UPLC BEH C18 column (50mm x 2.1mm internal diameter 1.7μιη packing diameter) at 40°C.

The solvents employed were:

A = 10 mM ammonium bicarbonate in water adjusted to pH 10 with ammonia solution. B = acetonitrile. The gradient employed was as follows:

(minutes) (mL/min)

0 1 99 1

1.5 1 3 97

1.9 1 3 97

2.0 1 99 1

The following illustrates the mobile phases and gradients used when compounds underwent purification by mass-directed autopreparative HPLC.

Mass-Directed Autopreparative HPLC (Formic Acid Modifier)

The HPLC analysis was conducted on a Sunfire C18 column (150mm x 30mm internal diameter, 5μιη packing diameter) at ambient temperature.

The solvents employed were:

A = 0.1% v/v solution of formic acid in water.

B = 0.1% v/v solution of formic acid in acetonitrile. Mass-Directed Autopreparative HPLC (Trifluoroacetic Acid Modifier)

The solvents employed were:

A = 0.1% v/v solution of trifluoroacetic acid in water.

B = 0.1% v/v solution of trifluoroacetic acid in acetonitrile.

Mass-Directed Autopreparative HPLC (Ammonium Bicarbonate Modifier)

The HPLC analysis was conducted on an XBridge C18 column (150mm x 30mm internal diameter, 5μιη packing diameter) at ambient temperature.

The solvents employed were:

A = 10 mM ammonium bicarbonate in water adjusted to pH 10 with ammonia solution. B = acetonitrile. For each of the mass-directed autopreparative purifications, irrespective of the modifier used, the gradient employed was dependent upon the retention time of the particular compound undergoing purification as recorded in the analytical LCMS, and was as follows:

For compounds with an analytical LCMS retention time below 0.6 minutes the following gradient was used:

For compounds with an analytical LCMS retention time between 0.6 and 0.9 minutes following gradient was used:

10 40 45 55

11 40 1 99

15 40 1 99

For compounds with an analytical LCMS retention time between 0.9 and 1.2 minutes the following gradient was used:

For compounds with an analytical LCMS retention time between 1.2 and 1.4 minutes the following gradient was used:

1 40 50 50

10 40 1 99

11 40 1 99

15 40 1 99

For compounds with an analytical LCMS retention time greater than 1.4 minutes (LCMS method A) or greater than 3.6 minutes (LCMS method B) the following gradient was used:

The chemical names were generated using ChemBioDraw Ultra vl2 from CambridgeSoft.

Intermediate 1 5- 4-Bromo-3-methoxyphenyl)amino)methylene)-2,2-dimethyl-l,3-dioxane-4,6-dione

2,2-Dimethyl-l,3-dioxane-4,6-dione (8.5 g, 58 mmol) in trimethyl orthoformate (50 mL, 450 mmol) was refluxed at 105°C for 1 hr. 4-Bromo-3-methoxyaniline (commercially available from, for example, Aldrich) (10.5 g, 50.4 mmol) was then added and refluxing was continued for an additional hour. The suspension was filtered, and the solid was washed with methanol and vacuum dried to yield the title compound (17.0 g, 49 mmol, 96 % yield). LCMS RT= l.lOmin, ES+ve 356,358

Intermediate 2

6-Bromo-7-methoxyquinolin-4-ol

To diphenyl ether (68 mL, 420 mmol) at 230°C was added 5-({[4-bromo-3- (methyloxy)phenyl]amino}methylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione (15 g, 42 mmol), and the mixture was stirred for 1 hr. The reaction mixture was poured into hexane after being cooled to room temperature. The precipitate was filtered and washed with hexane. The brown solid was dried under vacuum overnight to afford the title compound (10.0 g, 33 mmol, 79 % yield). LCMS RT= 0.63 min, ES+ve 254,256 Intermediate 3

6-Bromo-4-chloro-7-methoxyquinoline

6-Bromo-7-(methyloxy)-4-quinolinol (4.17 g, 16.4 mmol) in phosphorus oxychloride (8 mL, 82 mmol) was stirred at 110 °C for 1 hr. The reaction mixture was cooled and cautiously poured into saturated aqueous sodium carbonate with ice while stirring. The resulting suspension was filtered, the solid was washed with water and vacuum-dried overnight to yield the title compound (4.6 g, 16 mmol, 97 % yield). LCMS RT= 1.18 min, ES+ve 272,274 Intermediate 4

6- Tert-butylthio)-4-chloro-7-methoxyquinol

A mixture of 6-bromo-4-chloro-7-methoxyquinoline (50 g, 183 mmol), Pd(PPh₃)₄ (5.30 g, 4.59 mmol), sodium carbonate (48.6 g, 459 mmol) and 1,4-dioxane (895 mL) was purged with nitrogen for 10 minutes. 2-Methyl-2-propanethiol (22.8 mL, 202 mmol) was added and the reaction was heated at 70°C for 4 d. The reaction was cooled to room temperature and flushed through a silica gel plug that had been pre-wetted with EtOAc using 100% EtOAc as the eluent. The product-containing fractions were combined and triturated with MeOH to afford the title compound (37.5 g, 128 mmol, 70 % yield). LCMS RT= 1.31 min, ES+ve 282

Intermediate 5

-(Tert-butylsulfonyl)-4-chloro-7-methoxyquinoline

(Tert-butylthio)-4-chloro-7-methoxyquinoline (18.5 g, 63.0 mmol) in ethyl acetate (315 mL) and water (315 mL) was treated with Oxone^® (44.6 g, 72.5 mmol) and stirred at rt for 18 hours. The mixture was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were concentrated to dryness. The residue was dissolved in a minimal amount of 10% methanol/dichloromethane, loaded onto a 340g prepacked silica cartridge and purified via column chromatography (100% ethyl acetate, then 0- 20% methanol in ethyl acetate). Product-containing fractions were evaporated to dryness and triturated with EtOAc to yield the title compound (15.2g, 48.4 mmol, 77% yield). LCMS RT= 0.97 min, ES+ve 314

Intermediate 6 N-(6-(Tert-butylsulfonyl)-7-methoxyquinolin-4-yl)benzo[d]thiazol-5-amine

A mixture of 6-(tert-butylsulfonyl)-4-chloro-7-methoxyquinoline (2 g, 6.37 mmol) and benzo[d]thiazol-5-amine (0.957 g, 6.37 mmol) in ethanol (10 mL) was irradiated by microwave at 150°C for 15 mins. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The aqueous layer was extracted with EtOAc twice and the combined EtOAc layers were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified via flash chromatography (100 g prepacked silica cartridge, 0-75% ethyl acetate/cyclohexane) to yield the title compound (2.11 g, 4.94 mmol, 77 % yield). LCMS RT= 0.58 min, ES+ve 428

Intermediate 7

4- Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-ol

To a solution of N-(6-(tert-butylsulfonyl)-7-methoxyquinolin-4-yl)benzo[d]thiazol-5-amine hydrochloride (5.35g, 11.53 mmol) in DMF (50mL) was added sodium propane-2-thiolate (5.66 g, 57.7 mmol). The reaction was then heated to 150°C for 1 hour. It was cooled to rt and concentrated under vacuum. The residue was treated with ethanol (70 mL) and stirred at 60°C for 15 minutes, cooled in ice then the yellow precipitated product was filtered off, washed with minimum ethanol and dried under vacuum to afford the title compound (4.55 g, llmmol, 95 % yield). LCMS RT= 0.57 min, ES+ve 414

Intermediate 8

l-Phen l-2,5,8,ll-tetraoxatridecan-13-ol

An ice-cooled solution of 2,2'-((oxybis(ethane-2,l-diyl))bis(oxy))diethanol (27.3 g, 140 mmol) in tetrahydrofuran (30 mL) under an atmosphere of nitrogen was treated with sodium hydride, 60 % w/w in mineral oil (1.54 g, 38.6 mmol). After stirring for 25 min at 0°C, the reaction mixture was treated dropwise with (bromomethyl)benzene (4.17 mL, 35.1 mmol). The mixture was heated to reflux under nitrogen for 24 h then concentrated in vacuo. The residue was taken up in EtOAc (50 mL) and washed with brine (3x30 mL), dried (MgS0₄)and evaporated under vacuum. The product was purified using reverse phase chromatography (C18) eluting with 5-95% acetonitrile (+ 0.1% formic acid) and water (+ 0.1% formic acid). The appropriate fractions were combined and evaporated in vacuo to afford the title compound (5.76 g, 0.020 mmol, 58% yield) as a colourless oil. ¹H NMR (400 MHz, CDCI₃ ) δ ppm 3.69 (m, 16H), 4.59 (s, 2H), 7.29 (m, 1H), 7.35 (m, 4H). MS (m/z) 285

Intermediate 9

Tert-but l l-phenyl-2,5,8,ll,14-pentaoxahexadecan-16-oate

Potassium tert-butoxide (2.23 g, 19.8 mmol) was added to a stirred solution of 1-phenyl- 2,5,8,ll-tetraoxatridecan-13-ol (5.76 g, 18.0 mmol) in tert-butanol (60 mL) and the mixture was stirred at room temperature for 2 h. Tert-butyl 2-bromoacetate (4.79 mL, 32.5 mmol) was then added, and the mixture was stirred at room temperature overnight. The mixture was diluted with DCM (50 mL) and washed with water (50 mL) and then brine (2 x 50 mL). The organic extract was dried and concentrated under vacuum. The product was purified via flash chromatography using a gradient of 0-100% methyltert-butyl ether-cyclohexane to afford the title compound (4.22 g, 10.1 mmol, 56 % yield) as a colourless oil. ¹H NMR (400 MHz, CDCI₃ ) δ ppm 1.47 (s, 9H), 3.66 (m, 16H), 4.01 (s, 2H), 4.57 (s, 2H), 7.27 (m, 1H), 7.34 (m, 4H). MS (m/z) 399.

Intermediate 10

Tert-but l 14-hydroxy-3,6,9,12-tetraoxatetradecan-l-oate

A mixture of tert-butyl l-phenyl-2,5,8,ll,14-pentaoxahexadecan-16-oate (4.22 g, 10.1 mmol) and palladium on carbon (10%) (1.61 g, 1.51 mmol) in ethanol (40 mL) was stirred at room temperature under an atmosphere of hydrogen for 1.5 hours. The catalyst was filtered through celite and the fitrate evaporated under vacuum to afford the title compound (2.96 g, 7.68 mmol, 76 % yield) as a colourless oil. ¹H NMR (400 MHz, CDCI₃ ) δ ppm 1.44 (s, 9H), 3.66 (m, 16H), 3.99 (s, 2H). MS (m/z) 309.

Intermediate 11

Tert-but l 14-(tosyloxy)-3,6,9,12-tetraoxatetradecan-l-oate

4-Toluenesulfonyl chloride (2.49 g, 13.1 mmol) was added to an ice-cooled solution of tert- butyl 14-hydroxy-3,6,9,12-tetraoxatetradecan-l-oate (2.96 g, 7.68 mmol) in pyridine (30 mL). The reaction was stirred at room temperature for 5 hours. The reaction mixture was partitioned between ethyl acetate (50 mL) and 2 M aq. HCI (40 mL). The organic extract was separated, washed with 2M aq HCI (40 mL), followed by saturated sodium bicarbonate (50 mL) and brine (50 mL). The organic extract was then dried and concentrated under reduced pressure and the product was purified by chromatography on silica 330g, using a gradient elution from 0-100% methyl tert-butyl ether in cyclohexane to yield tert-butyl 14-(tosyloxy)- 3,6,9,12-tetraoxatetradecan-l-oate (2.17 g, 4.50 mmol, 59 % yield), as a colourless oil. ¹H NMR (400 MHz, CDCI₃ ) δ ppm 1.47 (s, 9H), 2.45 (s, 3H), 3.58 (s, 4H), 3.63 (m, 4H), 3.68 (m, 8H), 4.01 (s, 2H), 4.16 (m, 2H), 7.34 (d, 2H, J=8.3Hz), 7.78 (d, 2H, J=8.3Hz) . MS (m/z) 463

Intermediate 12

Tert-butyl 14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)- 3,6,9,12-tetraoxatetradecan-l-oate

A mixture of 4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-ol (50 mg, 0.12 mmol), tert-butyl 14-(tosyloxy)-3,6,9,12-tetraoxatetradecan-l-oate (84 mg, 0.18 mmol) and potassium carbonate (50 mg, 0.36 mmol) in N-methyl-2-pyrrolidone (2.4mL) was stirred and heated at 95°C for 4 hours. The product was subjected directly to purification by mass- directed automated preparative HPLC (formic acid modifier) to afford the title compound (55 mg, 0.078 mmol, 65% yield). ¹H NMR (400 MHz, CDCI₃ ) δ ppm 1.37 (s, 9H), 1.46 (s, 9H), 3.64 (m, 14H), 3.87 (s, 2H), 4.01 (s, 2H), 4.31 (s, 2H), 6.75 (d, IH, J=6.4Hz), 7.12 (d, IH, J=8.1Hz), 7.52 (d, IH, J=7.3Hz) , 7.73 (s, IH) , 7.52 (d, IH, J=7.3Hz) , 7.81 (d, IH, J=7.3Hz) , 8.01 (d, IH, J=8.6Hz) , 8.12 (s, IH), 8.29 (d, IH, J=6.4Hz), 8.12 (s, IH), 9.00 (s, IH), 9.09 (s, IH). MS (m/z) 704

Intermediate 13

14-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-3,6,9,12- tetraoxatetradecan-l-oic acid, Hydrochloride

A solution of tert-butyl 14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7- yl)oxy)-3,6,9,12-tetraoxatetradecan-l-oate (52 mg, 0.074 mmol) in THF (2 mL) was treated with hydrochloric acid (4M in 1,4-dioxane) (0.018 mL, 0.074 mmol), After 3 hours the mixture was evaporated to dryness to afford the title compound (45 mg, 0.066 mmol, 89 % yield). ¹H NMR (400 MHz, DMSO-d ) δ ppm 1.38 (s, 9H), 3.53 (m, 6H), 3.57 (m, 12H), 3.65 (m, 2H), 3.88 (m, 2H), 4.02 (s, 2H), 4.39 (t, 3H, J=3.7 Hz), 6.81 (d, IH, J=7.3Hz), 7.12 (d, IH, J=7.8Hz), 7.49 (d, IH, J=8.1Hz) , 7.62 (dd, IH, J=8.3Hz, 2.0Hz) , 7.72 (s, IH), 8.23 (d, IH,

J=2.0Hz) , 8.38 (s, IH) , 8.40(s, IH), 8.47(s, IH), 8.49(s, IH), 9.28 (s, IH), 9.54 (s, IH), 11.60 (s, IH), 14.54 (bs, IH). MS (m/z) 648

Intermediate 14

Methyl 2-(4-(tert-butoxycarbonyl)piperazin-l-yl)pyrimidine-5-carboxylate

Methyl 2-chloropyrimidine-5-carboxylate (0.927 g, 5.37 mmol) was added to a mixture of tert-butyl piperazine-l-carboxylate (1 g, 5.37 mmol) and DIPEA (2.34 mL, 13.4 mmol) in DCM (10 mL) in a 20 mL vial (exotherm). The reaction was then stirred at room temperature (bath temp). After 40 min, additional DCM (5 mL) was added along with an aqueous solution of 10 wt% citric acid (45 mL). The layers were separated, and the aqueous layer was extracted with DCM (10 mL). The combined organic layers were dried (Na₂S0₄), concentrated under reduced pressure, and dried under high vacuum, giving 1.74 g (100%) of the title compound as a pale yellow-tan solid. LC/MS: m/z 323.0 (M+H)⁺, RT=1.00 min H NMR (400MHz, DICHLOROMETHANE-d₂) δ = 8.82 (s, 2H), 3.89 (d, 7=4.5 Hz, 4H), 3.85 (s, 3H), 3.49 (t, 7=4.9 Hz, 4H), 1.47 (s, 9H)

Intermediate 15

2-(4-(Tert-butoxycarbonyl)piperazin-l-yl)pyrimidine-5-carboxylic acid

A mixture of methyl 2-(4-(tert-butoxycarbonyl)piperazin-l-yl)pyrimidine-5-carboxylate (1.72 g, 5.34 mmol) and LiOH (0.319 g, 13.3 mmol) was taken up in THF (5 mL), MeOH (5 mL), and water (5 mL) in a 20 mL vial. The reaction mixture was sealed and heated at 70 °C (bath temp) for 2 h.The mixture was concentrated under a stream of nitrogen at 50 ^c and the residue was taken up in water (10 mL) and adjusted to a pH of about 5 with 1 M HCI. The mixture was then extracted with EtOAc (3 x 5 mL) and the combined organic layers were dried (Na₂S0₄) and concentrated under reduced pressure. Water (10 mL) was added to the residue, and the mixture was brought carefully to pH = 3 (as determined by pH paper) by cautious addition of 6 M HCI with stirring. This resulted in the formation of a white precipitate, which was filtered and allowed to aspirate dry overnight, providing the title compound (1.49 g, 90%) as a white solid. LC/MS: m/z 309.0 (M+H; weak)⁺, RT= 0.82 min, H NMR (400MHz, METHANOL-d₄) δ = 8.83 (s, 2H), 4.02 - 3.81 (m, 4H), 3.52 (br. s., 4H), 1.49 (s, 9H). Intermediate 16

-Methyl 5-amino-4-(4-nitro-l-oxoisoindolin-2-yl)-5-oxopentanoate

To a suspension of methyl 2-(bromomethyl)-3-nitrobenzoate (15 g, 54.7 mmol) and (S)- methyl 4,5-diamino-5-oxopentanoate, Hydrochloride (16.14 g, 82 mmol) in N,N- dimethylformamide (300 mL) stirred at room temp was added K₂C0₃ (18.9 g, 137 mmol). The reaction mixture was stirred at 22 °C (room temperature) for 17 hrs. The reaction mixture was treated with water (200 mL) and IN HCI (140 mL) and then extracted with DCM (200 mL). The phases were separated, and the aqueous phase was extracted with DCM (2 x 200 mL). The combined organic phase was washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated to give 23 g of the crude product as a yellow syrup. The crude residue was preabsorbed on silica and purified by flash chromatography on silica gel (ISCO Combiflash Rf, 330 g ISCO RediSep Rf column, Hex/(EtOAc:EtOH, 3:1) 10% -> 75%), giving 17.3 g (93 %) the title compound as a light-yellow solid. LC/MS: m/z 321.9 (M+H)⁺, RT=0.54 min.

Intermediate 17

-Methyl 5-amino-4-(4-amino-l-oxoisoindolin-2-yl)-5-oxopentanoate

A solution of (S)-methyl 5-amino-4-(4-nitro-l-oxoisoindolin-2-yl)-5-oxopentanoate (17 g, 52.9 mmol) in EtOAc (1000 mL) was hydrogenated using an H-cube Pro (settings: 50 °C, 1 bar, lmL/min flow rate) and 10% Pd/C CatCart 70 as the catalyst for 1 complete pass overnight. The reaction mixture was evaporated and the residue was diluted with DCM and reconcentrated, giving 15.4 g (95%) of the title compound as a light-yellow solid. LC/MS: m/z 292.1 (M+H)⁺, RT=0.39 min. Intermediate 18

(S)-Tert-butyl 4-(5-((2-(l-amino-5-methoxy-l,5-dioxopentan-2-yl)-l-oxoisoindolin-4- yl)carbamoyl)pyrimidin-2-yl)piperazine-l-carboxylate

Oxalyl chloride (90 μΙ, 1.030 mmol) was added to a slurry of 2-(4-(tert- butoxycarbonyl)piperazin-l-yl)pyrimidine-5-carboxylic acid (265 mg, 0.858 mmol) in DCM (4mL) in a 20 mL vial. DMF (10 μΙ, 0.129 mmol) was added and the reaction mixture was stirred at room temperature for 45 min. (S)-Methyl 5-amino-4-(4-amino-l-oxoisoindolin-2- yl)-5-oxopentanoate (250 mg, 0.858 mmol) was added, followed by DIPEA (600 ul, 3.43 mmol)and stirring was continued at room temperature for 50 min. The reaction mixture was then washed with 10% citric acid (3 mL). The aqueous phase was extracted with DCM (2 x 1 mL). Isolute was added to the combined organic layers, and the mixture was concentrated under a stream of nitrogen at 50°C. The Isolute-adsorbed crude product was then purified on a silica cartridge (24 g; Redisep) with a ISCO Combiflash Rf 200i, eluting at 24 mL/min with a gradient running from 100% hexanes to 100% EtOAc over 35 min, then from 100% DCM to 20% DCM/MeOH over another 35 min. The desired fractions were concentrated under reduced pressure and dried under high vacuum, giving 309 mg (62%) of the title compound.LC/MS: m/z 582.2 (M+H)⁺, RT=0.88 min H NMR (400MHz, METHANOL- d₄) δ = 8.91 (s, 2H), 7.73 - 7.66 (m, 2H), 7.60 - 7.51 (m, 1H), 5.01 - 4.93 (m, 1H), 4.75 - 4.67 (m, 1H), 4.61 - 4.53 (m, 1H), 3.95 (t, 7=4.9 Hz, 4H), 3.59 (s, 3H), 3.54 (br. s., 4H), 2.43 - 2.30 (m, 3H), 2.28 - 2.13 (m, 1H), 1.50 (s, 9H).

Intermediate 19

(S)-Methyl 5-amino-5-oxo-4-(l-oxo-4-(2-(piperazin-l-yl)pyrimidine-5-carboxamido) isoindolin-2-yl)pentanoate, trifluoroacetic acid salt

(S)-Tert-butyl 4-(5-((2-(l-amino-5-methoxy-l,5-dioxopentan-2-yl)-l-oxoisoindolin-4- yl)carbamoyl)pyrimidin-2-yl)piperazine-l-carboxylate (296 mg, 0.509 mmol) was taken up in trifluoroacetic acid (2 mL) and the reaction was stirred at room temperature for 25 min., The reaction mixture was concentrated under reduced pressure. MeOH (3 mL) was added, and the mixture was concentrated under reduced pressure to help drive off the residual TFA. This process was repeated one more time and the residue was and dried under high vacuum, giving the title compound (364 mg , 100%).LC/MS: m/z 482.2 (M+H)⁺, RT=0.44 min, H NMR (400MHz, M ETHAN OL-d₄) δ = 8.98 (s, 2H), 7.74 - 7.63 (m, 2H), 7.60 - 7.50 (m, 1H), 5.03 - 4.94 (m, 1H), 4.75 - 4.64 (m, 1H), 4.61 - 4.51 (m, 1H), 4.22 (d, 7=4.8 Hz, 4H), 3.59 (s, 3H), 3.34 (br. s., 4H), 2.45 - 2.09 (m, 4H).

Intermediate 20

6-(Tert-butylsulfonyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-iodopropoxy)quinazolin-4- amine

1,3-Diiodopropane (0.04 mL, 0.346 mmol) was added to a mixture of 6-(tert-butylsulfonyl)- 4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7-ol (125 mg, 0.333 mmol) and Cs₂C0₃ (217 mg, 0.666 mmol) in DMF (3 mL). The reaction mixture was sealed and heated at 80 °C (bath temp)for 30 min. Water (5 mL) was added and the resulting precipitate was filtered off, and washed with water (2 x 3 mL). which caused additional precipitate to form in the filtrate. The combined precipitate was taken up in MeOH, Isolute was added, and the mixture was concentrated under a stream of nitrogen at 50°C. The Isolute-adsorbed crude product was then purified on a silica cartridge (24 g; Redisep) using an ISCO Combiflash Rf 200i, eluting at 24 mL/min with a gradient running from 100% DCM to 20% MeOH/DCM over 35 min to give the title compound (48 mg, 27%). LC/MS: m/z 544.0 (M+H)⁺, RT=0.80 min, H NMR (400MHz, METHANOL-d₄) δ = 8.91 (s, 1H), 8.42 (br. s., 1H), 7.32 (s, 1H), 4.32 (t, 7=5.3 Hz, 2H), 3.56 (t, 7=6.7 Hz, 2H), 2.34 (t, 7=6.0 Hz, 2H), 2.27 (s, 3H), 1.94 (s, 2H), 1.89 (s, 3H), 1.40 (s, 9H).

Intermediate 21 (S)-Methyl 5-amino-4-(4-(2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-l-yl)pyrimidine-5-carboxamido)-l- oxoisoindolin-2-yl)-5-oxopentanoate trifluoroacetic acid salt

DIPEA (0.06 mL, 0.344 mmol) was added to a mixture of 6-(tert-butylsulfonyl)-N-(4,5- dimethyl-lH-pyrazol-3-yl)-7-(3-iodopropoxy)quinazolin-4-amine (48 mg, 0.088 mmol) and (S)-methyl 5-amino-5-oxo-4-(l-oxo-4-(2-(piperazin-l-yl)pyrimidine-5- carboxamido)isoindolin-2-yl)pentanoate trifluoroacetic acid salt (52.6 mg, 0.088 mmol) in anhydrous DMF (1 mL). The reaction was stirred at room temperature. After 22 h, the reaction mixture was purified on a Gilson HPLC (Luna 5 urn C18(2) 100A Axia 50 x 21.2 mm preparatory column), eluting at 20 mL/min with a linear gradient running from 20%

CH₃CN/H2O (0.1% TFA) to 70% CH₃CN/H2O (0.1% TFA) over 10 min. The desired fractions were concentrated under a stream of nitrogen at 50 °C, giving the title compound (35.4 mg, 40%). LC/MS: m/z 897.2 (M+H)⁺, RT=0.65 min.

Intermediate 22

6- Tert-butylsulfonyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-fluoroquinazolin-4-amine

6-(Tert-butylsulfonyl)-7-fluoroquinazolin-4-ol (18.95 g, 66.7 mmol) in acetonitrile (85 mL) was treated with POCI₃ (9.3 mL, 100 mmol) and then Et₃N (14 mL, 100 mmol) and heated at 80°C overnight. The bath temperature was then decreased to 50°C. A solution of 4,5- dimethyl-lH-pyrazol-3-amine (8.176 g, 73.6 mmol) in acetonitrile (20 mL) was added over 30 minutes and the mixture heated for 1 hour. The reaction mixture was partially concentrated, the solid product was filtered off, washed with acetonitrile and then dried under vacuum. A second crop of product was recovered from the filtrate, combined with the first and thoroughly dried to afford the title compound (15.48 g, 41.0 mmol, 62% yield, as a yellow powder. LC/MS: RT= 0.72 min, m/z = 378.1.

Intermediate 23

Tert-butyl 4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- l)oxy)methyl)piperidine-l-carboxylate

A mixture of 6-(tert-butylsulfonyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-fluoroquinazolin-4- amine (4.059 g, 10.75 mmol)and tert-butyl 4-(hydroxymethyl)piperidine-l-carboxylate (from for example Aldrich, 3.475 g, 16.14 mmol) in dioxane (50 mL) was treated portion-wise with NaH, 60% (0.654 g, 16.35 mmol) over 4 minutes. After 1 hour the reaction was heated at 80°C for 1.5 hours and then at 90°C for 36 hours. After cooling, additional NaH, 60% (0.656 g, 16.40 mmol) was added in one portion and the mixture heated at 90°C overnight. The reaction was quenched with 10 mL saturated NH₄CI and treated with 50 mL Et₂0. The solids were filtered off and rinsed with Et₂0. The filtrate was concentrated under reduced pressure and treated with DCM. The resulting solids were filtered off and rinsed with DCM and the filtrate was absorbed onto silica gel. The product was purified by chromatography (ISCO Combiflash, 120 g column, 85 ml/min, 0-11.1% (10% NH₄OH in MeOH) / DCM over 33 minutes). The product fractions were collected and concentrated under reduced pressure to yield the title compound (3.856 g, 6.73 mmol, 63% yield) as a yellow powder. LC/MS:RT= 0.91 min, m/z = 573.2.

Intermediate24

6-(Tert-butylsulfonyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(piperidin-4-ylmethoxy) quinazolin-4-amine

A solution of tert-butyl 4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)methyl)piperidine-l-carboxylate (3.86 g, 6.73 mmol) in DCM (50 mL) was treated with TFA (5 mL, 64.9 mmol). After 6 hours the reaction was

concentrated under reduced pressure. 50 mL of DCM and 25 mL of 1M K₂C0₃ were added and the resulting precipitate was filtered off and washed with water and DCM. The aqueous portion was concentrated under reduce pressure, treated with MeOH and the resulting solids were filtered off and washed with MeOH. The precipitated solids and the MeOH filtrate were combined in a mixture of MeOH + DCM and absorbed onto silica gel. The product was purified by chromatography (ISCO Combiflash, 40 g column, 40 ml/min, 0- 50% (10% NH₄OH in MeOH) / DCM over 60 minutes). The product fractions were concentrated under reduce pressure to yield the title compound (3.102 g, 6.56 mmol, 97% yield) as a yellow powder. LC/MS: RT= 0.51 min, m/z = 473.2,

Intermediate 25

6-(Tert-butylsulfonyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(2-(piperidin-4- l)ethoxy)quinazolin-4-amine

A solution of tert-butyl 4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)ethyl)piperidine-l-carboxylate (1.25 g, 2.130 mmol) in DCM (20 mL) was treated with TFA (2 mL, 26.0 mmol). After 3.5 hours the reaction was concentrated under reduced pressure. The residue was partitioned between Et₂0 (25 mL) and 1M K₂C0₃ (50 mL) and the resulting solids were filtered off and the filtrate removed of organic solvent in vacuo and the solids filtered off The combined solids were dissolved in DCM/MeOH, absorbed on to silica and the product purified by chromatography (ISCO Combiflash, 40 g, 40 ml/min, 0-31.5% (10% NH40H in MeOH) / DCM over 38 minutes) to yield the title compound (0.732 g, 1.504 mmol, 71% yield) as a yellow solid. LC/MS: RT= 0.41 min, m/z = 487.2. Intermediate 26

Methyl 3-bromo-2-(bromomethyl)benzoate

A solution of methyl 3-bromo-2-methylbenzoate (from for example AstaTech, 24.35 g, 106 mmol) in benzene (300 mL) was treated with N-bromosuccinimide (22.7 g, 128 mmol) followed by benzoyl peroxide, 95% (1.3 g, 5.35 mmol). The reaction mixture was flushed with nitrogen and kept under nitrogen. The reaction mixture was heated at 80°C for 2 days. The reaction mixture was concentrated under reduced pressure and treated with hexanes (200 mL). The resulting solids were filtered off, washed with hexanes then with 25% EtOAc / hexanes. The filtrate was concentrated under reduced pressure and the residue was absorbed directly onto silica gel. The product was purified by chromatography (ISCO

Combiflash, 330 g, 200 ml/min, 0-8.7% EtOAc / Hexanes over 30 minutes) to yield the title compound (32.4 g, 105 mmol, 99% yield) as an orange liquid. LC/MS: RT= 1.13 min, m/z = 226.8/228.9.

Intermediate 27

(S)-Methyl 5-amino-4-(4-bromo-l-oxoisoindolin-2-yl)-5-oxopentanoate

A solution of methyl 3-bromo-2-(bromomethyl)benzoate (15.48 g, 50.3 mmol) in DMF (400 mL) was treated with (S)-methyl 4,5-diamino-5-oxopentanoate, Hydrochloride (14.83 g, 75 mmol) and K₂C0₃ (17.38 g, 126 mmol) and the reaction stirred overnight at room

temperature. The mixture was treated with water (375 mL) and IN HCI (125 mL). The aqueous phase was washed with 1:1 hexanes/Et₂0 (3 x 100 mL) and then extracted with DCM (5 x 100 mL). The organics were dried with MgS0₄, filtered and concentrated under reduced pressure. Chromatographic purification (ISCO Combiflash, 330 g column, 200 ml/min, 0-56.5% (3:1 EtOAc / EtOH) / hexanes over 51 minutes) yielded the title compound (16.69 g, 47.0 mmol, 89% yield) as a yellow-orange viscous oil. LC/MS RT= 0.75 min, m/z = 355.0/357.0.

Intermediate 28

(S)-Methyl 5-amino-4-(4-(3-(2-hydroxyethoxy)prop-l-yn-l-yl)-l-oxoisoindolin-2-yl)-5- oxopentanoate

A solution of (S)-methyl 5-amino-4-(4-bromo-l-oxoisoindolin-2-yl)-5-oxopentanoate (6.93 g) in DMF (40 mL) was treated with Et₃N (40 mL). Nitrogen was bubbled through the mixture for 25 minutes and the mixture was split equally into 4 giving (S)-methyl 5-amino-4-(4- bromo-l-oxoisoindolin-2-yl)-5-oxopentanoate (1.732 g, 4.88 mmol) in DMF (10 mL) and triethylamine (10 mL) per vial. To each was added 2-(prop-2-yn-l-yloxy)ethanol (from for example Matrix, 0.93 mL, 9.75 mmol) and copper(l) iodide (0.074 g, 0.389 mmol). Nitrogen was again bubbled through for 2 minutes. To each reaction was then added

bis(triphenylphosphine)palladium(ll) dichloride (0.265 g, 0.378 mmol) and the sealed mixtures heated at 80°C overnight. Additional 2-(prop-2-yn-l-yloxy)ethanol (0.93 mL, 9.75 mmol) was added and heating continued for a further day. The reaction mixtures were concentrated under reduced pressure and absorbed onto silica gel. Purification via chromatography (ISCO Combiflash, 80 g column, 60 ml/min, 0-93.5% (3:1 EtOAc / EtOH) / hexanes over 33 minutes) yielded the title compound (0.549 g, 1.47 mmol, 30% yield) as an orange oil. LC/MS: RT= 0.56 min, m/z = 375.1.

Intermediate 29

(S)-Methyl 5-amino-4-(4-(6-hydroxyhex-l-yn-l-yl)-l-oxoisoindolin-2-yl)-5-oxopentanoate

A solution of (S)-methyl 5-amino-4-(4-bromo-l-oxoisoindolin-2-yl)-5-oxopentanoate (6.93 g) in DMF (40 mL) and Et₃N (40 mL). Nitrogen was bubbled through the mixture for 25 minutes. The mixture was split equally into 4 giving (S)-methyl 5-amino-4-(4-bromo-l- oxoisoindolin-2-yl)-5-oxopentanoate (1.732 g, 4.88 mmol) in DMF (10 mL) and triethylamine (10 mL) per vial. Each vial was treated with hex-5-yn-l-ol (0.80 mL, 7.38 mmol) and copper(l) iodide (0.048 g, 0.252 mmol). Nitrogen was again bubbled through the reaction mixtures for 2 minutes. To each was added bis(triphenylphosphine) palladium(ll) dichloride (0.176 g, 0.251 mmol) and the sealed reaction mixtures were heated at 80°C overnight. The reaction mixture was concentrated under reduced pressure and the residue was absorbed onto silica gel. Purification via chromatography (ISCO Combiflash, 80 g column, 60 ml/min, 0-78.4% (3:1 EtOAc / EtOH) / hexanes over 30minutes). The product fractions were collected and concentrated under reduced pressure to yield the title compound (1.72 g, 4.61 mmol, 94%) as an orange oil. LC/MS: RT= 0.68 min, m/z = 373.1.

Intermediate 30

S)-Methyl 5-amino-4-(4-(8-hydroxyoct-l-yn-l-yl)-l-oxoisoindolin-2-yl)-5-oxopentanoate

The title compound was prepared in a manner similar to the preparation of Intermediate 29, but starting from oct-7-yn-l-ol LC/MS: RT= 0.81 min, m/z = 401.2.

Intermediate 31

(S)-Methyl 5-amino-4-(4-(10-hydroxydec-l-yn-l-yl)-l-oxoisoindolin-2-yl)-5-oxopentanoate

The title compound was prepared in a manner similar to the preparation of Intermdiate 29, but starting from dec-9-yn-l-ol. LC/MS: RT= 0.94 min, m/z = 429.2. Intermediate 32

(S)-Methyl 5-amino-4-(4-(3-(2-hydroxyethoxy)propyl)-l-oxoisoindolin-2-yl)-5- oxo entanoate

A solution of (S)-methyl 5-amino-4-(4-(3-(2-hydroxyethoxy)prop-l-yn-l-yl)-l-oxoisoindolin- 2-yl)-5-oxopentanoate (0.549 g, 1.466 mmol) in MeOH (30 mL) was hydrogenated using the H-Cube Pro (10% Pd/C, 1 mL/min, 25 bar, ambient temperature). The reaction mixture was concentrated under reduced pressure and dried under vacuum to yield the title compound (0.455 g, 1.20 mmol, 82% yield) as a tan oil. LC/MS: Product at 0.57 min, m/z = 379.1. Intermediate 33

-Methyl 5-amino-4-(4-(6-hydroxyhexyl)-l-oxoisoindolin-2-yl)-5-oxopentanoate

The title compound was prepared in a manner similar to the preparation of Intermediate 32, but starting with (S)-methyl 5-amino-4-(4-(6-hydroxyhex-l-yn-l-yl)-l-oxoisoindolin-2-yl)-5- oxopentanoate (Intermediate 29). LC/MS: RT= 0.71 min, m/z = 377.1.

Intermediate 34

(S)-Methyl 5-amino-4-(4-(8-hydroxyoctyl)-l-oxoisoindolin-2-yl)-5-oxopentanoate

(S)-Methyl 5-amino-4-(4-(8-hydroxyoctyl)-l-oxoisoindolin-2-yl)-5-oxopentanoate was prepared in a similar manner to the preparation of Intermediate 32, but starting from (S)- methyl 5-amino-4-(4-(8-hydroxyoct-l-yn-l-yl)-l-oxoisoindolin-2-yl)-5-oxopentanoate (Intermediate 30). LC/MS: Product at 0.85 min, m/z = 405.2.

Intermediate 35

-Methyl 5-amino-4-(4-(10-hydroxydecyl)-l-oxoisoindolin-2-yl)-5-oxopentanoate

The title compound was prepared in a similar manner to the preparation Intermediate 32, but starting from (S)-methyl 5-amino-4-(4-(10-hydroxydec-l-yn-l-yl)-l-oxoisoindolin-2-yl)-5- oxopentanoate ( Intermediate 31).

Intermediate 36

(S)-Methyl 5-amino-4-(4-(3-(2-bromoethoxy)propyl)-l-oxoisoindolin-2-yl)-5- xopentanoate

To a solution of (S)-methyl 5-amino-4-(4-(3-(2-hydroxyethoxy)propyl)-l-oxoisoindolin-2-yl)- 5-oxopentanoate (0.455 g, 1.202 mmol) in DCM (6 mL) was added triphenylphosphine (0.414 g, 1.58 mmol) and the mixture cooled in a freezer (-18°C). While still cold the mixture was treated with a solution of carbon tetrabromide (0.519 g, 1.57 mmol) in DCM (1 mL) in one portion and stirred overnight. Purification via chromatography (ISCO Combiflash, 40 g column, 40 ml/min, 0-60% (3:1 EtOAc / EtOH) / Hexanes over 25 minutes) yielded the title compound (0.400 g, 0.906 mmol, 75% yield) as a tan oil. LC/MS: RT= 0.80 min, m/z = 441.0/443.1,. Intermediate 37

-Methyl 5-amino-4-(4-(6-bromohexyl)-l-oxoisoindolin-2-yl)-5-oxopentanoate

The title compound was prepared in a similar manner to the preparation of Intermediate 36, but starting from (S)-methyl 5-amino-4-(4-(6-hydroxyhexyl)-l-oxoisoindolin-2-yl)-5- oxopentanoate (Intermediate 33). LC/MS: RT= 1.02 min, m/z = 439.0/441.13.

Intermediate 38

-Methyl 5-amino-4-(4-(8-bromooctyl)-l-oxoisoindolin-2-yl)-5-oxopentanoate

The title compound was prepared in a similar manner to the preparation of Intermed but starting from (S)-methyl 5-amino-4-(4-(8-hydroxyoctyl)-l-oxoisoindolin-2-yl)-5- oxopentanoate (Intermediate 34). LC/MS: Product at 1.16 min, m/z = 467.1/469.1.

Intermediate 39

-Methyl 5-amino-4-(4-(10-bromodecyl)-l-oxoisoindolin-2-yl)-5-oxopentanoate

The title compound was prepared in a similar manner to the preparation of Intermediate 36, but starting from (S)-methyl 5-amino-4-(4-(10-hydroxydecyl)-l-oxoisoindolin-2-yl)-5- oxopentanoate (Intermediate 35). LC/MS: RT= 1.30 min, m/z = 495.1/497.1.

Intermediate 40

(S)-Methyl 5-amino-4-(4-(3-(2-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-l-yl)ethoxy)propyl)-l-oxoisoindolin-2-yl)-5- xopentanoate

A solution of (S)-methyl 5-amino-4-(4-(3-(2-bromoethoxy)propyl)-l-oxoisoindolin-2-yl)-5- oxopentanoate (0.201 g, 0.455 mmol) in DMF (4 mL) was treated with 6-(tert- butylsulfonyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(piperidin-4-ylmethoxy)quinazolin-4- amine (0.199 g, 0.421 mmol) and DIPEA (0.11 mL, 0.630 mmol). After 1.5 hours the mixture was heated at 50 °C for 2 hours then at 40°C overnight, 50°C for 9 hours and at ambient temperature for 8 days. The reaction mixture was concentrated under reduced pressure. Purification via chromatography (ISCO Combflash, 24 g column, 35 ml/min, 0-15.1% (10% NH₄OH in MeOH) / DCM over 18 minutes) yielded the title compound (0.263 g, 0.316 mmol, 75.0% yield) as a yellow powder. LC/MS: RT= 0.69 min, m/z = 833.3.

Intermediate 41

(S)-Methyl 5-amino-4-(4-(6-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-l-yl)hexyl)-l-oxoisoindolin-2-yl)-^^ oxopentanoate

The title compound was prepared in a similar manner to Intermediate 40, but starting from (S)-methyl 5-amino-4-(4-(6-bromohexyl)-l-oxoisoindolin-2-yl)-5-oxopentanoate

(Intermediate 37). LC/MS: RT= 0.74 min, m/z = 831.3.

Intermediate 42

(S)-Methyl 5-amino-4-(4-(8-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-l-yl)octyl)-l-oxoisoindolin-2-yl)-5- oxopentanoate

The title compound was prepared in a similar manner to Intermediate 40, but starting from (S)-methyl 5-amino-4-(4-(8-bromooctyl)-l-oxoisoindolin-2-yl)-5-oxopentanoate

(Intermediate 38). LC/MS: RT= 0.82 min, m/z = 859.3.

Intermediate 43

(S)-Methyl 5-amino-4-(4-(10-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-l-yl)decyl)-l-oxoisoindolin-2-yl)-5- oxopentanoate

The title compound was prepared in a similar manner to Intermediate 40, but starting from (S)-methyl 5-amino-4-(4-(10-bromodecyl)-l-oxoisoindolin-2-yl)-5-oxopentanoate

(Intermediate 39). LC/MS: RT= 0.89 min, m/z = 887.3.

Intermediate 44

(S)-Methyl 5-amino-4-(4-(6-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)ethyl)piperidin-l-yl)hexyl)-l-oxoisoindolin-2-yl)-5- oxo entanoate

A solution of (S)-methyl 5-amino-4-(4-(6-bromohexyl)-l-oxoisoindolin-2-yl)-5- oxopentanoate (0.156 g, 0.355 mmol) in DMF (3 mL) was treated with 6-(tert-butylsulfonyl)- N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(2-(piperidin-4-yl)ethoxy)quinazolin-4-amine (0.151 g, 0.310 mmol) and DIPEA (0.09 ml_, 0.515 mmol) sealed and heated at 40°C for 2 hours . After standing for 3 days, the mixture was concentrated under reduced pressure and Purified by chromatography (ISCO Combiflash, 24 g column, 35 ml/min, 0-11.8% (10% NH₄OH in MeOH) / DCM over 22 minutes) to yield the title compound (0.178 g, 0.211 mmol, 68% yield) as a yellow powder. LC/MS: RT= 0.61 min, m/z = 845.3.

Intermediate 45

(S)-Methyl 5-amino-4-(4-(8-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)ethyl)piperidin-l-yl)octyl)-l-oxoisoindolin-2-yl)-5- oxopentanoate

The title compound was prepared in a similar manner to Intermediate 43, but starting from (S)-methyl 5-amino-4-(4-(8-bromooctyl)-l-oxoisoindolin-2-yl)-5-oxopentanoate

(Intermediate 38). LC/MS: RT= 0.67 min, m/z = 873.3.

Intermediate 46

(S)-Methyl 5-amino-4-(4-(10-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)ethyl)piperidin-l-yl)decyl)-l-oxoisoindolin-2-yl)-5- oxopentanoate

The title compound was prepared in a similar manner to Intermediate 43 but starting from (S)-methyl 5-amino-4-(4-(10-bromodecyl)-l-oxoisoindolin-2-yl)-5-oxopentanoate

(Intermediate 39). LC/MS: RT= 0.75 min, m/z = 901.4. Intermediate 47 6- Tert-butylsulfonyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-ethoxyquinazolin-4-amine

Under nitrogen, a mixture of 6-(tert-butylsulfonyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-7- fluoroquinazolin-4-amine, Hydrochloride (5.41 g, 13.07 mmol) and 6-(tert-butylsulfonyl)-N- (4,5-dimethyl-lH-pyrazol-3-yl)-7-fluoroquinazolin-4-amine (4.55 g, 12.06 mmol) in EtOH (20 mL) was treated with sodium ethoxide, (21% solution in EtOH, 94 mL, 252 mmol) and heated at 80°C.for 2.5 hours. The reaction mixture was concentrated under reduced pressure and the residue treated with water (100 mL), cooled in an ice bath and treated with 6N HCI (42 mL). The mixture was neutralized with solid NaHC0₃ and the resulting suspension was stirred overnight. The solids were filtered off, washed with water and retained. The filtrate was removed of volatiles under reduced pressure and the resulting aqueous mixture was extracted with DCM (2 x 100 mL). The retained solids and the organic layer were combined with additional DCM (100 mL) and washed with brine. The resulting emulsion/suspension was concentrated under reduced pressure to remove the organics and then stirred vigorously. The solids were filtered off washed with water, air-dried then dried under vacuum to yield the title compound (9.91 g, 24.6 mmol, 98% yield) as a tan powder. LC/MS: RT= 0.74 min, m/z = 404.1.

Intermediate 48

6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazol

Sodium 2-propanethiolate (14.26 g, 145 mmol) was added to a solution of 6-(tert- butylsulfonyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-ethoxyquinazolin-4-amine (9.702 g, 24.04 mmol) in DMF (150 mL) and then heated at 150°C for a total of 7 hours The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water (100 mL) and washed with Et₂0 (3 x 50 mL). The aqueous layer was concentrated under reduced pressure to remove any volatiles and then treated with IN HCI (50 mL). The resulting precipitate was filtered off and washed with water. The filtrate was extracted with DCM (3 x 50 mL). The precipitate and DCM extracts were combined and concentrated under reduced pressure. Purification via chromatography (ISCO Combiflash, 120 g column, 85 ml/min, 0-22.6% MeOH / DCM over 34 minutes) yielded the title compound (7.302 g, 19.45 mmol, 81% yield,) as a yellow powder. LC/MS: RT= 0.64 min, m/z = 376.1.

Intermediate 49

(S)-Methyl 5-amino-4-(4-(3-(2-(4-(2-hydroxyethyl)piperazin-l-yl)ethoxy)propyl)-l- xoisoindolin-2-yl)-5-oxopentanoate

To a solution of (S)-methyl 5-amino-4-(4-(3-(2-bromoethoxy)propyl)-l-oxoisoindolin-2-yl)-5- oxopentanoate (0.495 g, 1.122 mmol) in DMF (11 mL) was added 2-(piperazin-l-yl)ethanol (0.21 mL, 1.711 mmol) and DIPEA (0.59 mL, 3.39 mmol). The sealed reaction was heated at 50°C for 3 hours. After 6 days the reaction mixture was blown down Purification via chromatography (ISCO Combiflash, 24 g, 35 ml/min, 0-15% (10% NH₄OH in MeOH) / DCM over 18 minutes) yielded the title compound (0.567 g, 1.156 mmol, 103% yield) as a tan oil. LC/MS: RT=0.46 min, m/z = 491.2.

Intermediate 50

(S)-Methyl 5-amino-4-(4-(3-(2-(4-(3-hydroxypropyl)piperazin-l-yl)ethoxy)propyl)-l- oxoisoindolin-2- l)-5-oxopentanoate

The title compound was prepared in a similar manner to Intermediate 49 but starting from 3-(piperazin-l-yl)propan-l-ol rather than 2-(piperazin-l-yl)ethanol. LC/MS: RT= 0.47 min, m/z = 505.2.

Intermediate 51

(S)-Methyl 5-amino-4-(4-(3-(2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-l-yl)ethoxy)propyl)-l-oxoisoindolin-2-yl)-5^ oxo entanoate

To a solution of (S)-methyl 5-amino-4-(4-(3-(2-(4-(2-hydroxyethyl)piperazin-l- yl)ethoxy)propyl)-l-oxoisoindolin-2-yl)-5-oxopentanoate (0.294 g, 0.599 mmol) in THF (5 mL) and DMF (5 mL) was added 6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-ol (0.215 g, 0.573 mmol) and Ph₃P (0.200 g, 0.763 mmol). The mixture was cooled in a freezer (-18°C). When cold the mixture was treated with a solution of DIAD (0.15 mL, 0.762 mmol) in THF (1 mL) was added and stirred overnight. The reaction mixture was warmed to 40°C for 2 hours, then to 60°C for 2 hours. The reaction mixture was concentrated under reduced pressure and the product purified by chromatography (ISCO Combiflash, 40 g column, 40 ml/min, 0-22.6% (10% NH40H in MeOH) / DCM over 27 minutes) to yield the title compound (0.267 g, 0.315 mmol, 55% yield) as a yellow powder. LC/MS: RT= 0.66 min, m/z = 848.3. Intermediate 52

(S)-Methyl 5-amino-4-(4-(3-(2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-l-yl)ethoxy)propyl)-l-oxoisoindolin-2-yl)-5- oxopentanoate

The title compound was prepared in a similar manner to Intermediate 51, but starting from (S)-methyl 5-amino-4-(4-(3-(2-(4-(3-hydroxypropyl)piperazin-l-yl)ethoxy)propyl)-l- oxoisoindolin-2-yl)-5-oxopentanoate (Intermediate 50).

LC/MS: RT= 0.65 min, m/z = 862.3. Intermediate 53

(S)-Methyl 5-amino-4-(4-(3-(2-bromoethoxy)prop-l-yn-l-yl)-l-oxoisoindolin-2-yl)-5- oxo entanoate

Under nitrogen, an ice-cooled solution of (S)-methyl 5-amino-4-(4-(3-(2- hydroxyethoxy)prop-l-yn-l-yl)-l-oxoisoindolin-2-yl)-5-oxopentanoate (0.400 g, 1.068 mmol) in DCM (10 mL) was treated with triphenylphosphine (0.311 g, 1.186 mmol) A solution of carbon tetrabromide (0.404 g, 1.218 mmol) in DCM (5 mL) was added over 2.5 min. After 30 minutes the cooling was was removed and the mixture stirred overnight. The reaction mixture was concentrated under reduced pressure and the product purified by

chromatography (ISCO Combiflash, 24 g column, 35 ml/min, 0-75% (3:1 EtOAc / EtOH) /

Hexanes over 30 minutes) to yield the title compound (0.327 g, 0.748 mmol, 70% yield) as a yellow solid. LC/MS: RT= 0.87 min, m/z = 437.0/439.1.

Intermediate 54

(S)-Methyl 5-amino-4-(4-(3-(2-(4-(2-hydroxyethyl)piperazin-l-yl)ethoxy)prop-l-yn-l-yl)-l- oxoisoindolin-2-yl)-5-oxopentanoate

To a solution of (S)-methyl 5-amino-4-(4-(3-(2-bromoethoxy)prop-l-yn-l-yl)-l-oxoisoindolin- 2-yl)-5-oxopentanoate (0.237 g, 0.542 mmol) in DMF (6 mL) was added 2-(piperazin-l- yl)ethanol (0.10 ml_, 0.815 mmol) and DIPEA (0.28 ml_, 1.608 mmol). After 1 hour the mixture was heated at 80°C for 3.5 hours. The mixture was concentrated under reduced pressure and the product was purified by chromatography (ISCO Combiflash, 24 g, 35 ml/min, 0-15.8% (10% NH₄OH in MeOH) / DCM over 19 minutes) to yield the title compound (0.227 g, 0.467 mmol, 86% yield) as a viscous yellow oil. LC/MS: RT=0.52 min, m/z = 487.2.

Intermediate 55

(S)-Methyl 5-amino-4-(4-(3-(2-(4-(2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butyl sulfonyl)quinolin-7-yl)oxy)ethyl)piperazin-l-yl)ethoxy)prop-l-yn-l-yl)-l-oxoisoindolin-2- l)-5-oxopentanoate

To a solution of (S)-methyl 5-amino-4-(4-(3-(2-(4-(2-hydroxyethyl)piperazin-l- yl)ethoxy)prop-l-yn-l-yl)-l-oxoisoindolin-2-yl)-5-oxopentanoate (0.227 g, 0.467 mmol) in THF (4 mL) was added 4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-ol (0.195 g, 0.472 mmol) and Ph₃P (0.160 g, 0.610 mmol) and the mixture was cooled in a freezer (-18°C). The cooled mixture was treated with a solution of DIAD (0.12 mL, 0.609 mmol) in THF (1 mL) over 3 minutes and allowed to stir overnight at ambient temperature. The reaction mixture was treated with DMF (5 mL) and additional Ph₃P (0.156 g, 0.595 mmol) and DIAD (0.12 mL, 0.609 mmol) were added. After 2.5 hours the reaction mixture was concentrated under reduced pressure and the product was purified by chromatography (ISCO Combiflash, 40 g Gold, 40 ml/min, 0-16.1% (10% NH₄OH in MeOH) / DCM over 32 minutes) to yield the (title compound (0.190 g, 0.215 mmol, 46% yield) as a yellow powder. LC/MS: RT= 0.66 min, m/z = 882.2.

Intermediate 56

2-(2-Chloroethoxy)acetyl chloride

combined with thionyl chloride (9.51 ml, 130 mmol) and heated at 60 °C for lh. Thionyl chloride was removed in vacuum and resulting liquid was used without purification.

Intermediate 57

Tert-butyl 4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin- 7yl)oxy)ethyl)piperazine-l-carboxylate

Under nitrogen, an ice-cooled mixture of tert-butyl 4-(2-hydroxyethyl)piperazine-l- carboxylate (From for exammple Aldrich, 2.337 g, 10.15 mmol) and 6-(tert-butylsulfonyl)-N- (4,5-dimethyl-lH-pyrazol-3-yl)-7-fluoroquinazolin-4-amine, Hydrochloride (2g, 4.83 mmol) in 1,4-dioxane (40 mL) was treated portion-wise over 10 minutes with sodium hydride (1.160 g, 29.0 mmol) and stirred for a further 30 minutes. The mixture was then heated at 120°C (oil bath temperature) for 3 hours and allowed to cool to ambient temperature. The mixture was treated with 5% aqueous ammonium chloride until effervescence subsided (40 mL) and then evaporated to dryness. The product was purified by chromatography on silica using a gradient elution from 0% to 15% methanol in dichloromethane to afford the title compound (1.04 g, 1.770 mmol, 37% yield) LCMS RT= 0.77 min,(M+H) 588.

Intermediate 58

6-(Tert-butylsulfonyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(2-(piperazin- lyl)ethoxy)quinazolin-4-amine, 3Hydrochloride

To a solution of tert-butyl 4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)ethyl)piperazine-l-carboxylate (700 mg, 1.191 mmol) in THF (5 mL) and methanol (5 mL) was added HCI (4M in dioxane, 2.084 mL, 8.34 mmol). Stirred at room temperature for 16h. The solvent was evaporated and triturated with ether. Filtered to give the crude title compound (845 mg, 1.42 mmol, 119 % yield).

LCMS RT= 0.56 min,(M+H) 488

Intermediate 59

2- 2-Chloroethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)acetamide

3-(4-Amino-l-oxoisoindolin-2-yl)piperidine-2,6-dione (Astatech) (500 mg, 1.929 mmol) in THF (5ml) was heated at 60 °C with 2-(2-chloroethoxy)acetyl chloride (303 mg, 1.929 mmol) for lh. The solvent was removed in vacuo and the mixture triturated with ether and the proct filtered off and dried under vacuum to give the title compound (675 mg, 1.777 mmol, 92 % yield) LCMS RT= 0.6 min,(M+H) 380

Intermediate 60

-Bromo-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)propanamide

A mixture of 3-(4-amino-l-oxoisoindolin-2-yl)piperidine-2,6-dione (from for example Astatech, 512 mg, 1.975 mmol) and 3-bromopropanoyl chloride (from for example Aldrich, 339 mg, 1.975 mmol) in THF (5 mL) was heated at 60 °C for lh. The product was triturated with ether, filtered and dried under vacuum to give the crude title product (600 mg, 1.522 mmol, 77 % yield). LCMS RT= 0.65 min,(M+H) 395 Intermediate 61

Tert-butyl 4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)methyl)piperidine-l-carboxylate

Under nitrogen, an ice-cooled mixture of tert-butyl 4-(hydroxymethyl)piperidine-l- carboxylate (from for example Aldrich, 2.081 g, 9.66 mmol) and 6-(tert-butylsulfonyl)-N- (4,5-dimethyl-lH-pyrazol-3-yl)-7-fluoroquinazolin-4-amine, Hydrochloride (2g, 4.83 mmol) in 1,4-dioxane (20 mL) was treated portion-wise over 10 minutes with sodium hydride (Aldrich; 60% dispersion) (1.160 g, 29.0 mmol) and stirred for a further 30 minutes. The mixture was then heated at 90°C (oil bath temperature) for 3 hours and then allowed to cool to ambient temperature. The mixture was treated with 5% aqueous ammonium chloride until effervescence subsided (40 mL) and then evaporated to dryness. The product was purified by chromatography on silica using a gradient elution from 0% to 15% methanol in dichloromethane to afford the title compound (884 mg, 1.54 mmol, 32% yield) LCMS RT= 0.97 min,(M+H) 573

Intermediate 62

6-(Tert-butylsulfonyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(piperidin-4-ylmethoxy) quinazolin-4-amine, 3Hydrochloride

To a solution of tert-butyl 4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)methyl)piperidine-l-carboxylate (884 mg, 1.54 mmol) mL) and methanol (5 mL) was added HCI (4M in dioxane, 2.7 mL, 10.8 mmol). The solvent was removed under vacuum. The residue was triturated with ether and filtered to give the title compound (850 mg, 1.46 mmol, 95 % yield). LCMS RT= 0.59 min,(M+H) 473

Intermediate 63

4-Bromo-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)butanamide

To a solution of 3-(4-amino-l-oxoisoindolin-2-yl)piperidine-2,6-dione (from for example Astatech, 500 mg, 1.93 mmol) in THF (5 mL) was added 4-bromobutanoyl chloride (Aldrich) (0.223 mL, 1.929 mmol) and the mixture was stirred at room temperature for 2h. The solvent was removed in vacuo and the residue was triturated with ether, filtered, washed with ether and dried to give the title compound (700 mg, 1.715 mmol, 89 % yield). LCMS RT= 0.7 min,(M+H) 409.

Intermediate 64

2-(2-(2-Chloroethoxy)ethoxy)acetic acid

To a solution of 2-(2-(2-chloroethoxy)ethoxy)ethanol (Aldrich, 1.72 mL, 11.9 mmol) in acetone (60 mL) was added dropwise Jones reagent (Aldrich, 23.7 mL, 47.4 mmol) at 0 °C The reaction was stirred at room temperature for 18h then filtered. The solvent was removed in vacuo and the residue was extracted with DCM (3X100 ml), dried over sodium sulfate, filtered and evaporated in vacuo to give crude title compound (1.9g, 10.41 mmol, 88 % yield). LCMS RT= 0.5 min,(M+H) 183.

Intermediate 65

2-(2-(2-Chloroethoxy)ethoxy)acetyl chloride

2-(2-(2-Chloroethoxy)ethoxy)acetic acid (1.9 g, 10.4 mmol) was treated with thionyl chloride (5.32 ml, 72.8 mmol) and heated at 60 °C for lh. Thionyl chloride was removed in vacuo and the residual liquid was used without purification.

LCMS with methanol quench showed desired compound. RT= 0.6 min,(M+H) 197

Intermediate 66

2-(2-(2-Chloroethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yljacetamide

3-(4-Amino-l-oxoisoindolin-2-yl)piperidine-2,6-dione (From for example Astatech, 500 mg, 1.93 mmol) in THF (5ml) was treated with 2-(2-(2-chloroethoxy)ethoxy)acetyl chloride (388 mg, 1.93 mmol) and heated at 60 °C for lh. The solvent was removed in vacuo and the residue was triturated with ether. The solid product was filtered off and dried under vacuum to give the title compound (700 mg, 1.65 mmol, 86 % yield). LCMS RT= 0.4 min,(M+H) 424

Intermediate 67

N-(2-(2,6-Dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-ll-hydroxyundecanamide

To a solution of 11-hydroxyundecanoic acid (Aldrich) (0.5 g, 2.472 mmol) in DMF (5 mL) was added 3-(4-amino-l-oxoisoindolin-2-yl)piperidine-2,6-dione (0.641 g, 2.47 mmol) followed by HATU (1.222 g, 3.21 mmol) and DIPEA (1.727 mL, 9.89 mmol). The reaction mixture was stirred at room temeprature overnight. The solvent was removed and the residue was subjected to cromatography on 12g ISCO Combiflash column eluting with 0-10%

MeOH:DCM to give the title compound (196 mg, 0.442 mmol, 18% yield). LCMS RT= 0.86 min,(M+H) 444

Intermediate 68

N-(2-(2,6-Dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-ll-oxoundecanamide

To a solution of N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-ll- hydroxyundecanamide (59 mg, 0.133 mmol) in DCM (3mL) at room temeperature was added Dess-Martin periodinane (113 mg, 0.266 mmol). The reaction was stirred at room temperature for lh. The solvent was removed and the mixture subjected to

chromatography on a 4g ISCO Combiflash column eluting with 0-30% MeOH:DCM to give the title compound (11 mg, 0.025 mmol, 19 % yield). LCMS RT= 0.9 min,(M+H) 442

Intermediate 69

Tert-but l 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)acetate

KOtBu (0.747 g, 6.66 mmol) was added to a solution of triethylene glycol (1 g, 6.66 mmol) in anhydrous THF (50 mL) and heated at 50 °C (bath temp) for 1 h. The reaction mixture was cooled to 0 °C (bath temp) stirred for 1 h. Tert-butyl bromoacetate (0.99 mL, 6.70 mmol) was added, the ice bath was removed and the mixture was heated at 65 °C for 21 h. EtOAc (25 mL) and water (50 mL) were added, the layers were separated, and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic fraction was washed with saturated NaCI (1 x 25 mL). Isolute was added, and the mixture was concentrated under reduced pressure. The Isolute-adsorbed crude product was then purified on a silica cartridge (40 g; Redisep) with a Combiflash 200i, eluting at 30 mL/min with a gradient running from 100% hexanes to 100% EtOAc over 40 min, then holding at 100% EtOAc for another 10 min to give the title compound (423 mg (24% yield)) as a colorless oil. LC/MS: m/z 287.1 (M+Na)⁺, rt 0.61 min H NMR (400MHz, CHLOROFORM-d) δ = 4.03 (s, 2H), 3.76 - 3.66 (m, 10H), 3.64 - 3.58 (m, 2H), 1.48 (s, 9H)

Intermediate 70

t rt-butyl 2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetate

N-Methylmorpholine (0.370 mL, 3.37 mmol) and tosyl-CI (589 mg, 3.09 mmol) were added to a solution of tert-butyl 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)acetate (371 mg, 1.40 mmol) in DCM (3 mL) and the reaction was stirred at room temperature for 22 h. A solution of saturated NaCI (5 mL) was added, the layers were separated, and the aqueous layer was extracted with DCM (3 x 5 mL). Isolute was added to the combined organic layers, and the mixture was concentrated under a stream of nitrogen at 50 ^c. The Isolute-adsorbed crude product was then purified on a silica cartridge (24 g; Redisep Gold) with a Combiflash Rf 200i, eluting at 24 mL/min with a gradient running from 100% hexanes to 80%

EtOAc/hexanes over 45 min to give the title compound (495 mg (80% yield)) as a clear, colorless oil. LC/MS: m/z 441.1 (M+Na)⁺, RT=1.06 min. H NMR (400MHz,

DICHLOROMETHANE-dz) δ = 7.78 (d, 7=7.5 Hz, 2H), 7.38 (d, 7=7.8 Hz, 2H), 4.13 (t, 7=4.0 Hz, 2H), 3.96 (s, 2H), 3.67 - 3.61 (m, 4H), 3.59 (d, 7=4.0 Hz, 2H), 3.55 (s, 4H), 2.45 (s, 3H), 1.46 (s, 9H)

Intermediate 71

Tert-butyl 2-(2-(2-(2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7- yl)oxy)ethoxy)ethoxy)ethoxy)acetate

A solution of tert-butyl 2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetate (152 mg, 0.363 mmol) in DMF (0.25 mL) was added to a mixture of 4-(benzo[d]thiazol-5-ylamino)-6-(tert- butylsulfonyl)quinolin-7-ol (100 mg, 0.242 mmol) and Cs₂C0₃ (118 mg, 0.363 mmol) in DMF (0.250 mL). The mixture was sealed and heated at 55 °C (bath temp) for 22.5 h. Water (3 mL) and EtOAc (1 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 1 mL). Isolute was added to the combined organics and the mixture was concentrated under a stream of nitrogen at 50 ^c. The Isolute-adsorbed crude product was then purified on a silica cartridge (12 g; Redisep) with a Combiflash Rf 200i, eluting at 20 mL/min with a gradient running from 100% DCM to 20 % MeOH/DCM over 35 min. The desired fractions were concentrated under reduced pressure and dried under high vacuum to give the title compound (60.4 mg (65% yield). LC/MS: m/z 660.1(M+H)⁺, RT=0.89 min.

Intermediate 72

2-(2-(2-(2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7- yl)oxy)ethoxy)ethoxy)ethoxy)acetic acid

A solution of 4 M HCI in dioxane (0.33 mL, 1.32 mmol) was added to a solution of tert-butyl 2-(2-(2-(2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7- yl)oxy)ethoxy)ethoxy)ethoxy)acetate (97 mg, 0.147 mmol) in DCM (1 mL). The reaction mixture was sealed and stirred at room temperature for 20 h. The reaction mixture was concentrated under a stream of nitrogen to give the crude title compound. LC/MS: m/z 604.2 (M+H)⁺, RT=0.65 min.

Example 1

A mixture of 14-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)- 3,6,9,12-tetraoxatetradecan-l-oic acid hydrochloride (27 mg, 0.042 mmol) and (S)-3-(4- amino-l-oxoisoindolin-2-yl)piperidine-2,6-dione (commercially available from, for example, Matrix Scientific) (11 mg, 0.042 mmol) in DMF (0.7 mL) was treated with DIPEA (0.029 mL, 0.167 mmol) and then with HATU (19 mg, 0.050 mmol) and then stirred at ambient temperature overnight. The product was subjected directly to purification by mass-directed automated preparative HPLC (formic acid modifier) to afford the title compound (17 mg, 0.019 mmol, 46 % yield). LCMS RT= 0.65 min, ES+ve 890

Example 2

(S)-2-(4-(3-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)propyl)piperazin-l-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)pyrimidine-5-carboxamide dihydrochloride

A solution of 1 M KOtBu in THF (0.16 mL, 0.16 mmol) was added to a mixture of (S)-methyl 5-amino-4-(4-(2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-l-yl)pyrimidine-5-carboxamido)-l- oxoisoindolin-2-yl)-5-oxopentanoate, trifluoroacetic acid salt (34 mg, 0.034 mmol) in THF (1 mL). The reaction mixture was stirred at room temperature for 10 min and then treated with a solution of 1 M HCI (0.16 mL). The mixture was concentrated under a stream of nitrogen at 50°C and the residue was dissolved in DMSO (1 mL), filtered through a 0.45 um acrodisc, and purified on a Gilson HPLC (Sunfire 5 um C18 OBD 19x100 mm preparatory column), eluting at 20 mL/min with a linear gradient running from 10% CH₃CN/H₂0 (0.1% TFA) to 80% CH₃CN/H₂0 (0.1% TFA) over 12 min. The desired fractions were concentrated under a stream of nitrogen at 50 °C, giving 16.3 mg of product. The product was transferred to a vial with 1.25 M HCI/MeOH and concentrated under a stream of nitrogen at 50°C. 1 mL of 1.25 M HCI/MeOH was added, and the solution was concentrated under a stream of nitrogen at 50 °C. This process was repeated once more to ensure full conversion to the HCI salt. MeCN (0.5 mL) and water (0.5 mL) were added to the residue, and the mixture was lyophilized with a Virtis BenchTop Pro lyophilizer, giving) the title compound (10.9 mg (35% yield)). LC/MS: m/z 865.2 (M+H)⁺,RT= 0.62 min. H NMR (400MHz, M ETHAN OL-d₄) δ = 9.17 (br. s., 1H), 8.99 (s, 2H), 8.77 (s, 1H), 7.77 - 7.65 (m, 2H), 7.63 - 7.55 (m, 1H), 7.44 (s, 1H), 5.18 (dd, 7=4.9, 13.2 Hz, 1H), 5.07 (d, 7=14.3 Hz, 2H), 4.61 - 4.49 (m, 4H), 3.81 (d, 7=11.3 Hz, 2H), 3.60 (br. s., 4H), 3.25 (br. s., 3H), 2.98 - 2.85 (m, 1H), 2.83 - 2.71 (m, 1H), 2.48 (br. s., 3H), 2.32 (s, 3H), 2.19 (d, 7=13.1 Hz, 1H), 1.97 (s, 3H), 1.49 - 1.39 (m, 9H)

Example 3

2-(4-(3-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)propyl)piperazin-l-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl) pyrimidine-5-carboxamide di-trifluoroacetic acid salt

DIPEA (0.06 mL, 0.344 mmol) was added to a mixture of 6-(tert-butylsulfonyl)-N-(4,5- dimethyl-lH-pyrazol-3-yl)-7-(3-iodopropoxy)quinazolin-4-amine (48 mg, 0.088 mmol) and N- (2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-2-(piperazin-l-yl)pyrimidine-5- carboxamide di-trifluoroacetic acid salt (59.8 mg, 0.088 mmol) in anhydrous DMF (1 mL). The reaction was stirred at room temperature for 25 h. The product was purified on a Gilson HPLC (Luna 5 urn C18(2) 100A Axia 50 x 21.2 mm preparatory column), eluting at 20 mL/min with a linear gradient running from 20% CH₃CN/H₂0 (0.1% TFA) to 70% CH₃CN/H₂0 (0.1% TFA) over 10 min. The desired fractions were concentrated under a stream of nitrogen at 50 °C, giving 160 mg of the title compound. The impure product was repurified (Waters Sunfire 20x100mm Water +0.1%TFA (A) : Acetonitrile+0.1%TFA (B) 10-30% B; 18 mL/min over 10 min; 2 injections), giving 36 mg (37%) of the title compound. LC/MS: m/z 865.3 (M+H)⁺, RT=0.50 min). H NMR (400MHz, METHANOL-d₄) δ = 9.06 - 8.95 (m, 3H), 8.66 (s, IH), 7.73 (d, 7=7.5 Hz, IH), 7.68 (d, 7=8.0 Hz, IH), 7.62 - 7.54 (m, IH), 7.43 (s, IH), 5.18 (dd, 7=5.1, 13.2 Hz, IH), 4.54 (s, 2H), 4.49 (br. s., 2H), 4.22 (br. s., IH), 3.84 - 3.47 (m, 7H), 2.98 - 2.84 (m, IH), 2.83 - 2.71 (m, IH), 2.57 - 2.33 (m, 4H), 2.30 (s, 3H), 2.24 - 2.13 (m, IH), 1.94 (s, 3H), 1.50 - 1.35 (m, 10H).

Example 4

(S)-3-(4-(3-(2-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino) quinazolin-7-yl)oxy)methyl)piperidin-l-yl)ethoxy)propyl)-l-oxoisoindolin-2-yl)piperidine- 2 6-dione

A solution of (S)-methyl 5-amino-4-(4-(3-(2-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH- pyrazol-3-yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-l-yl)ethoxy)propyl)-l- oxoisoindolin-2-yl)-5-oxopentanoate (0.263 g, 0.316 mmol) in THF (6 mL) was cooled in a freezer (-18°C). When cold, the vial was removed from the freezer and 1M KOtBu in THF (0.38 mL, 0.380 mmol) was added and the mixture stirred overnight Acetonitrile (1 mL) was added and after 8 hours DMF (1 mL) was added. After 4 days the reaction was cooled in a freezer. When cold, the reaction was removed from the freezer and 0.38 mL IN HCI was added. After 3 hours the reaction was blown down. DCM + MeOH were added to the residue and the mixture was absorbed onto silica gel. Purification was then conducted via chromatography (ISCO Combiflash, 24 g Gold, 35 ml/min, 0-31.6% MeOH / DCM over 25.3 minutes) to yield the title compound (0.109 g, 0.136 mmol, 43% yield) as a yellow powder. LC/MS: RT=0.66 min, m/z = 801.2. H NMR (400 MHz, METHANOL-d₄) δ 8.90 (br. s., IH), 8.44 (br. s., IH), 7.62-7.72 (m, IH), 7.44-7.55 (m, 2H), 7.33 (br. s., IH), 5.19 (dd, 7=5.02, 13.30 Hz, IH), 4.44-4.59 (m, 2H), 4.09-4.37 (m, 2H), 3.69-3.85 (m, 2H), 3.50-3.69 (m, 4H), 3.26-3.49 (m, 2H, overlap with MeOH), 2.73-3.18 (m, 6H), 2.45-2.61 (m, IH), 2.14-2.38 (m, 7H), 1.97-2.13 (m, 2H), 1.89 (s, 3H), 1.60-1.81 (m, 2H), 1.39 (s, 9H) Example 5 (S)-3-(4-(6-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin- -yl)oxy)methyl)piperidin-l-yl)hexyl)-l-oxoisoindolin-2-yl)piperidine-2,6- dione

The title compound was prepared in a similar manner to Example 4, but starting from (S)- methyl 5-amino-4-(4-(6-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-l-yl)hexyl)-l-oxoisoindolin-2-yl)-5- oxopentanoate.LC/MS: rt 0.71 min, m/z = 799.4.

H NMR (400 MHz, METHANOL-d₄) δ 8.90 (s, IH), 8.45 (br. s., IH), 7.62-7.69 (m, IH), 7.44- 7.52 (m, 2H), 7.32 (br. s., IH), 5.19 (dd, 7=5.02, 13.30 Hz, IH), 4.42-4.58 (m, 2H), 4.11-4.25 (m, 2H), 3.50-3.69 (m, 2H), 2.99-3.20 (m, 4H), 2.85-2.98 (m, IH), 2.68-2.84 (m, 3H), 2.46-2.60 (m, IH), 2.12-2.35 (m, 7H), 1.88 (br. s., 3H), 1.62-1.83 (m, 6H), 1.42-1.53 (m, 4H), 1.40 (s, 9H)

Example 6

(S)-3-(4-(8-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin- 7- l)oxy)methyl)piperidin-l-yl)octyl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione

The title compound was prepared in a similar manner to Example 4, but starting from (S)- methyl 5-amino-4-(4-(8-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-l-yl)octyl)-l-oxoisoindolin-2-yl)-5- oxopentanoate. LC/MS: RT=0.79 min, m/z = 827.3. H NMR (400 MHz, METHANOL-d₄) δ 8.92 (s, IH), 8.47 (br. s., IH), 7.63-7.71 (m, IH), 7.44-7.54 (m, 2H), 7.34 (br. s., IH), 5.20 (dd, 7=5.02, 13.30 Hz, IH), 4.43-4.59 (m, 2H), 4.13-4.29 (m, 2H), 3.52-3.68 (m, 2H), 2.87-3.17 (m, 5H), 2.69-2.86 (m, 3H), 2.47-2.63 (m, IH), 2.14-2.35 (m, 7H), 1.89 (br. s., 3H), 1.62-1.83 (m, 6H), 1.28-1.49 (m, 17H)

Example 7 (S)-3-(4-(10-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin- 7- l)oxy)methyl)piperidin-l-yl)decyl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione

The title compound was prepared in a similar manner to Example 4, but starting from (S)- methyl 5-amino-4-(4-(10-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)methyl)piperidin-l-yl)decyl)-l-oxoisoindolin-2-yl)-5- oxopentanoate. LC/MS: RT= 0.88 min, m/z = 855.3, H NMR (400 MHz, M ETHAN OL-d₄) δ 8.92 (br. s., 1H), 8.47 (br. s., 1H), 7.62-7.72 (m, 1H), 7.44-7.53 (m, 2H), 7.34 (br. s., 1H), 5.20 (dd, 7=5.02, 13.55 Hz, 1H), 4.42-4.58 (m, 2H), 4.15-4.27 (m, 2H), 3.52-3.67 (m, 2H), 2.87-3.14 (m, 5H), 2.68-2.86 (m, 3H), 2.48-2.63 (m, 1H), 2.15-2.35 (m, 7H), 1.90 (br. s., 3H), 1.63-1.84 (m, 6H), 1.27-1.51 (m, 21H)

Example 8

(S)-3-(4-(6-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)ethyl)piperidin-l-yl)hexyl)-l-oxoisoindolin-2-yl)piperidine- 2,6-dione

A solution of (S)-methyl 5-amino-4-(4-(6-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH- pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperidin-l-yl)hexyl)-l-oxoisoindolin-2-yl)-5- oxopentanoate (0.178 g, 0.211 mmol) in THF (4 mL) was treated with DMF (1 mL) and cooled in a freezer (-18°C). When cold, they were removed from the freezer and 1M KOtBu in THF (0.26 mL, 0.260 mmol) was added. After 3 days the mixture was cooled in a freezer and when cold, they were removed from the freezer and 0.26 mL IN HCI was added. After 45 minutes the reaction mixture was blown down. DCM + MeOH were added to the residue and the mixture concentrated under reduced pressure. DCM + MeOH were added and the mixture was absorbed onto silica gel followed by chromatography (ISCO Combiflash, 24 g column Gold, 35 ml/min, 0-27.8% MeOH / DCM over 28 minutes) to yield the title compound (0.052 g, 0.064 mmol, 30.4%, as a yellow powder. LC/MS: RT 0.59 min, m/z = 813.3, ~95% at 210-350 nm H NMR (400 MHz, METHANOL-d₄) δ 8.92 (br. s., IH), 8.44 (br. s, IH), 7.62-7.69 (m, IH), 7.43-7.51 (m, 2H), 7.32 (s, IH), 5.14-5.22 (m, IH), 4.42-4.56 (m, 2H), 4.30-4.38 (m, 2H), 3.52-3.62 (m, 2H), 3.02-3.10 (m, 2H), 2.86-3.01 (m, 3H), 2.69-2.84 (m, 3H), 2.45-2.60 (m, IH), 2.27 (s, 3H), 2.03-2.23 (m, 4H), 1.84-1.96 (m, 5H), 1.67-1.80 (m, 4H), 1.49- 1.61 (m, 2H), 1.35-1.49 (m, 13H) Example 9

(S)-3-(4-(8-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)ethyl)piperidin-l-yl)octyl)-l-oxoisoindolin-2-yl)piperidi

2 6-dione

The title compound was prepared in a similar manner to Example 8 but starting from (S)- methyl 5-amino-4-(4-(8-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)ethyl)piperidin-l-yl)octyl)-l-oxoisoindolin-2-yl)-5- oxopentanoate. LC/MS: RT= 0.66 min, m/z = 841.3,

H NMR (400 MHz, METHANOL-d₄) δ 8.91 (br. s, IH), 8.44 (br. s., IH), 7.61-7.68 (m, IH), 7.43-7.50 (m, 2H), 7.33 (s, IH), 5.14-5.22 (m, IH), 4.41-4.56 (m, 2H), 4.28-4.39 (m, 2H), 3.44- 3.60 (m, 2H), 2.86-3.09 (m, 5H), 2.67-2.84 (m, 3H), 2.46-2.59 (m, IH), 2.27 (s, 3H), 2.00-2.23 (m, 4H), 1.81-1.97 (m, 5H), 1.63-1.76 (m, 4H), 1.46-1.62 (m, 2H), 1.27-1.46 (m, 17H) Example 10

(S)-3-(4-(10-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)ethyl)piperidin-l-yl)decyl)-l-oxoisoindolin-2-yl)piperidine-

2,6-dione

The title compound was prepared in a similar manner to Example 8 but starting from (S)- methyl 5-amino-4-(4-(10-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)ethyl)piperidin-l-yl)decyl)-l-oxoisoindolin-2-yl)-5- oxopentanoate. LC/MS RT= 0.74 min, m/z = 869.3. H NMR (400 MHz, M ETHAN OL-d₄) δ 8.91 (br. s, 1H), 8.44 (br. s., 1H), 7.60-7.68 (m, 1H), 7.42-7.50 (m, 2H), 7.33 (s, 1H), 5.12-5.22 (m, 1H), 4.40-4.55 (m, 2H), 4.27-4.39 (m, 2H), 3.45-3.61 (m, 2H), 2.85-3.10 (m, 5H), 2.66-2.84 (m, 3H), 2.46-2.60 (m, 1H), 2.27 (s, 3H), 2.00-2.23 (m, 4H), 1.82-1.97 (m, 5H), 1.62-1.77 (m, 4H), 1.47-1.62 (m, 2H), 1.25-1.46 (m, 21H)

Example 11

(S)-3-(4-(3-(2-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-l-yl)ethoxy)propyl)-l-oxoisoindolin-2- yl)piperidine-2,6-dione

A solution of (S)-methyl 5-amino-4-(4-(3-(2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl- lH-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-l-yl)ethoxy)propyl)-l- oxoisoindolin-2-yl)-5-oxopentanoate (0.264 g, 0.311 mmol) in THF (6 mL) was cooled in a freezer (-18°C). When cold, it was removed from the freezer and 1M KOtBu in THF (0.31 mL, 0.310 mmol) was added. After 3 days it was cooled back down in a freezer and when cold treated with more 1M KOtBu in THF (0.04 mL, 0.040 mmol). After 8 hours more 1M KOtBu in THF (0.04 mL, 0.040 mmol) was added. After overnight it was cooled back down in a freezer. It was removed from the freezer and 0.39 mL IN HCI was added. After 3.5 hours the reaction mixture concentrated under reduced pressure and the product was purified by chromatography (ISCO, 24 g Gold, 35 ml/min, 0-38.6% MeOH / DCM over 39 minutes) to yield the title compound (0.124 g, 0.152 mmol, 49% yield,) as a yellow powder. LC/MS: RT= 0.63 min, m/z = 816.2. H NMR (400 MHz, METHANOL-d₄) δ 8.90 (s, IH), 8.44 (br. s., IH), 7.59-7.69 (m, IH), 7.42-7.52 (m, 2H), 7.35 (br. s., IH), 5.18 (dd, 7=4.89, 13.18 Hz, IH), 4.44- 4.57 (m, 2H), 4.35-4.44 (m, 2H), 3.58-3.72 (m, 2H), 3.44-3.57 (m, 2H), 2.62-3.11 (m, 16H), 2.45-2.59 (m, IH), 2.27 (s, 3H), 2.13-2.23 (m, IH), 1.92-2.03 (m, 2H), 1.88 (s, 3H), 1.39 (s, 9H)

Example 12

(S)-3-(4-(3-(2-(4-(3-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-l-yl)ethoxy)propyl)-l-oxoisoindolin-2- l)piperidine-2,6-dione

The title compound was prepared in a similar manner to Example 11, but starting from (Si- methyl 5-amino-4-(4-(3-(2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-l-yl)ethoxy)propyl)-l-oxoisoindolin-2-yl)-5- oxopentanoate. LC/MS RT= 0.63 min, m/z = 830.3, H NMR (400 MHz, METHANOL-d₄) δ 8.90 (s, IH), 8.44 (br. s., IH), 7.61-7.69 (m, IH), 7.43-7.52 (m, 2H), 7.33 (br. s., IH), 5.14-5.23 (m, IH), 4.42-4.57 (m, 2H), 4.28-4.39 (m, 2H), 3.56-3.66 (m, 2H), 3.43-3.55 (m, 2H), 2.62-3.10 (m, 16H), 2.44-2.59 (m, IH), 2.27 (s, 3H), 2.08-2.23 (m, 3H), 1.91-2.02 (m, 2H), 1.88 (s, 3H), 1.40 (s, 9H)

Example 13

(S)-3-(4-(3-(2-(4-(2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7- yl)oxy)ethyl)piperazin-l-yl)ethoxy)prop-l-yn-l-yl)-l-oxoisoindolin-2-yl)piperidine-2,6- dione)

Under nitrogen, an ice-cooled solution of (S)-methyl 5-amino-4-(4-(3-(2-(4-(2-((4- (benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)ethyl)piperazin-l- yl)ethoxy)prop-l-yn-l-yl)-l-oxoisoindolin-2-yl)-5-oxopentanoate (0.044 g, 0.050 mmol) in THF (1 mL) was treated with 1M KOtBu in THF (0.05 mL, 0.050 mmol) the reaction mixture was allowed to warm up slowly. After 3 days the reaction was ice-cooled and quenched with 0.05 mL IN HCI. After 10 minutes the ice bath was removed and after 5.5 hours the reaction mixture was absorbed directly onto a silica gel cartridge and subjected to chromatography (ISCO Combiflash, 12 g Gold, 30 ml/min, 0-47.0% MeOH / DCM over 28 minutes) to yield the title compound (0.028 g, 66% yield) as a yellow powder. LC/MS: RT 0.75 min, m/z = 850.3, H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, IH), 9.67 (s, IH), 9.43 (s,

IH), 8.94 (s, IH), 8.49 (d, 7=5.27 Hz, IH), 8.20 (d, 7=8.78 Hz, IH), 8.03 (s, IH), 7.77 (d, 7=7.53 Hz, IH), 7.73 (d, 7=7.53 Hz, IH), 7.51-7.61 (m, 2H), 7.49 (s, IH), 6.89 (d, 7=5.27 Hz, IH), 5.10- 5.20 (m, IH), 4.47-4.55 (m, IH), 4.46 (s, 2H), 4.32-4.39 (m, IH), 4.24-4.32 (m, 2H), 3.66 (t, 7=5.14 Hz, 2H), 2.85-2.98 (m, IH), 2.72-2.80 (m, 2H), 2.36-2.69 (m, 12H, DMSO overlap), 1.97-2.09 (m, IH), 1.33 (s, 9H).

Example 14

2-(2-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)ethyl)piperazin-l-yl)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yljacetamide

A mixture of 6-(tert-butylsulfonyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(2-(piperazin-l- yl)ethoxy)quinazolin-4-amine,3Hydrochloride (30mg, 0.050 mmo), 2-(2-chloroethoxy)-N-(2- (2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)acetamide (19.1 mg, 0.05 mmol), DIPEA (0.088 mL, 0.503 mmol) and sodium iodide (37.7 mg, 0.251 mmol) in DMF (1 mL) was heated at 80 °C overnight. Cooled and the crude mixture was subjected to chromatography on 12g Gold ISCO Combiflash column eluting with 0-25%-methanol (1% ammonium hydroxide):DCM to give the title compound (24 mg, 55 % yield)

NMR (400 MHz, DMSO-d ) δ ppm 1.16 - 1.31 (m, 7 H) 1.32 (s, 6 H) 1.77 (s, 2 H) 2.00 (br. s., 1 H) 2.18 (s, 2 H) 2.30 - 2.49 (m, 4 H) 2.53 - 2.70 (m, 3 H) 2.81 - 3.02 (m, 1 H) 3.18 (d, J=5.27 Hz, 1 H) 3.69 (br. s., 1 H) 4.14 (s, 1 H) 4.27 (br. s., 1 H) 4.38 (d, J=11.04 Hz, 1 H) 5.06 - 5.28 (m, 1H) 7.34 (s, 1 H) 7.45 - 7.83 (m, 3 H) 8.46 (s, 1 H) 8.98 (br. s., 1 H) 9.87 (s, 1 H) 10.34 (s, 1 H) 11.02 (s, 1 H) 12.18 (br. s., 1 H).; LCMS RT= 0.65 min,(M+H) 831

Example 15

3-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)ethyl)piperazin-l-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- l)propanamide

A mixture of 6-(tert-butylsulfonyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(2-(piperazin-l- yl)ethoxy)quinazolin-4-amine 3Hydrochloride (50 mg, 0.084 mmol), 3-bromo-N-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)propanamide (33 mg, 0.084 mmol). DIPEA (0.146 mL, 0.838 mmol) in DMF (1 mL) was heated at 80 °C overnight. The reaction mixture was cooled and the crude mixture subjected to chromatography on a 12g Gold ISCO Combiflash column eluting with 0-25%-methanol(l% ammonium hydroxide):DCM to give the title compound (34 mg, 48.2 % yield). NMR (400 MHz, DMSO-d ) δ ppm 1.16 - 1.31 (m, 7 H) 1.32 (s, 6 H) 1.75 (s, 2 H) 2.00 (br. s., 1 H) 2.19 (s, 2 H) 2.30 - 2.47 (m, 4 H) 2.53 - 2.70 (m, 3 H) 2.83 - 3.02 (m, 1 H) 3.18 (d, J=5.27 Hz, 1 H) 3.69 (br. s., 1 H) 4.27 (br. s., 1 H) 4.38 (d, J=11.04 Hz, 1 H) 5.06 - 5.28 (m, 1H) 7.34 (s, 1 H) 7.45 - 7.83 (m, 3 H) 8.46 (s, 1 H) 8.98 (br. s., 1 H) 9.87 (s, 1 H) 10.34 (s, 1 H) 11.02 (s, 1 H) 12.18 (br. s., 1 H).; LCMS RT= 0.67 min,(M+H) 801 Example 16

2-(2-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)methyl)piperidin-l-yl)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yljacetamide

A mixture of 6-(tert-butylsulfonyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(piperidin-4- ylmethoxy)quinazolin-4-amine, 3Hydrochloride (50 mg, 0.086 mmol) and 2-(2- chloroethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)acetamide (32.6 mg, 0.086 mmol) in DMF (1 mL) was treated with DIPEA (0.150 mL, 0.859 mmol) and sodium iodide (64.4 mg, 0.430 mmol) and the mixture heated at 80°C overnight. On cooling, the entire mixture was subjected to chromatography on a 12g Gold ISCO Combiflash column eluting with 0-25%-methanol (+1% ammonium hydroxide) :DCM to give the title compound (26 mg,

34 % yield)

NMR (400 MHz, DMSO-d ) δ ppm 1.16 - 1.31 (m, 7 H) 1.34 (s, 6 H) 1.76 (s, 2 H) 2.01 (br. s., 1 H) 2.18 (s, 2 H) 2.30 - 2.45 (m, 4 H) 2.53 - 2.74 (m, 4 H) 2.81 - 3.02 (m, 1 H) 3.18 (d, J=5.27 Hz, 1 H) 3.69 (br. s., 1 H) 4.27 (br. s., 1 H) 4.38 (d, J=11.04 Hz, 1 H) 5.06 - 5.28 (m, 1H) 7.34 (s, 1 H) 7.45 - 7.83 (m, 3 H) 8.46 (s, 1 H) 8.98 (br. s., 1 H) 9.87 (s, 1 H) 10.34 (s, 1 H) 11.02 (s, 1 H) 12.18 (br. s., 1 H).; LCMS RT= 0.68 min,(M+H) 816

Example 17

3-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)methyl)piperidin-l-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yljpropanamide

To a mixture of 6-(tert-butylsulfonyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(2-(piperazin-l- yl)ethoxy)quinazolin-4-amine, 3Hydrochloride (50mg, 0.084 mmol) and 4-bromo-N-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)butanamide (34.2 mg, 0.084 mmol) in DMF(1 mL) was added DIPEA (0.146 mL, 0.838 mmol) and the mixture heated at 80 °C overnight. On cooling the entire mixture was subjected to chromatography on a 12g Gold ISCO Combiflash column eluting with 0-25%-methanol(+l% ammonium hydroxide):DCM . to give the title compound (12 mg, 17 % yield). NMR (400 MHz, DMSO-d ) δ ppm 1.16 - 1.33 (m, 7 H) 1.32 (s, 6 H) 1.75 (s, 2 H) 2.00 (br. s., 1 H) 2.15 (s, 2 H) 2.30 - 2.47 (m, 4 H) 2.53 - 2.70 (m, 4 H) 2.81 - 3.05 (m, 1 H) 3.18 (d, J=5.27 Hz, 1 H) 3.69 (br. s., 1 H) 4.27 (br. s., 1 H) 4.38 (d, J=11.04 Hz, 1 H) 5.06 - 5.28 (m, 1H) 7.34 (s, 1 H) 7.45 - 7.83 (m, 3 H) 8.46 (s, 1 H) 8.98 (br. s., 1 H) 9.87 (s, 1 H) 10.34 (s, 1 H) 11.02 (s, 1 H) 12.18 (br. s., 1 H).; LCMS RT= 0.7 min,(M+H) 786.

Example 18

4-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)ethyl)piperazin-l-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- l)butanamide

A mixture of 6-(tert-butylsulfonyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(2-(piperazin-l- yl)ethoxy)quinazolin-4-amine, 3Hydrochloride (50mg, 0.084 mmol) and 4-bromo-N-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)butanamide (34.2 mg, 0.084 mmol) in DMF (1 mL) was treated with DIPEA (0.146 mL, 0.838 mmol) and the mixture was heated at 80 °C overnight. On cooling, the entire mixture was subjected to chromatography on a 12g Gold ISCO Combiflash column eluting with 0-25%-methanol (+1% ammonium hydroxide):DCM to give the title compound (12 mg, 17 % yield). NMR (400 MHz, DMSO-d ) δ ppm 1.16 - 1.36

(m, 7 H) 1.32 (s, 6 H) 1.73 (s, 2 H) 2.00 (br. s., 1 H) 2.18 (s, 2 H) 2.30 - 2.47 (m, 6 H) 2.53 - 2.70 (m, 3 H) 2.81 - 3.02 (m, 1 H) 3.18 (d, J=5.27 Hz, 1 H) 3.69 (br. s., 1 H) 4.27 (br. s., 1 H) 4.38 (d, J=11.04 Hz, 1 H) 5.06 - 5.28 (m, 1H) 7.34 (s, 1 H) 7.45 - 7.83 (m, 3 H) 8.46 (s, 1 H) 8.98 (br. s., 1 H) 9.87 (s, 1 H) 10.34 (s, 1 H) 11.02 (s, 1 H) 12.18 (br. s., 1 H); LCMS RT= 0.67 min,(M+H) 815

Example 19

2-(2-(4-(3-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)propyl)piperazin-l-yl)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yljacetamide

A mixture of 6-(tert-butylsulfonyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-(piperazin-l- yl)propoxy)quinazolin-4-amine (70 mg, 0.140 mmol) and 2-(2-chloroethoxy)-N-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)acetamide (53.0 mg, 0.140 mmol) in DMF (1 mL) was treated with sodium iodide (105 mg, 0.698 mmol) and DIPEA (0.122 mL, 0.698 mmol) and the mixture was heated at 80 °C overnight. On cooling, the entire mixture was subjected to chromatography on a GILSON hplc system to give the title compound (13 mg, 9. % yield). NMR (400 MHz, MeOD-d4 ) δ ppm 1.4 (m, 9 H) 1.9 (s, 3H) 2.30 - 2.47 (m, 4 H) 2.4 (s, 3 H) 2.5 (m, 2 H) 2.6 (m, 1H) 3.0 (d, J=5.27 Hz, 1 H) 3.20 (m, 3H) 3.5 (br. s., 4 H) 4.0 (s, 2 H) 4.4 (br. s., 2 H) 4.5 (t, 2 H) 4.51 (s, 2H) 5.28 (m, 1H) 7.40 (s, 1 H) 7.6 (m, 1 H) 7.7 (m, 2 H) 8.7 (s., 1 H) 9.0 ( br.s, 1 H).; LCMS RT= 0.72 min,(M+H) 845 Example 20

2-(2-(2-(4-(2-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)ethyl)piperazin-l-yl)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin- 4-yl)acetamide, Trifluoroacetate

A mixture of 6-(tert-butylsulfonyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(2-(piperazin-l- yl)ethoxy)quinazolin-4-amine, 3Hydrochloride (50mg, 0.084 mmol) and 2-(2-(2- chloroethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)acetamide (35.5 mg, 0.084 mmol) in DMF (1 mL) was treated with DIPEA (0.146 mL, 0.838 mmol) and sodium iodide (62.8 mg, 0.419 mmol) and the mixture was heated at 80°C overnight. On cooling the entire mixture was subjected to chromatography on a 12g Gold ISCO Combiflash column eluting with 0-25%-methanol(+l% ammonium hydroxide):DCM . This was converted to a TFA salt to give the title compound (40 mg, 44 % yield). NMR (400 MHz, MeOD-d4 ) δ ppm 1.4 (m, 9 H) 1.9 (s, 3H) 2.34 - 2.47 (m, 4 H) 2.4 (s, 3 H) 2.6 (m, 2 H) 2.6 (m, 1H) 3.0 (d, J=5.27 Hz, 1 H) 3.20 (m, 5H) 3.5 (br. s., 6 H) 4.0 (s, 2 H) 4.4 (br. s., 2 H) 4.5 (t, 2 H) 4.51 (s, 2H) 5.28 (m, 1H) 7.40 (s, 1 H) 7.6 (m, 1 H) 7.7 (m, 2 H) 8.7 (s., 1 H) 9.0 ( br.s, 1 H).; LCMS RT= 0.67 min,(M+H) 875

Example 21

2-(2-(2-(4-(3-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)propyl)piperazin-l-yl)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin -yl)acetamide, Trifluoroacetate

A mixture of 6-(tert-butylsulfonyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(3-(piperazin-l- yl)propoxy)quinazolin-4-amine (50 mg, 0.100 mmol) and 2-(2-(2-chloroethoxy)ethoxy)-N-(2- (2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)acetamide (42 mg, 0.100 mmol) in DMF (1 mL)was treated with sodium iodide (74.7 mg, 0.498 mmol) and DIPEA (0.087 mL, 0.498 mmol) and the mixture heated at 80°C overnight. On cooling, the entire mixture was subjected to chromatography on a Mega Gilson to give the title compound (23 mg, 20.73 % yield). NMR (400 MHz, MeOD-d4 ) δ ppm 1.4 (m, 9 H) 1.9 (s, 3H) 2.30 - 2.44 (m, 6 H) 2.4 (s, 3 H) 2.5 (m, 2 H) 2.5 (m, 1H) 3.0 (d, J=5.27 Hz, 1 H) 3.20 (m, 5H) 3.5 (br. s., 6 H) 4.0 (s, 2 H) 4.4 (br. s., 2 H) 4.5 (t, 2 H) 4.51 (s, 2H) 5.28 (m, 1H) 7.40 (s, 1 H) 7.6 (m, 1 H) 7.7 (m, 2 H) 8.7 (s., 1 H) 9.0 ( br.s, 1 H).; LCMS RT= 0.65 min,(M+H) 889.

Example 22

2-(2-(2-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)methyl)piperidin-l-yl)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l- oxoisoindolin-4-yl)acetamide, Trifluoroacetic acid salt

A mixture of 6-(tert-butylsulfonyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(piperidin-4- ylmethoxy)quinazolin-4-amine, 3Hydrochloride (50 mg, 0.086 mmol) and 2-(2-(2- chloroethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)acetamide (36.4 mg, 0.086 mmol) in DMF (1 mL) was treated with DIPEA (0.150 mL, 0.859 mmol) and sodium iodide (64.4 mg, 0.430 mmol) and mixture was heated at 80 °C overnight. Cooled and entire mixture chromatographed on a GILSON HPLC to give the title compound (5.7 mg, 6 % yield). ). NMR (400 MHz, MeOD-d4 ) δ ppm 1.4 (m, 9 H) 1.9 (s, 3H) 2.30 - 2.47 (m, 2H) 2.5 (s, 3 H) 2.5 (m, 2 H) 2.65 (m, 1H) 3.0 (d, J=5.27 Hz, 1 H) 3.20 (m, 5H) 3.5 (br. s., 6 H) 4.0 (s, 2 H) 4.4 (br. s., 2 H) 4.5 (t, 2 H) 4.51 (s, 2H) 5.28 (m, 1H) 7.40 (s, 1 H) 7.6 (m, 1 H) 7.7 (m, 2 H) 8.7 (s., 1 H) 9.0 ( br.s, 1 H).; LCMS RT= 0.67 min,(M+H) 860

Example 23

ll-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-N-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)undecanamide, Trifluoroacetic acid salt

To a solution of 4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-ol (30 mg, 0.073 mmol) and N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-ll- hydroxyundecanamide (32.2 mg, 0.073 mmol) in THF (2 mL) at room temperature was added Ph₃P (38.1 mg, 0.145 mmol) followed by DIAD (0.028 mL, 0.145 mmol) and the mixture was stirred at room temperature for 3h. The crude reaction mixture was subjected to chromatography on a 12g Gold ISCO Combiflash column eluting with 0-20% MeOH:DCM. Further purification was conducted on a GILSON HPLC eluting with 10-90%

Acetonitrile:water with 0.1% TFA to give the title compound (12mg, 17% yield). ¹H NMR (400 MHz, MeOD-d4) d ppm 1.46 (s, 13 H) 1.59 - 1.70 (m, 3 H) 1.70 - 1.80 (m, 3 H) 1.87 - 2.00 (m, 3 H) 2.17 - 2.29 (m, 2 H) 2.46(m, 4 H) 2.65 - 2.72 (m, 1 H) 2.75 - 3.01 (m, 3 H) 4.31 (s, 2 H) 4.50 (s, 2 H) 5.12 - 5.25 (m, 1 H) 6.80 - 6.89 (m, 1 H) 7.40 (s, 1 H) 7.47 - 7.58 (m, 1H) 7.64 (s, 2 H) 7.69 - 7.77 (m, 1 H) 8.20 (s, 1 H) 8.25 - 8.41 (m, 2 H) 9.21 (s, 1 H) 9.42 (s, 1 H). LCMS RT= 1 min,(M+H) 839

Example 24 ll-((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)-N- -(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)undecanamide, Trifluoroacetic acid salt

To a solution of 6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- ol (30 mg, 0.080 mmol) and N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-ll- hydroxyundecanamide (35.4 mg, 0.080 mmol) in THF (2 mL) at room temeprature was added Ph₃P (41.9 mg, 0.160 mmol) followed by DIAD (0.031 mL, 0.160 mmol) and the mixture was stirred at room temeprature for 3h. The solvent was then removed and the residue diluted with DMSO and filtered. The residue was purified on a GILSON HPLC eluting with 10-90% Acetonitrile:water with 0.1% TFA to give the title compound (7mg, 8% yield). ¹H NMR (400 MHz, MeOD-d4) d ppm 1.46 (s, 13 H) 1.59 - 1.70 (m, 3 H) 1.70 - 1.80 (m, 3 H) 1.87 - 2.00 (m, 3 H) 1.9 (s, 3H) 2.17 - 2.29 (m, 2 H) 2.46(m, 4 H) 2.4 (s, 3 H) 2.65 - 2.72 (m, 1 H) 2.75 - 3.01 (m, 3 H) 4.31 (s, 2 H) 4.50 (s, 2 H) 5.12 - 5.25 (m, 1 H) 7.40 (s, 1 H) 7.6 (m, 1 H) 7.7 (m, 2 H) 8.7 (s., 1 H) 9.0 ( br.s, 1 H). LCMS RT= 1 min,(M+H) 801

Example 25

ll-(4-(((6-(Tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)methyl)piperidin-l-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yljundecanamide, Trifluoroacetic acid salt

To a solution of 6-(tert-butylsulfonyl)-N-(4,5-dimethyl-lH-pyrazol-3-yl)-7-(piperidin-4- ylmethoxy)quinazolin-4-amine, 3Hydrochloride (14.5 mg, 0.025 mmol) and N-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-ll-oxoundecanamide (11 mg, 0.025 mmol) in DCM (3 mL) was added triethylamine (10.4 μΙ, 0.075 mmol) followed by sodium

triacetoxyborohydride (10.6 mg, 0.050 mmol). The mixture stirred at room temeprature for 12h. The reaction mixture was then filtered and the filtrate subjected to chromatography on a GILSON HPLC to give the title compound (8 mg, 30% yield). H NMR (400 MHz, MeOD-d4) δ ppm 1.46 (s, 13 H) 1.59 - 1.70 (m, 3 H) 1.70 - 1.80 (m, 3 H) 1.87 - 2.00 (m, 3 H) 1.9 (s, 3H) 2.17 - 2.29 (m, 2 H) 2.46(m, 4 H) 2.4 (s, 3 H) 2.65 - 2.72 (m, 1 H) 2.75 - 3.01 (m, 3 H) 4.4 (br. s., 2 H) 4.5 (t, 2 H) 4.51 (s, 2H) 5.28 (m, IH) 7.40 (s, 1 H) 7.6 (m, 1 H) 7.7 (m, 2 H) 8.7 (s., 1 H) 9.0 ( br.s, 1 H). LCMS RT= 0.86 min,(M+H) 898

Example 26

2-(2-(2-(2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7- yl)oxy)ethoxy)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yljacetamide

HATU (84 mg, 0.220 mmol) was added to a solution of 2-(2-(2-(2-((4-(benzo[d]thiazol-5- ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)acetic acid

hydrochloride (94 mg, 0.147 mmol), 3-(4-amino-l-oxoisoindolin-2-yl)piperidine-2,6-dione (38.1 mg, 0.147 mmol), and DIPEA (0.077 mL, 0.441 mmol) in DMF (1 mL). The reaction mixture was sealed and stirred at room temperature for 30 min. EtOAc (1 mL) and water (3 mL) were added and the layers were separated.The aqueous layer was extracted with EtOAc (3 x 2 mL) and the combined organic layers were washed with saturated NaCI (4 x 1 mL), and concentrated under a stream of nitrogen at 50 ^c. DMSO (1.5 mL) was added to the residue, the mixture was filtered through a 0.45 μιη acrodisc, and purified on a Gilson HPLC (Sunfire 5 μιη C18 OBD 30x100 mm preparatory column), eluting at 30 mL/min with a linear gradient running from 10% CH₃CN/H₂0 (0.1% TFA) to 90% CH₃CN/H₂0 (0.1% TFA) over 10 min to give 11.3 mg (9%) of the title compound as a yelllow solid. LC/MS: m/z 845.6 (M+H)⁺, RT=0.70 min ¹H NMR (400MHz, METHANOL-d4) δ = 9.40 (s, IH), 9.08 (s, IH), 8.30 (d, 7=7.0 Hz, 2H), 8.22 (s, IH), 7.65 (dd, 7=8.0, 14.6 Hz, 2H), 7.53 - 7.45 (m, IH), 7.44 - 7.35 (m,

IH), 7.24 (s, IH), 6.84 (d, 7=7.0 Hz, IH), 5.15 (dd, 7=5.1, 13.2 Hz, IH), 4.58 - 4.40 (m, 2H), 4.22 (s, 4H), 3.88 (br. s., 2H), 3.80 (br. s., 2H), 3.78 - 3.74 (m, 6H), 2.99 - 2.71 (m, 2H), 2.58 - 2.38 (m, IH), 2.22 (br. s., IH), 1.41 (s, 9H) Western Blot Quatification of RIP2 levels in THP1 cells

Compounds were tested in THP1 cells (acute myeloid leukaemia - BioCat 106491) and the effect on RIP2 protein levels were assessed by Western blotting. For each sample 7.5 xlO⁶ cells were resuspended in media containing the indicated concentrations of PROTAC and incubated 37°C and 5% C0₂ overnight. The following day, cells were harvested, and the total amount of protein was quantified using the Pierce™ BCA Protein Assay kit (Thermo Scientific, 23227). 25 μg of total protein were separated on a polyacrylamide Bis-Tris gel at constant voltage and further transfered onto PVDF membranes (Millipore, IPFL00010). Membranes were blocked against non-specific binding with Odyssey blocking buffer (Licor, 927-40000) for 1 hour at room temperature, then incubated with the primary antibodies rabbit anti-RIPK2 (Cell Signaling, 4142) oevrnight at 4°C. Next day the mouse anti-actin (Sigma, A2228) at a 1: 20 000 dilution was added and the membranes were further incubated for 2 hours at room temperature. Membranes were washed 3 times with PBS +0.1% Tween 20 then incubated with donkey anti-mouse 800CW (Licor, 926-32212) and donkey anti-mouse IRdye 680RD (Licor, 926-68072) diluted 1:5 000 in Odyssey blocking buffer + 0.1% Tween 20 + 0.01% SDS, 1 hour at room temperature, followed by washing in PBS +0.1% Tween 20. The infrared signal was detected using an Odyssey scanner (Licor Biosciences) and densitometry was performed using the Odyssey 2.1 Analyser software (Licor Biosciences).

RIPK2 degradation was expressed relative to the DMSO only treated sample. Compounds displayed > 80% degradation of RIP2 at concentrations <luM.

Claims

1. A PROTAC compound which modulates RIP2 kinase activity which is acompound of formula (I):

ubiquitin ligase cereblon binding moiety

X represents N or CH;

Linker is a linking group comprising a length of 4-16 atoms in shortest length,

R¹ is H, -S0₂(Ci-C₄)alkyl, -CO(C C₄)alkyl, or (C C₄)alkyl;

R² is - SR^a, -SOR^a, -S0₂R^a, -S0₂NH₂, or -S0₂NR^bR^c,

R^b is (Ci-C₆)alkyl or 4-7 membered heterocycloalkyi, wherein:

(Ci-C₄)alkoxycarbonyl-, hydroxy(Ci-C₄)alkyl-, oxo and (Ci-C₄)alkoxy, and

R^c is H, (Ci-C₄)alkoxy or (Ci-C₆)alkyl;

or R^b and R^c taken together with the nitrogen atom to which they are attached form a 3-7 membered heterocycloalkyi group, optionally containing one or two additional ring heteroatoms each independently selected from nitrogen and oxygen, wherein said 3-7 membered heterocycloalkyi is optionally substituted by 1-3 groups each independently selected from the group consisting of (Ci-C₄)alkyl, hydroxy, -C0₂H and -CO(Ci-C₄)alkyl;

Z is phenyl or aryl(Ci-C₄)alkyl-, wherein in the phenyl group or the aryl moiety of the aryl(Ci-C₄)alkyl- group is substituted by R⁴, R⁵, R⁶ and R⁷, wherein:

R⁴ is H, halogen, cyano, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, (Ci-C₄)alkoxy, phenoxy, phenyl(Ci-C₄)alkoxy, hydroxyl, hydroxy(Ci-C₄)alkyl-, or aminocarbonyl, wherein the ph moiety of said phenoxy or phenyl(Ci-C₄)alkoxy- is optionally substituted by 1-3 substituents each independently selected from the group consisting of halogen, -CF₃, (Ci-C₄)alkyl and (Ci-C₄)alkoxy; and

each of R⁵, R⁶ and R⁷is independently selected from the group consisting of H, hydroxyl, halogen, -CF₃, hydroxy(Ci-C₄)alkyl, (Ci-C₄)alkyl and (Ci-C₄)alkoxy; or

Z is phenyl or pyridyl, substituted by R⁸, R⁹ and R¹⁰, wherein:

pyrazolyl, having the form wherein:

R is H, methyl or hydroxymethyl;

R¹³ is methyl, trifluoromethyl or hydroxymethyl;

R¹⁴ is H, OH, or (Ci-C₃)alkyl; or

R and R , taken together with the atoms to which they are attached, form a 6-membered ring substituted by R¹⁵ and R¹⁶, wherein the 6-membered ring optionally contains 1 nitrogen atom;

(Ci-C₄)alkoxy; or a pharmaceutically acceptable salt thereof

2. A compound of Formula (II) (III) (IV) or (V):

(Ml)

(iv)

o

(V)

Wherein the definitions of R¹, Z, X and R² in the RIP2 inhibitor moiety in the compounds of formula (II) (V)are as defined in formula (I) above.

The linker is as defined for formula (I) above, or a pharmaceutically acceptable salt thereof.

3. A compound or pharmaceutically acceptable salt thereof according to claims 1-2 wherein the RIP2 Kinase inhibitor is

wherein the wavy bind denotes the attachment point of the linker.

4. A compound or pharmaceutically acceptable salt thereofaccording to claims 1-3 wherein the Cereblon binding moiety is a compound

thalidomide (7), pomalidomide (8) and lenalidomide (9):

5. A compound or pharmaceutically acceptable salt thereof according to claims 1-3 wherein the cereblon binding moiety is

wherein the wavy bond denotes the attachment point of the linker.

6. A compound or pharmaceutically acceptable salt there according to preceding claims which is of Formula I) are of formula (VI) and (VII):

(VII)

7. A compound or pharmaceutically acceptable salt thereof according to any preceding claims wherein the linker (in the direction RIP2 binder - cereblon binder) is selected from the following

-0(CH₂)_5-ioCO- ,

-0(CH₂ CH₂0)₂-5 CH₂ CO- '

wherein L¹ is:

L²is:

-(CH₂CH₂0)i_4-CH₂CO-, -(CH₂)i-ioCO-,

-CO-, - -, -(CH₂)₅-io.

8. A compound or a pharmaceutically acceptable salt thereof wherein the linker is accordin to claim 7

-O(CH₂)₁₀CO-

-0(CH₂CH₂0)₄CH₂CO-

-0(CH₂CH₂0)₃CH₂CO-

OCH₂CH₂CH₂ / \ CH2CH2OCH2CH2CH2

0CH₂ "CH2CH20CH2CH CH2

-0(CH₂CH₂0)₅-

9. A compound according to claim lselected from

14-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinolin-7-yl)oxy)-N-(2-(2,6- dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)-3,6,9,12-tetraoxatetradecan-l-amide _(S)-2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)propyl)piperazin-l-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)pyrimidine- 5-carboxamide dihydrochloride

2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)propyl)piperazin-l-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl) pyrimidine- 5-carboxamide

_(S)-3-(4-(3-(2-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino) quinazolin- 7-yl)oxy)methyl)piperidin-l-yl)ethoxy)propyl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione

_(S)-3-(4-(6-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)methyl)piperidin-l-yl)hexyl)-l-oxoisoindolin-2-yl)piperidine-2,6- dione

_(S)-3-(4-(8-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)methyl)piperidin-l-yl)octyl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione

(S)-3-(4-(10-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)methyl)piperidin-l-yl)decyl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione jS)-3-(4-(6-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quina 7-yl)oxy)ethyl)piperidin-l-yl)hexyl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione jS)-3-(4-(8-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin- 7-yl)oxy)ethyl)piperidin-l-yl)octyl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione jS)-3-(4-(10-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazoli 7-yl)oxy)ethyl)piperidin-l-yl)decyl)-l-oxoisoindolin-2-yl)piperidine-2,6-dione _(S)-3-(4-(3-(2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)ethyl)piperazin-l-yl)ethoxy)propyl)-l-oxoisoindolin-2- yl)piperidine-2,6-dione

_(S)-3-(4-(3-(2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3- yl)amino)quinazolin-7-yl)oxy)propyl)piperazin-l-yl)ethoxy)propyl)-l-oxoisoindolin-2- yl)piperidine-2,6-dione

2-(2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)ethyl)piperazin-l-yl)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)acetamide 3-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)ethyl)piperazin-l-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)propanamide

2- (2-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)methyl)piperidin-l-yl)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)acetamide

3- (4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)methyl)piperidin-l-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)propanamide 4-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)ethyl)piperazin-l-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)butanamide 2-(2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)propyl)piperazin-l-yl)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)acetamide

2-(2-(2-(4-(2-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)ethyl)piperazin-l-yl)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)acetamide.

2-(2-(2-(4-(3-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)propyl)piperazin-l-yl)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin 4- yl)acetamide.

2-(2-(2-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)methyl)piperidin-l-yl)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-

4-yl)acetamide.

ll-((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)-N-(2- (2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)undecanamide. ll-(4-(((6-(tert-butylsulfonyl)-4-((4,5-dimethyl-lH-pyrazol-3-yl)amino)quinazolin-7- yl)oxy)methyl)piperidin-l-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4- yl)undecanamide,

or pharmaceutically acceptable salt thereof

10. A compound or a pharmaceutically acceptable salt thereof according to claims 1-9 for use in therapy.

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claims 1-9 for use in the treatment of diseases conditions mediated by RIP2 Kinase.

12. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt according to claims 1-9 and one or more of pharmaceutically acceptable carriers, diluents and excipients.

13. A method of treating diseases and conditions mediated by the RIP2 Kinase in a subject comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claims 1-9.

14. The use of a compound of formula (I), or a pharmaceutically acceptable salt thereof according to claims 1-9 in the manufacture of a medicament for use in treating diseases and conditions mediated by the RIP2 Kinase.

15. A combination comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof according to claims 1-9 and at least one further therapeutic agent.

16. A combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claims 1-9 and at least one further therapeutic agent for use in therapy, particularly for treating diseases and conditions mediated by the RIP2 Kinase.

17. A combination comprising compound of formula (I) or a pharmaceutically acceptable salt thereof according to claims 1-9 and at least one further therapeutic agent for use in treating diseases and conditions mediated by the RIP2 Kinase.

18. A method of treating diseases and conditions mediated by the RIP2 Kinase comprising administering to a human in need thereof a therapeutically effective amount of a combination comprising compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claims 1-9 and at least one further therapeutic agent.

19. The use of a combination comprising compound of formula (I) or a pharmaceutically acceptable salt thereof according to claims 1-9 and at least one further therapeutic agent in the manufacture of a medicament for treating diseases and conditions mediated by the RIP2 Kinase.

20. A method of degrading RIP2 kinase comprising administering to a human in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claims 1-9.