Purine compounds and their pharmaceutical use

Abstract

The current invention relates to a compound of formula (I), a pharmaceutical composition comprising said compound, a combination therapy and use thereof in a medicament or as therapy in a subject.

Description

[0001] PURINE COMPOUNDS AND THEIR PHARMACEUTICAL USE

[0002] FIELD OF THE INVENTION

[0003] The present invention new pharmaceutical compounds able to act as Src family kinase modulator, pharmaceutical compositions and their uses.

[0004] BACKGROUND

[0005] The field of small molecule therapeutics in cancer treatment is advancing rapidly, providing an expanding range of promising options aimed at improving patient outcomes. Yet, despite this progress, there remains a need for therapies that can offer greater anti-tumor efficacy at lower doses, reduce potential toxicity, and safely integrate into combination regimens with existing inhibitors. The challenge is to develop new compounds characterized by novel mechanisms of action that surpass the therapeutic benefits of established therapies, including kinase inhibitors. Ideally, these compounds would maintain robust potency at minimal concentrations, thereby minimizing adverse effects and enhancing patient safety. Furthermore, there is significant value in engineering these novel chemical entities so that they can be effectively administered alongside other targeted inhibitors, allowing for synergistic treatment approaches and the optimization of clinical efficacy. The present disclosure addresses these unmet needs.

[0006] SUMMARY OF THE INVENTION

[0007] The present disclosure relates in the first aspect to a compound or a pharmaceutically acceptable salt thereof according to claim 1.

[0008] Potent novel small molecules with promising anti-tumor effects are described herein. Additionally, patient-specific sensitivities have been identified, suggesting a distinct molecular mechanism of action (MOA) for these compounds.

[0009] Preferred embodiments of the device are shown in any of the claims 2 to 6.

[0010] In a second aspect, the present disclosure relates to a pharmaceutical composition according to claim 7 and a combination therapy according to claim 8. In a third aspect the present disclosure relates to a compound or composition for use according to claim 10.DETAILED DESCRIPTION OF THE INVENTION

[0011] Definitions

[0012] Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions are included to better appreciate the teaching of the present invention.

[0013] As used herein, the following terms have the following meanings:

[0014] " Alkyl" refers to a straight-chain (linear), or branched-chain (non-linear) saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-l-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-l-propyl, 2-methyl-l-pentyl, 3-methyl-l-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-l-butyl, 3, 3-dimethyl-l-butyl, 2-ethyl-l-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as " Cl-C6alkyl" or " Cl-6alkyl", means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated. In some embodiments, the alkyl is a Cl-lOalkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like, "oxo" refers to =0. " Carboxyl" refers to -COOH.

[0015] " Alkoxy" refers to a radical of the formula -ORa where Ra is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like." Carbocycle" refers to a saturated, unsaturated, or aromatic rings in which each atom of the ring is carbon. Carbocycle may include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless stated otherwise specifically in the specification, a carbocycle may be optionally substituted.

[0016] " Cycloalkyl" refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5-to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like." Halo" or "halogen" refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0017] " Hydroxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0018] " Heterocycloalkyl" refers to a 3- to-24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C6heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturatedheterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1, 1-dioxo-thiomorpholinyl, 1, 3-dihydroisobenzofuran-l-yl, 3-oxo-1, 3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l, 3-dioxol-4-yl, and 2-oxo-l, 3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.

[0019] " Heteroaryl" refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, theheteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.

[0020] The term "substituted" refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure. It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments,substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino orthioxo group. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched, and unbranched, carbocyclic, and heterocyclic, aromatic, and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0021] " Biaryl group" refers to a functional group comprising two aromatic rings that are directly connected to each other by a bond between ring atoms, typically a carboncarbon single bond, but may also include a heteroatom. The two aromatic rings may be carbocyclic (such as phenyl) or heteroaromatic (such as pyridyl, thienyl, furyl, imidazolyl, etc.), and the inter-ring bond may involve either carbon or heteroatoms that are part of the aromatic n-system. Both aromatic rings may be substituted.

[0022] The term "combination therapy" refers to a method of treatment comprising administering to a subject at least two therapeutic agents, optionally as one or more pharmaceutical compositions. For example, a combination therapy may comprise administration of a single pharmaceutical composition comprising at least two therapeutic agents and one or more pharmaceutically acceptable carrier, excipient, diluent, and / or surfactant. A combination therapy may comprise administration of two or more pharmaceutical compositions, each composition comprising one or more therapeutic agent and one or more pharmaceutically acceptable carrier, excipient, diluent, and / or surfactant. The agents may optionally be administered simultaneously (as a single or as separate compositions) or sequentially (as separate compositions). The therapeutic agents may be administered in an effective amount. The therapeutic agent may be administered in a therapeutically effective amount. In some embodiments, the effective amount of one or more of the therapeutic agents may be lower when used in a combination therapy than the therapeutic amount of the same therapeutic agent when it is used as a monotherapy, e.g., due an additive or synergistic effect of combining the two or more therapeutics.

[0023] The term "administer", "administering", or "administration" as used in this disclosure refers to either directly administering a disclosed compound or pharmaceuticallyacceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.

[0024] The term "parenteral administration" refers to the administration of a substance by a route other than the digestive tract, such as intravenous, subcutaneous, or intramuscular routes. It may be any molecule which may improve the polypeptide's selectivity, effectiveness and / or safety of administration to a human or animal body, such as by continuous or triggered release or by allowing membrane permeation of the polypeptide.

[0025] The term "treatment" refers to both therapeutic or prophylactic measures to reduce or prevent pathological conditions or disorders from developing or progressing. " Cancer treatment" or "treatment of cancer" as used herein can refer to, but is not limited to, measures resulting in full abrogation of the primary tumor, reduction of the size of the primary tumor, reduction of the growth rate of the primary tumor or to measures inhibiting metastasis of the primary tumor.

[0026] The term "immunotherapy" relates to a therapy that stimulates, enhances, or modifies the immune system to fight diseases such as cancer, autoimmune disorders, or infections. It includes therapies such as monoclonal antibodies, immune checkpoint inhibitors, vaccines, or cytokine- based treatments.

[0027] The term "chemotherapy" relates to a therapy that uses therapeutic agents to destroy or inhibit the growth of rapidly dividing cells, such as cancer cells.

[0028] The term "cell therapy" relates to a therapy in which living cells are administered to a patient to treat diseases or repair damaged tissue. This may involve stem cell transplants, genetically engineered cells like CAR-T and CAR-NK cell therapy, or the use of autologous or allogeneic cells.

[0029] The terms "patient", "subject", "animal", or "mammal" are used interchangeably and refer to a mammalian subject to be treated. Preferably, the mammal is human.

[0030] As used herein, the term "pharmaceutically effective amount" in the context of the administration of a therapy to a subject refers to the amount of a therapy that achieves a desired therapeutic, preventive / prophylactic or ameliorating effect.The term "characterized by one or more mutations in the KRAS gene that result in altered KRAS activity" refer to cancers / tumor types that have mutations in the KRAS gene. KRAS is a part of the RAS gene family, which plays a role in cell signaling pathways that control cell growth, proliferation, and survival. Mutations in KRAS can lead to uncontrolled cell division, contributing to cancer formation and progression.

[0031] The term " Lymphocyte-specific protein tyrosine kinase (LcK)" refers to a tyrosine kinase from the SRC family that plays a role in T cell activation and immune signaling.

[0032] The term " FYN" refers to a tyrosine kinase from the SRC family that plays a role in T cell signaling, neural development, and cell adhesion.

[0033] The term " Lck / Yes-related novel protein tyrosine kinase (LYN)" refers to a tyrosine kinase from the SRC family that regulates B cell activation and innate immune responses.

[0034] The term " Proto-oncogene tyrosine-protein kinase Src (SRC)" refers to a tyrosine kinase from the SRC family that controls cell growth, differentiation, and migration.

[0035] " A", "an", and "the" as used herein refers to both singular and plural referents unless the context clearly dictates otherwise. By way of example, "a compartment" refers to one or more than one compartment.

[0036] " About" as used herein referring to a measurable value such as a parameter, an amount, a temporal duration, and the like, is meant to encompass variations of + / -20% or less, preferably + / -10% or less, more preferably + / -5% or less, even more preferably + / -1% or less, and still more preferably + / -0.1% or less of and from the specified value, in so far such variations are appropriate to perform in the disclosed invention. However, it is to be understood that the value to which the modifier "about" refers is itself also specifically disclosed.

[0037] " Comprise", "comprising", and "comprises" and "comprised of" as used herein are synonymous with "include", "including", "includes" or "contain", "containing", "contains" and are inclusive or open-ended terms that specifies the presence of what follows e.g. component and do not exclude or preclude the presence of additional,non-recited components, features, element, members, steps, known in the art or disclosed therein.

[0038] Furthermore, the terms first, second, third and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order, unless specified. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein.

[0039] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within that range, as well as the recited endpoints.

[0040] The expression "% by weight", "weight percent", "%wt" or "wt%", here and throughout the description unless otherwise defined, refers to the relative weight of the respective component based on the overall weight of the formulation.

[0041] Whereas the terms "one or more" or "at least one", such as one or more or at least one member(s) of a group of members, is clear per se, by means of further exemplification, the term encompasses inter alia a reference to any one of said members, or to any two or more of said members, such as, e.g., any >3, >4, >5, >6 or >7 etc. of said members, and up to all said members.

[0042] Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, definitions for the terms used in the description are included to better appreciate the teaching of the present invention. The terms or definitions used herein are provided solely to aid in the understanding of the invention.

[0043] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more embodiments.Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art. For example, in the following claims, any of the claimed embodiments can be used in any combination.

[0044] Compounds

[0045] In a first aspect, the current disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0046]

[0047] wherein A is an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl comprising 1 to 3 nitrogen atoms or an optionally substituted heteroaryl comprising 1 to 3 nitrogen atoms,

[0048] wherein R4 is -H or -CH3,

[0049] wherein B is a direct bond, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl,

[0050] wherein R5 is -H, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl, wherein R6 and R7 are independently -H or halogen, and

[0051] wherein n is 1 or 2.

[0052] In an embodiment, A is an optionally substituted heterocycloalkyl comprising 1 to 3 nitrogen atoms or an optionally substituted heteroaryl comprising 1 to 3 nitrogen atoms, preferably A is an optionally substituted heterocycloalkyl comprising 1 to 3 nitrogen atoms. The heterocycloalkyl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, spiro, or bridged ring system.In embodiments in which R1 is described as a ketone-containing group, this terminology refers to the nature of the substituent prior to its attachment to the remainder of the molecule. In such embodiments, the ketone-containing group is attached to a nitrogen atom via the carbonyl carbon, thereby forming an amide linkage in the final compound. Accordingly, while the substituent originates from a ketone-containing group, the resulting compound comprises a carbonyl group forming part of an amide functionality.

[0053] In a further embodiment, A is selected from:

[0054]

[0055]

[0056] wherein R1 is -H, a halogen, an alkyl, a cycloalkyl, an aryl, a heterocycloalkyl or heteroaryl comprising 1 to 3 nitrogen atoms and optionally substituted with an alkyl, a carbonyl, or a halogen, preferably R1 is a halogen, an alkyl, a cycloalkyl, an aryl, a heterocycloalkyl or heteroaryl comprising 1 to 3 nitrogen atoms and optionally substituted with an alkyl, a carbonyl, or a halogen.

[0057] In another or further embodiment, R1 is a ketone-containing group. Preferably, A is an optionally substituted heterocycloalkyl comprising 1 to 3 nitrogen atoms or an optionally substituted heteroaryl comprising 1 to 3 nitrogen atoms, wherein the ketone-containing group forms an amide bond with the nitrogen to which it is bound.

[0058] H

[0059] Additionally, A can

[0060]

[0061] be

[0062] In another or further embodiment, R1 is a carbonyl-containing group. Preferably, A is an optionally substituted heterocycloalkyl comprising 1 to 3 nitrogen atoms or an optionally substituted heteroaryl comprising 1 to 3 nitrogen atoms, wherein the carbonyl-containing group forms an amide bond with the nitrogen to which it is bound.

[0063] Additionally, A can

[0064]

[0065] be

[0066] In a particular embodiment, A is selected from:

[0067]

[0068] wherein R1 is -H, a halogen, an alkyl, a cycloalkyl, an aryl, a heterocycloalkyl or heteroaryl comprising 1 to 3 nitrogen atoms and optionally substituted with an alkyl, a carbonyl, or a halogen, preferably R1 is a halogen, an alkyl, a cycloalkyl, an aryl,a heterocycloalkyl or heteroaryl comprising 1 to 3 nitrogen atoms and optionally substituted with an alkyl, a carbonyl, or a halogen.

[0069] " A

[0070] XN

[0071] In a preferred embodiment, A

[0072]

[0073] isR", wherein R1 is a halogen, an alkyl, a cycloalkyl, an aryl, a heterocycloalkyl or heteroaryl comprising 1 to 3 nitrogen atoms and optionally substituted with an alkyl, a carbonyl, or a halogen, preferably wherein R1 is an alkyl, a cycloalkyl, an aryl, a heterocycloalkyl or heteroaryl comprising 1 to 3 nitrogen atoms and optionally substituted with an alkyl, a carbonyl, or a halogen, and wherein R1 is not -CH3.

[0074] In an embodiment, R1 is selected from:

[0075]

[0076] 0

[0077] o 0 0

[0078]

[0079]

[0080] Additionally, R1 can be selected from:

[0081]

[0082]

[0083]

[0084]

[0085] In an embodiment R1 is a ketone-containing group. In another or further embodiment, R1 is selected from:

[0086]

[0087]

[0088]

[0089] 0

[0090]

[0091] In an embodiment R1 is

[0092] a carbonyl-containing

[0093] group. In another orfurther embodiment, R1 is selected from:

[0094] 0

[0095]

[0096] o

[0097]

[0098] 0 0

[0099]

[0100]

[0101] R2 is -H, a halogen, an optionally substituted alkyl, an optionally substituted amine, an optionally substituted alkylamide, an optionally substituted sulfonamide, a carbamate, a carbonate, an aryl, or an optionally substituted heterocycloalkyl, an optionally substituted heteroaryl, or a functional group comprising two or more of these functional groups.

[0102] In an embodiment R2 is selected from H, halogen or substituted alkyl, amide, alkylamide, sulfonamide, carbamate, carbonate, aryl, heteroaryl, or

[0103]

[0104] 

[0105]

[0106]

[0107] Additionally, R2 can be selected from:

[0108]

[0109] In an embodiment, R3 is -H, a halogen or a substituted alkyl.

[0110] In another embodiment, R2 and R3 are connected to the same atom and together form a cyclopropyl or cyclobutyl group.

[0111] In an embodiment, R3 is -CH3, -F or -NH2.In an embodiment, B is selected from: a direct bond, a phenyl,

[0112]

[0113] wherein R6 and R7 are independently selected from H or halogen.W

[0114] Additionally, B can be selected from

[0115]

[0116] ;

[0117]

[0118] In particular embodiment, B is selected from a phenyl,

[0119] W

[0120]

[0121] and, wherein R6 and R7 are independently selected from H or halogen.

[0122] Preferably, B is selected from a phenyl,

[0123]

[0124] In an embodiment, R5 is selected from: -H, a phenyl,

[0125]

[0126] ^sxsxrxrf

[0127] R8

[0128]

[0129] R8

[0130] a

[0131]

[0132] nd SAAAJ- wherein R8 and R9 are independently -H, halogen, alkyl, O-alkyl, -alkyl optionally substituted with 1 to 3 halogens, or a heteroaryl.

[0133] In an embodiment, R8 and R9 are independently selected from:

[0134]

[0135] Additionally, R5 can be selected from:

[0136]

[0137] In a particular embodiment, R5 is selected from:

[0138]

[0139] wherein R8 and R9 are independently -H, halogen, alkyl, O-alkyl, S-alkyl optionally substituted with 1 to 3 halogens, or a heteroaryl, preferably R8 and R9 are independently -H or alkyl.

[0140] In a particular embodiment, B and R5 together form a biaryl group. It was found that B and R5 are advantageously not too hydrophilic, nor too short. In a particular embodiment, B and R5 together form a group selected from:ci

[0141]

[0142] 5

[0143] In an embodiment, the compound is chosen from:0 0

[0144] \ O. 0 0

[0145] HNX^

[0146] - A JO

[0147] J

[0148] y XM h>7(1-1)0d-2)

[0149] 11—

[0150] CH

[0151] 0

[0152] 0

[0153] ^ X X >

[0154] X

[0155] / LX- XXx >

[0156] X

[0157] z

[0158] d-3)0(1-4)

[0159] x £l >

[0160] d-6)

[0161]

[0162]

[0163]

[0164] Q

[0165] 0

[0166] 0

[0167] c

[0168] T jT ) ^ jv n >

[0169] I V

[0170] 7(I- ° d-19) 20)

[0171] 0

[0172] 0

[0173] p jp

[0174] <1 1 XJO

[0175] d-21) (I- 22)

[0176] i _ X X >

[0177] d-23) d-24)

[0178]

[0179] 0

[0180] 0

[0181] ijO

[0182] N

[0183] V1 0 l

[0184] / O / N(I- d-25)

[0185] 26)

[0186] x X> jX >

[0187] S' X. / XN / ^ /

[0188] VJ (1-27) V (1-28)

[0189] Q

[0190] 0

[0191] x X>

[0192] jX > \ / I \ z

[0193] 1 (1-29) V -O x

[0194] <yh(1-30)

[0195]

[0196]

[0197]

[0198] ^" NH

[0199] 0

[0200] HN^^A AX> 0

[0201] 1 \z X -Z ^^N''" XjO

[0202] N?\ I

[0203] (1-41) (I- 42)

[0204] [f

[0205] Q

[0206] [f

[0207] 0

[0208] ^NH

[0209] - JTX >

[0210] ' z * J

[0211] / (1-43) (1-44)

[0212] 0 Q

[0213] u

[0214] ai i >

[0215] °=4 °^ ^AX> \

[0216] \...«I«V / '"-■'

[0217] (1-46)

[0218]

[0219]

[0220] ? T) Q-,rA >

[0221] ,0 I

[0222] 8 (1-54) W (1-53)

[0223] Q

[0224] 0

[0225] ^AX>r. Al>

[0226] Br‘~~- / 'l' (1-56) (1-55)

[0227] 0 0

[0228] 0 0

[0229] \ ° ^XJO

[0230] \ VN- z \ ° / ^XX>

[0231] ^ \V\> V y\\ ^

[0232] 1 (1-58) \ d-57)

[0233]

[0234]

[0235] (1-69) (1-70)

[0236]

[0237] X7 \y''" \h< I X ^S

[0238] I £ 1H1 1

[0239] H J I i.

[0240] d-72)

[0241] d-71)

[0242] -

[0243] JuC>

[0244] ^AX>

[0245] 8 (1-73)

[0246] 8 (1-74)

[0247] 0

[0248] A

[0249] XK ^N jdx> ^AX>

[0250] s ' —

[0251] VsxX^ '

[0252] 8 (1-76) (1-75)

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271] Q 0

[0272] 0 0

[0273] / -• / ^AJO AX:> \^X / 8XJ A (I-180) -x T i X

[0274] \ / / (I-179)

[0275] / ~J^«

[0276] A x>

[0277] X y-AX)

[0278] (I-181) (I-182)

[0279] AxCo

[0280] CV-AI> AX>

[0281] (I-183)

[0282] Q

[0283] » (I-184)

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293] c

[0294] x X> ^ jic>

[0295] AJ (1-233) (1-234)

[0296] ^ ZXA / YNI^N>. x X>

[0297] 0V

[0298] / — VN^

[0299] (1-235) Y'

[0300] rA >

[0301] 0V

[0302] , V"^1VN^

[0303] Fy^ (1-238) > (1-237)

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312] JO r yl

[0313] \ / \\

[0314] - - Y)

[0315] rA >

[0316] (1-281)

[0317] (1-282)

[0318] K

[0319] / <

[0320] 4

[0321] HN

[0322] o OO / x I U pXN^ <r. A >

[0323] ■^Y^J y ■ ° ° >- 0 11 — KJ

[0324] (1-284) 00 (1-283) Ch

[0325] HN'X^

[0326] ^AX>

[0327] ^'Qr '

[0328] (1-285)

[0329]

[0330]

[0331]

[0332] Hhr

[0333] HN"^

[0334] ^-N ^. N

[0335] JuC > xx >

[0336] \ / \ N / — \ N J

[0337] (1-293) (1-294)

[0338] NJ

[0339] \O I

[0340] HN^^ 0

[0341] ^. N HN"^

[0342] ^_N o x l) JLX> \ N /

[0343] kv5N ^ _ \ /

[0344] (1-296)

[0345] (1-295)

[0346] F

[0347] \ ^ 1 -F

[0348] HN^

[0349] ^AX>

[0350] \|X /

[0351] (1-297)

[0352]

[0353]

[0354]

[0355] cr'xr

[0356] UJ O

[0357] \ w

[0358] o

[0359] °nr^

[0360] d-311)

[0361] b'3M>v

[0362] / w

[0363] 45A > O

[0364] (1-314)

[0365] J^SO

[0366] Hhr y _N ^AJO x X>

[0367] '

[0368] (1-316)

[0369] (1-315)

[0370]

[0371]

[0372]

[0373] N J0 HN"^

[0374] Hr 9rrA l>

[0375] \ N 7 7 ^^ ^ A > ^0^

[0376] . _ N J 7^-^

[0377] (1-330)

[0378] (1-329)

[0379] pA >

[0380] \ N J 7^ "^rx X> ^77 ^rf^ '

[0381] (1-331) (1-332)

[0382] T Ji

[0383] >7 \7 \N / \N / J T' X

[0384] L J L

[0385] L ^^7 N ^AX>

[0386] ^77 ^Tf^ '

[0387] (1-333) (1-334)

[0388]

[0389]

[0390]

[0391]

[0392] F

[0393] T^A j " |j ^NH

[0394] x--"' NrHC« \ x-N\ >*<.

[0395] N' J r Y

[0396] 1? N ^1 /

[0397] (1-353) (1-354)

[0398] °\ / X. JAI

[0399] NMY\ / Y /

[0400] '\^NX^Nx / NH

[0401] A?!(<oAJT N. T J,,XX^NX^N^^, NH

[0402] / NN* J

[0403] N-^-Y

[0404] T / N

[0405] Y

[0406] (1-355)

[0407] (1-356)

[0408] F

[0409] o \ ^°

[0410] < XX)

[0411] G^'"-^\ X Jj '^

[0412] I, Y Yv-^1

[0413] N' 1

[0414] \A 1 / N

[0415] ^ / N-Y

[0416] (1-358)

[0417] (1-357)

[0418]

[0419] / ^~\

[0420] / - NH A < C -A A # V-'NH

[0421] H M

[0422] N1 / N

[0423] \^ '-y

[0424] (1-359)

[0425] (1-360)

[0426] r— -o 0^

[0427] \, X=o

[0428] / — ~N

[0429] V_y ~A N~- / N

[0430] A 'A N Il \^L

[0431] u

[0432] (1-361)

[0433] (1-362)

[0434] o— 1

[0435] □

[0436] / ’V^NH N / 'tNx J

[0437] (1-363) (1-364)

[0438]

[0439]

[0440] /

[0441] 0

[0442] °X\ ^=\ ■■ ■ - ■;, • <

[0443] V-\ [

[0444] Il

[0445] M, N

[0446] ■ / N

[0447] d-371) (1-372)

[0448] \ / °

[0449] kZNH f^'''"'') HN— /

[0450] o=K

[0451] (X — |SJ /

[0452] N / - -~-\ / \ X\ ^X

[0453] H J4X J,-NH

[0454] N r 1

[0455] ^,N Nv^N

[0456] (1-374)

[0457] (1-373)

[0458] /

[0459] 00 / X--'x / f^X v_j / \ -x X o::=:=:\ N — ° Q XX

[0460] N F V J *

[0461] '■ < „ - X— -NH 1 / N■ ■

[0462] 1 / N

[0463] (1-376)

[0464] (1-375)

[0465]

[0466] ' r~~ — / °

[0467] ANHXX ( \x°

[0468] jj ^V) XX^N\ J

[0469] T / N, H

[0470] (1-377)

[0471] (1-378)

[0472] px

[0473] / A

[0474] 0V-xH A^A

[0475] ■J / • X^ NH O - - ' X N J V^-A'N

[0476] T / N

[0477] (1-380)

[0478] (1-379)

[0479] F X XI XX C XxX XNHX" |T^ XJ

[0480] l\x^NX^ I bk, N., NH X / y V

[0481] X XX

[0482] / NNx A\

[0483] N — -J / V /

[0484] (1-381) (1-382)

[0485]

[0486]

[0487]

[0488] 9 N / ZX9^^ oX ^ 9xX5

[0489] 1

[0490] HN 1 ^X N XXF 99x X^ \

[0491] J X

[0492] 99 ^1. X ^-' N XxX / ^

[0493] (1-395)

[0494] (1-396)

[0495] NH2

[0496] o^\

[0497] 9^ \

[0498] ”9 r> X ', \^-N / o

[0499] / / 'X^NH

[0500] N\ / M J

[0501] F zN / H

[0502] (1-397) (1-398)

[0503] HO-^X / -— N

[0504] 0X 9^9 G i j lT^ ” Gt O';?::::^N-^X^ p9^Gx_9

[0505] v----. INrH€9J

[0506] N J

[0507] 1 / N

[0508] Xx 9"^

[0509] (1-399)

[0510] (1-400)

[0511]

[0512]

[0513]

[0514] HO. OH

[0515] r<^\

[0516] ■

[0517] x / / X '

[0518] \ —N / X j

[0519] II '''\ - -NH

[0520] N /

[0521] ^Xx'N\x'N\ xNM

[0522] n T I

[0523] ,i

[0524] v*

[0525] (1-413)

[0526] (1-414)

[0527] \^^OH r^\

[0528] cxx S 4'T"”^^ X f"

[0529] X I, X X ^NH

[0530] I N. 7 J T

[0531] ZN

[0532] X"

[0533] (1-415) (1-416)

[0534] X. X®

[0535] ■

[0536] °^ x / n \ J; / '

[0537] XXwf X- / / ^X^NHX X- K / J

[0538] il NX _^-NH

[0539] /

[0540] XT

[0541] 1 / N

[0542] .yO

[0543] (1-417)

[0544] (1-418)

[0545]

[0546]

[0547]

[0548]

[0549] no

[0550] (1-437) (1-438) (1-439)

[0551] (I-44O)

[0552]

[0553] Ill

[0554] (1-443)

[0555] (1-444)

[0556] (1-446)

[0557] (1-445)

[0558]

[0559] In particular embodiment, B and R5 are both phenyl to form a biphenyl group.

[0560] In a particular embodiment, A

[0561]

[0562] is, wherein R2 and R3 are -H (such that piperazine is obtained), wherein R1 is as described herein, and B and R5 are phenyl, to form a biphenyl group. Preferably, R1 is a ketone-containing group, a sulfonyl-containing group, an optionally substituted phenyl, an optionally substituted heterocycloalkyl, or an optionally substituted C4-6 alkyl.

[0563]

[0564] , wherein R2 and R3 are -H (such that piperazine is obtained), wherein R1 is as described herein, and B and R5 are phenyl, to form a biphenyl group. Preferably, R1 is a carbonyl-containing group, a sulfonyl-containing group, an optionally substituted phenyl, an optionally substituted heterocycloalkyl, or an optionally substituted C4-6 alkyl.

[0565] In a particular embodiment, the compound is a compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0566]

[0567] (II),

[0568] wherein R1 is a ketone-containing group, a sulfonyl-containing group, an optionally substituted phenyl, an optionally substituted heterocycloalkyl, or an optionally substituted C4-6 alkyl, and wherein R4 is a -H or -CH3.

[0569] In a particular embodiment, the compound is a compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0570]

[0571] wherein R1 is a carbonyl-containing group, a sulfonyl-containing group, an optionally substituted phenyl, an optionally substituted heterocycloalkyl, or an optionally substituted C4-6 alkyl, and wherein R4 is a -H or -CH3.

[0572] In an embodiment, R1 is an optionally substituted linear or non-linear C3-6 alkyl, an optionally substituted heterocycloalkyl, an optionally substituted phenyl,

[0573]

[0574] wherein RIO is an optionally substituted linear or non-linear Cl-3 alkyl, or an optionally substituted heterocycloalkyl,

[0575] wherein Rll is -H, a linear or non-linear Cl-3 alkyl, or a Cl-3 hydroxyalkyl, wherein R12 is -H, or -CH3, or wherein Rll and R12 together form an optionally substituted heterocycloalkyl,

[0576] wherein R13 is a linear or non-linear Cl-3 alkyl, a linear or non-linear Cl-4 alkoxy, an optionally substituted heterocycloalkyl,

[0577] wherein R14 is H, a linear or non-linear Cl-4 alkyl, an optionally substituted aliphatic ring, or an optionally substituted phenyl,

[0578] wherein R15 is -H, or -CH3, or wherein R14 and R15 together form an optionally substituted heterocycloalkyl, and wherein X is O or S.In an embodiment, R1 is chosen from:

[0579]

[0580] wherein RIO is an optionally substituted linear or non-linear Cl-3 alkyl, or an optionally substituted heterocycloalkyl,

[0581] wherein Rll is -H, a linear or non-linear Cl-3 alkyl, or a Cl-3 hydroxyalkyl, wherein R12 is -H, or -CH3, or wherein Rll and R12 together form an optionally substituted heterocycloalkyl,

[0582] wherein R13 is a linear or non-linear Cl-3 alkyl, a linear or non-linear Cl-4 alkoxy, an optionally substituted heterocycloalkyl,

[0583] wherein R14 is H, a linear or non-linear Cl-4 alkyl, an optionally substituted aliphatic ring, or an optionally substituted phenyl,

[0584] wherein R15 is -H, or -CH3, or wherein R14 and R15 together form an optionally substituted heterocycloalkyl, and wherein X is O or S.

[0585] In an embodiment, R1 is chosen from:

[0586]

[0587]

[0588]

[0589] In an embodiment, the compound is chosen from: 1-1, 1-2, 1-9, 1-51, 1-53, 1-54, I-55, 1-57, 1-58, 1-59, 1-65, 1-101, 1-107, 1-119, 1-128, 1-131, 1-133, 1-137, 1-138, I-139, 1-140, 1-145, 1-216, 1-219, 1-221, 1-229, 1-232, 1-237, 1-238, 1-269.

[0590] In an embodiment, R1 is a 2-methoxy ethan-l-one. In a preferred embodiment, the compound is of formula (1-1) or (1-269), preferably of formula (1-1), namely l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-methoxyethan-l-one.

[0591] In an embodiment, R1 is not -H or -CH3.

[0592] R-

[0593] In another particular embodiment, A

[0594]

[0595] is ', wherein R2 and R3 are - H (such that piperazine is obtained), wherein R1 is a ketone-containing group such that an amide functionality is formed with the nitrogen of the piperazine.

[0596] R-

[0597] In another particular embodiment, A

[0598]

[0599] is ', wherein R2 and R3 are - H (such that piperazine is obtained), wherein R1 is a carbonyl-containing group such that an amide functionality is formed with the nitrogen of the piperazine.

[0600] In a further embodiment, R1 is selected from:

[0601]

[0602]

[0603] 0 O O o

[0604]

[0605]

[0606] In a further embodiment, B is an optionally substituted aryl or an optionally substituted heteroaryl, and wherein R5 is an optionally substituted aryl or an optionally substituted heteroaryl.

[0607] In a further embodiment, B is selected from: a phenyl,

[0608]

[0609]

[0610] wherein R8 and R9 are independently -H, halogen, alkyl, O-alkyl, S-alkyl optionally substituted with 1 to 3 halogens, or a heteroaryl, preferably R8 and R9 are independently -H or alkyl.

[0611] In an embodiment, the compound is chosen from: 1-1, 1-364, 1-371, 1-377, 1-378, 1-379, 1-383, 1-389, 1-390, 1-391, 1-392, 1-395, 1-396, 1-397, 1-398, 1-399, 1-400, 1-402, 1-403, 1-404, 1-406, 1-407, 1-408, 1-409, 1-410, 1-411, 1-413, 1-414, 1-415, 1-417, 1-420, 1-421, 1-423, 1-428, 1-429, 1-431, 1-432, 1-433, 1-435, 1-436, 1-438, 1-439, 1-440, 1-441, 1-442, 1-443, 1-444.

[0612] In an embodiment, the compound is a C-terminal Src Kinase (CSK) modulator, preferably a CSK inhibitor. In an embodiment, the compound is a LCK, FYN, LYN, and / or SRC kinase modulator, preferably a LCK, FYN, LYN, and / or SRC kinase modulator.

[0613] In an embodiment, the compound is a CSK modulator, preferably inhibitor, and a LCK, FYN, LYN, and / or SRC kinase modulator. This makes the compound suitable for immunotherapies.

[0614] The compound of the current invention functions as a molecular glue. The term "molecular glue" refers to small molecules that promote protein-protein interactions, which occur through the direct binding interactions between both protein targets with the small molecule at the protein-protein interface, or through the allosteric modification of protein structure that promotes formation of the new multiprotein complex.

[0615] The compound can function as a molecular glue by stabilizing an interaction between a target protein and an E3 ubiquitin ligase complex. In this manner, the compoundinduces recruitment of the target protein as a neosubstrate to the ubiquitin-proteasome pathway. Upon recruitment, the target protein is ubiquitinated and subsequently degraded by the proteasome. This degradation-based mechanism differs fundamentally from conventional inhibitors, which rely on transient blockade of enzymatic activity.

[0616] The compound can function induce selective degradation of cyclin K, a regulatory binding partner of CDK12 / 13, thereby reducing CDK12 / 13 complex stability and impairing transcriptional processes that drive tumor progression. By minimizing ATP-competitive inhibition and promoting targeted protein degradation, the compounds disclosed herein provide improved selectivity and reduced off-target activity compared to conventional ATP-competitive kinase inhibitors.

[0617] Pharmaceutical Compositions and Formulations

[0618] In an aspect, the current disclosure relates to a pharmaceutical composition or formulation comprising a compound as disclosed herein and at least one pharmaceutically acceptable carrier, diluent, excipient, or adjuvant. The present invention includes pharmaceutical compositions or formulations comprising a compound as detailed herein or a salt thereof and a pharmaceutically acceptable carrier or excipient. In an embodiment, the pharmaceutically acceptable salt is an acid addition salt.

[0619] A compound according to the present invention may in one embodiment be in a purified form. In an embodiment, the composition comprises a compound as detailed herein or a salt thereof. In some embodiments, the composition comprises a compound as detailed herein or a salt thereof in substantially pure form.

[0620] In an embodiment, the compounds herein are synthetic compounds prepared for administration to an individual. In another embodiment, compositions are provided containing a compound in substantially pure form. In another embodiment, the present invention embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another embodiment, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.

[0621] A carrier is considered as being pharmaceutically acceptable, when it does not have any or not substantially adverse unwanted effects on the human or animal body,e.g. it is considered generally safe, nontoxic and / or does not cause unwanted biological side reactions. Suitable pharmaceutically acceptable carriers are well known to the person skilled in the art. The choice of carrier may depend upon the route of administration and concentration of the polypeptide and the carrier may be in the form of a lyophilised composition or an aqueous solution. Generally, an appropriate amount of pharmaceutically acceptable salt is used in the carrier to render the composition isotonic. Examples of the carriers include but are not limited to saline, Ringer's solution and dextrose solution. Preferably, acceptable excipients, carriers, or stabilisers are non- toxic at the dosages and concentrations employed, including buffers such as citrate, phosphate, and other organic acids; salt-forming counter-ions, e.g. sodium and potassium; low molecular weight (> 10 amino acid residues) polypeptides; proteins, e.g. serum albumin, or gelatine; hydrophilic polymers, e.g. polyvinylpyrrolidone; amino acids such as histidine, glutamine, lysine, asparagine, arginine, or glycine; carbohydrates including glucose, mannose, or dextrins; monosaccharides; disaccharides; other sugars, e.g. sucrose, mannitol, trehalose or sorbitol; chelating agents, e.g. EDTA; non-ionic surfactants, e.g. Tween, Pluronics or polyethylene glycol; antioxidants including methionine, ascorbic acid and tocopherol; and / or preservatives, e.g. octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens, e.g. methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol). The composition may also optionally include other components, such as buffering agents or stabilizing agents.

[0622] A compound detailed herein or salt thereof may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation. A compound or salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.One or several compounds described herein or a salt thereof can be used in the preparation of a composition, such as a pharmaceutical composition, by combining the compound or compounds, or a salt thereof, as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above. Depending on the therapeutic form of the system (e.g. transdermal patch versus oral tablet), the carrier may be in various forms. In addition, pharmaceutical compositions may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Compositions comprising the compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical compositions may be prepared by known pharmaceutical methods.

[0623] Compositions as described herein may be administered to individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, com starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-oils, and so on. In addition, pharmaceutical compositions may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.

[0624] In some embodiments, the composition is for use as a human or veterinary medicament. In some embodiments, the composition is for use in a method described herein. In some embodiments, the composition is for use in the treatment of a disease or disorder described herein.

[0625] By means of non-limiting examples, such a composition may be in a form suitable for oral administration, parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc. Such suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person.Some preferred, but non-limiting examples of preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, eye drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and / or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such compositions, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. The compositions can optionally contain other pharmaceutically active substances (which may or may not lead to a synergistic effect with the compounds of the invention) and other substances that are commonly used in pharmaceutical compositions, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc. The compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein, for example using liposomes or hydrophilic polymeric matrices based on natural gels or synthetic polymers. In order to enhance the solubility and / or the stability of the compounds of a pharmaceutical composition according to the invention, it can be advantageous to employ a-, p- or y-cyclodextrins or their derivatives.

[0626] In addition, co-solvents such as alcohols may improve the solubility and / or the stability of the compounds. In the preparation of aqueous compositions, addition of salts of the compounds of the invention can be more suitable due to their increased water solubility.

[0627] The preparations may be prepared in a manner known per se, which usually involves mixing at least one compound according to the invention with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary, under aseptic conditions.

[0628] For an oral administration form, the compositions of the present invention can be mixed with suitable additives, such as excipients, stabilizers, or inert diluents, and brought by means of the customary methods into the suitable administration forms,such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions. Examples of suitable inert carriers are Arabic gum, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, corn starch. In this case, the preparation can be carried out both as dry and as moist granules. Suitable oily excipients or solvents are vegetal or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof. Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and / or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art. When administered by nasal aerosol or inhalation, these compositions may be prepared according to techniques well-known in the art of pharmaceutical composition and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. Suitable pharmaceutical compositions for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of the invention or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents. If required, the composition can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant. For subcutaneous administration, the compound according to the invention, if desired with the substances customary therefore such as solubilizers, emulsifiers or further auxiliaries are brought into solution, suspension, or emulsion. The compounds of the invention can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations. Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, in addition also sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of the various solvents mentioned. The injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

[0629] When rectally administered in the form of suppositories, these compositions may be prepared by mixing the compounds according to the invention with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and / or dissolve in the rectal cavity to release the drug. In a preferred embodiment, the compounds of the present invention are useful in human or veterinary medicine, in particular for use as FAP (fibroblast activation protein) inhibitors.

[0630] In an embodiment, the pharmaceutical composition may comprise a chelator selected from the group of: EUpypa, EDTA (ethylenediamine tetraacetate), EDTMP (diethylenetriaminepenta (methylenephosphonic acid)), DTPA (diethylenetriaminepentaacetate) and its derivatives, DOTA (Dodeca-1,4,7,10-tetraamine-tetraacetate), DOTAGA (2- (I, 4,7, 10-tetraazacyclododecane-4, 7,10) pentanedioic acid) and other DOTA derivatives, TRITA (trideca- 1, 4,7,10-tetraamine-tetraacetate), TETA (tetradeca-l, 4,8, ll-tetraamine-tetraacetate) and its derivatives, NOTA (Nona-1, 4,7-triamine-triacetate) and its derivatives such as NOTAGA (I, 4,7-triazacyclononane, l-g lutaric acid, 4,7-acetate), TRAP (triazacyclononane phosphinic acid), NOPO (I, 4,7-triazacyclononane-l,4-bis [methylene (hydroxymethyl) phosphinic acid] -7- [methylene (2-carboxyethyl) phosphinic acid]), PEPA (pentadeca-1, 4,7,10,13-pentaamine pentaacetate), NETA ({4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[l,4,7]triazonan-l-yl}-acetic acid), 3p-C-NEPA (2-{[2-(4-{2-[Bis(carboxymethyl)amino]-5-(4-nitrophenyl)pentyl}-7-(carboxymethyl)-l,4,7-triazonan-l-yl)ethyl] (carboxymethyl) amino} acetic acid), 3p-C-NETA ({4-[2-(bis-carboxy-methylamino)-5-(4-nitrophenyl)-entyl]-7-carboxymethyl-[l,4,7]tri-azonan-l-yl} acetic acid), 3p-C-NETA-NCS ({4-[2-(Bis-carboxymethylamino)-5-(4-isothiocyanatophenyl) pentyl]-7-carboxymethyl-[l,4,7]triazonan-l-yl}acetic acid), HEHA (hexadeca-1, 4,7,10,13,16-hexaamine -hexaacetate) and its derivatives, HBED (hydroxybenzyl-ethylene-di amine) and its derivatives, DEDPA and its derivatives, such as H2DEDPA (I, 2 - [[6- (carboxylate) pyridin-2-yl] methylamine] ethane), DFO (deferoxamine) and its derivatives, trishydroxypyridinone (THP) and its derivatives such as YM103, TEAP (tetraazycyclodecanephosphinic acid) and its derivatives, AAZTA (6-amino-6-methylperhydro-l,4-diazepine- tetraacetate) and derivatives such as DATA ((6 -Pentanoic acid) -6- (amino) methyl-l,4-diazepine triacetate); SarAr (IN- (4-aminobenzyl) -3,6,10,13,16,19-hexaazabicyclo [6.6.6] -eicosane-l,8-diamine) and salts thereof, (Nhh SAR (1,8-diamino-B, 6,10,13,16,19-hexaazabicyclo [6.6.6] icosane), 6-Hydrazinopyridine-3 -carboxylic acid, HYNIC (bis- (carboxymethylimidazole)glycine and salts and derivatives thereof, aminothiols and their derivatives.The composition comprising the compound as disclosed herein can also be formulated for parenteral administration. The administration of the compound or composition via parenteral routes includes but is not limited to, intravenous, intramuscular, subcutaneous, or intraperitoneal routes. The parenteral administration of the composition allows for the rapid delivery of the therapeutic agent directly into the systemic circulation, bypassing the gastrointestinal tract and potential enzymatic degradation or alteration.

[0631] Preferably, the composition for parenteral administration is prepared in a sterile environment and is formulated as a solution, a suspension, an emulsion, a lyophilized powder for reconstitution, or other suitable forms for parenteral administration.

[0632] In an embodiment, the composition may be administered in a single dose or multiple doses depending on the severity of the disease or condition. The dosage may be adjusted according to the weight, age, sex, and overall health condition of the subject. The exact dosage and frequency of administration may be determined by a healthcare provider based on clinical judgment and patient response to treatment.

[0633] The content of the compound in the pharmaceutical composition is not limited as far as it is useful for treatment, prevention, or amelioration but preferably contains 0.0000001 -10% by weight per total composition.

[0634] The compound has been proven effective in low dosages. In an embodiment, the pharmaceutical composition comprises the compound in an amount between 0,1 and 5 pM, or even between 0,1 and 4 pM, or even between 0,1 and 3 pM, or even between 0,1 and 2 pM, or even between 0,1 and 1,5 pM, or even between 0,1 pM and 1,1 pM.

[0635] Therapeutic use

[0636] In another aspect, the current disclosure relates to methods of treatment and prevention of various diseases using the compound or a composition comprising the compound of the invention. In an embodiment, the current disclosure relates to the compound or a composition comprising the compound of the invention for use in the treatment, prevention or amelioration of a disease or condition.

[0637] In an embodiment, the current disclosure relates to the compound as disclosed herein or composition comprising said compound for use in a medicament or for useas therapy in a subject. In an embodiment, said therapy is the prevention and / or treatment of cancer.

[0638] In an embodiment, the present disclosure provides a method of treating a subject having cancer, comprising providing to the subject a compound as described herein.

[0639] In all such embodiments, wherein said therapy is the prevention and / or treatment of cancer, the cancer may be selected from cancer of colorectal cancer, pancreatic cancer, renal cancer, lung cancer, liver cancer, leukemia, breast cancer, prostate cancer, gastrointestinal cancer, peritoneal cancer, melanoma, endometrial cancer, ovarian cancer, cervical cancer, uterine cancer, bladder cancer, glioblastoma, ampullary adenocarcinoma, brain metastasis, salivary gland cancer, thyroid cancer, brain cancer, lymphoma, myeloma, and head and neck cancer.

[0640] In an embodiment, the cancer characterized by one or more mutations in the KRAS gene that result in altered KRAS activity. In an embodiment, the cancer is one or more selected from the group consisting of ampullary adenocarcinoma, pancreatic ductal adenocarcinoma (PDAC), cholangiocarcinoma (bile duct cancer), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), endometrial cancer, ovarian cancer, gastric cancer (stomach cancer), and breast cancer.

[0641] In an embodiment, the current disclosure relates to a compound or composition as disclosed herein, for use in the inhibition of growth of a tumor cell in a subject. In an embodiment, the present disclosure provides a method of inhibiting the growth of a tumor cell, comprising contacting the tumor cell with a compound or composition as disclosed herein. In an embodiment, the present disclosure provides a method of treating a subject having a tumor, comprising providing to the subject a compound or composition as disclosed herein.

[0642] In an embodiment, the current disclosure relates to Compound 1-1 or a composition comprising said compound, for use in the inhibition of growth of a tumor cell in a subject. In an embodiment, the present disclosure provides a method of inhibiting the growth of a tumor cell, comprising contacting the tumor cell with Compound 1-1 or a composition comprising said compound. In an embodiment, the present disclosure provides a method of treating a subject having a tumor, comprising providing to the subject Compound 1-1 or a composition comprising said compound.In all such embodiments, the tumor cell may be a cell from a tumor selected from colorectal cancer, pancreatic cancer, renal cancer, lung cancer, liver cancer, leukemia, breast cancer, prostate cancer, gastrointestinal cancer, peritoneal cancer, melanoma, endometrial cancer, ovarian cancer, cervical cancer, uterine cancer, bladder cancer, glioblastoma, ampullary adenocarcinoma, brain metastasis, salivary gland cancer, thyroid cancer, brain cancer, lymphoma, myeloma, and head and neck cancer.

[0643] For example, in an embodiment, the present disclosure provides a method of inhibiting the growth of a tumor cell, wherein the tumor cell is a tumor type characterized by one or more mutations in the KRAS gene that result in altered KRAS activity, comprising ampullary adenocarcinoma, pancreatic ductal adenocarcinoma (PDAC), cholangiocarcinoma (bile duct cancer), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), endometrial cancer, ovarian cancer, gastric cancer (stomach cancer), and breast cancer.

[0644] In an embodiment, the compound or composition as disclosed herein is administered to a subject, wherein prior to said administration the activity of C-terminal Src Kinase is determined in a biological sample of said subject.

[0645] In an embodiment, said therapy is a mono-therapy or a combination therapy, said combination therapy is preferably chosen from immunotherapy, chemotherapy, or cell therapy.

[0646] The present disclosure also provides a combination therapy, wherein said combination therapy comprises a CSK inhibitor and one or more additional therapeutic agents. Said additional therapeutic agent is preferably an immunotherapeutic, a chemotherapeutic, a cell therapy or a combination thereof.

[0647] In an embodiment, the combination therapy comprises a CSK inhibitor and an immunotherapeutic. In an embodiment, the combination therapy comprises a CSK inhibitor and a chemotherapeutic. In an embodiment, the combination therapy comprises a CSK inhibitor and a cell therapy.

[0648] In an embodiment, the present disclosure provides a combination therapy, wherein said combination therapy comprises a compound or composition as disclosed herein, and one or more additional therapeutic agents. Said additional therapeutic agent is preferably an immunotherapeutic, a chemotherapeutic, a cell therapy or acombination thereof. In an embodiment, the present disclosure provides a combination therapy, comprising administering to a subject in need thereof a compound or composition as disclosed herein, and one or more additional therapeutic agents.

[0649] In an embodiment, the combination therapy comprises a compound or composition as disclosed herein, and an immunotherapeutic. In an embodiment, the combination therapy comprises a compound or composition as disclosed herein, and a chemotherapeutic. In an embodiment, the combination therapy comprises a compound or composition as disclosed herein, and a cell therapy.

[0650] In an embodiment, the combination therapy comprises the compound or composition as disclosed herein, and one or more additional therapeutic agents, the additional therapeutic agent being chosen from a KRAS inhibitor, a PD1-PDL1 inhibitor, a MEK inhibitor, a PI3K inhibitor, a CDK inhibitor, a MAPK inhibitor, an EGFR inhibitor, an HER2 inhibitor, a PRMT5 inhibitor, an NF-κB pathway modulator, a cytotoxic chemotherapeutic, a Car-T therapy, a Car-NK therapy, or a combination thereof. Additionally, the additional therapeutic agent can be an ERK inhibitor.

[0651] In an embodiment, the additional therapeutic agent is a KRAS inhibitor. In a further embodiment, the KRAS inhibitor is selected from one or more of Sotorasib, Adagrasib, Divarasib (GDC-6036), Opnurasib (JDQ443), Olomorasib (LY3537982), MK-1084, Garsorasib (D1553), Glesirasib (JAB-21822), Fulzerasib (IBI-351), BI-1823911, JNJ-74699157, ZG19018, D3S-001, GEC255, HBI-2438, YL-15293, HS-10370, MRTX1133, HRS-4642, JAB-22000, KAL-21404358, KRAS-533, ERAS-4, THZ-835, JAB-23000, BI-2852, RMC-6236.

[0652] In an embodiment, the additional therapeutic agent is a PD1 inhibitor. In a further embodiment, the PD1 inhibitor is selected from one or more of Pembrolizumab (Keytruda), Nivolumab, AUNP-12, AMG 404, or Pidilizumab.

[0653] In an embodiment, the additional therapeutic agent is a PDL1 inhibitor. In a further embodiment, the PDL1 inhibitor is selected from one or more of Atezolizumab, MPDL3280A, Avelumab or Durvalumab.

[0654] In an embodiment, the additional therapeutic agent is a CDK inhibitor. In a further embodiment, the CDK inhibitor is selected from one or more of abemaciclib, or palbociclib.In an embodiment, the additional therapeutic agent is a PI3K inhibitor. In a further embodiment, the PI3K inhibitor is selected from one or more of AMG 511, Alpelisib, Inavolisib, idelalisib or buparlisib.

[0655] In an embodiment, the additional therapeutic agent is a MEK inhibitor. In a further embodiment, the MEK inhibitor is selected from one or more of Trametinib (GSK1120212); Selumetinib (AZD6244); Cobimetinib (GDC-0973 / XL581); Binimetinib (MEK162); Vemurafenib; Pimasertib; TAK733; RO4987655 (CH4987655); CI-1040; PD-0325901; CH5126766; MAP855; Refametinib (RDEA 119 / BAY 86-9766); RO5126766; AZD8330 (ARRY-424704 / ARRY-704); and GSK1120212.

[0656] In an embodiment, the additional therapeutic agent is a MAPK inhibitor, such as an inhibitor acting on one or more nodes of the RAS-RAF-MEK-ERK pathway. In a further embodiment, the MAPK inhibitor is selected from one or more of Farnesyltransferase inhibitors (FTIs), Sorafenib, Vemurafenib, PLX8394, Dabrafenib, Ulixertinib, Simvastatin, Alisertib, and Teriflunomide.

[0657] In a further embodiment, the additional therapeutic agent is an ERK inhibitor. Suitable ERK inhibitors include, but are not limited to, ERK1 / 2 inhibitors and ERK5 inhibitors such as ERK1 / 2 inhibitor 1, Ulixertinib, KO-947, ASN007, BAY885, Ravoxertinib, AX-15836, ERK5-IN-1, Tizaterkib, XMD17-109, AG126, VX-lle, SCH772984, and Temuterkib.

[0658] In an embodiment, the additional therapeutic agent is a non-chemotherapy DNA-damaging agent. Suitable non-chemotherapy DNA-damaging agent include, but are not limited to, radioligand therapy, radiotherapy, (e.g., using Lutetium-177, Actinium-225), photodynamic therapy, targeted alpha therapies, Auger electronemitting agents. In an embodiment, the additional therapeutic agent is a DNA damage response inhibitor. Suitable DNA damage response inhibitors are PARP inhibitors, WEE1 inhibitors, ATR inhibitors, ATM inhibitors, CHK1 inhibitors, CHK2 inhibitors, DNA-PK inhibitors, POLQ inhibitors, MRE11 inhibitors, RAD51 inhibitors, BRCA2 pathway inhibitors, USP1 inhibitors. Administration in combination with the present compound can enhance the cytotoxic efficacy of the treatment.

[0659] In an embodiment, the additional therapeutic agent is a cytotoxic chemotherapeutic selected from one or more of cyclophosphamide; methotrexate; 5-fluorouracil;vinorelbine; doxorubicin; docetaxel; bleomycin; vinblastine; dacarbazine; mustine; vincristine; procarbazine; etoposide; cisplatin; epirubicin; capecitabine; oxaliplatin; gemcitabine; ifosfamide. The cytotoxic chemotherapy itself can also be a combination therapy such as a combination chemotherapy selected from cyclophosphamide, methotrexate, 5-fluorouracil, vinorelbine (CMF); doxorubicin, cyclophosphamide (AC); docetaxel, doxorubicin, cyclophosphamide (TAC); doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD); mustine, vincristine, procarbazine, prednisolone (MOPP); cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP); bleomycin, etoposide, cisplatin (BEP); epirubicin, cisplatin, 5-fluorouracil (ECF); epirubicin, cisplatin, capecitabine (ECX); methotrexate, vincristine, doxorubicin, cisplatin (MVAC); 5-fluorouracil, folinic acid, oxaliplatin (FOLFOX); gemcitabine, 5-fluorouracil; doxorubicin, cisplatin, methotrexate, ifosfamide, etoposide (MAP / MAPIE).

[0660] In an embodiment, the additional therapeutic agent is a Car-T therapy, a Car-NK therapy, or a combination thereof.

[0661] In an embodiment, the additional therapeutic agent is an EGFR inhibitor. EGFR inhibitors may include both antibodies, such as Cetuximab and Panitumumab, as well as small molecules, such as Erlotinib, Gefitinib, and Osimertinib. These agents are effective in targeting the epidermal growth factor receptor (EGFR), which plays a role in cell signaling pathways involved in cancer proliferation and survival.

[0662] In an embodiment, the additional therapeutic agent is an HER2 inhibitor. HER2 inhibitors include both antibodies, such as Trastuzumab and Pertuzumab, as well as small molecules, such as Lapatinib, Neratinib, and Tucatinib. These agents target the human epidermal growth factor receptor 2 (HER2), which is overexpressed in various cancers, including breast and gastric cancers.

[0663] In an embodiment, the additional therapeutic agent is a PRMT5 inhibitor. PRMT5 inhibitors include small molecules, such as GSK3326595, JNJ-64619178, and PF-06939999. These compounds target protein arginine methyltransferase 5 (PRMT5), an enzyme that plays a role in gene expression.

[0664] In an embodiment, the additional therapeutic agent is a compound that modulates the NF-KB (Nuclear factor kappa-light-chain-enhancer of activated B-cells) pathway.In an embodiment, the additional therapeutic agent is selected from one or more of Sotorasib, Adagrasib, Divarasib (GDC-6036), Opnurasib (JDQ443), Olomorasib (LY3537982), MK-1084, Garsorasib (D1553), Glesirasib (JAB-21822), Fulzerasib (IBI-351), BI-1823911, JNJ-74699157, ZG19018, D3S-001, GEC255, HBI-2438, YL-15293, HS-10370, MRTX1133, HRS-4642, JAB-22000, KAL-21404358, KRAS-533, ERAS-4, THZ-835, JAB-23000, BI-2852, RMC-6236; Pembrolizumab (Keytruda), Nivolumab, AUNP-12, AMG 404, or Pidilizumab; Atezolizumab, MPDL3280A, Avelumab or Durvalumab; abemaciclib, or palbociclib; AMG 511, Alpelisib, Inavolisib, idelalisib or buparlisib; Trametinib (GSK1120212); Selumetinib (AZD6244); Cobimetinib (GDC-0973 / XL581); Binimetinib (MEK162); Vemurafenib; Pimasertib; TAK733; RO4987655 (CH4987655); CI-1040; PD-0325901; CH5126766; MAP855; Refametinib (RDEA 119 / BAY 86-9766); RO5126766; AZD8330 (ARRY- 424704 / ARRY-704); GSK1120212; cyclophosphamide; methotrexate; 5-fluorouracil; vinorelbine; doxorubicin; docetaxel; bleomycin; vinblastine; dacarbazine; mustine; vincristine; procarbazine; etoposide; cisplatin; epirubicin; capecitabine; oxaliplatin; gemcitabine; ifosfamide; a Car-T therapy; a Car-NK therapy; Cetuximab; Panitumumab; Erlotinib; Gefitinib; Osimertinib Trastuzumab; Pertuzumab; Lapatinib; Neratinib; Tucatinib; GSK3326595; JNJ-64619178; and PF-06939999.

[0665] In an embodiment, the combination therapy comprises the compound or composition as disclosed herein, and a KRAS inhibitor selected from one or more of Sotorasib, Adagrasib, Divarasib (GDC-6036), Opnurasib (JDQ443), Olomorasib (LY3537982), MK-1084, Garsorasib (D1553), Glesirasib (JAB-21822), Fulzerasib (IBI-351), BI-1823911, JNJ-74699157, ZG19018, D3S-001, GEC255, HBI-2438, YL-15293, HS-10370, MRTX1133, HRS-4642, JAB-22000, KAL-21404358, KRAS-533, ERAS-4, THZ-835, JAB-23000, BI-2852, RMC-6236.

[0666] In an embodiment, the combination therapy comprises Compound 1-1 and a KRAS inhibitor selected from one or more of Sotorasib, Adagrasib, Divarasib (GDC-6036), Opnurasib (JDQ443), Olomorasib (LY3537982), MK-1084, Garsorasib (D1553), Glesirasib (JAB-21822), Fulzerasib (IBI-351), BI-1823911, JNJ-74699157, ZG19018, D3S-001, GEC255, HBI-2438, YL-15293, HS-10370, MRTX1133, HRS-4642, JAB-22000, KAL-21404358, KRAS-533, ERAS-4, THZ-835, JAB-23000, BI-2852, RMC-6236.

[0667] The combination therapy as disclosed herein may comprise separate formulations or compositions but may also be formulated together in one pharmaceuticalcomposition. In an embodiment, the combination therapy is a pharmaceutical composition comprising a CSK inhibitor, one or more additional therapeutic agents, and one or more pharmaceutically acceptable carrier, excipient, diluent, and / or surfactant. In a further embodiment, the CSK inhibitor is a compound according to formula (I) as disclosed herein.

[0668] In an embodiment, the combination therapy is a pharmaceutical composition comprising compound (1-1) and one or more additional therapeutic agents as disclosed herein, and one or more pharmaceutically acceptable carrier, excipient, diluent, and / or surfactant.

[0669] In another aspect, the current disclosure relates to methods of treatment and prevention of various diseases using a combination therapy as disclosed herein. In an embodiment, the current disclosure relates to a combination therapy, for use in the treatment, prevention or amelioration of a disease or condition.

[0670] In an embodiment, the current disclosure relates to the combination therapy for use in a medicament or for use as therapy in a subject.

[0671] In an embodiment, said therapy is the prevention and / or treatment of cancer. In an embodiment, the present disclosure provides a method of treating a subject having cancer, comprising providing to the subject a combination therapy as described herein.

[0672] In an embodiment, the compound or composition as disclosed herein and one or more therapeutic agents are administered simultaneously or sequentially to said subject. In an embodiment, the compound or composition as disclosed herein and one or more therapeutic agents are administered together or separately to said subject.

[0673] In an embodiment, the compound or composition as disclosed herein is administered to a subject in combination with one or more additional therapeutic agents, said additional therapeutic agent is chosen from a KRAS inhibitor, a PD1-PDL1 inhibitor, a MEK inhibitor, a PI3K inhibitor, a CDK inhibitor and a MAPK inhibitor, a cytotoxic chemotherapy, a Car-T therapy, a Car-NK therapy or a combination thereof. Additionally, the additional therapeutic agent can be an ERK inhibitor.In an embodiment, the present disclosure provides a method of inhibiting the growth of a tumor cell, comprising contacting the tumor cell with a combination therapy comprising a CSK inhibitor and an additional therapeutic agent. Such contacting may be, for example, in vivo, in a subject (e.g., a mammal, preferably a human). Furthermore, such a method may, e.g., in one non-limiting embodiment, comprise contacting the tumor cell with a combination therapy comprising a compound as disclosed herein and an additional therapeutic agent selected from one or more of Sotorasib, Adagrasib, Divarasib (GDC-6036), Opnurasib (JDQ443), Olomorasib (LY3537982), MK-1084, Garsorasib (D1553), Glesirasib (JAB-21822), Fulzerasib (IBI-351), BI-1823911, JNJ-74699157, ZG19018, D3S-001, GEC255, HBI-2438, YL-15293, HS-10370, MRTX1133, HRS-4642, JAB-22000, KAL-21404358, KRAS-533, ERAS-4, THZ-835, JAB-23000, BI-2852, RMC-6236; Pembrolizumab (Keytruda), Nivolumab, AUNP-12, AMG 404, or Pidilizumab; Atezolizumab, MPDL3280A, Avelumab or Durvalumab; abemaciclib, or palbociclib; AMG 511, Alpelisib, Inavolisib, idelalisib or buparlisib; Trametinib (GSK1120212); Selumetinib (AZD6244); Cobimetinib (GDC-0973 / XL581); Binimetinib (MEK162); Vemurafenib; Pimasertib; TAK733; RO4987655 (CH4987655); CI-1040; PD-0325901; CH5126766; MAP855; Refametinib (RDEA 119 / BAY 86-9766); RO5126766; AZD8330 (ARRY- 424704 / ARRY-704); GSK1120212; cyclophosphamide; methotrexate; 5-fluorouracil; vinorelbine; doxorubicin; docetaxel; bleomycin; vinblastine; dacarbazine; mustine; vincristine; procarbazine; etoposide; cisplatin; epirubicin; capecitabine; oxaliplatin; gemcitabine; ifosfamide.

[0674] In an embodiment, the tumor cell may be contacted with a combination therapy comprising a compound as disclosed herein and a KRAS inhibitor selected from one or more of Sotorasib, Adagrasib, Divarasib (GDC-6036), Opnurasib (JDQ443), Olomorasib (LY3537982), MK-1084, Garsorasib (D1553), Glesirasib (JAB-21822), Fulzerasib (IBI-351), BI-1823911, JNJ-74699157, ZG19018, D3S-001, GEC255, HBI-2438, YL-15293, HS-10370, MRTX1133, HRS-4642, JAB-22000, KAL-21404358, KRAS-533, ERAS-4, THZ-835, JAB-23000, BI-2852, RMC-6236.

[0675] In an embodiment, the tumor cell may be contacted with a combination therapy comprising Compound 1-1 and a KRAS inhibitor selected from one or more of Sotorasib, Adagrasib, Divarasib (GDC-6036), Opnurasib (JDQ443), Olomorasib (LY3537982), MK-1084, Garsorasib (D1553), Glesirasib (JAB-21822), Fulzerasib (IBI-351), BI-1823911, JNJ-74699157, ZG19018, D3S-001, GEC255, HBI-2438, YL-15293, HS-10370, MRTX1133, HRS-4642, JAB-22000, KAL-21404358, KRAS-533, ERAS-4, THZ-835, JAB-23000, BI-2852, RMC-6236.In an embodiment, the compound is administered to a subject in an amount of at least 1 mg / kg, preferred at least 10 mg / kg, or even at least 50 mg / kg per dosage. In an embodiment, the compound is administered to a subject in an amount of between 1 and 50 mg / kg, preferred between 1 and 20 mg / kg per dosage.

[0676] The compound has been proven effective in low dosages. In an embodiment, compound is administered to a subject in an amount of between 0,1 and 5 pM, or even between 0,1 and 4 pM, or even between 0,1 and 3 pM, or even between 0,1 and 2 pM, or even between 0,1 and 1,5 pM, or even between 0,1 pM and 1,1 pM per dosage.

[0677] The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to treat disorders including: disorders that are associated with CDK, especially CDK12 and / or CDK13; disorders that result from an inappropriate activity of a CDK, especially CDK12 and / or CDK13; disorders that are associated with CDK mutation, especially CDK12 and / or CDK13mutation; disorders that are associated with CDK overexpression, especially CDK12 and / or CDK13 overexpression; disorders that are associated with upstream pathway activation of CDK, especially CDK12 and / or CDK13; disorders that are ameliorated by the inhibition of CDK, especially CDK12 and / or CDK13; proliferative disorders; cancer; viral infections (including HIV); neurodegenerative disorders (including Alzheimer's disease and Parkinson's disease); ischaemia; renal diseases; cardiovascular disorders (including atherosclerosis); autoimmune disorders (including rheumatoid arthritis); and disorders caused by dysfunction of translation in cells (including muscular dystrophy). Optionally, the treatment further comprises treatment (e.g., simultaneous or sequential treatment) with a further active agent which is, e.g., a DNA repair inhibitor, an immune checkpoint inhibitor, an agent stimulating the immune system, a cell cycle checkpoint inhibitor, a Her2 blocker, a transcriptional inhibitor, a cytotoxic chemotherapeutic agent, etc.

[0678] Diagnostic use

[0679] In an embodiment, the current disclosure provides a method of diagnosing and / or treating a subject. Said method involves determining the activity of C-terminal Src Kinase is determined in a biological sample obtained from said subject. The term "biological sample" can be defined broadly to encompass any material derived from or associated with a living or once-living organism, including its constituent cells,tissues, bodily fluids, or molecular components. This may include, but is not limited to cells, tissues, bodily fluids, molecular components such as DNA, RNA or proteins.

[0680] In an embodiment, the biological sample is selected from Blood Samples, such as Whole Blood, Serum / Plasma, or Isolated Leukocytes, Tissue Samples, such as Fresh Tissue Biopsies, Frozen or Fixed Tissues, and Tumor Biopsies, Cell Samples, Cerebrospinal Fluid, Urine or Saliva, Bone Marrow Aspirates, Synovial Fluid, Lymphatic Fluid, Amniotic Fluid or Placental Tissue, Exosomes or Extracellular Vesicles, Microbiome-Associated Samples, Pathological Samples.

[0681] In an embodiment, said biological sample is a biopsy.

[0682] In certain embodiments, the methods described herein include obtaining a biological sample from a subject, such as a tissue biopsy, blood, or other bodily fluid, and subsequently assessing the C-terminal Src kinase (Csk) activity within this sample. The sample may be processed to isolate cells, cellular fractions, or purified protein components, which can then be analyzed for Csk activity using established biochemical assays, immunoassays, or molecular diagnostic techniques. By determining the level of Csk activity, it becomes possible to stratify patients based on their underlying molecular profile and guide therapeutic decision-making more precisely.

[0683] The Csk activity can be determined using procedures selected from Kinase Activity Assays, such as Radioactive Kinase Assay or Non-Radioactive Kinase Assay, Western Blotting, Enzyme-Linked Immunosorbent Assay (ELISA), Mass Spectrometry, Fluorescence Resonance Energy Transfer (FRET)-Based Assays, Activity-Specific Antibodies, Re porter- Based Assays, Surface Plasmon Resonance (SPR) or Biolayer Interferometry (BLI), Protein Arrays, Genetic and Cellular Approaches, such as Knock-In / Knock-Out Studies and Cellular Phosphorylation Assays.

[0684] Once the Csk activity in the biological sample has been determined, a clinician can select a therapy regimen tailored to the patient's specific needs. In one aspect, if the measured Csk activity meets or exceeds a predetermined threshold, the patient may be administered a therapeutically effective amount of a compound as described herein. Such a compound may be designed to modulate Csk activity, inhibit downstream signaling pathways, or otherwise influence cellular processes associated with disease progression. Where appropriate, this compound can be administered alone or in combination with other therapeutic agents, including chemotherapeuticdrugs, targeted inhibitors, immunomodulatory compounds, or supportive therapies known in the art.

[0685] In certain embodiments, the combination therapies may include the discussed compound administered concurrently, sequentially, or in a staggered protocol with additional agents that synergize to enhance the overall therapeutic effect. For example, the compound may be co-administered with an immunotherapeutic antibody, a tyrosine kinase inhibitor, or a metabolic modulator to achieve improved clinical outcomes.

[0686] Thus, through the initial measurement of Csk activity, medical practitioners are better equipped to prescribe an individualized treatment plan that leverages the selected compound, alone or in combination, ultimately optimizing the therapeutic efficacy and improving patient prognosis.

[0687] In certain embodiments, the methods described herein include obtaining a biological sample from a subject, such as a tissue biopsy, blood, or other bodily fluid, and subsequently assessing the C-terminal Src kinase (Csk) activity and assessing at least one additional biomarker within this sample. The additional biomarkers include KRAS mutation status, HER2 expression or amplification status, and EGFR mutation or expression status. These biomarkers can be assessed using standard molecular and histological techniques to provide insights into the sample's molecular profile and potential therapeutic targets.

[0688] In a further embodiment, the additional biomarker relates to NF-KB signaling. It has been observed that activity of the NF-KB pathway, including NLRP2 mRNA expression and IKBKB protein expression, correlates with treatment response to the compounds described herein. In particular, low NF-KB activity is associated with improved sensitivity to treatment, whereas elevated NF-KB activity is associated with reduced sensitivity. Accordingly, assessment of NF-KB pathway activity, including but not limited to NLRP2 mRNA expression and IKBKB protein expression, provides a predictive biomarker for stratifying patients and guiding therapeutic decisionmaking.

[0689] In certain embodiments, the methods described herein include obtaining a biological sample from a subject, such as a tissue biopsy, blood, or other bodily fluid, and subsequently assessing activity of the NF-KB pathway.In an embodiment, the NF-KB biomarker comprises one or more components selected from NLRP2 mRNA expression, IKBKB protein expression, or other downstream NF-KB signalling components.

[0690] Subjects

[0691] In some embodiments, the subject is an animal, preferably a mammal. In some embodiments, the individual is a primate, bovine, ovine, porcine, equine, canine, feline, or rodent. In preferred embodiments, the subject is a human.

[0692] The subjects may be those patients of whom the activity of C-terminal Src Kinase is determined in a biological sample.

[0693] In an embodiment, the activity of C-terminal Src Kinase in the subject is elevated

[0694] In another aspect, the current disclosure provides a compound for use in the treatment and / or prevention of cancer, wherein said compound inhibits C-terminal Src kinase activity. The compound may be a small molecule, an antibody (such as a monoclonal antibody), a peptide, a RNA-based inhibitor (such as siRNA or antisense oligonucleotides), a protein-based inhibitor, an allosteric inhibitor, or a covalent inhibitor.

[0695] The subjects may be those patients of whom the activity of the NF-κB pathway is determined in a biological sample.

[0696] In an embodiment, the NF-KB pathway activity in the subject is low, wherein low NF-KB activity is associated with improved sensitivity to the compounds described herein, whereas elevated NF-KB activity is associated with reduced sensitivity.

[0697] In an embodiment, NLRP2 mRNA expression in the subject is elevated, wherein elevated NLRP2 expression is associated with improved sensitivity to the compounds described herein, whereas reduced NLRP2 expression is associated with reduced sensitivity.

[0698] In an embodiment, IKBKB protein expression in the subject is low, wherein low IKBKB expression is associated with improved sensitivity to the compounds described herein, whereas elevated IKBKB expression is associated with reduced sensitivity.Articles of Manufacture and Kits

[0699] The present disclosure further provides articles of manufacture comprising a compound described herein or a salt thereof, a composition described herein, or one or more-unit dosages described herein in suitable packaging. In certain embodiments, the article of manufacture is for use in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging, and the like. An article of manufacture may further be sterilized and / or sealed.

[0700] The present disclosure further provides kits for carrying out the methods of the invention, which comprises one or more compounds described herein or a composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one embodiment, the kit employs a compound described herein or a salt thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment any disease or described herein, for example for the treatment of cancer. Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit. The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein and / or an additional pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0701] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present invention. The instructions included with the kit generally include information as to the components and their administration to an individual.

[0702] SynthesisThe compounds of the invention can be prepared by various synthetic routes, including but not limited to the following representative procedures:

[0703] 1. A starting amine or acid is reacted with a key intermediate under appropriate reaction conditions (e.g., temperature, solvent, and pH) in the presence of a base or coupling agent, such as DIPEA, EDC, or HOAt.

[0704] 2. The reaction mixture is typically stirred for a designated time (e.g., 16- 18 hours) at a controlled temperature, depending on the desired transformation.

[0705] 3. Upon completion, the reaction mixture is cooled, and the solvent is removed under reduced pressure. The crude product is dissolved in a suitable solvent (e.g., DMSO) and filtered.

[0706] 4. Analytical methods, such as LCMS, are used to monitor the reaction progress and analyze the crude product.

[0707] 5. Purification is performed using preparative HPLC with appropriate columns and eluents (e.g., water, acetonitrile, or methanol) and may include additives like TFA or ammonia to optimize separation.

[0708] These procedures are adaptable based on the specific reagents and intermediates used and may involve modifications to optimize yields, purity, or reaction conditions.

[0709] The present invention will be now described in more details, referring to examples that are not limitative.

[0710] EXAMPLES EXAMPLE 1

[0711] Materials and methods

[0712] Patient-derived Drug screening

[0713] Drug screening on 3D patient-derived tumor samples was performed using a prevalidated drug screening pipeline for which a detailed protocol is available in the Journal of Visualized Experiments (Le Compte et al., J Vis Exp, 2022).

[0714] For patient-derived 3D models: Established organoid lines were expanded in extracellular matrix (ECM) domes (Cultrex type 2, Bio-Techne Ltd). Next, 3-day-old organoids were harvested from ECM drops using the Cultrex Organoid Harvesting Solution (Bio-Techne Ltd), collected in a 15 mL tube coated with 0.1% BSA / PBS, washed, and resuspended in medium. Next, the number of organoids was quantified using imaging and diluted in full medium supplemented with 4% Cultrex at aconcentration of 4000 organoids / mL. Next, 50pL (200 organoids) of this solution was dispensed into a 384-well ultra-low attachment microplate (Corning, #4588) using the OT-2 pipetting robot (Opentrons) in a cooled environment. Thereafter, the plate was centrifuged (100 ref, 30 sec, 4°C) and incubated overnight at 37°C. All drugs and fluorescent reagents were added to the plate using the Tecan D300e Digital Dispenser and dissolved in either DMSO or 0.3% Tween-20 / H2O. Cytotox Green (60 nM / well, Sartorius, DMSO) was uses as fluorescent cell death marker and Staurosporine (2 pM, Tocris Bioscience, DMSO) as positive control. For each drug, a 4-point logarithmic titration was dispensed (100 - 3000 nM) and DMSO concentrations were normalized to the same level in each well (< 1%). Brightfield and green fluorescence whole-well images (4x objective) were taken every 24 hours with the Tecan Spark Cyto set at 37°C I 5% CO2 for 5 days.

[0715] Image and data analysis

[0716] Images and data were analysed with the Orbits label-free organoid detection module. Viability (V) was quantified as Total Brightfield Organoid Area - Total Green Area and used to calculate the Normalised Organoid Growth Rate (NOGR) (Deben et al., Commun. Biol., 2024). Based on the NOGR, the drug effects can be classified as: >1, proliferative effect; = 1, normal growth as in vehicle control; = 0, complete growth inhibition; = -1, complete killing as in positive control.

[0717] Synergy score calculation patient derived organoids:

[0718] The HSA (Highest Single Agent) synergy score was calculated using the SynergyFinder R-package (Zheng et al., Genomics Proteomics Bioinformatics, 2022). A synergy score > 10: Indicates a synergistic interaction between the drugs. -10 < Score < 10: Implies an additive effect where the combined impact of the drugs is approximately equal to their individual effects summed. <-10: Signifies an antagonistic interaction between the drugs.

[0719] Immune cell killing assays NK cells In vitro:

[0720] NK cells were cultured in GlutaMAX alpha Minimum Essential Medium (o-MEM; Life Technologies) supplemented with 12.5% Fetal Bovine Serum (FBS; Life Technologies), 12.5% horse serum (Life Technologies), 2mM L-glutamine (Life Technologies), 1% Penicillin / Streptomycin (P / S; Life Technologies) and 150 U / mL recombinant IL-2 (ImmunoTools). 3uM of compound was added to a human ovarium cancer cell line (OVCAR-3) in combination with NK cells and images were taken every 4 hours for 2 days. Remaining tumor cell counts were calculated using the Tecan Spark Cyto imaging software.CAR-NK microtumor killing assay

[0721] Longitudinal cytotoxic activity of (CAR) NK cells toward CD70+ CAFs in an advanced in vitro model was evaluated using 3D patient-derived colorectal cancer (CRC) microtumors containing CRC tumor organoids with patient-derived CAF cells (RLT-PSC). Patient-derived CRC organoids (CRC014, CRC013 and GI038) from our inhouse organoid bank, were cultured as previously described. For downstream microtumor generation, organoids were mixed with patient-derived CAF cells, seeded in Advanced DMEM / F12 medium containing 3% Cultrex, supplemented with 1% GlutaMAX, 1% HEPES, and 1% P / S in 384-well ultra-low attachment microplates (Corning), and incubated at 37°C for two days to allow assembling of microtumors. On day three, microtumors were treated with 4000 CD70-CAR, or MOCK NK cells were followed up by the ZEISS CellDiscoverer 7 live-cell imager every 2 h for 36 h.

[0722] Immunohistochemistry

[0723] Immunohistochemical (IHC) staining was performed to evaluate the expression of CD8, F4 / 80, and PD-L1 in the tumor microenvironment (TME) of KPC mice, including both treated and untreated groups. Six tumor resections were analyzed per condition.

[0724] Tumor sections, 5 pm thick, were baked at 60°C for 2 hours. Antigen retrieval was conducted using heat-induced epitope retrieval in Envision FLEX+ antigen retrieval solution (DAKO) at 97°C for 20 minutes, using the PT-Link instrument (DAKO). Following antigen retrieval, endogenous peroxidase activity was blocked by incubating the sections in peroxidase blocking buffer (DAKO) for 5 minutes.

[0725] Primary Antibody Staining:

[0726] • CD8: Sections were incubated with an anti-CD8 polyclonal antibody (#clone 45M15, Thermo Fisher) at a 1:250 dilution.

[0727] • F4 / 80: A mouse monoclonal antibody (clone BM8, Bio-Rad) was applied at a 1:500 dilution.

[0728] • PD-L1: A mouse monoclonal antibody (clone 17952-1-AP, Thermo Fisher) was used at a 1:200 dilution.

[0729] Primary antibody stainings were followed by rabbit enhanced polymer-based linker (15 min), secondary HRP antibody (25 min) and visualized via a DAKO autostainer Link 48 instrument using the Envision FLEX+ detection kit (DAKO) according to the instructions of the manufacturer.In vivo testing

[0730] 1) Formulation

[0731] The compound was administered via intraperitoneal (IP) injection. The formulation consisted of a mixture of 5% DMSO, 5% TWEEN-80, and 90% sterile PBS, prepared to a final volume of 300 pL. Initially, the compound was dissolved in DMSO to achieve a homogeneous solution. Subsequently, the solution was mixed with TWEEN-80 as an emulsifier and further diluted with PBS to create a stable oil-in-water (O / W) emulsion without precipitation. The resulting solution was vortexed thoroughly to ensure uniformity and readiness for IP injection.

[0732] 2) Mice species

[0733] Female C57BL / 6J mice aged 6-8 weeks were either bred in-house at the Peter MacCallum Cancer Centre or sourced from Jackson Laboratories (L'Arbresle, France). All mice were housed at the Animal Core Facilities of the Peter MacCallum Cancer Centre. Animal procedures complied with the guidelines concerning animal ethics. Mice were housed in filter-top cages enriched with shelters and nesting material and were monitored daily for health and wellbeing. A 7-day acclimatization period was provided before experiments to minimize stress.

[0734] 3) General toxicity studies in C57BL / 6J Mice

[0735] A total of 12 female C57BL / 6J mice were used for in vivo toxicity studies. Mice were randomized based on body weight and assigned to four treatment groups (N=3 per group) as follows:

[0736] • Group 1: Compound 1-1 at 5 mg / kg

[0737] • Group 2: Compound 1-1 at 10 mg / kg

[0738] • Group 3: Compound 1-1 at 20 mg / kg

[0739] • Group 4: Untreated vehicle (DMSO) control

[0740] Mice received IP injections three times per week for three consecutive weeks. Daily health and body weight assessments were conducted during this period. At the end of the study, animals were euthanized using sodium pentobarbital (75 mg / kg, IP; Sanofi, Belgium). Organs, including the heart, liver, spleen, and kidneys, were harvested and weighed.

[0741] 4) Serum collection and biomarker analysis

[0742] Serum samples were collected from sacrificed mice for toxicity analysis based on biomarkers of interest. Biomarkers indicative of general and organ-specific toxicitywere measured, including creatinine, lipase, C-reactive protein (CRP), alkaline phosphatase (ALP), direct bilirubin, and total bilirubin. The animals were anesthetized with an intraperitoneal injection of sodium pentobarbital (150 mg / kg, Sanofi, Belgium). Once complete anesthesia was confirmed by the absence of a pedal reflex, blood was collected via retro-orbital sinus puncture and subsequently euthanized by cervical dislocation. The blood was allowed to clot at room temperature for 30 minutes in Microvette® Z-gel tubes before centrifugation at 10,000 x g for 5 minutes at room temperature. The resulting serum was carefully aspirated and stored at -80°C until further analysis.

[0743] 5) KPC Cell line

[0744] A mouse pancreatic ductal adenocarcinoma (PDAC) cell line (KPC), derived from an orthotopic tumor bearing KRAS and p53 mutations, was utilized. Cells were cultured in DMEM (Life Technologies, Merelbeke, Belgium) supplemented with 10% fetal bovine serum (FBS), 10 mM L-glutamine (Life Technologies), and maintained at 37°C with 5% CO2. Mycoplasma contamination was routinely checked, and only cells between passages two and six were used for experiments.

[0745] 6) Tumor kinetics and survival studies

[0746] KPC cells were harvested using TrypLE (Life Technologies), washed three times with sterile PBS, and filtered through a 70-pm cell strainer to obtain a single-cell suspension. Mice were injected subcutaneously in the left abdominal flank with 0.5 x 106KPC cells suspended in 100 pL sterile PBS. Upon tumors reaching an average size of 20-30 mm2, mice were randomized based on tumor size into two treatment groups:

[0747] • Group 1: Compound 1-1 at 25 mg / kg

[0748] • Group 2: DMSO-treated vehiculum control

[0749] Mice received IP injections five times per week for two weeks. Tumor size was measured thrice weekly using a digital caliper (Chicago Brand, Medford, OR, USA). Tumor area was calculated using the formula: length x width. Mice were sacrificed when tumor size exceeded 150 mm2.

[0750] Results

[0751] The anti-tumor effects of Compound 1-1 on a patient-derived sample was evaluated. Reference is made to figure 1, in which the result is shown. At 300nM, the tumor cells were complete death. It shows that compound 1-1 exhibits anti-tumor effects at low doses.The efficacy of compound 1-1 was also assessed across various tumor types (figure 2), including breast cancer, colorectal cancer, and cholangiocarcinoma. The results revealed that especially cholangiocarcinoma and colorectal cancer cells demonstrated an increased response (NOGR: -0.25 vs -0.75) to the treatment.

[0752] High-throughput screen on a panel of FDA approved and late-preclinical drugs show that Compound 1-1 ("compound 1") is one of the best performing compounds (low NOGR max value) in PDAC (KRAS mutant) patient-derived models (figure 3).

[0753] As shown in figures 4 and 5, Compound 1-1 shows synergistic properties in more resistant patients to compound 1-1. Synergism is shown in PDAC044 (patient-derived model), which was originally less sensitive but the combination of Compound 1-1 and a KRAS inhibitor (MRTX1133) shows the synergistic effects of the combination.

[0754] As shown in figure 6, Compound 1-1 shows strong synergistic properties in sensitive patients to compound 1-1. Dose response (NOGR) curves (figure 7) show the shift in response when luM of a KRAS inhibitor is added.

[0755] As shown in figures 8 and 9, Compound 1-1 shows synergy combined with 5-fluorouracil based chemotherapy regimen over a broad concentration range (500nM to 3000nM). Microscopy images (figure 8) show that untreated cells are densely populated, indicating no cytotoxicity. Treatment with Compound 1-1 (1 pM) alone results in a slight reduction in cell density, while 5-FU (4 pM) alone moderately reduces cell density. However, the combination of 5-FU (4 pM) and Compound 1-1 (1 pM) dramatically decreases cell density, with most cells appearing non-viable, highlighting a strong synergistic effect.

[0756] Figure 9 quantifies this synergy using the HSA (Highest Single Agent) synergy score, where a mean synergy score of 17.49 (p < 2e-324) indicates statistically significant synergy between the two agents. Across various concentrations, positive synergy scores (>10) are observed, confirming enhanced effectiveness of the combination compared to either agent alone.

[0757] The image panel in figure 10 illustrates the results of an immune cell synergy assay using NK cells to evaluate the effects of different treatments on tumor cells (KPC). In the untreated control, the tumor cells are densely populated and highly fluorescent, indicating no significant cell death. Treatment with Compound 1-1 alone(3 |J M) shows a modest reduction in fluorescent cell density, suggesting cytotoxicity. Exposure to NK cells alone results in a slight reduction in tumor cell fluorescence, indicating some killing by NK cells. However, the combination of Compound 1-1 (3 pM) and NK cells results in a dramatic reduction in fluorescent tumor cells, leaving almost no surviving cells. This highlights a clear synergistic effect between Compound 1-1 and NK cells in effectively killing tumor cells.

[0758] Visual representation of microtumors (PDOs+ stromal cells) treated with either patient-derived CAR-NK cells, Compound 1-1 or the combination are shown in figure 11. After 48h, the combination clearly shows an increased killing of the tumor while having limited toxicity towards the immune cells.

[0759] In vivo CD8 (T cells) and F4 / 80 (macrophages) immunohistochemistry stainings of vehicle and Compound 1-1 treated mice harboring KPC tumors, are shown in figures 12 and 13. This data clearly shows an increased infiltration of the immune system.

[0760] PD-L1 expression was quantified using IHC (figure 14). Images show clear expression in tumor microenvironment, which in combination with the increased CD8+ T cell infiltration provides rationale for combination with PD-1 / PD-L1 immunotherapies.

[0761] The bar graph in figure 15 shows the percentage change in tumor size relative to baseline (Day 0). The vehicle-treated group shows a significant increase in tumor size over time, while the Compound I-l-treated group shows a much smaller increase, suggesting tumor growth inhibition by Compound 1-1.

[0762] Figure 16 depicts tumor size over time. The vehicle group experiences steady tumor growth, with a sharp increase after stopping treatment, while the Compound 1-1 group maintains a much slower growth rate, indicating effective tumor size control by the treatment.

[0763] Figure 17 shows a Kaplan-Meier survival curve. Mice treated with Compound 1-1 exhibit improved survival compared to the vehicle group, suggesting a potential survival benefit with this compound in the KPC pancreatic cancer model. P-value was calculated using a log-rank test. Overall, these results suggest that Compound 1-1 inhibits tumor growth and improves survival in this mouse model of pancreatic cancer.Figures 18 and 19 assess the safety profile of Compound 1-1 at doses of 5 mg / kg, 10 mg / kg, and 20 mg / kg compared to a vehicle control, evaluating body weight changes over 22 days and organ weights (kidney, liver, heart, spleen). Body weight remained stable across all groups, with no significant losses or indications of toxicity, as no group approached the humane endpoint threshold. Similarly, normalized organ weights for the kidney, liver, heart, and spleen were consistent across all treatment groups, showing no significant differences compared to the control. These results suggest that the compound is well-tolerated at all tested doses, with no evidence of systemic toxicity.

[0764] Figure 20 evaluates biomarkers for organ function and inflammation in mice treated with Compound 1-1 at doses of 5 mg / kg, 10 mg / kg, and 20 mg / kg, compared to a control group. Creatinine levels remain stable across groups, indicating no kidney toxicity, while CRP levels, a marker of systemic inflammation, show no significant differences, suggesting no inflammatory response. Alkaline phosphatase (ALP) levels remain consistent across groups, reflecting no adverse liver or bone effects, and lipase levels show no significant changes, indicating no pancreatic toxicity. Additionally, both direct and total bilirubin levels are stable across all groups, confirming no hepatotoxicity. These results suggest that Compound 1-1 is well-tolerated across all tested doses, with no significant impact on key organ functions or systemic inflammation.

[0765] Figures 21-24 illustrate the synergistic effects of the compound 1-1 in combination with the HER.2 inhibitors Neratinib (figure 21) and Lapatinib (figure 22) on cell viability. Brightfield images in figure 21 and 22 compare untreated cells (top left), compound 1-1 alone (200 nM) (top right), HER.2 inhibitors alone (1 pM) (bottom left), and their combinations (bottom right). The enhanced efficacy of the combinations is highlighted, showing reduced cell viability compared to single treatments. Heatmaps in figures 23 and 24 quantify the synergy scores for varying concentrations of compound 1-1 and the HER2 inhibitors. The heatmaps reveal a strong synergy (Up to 31 HSA value) with Neratinib and Lapatinib. Overall, this preclinical data demonstrate that compound 1-1 exhibits synergistic properties with HER2 inhibitors.

[0766] The above tests were repeated with all compounds 1-2 to 1-348 as disclosed herein, and similar results were obtained.

[0767] EXAMPLE 2The compounds of this invention may be prepared by a variety of procedures and synthetic routes. Exemplary synthetic routes are shown in the procedures below.

[0768] General Procedure 1

[0769] DIPEA NH₂ → NMP, 80°C, 16 h

[0770] intermediate 1 A B

[0771] DIPEA NMP, 150°C, 16h

[0772]

[0773] B C D

[0774] Amine A (1 eq.) and DIPEA (typically 4 eq.) are mixed in dry NMP (approximately 0.7 ml per 100 mg of product). The key intermediate 1 (1 eq.) is then added in one portion, and the mixture is sealed and stirred at 80°C for 16 hours. Amine C (2 eq.) is then added, and the resulting mixture is stirred at 150°C for 16 hours. The mixture is cooled, the solvent is evaporated under reduced pressure, and the residue is dissolved in DMSO (approximately 1 ml per 300 mg of product). The DMSO solution is filtered, analyzed by LCMS, and transferred for HPLC purification.

[0775] The purification is performed using Agilent 1260 Infinity systems equipped with DAD and a mass-detector. A Waters Sunfire C18 OBD Prep Column, 100 A, 5 pm, 19 mm x 100 mm with a SunFire C18 Prep Guard Cartridge, 100 A, 10 pm, 19 mm x 10 mm is used. Deionized Water (phase A) and HPLC-grade Methanol or Acetonitrile (phase B) are used as the eluent. In some cases, ammonia or TFA is used as an additive to improve the separation of the products. In these cases, free bases and TFA salts of the products are formed, respectively.

[0776] General Procedure 2DIPEA

[0777] NMP, 1500, 16 tl

[0778]

[0779] Key intermediate 2 A B The key intermediate 2 (1 eq.), Amine A (2 eq.), and DIPEA (typically 5 eq.) are mixed in dry NMP (approximately 0.7 ml per 100 mg of product). If a salt of any reagent is used, an additional amount of DIPEA is added to the reaction mixture to convert the reagent to its base form. The mixture is sealed and stirred at 150°C for 16 hours. The mixture is cooled, and the solvent is evaporated under reduced pressure. The residue is dissolved in DMSO (approximately 1 ml per 100 mg of product). The solution is filtered, analyzed by LCMS, and transferred for HPLC purification. The purification is performed as described in general procedure 1.

[0780] General Procedure 3

[0781]

[0782] Key Intermediate 3 A B

[0783] The key intermediate 3 (1 eq.), Acid A (1.2 eq.), EDC (1.3 eq.), HOAt (1 eq), and DIPEA (2.5 eq.) are mixed in DMSO (approximately 0.7 ml per 100 mg of product). If a salt of any reagent is used, an additional amount of DIPEA is added to the reaction mixture to convert the reagent to its base form. The mixture is sealed and stirred at ambient temperature for 18 hours. The solution is filtered, analyzed by LCMS, and transferred for HPLC purification. The purification is performed as described in general procedure 1.General Procedure 4

[0784]

[0785] Key intermediate 3 A B

[0786] The key intermediate 3 (1 eq.) and DIPEA (2.5 eq.) are mixed in dry MeCN (approximately 0.7 ml per 100 mg of product), and Reagent A (1 eq.) is added in one portion. The reaction mixture is sealed and stirred at 60°C for 16 hours. The mixture is cooled to ambient temperature, and the solvent is evaporated under reduced pressure. The residue is dissolved in DMSO (approximately 1 ml per 100 mg of product). The solution is filtered, analyzed by LCMS, and transferred for HPLC purification. The purification is performed as described in general procedure 1.

[0787] General Procedure 5

[0788]

[0789] Kay Intermediate 3 A B

[0790] The key intermediate 3 (1 eq.) and DIPEA (2.5 eq.) are mixed in dry MeCN (approximately 0.7 ml per 100 mg of product), and Reagent A (1 eq.) is added in one portion. The reaction mixture is sealed and stirred at 80°C for 16 hours. The mixture is cooled to ambient temperature, and the solvent is evaporated under reduced pressure. The residue is dissolved in DMSO (approximately 1 ml per 100 mg of product). The solution is filtered, analyzed by LCMS, and transferred for HPLC purification. The purification is performed as described in general procedure 1.

[0791]

[0792] 1-1

[0793] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-methoxyethan-l-one was obtained by General procedure 1 using 261.7 mg (1.195 mmol) of l-{[l l'-biphenyl]-4- yl}methanamine hydrochloride, 277.4 mg (1.206 mmol) of 2,6-dichloro-9-(propan-2-yl)-9H-purine, 382.5 mg (2.419 mmol) of 2-methoxy-l-(piperazin-l-yl)ethan-l-one, and 775.5 mg (6.005 mmol) of DIPEA. Yield 76.6 mg (13%), LCMS Purity: 100% (Calc. MW: 499.61, found pos.: 500.2).

[0794]

[0795] 1-349

[0796] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-(l,4-dioxan-2-yl)ethan-l- one was obtained by General procedure 3 using 39.2 mg (0.092 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 17.2 mg (0.118 mmol) of 2-(1,4-dioxan- 2-yl)acetic acid (, 19.5 mg (0.126 mmol) of EDC, 29.1 mg (0.225 mmol) of DIPEA, and 12.9 mg (0.095 mmol) of HOAt. Purified by HPLC on XBridge Prep C185MKM OBD (Waters) using gradient from 60% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 24.8 mg (50%), LCMS Purity: 100% (Calc. MW: 555.67, found pos.: 556.2).

[0797]

[0798] 1-350

[0799] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-(2-methyl-l,3-oxazol-4- yl)ethan-l-one was obtained by General procedure 3 using 41.9 mg (0.098 mmol) of N-({[1,1'- biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 18.6 mg (0.132 mmol) of 2- (2-methyl-l,3-oxazol-4-yl)acetic acid, 19.7 mg (0.127 mmol) of EDC, 29.3 mg (0.227 mmol) of DIPEA, and 13 mg (0.096 mmol) of HOAt. Purified by HPLC on XBridge Prep C185MKM OBD (Waters) using gradient from 60% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 30.8 mg (62%), LCMS Purity: 100% (Calc. MW: 550.66, found pos.: 551.2, 276.2).

[0800] Synthesis compound 1-351

[0801] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-(4-methyl-l,2-oxazol-3- yl)ethan-l-one was obtained by General procedure 3 using 35.6 mg (0.083 mmol) of N-({[1,1'- biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 19 mg (0.135 mmol) of 2-(4- methyl-l,2-oxazol-3-yl)acetic acid, 19.7 mg (0.127 mmol) of EDC,29.3 mg (0.227 mmol) of DIPEA, and 13 mg (0.096 mmol) of HOAt. Purified by HPLC on XBridge Prep C185MKM OBD (Waters) using gradient from 60% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 27.8 mg (56%), LCMS Purity: 100% (Calc. MW: 550.66, found pos.: 551.2).

[0802] Synthesis compound 1-352

[0803] 1-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-(methylsulfanyl)ethan-l- one was obtained by General procedure 1 using 41.4 mg (0.197 mmol) of 2-(methylsulfanyl)-l- (piperazin-1-yl)ethan-l-one hydrochloride, 34.7 mg (0.092 mmol) of N-({[l,l'-biphenyl]-4-yl}methyl)-2- chloro-9-(propan-2-yl)-9H-purin-6-amine, and 87.7 mg (0.679 mmol) of DIPEA. Purified by HPLC on XBridge Prep Phenyl 5MKM OBD using gradient from 40% to 65% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in the mixture of MeCN and water (vol% 95:5)). Yield 11.7 mg (23%), LCMS Purity: 100% (Calc. MW: 515.68, found pos.: 516.4)

[0804] Synthesis compound 1-353

[0805] N-({[l,l'-biphenyl]-4-yl}methyl)-2-{4-[(2S,4S)-4-fluoro-l-methylpyrrolidine-2-carbonyl]piperazin-l-yl}-9-(propan-2- yl)-9H-purin-6-amine was obtained by General procedure 3 using 37.4 mg (0.087 mmol) of N- ({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 21.1 mg (0.115 mmol) of (2S,4S)-4-fluoro-l-methylpyrrolidine-2-carboxylic acid hydrochloride, 19.5 mg (0.126 mmol) of EDC, 40.6 mg (0.314 mmol) of DIPEA, and 12.8 mg (0.094 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 65% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 21.3 mg (43%), LCMS Purity: 100% (Calc. MW: 556.68, found pos.: 279.2, 557.2).

[0806] Synthesis compound 1-354

[0807] 4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}-N-(3,3-difluorocyclobutyl)piperazine-l- carboxamide (Z9377899606) was obtained by General procedure 5 using 15 mg (0.113 mmol) of l,l-difluoro-3-isocyanatocyclobutane, 34 mg (0.08 mmol) of N-({[l,l'-biphenyl]-4-yl}methyl)- 2-(piperazin-l-yl)-9- (propan-2-yl)-9H-purin-6-amine, and 34.6 mg (0.268 mmol) of DIPEA. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 65% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 24.3 mg (49%), LCMS Purity: 100% (Calc. MW: 560.64, found pos.: 561.2, found neg.: 595.2, 559.2).

[0808]

[0809] 1-355

[0810] 4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}-N-(oxan-3-yl)piperazine-l-carboxamide was obtained by General procedure 5 using 14 mg (0.11 mmol) of 3-isocyanatooxane, 38 mg (0.089 mmol) of N-({[1,1'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, and 34.9 mg (0.27 mmol) of DIPEA. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 65% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 32.4 mg (65%), LCMS Purity: 100% (Calc. MW: 554.69, found pos.: 555.2, 278.2).

[0811]

[0812] 1-356

[0813] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-(l,3-thiazol-4-yl)ethan-l- one was obtained by General procedure 3 using 37.2 mg (0.087 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 16.2 mg (0.113 mmol) of 2-(1,3-thiazol- 4-yl)acetic acid, 19.6 mg (0.126 mmol) of EDC, 29.2 mg (0.226 mmol) of DIPEA, and 12.9 mg (0.095 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 60% to 100% of phase B in phase A (A -0.1% NH in water, B - 0.1% NH in methanol). Yield 25.2 mg (50%), LCMS Purity: 100% (Calc. MW: 552.7, found pos.: 553.2, 277.2).

[0814]

[0815] 1-357

[0816] N-({[l,l'-biphenyl]-4-yl}methyl)-2-{4-[(2S,4S)-4-fluoro-l-methylpyrrolidine-2-carbonyl]piperazin-l-yl}-9-(propan-2- yl)-9H-purin-6-amine was obtained by General procedure 3 using 37.4 mg (0.087 mmol) of N- ({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 21.1 mg (0.115 mmol) of (2S,4S)-4-fluoro-l-methylpyrrolidine-2-carboxylic acid hydrochloride, 19.5 mg (0.126 mmol) of EDC, 40.6 mg (0.314 mmol) of DIPEA, and 12.8 mg (0.094 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 65% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 21.3 mg (43%), LCMS Purity: 100% (Calc. MW: 556.68, found pos.: 279.2, 557.2)

[0817]

[0818] 1-358

[0819] 2-[4-(oxolane-2-carbonyl)piperazin-l-yl]-9-(propan-2-yl)-N-{[6-(lH-pyrazol-l-yl)pyridin-3-yl]methyl}-9H-purin-6-amine was obtained by Genaral procedure 1using 31 mg (0.178 mmol) of l-[6-(lH-pyrazol-l-yl)pyridin- 3-yl]methanamine, 43 mg (0.187 mmol) of 2,6-dichloro-9-(propan-2-yl)-9H-purine, 70 mg (0.38 mmol) of l-(oxolane-2-carbonyl)piperazine, and 100 mg (0.774 mmol) of DIPEA. Purified by HPLC on XBridge Prep Phenyl 5MKM OBD using gradient from 40% to 90% of phase B in phase A (A - 0.1% HCI in water, B - 0.1% HCI in the mixture of MeCN and water (vol% 95:5)). Yield 24.7 mg (25%), LCMS Purity: 97.91% (Calc. MW: 516.6, found pos.: 517.2, 539.2, 259.2).

[0820] Synthesis compound 1-359

[0821] 1-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}-3-(dimethylamino)piperidine-3-carboxamide was obtained by General procedure 1 using 49.4 mg (0.203 mmol) of 3- (dimethylamino)piperidine-3-carboxamide dihydrochloride, 33 mg (0.087 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-chloro-9-(propan-2-yl)-9H-purin-6-amine, and 113.4 mg (0.878 mmol) of DIPEA. Purified by HPLC on XBridge BEH C18 5um 130A (Waters) using gradient from 60% to 90% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 18.7 mg (37%), LCMS Purity: 100% (Calc. MW: 512.65, found pos.: 513.2, 257.2, 234.6).

[0822] Synthesis compound 1-360

[0823] N-({[l,l'-biphenyl]-4-yl}methyl)-2-[3-(morpholine-4-carbonyl)piperidin-l-yl]-9-(propan-2-yl)-9H-purin-6-amine was obtained by General procedure 1 using 40.7 mg (0.174 mmol) of 4-(piperidine-3- carbonyl)morpholine hydrochloride, 35.6 mg (0.094 mmol) of N-({[l,l'-biphenyl]-4-yl}methyl)-2-chloro- 9-(propan-2-yl)-9H-purin-6-amine, and 83.8 mg (0.649 mmol) of DIPEA. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 40% to 65% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in the mixture of MeCN and water (vol% 95:5)). Yield 21 mg (42%), LCMS Purity: 100% (Calc. MW: 539.67, found pos.: 540.2).

[0824] Synthesis compound 1-361

[0825] 2-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}-octahydropyrazino[l,2-c][l,3]oxazin-6-one; trifluoroacetic acid was obtained by General procedure 1 using 36.1 mg (0.188 mmol) of octahydropyrazino[l,2-c][l,3]oxazin-6-one hydrochloride, 37.2 mg (0.098 mmol) of N-({[1,1'- biphenyl]-4-yl}methyl)-2-chloro-9-(propan-2-yl)-9H-purin-6-amine, and 90.8 mg (0.703 mmol) of DIPEA. Purified by HPLC on Chromatorex 18 SMB 100-5T (Waters) using gradient from 25% to 40% of phase B in phase A (A - 0.1% trifluoroacetic acid inwater, B - 0.1% trifluoroacetic acid in the mixture of MeCN and water (vol% 95:5)). Yield 4.7 mg (9%), LCMS Purity: 95.24% (Calc. MW: 611.62, found pos.: 498.2).

[0826] Synthesis compound 1-362

[0827] 7-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}-8a-methyl-hexahydro-lH-[l,3]oxazolo[3,4- a]pyrazin-3-one; trifluoroacetic acid was obtained by General procedure 1 using 33.6 mg (0.215 mmol) of 8a-methyl-hexahydro-lH-[l,3]oxazolo[3,4-a]pyrazin-3-one, 36.1 mg (0.096 mmol) of N-({[1,1'- biphenyl]-4-yl}methyl)-2-chloro-9-(propan-2-yl)-9H-purin-6-amine, and 64.9 mg (0.503 mmol) of DIPEA. Purified by HPLC on Chromatorex 18 SMB 100-5T (Waters) using gradient from 30% to 55% of phase B in phase A (A - 0.1% trifluoroacetic acid in water, B - 0.1% trifluoroacetic acid in the mixture of MeCN and water (vol% 95:5)). Yield 5.2 mg (10%), LCMS Purity: 100% (Calc. MW: 611.62, found pos.: 498.2, found neg.: 376.2, 496.2).

[0828] Synthesis compound 1-363

[0829] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-methylpropan-l-one was obtained by General procedure 1 using 40.4 mg (0.21 mmol) of 2-methyl-l-(piperazin-l- yl)propan-l-one hydrochloride, 34.2 mg (0.091 mmol) of N-({[l,l'-biphenyl]-4-yl}methyl)-2-chloro-9- (propan-2-yl)-9H-purin-6-amine, and 90.8 mg (0.703 mmol) of DIPEA. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 40% to 65% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in the mixture of MeCN and water (vol% 95:5)). Yield 14.7 mg (29%), LCMS Purity: 100% (Calc. MW: 497.64, found pos.: 498.4, 520.2, found neg.: 496.2).

[0830] Synthesis compound 1-364

[0831] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-(oxetan-3-yl)ethan-l-one was obtained by General procedure 3 using 38.7 mg (0.091 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 16 mg (0.131 mmol) of lithium(l+) 2-(oxetan-3-yl)acetate, 20.7 mg (0.133 mmol) of EDC, 30.7 mg (0.238 mmol) of DIPEA, 13.6 mg (0.1 mmol) of HOAt, and 14.3 mg (0.104 mmol) of triethylamine hydrochloride. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 50% to 90% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 12.6 mg (25%), LCMS Purity: 90.76% (Calc. MW: 525.65, found pos.: 526.4, found neg.: 524).

[0832]

[0833] 1-365

[0834] l-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}-3-methylpyrrolidine-3-carboxamide was obtained by General procedure 1 using 29.5 mg (0.23 mmol) of 3-methylpyrrolidine-3- carboxamide, 37.4 mg (0.099 mmol) of N-({[l,l'-biphenyl]-4-yl}methyl)-2-chloro-9-(propan-2-yl)-9H- purin-6-amine, and 68.8 mg (0.533 mmol) of DIPEA. Purified by HPLC on XBridge Prep Phenyl 5MKM OBD using gradient from 60% to 90% of phase B in phase A (A - 0.1% NH in water, B -0.1% NH in methanol). Yield 13.5 mg (27%), LCMS Purity: 100% (Calc. MW: 469.58, found pos.: 470.2).

[0835] Synthesis compound 1-366

[0836] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-(l,2,3-thiadiazol-5- yl)ethan-l-one (Z9377899325) was obtained by General procedure 3 using 39.3 mg (0.092 mmol) of N-({[1,1'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 17.6 mg (0.122 mmol) of 2- (l,2,3-thiadiazol-5-yl)acetic acid, 14.7 mg (0.095 mmol) of EDC, 29.2 mg (0.226 mmol) of DIPEA, and 12.9 mg (0.095 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 40% to 65% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in the mixture of MeCN and water (vol% 95:5)). Yield 17.7 mg (35%), LCMS Purity: 100% (Calc. MW: 553.68, found pos.: 554.2, found neg.: 588, 552)

[0837]

[0838] 1-367

[0839] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-(2-methyl-l,3-dioxolan-2- yl)ethan-l-one was obtained by General procedure 3 using 40.5 mg (0.095 mmol) of N-({[1,1'- biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 15.9 mg (0.109 mmol) of 2- (2-methyl-l,3-dioxolan-2-yl)acetic acid, 19.5 mg (0.126 mmol) of EDC, 29.1 mg (0.225 mmol) of DIPEA, and 12.9 mg (0.095 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 65% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 33.1 mg (66%), LCMS Purity: 100% (Calc. MW: 555.67, found pos.: 556.2).

[0840]

[0841] 1-368

[0842] N-({[l,l'-biphenyl]-4-yl}methyl)-2-{4-[(2R)-l-methylpyrrolidine-2-carbonyl]piperazin-l-yl}-9-(propan-2-yl)-9H-purin-6- amine was obtained by General procedure 3 using 39.6 mg (0.093 mmol) of N-({[1,1'- biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 15.1 mg (0.117mmol) of (2R)-l-methylpyrrolidine-2-carboxylic acid, 20.2 mg (0.13 mmol) of EDC, 30 mg (0.232 mmol) of DIPEA, and 13.3 mg (0.098 mmol) of HOAt. Purified by HPLC on XBridge Prep C185MKM OBD (Waters) using gradient from 65% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 21 mg (42%), LCMS Purity: 100% (Calc. MW: 538.69, found pos.: 270.2, 539.4, 167.2).

[0843] Synthesis compound 1-369

[0844] N-({[l,l'-biphenyl]-4-yl}methyl)-2-[4-(oxetane-2-carbonyl)piperazin-l-yl]-9-(propan-2-yl)-9H-purin-6-amine was obtained by General procedure 3 using 41.1 mg (0.096 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 12.6 mg (0.123 mmol) of oxetane-2- carboxylic acid, 21.2 mg (0.137 mmol) of EDC, 31.6 mg (0.245 mmol) of DIPEA, and 14 mg (0.103 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 60% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 24.9 mg (50%), LCMS Purity: 100% (Calc. MW: 511.62, found pos.: 512.2).

[0845] Synthesis compound 1-370

[0846] 1-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-(l,2-thiazol-4-yl)ethan-l- one was obtained by General procedure 3 using 35.9 mg (0.084 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 13.9 mg (0.097 mmol) of 2-(1,2-thiazol- 4-yl)acetic acid, 14.7 mg (0.095 mmol) of EDC, 29.2 mg (0.226 mmol) of DIPEA, and 12.9 mg (0.095 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 35% to 60% of phase B in phase A (A -0.1% NH in water, B - 0.1% NH in the mixture of MeCN and water (vol% 95:5)). Yield 23.8 mg (48%), LCMS Purity: 100% (Calc. MW: 552.7, found pos.: 553.2, 277.2).

[0847] Synthesis compound 1-371

[0848] 2-methoxy-l-[4-(6-{[(5-phenylpyrazin-2-yl)methyl]amino}-9-(propan-2-yl)-9H-purin-2-yl)piperazin-l-yl]ethan-l-one was obtained by General procedure 2 using 32 mg (0.173 mmol) of l-(5-phenylpyrazin-2- yl)methanamine, 43 mg (0.187 mmol) of 2,6-dichloro-9-(propan-2-yl)-9H-purine, 61.9 mg (0.392 mmol) of 2-methoxy-l-(piperazin-l-yl)ethan-l-one, and 103 mg (0.798 mmol) of DIPEA. Purified by HPLC on XBridge BEH C18 5um 130A (Waters) using gradient from 45% to 70% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol).Yield 29.8 mg (30%), LCMS Purity: 100% (Calc. MW: 501.58, found pos.: 502.4, found neg.: 500.2).

[0849] Synthesis compound 1-372

[0850] N-({[l,l'-biphenyl]-4-yl}methyl)-2-{4-[(oxetan-3-yl)methanesulfonyl]piperazin-l-yl}-9-(propan-2-yl)-9H-purin-6-amine was obtained by General procedure 4 using 38.1 mg (0.089 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 23.4 mg (0.152 mmol) of (oxetan-3-yl)methanesulfonyl fluoride, and 28.7 mg (0.222 mmol) of DIPEA. Purified by HPLC on Chromatorex 18 SMB 100-5T (Waters) using gradient from 45% to 70% of phase B in phase A (A - 0.1% NH HCO in water, B - 0.1% NH HCO in the mixture of MeCN and water (vol% 95:5)). Yield 22.1 mg (44%), LCMS Purity: 100% (Calc. MW: 561.7, found pos.: 562.4, found neg.: 560.4).

[0851] Synthesis compound 1-373

[0852] (3R,5S)-5-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazine-l-carbonyl)-3- fluoropyrrolidin-2-one was obtained by General procedure 3 using 36.1 mg (0.084 mmol) of N- ({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 14 mg (0.095 mmol) of (2S,4R)-4-fluoro-5-oxopyrrolidine-2-carboxylic acid, 19.5 mg (0.126 mmol) of EDC, 29 mg (0.225 mmol) of DIPEA, and 12.8 mg (0.094 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 30% to 55% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in the mixture of MeCN and water (vol% 95:5)). Yield 14.3 mg (29%), LCMS Purity: 100% (Calc. MW: 556.64, found pos.: 557.2, found neg.: 555.2, 591).

[0853] Synthesis compound 1-374

[0854] 4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}-6-(propan-2-yl)piperazin-2-one was obtained by General procedure 1 using 26 mg (0.183 mmol) of 6-(propan-2-yl)piperazin-2- one, 40 mg (0.106 mmol) of N-({[1, 1'-biphenyl]-4-yl}methyl)-2-chloro-9-(propan-2-yl)-9H-purin-6-amine, and 80.1 mg (0.62 mmol) of DIPEA. Purified by HPLC on XBridge Prep C18 5MKM OBD using gradient from 35% to 60% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in the mixture of MeCN and water (vol% 95:5)). Yield 9.2 mg (18%), LCMS Purity: 100% (Calc. MW: 483.61, found pos.: 484.2).

[0855] Synthesis compound 1-3752-methoxy-l-{4-[9-(propan-2-yl)-6-({[4-(l,3-thiazol-2-yl)phenyl]methyl}amino)-9H-purin-2-yl]piperazin-l-yl}ethan-l- one was obtained by General procedure 2 using 40 mg (0.21 mmol) of l-[4-(l,3-thiazol-2- yl)phenyl]methanamine, 47 mg (0.204 mmol) of 2,6-dichloro-9-(propan-2-yl)-9H-purine, 61 mg (0.386 mmol) of 2-methoxy-l-(piperazin-l-yl)ethan-l-one, and 102 mg (0.79 mmol) of DIPEA. Purified by HPLC on XBridge BEH C18 5um 130A using gradient from 20% to 45% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in the mixture of MeCN and water (vol% 95:5)). Yield 29.3 mg (29%), LCMS Purity: 100% (Calc. MW: 506.63, found pos.: 507.2, 254.2, found neg.: 505).

[0856] Synthesis compound 1-376

[0857] N-({[l,l'-biphenyl]-4-yl}methyl)-2-{4-[(oxolan-3-yl)methanesulfonyl]piperazin-l-yl}-9-(propan-2-yl)-9H-purin-6-amine was obtained by General procedure 4 using 36.7 mg (0.086 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 22.4 mg (0.133 mmol) of (oxolan-3-yl)methanesulfonyl fluoride, and 28 mg (0.217 mmol) of DIPEA. Purified by HPLC on XBridge Prep Phenyl 5MKM OBD using gradient from 40% to 65% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in the mixture of MeCN and water (vol% 95:5)). Yield 10.5 mg (21%), LCMS Purity: 100% (Calc. MW: 575.73, found pos.: 576.2, found neg.: 574).

[0858] Synthesis compound 1-377

[0859] (3S,5S)-5-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazine-l-carbonyl)-3- fluoropyrrolidin-2-one was obtained by General procedure 3 using 35.4 mg (0.083 mmol) of N- ({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 19.3 mg (0.131 mmol) of (2S,4S)-4-fluoro-5-oxopyrrolidine-2-carboxylic acid, 19.5 mg (0.126 mmol) of EDC, 29 mg (0.225 mmol) of DIPEA, and 12.8 mg (0.094 mmol) of HOAt. Purified by HPLC on XBridge Prep Phenyl 5MKM OBD using gradient from 30% to 45% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in the mixture of MeCN and water (vol% 95:5)). Yield 18.2 mg (36%), LCMS Purity: 100% (Calc. MW: 556.64, found pos.: 557.4, found neg.: 555.2)

[0860] Synthesis compound 1-378

[0861] N-({[l,l'-biphenyl]-4-yl}methyl)-2-[4-(oxolane-2-carbonyl)piperazin-l-yl]-9-(propan-2-yl)-9H-purin-6-amine was obtained by General procedure 1 using 32.4 mg (0.176 mmol) of l-(oxolane-2- carbonyl)piperazine, 34.3 mg (0.091 mmol) of N-({[l,l'-biphenyl]-4-yl}methyl)-2-chloro-9-(propan-2- yl)-9H-purin-6-amine, and 61.4 mg (0.475 mmol) of DIPEA. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 35% to 60% of phase B in phase A (A -0.1% NH in water, B - 0.1% NH in the mixture of MeCN and water (vol% 95:5)). Yield 12 mg (24%), LCMS Purity: 100% (Calc. MW: 525.65, found pos.: 526.2).

[0862] Synthesis compound 1-379

[0863] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-(l,2-oxazol-4-yl)ethan-l- one was obtained by General procedure 3 using 37.5 mg (0.088 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 19.1 mg (0.15 mmol) of 2-(l,2-oxazol-4- yl)acetic acid, 15.2 mg (0.098 mmol) of EDC, 30.1 mg (0.233 mmol) of DIPEA, and 13.3 mg (0.098 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 35% to 60% of phase B in phase A (A -0.1% NH in water, B - 0.1% NH in the mixture of MeCN and water (vol% 95:5)). Yield 20 mg (40%), LCMS Purity: 100% (Calc. MW: 536.63, found pos.: 537.2, found neg.: 535.2).

[0864] Synthesis compound 1-380

[0865] N-[(l-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperidin-3-yl)methyl]acetamide was obtained by General procedure 1 using 32.6 mg (0.209 mmol) of N-[(piperidin-3- yl)methyl]acetamide, 40.5 mg (0.107 mmol) of N-({[l,l'-biphenyl]-4-yl}methyl)-2-chloro-9-(propan-2- yl)-9H-purin-6-amine, and 64.9 mg (0.503 mmol) of DIPEA. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 60% to 90% of phase B in phase A (A -0.1% NH in water, B - 0.1% NH in methanol). Yield 18.9 mg (38%), LCMS Purity: 100% (Calc. MW: 497.64, found pos.: 498.4, found neg.: 496.2).

[0866] Synthesis compound 1-381

[0867] 4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}-N-(2-chloropyridin-3-yl)piperazine-l- carboxamide was obtained by General procedure 5 using 32 mg (0.126 mmol) of 2,2,2- trifluoroethyl N-(2-chloropyridin-3-yl)carbamate, 37 mg (0.087 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, and 33.3 mg (0.258 mmol) of DIPEA. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 70% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 9.3 mg (19%), LCMS Purity: 100% (Calc. MW: 582.1, found pos.: 582.4, 291.8, found neg.: 580.4)

[0868]

[0869] 1-382

[0870] 4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}-N-(3,5-difluorophenyl)piperazine-l- carboxamide was obtained by General procedure 5 using 17 mg (0.11 mmol) of l,3-difluoro-5- isocyanatobenzene, 34 mg (0.08 mmol) of N-({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan- 2-yl)-9H-purin-6-amine, and 33.2 mg (0.257 mmol) of DIPEA. Purified by HPLC on XBridge Prep C185MKM OBD (Waters) using gradient from 70% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 8.6 mg (17%), LCMS Purity: 97.08% (Calc. MW: 582.65, found pos.: 583.4, found neg.: 581.4).

[0871]

[0872] 1-383

[0873] 4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}-N-(3-methyl-l,2-oxazol-5-yl)piperazine-l- carboxamide was obtained by General procedure 5 using 26 mg (0.116 mmol) of 2,2,2- trifluoroethyl N-(3-methyl-l,2-oxazol-5-yl)carbamate, 37 mg (0.087 mmol) of N-({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, and 35.1 mg (0.272 mmol) of DIPEA. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 65% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 6.5 mg (13%), LCMS Purity: 97.25% (Calc. MW: 551.64, found pos.: 552.2, 276.6, found neg.: 550.2).

[0874]

[0875] 1-384

[0876] 4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}-N-(5-methyl-l,2-oxazol-3-yl)piperazine-l- carboxamide was obtained by General procedure 5 using 22 mg (0.098 mmol) of 2,2,2- trifluoroethyl N-(5-methyl-l,2-oxazol-3-yl)carbamate, 36 mg (0.084 mmol) of N-({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, and 35.1 mg (0.272 mmol) of DIPEA. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 65% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 5.9 mg (12%), LCMS Purity: 92.96% (Calc. MW: 551.64, found pos.: 552.2, 276.6, found neg.: 550.2).

[0877] Synthesis compound 1-385

[0878] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-(thietan-3-yl)ethan-l-one was obtained by General procedure 3 using 40.3 mg (0.094 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 17.4 mg (0.132 mmol) of 2-(thietan-3-yl)acetic acid, 20 mg (0.129 mmol) of EDC, 29.8 mg (0.231 mmol) of DIPEA, and13.2 mg (0.097 mmol) of HOAt. Purified by HPLC on XBridge BEH C18 5um 130A (Waters) using gradient from 50% to 75% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in the mixture of MeCN and water (vol% 95:5)). Yield 9.7 mg (19%), LCMS Purity: 100% (Calc. MW: 541.71, found pos.: 542.2).

[0879] Synthesis compound 1-386

[0880] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-hydroxy-2-(l- hydroxycyclobutyl)ethan-l-one was obtained by General procedure 3 using 40.7 mg (0.095 mmol) of N-({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 19.2 mg (0.131 mmol) of 2-hydroxy-2-(l-hydroxycyclobutyl)acetic acid, 19.5 mg (0.126 mmol) of EDC, 29.1 mg (0.225 mmol) of DIPEA, and 12.9 mg (0.095 mmol) of HOAt. Purified by HPLC on XBridge Prep C185MKM OBD (Waters) using gradient from 65% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 11.9 mg (24%), LCMS Purity: 100% (Calc. MW: 555.67, found pos.: 556.2).

[0881] Synthesis compound 1-387

[0882] N-({[l,l'-biphenyl]-4-yl}methyl)-2-{4-[(lS,2R,4R)-7-oxabicyclo[2.2.1]heptane-2-carbonyl]piperazin-l-yl}-9-(propan-2- yl)-9H-purin-6-amine was obtained by General procedure 3 using 34.9 mg (0.082 mmol) of N- ({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 17.7 mg (0.125 mmol) of (lS,2R,4R)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid, 19.7 mg (0.127 mmol) of EDC, 29.3 mg (0.227 mmol) of DIPEA, and 12.9 mg (0.095 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 65% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 10.2 mg (20%), LCMS Purity: 99% (Calc. MW: 551.68, found pos.: 552.2).

[0883] Synthesis compound 1-388

[0884] rac-(4aR,8aR)-6-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}-decahydropyrido[4,3- d]pyrimidin-2-one was obtained by General procedure 1 using 40.2 mg (0.21 mmol) of rac- (4aR,8aS)-decahydropyrido[4,3-d]pyrimidin-2-one hydrochloride, 40.2 mg (0.106 mmol) of N-({[1,1'- biphenyl]-4-yl}methyl)-2-chloro-9-(propan-2-yl)-9H-purin-6-amine, and 91 mg (0.705 mmol) of DIPEA. Yield 3.1 mg (6%), LCMS Purity: 97.89% (Calc. MW: 496.61, found pos.: 497.2, 249.2), NMR Purity: 95%.

[0885] Synthesis compound 1-3894-[2-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-oxoethyl]oxolan-2-one; trifluoroacetic acid was obtained by General procedure 3 using 36 mg (0.084 mmol) of

[0886]

[0887] biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 19.2 mg (0.133 mmol) of 2- (5-oxooxolan-3-yl)acetic acid), 19.6 mg (0.126 mmol) of EDC, 29.2 mg (0.226 mmol) of DIPEA, and 12.9 mg (0.095 mmol) of HOAt. Purified by HPLC on Chromatorex 18 SMB 100-5T (Waters) using gradient from 25% to 40% of phase B in phase A (A - 0.1% trifluoroacetic acid in water, B - 0.1% trifluoroacetic acid in the mixture of MeCN and water (vol% 95:5)). Yield 1.1 mg (2%), LCMS Purity: 98.74% (Calc. MW: 667.68, found pos.: 554.4, found neg.: 552.4, 553).

[0888] Synthesis compound 1-390

[0889] 2-[4-(oxolane-2-carbonyl)piperazin-l-yl]-9-(propan-2-yl)-N-{[4-(lH-pyrazol-5-yl)phenyl]methyl}-9H-purin-6-amine was obtained by General procedure 1 using 46 mg (0.188 mmol) of l-[4-(lH-pyrazol-5- yl)phenyl]methanamine dihydrochloride, 42 mg (0.183 mmol) of 2,6-dichloro-9-(propan-2-yl)-9H-purine, 72 mg (0.391 mmol) of l-(oxolane-2-carbonyl)piperazine, and 150.3 mg (1.164 mmol) of DIPEA. Purified by HPLC on XBridge Prep C185MKM OBD using gradient from 50% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 36 mg (36%), LCMS Purity: 95.05% (Calc. MW: 515.61, found pos.: 516.2, 258.6, 418.2, found neg.: 514.2).

[0890] Synthesis compound 1-391

[0891] l-[2-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-oxoethyl]-3-methylurea was obtained by General procedure 3 using 39 mg (0.091 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 15 mg (0.114 mmol) of 2-[(methylcarbamoyl)amino]acetic acid, 20 mg (0.129 mmol) of EDC, 29.8 mg (0.231 mmol) of DIPEA, and 15.1 mg (0.111 mmol) of HOAt. Purified by HPLC on XBridge Prep C185MKM OBD (Waters) using gradient from 60% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 8.3 mg (17%), LCMS Purity: 98.8% (Calc. MW: 541.65, found pos.: 542.4, 271.6, 243, found neg.: 586.4, 540.2).

[0892] Synthesis compound 1-392

[0893] N-[2-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2- oxoethyl]cyclopropanecarboxamide was obtained by General procedure 3 using 39 mg (0.091 mmol) of N-({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 13 mg (0.091 mmol) of 2-(cyclopropylformamido)acetic acid, 19.6 mg (0.126 mmol) of EDC, 29.2 mg (0.226 mmol) of DIPEA, and 14.8 mg (0.109 mmol) of HOAt. Purified by HPLC on XBridge Prep C185MKM OBD (Waters) using gradient from 60% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 4.8 mg (10%), NMR Purity: 91%.

[0894] Synthesis compound 1-393

[0895] (3R)-l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-4-fluoro-3- hydroxybutan-l-one was obtained by General procedure 3 using 37 mg (0.087 mmol) of N- ({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 15 mg (0.123 mmol) of (3R)-4-fluoro-3-hydroxybutanoic acid, 20.4 mg (0.131 mmol) of EDC, 30.4 mg (0.235 mmol) of DIPEA, and 15.4 mg (0.113 mmol) of HOAt. Purified by HPLC on XBridge Prep Phenyl 5MKM OBD using gradient from 60% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 29.6 mg (59%), LCMS Purity: 100% (Calc. MW: 531.63, found pos.: 532.2, found neg.: 576, 566, 530).

[0896] Synthesis compound 1-394

[0897] 2-[4-(oxolane-2-carbonyl)piperazin-l-yl]-9-(propan-2-yl)-N-{[6-(lH-pyrazol-l-yl)pyridin-3-yl]methyl}-9H-purin-6-amine was obtained by General procedure 1 using 31 mg (0.178 mmol) of l-[6-(lH-pyrazol-l-yl)pyridin- 3-yl]methanamine, 43 mg (0.187 mmol) of 2,6-dichloro-9-(propan-2-yl)-9H-purine, 70 mg (0.38 mmol) of 1-(oxolane-2-carbonyl)piperazine, and 100 mg (0.774 mmol) of DIPEA. Purified by HPLC on XBridge Prep Phenyl 5MKM OBD using gradient from 40% to 90% of phase B in phase A (A - 0.1% HCI in water, B - 0.1% HCI in the mixture of MeCN and water (vol% 95:5)). Yield 24.7 mg (25%), LCMS Purity: 97.91% (Calc. MW: 516.6, found pos.: 517.2, 539.2, 259.2).

[0898] Synthesis compound 1-395

[0899] 2-[4-(oxolane-2-carbonyl)piperazin-l-yl]-9-(propan-2-yl)-N-{[4-(l,3-thiazol-5-yl)phenyl]methyl}-9H-purin-6-amine was obtained by General procedure 1 using 45 mg (0.172 mmol) of l-[4-(l,3-thiazol-5- yl)phenyl]methanamine dihydrochloride, 40 mg (0.174 mmol) of 2,6-dichloro-9-(propan-2-yl)-9H-purine, 69 mg (0.375 mmol) of l-(oxolane-2-carbonyl)piperazine, and 145.5 mg (1.127 mmol) of DIPEA. Purified by HPLC on Chromatorex PHENYL SMB100-5 (Waters) using gradient from 50% to 100% of phase B in phase A (A - 0.1% HCI in water, B - 0.1%HCI in the mixture of MeCN and water (vol% 95:5)). Yield 37.7 mg (38%), LCMS Purity: 100% (Calc. MW: 532.66, found pos.: 533.2, 267.2).

[0900] Synthesis compound 1-396

[0901] 1-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-hydroxy-3- methoxypropan-l-one was obtained by General procedure 3 using 43 mg (0.101 mmol) of N- ({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 13 mg (0.092 mmol) of sodium 2-hydroxy-3-methoxypropanoate, 20.5 mg (0.132 mmol) of EDC, 30.5 mg (0.236 mmol) of DIPEA, 15.4 mg (0.113 mmol) of HOAt, and 14.2 mg (0.104 mmol) of triethylamine hydrochloride. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 60% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 17.8 mg (36%), LCMS Purity: 90.89% (Calc. MW: 529.63, found pos.: 530.2).

[0902] Synthesis compound 1-397

[0903] 3-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-3-oxopropanamide was obtained by General procedure 3 using 43 mg (0.101 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 19 mg (0.135 mmol) of potassium 2-carbamoylacetate, 21.2 mg (0.137 mmol) of EDC, 31.5 mg (0.244 mmol) of DIPEA, 15.9 mg (0.117 mmol) of HOAt, and 14.7 mg (0.107 mmol) of triethylamine hydrochloride. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 50% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 6.2 mg (12%), NMR Purity: 91%.

[0904] Synthesis compound 1-398

[0905] N-({[l,l'-biphenyl]-4-yl}methyl)-2-{4-[(3S,5S)-5-methylmorpholine-3-carbonyl]piperazin-l-yl}-9-(propan-2-yl)-9H- purin-6-amine was obtained by General procedure 3 using 36 mg (0.084 mmol) of N-({[1,1'- biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 23 mg (0.127 mmol) of (3S,5S)-5-methylmorpholine-3-carboxylic acid hydrochloride, 19.6 mg (0.126 mmol) of EDC, 40.7 mg (0.315 mmol) of DIPEA, and 14.7 mg (0.108 mmol) of HOAt. Yield 35.2 mg (70%), LCMS Purity: 90.72%.

[0906]

[0907] 1-399

[0908] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-3-hydroxybutan-l-one was obtained by General procedure 3using 44 mg (0.103 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin- 1-yl)-9-(propan-2-yl)-9H-purin-6-amine, 14 mg (0.111 mmol) of sodium 3-hydroxybutanoate, 21.1 mg (0.136 mmol) of EDC, 31.4 mg (0.243 mmol) of DIPEA, 15.9 mg (0.117 mmol) of HOAt, and 14.7 mg (0.107 mmol) of triethylamine hydrochloride. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 60% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 33.6 mg (67%), LCMS Purity: 100% (Calc. MW: 513.64, found pos.: 514.2, found neg.: 512).

[0909] Synthesis compound 1-400

[0910] rac-2-{4-[(3R,5S)-l,5-dimethylpyrrolidine-3-carbonyl]piperazin-l-yl}-N-{[4-(l,3-oxazol-4-yl)phenyl]methyl}-9-(propan- 2-yl)-9H-purin-6-amine was obtained by General procedure 4 using 28.1 mg (0.154 mmol) of 4- bromo-l,3-oxazole hydrochloride, 74.2 mg (0.123 mmol) of rac-2-{4-[(3R,5S)-l,5-dimethylpyrrolidine-3- carbonyl]piperazin-l-yl}-9-(propan-2-yl)-N-{[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]methyl}-9H-purin-6-amine, 46.4 mg (0.438 mmol) of sodium carbonate, and 5.1 mg (0.006 mmol) of XPhos PdG3. Purified by HPLC on XBridge Prep Phenyl 5MKM OBD using gradient from 55% to 85% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 10.2 mg (16%), LCMS Purity: 99.08% (Calc. MW: 543.66, found pos.: 544.2, 272.6, found neg.: 256.8).

[0911] Synthesis compound 1-401

[0912] 2-[4-(oxolane-2-carbonyl)piperazin-l-yl]-9-(propan-2-yl)-N-{[4-(pyrimidin-5-yl)phenyl]methyl}-9H-purin-6-amine was obtained by General procedure 1 using 48 mg (0.187 mmol) of l-[4-(pyrimidin-5- yl)phenyl]methanamine dihydrochloride, 42 mg (0.183 mmol) of 2,6-dichloro-9-(propan-2-yl)-9H-purine, 65 mg (0.353 mmol) of l-(oxolane-2-carbonyl)piperazine, and 146.9 mg (1.137 mmol) of DIPEA. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 50% to 100% of phase B in phase A (A - 0.1% HCI in water, B - 0.1% HCI in the mixture of MeCN and water (vol% 95:5)). Yield 28.9 mg (29%), LCMS Purity: 97.91% (Calc. MW: 527.62, found pos.: 528.2, 264.8, found neg.: 526.2).

[0913] Synthesis compound 1-402

[0914] 2-[4-(oxolane-2-carbonyl)piperazin-l-yl]-9-(propan-2-yl)-N-{[4-(pyridin-4-yl)phenyl]methyl}-9H-purin-6-amine was obtained by General procedure 1 using 30 mg (0.163 mmol) of l-[4-(pyridin-4- yl)phenyl]methanamine, 41 mg (0.178 mmol) of 2,6-dichloro-9-(propan-2-yl)-9H-purine, 66 mg (0.358 mmol) of 1-(oxolane-2-carbonyl)piperazine, and 98.1 mg (0.76 mmol) of DIPEA. Purified byHPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 50% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol).

[0915] Yield 27 mg (27%), LCMS Purity: 100% (Calc. MW: 526.63, found pos.: 264.2, 527.2).

[0916] Synthesis compound 1-403

[0917] 1-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-(morpholin-4-yl)ethan-l- one was obtained by General procedure 3 using 34 mg (0.08 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 18 mg (0.099 mmol) of 2-(morpholin-4- yl)acetic acid hydrochloride, 19.6 mg (0.126 mmol) of EDC, 40.7 mg (0.315 mmol) of DIPEA, and 14.7 mg (0.108 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 65% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 14.1 mg (28%), LCMS Purity: 100% (Calc. MW: 554.69, found pos.: 278.2, 555.2, found neg.: 569).

[0918] Synthesis compound 1-404

[0919] 2-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazine-l-carbonyl)oxan-4-ol was obtained by General procedure 3 using 36 mg (0.084 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 14 mg (0.096 mmol) of 4-hydroxyoxane- 2-carboxylic acid, 19.5 mg (0.126 mmol) of EDC, 29.1 mg (0.225 mmol) of DIPEA, and 14.7 mg (0.108 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 50% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 10.4 mg (21%), LCMS Purity: 100% (Calc. MW: 555.67, found pos.: 556.4, 278.8, found neg.: 570, 553.8).

[0920] Synthesis compound 1-405

[0921] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-3-(morpholin-4-yl)propan-l- one was obtained by General procedure 3 using 35 mg (0.082 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 19 mg (0.097 mmol) of 3-(morpholin-4- yl)propanoic acid hydrochloride, 19.1 mg (0.123 mmol) of EDC, 39.7 mg (0.307 mmol) of DIPEA, and 14.4 mg (0.106 mmol) of HOAt. Purified by HPLC on XBridge Prep C185MKM OBD (Waters) using gradient from 65% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 26.8 mg (54%), LCMS Purity: 99% (Calc. MW: 568.71, found pos.: 285.2, 569.4, 470.2).

[0922]

[0923] 1-406

[0924] 4-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazine-l-carbonyl)pyrrolidin-2-one was obtained by General procedure 3 using 38 mg (0.089 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 18 mg (0.139 mmol) of 5-oxopyrrolidine-3-carboxylic acid, 20.2 mg (0.13 mmol) of EDC, 30 mg (0.232 mmol) of DIPEA, and 15.2 mg (0.112 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 65% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 15 mg (30%), LCMS Purity: 98.01% (Calc. MW: 538.64, found pos.: 539.2, 270.2, found neg.: 537).

[0925]

[0926] 1-407

[0927] 5-[2-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-oxoethyl]pyrrolidin-2- one was obtained by General procedure 3 using 35 mg (0.082 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 18 mg (0.126 mmol) of 2-(5-oxopyrrolidin-2-yl)acetic acid, 19.6 mg (0.126 mmol) of EDC, 29.2 mg (0.226 mmol) of DIPEA, and 14.8 mg (0.109 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 50% to 100% of phase B in phase A (A -0.1% NH in water, B - 0.1% NH in methanol). Yield 8 mg (16%), LCMS Purity: 100% (Calc. MW: 552.67, found neg.: 551.2).

[0928]

[0929] 1-408

[0930] 2-[2-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-oxoethoxy]acetamide was obtained by General procedure 3 using 39 mg (0.091 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 13 mg (0.098 mmol) of 2-(carbamoylmethoxy)acetic acid, 20 mg (0.129 mmol) of EDC, 29.8 mg (0.231 mmol) of DIPEA, and 15 mg (0.11 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 50% to 100% of phase B in phase A (A -0.1% NH in water, B - 0.1% NH in methanol). Yield 14.5 mg (29%), LCMS Purity: 97.01% (Calc. MW: 542.63, found pos.: 543.2, found neg.: 577, 587, 541).

[0931]

[0932] 1-409

[0933] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-hydroxy-2-(lH-imidazol- 4-yl)ethan-l-one was obtained by General procedure 3 using 36 mg (0.084 mmol) of N-({[1,1'- biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 18 mg (0.101mmol) of 2- hydroxy-2-(lH-imidazol-4-yl)acetic acid hydrochloride, 19.7 mg (0.127 mmol) of EDC, 41 mg (0.317 mmol) of DIPEA, and 14.8 mg (0.109 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 50% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 22 mg (44%), LCMS Purity: 97.62% (Calc. MW: 551.64, found pos.: 276.8, 552.2, 253.6, found neg.: 550.2).

[0934] Synthesis compound 1-410

[0935] N-({[l,l'-biphenyl]-4-yl}methyl)-2-[4-(4-methylmorpholine-2-carbonyl)piperazin- 1-yl]-9-(propan-2-yl)-9H-purin-6- amine was obtained by General procedure 3 using 42 mg (0.098 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 17 mg (0.094 mmol) of 4-methylmorpholine-2-carboxylic acid hydrochloride, 19.6 mg (0.126 mmol) of EDC, 40.7 mg (0.315 mmol) of DIPEA, and 14.7 mg (0.108 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 65% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 20.9 mg (42%), LCMS Purity: 100% (Calc. MW: 554.69, found pos.: 278.2, 555.4).

[0936] Synthesis compound 1-411

[0937] 2-[4-(oxolane-2-carbonyl)piperazin-l-yl]-N-[(5-phenylpyrazin-2-yl)methyl]-9-(propan-2-yl)-9H-purin-6-amine was obtained by General procedure 1 using 35 mg (0.189 mmol) of l-(5-phenylpyrazin-2- yl)methanamine, 41 mg (0.178 mmol) of 2,6-dichloro-9-(propan-2-yl)-9H-purine, 74 mg (0.402 mmol) of l-(oxolane-2-carbonyl)piperazine, and 97.9 mg (0.758 mmol) of DIPEA. Purified by HPLC on XBridge Prep C18 5MKM OBD using gradient from 50% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 14.4 mg (14%), LCMS Purity: 100% (Calc. MW: 527.62, found pos.: 528.2).

[0938] Synthesis compound 1-412

[0939] 2-[4-(oxolane-2-carbonyl)piperazin-l-yl]-9-(propan-2-yl)-N-{[4-(thiophen-2-yl)phenyl]methyl}-9H-purin-6-amine was obtained by General procedure 1 using 39 mg (0.206 mmol) of l-[4-(thiophen-2- yl)phenyl]methanamine, 43 mg (0.187 mmol) of 2,6-dichloro-9-(propan-2-yl)-9H-purine, 73 mg (0.396 mmol) of 1-(oxolane-2-carbonyl)piperazine, and 97.2 mg (0.753 mmol) of DIPEA. Purified by HPLC on XBridge Prep Phenyl 5MKM OBD using gradient from 65% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 42.1 mg (42%), LCMS Purity: 97.34% (Calc. MW: 531.67, found pos.: 532.2).

[0940]

[0941] 1-413

[0942] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-hydroxyethan-l-one was obtained by General procedure 3 using 42 mg (0.098 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 14 mg (0.184 mmol) of 2 -hydroxyacetic acid, 22.4 mg (0.144 mmol) of EDC, 33.2 mg (0.257 mmol) of DIPEA, and 16.8 mg (0.123 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 60% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 20.5 mg (41%), LCMS Purity: 100% (Calc. MW: 485.58, found pos.: 486.2, found neg.: 484, 248.6).

[0943]

[0944] 1-414

[0945] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-3-[(2-hydroxyethyl) (methyl)amino]propan-l-one was obtained by General procedure 3 using 36 mg (0.084 mmol) of N-({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 13 mg (0.088 mmol) of 3-[(2-hydroxyethyl)(methyl)amino]propanoic acid, 19.5 mg (0.126 mmol) of EDC, 29 mg (0.225 mmol) of DIPEA, and 14.7 mg (0.108 mmol) of HOAt. Purified by HPLC on XBridge Prep C185MKM OBD (Waters) using gradient from 65% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 21.5 mg (43%), LCMS Purity: 100% (Calc. MW: 556.7, found pos.: 279.2, 557.2, 470.2).

[0946]

[0947] 1-415

[0948] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-3-(dimethylamino)-2- hydroxypropan-l-one was obtained by General procedure 3 using 36 mg (0.084 mmol) of N- ({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 14 mg (0.105 mmol) of 3-(dimethylamino)-2-hydroxypropanoic acid, 20 mg (0.129 mmol) of EDC, 29.7 mg (0.23 mmol) of DIPEA, and 15 mg (0.11 mmol) of HOAt. Purified by HPLC on XBridge Prep C185MKM OBD (Waters) using gradient from 65% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 29.1 mg (58%), LCMS Purity: 100% (Calc. MW: 542.68, found pos.: 272.2, 543.4, 486.2, found neg.: 248.8).

[0949]

[0950] 1-416

[0951] l-[3-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-3-oxopropyl]azetidin-2- one was obtained by General procedure 3 using 36 mg (0.084 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 22 mg (0.133 mmol) of sodium 3-(2-oxoazetidin-l-yl)propanoate, 19.6 mg (0.126 mmol) of EDC, 29.2 mg (0.226 mmol) of DIPEA, 14.8 mg (0.109 mmol) of HOAt, and 13.6 mg (0.099 mmol) of triethylamine hydrochloride. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 50% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 23.9 mg (48%), LCMS Purity: 100% (Calc. MW: 552.67, found pos.: 553.2, found neg.: 551).

[0952] Synthesis compound 1-417

[0953] 2-[4-(oxolane-2-carbonyl)piperazin-l-yl]-9-(propan-2-yl)-N-{[4-(lH-l,2,4-triazol- 3-yl)phenyl]methyl}-9H-purin-6-amine was obtained by General procedure 1 using 40 mg (0.19 mmol) of l-[4-(lH-l,2,4-triazol-3- yl)phenyl]methanamine hydrochloride, 46 mg (0.2 mmol) of 2,6-dichloro-9-(propan-2-yl)-9H-purine, 70 mg (0.38 mmol) of l-(oxolane-2-carbonyl)piperazine, and 125 mg (0.968 mmol) of DIPEA. Purified by HPLC on XBridge Prep C18 5MKM OBD using gradient from 50% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 35 mg (35%), LCMS Purity: 100% (Calc. MW: 516.6, found pos.: 259.2, 517.2, 419.2, found neg.: 515, 551.2).

[0954] Synthesis compound 1-418

[0955] 2-[4-(oxolane-2-carbonyl)piperazin-l-yl]-9-(propan-2-yl)-N-{[4-(pyridin-2-yl)phenyl]methyl}-9H-purin-6-amine was obtained by General procedure 1 using 52 mg (0.203 mmol) of l-[4-(pyridin-2- yl)phenyl]methanamine dihydrochloride, 44 mg (0.191 mmol) of 2,6-dichloro-9-(propan-2-yl)-9H-purine, 69 mg (0.375 mmol) of l-(oxolane-2-carbonyl)piperazine, and 147.1 mg (1.139 mmol) of DIPEA. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 50% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 43.1 mg (43%), LCMS Purity: 100% (Calc. MW: 526.63, found pos.: 264.2, 527.4).

[0956] Synthesis compound 1-419

[0957] N-{[4-(l,3-oxazol-5-yl)phenyl]methyl}-2-[4-(oxolane-2-carbonyl)piperazin-l-yl]-9-(propan-2-yl)-9H-purin-6-amine was obtained by General procedure 1 using 48 mg (0.195 mmol) of l-[4-(l,3-oxazol-5- yl)phenyl]methanamine dihydrochloride, 44 mg (0.191 mmol) of 2,6-dichloro-9-(propan-2-yl)-9H-purine, 67 mg (0.364 mmol) of l-(oxolane-2-carbonyl)piperazine, and 150 mg (1.161 mmol) of DIPEA. Purified by HPLC on Chromatorex PHENYL SMB100-5 (Waters) using gradient from 50% to 100% of phase B in phase A (A - 0.1% HCI in water, B - 0.1%HCI in the mixture of MeCN and water (vol% 95:5)). Yield 17.5 mg (18%), LCMS Purity: 96.54% (Calc. MW: 516.6, found pos.: 517.2, found neg.: 515).

[0958]

[0959] 1-420

[0960] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-(oxolan-3-yloxy)ethan-l- one (was obtained by General procedure 3 using 37 mg (0.087 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 20 mg (0.137 mmol) of 2-(oxolan-3- yloxy)acetic acid, 19.5 mg (0.126 mmol) of EDC, 29.1 mg (0.225 mmol) of DIPEA, and 14.7 mg (0.108 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 60% to 100% of phase B in phase A (A -0.1% NH in water, B - 0.1% NH in methanol). Yield 17.9 mg (36%), LCMS Purity: 98.14% (Calc. MW: 555.67, found pos.: 556.2).

[0961] Synthesis compound 1-421

[0962] 2-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-N, N-dimethyl-2- oxoacetamide was obtained by General procedure 3 using 38 mg (0.089 mmol) of N-({[1,1'- biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 15 mg (0.128 mmol) of (dimethylcarbamoyl)formic acid, 20.6 mg (0.133 mmol) of EDC, 30.7 mg (0.238 mmol) of DIPEA, and 15.5 mg (0.114 mmol) of HOAt. Purified by HPLC on XBridge Prep C185MKM OBD (Waters) using gradient from 60% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 24.3 mg (49%), LCMS Purity: 100% (Calc. MW: 526.63, found pos.: 527.2, found neg.: 525).

[0963]

[0964] 1-422

[0965] 3-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazine-l-carbonyl)-l-methylpyrrolidin- 2-one was obtained by General procedure 3 using 40 mg (0.094 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 16 mg (0.112 mmol) of 1-methyl-2- oxopyrrolidine-3-carboxylic acid, 19.6 mg (0.126 mmol) of EDC, 29.2 mg (0.226 mmol) of DIPEA, and 14.8 mg (0.109 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 60% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 35.7 mg (71%), LCMS Purity: 100% (Calc. MW: 552.67, found pos.: 553.2).

[0966]

[0967] 1-4232-[4-(oxolane-2-carbonyl)piperazin-l-yl]-9-(propan-2-yl)-N-{[4-(pyridin-3-yl)phenyl]methyl}-9H-purin-6-amine was obtained by General procedure 1 using 46 mg (0.18 mmol) of l-[4-(pyridin-3- yl)phenyl]methanamine dihydrochloride, 42 mg (0.183 mmol) of 2,6-dichloro-9-(propan-2-yl)-9H-purine, 67 mg (0.364 mmol) of l-(oxolane-2-carbonyl)piperazine, and 147.1 mg (1.139 mmol) of DIPEA. Purified by HPLC on Chromatorex PHENYL SMB100-5 (Waters) using gradient from 50% to 100% of phase B in phase A (A - 0.1% HCI in water, B - 0.1% HCI in the mixture of MeCN and water (vol% 95:5)). Yield 36.1 mg (36%), LCMS Purity: 97.97% (Calc. MW: 526.63, found pos.: 264.2, 527.2, 243).

[0968] Synthesis compound 1-424

[0969] N-{[4-(furan-2-yl)phenyl]methyl}-2-[4-(oxolane-2-carbonyl)piperazin-l-yl]-9-(propan-2-yl)-9H-purin-6-amine was obtained by General procedure 1 using 39 mg (0.187 mmol) of l-[4-(furan-2- yl)phenyl]methanamine hydrochloride, 46 mg (0.2 mmol) of 2,6-dichloro-9-(propan-2-yl)-9H-purine, 67 mg (0.364 mmol) of 1-(oxolane-2-carbonyl)piperazine, and 125.2 mg (0.969 mmol) of DIPEA. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 60% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 30.7 mg (31%), LCMS Purity: 100% (Calc. MW: 515.61, found pos.: 516.2).

[0970] Synthesis compound 1-425

[0971] 2-[4-(oxolane-2-carbonyl)piperazin-l-yl]-9-(propan-2-yl)-N-{[4-(l,3-thiazol-2-yl)phenyl]methyl}-9H-purin-6-amine was obtained by General procedure 1 using 38 mg (0.2 mmol) of l-[4-(l,3-thiazol-2- yl)phenyl]methanamine, 41 mg (0.178 mmol) of 2,6-dichloro-9-(propan-2-yl)-9H-purine, 67 mg (0.364 mmol) of 1-(oxolane-2-carbonyl)piperazine, and 97 mg (0.751 mmol) of DIPEA. Purified by HPLC on XBridge Prep C185MKM OBD (Waters) using gradient from 50% to 100% of phase B in phase A (A - 0.1% HCI in water, B - 0.1% HCI in the mixture of MeCN and water (vol% 95:5)). Yield 34.2 mg (34%), LCMS Purity: 100% (Calc. MW: 532.66, found pos.: 533.2).

[0972] Synthesis compound 1-426

[0973] 1-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-(oxetan-2-yl)ethan-l-one was obtained by General procedure 3 using 40 mg (0.094 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)- 2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 13 mg (0.107 mmol) of lithium(l+) 2- (oxetan-2-yl)acetate, 20.7 mg (0.133 mmol) of EDC, 30.7 mg (0.238 mmol) of DIPEA, 15.5 mg (0.114 mmol) of HOAt, and 14.3 mg (0.104 mmol) oftriethylamine hydrochloride. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 60% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 23.5 mg (47%), LCMS Purity: 97.12% (Calc. MW: 525.65, found pos.: 526.2).

[0974] Synthesis compound 1-427

[0975] N-{[3-fluoro-4-(pyridin-4-yl)phenyl]methyl}-2-[4-(oxolane-2-carbonyl)piperazin-l-yl]-9-(propan-2-yl)-9H-purin-6-amine was obtained by General procedure 1 using 52 mg (0.19 mmol) of l-[3-fluoro-4-(pyridin-4- yl)phenyl]methanamine dihydrochloride, 41 mg (0.178 mmol) of 2,6-dichloro-9-(propan-2-yl)-9H-purine, 65 mg (0.353 mmol) of l-(oxolane-2-carbonyl)piperazine, and 142.3 mg (1.102 mmol) of DIPEA. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 50% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 25.7 mg (26%), LCMS Purity: 100% (Calc. MW: 544.62, found pos.: 273.2, 545.2).

[0976] Synthesis compound 1-428

[0977] N-({[2,4'-bipyridin]-5-yl}methyl)-2-[4-(oxolane-2-carbonyl)piperazin-l-yl]-9-(propan-2-yl)-9H-purin-6-amine was obtained by General procedure 1 using 53 mg (0.181 mmol) of l-{ [2,4'-bipyridin]-5- yl}methanamine trihydrochloride, 40 mg (0.174 mmol) of 2,6-dichloro-9-(propan-2-yl)-9H-purine, 67 mg (0.364 mmol) of l-(oxolane-2-carbonyl)piperazine, and 171.3 mg (1.326 mmol) of DIPEA. Purified by HPLC on XBridge Prep Phenyl 5MKM OBD using gradient from 40% to 90% of phase B in phase A (A - 0.1% HCI in water, B - 0.1% HCI in the mixture of MeCN and water (vol% 95:5)). Yield 8.6 mg (9%), LCMS Purity: 91.88% (Calc. MW: 527.62, found pos.: 264.6, 528.2, 430.2, found neg.: 526).

[0978] Synthesis compound 1-429

[0979] 1-[2-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-oxoethyl]imidazolidin- 2-one was obtained by General procedure 3 using 34 mg (0.08 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 20 mg (0.139 mmol) of 2-(2- oxoimidazolidin-l-yl)acetic acid, 19.6 mg (0.126 mmol) of EDC, 29.2 mg (0.226 mmol) of DIPEA, and 14.7 mg (0.108 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 60% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 10.5 mg (21%), LCMS Purity: 100% (Calc. MW: 553.66, found pos.: 554.4, 277.8, found neg.: 552.2).

[0980]

[0981] 1-430

[0982] 4-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazine-l-carbonyl)oxolan-3-ol was obtained General procedure 3 using 43 mg (0.101 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 17 mg (0.129 mmol) of 4- hydroxyoxolane-3-carboxylic acid, 20 mg (0.129 mmol) of EDC, 29.8 mg (0.231 mmol) of DIPEA, and 15.1 mg (0.111 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 65% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 24.3 mg (49%), LCMS Purity: 100% (Calc. MW: 541.65, found pos.: 542.2, found neg.: 540, 248.6).

[0983]

[0984] 1-431

[0985] N-({[l,l'-biphenyl]-4-yl}methyl)-2-[4-(4-methylmorpholine-3-carbonyl)piperazin-l-yl]-9-(propan-2-yl)-9H-purin-6- amine was obtained by General procedure 3 using 36 mg (0.084 mmol) of N-({[l,l'-biphenyl]-4- yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 23 mg (0.127 mmol) of 4-methylmorpholine-3-carboxylic acid hydrochloride, 19.6 mg (0.126 mmol) of EDC, 40.7 mg (0.315 mmol) of DIPEA, and 14.7 mg (0.108 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 65% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 19.7 mg (39%), LCMS Purity: 100% (Calc. MW: 554.69, found pos.: 278.2, 555.2).

[0986]

[0987] 1-432

[0988] l-[3-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazine-l-carbonyl)azetidin-l- yl]ethan-l-one; trifluoroacetic acid was obtained by General procedure 3 using 58 mg (0.136 mmol) of N-({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 14 mg (0.098 mmol) of l-acetylazetidine-3-carboxylic acid, 23.6 mg (0.152 mmol) of EDC, 40.9 mg (0.317 mmol) of DIPEA, and 20.7 mg (0.152 mmol) of HOAt. Yield 11.9 mg (17%), LCMS Purity: 98.68% (Calc. MW: 666.69, found pos.: 553.2, 277.2, 575.2, found neg.: 551).

[0989]

[0990] 1-433

[0991] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-(piperidin-l-yl)ethan-l- one; trifluoroacetic acid was obtained by General procedure 3 using 36 mg (0.084 mmol) of N- ({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 16 mg (0.089mmol) of 2-(piperidin-l-yl)acetic acid hydrochloride, 19.6 mg (0.126 mmol) of EDC, 40.9 mg (0.317 mmol) of DIPEA, and 14.8 mg (0.109 mmol) of HOAt. Purified by HPLC on Chromatorex C18 SMB 100-5T (Waters) using gradient from 40% to 90% of phase B in phase A (A - 0.1% trifluoroacetic acid in water, B - 0.1% trifluoroacetic acid in methanol). Yield 39.2 mg (78%), LCMS Purity: 98.1% (Calc. MW: 666.74, found pos.: 277.2, 553.2, 200).

[0992] Synthesis compound 1-434

[0993] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-(pyrrolidin-l-yl)propan-l- one; trifluoroacetic acid was obtained by General procedure 3 using 36 mg (0.084 mmol) of N- ({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 22 mg (0.123 mmol) of 2-(pyrrolidin-l-yl)propanoic acid hydrochloride, 19.6 mg (0.126 mmol) of EDC, 40.9 mg (0.317 mmol) of DIPEA, and 14.8 mg (0.109 mmol) of HOAt. Purified by HPLC on Chromatorex C18 SMB 100-5T (Waters) using gradient from 40% to 90% of phase B in phase A (A - 0.1% trifluoroacetic acid in water, B - 0.1% trifluoroacetic acid in methanol). Yield 28.9 mg (58%), LCMS Purity: 100% (Calc. MW: 666.74, found pos.: 277.2, 553.4).

[0994] Synthesis compound 1-435

[0995] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-(pyrrolidin-l-yl)ethan-l- one; trifluoroacetic acid was obtained by General procedure 3 using 36 mg (0.084 mmol) of N- ({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 20 mg (0.121 mmol) of 2-(pyrrolidin-l-yl)acetic acid hydrochloride, 20.2 mg (0.13 mmol) of EDC, 42 mg (0.325 mmol) of DIPEA, and 15.2 mg (0.112 mmol) of HOAt. Purified by HPLC on Chromatorex C18 SMB 100-5T (Waters) using gradient from 40% to 90% of phase B in phase A (A - 0.1% trifluoroacetic acid in water, B - 0.1% trifluoroacetic acid in methanol). Yield 29.6 mg (59%), LCMS Purity: 98.58% (Calc. MW: 652.71, found pos.: 270.2, 539.4, 193.2).

[0996] Synthesis compound 1-436

[0997] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-(3-methylpyrrolidin-l- yl)ethan-l-one; trifluoroacetic acid was obtained by General procedure 3 using 41 mg (0.096 mmol) of N-({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 24 mg (0.134 mmol) of 2-(3-methylpyrrolidin-l-yl)acetic acid hydrochloride, 19.6 mg (0.126 mmol) of EDC, 40.9 mg (0.317 mmol) of DIPEA, and 14.8 mg (0.109 mmol)of HOAt. Purified by HPLC on Chromatorex C18 SMB 100-5T (Waters) using gradient from 40% to 90% of phase B in phase A (A - 0.1% trifluoroacetic acid in water, B -0.1% trifluoroacetic acid in methanol). Yield 51.3 mg (103%), LCMS Purity: 97.3% (Calc. MW: 666.74, found pos.: 277.2, 553.4, 200).

[0998] Synthesis compound 1-437

[0999] 5-[2-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-oxoethyl]-l,3- oxazolidin-2-one; trifluoroacetic acid was obtained by General procedure 3 using 35 mg (0.082 mmol) of N-({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 19 mg (0.131 mmol) of 2-(2-oxo-l,3-oxazolidin-5-yl)acetic acid, 19.6 mg (0.126 mmol) of EDC, 29.1 mg (0.225 mmol) of DIPEA, and 14.7 mg (0.108 mmol) of HOAt. Purified by HPLC on Chromatorex C18 SMB 100-5T (Waters) using gradient from 35% to 60% of phase B in phase A (A - 0.1% trifluoroacetic acid in water, B - 0.1% trifluoroacetic acid in the mixture of MeCN and water (vol% 95:5)). Yield 31.7 mg (63%), LCMS Purity: 100%.

[1000] Synthesis compound 1-438

[1001] 2-(4-{l-azabicyclo[2.2.1]heptane-3-carbonyl}piperazin-l-yl)-N-({[l,l'-biphenyl]-4-yl}methyl)-9-(propan-2-yl)-9H-purin- 6-amine; trifluoroacetic acid was obtained by General procedure 3 using 37 mg (0.087 mmol) of N-({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 20 mg (0.113 mmol) of l-azabicyclo[2.2.1]heptane-3-carboxylic acid hydrochloride, 19.7 mg (0.127 mmol) of EDC, 41 mg (0.317 mmol) of DIPEA, and 14.8 mg (0.109 mmol) of HOAt. Purified by HPLC on Chromatorex C18 SMB 100-5T (Waters) using gradient from 40% to 90% of phase B in phase A (A - 0.1% trifluoroacetic acid in water, B -0.1% trifluoroacetic acid in methanol). Yield 30.4 mg (61%), LCMS Purity: 100% (Calc. MW: 664.72, found pos.: 276.2, 551.4).

[1002] Synthesis compound 1-439

[1003] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-2-[(2R)-l-methylpyrrolidin- 2-yl]ethan-l-one; trifluoroacetic acid was obtained by General procedure 3 using 41 mg (0.096 mmol) of N-({[1,1'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 17 mg (0.095 mmol) of 2-[(2R)-l-methylpyrrolidin-2-yl]acetic acid hydrochloride, 19.6 mg (0.126 mmol) of EDC, 40.9 mg (0.317 mmol) of DIPEA, and 14.8 mg (0.109 mmol) of HOAt. Purified by HPLC on Chromatorex C18 SMB 100-5T (Waters) using gradient from 40% to 90% of phase B in phase A (A - 0.1% trifluoroacetic acid inwater, B - 0.1% trifluoroacetic acid in methanol). Yield 32.8 mg (66%), LCMS Purity: 100% (Calc. MW: 666.74, found pos.: 277.2, 553.4, 470.4).

[1004] Synthesis compound 1-440

[1005] N-({[l,l'-biphenyl]-4-yl}methyl)-9-(propan-2-yl)-2-{4-[l-(propan-2-yl)azetidine- 3-carbonyl]piperazin-l-yl}-9H-purin-6- amine; trifluoroacetic acid was obtained by General procedure 3 using 38 mg (0.089 mmol) of N- ({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 17 mg (0.119 mmol) of l-(propan-2-yl)azetidine-3-carboxylic acid, 19.6 mg (0.126 mmol) of EDC, 29.2 mg (0.226 mmol) of DIPEA, and 14.8 mg (0.109 mmol) of HOAt. Purified by HPLC on Chromatorex C18 SMB 100-5T (Waters) using gradient from 40% to 90% of phase B in phase A (A - 0.1% trifluoroacetic acid in water, B - 0.1% trifluoroacetic acid in methanol). Yield 32.1 mg (64%), LCMS Purity: 95.75% (Calc. MW: 666.74, found pos.: 277.2, 553.4).

[1006] Synthesis compound 1-441

[1007] N-({[l,l'-biphenyl]-4-yl}methyl)-2-[4-(l-methylpyrrolidine-3-carbonyl)piperazin-l-yl]-9-(propan-2-yl)-9H-purin-6-amine; trifluoroacetic acid was obtained by General procedure 3 using 41 mg (0.096 mmol) of N- ({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 19 mg (0.115 mmol) of l-methylpyrrolidine-3-carboxylic acid hydrochloride, 20.2 mg (0.13 mmol) of EDC, 42 mg (0.325 mmol) of DIPEA, and 15.2 mg (0.112 mmol) of HOAt. Purified by HPLC on Chromatorex C18 SMB 100-5T (Waters) using gradient from 40% to 90% of phase B in phase A (A - 0.1% trifluoroacetic acid in water, B - 0.1% trifluoroacetic acid in methanol). Yield 27.7 mg (55%), LCMS Purity: 98.7% (Calc. MW: 652.71, found pos.: 270.2, 539.4, 193).

[1008] Synthesis compound 1-442

[1009] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-3-(dimethylamino)propan- 1-one; trifluoroacetic acid was obtained by General procedure 3 using 40 mg (0.094 mmol) of N- ({[l,l'-biphenyl]- 4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 20 mg (0.131 mmol) of 3-(dimethylamino)propanoic acid hydrochloride, 20.6 mg (0.133 mmol) of EDC, 42.9 mg (0.332 mmol) of DIPEA, and 15.5 mg (0.114 mmol) of HOAt. Purified by HPLC on Chromatorex C18 SMB 100-5T (Waters) using gradient from 40% to 90% of phase B in phase A (A - 0.1% trifluoroacetic acid in water, B - 0.1% trifluoroacetic acid in methanol). Yield 37.5 mg (75%), LCMS Purity: 100% (Calc. MW: 640.7, found pos.: 264.4, 527.4, 470.2).

[1010]

[1011] 1-443

[1012] N-({ [ l,l'-biphenyl]-4-yl}methyl)-2-[4-( l-methylpiperidine-2-carbonyl)piperazin- 1-yl]-9-(propan-2-yl)-9H-purin-6-amine; trifluoroacetic acid was obtained by General procedure 3 using 36 mg (0.084 mmol) of N-({[1,1'- biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 17 mg (0.095 mmol) of 1-methylpiperidine-2-carboxylic acid hydrochloride, 19.6 mg (0.126 mmol) of EDC, 40.9 mg (0.317 mmol) of DIPEA, and 14.8 mg (0.109 mmol) of HOAt. Purified by HPLC on Chromatorex C18 SMB 100-5T (Waters) using gradient from 40% to 90% of phase B in phase A (A - 0.1% trifluoroacetic acid in water, B - 0.1% trifluoroacetic acid in methanol). Yield 33 mg (66%), LCMS Purity: 100% (Calc. MW: 666.74, found pos.: 277.2, 553.2, 98).

[1013]

[1014] 1-444

[1015] N-({[l,l'-biphenyl]-4-yl}methyl)-2-{4-[l-(2-fluoroethyl)azetidine-3-carbonyl]piperazin-l-yl}-9-(propan-2-yl)-9H-purin-6- amine; trifluoroacetic acid was obtained by General procedure 3 using 35 mg (0.082 mmol) of N- ({[1,1'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 19 mg (0.112 mmol) of sodium l-(2-fluoroethyl)azetidine-3-carboxylate, 19.5 mg (0.126 mmol) of EDC, 29 mg (0.225 mmol) of DIPEA, 14.7 mg (0.108 mmol) of HOAt, and 13.5 mg (0.098 mmol) of triethylamine hydrochloride. Purified by HPLC on Chromatorex C18 SMB 100-5T (Waters) using gradient from 40% to 90% of phase B in phase A (A - 0.1% trifluoroacetic acid in water, B - 0.1% trifluoroacetic acid in methanol). Yield 35.4 mg (71%), LCMS Purity: 98.25% (Calc. MW: 670.7, found pos.: 279.2, 557.4, 579.4).

[1016] Synthesis compound 1-445

[1017] l-(4-{6-[({[l,l'-biphenyl]-4-yl}methyl)amino]-9-(propan-2-yl)-9H-purin-2-yl}piperazin-l-yl)-4-(dimethylamino)butan-l- one; trifluoroacetic acid was obtained by General procedure 3 using 37 mg (0.087 mmol) of N- ({[l,l'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 19 mg (0.114 mmol) of 4-(dimethylamino)butanoic acid hydrochloride, 20.1 mg (0.13 mmol) of EDC, 41.8 mg (0.324 mmol) of DIPEA, and 15.1 mg (0.111 mmol) of HOAt. Purified by HPLC on Chromatorex C18 SMB 100-5T (Waters) using gradient from 40% to 90% of phase B in phase A (A - 0.1% trifluoroacetic acid in water, B - 0.1% trifluoroacetic acid in methanol). Yield 38.9 mg (78%), LCMS Purity: 98.86% (Calc. MW: 654.73, found pos.: 271.2, 541.4, 248.6).Synthesis compound 1-446

[1018] N-({[l,l'-biphenyl]-4-yl}methyl)-2-{4-[(2S)-l-methylazetidine-2-carbonyl]piperazin-l-yl}-9-(propan-2-yl)-9H-purin-6- amine; trifluoroacetic acid was obtained by General procedure 3 using 37 mg (0.087 mmol) of N- ({[1,1'-biphenyl]-4-yl}methyl)-2-(piperazin-l-yl)-9-(propan-2-yl)-9H-purin-6-amine, 16 mg (0.139 mmol) of (2S)-l-methylazetidine-2-carboxylic acid, 20.7 mg (0.133 mmol) of EDC, 30.8 mg (0.238 mmol) of DIPEA, and 15.6 mg (0.115 mmol) of HOAt. Purified by HPLC on XBridge Prep C18 5MKM OBD (Waters) using gradient from 65% to 100% of phase B in phase A (A - 0.1% NH in water, B - 0.1% NH in methanol). Yield 25.5 mg (51%), LCMS Purity: 100% (Calc. MW: 638.68, found pos.: 263.2, 525.4, 186).

[1019] EXAMPLE 3

[1020] Materials and methods

[1021] Patient-derived Drug screening

[1022] Drug screening on 3D patient-derived tumor samples was performed using a prevalidated drug screening pipeline for which a detailed protocol is available in the Journal of Visualized Experiments.

[1023] For patient-derived 3D models: Established organoid lines were expanded in extracellular matrix (ECM) domes (Cultrex type 2, Bio-Techne Ltd). Next, 3-day-old organoids were harvested from ECM drops using the Cultrex Organoid Harvesting Solution (Bio-Techne Ltd), collected in a 15 mL tube coated with 0.1% BSA / PBS, washed, and resuspended in medium. Next, the number of organoids was quantified using imaging and diluted in full medium supplemented with 4% Cultrex at a concentration of 4000 organoids / mL. Next, 50pL (200 organoids) of this solution was dispensed into a 384-well ultra-low attachment microplate (Corning, #4588) using the OT-2 pipetting robot (Opentrons) in a cooled environment. Thereafter, the plate was centrifuged (100 ref, 30 sec, 4°C) and incubated overnight at 37°C. All drugs and fluorescent reagents were added to the plate using the Tecan D300e Digital Dispenser and dissolved in either DMSO or 0.3% Tween-20 / H2O. Cytotox Green (60 nM / well, Sartorius, DMSO) was uses as fluorescent cell death marker and Staurosporine (2 pM, Tocris Bioscience, DMSO) as positive control. For each drug, a logarithmic titration was dispensed (0 - lOOOOnM for AOC / rescue assay and O-lOOOnM for synergy) and DMSO concentrations were normalized to the same level in each well (< 1%). Brightfield and green fluorescence whole-well images (4x objective) were taken every 24 hours with the Tecan Spark Cyto set at 37°C / 5%C02 for 5 days. Drug screening data was performed on patient-derived pancreatic cancer and gastric-esophageal junction cancer (HER.2 synergy) organoid lines.

[1024] Image and data analysis

[1025] 1. Drug response

[1026] Images and data were analysed with the Orbits® label-free organoid detection modul Viability (V) was quantified as Total Brightfield Organoid Area - Total Green Area and excluding organoids that were classified as death by the label-free cell death detection module. V was used to calculate the Normalised Organoid Growth Rate (NOGR):

[1027] _ V(x) - V(0)

[1028]

[1029] y(0)

[1030] if G > 0: NOGR = Gdrug / GmedNeg

[1031] if G < 0: NOGR = Gdrug / GmedPos

[1032] NOGR = clip(NOGR, [— 1, 1])

[1033] where V(0) is the viability at timepoint 0, V(x) is the viability at timepoint x, Gdrug is the G corresponding to the drug treated condition, GmedPos is the median G of the positive control and GmedNeg is the median G of the vehicle control.

[1034] Based on the NOGR, the drug effects can be classified as: >1, proliferative effect; = 1, normal growth as in negative control; = 0, complete growth inhibition; = -1, complete killing as in positive control.

[1035] The dose-response relationship was modeled using the Growth Rate (GR) equation:

[1036] 1

[1037] GR = GRinf + (1 - GRinf)( -c

[1038]

[1039] 1 +\GEC5o)

[1040] Where GRinf is the response at infinite concentration, GEC50 is the concentration that produces half the maximum possible effect, hGRis the Hill coefficient, determining the steepness of the curve, and c is the concentration. Next, the Python SciPy library's 'curve-fit' function was employed to fit the GR model to the observed data for each biological replicate. Initial guesses for GRinf, GEC50, and hGRwere set to 0.1, median concentration and 2, respectively. Residual errors between observed and predicted responses were calculated for each data point using the Root Mean Square Error approach. Points exhibiting an error greater than 2.5 times the mean error and an absolute error greater than 0.25 were deemed outliers and the model was refitted to this refined dataset. The following metrics were derived from thefitted curve: NOGR50 as the concentration at which the response is 0.5 and NOGR_AOC_l_fitted_n as the area over the curve (AOC) up to y = 1, normalized to the maximum area. This is represented by figure 25.

[1041] To quantify anti-tumor cell death and degradation rescue in vitro, two metrics were evaluated: AOC (Anti-Oncogenic Cytotoxicity) and % Rescue. AOC was scored based on the following thresholds: **** for values >0.8, *** for 0.8-0.7, ** for 0.7-0.5, and * for values <0.5. Similarly, degradation rescue was assessed using % Rescue, with **** assigned to values >50%, *** for 50-30%, ** for 30-10%, and * for values <10%. These thresholds allowed for standardized evaluation and comparison of treatment efficacy across experimental conditions.

[1042] 2. Synergy

[1043] For synergy, a new derived variable Normalised (N)NOGR was computed to scale NOGR values between 0 and 100. The formula used for this computation is as follows:

[1044] NNOGR / NNDR = (NOGR / NDR + 1) * 50

[1045] The HSA synergy scores were calculated using the SynergyFinder R-package (2). A synergy score > 10: Indicates a synergistic interaction between the drugs. -10 < Score < 10: Implies an additive effect where the combined impact of the drugs is approximately equal to their individual effects summed. <-10: Signifies an antagonistic interaction between the drugs.

[1046] Finally, for all drug combinations with an HSA value greater than 5, a Synergy Score (NOGR x HSA) was computed, with increasingly negative values denoting stronger cytotoxic synergy, and the resulting scores were stratified into three predefined categories: * (> -2.5), ** (-2.5 to -5), and *** (< -5), to facilitate systematic comparison of combination effects.

[1047] Rescue assay

[1048] To assess protein degradation dependency, a rescue assay was performed in the presence of 100 nM MLN4924. The rescue effect was quantified as

[1049] -. - - -, / 40CMLW\

[1050] % Rescue =

[1051]

[1052] *100)

[1053] where AOC represents the area over the fitted dose-response curve of a four-point drug titration, and AOCMLN is the corresponding area in the presence of MLN4924.Higher % Rescue values indicate a stronger rescue effect, reflecting a greater proportional reduction of the AOC.

[1054] Kinase activity

[1055] Protein kinase activity was assessed using the radiometric 33PanQinase™ Activity Assay (Reaction Biology Corp.) for a panel of 10 protein kinases. All assays were conducted in 96 well ScintiPlates™ (PerkinElmer, Boston, MA, USA) with a final reaction volume of 50 pl per well. The reaction mixture was assembled in four steps as follows: (1) 25 pl of assay buffer containing standard buffer and [y 33P] ATP, (2) 10 pl of ATP solution (prepared in H2O), (3) 5 pl of the test compound (dissolved in 10% DMSO), and (4) 10 pl of an enzyme / substrate mixture. The assay buffer used for all kinases consisted of 70 mM HEPES NaOH (pH 7.5), 3 mM MgCl₂, 3 mM MnCl₂, 3 pM sodium orthovanadate, 1.2 mM DTT, and 50 pg / ml PEG20000. ATP was added at concentrations corresponding to the apparent Km for each kinase.

[1056] Spike-in quantitative mass spectrometry assay

[1057] Cells derived from treated (200nM) patient-derived organoids were lysed by sonication followed by treatment with RIPA lysis and extraction buffer. After protein extraction, samples were subjected to reduction and alkylation, followed by enzymatic digestion using trypsin. The resulting peptide mixtures were analyzed using a 110 cm long pPAC™ Neo RP C18 column coupled to a Vanquish Neo™ UHPLC system (Thermo Fisher Scientific), connected to a high-resolution Orbitrap Exploris™ 240 mass spectrometer (Thermo Fisher Scientific). Peptides were separated using a 120-minute two-step solvent gradient at a flow rate of 300 nL / min. A highly sensitive targeted acquisition method using parallel reaction monitoring (PRM) was applied. For absolute quantification, 100 fg of a stable isotopically labelled (SIL) proteotypic peptide of cyclin K was spiked into each digested sample. Multiple transitions were monitored, and quantification was performed based on the response of the product ion scan of the endogenous peptide, normalized to the response of the product ion scan of the SIL peptide. Additionally, a proteome-wide mass spectrometry analysis was performed using a data-dependent acquisition (DDA) mode. MS1 scans were acquired at 60,000 resolution over an m / z range of 375-1200, followed by selection of the top 20 precursors for fragmentation using higher-energy collisional dissociation (HCD) with a normalized collision energy of 30%. MS2 spectra were acquired at 15,000 resolution. The resulting MS2 spectra were analyzed using Proteome Discoverer 3.1 (Thermo Fisher Scientific) and searched against the UniProt human reference proteome (UP000005640) and a contaminant database for protein identification.Results

[1058] The compounds disclosed in the present application demonstrate functional and mechanistic advantages over known compounds such as UB10 (WO2024041661) and CRB, as shown in table 1. Specifically, while UB10 and CR8 exhibit high cytotoxic activity in the primary live-cell imaging assay (AOC = ****), both compounds show limited phenotypic rescue activity (*). This suggests that although these molecules engage their intended target, they fail to translate target inhibition into a meaningful biological or therapeutic effect. In contrast, several of the presently claimed compounds exhibit both strong AOC activity (***-****) and markedly improved phenotypic rescue (****). These compounds therefore demonstrate dual functional efficacy, achieving not only robust anti-tumor activity but also a broader biological rescue profile in relevant cellular models. This dual profile strongly suggests that target degradation is the primary driver of the observed anti-tumor effects. Such an outcome is less observed in the prior art compounds (potentially indicating more atp competitive inhibition / off target effects), which fail to couple high target activity with downstream biological efficacy, and was not predictable based on known structure-activity relationships. This dual profile (high cytotoxicity with high degradation dependency) is not observed in the prior art, nor would it have been predictable based on the known structure-activity relationships (SAR) of related compounds.

[1059] Importantly, this enhanced rescue effect was demonstrated using a phenotypic assay based on patient-derived organoids, which are both clinically and translationally relevant models. The use of these models confirms that the observed biological effects are not limited to standard cell lines, but instead reflect meaningful responses in complex, patient-specific tumor biology.

[1060] Table 1

[1061] Compound AOC % Rescue Compound AOC % Rescue UB10 (prior art) =1= 1-397 ****

[1062] CR8 (prior art) =1= 1-398 ****

[1063] 1-1 **** 1-399 ****

[1064] 1-349 ** 1-400 ****

[1065] 1-350 ** **** 1-401 ** **** 1-351 ** 1-402 ****

[1066] 1-352 ** **** 1-403 ****

[1067] 1-353 ** 1-404 ****

[1068]

[1069] -354 ** **** 1-405 ** **** -355 **** ** 1-406 **** 5K5K5K -356 ** 5K5K5K 1-407 5K5K5K **** -357 **** ** 1-408 **** 5K5K5K -358 **** ** 1-409 5K5K5K **** -359 **** =1= 1-410 5K5K5K 5K5K5K -360 ** 5K5K5K 1-411 5K5K5K 5K5K5K -361 **** =1= 1-412 **** ** -362 ** 1-413 **** 5K5K5K -363 ** ** 1-414 **** 5K5K5K -364 5K5K5K 1-415 **** 5K5K5K5K -365 ** ** 1-416 ** 5K5K5K5K -366 =1= 1-417 5K5K5K 5K5K5K5K -367 ** 1-418 **** ** -368 **** ** 1-419 ** 5K5K5K5K -369 **** ** 1-420 5K5K5K 5K5K5K5K -370 ** **** 1-421 5K5K5K 5K5K5K5K -371 **** 5K5K5K 1-422 **** ** -372 ** 5K5K5K 1-423 **** 5K5K5K -373 **** ** 1-424 **** =1= -374 ** ** 1-425 **** =1= -375 **** =1= 1-426 ** 5K5K5K5K -376 ** =1= 1-427 ** 5K5K5K5K -377 **** 5K5K5K 1-428 5K5K5K 5K5K5K -378 **** 5K5K5K 1-429 **** 5K5K5K -379 5K5K5K 1-430 **** ** -380 ** ** 1-431 **** 5K5K5K -381 **** ** 1-432 **** 5K5K5K -382 **** ** 1-433 **** 5K5K5K5K -383 **** 5K5K5K 1-434 **** =1= -384 5K5K5K ** 1-435 **** 5K5K5K -385 ** 5K5K5K 1-436 **** 5K5K5K -386 **** ** 1-437 ** 5K5K5K5K -387 **** ** 1-438 **** 5K5K5K -388 **** ** 1-439 **** 5K5K5K -389 5K5K5K 5K5K5K 1-440 5K5K5K 5K5K5K

[1070]

[1071] 1-390 1-441 **** 1-391 **** 1-442

[1072] 1-392 **** 1-443 ****

[1073] 1-393 ** 1-444 **** 1-394 =1= 1-445 ** **

[1074] 1-395 **** 1-446 **** **

[1075] 1-396 ****

[1076]

[1077] Figure 26 shows that the tested compounds exhibit minimal ATP competitive inhibition of CDK complexes, indicating that their biological activity is not primarily mediated through kinase inhibition. This implies that the compounds of the invention exert their effect predominantly through a degradation-based mechanism rather than by interfering with ATP binding at the kinase active site. This mechanistic selectivity is particularly advantageous in the context of cyclin K degradation. CDK12 / 13 complexes are tightly associated with cyclin K, and conventional ATP-competitive CDK inhibitors often suffer from poor selectivity, affecting a broad range of kinases and leading to off-target effects. In contrast, the compounds of the invention appear to engage the target complex in a manner that promotes selective degradation of cyclin K, likely via molecular glue-induced neosubstrate recruitment to an E3 ligase complex. Importantly, prior art describing other molecular glues (such as WO2022263604A1) report molecules with significant ATP competitive inhibition in the nanomolar range. While effective, such compounds may retain residual kinase inhibition activity, which can confound degradation-dependent mechanisms and complicate target validation. By minimizing ATP-competitive binding, the compounds of the invention provide a cleaner pharmacological profile, which allows to attribute functional effects more directly to targeted degradation of cyclin K. This distinction not only enhances mechanistic clarity but also opens the door to developing more selective degraders with reduced off-target toxicity, particularly valuable in transcriptional regulation and cancer therapies where cyclin K plays a central role.

[1078] Since the compounds of the invention primarily function through a targeted degradation mechanism and exhibit limited ATP-competitive activity overall, it was assessed, as shown in figure 27, whether any residual ATP binding affects Cyclin K degradation efficacy. Two representative compounds were evaluated: one with mild ATP-competitive activity (1-375, still lower than the prior art compound CR8), and one with minimal ATP-competitive character (1-378). When tested at 200 nM for 24htreatment in a quantitative mass spectrometry-based spike-in assay, both compounds induced high levels of Cyclin K degradation, indicating that modest ATP binding does not significantly impair degradation capacity. These results support the conclusion that Cyclin K degradation remains robust across the series, irrespective of their lower ATP-competitive properties. Together with the observed potency in patient-derived organoid models and strong phenotypic rescue, these findings establish a consistent mechanistic profile and underscore potential therapeutic relevance with a cleaner off target profile.

[1079] In Table 2, increased synergy can be observed between various compounds and HER2-targeted therapies, as evidenced by synergy scores across a broad set of molecules. Notably, the compounds exhibited high synergy levels which were equal to or greater than those seen with the prior art compound UB10. Synergy was broadly observed across different structural classes, highlighting the potential for a mechanisms of action to complement targeted or standard of care therapies such as treatments. This suggests that the compounds of the current invention is capable of delivering synergy that is at least on par with, and often superior to, prior art such as UB10.

[1080] Table 2

[1081] Compound Synergy score Compound Synergy score UB10 =1= 1-387 ***

[1082] 1-1 =1= 1-388 =1=

[1083] 1-350 1-389 =1=

[1084] 1-353 1-390

[1085] 1-355 1-393 =1=

[1086] 1-356 =1= 1-394

[1087] 1-357 =1= 1-397 =1=

[1088] 1-358 =1= 1-399

[1089] 1-359 1-400 =1=

[1090] 1-361 =1= 1-403 =1=

[1091] 1-362 1-404 =1=

[1092] 1-364 ** 1-408 =1=

[1093] 1-366 ** 1-414 =1=

[1094] 1-367 =1= 1-415 =1=

[1095] 1-368 =1= 1-418

[1096] 1-369 =1= 1-422 =1=

[1097] 1-371 ** 1-423 **

[1098]

[1099] 1-373 *** 1-424 ***

[1100] 1-375 =1= 1-429 =1=

[1101] 1-377 1-431 =1=

[1102] 1-378 =1= 1-432 =1=

[1103] 1-379 ** 1-434 **

[1104] 1-381 =1= 1-435 =1=

[1105] 1-382 ** 1-439 =1=

[1106] 1-383 ** 1-441 =1=

[1107] 1-384 1-442

[1108] 1-385 =1= 1-446

[1109] 1-386 =1=

[1110]

[1111] Figures 28A, 28B, 28C and 28D relate to potential biomarkers of the compounds of the invention. Figure 28A shows the identification of NF-KB-related biomarkers of response in patient-derived organoids. Dose-response curves (120 h) for compound 1-1 across patient-derived organoids showed variation in response, with organoids classified into resistant, intermediate, and sensitive groups based on NOGR AOC. Figure 28B shows a decision tree from machine-learning analysis identified NLRP2 mRNA expression as the primary discriminator of resistant organoids versus intermediate / sensitive responders. Figure 28C shows the boxplot analysis of NLRP2 mRNA expression across the three groups demonstrated markedly lower expression in resistant organoids. Additionally, in figure 28D, IKBKB protein expression was significantly upregulated after treatment compared to vehicle, highlighting the activation of this NF-KB signaling component following treatment. Together, these analyses implicate increased NF-KB signaling as a potential predictive biomarker.

[1112] This pattern of increased treatment sensitivity with low NFKB activation mirrors findings by Houles et al. (PMC9617877), linking NF-KB signaling to CDK12 inhibitor resistance.

[1113] The present invention is in no way limited to the embodiments described in the examples and / or shown in the figures. On the contrary, methods according to the present invention may be realized in many different ways without departing from the scope of the invention.

[1114] The invention may thus be described according to the following embodiments:A compound of formula (I) or a pharmaceutically acceptable salt thereof,

[1115]

[1116] wherein A is an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl comprising 1 to 3 nitrogen atoms or an optionally substituted heteroaryl comprising 1 to 3 nitrogen atoms,

[1117] wherein R4 is -H or -CH3,

[1118] wherein B is a direct bond, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl,

[1119] wherein R5 is -H, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl,

[1120] wherein R6 and R7 are independently -H or halogen, and

[1121] wherein n is 1 or 2.

[1122] The compound according to embodiment 1, wherein A is an optionally substituted heterocycloalkyl comprising 1 to 3 nitrogen atoms.

[1123] The compound according to embodiment 2, wherein A is selected from:

[1124] R2,Ra5

[1125]

[1126]

[1127]

[1128] wherein R1 is -H, a halogen, an alkyl, a cycloalkyl, an aryl, a heterocycloalkyl or heteroaryl containing 1 to 3 nitrogen atoms and optionally substituted with an alkyl, a carbonyl, or a halogen,

[1129] wherein R2 is -H, a halogen, an optionally substituted alkyl, an optionally substituted amine, an optionally substituted alkylamide, an optionally substituted sulfonamide, a carbamate, a carbonate, an aryl, or an optionally substituted heterocycloalkyl, an optionally substituted heteroaryl, or a functional group comprising two or more of these functional groups, and wherein R3 is -H, a halogen or a substituted alkyl, or R2 and R3 are connected to the same atom and together form a cyclopropyl or cyclobutyl group.The compound according to any of the previous embodiments, wherein B is selected from: a direct bond, a phenyl,

[1130]

[1131] wherein R6 and R7 are independently selected from H or halogen. The compound according to any of the previous embodiments, wherein R5 is selected from -H, a phenyl,

[1132]

[1133]

[1134] 196

[1135]

[1136] o

[1137]

[1138] r ww', and wherein R8 and R9 are independently -H, halogen, alkyl, O-alkyl, S-alkyl optionally substituted with 1 to 3 halogens, or heteroaryl.

[1139] 6. The compound of any of the previous embodiments, wherein said compound is a C-terminal Src Kinase (CSK) modulator, preferably a C-terminal Src Kinase (CSK) inhibitor.

[1140] 7. A pharmaceutical composition comprising a therapeutically effective amount of said compound according to any one of the preceding embodiments and a pharmaceutically acceptable excipient.

[1141] 8. A combination therapy, wherein said combination therapy comprises the compound according to any of the embodiments 1 to 6 or the pharmaceutical composition according to embodiment 7, and one or more additional therapeutic agents, said additional therapeutic agent is preferably an immunotherapeutic, a chemotherapeutic, a cell therapy or a combination thereof.

[1142] 9. The combination therapy according to embodiment 8, wherein said additional therapeutic agent is chosen from a KRAS inhibitor, a PD1-PDL1 inhibitor, a MEK inhibitor, a PI3K inhibitor, a CDK inhibitor and a MAPK inhibitor, an EGFR inhibitor, an HER2 inhibitor, a PRMT5 inhibitor, an NF-κB pathway modulator, a Car-T therapy, a Car-NK therapy or a combination thereof.

[1143] 10. The compound according to any one of embodiments 1 to 6 or the pharmaceutical composition according to embodiment 7 for use in a medicament or for use as therapy in a subject.

[1144] 11. The compound or pharmaceutical composition for use according to embodiment 10 wherein said therapy is the prevention and / or treatment of cancer.12. The compound or pharmaceutical composition for use according to embodiment 10 or 11, wherein said therapy is a monotherapy or a combination therapy, said combination therapy is preferably chosen from immunotherapy, chemotherapy, or cell therapy.

[1145] 13. The compound or pharmaceutical composition for use according to any of the embodiments 10 to 12, wherein said compound or composition is administered to a subject in combination with one or more additional therapeutic agents, said additional therapeutic agent is chosen from a KRAS inhibitor, a PD1-PDL1 inhibitor, a MEK inhibitor, a PI3K inhibitor, a CDK inhibitor, a MARK inhibitor, an EGFR inhibitor, an HER2 inhibitor, a PRMT5 inhibitor, an NF-κB pathway modulator, a cytotoxic chemotherapy, a Car-T therapy, a Car-NK therapy or a combination thereof.

[1146] 14. The compound or pharmaceutical composition for use according to any of the embodiments 10 to 13, wherein said compound or composition and one or more therapeutic agents are administered simultaneously or sequentially to said subject.

[1147] 15. The compound or pharmaceutical composition for use according to any of the embodiments 10 to 14, wherein said compound or composition are formulated together with said one or more additional therapeutic agents, or separately.

[1148] 16. The compound or composition for use according to any of the previous embodiments 10 to 15, wherein said compound or composition is administered to a subject, and wherein prior to said administration the activity of C-terminal Src Kinase is determined in a biological sample of said subject.

[1149] 17. A compound for use in the treatment and / or prevention of cancer, wherein said compound modulates the activity of C-terminal Src kinase.

[1150] 18. The compound of embodiment 17, wherein said compound activates LCK, FYN, LYN, and / or SRC kinases

Claims

CLAIMS1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,aryl, an optionally substituted heterocycloalkyl comprising 1 to 3 nitrogen atoms or an optionally substituted heteroaryl comprising 1 to 3 nitrogen atoms,wherein R4 is -H or -CH3,wherein B is a direct bond, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl, or an optionally substituted heteroaryl,wherein R5 is -H, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl, preferably an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocycloalkyl or an optionally substituted heteroaryl,wherein R6 and R7 are independently -H or halogen, andwherein n is 1 or 2.

2. The compound according to claim 1, wherein A is an optionally substituted heterocycloalkyl comprising 1 to 3 nitrogen atoms.

3. The compound according to claim 2, wherein A is selected from:wherein R1 is -H, a halogen, an alkyl, a cycloalkyl, an aryl, a heterocycloalkyl or heteroaryl containing 1 to 3 nitrogen atoms and optionally substituted with an alkyl, a carbonyl, or a halogen,wherein R2 is -H, a halogen, an optionally substituted alkyl, an optionally substituted amine, an optionally substituted alkylamide, an optionally substituted sulfonamide, a carbamate, a carbonate, an aryl, or an optionally substituted heterocycloalkyl, an optionally substituted heteroaryl, or a functional group comprising two or more of these functional groups, and wherein R3 is -H, a halogen or a substituted alkyl, or R2 and R3 are connected to the same atom and together form a cyclopropyl or cyclobutyl group.

4. The compound according to any of the previous claims, wherein R1 is an alkyl, cycloalkyl, an aryl, a heterocycloalkyl containing 1 to 3 nitrogen atoms, and substituted with a carbonyl.

5. The compound according to any of the previous claims, wherein A iswherein R1 is an alkyl, a cycloalkyl, an aryl, a heterocycloalkyl or heteroaryl containing 1 to 3 nitrogen atoms and optionally substituted with an alkyl, a carbonyl, or a halogen, and wherein R2 is -H, a halogen, an optionally substituted alkyl, an optionally substituted amine, an optionally substituted alkylamide, an optionally substituted sulfonamide, a carbamate, a carbonate, an aryl, or an optionally substituted heterocycloalkyl, an optionally substituted heteroaryl, or a functional group comprising two or more of these functional groups, and wherein R3 is -H, a halogen or a substituted alkyl, or R2 and R3 are connected to the same atom and together form a cyclopropyl or cyclobutyl group, preferably wherein R1 is not -CH3.

6. The compound according to claim 5, wherein R2 and R3 are -H, and wherein R1 is not -CH3.

7. The compound according to claim 5 or 6, wherein R1 forms an amide functionality.

8. The compound according to any one of the claims 4-7, wherein R1 is selected from:o 0 o204205wherein R6 and R7 are independently selected from H or halogen.

10. The compound according to any of the previous claims, wherein B is selected from a phenyl,JVW' andwherein R6 and R7 are independently selected from H or halogen.

11. The compound according to any of the previous claims, wherein R5 is selected from -H, a phenyl,208wherein R8 and R9 are independently -H, halogen, alkyl, O-alkyl, S-alkyl optionally substituted with 1 to 3 halogens, or heteroaryl.

12. The compound according to any of the previous claims, wherein R5 is selected from:

13. wherein R8 and R9 are independently -H, halogen, alkyl, O-alkyl, S-alkyl optionally substituted with 1 to 3 halogens, or a heteroaryl, preferably R8 and R9 are independently -H or alkyl. The compound according to any of the previous claims, wherein B is an optionally substituted aryl or an optionally substituted heteroaryl, and wherein R5 is an optionally substituted aryl or an optionally substituted heteroaryl.

14. The compound according to claim 13, wherein A is, wherein R1 is a carbonyl-containing group such that an amide functionality is formed, wherein R2 and R3 are -H.

15. The compound of any of the previous claims, wherein said compound is a C- terminal Src Kinase (CSK) modulator, preferably a C-terminal Src Kinase (CSK) inhibitor.

16. A pharmaceutical composition comprising a therapeutically effective amount of said compound according to any one of the preceding claims and a pharmaceutically acceptable excipient.

17. A combination therapy, wherein said combination therapy comprises the compound according to any of the claims 1 to 15 or the pharmaceutical composition according to claim 16, and one or more additional therapeutic agents, said additional therapeutic agent is preferably an immunotherapeutic, a chemotherapeutic, a cell therapy or a combination thereof.

18. The combination therapy according to claim 17, wherein said additional therapeutic agent is chosen from a KRAS inhibitor, a PD1-PDL1 inhibitor, a MEK inhibitor, a PI3K inhibitor, a CDK inhibitor and a MAPK inhibitor, an EGFR inhibitor, an HER2 inhibitor, a PRMT5 inhibitor, an NF-κB pathway modulator, a Car-T therapy, a Car-NK therapy, an ERK inhibitor, a non-chemotherapyDNA-damaging agent, a DNA damage response inhibitor, or a combination thereof.

19. The compound according to any one of claims 1 to 15 or the pharmaceutical composition according to claim 16 for use in a medicament or for use as therapy in a subject.

20. The compound or pharmaceutical composition for use according to claim 19 wherein said therapy is the prevention and / or treatment of cancer.

21. The compound or pharmaceutical composition for use according to claim 19 or 20, wherein said compound or composition is administered to a subject in combination with one or more additional therapeutic agents, said additional therapeutic agent is chosen from a KRAS inhibitor, a PD1-PDL1 inhibitor, a MEK inhibitor, a PI3K inhibitor, a CDK inhibitor, a MAPK inhibitor, an EGFR inhibitor, an HER2 inhibitor, a PRMT5 inhibitor, an NF-κB pathway modulator, a cytotoxic chemotherapy, a Car-T therapy, a Car-NK therapy, an ERK inhibitor, a non-chemotherapy DNA-damaging agent, a DNA damage response inhibitor, or a combination thereof.

22. The compound or pharmaceutical composition for use according to any of the claims 19 to 21, wherein said compound or composition and one or more therapeutic agents are administered simultaneously or sequentially to said subject.

23. The compound or composition for use according to any of the previous claims 19 to 22 wherein said compound or composition is administered to a subject, and wherein prior to said administration the activity of C-terminal Src Kinase or the activity of the NF-κB pathway is determined in a biological sample of said subject.

24. A compound for use in the treatment and / or prevention of cancer, wherein said compound modulates the activity of C-terminal Src kinase.

Images