The present invention relates to compounds targeting the Hippo pathway, e.g. YAP/TAZ and/or the TEAD family, and their use in the treatment of neoplastic diseases such as cancer.

The Hippo pathway plays a conserved role in cell proliferation and organ size. YAP and TAZ are transcriptional co-activators, negatively regulated by the Hippo pathway. Thus, when the Hippo pathway is off, YAP and TAZ can translocate to the nucleus. To further function in transcriptional activation, YAP/TAZ work together with the transcriptional enhancer associated domain (TEAD) transcription factor family. Constitutive activity of YAP/TAZ and/or the TEAD family is present in different tumor types, consistent with these factors driving the expression of growth-promoting genes not only during development but also in cancer (See Holden and Cunningham "Targeting the Hippo Pathway and Cancer through the TEAD Family of Transcription Factors", Cancers, 2018, 10, 81; Liu-Chittenden et al. "Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP", Genes & Development, 2012, 26, 1300-1305; Santucci et al. "The Hippo Pathway and YAP/TAZ-TEAD Protein-Protein Interaction as Targets for Regenerative Medicine and Cancer Treatment", J. Med. Chem., 2015, 58, 4857-4873; Pobbati et al. "Targeting the Central Pocket in Human Transcription Factor TEAD as a Potential Cancer Therapeutic Strategy", Structure, 2015, 23(11), 2076- 2086). Therefore, targeting of YAP/TAZ and/or the TEAD family harbors potential for anti-cancer therapy.

WO2013/188138, WO2015/022283, WO2015/063747, WO2017/064277, WO2018/204532, WO2018/185266, WO2019/040380, WO2019/113236, WO2019/222431, W02020/097389, WO2020/214734 and W02021/102204 describe inhibitors associated with one or more members of the Hippo pathway network, such as inhibitors of YAP/TAZ or inhibitors that modulate the interaction between YAP/TAZ and TEAD.

In a first aspect the present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein R1 is -Y-R2;

Y is -Cl-C6alkylene- wherein one non-terminal -CH2- may be replaced by -N(R3)- or -O- and wherein Y may be substituted by one -OH on a carbon atom that is not bound to an oxygen atom or a nitrogen atom; R2 is -OH, -NH2, -NH-S(O)2-Cl-C2alkyl, -N(CH3)-S(O)2-Cl-C2alkyl, Cycle P or Cycle Q and wherein R2 may be hydrogen when Y includes an -N(R3)- or -O-;

R3 is hydrogen or Cl-C4alkyl;

Cycle P is a 5- to 6-membered heterocyclic ring containing one or two heteroatoms as ring members selected from nitrogen and oxygen and containing at least one nitrogen atom as a ring member, the heterocyclic ring optionally substituted by one to three R4;

Cycle Q is a 5- to 6-membered heteroaryl containing one to four heteroatoms selected from nitrogen and oxygen and containing at least one nitrogen and not more than one oxygen atom as a ring member, the heteroaryl optionally substituted by one to three R5; and each R4 and R5 is independently Cl-C4alkyl.

In a further aspect, the invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof for use in the treatment of neoplastic diseases in a subject selected from a mammal, in particular a human.

In a further aspect, the invention provides use of compounds of formula (I) and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of neoplastic diseases in a subject selected from a mammal, in particular a human.

In a further aspect, the invention provides methods of treating neoplastic diseases in a subject selected from a mammal, in particular a human, comprising administering a compound of formula (I) or pharmaceutically acceptable salt thereof, e.g. in a therapeutically effective amount, to said subject. In a further aspect, the invention provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients.

Each alkyl moiety either alone or as part of a larger group is a straight or branched chain. Examples include methyl, ethyl, w-propyl. prop-2 -yl, w-butyl. but-2-yl, 2-methyl-prop-l-yl or 2-methyl-prop-2-yl. Each alkylene moiety either alone or part of a larger group is a straight or branched chain and is, for example, -CH ₂ -, -CH2-CH2-, -CH(CH ₃ )-, -CH ₂ -CH ₂ -CH ₂ -, -CH(CH ₃ )-CH ₂ - or -CH(CH ₂ CH ₃ )-. Heteroaryl refers to an aromatic ring system containing at least one heteroatom as defined herein. Heteroaryl rings do not contain adjacent oxygen atoms within the ring. Examples include pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, oxadiazolyl and tetrazolyl. Heterocyclic ring refers to a saturated or partially unsaturated carbocyclic ring containing at least one heteroatom as defined herein. Such rings do not contain adjacent oxygen atoms within the ring. Examples include tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.

Where a group is said to be optionally substituted, it may be substituted or unsubstituted.

Where ring nomenclature is provided for a specific moiety it is applied assuming no substituents on the ring. For example piperidin-l-yl places the nitrogen atom at the point of attachment irrespective of the identity of any substituents which might be present on the piperidine moiety.

Whenever compounds of formula (I) contain one or two or more centers of chirality (for example when Y is a branched alkylene moiety) such compounds may be provided as pure enantiomers or pure diastereoisomers as well as mixtures thereof in any ratio and all such isomers are included within the scope of the compounds of formula (I). The compounds of the invention also include all cis/trans-isomers as well as mixtures thereof in any ratio. The compounds of the invention also include all /■.' Z-isomcrs as well as mixtures thereof in any ratio. Isotopically labeled compounds including deuterium substitutions as well as carbon-13 and/or carbon-14 labels are also included within the scope of compounds of formula (I).

The compounds of the invention also include all tautomeric forms of the compounds of formula (I) and intermediates thereof. For example the 4H-l,2,4-oxadiazole-5-one moiety exhibits tautomeric forms as shown below. All forms are included within the scope of the compounds of formula (I).

The compounds of formula (I) may also be solvated, especially hydrated, and such solvated and hydrated forms of the compound of formula (I) are also included in the scope of the compounds of formula (I). Solvation and hydration may take place during the preparation process.

Reference to compounds of the invention includes pharmaceutically acceptable salts of said compounds. Such salts may also exist as hydrates and solvates. Examples of pharmacologically acceptable salts of the compounds of formula (I) are salts of physiologically acceptable mineral acids, such as hydrochloric acid, sulfuric acid and phosphoric acid, or salts of organic acids, such as methane -sulfonic acid, p- toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid. Further examples of pharmacologically acceptable salts of the compounds of formula (I) are alkali metal and alkaline earth metal salts such as, for example, sodium, potassium, lithium, calcium or magnesium salts, ammonium salts or salts of organic bases such as, for example, methylamine, dimethylamine, triethylamine, piperidine, ethylenediamine, lysine, choline hydroxide, meglumine, morpholine or arginine salts.

The following examples of substituent definitions and embodiments may be combined in any combination where possible.

R1 is -Y-R2.

Specific examples of R1 are -CH ₂ CH ₂ -OH, -CH ₂ CH(CH ₃ )-OH, -CH ₂ CH ₂ CH ₂ -OH, -CH ₂ CH ₂ -O-CH ₂ CH ₂ - OH, -CH ₂ CH ₂ -pyridinyl (e.g. -CH ₂ CH ₂ -pyridin-2-yl, -CH ₂ CH ₂ -pyridin-3-yl and -CH ₂ CH ₂ -pyridin-4-yl), - CH ₂ CH ₂ -imidazolyl (e.g. -CH ₂ CH ₂ -imidazol-l-yl), -CH ₂ CH ₂ -l,2,4-triazolyl (e.g. -CH ₂ CH ₂ -l,2,4-triazol- 1-yl), -CH ₂ CH ₂ -N(CH ₃ ) ₂ , -CH ₂ CH ₂ -NHS(O ₂ )CH ₃ , -CH ₂ CH ₂ -N(CH ₃ )S(O ₂ )CH ₃ ,-CH ₂ CH ₂ -morpholinyl (e.g. -CH ₂ CH ₂ -morpholin-4-yl), -CH ₂ CH ₂ -piperazinyl (e.g. -CH ₂ CH ₂ -piperazin-l-yl), -CH ₂ CH ₂ -(1- methyl)piperazinyl (e.g. -CH ₂ CH ₂ -(l-methyl)piperazin-4-yl), -CH ₂ CH(OH)CH ₂ -OH and - CH ₂ CH ₂ N(CH ₃ )CH ₂ -pyridinyl (e.g. -CH ₂ CH ₂ N(CH ₃ )CH ₂ -pyridin-2-yl).

In some embodiments R1 is -Y-OH.

In some embodiments R1 is -Y-OH wherein Y is -Cl-C6alkylene-.

Y is -Cl-C6alkylene- wherein one non-terminal -CH ₂ - may be replaced by -N(R3)- or -O- and wherein Y may be substituted by one -OH on a carbon atom that is not bound to an oxygen atom or a nitrogen atom. Reference to a “non-terminal -CH ₂ -” refers a -CH ₂ - moiety which is not at either end of the alkylene moiety (i.e. not the terminal -CH ₂ - moiety which is connected to R1 and not the terminal -CH ₂ - moiety which connected to R2).

Specific examples of Y are -CH ₂ CH ₂ -x, -CH ₂ CH(CH ₃ )-x, -CH ₂ CH ₂ CH ₂ -x, -CH ₂ CH ₂ OCH ₂ CH ₂ -x, - CH ₂ CH(OH)CH ₂ -X and -CH ₂ CH ₂ N(CH ₃ )CH ₂ -x, wherein “x” indicates the connection to R2.

In some embodiments Y is -Cl-C6alkylene-.

In some embodiments Y is -Cl-C6alkylene- wherein one non-terminal -CH ₂ - is replaced by -N(R3)-.

In some embodiments Y is -Cl-C6alkylene- wherein one non-terminal -CH ₂ - is replaced by -O-.

In some embodiments Y is -Cl-C6alkylene- wherein Y is substituted by one -OH on a carbon atom that is not bound to an oxygen atom or a nitrogen atom.

R2 is -OH, -NH ₂ , -NH-S(O) ₂ -Cl-C2alkyl, -N(CH ₃ )-S(O) ₂ -Cl-C2alkyl, Cycle P or Cycle Q and wherein R2 may be hydrogen when Y includes an -N(R3)- or -O-.

Specific examples of R2 are -OH, pyridinyl (e.g. pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), imidazolyl (e.g. imidazol-l-yl), 1,2,4-triazolyl (e.g. 1,2,4-triazol-l-yl), -N(CH ₃ ) ₂ , -NHS(O ₂ )CH ₃ , -N(CH ₃ )S(O ₂ )CH ₃ , morpholinyl (e.g. morpholin-4-yl) and piperazinyl (e.g. piperazin- 1-yl).

In some embodiments R2 is -OH, -NH ₂ , -NH-S(O) ₂ -Cl-C2alkyl or -N(CH ₃ )-S(O) ₂ -Cl-C2alkyl.

In some embodiments R2 is Cycle P or Cycle Q. R3 is hydrogen or Cl-C4alkyl.

Specific examples are hydrogen and methyl.

Cycle P is a 5- to 6-membered heterocyclic ring containing one or two heteroatoms as ring members selected from nitrogen and oxygen and containing at least one nitrogen atom as a ring member, the heterocyclic ring optionally substituted by one to three R4. Cycle P does not contain a quaternary nitrogen atom.

Specific examples of Cycle P are morpholinyl (e.g. morpholin-4-yl) and piperazinyl (e.g. piperazin- 1-yl). In some embodiments Cycle P is a saturated heterocyclic ring.

In some embodiments Cycle P contains a nitrogen atom as ring member which is connected to Y.

In some embodiments Cycle P contains a nitrogen atom as ring member which is not connected to Y.

In some embodiments Cycle P is unsubstituted.

In some embodiments Cycle P is substituted by no more than one R4.

Cycle Q is a 5- to 6-membered heteroaryl containing one to four heteroatoms selected from nitrogen and oxygen and containing at least one nitrogen as ring member which is not connected to Y and not more than one oxygen atom as a ring member, the heteroaryl optionally substituted by one to three R5. Cycle Q does not contain a quaternary nitrogen atom.

Specific examples of Cycle Q are pyridinyl (e.g. pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), imidazolyl (e.g. imidazol-l-yl) and 1,2,4-triazolyl (e.g. 1,2,4-triazol-l-yl).

In some embodiments Cycle Q is unsubstituted.

In some embodiments Cycle Q is substituted by no more than one R5.

Each R4 is independently Cl-C4alkyl. A specific example of R4 is methyl.

Each R5 is independently Cl-C4alkyl.

In an embodiment the compound is a compound of formula (I), wherein

R1 is -Y-R2;

Y is -CH2CH2-X, -CH ₂ CH(CH ₃ )-X, -CH2CH2CH2-X, -CH2CH2OCH2CH2-X, -CH ₂ CH(OH)CH ₂ -x or - CH2CH2N(CH ₃ )CH2-X, wherein “x” indicates the connection to R2; and

R2 is -OH, pyridinyl (e.g. pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), imidazolyl (e.g. imidazol-l-yl), 1,2,4- triazolyl (e.g. 1,2,4-triazol-l-yl), -N(CH ₃ )2, -NHS(O2)CH ₃ , -N(CH ₃ )S(O2)CH ₃ , morpholinyl (e.g. morpholin-4-yl) or piperazinyl (e.g. piperazin- 1-yl).

In further embodiments the invention provides the following compounds and pharmaceutically acceptable salts thereof:

The above compounds may be referred to according to their UPAC names as follows:

3 -[4-(2-hydroxyethoxy)-5 ,6-dimethyl-2-[4-(trifhioromethyl)anilino] -3 -pyridyl] -4H- 1 ,2,4-oxadiazol-5 - one; 3-[4-[2-hydroxypropoxy]-5,6-dimethyl-2-[4-(trifluoromethyl)a nilino]-3-pyridyl]-4H-l,2,4-oxadiazol-5- one;

3-[4-(3-hydroxypropoxy)-5,6-dimethyl-2-[4-(trifluoromethy l)anilino]-3-pyridyl]-4H-l,2,4-oxadiazol-5- one;

3-[4-[2-(2-hydroxyethoxy)ethoxy]-5,6-dimethyl-2-[4-(trifl uoromethyl)anilino]-3-pyridyl ]-4H-l,2,4- oxadiazol-5-one;

3-[5,6-dimethyl-4-[2-(2-pyridyl)ethoxy]-2-[4-(trifluorome thyl)anilino]-3-pyridyl]-4H-l,2,4-oxadiazol-5- one; 3 -[5 ,6-dimethyl-4-[2-(3 -pyridyl)ethoxy] -2-[4-(trifluoromethyl)anilino] -3 -pyridyl] -4H- 1 ,2,4-oxadiazol-5 - one;

3-[5,6-dimethyl-4-[2-(4-pyridyl)ethoxy]-2-[4-(trifluorome thyl)anilino]-3-pyridyl]-4H-l,2,4-oxadiazol-5- one;

3-[4-(2-imidazol-l-ylethoxy)-5,6-dimethyl-2-[4-(trifluoro methyl)anilino]-3-pyridyl]-4H-l,2,4-oxadiazol- 5 -one;

3-[5,6-dimethyl-4-[2-(l,2,4-triazol-l-yl)ethoxy]-2-[4-(tr ifluoromethyl)anilino]-3-pyridyl]-4H-l,2,4- oxadiazol-5-one;

3-[4-[2-(dimethylamino)ethoxy]-5,6-dimethyl-2-[4-(trifluo romethyl)anilino]-3-pyridyl]-4H-l,2,4- oxadiazol-5-one;

A-[2-[[2,3-dimethyl-5-(5-oxo-4H-l,2,4-oxadiazol-3-yl)-6-[ 4-(trifluoromethyl)anilino]-4- pyridyl] oxy] ethyl] methanesulfonamide ;

3-[5,6-dimethyl-4-(2-morpholinoethoxy)-2-[4-(trifluoromet hyl)anilino]-3-pyridyl]-4H-l,2,4-oxadiazol-5- one;

3-[5,6-dimethyl-4-(2 -piperazin- l-ylethoxy)-2-[4-(trifluoromethyl)anilino] -3 -pyridyl] -4H-1, 2, 4-oxadiazol- 5 -one;

3-[5,6-dimethyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]-2-[4 -(trifluoromethyl)anilino]-3-pyridyl ]-4H-l,2,4- oxadiazol-5-one;

3-[4-(2,3-dihydroxypropoxy)-5,6-dimethyl-2-[4-(trifluorom ethyl)anilino]-3-pyridyl]-4H-l,2,4-oxadiazol- 5 -one;

3-[5,6-dimethyl-4-[2-[methyl(3-pyridyhnethyl)amino]ethoxy ]-2-[4-(trifluoromethyl)anilino]-3-pyridyl]- 4H-l,2,4-oxadiazol-5-one; and

A-[2-[[2,3-dimethyl-5-(5-oxo-4H-l,2,4-oxadiazol-3-yl)-6-[ 4-(trifluoromethyl)anilino]-4- pyridyl] oxy] ethyl] - '-m eth l -methanesulfonamide .

Some intermediates useful for the preparation of compounds of formula (I) are new and form further aspects of the invention. Accordingly, in a further aspect the invention provides compounds of formula (Int-I)

(Int-I) wherein PG is hydrogen or a protecting group such as tert-butyloxycarbonyl (BOC), 9- fluorenylmethoxycarbonyl (Fmoc), benzyloxycarbonyl, acetyl, trifluoroacetyl, benzyl, trityl, benzylidene or p-toluenesulfonyl, preferably tert-butyloxycarbonyl (BOC). In a further aspect the invention provides compounds of formula (Int-II)

(Int-II) wherein R1 ’ is R1 as defined for the compound of formula (I), wherein any -OH group within R1 may be protected with a suitable protecting group such as trimethylsilyl, / -butyldimcthylsilyl (TBDMS), tert- butyldiphenylsilyl or acetyl, preferably / -butyldimcthylsilyl (TBDMS), and PG is hydrogen or a protecting group such as tert-butyloxycarbonyl (BOC), 9-fluorenyhnethoxy carbonyl (Fmoc), benzyloxycarbonyl, acetyl, trifluoroacetyl, benzyl, trityl, benzylidene or p-toluenesulfonyl, preferably tert-butyloxycarbonyl (BOC).

In a further aspect the invention provides compounds of formula (Int-III)

(Int-III) wherein R1 ’ is R1 as defined for the compound of formula (I), wherein any -OH group within R1 may be protected with a suitable protecting group such as trimethylsilyl, / -butyldimcthylsilyl (TBDMS), tert- butyldiphenylsilyl or acetyl, preferably / -butyldimcthylsilyl (TBDMS), and PG is hydrogen or a protecting group such as tert-butyloxycarbonyl (BOC), 9-fluorenyhnethoxy carbonyl (Fmoc), benzyloxycarbonyl, acetyl, trifluoroacetyl, benzyl, trityl, benzylidene or p-toluenesulfonyl, preferably tert-butyloxycarbonyl (BOC).

The present invention relates also to pharmaceutical compositions that comprise a compound of formula (I) as active ingredient or a pharmaceutically acceptable salt thereof, which can be used especially in the treatment of neoplastic diseases, in particular cancer, as described herein. Compositions may be formulated for non-parenteral administration, such as nasal, buccal, rectal, pulmonary, vaginal, sublingual, topical, transdermal, ophthalmic, or, especially, for oral administration, e.g. in the form of oral solid dosage forms, e.g. granules, pellets, powders, tablets, fdm or sugar-coated tablets, effervescent tablets, hard and soft gelatin or hydroxypropylmethylcellulose (HPMC) capsules, coated as applicable, orally disintegrating tablets, oral solutions, lipid emulsions or suspensions, or for parenteral administration, such as intravenous, intramuscular, or subcutaneous, intrathecal, intradermal or epidural administration, to mammals, especially humans, e.g. in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles. The compositions may comprise the active ingredient alone or, preferably, together with a pharmaceutically acceptable excipient.

The compounds of formula (I) or pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic excipients for the production of oral solid dosage forms, e.g. granules, pellets, powders, tablets, fdm or sugar coated tablets, effervescent tablets, hard gelatin or HPMC capsules or orally disintegrating tablets. Fillers e.g. lactose, cellulose, mannitol, sorbitol, calcium phosphate, starch or derivatives thereof, binders e.g. cellulose, starch, polyvinylpyrrolidone, or derivatives thereof, glidants e.g. talcum, stearic acid or its salts, flowing agents e.g. fumed silica, can be used as such excipients for formulating and manufacturing of oral solid dosage forms, such as granules, pellets, powders, tablets, fdm or sugar coated tablets, effervescent tablets, hard gelatin or HPMC capsules, or orally disintegrating tablets. Suitable excipients for soft gelatin capsules are e.g. vegetable oils, waxes, fats, semisolid and liquid polyols etc..

Suitable excipients for the manufacture of oral solutions, lipid emulsions or suspensions are e.g. water, alcohols, polyols, saccharose, invert sugar, glucose etc..

Suitable excipients for parenteral formulations are e.g. water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants etc..

Moreover, the pharmaceutical preparations can contain preservatives, solubilizers (e.g. cyclodextrin), stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically valuable substances.

The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 1 to 1000 mg per person of a compound of general formula (I) should be appropriate, although the above lower or upper limit can also be exceeded when necessary.

The compounds of formula (I) can also be used in combination with one or more other pharmaceutically active compounds, which are either effective against the same disease, preferably using a different mode of action, or which reduce or prevent possible undesired side effects of the compounds of formula (I). The combination partners can be administered in such a treatment either simultaneously, e.g. by incorporating them into a single pharmaceutical formulation, or consecutively by administration of two or more different dosage forms, each containing one or more than one of the combination partners.

Compounds of formula (I) according to the invention as described above or pharmaceutically acceptable salts thereof are particularly useful for the treatment of neoplastic diseases such as cancer, in particular carcinoma, sarcoma, leukemia, myeloma and lymphoma and cancers of the brain and spinal cord, e.g. when administered in therapeutically effective amounts . In some embodiments, the cancer to be treated by the compounds of the present invention is mediated by modulation of the interaction of YAP/TAZ with TEAD. In some embodiments the compounds of the invention may treat the cancer by modulating the interaction between YAP/TAZ and TEAD. In some embodiments the compounds of the invention may inhibit the interaction between YAP/TAZ and TEAD, In some embodiments, the cancer is a solid tumour. In some embodiments, the cancer is a hematologic malignancy. In some instances, the solid tumour is a sarcoma or carcinoma. In some embodiments, the solid tumour is a sarcoma. In some instances, the solid tumour is a carcinoma.

Examples of neoplastic diseases include, but are not limited to, epithelial neoplasms, squamous cell neoplasms, basal cell neoplasms, transitional cell papillomas and carcinomas, adenomas and adenocarcinomas, adnexal and skin appendage neoplasms, mucoepidermoid neoplasms, cystic neoplasms, mucinous and serous neoplasms, ducal-, lobular and medullary neoplasms, acinar cell neoplasms, complex epithelial neoplasms, specialized gonadal neoplasms, paragangliomas and glomus tumours, naevi and melanomas, soft tissue tumours and sarcomas, fibromatous neoplasms, myxomatous neoplasms, lipomatous neoplasms, myomatous neoplasms, complex mixed and stromal neoplasms, fibroepithelial neoplasms, synovial-like neoplasms, mesothelial neoplasms, germ cell neoplasms, trophoblastic neoplasms, mesonephromas, blood vessel tumours, lymphatic vessel tumours, osseous and chondromatous neoplasms, giant cell tumours, miscellaneous bone tumours, odontogenic tumours, gliomas, neuroepitheliomatous and neuroendocrine neoplasms, meningiomas, nerve sheath tumours, granular cell tumours and alveolar soft part sarcomas, Hodgkin's and non-Hodgkin's lymphomas, B-cell lymphoma, T-cell lymphoma, hairy-cell lymphoma, Burkitts lymphoma and other lymphoreticular neoplasms, plasma cell tumours, mast cell tumours, immunoproliferative diseases, leukemias, miscellaneous myeloproliferative disorders, lymphoproliferative disorders and myelodysplastic syndromes.

Examples of cancers in terms of the organs and parts of the body affected include, but are not limited to, the breast, endometrium (endometrial cancer), cervix, ovaries, colon, rectum (including colon and rectum i.e. colorectal cancer), lung (including small cell lung cancer, non-small cell lung cancer, large cell lung cancer and mesothelioma), endocrine system, bone, adrenal gland, thymus, liver, stomach (gastric cancer), intestine, pancreas, bone marrow, hematological malignancies (such as lymphoma, leukemia, myeloma or lymphoid malignancies), bladder, urinary tract, kidneys, skin, thyroid, brain, head, neck, prostate and testis. Preferably the cancer is selected from the group consisting of breast cancer, prostate cancer, cervical cancer, ovarian cancer, gastric cancer, colorectal cancer, pancreatic cancer, liver cancer, brain cancer, neuroendocrine cancer, lung cancer, kidney cancer, bladder cancer, mesothelioma, hematological malignancies, melanomas and sarcomas. The term "treatment" or “treating” as used herein in the context of treating a disease or disorder, pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the disease or disorder, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviation of symptoms of the disease or disorder, amelioration of the disease or disorder, and cure of the disease or disorder. Treatment as a prophylactic measure (i.e., prophylaxis) is also included. For example, use with patients who have not yet developed the disease or disorder, but who are at risk of developing the disease or disorder, is encompassed by the term "treatment." For example, treatment includes the prophylaxis of cancer, reducing the incidence of cancer, alleviating the symptoms of cancer, etc..

The term "therapeutically-effective amount," as used herein, pertains to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.

The term "pharmaceutical composition" is defined herein to refer to a solid or liquid formulation containing at least one therapeutic agent to be administered to a subject, e.g., a mammal or human, optionally with one or more pharmaceutically acceptable excipients, in order to prevent or treat a particular disease or condition affecting the mammal.

The term "pharmaceutically acceptable" as used herein refers to items such as compounds and salts thereof, materials, compositions and/or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues of a warm-blooded animal, e.g., a mammal or human, without excessive toxicity or other complications commensurate with a reasonable benefit/risk ratio.

The compounds of formula (I) can be synthesized by methods given below, by methods given in the experimental part below or by analogous methods. The schemes described herein are not intended to present an exhaustive list of methods for preparing the compounds of formula (I); rather, additional techniques of which the skilled chemist is aware may be also used for the compound synthesis.

It is understood by one skilled in the art of organic synthesis that optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by routine optimization procedures. In some cases, the order of performing the following reaction schemes, and/or reaction steps, may be varied to facilitate the reaction or to avoid the formation of unwanted side products. In addition, the functionality present at various positions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents, which are compatible with the reaction conditions, will be readily apparent to one skilled in the art and alternate methods must then be used. Furthermore in some of the reactions mentioned herein it may be necessary or desirable to protect any sensitive groups in compounds and it will be assumed that such protecting groups (PG) as necessary are in place. Conventional protecting groups may be used in accordance with standard practice, well known in the art (for illustration see Greene T.W, Wuts P.G.M, Protective Groups in Organic Synthesis, 5th Edition, Publisher: John Wiley & Sons, 2014). The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the art, or they may be removed during a later reaction step or work-up.

In the general sequence of reactions outlined below, the generic group R1 is as defined for formula (I), unless otherwise specified. Other abbreviations used herein are explicitly defined, or are as defined in the experimental section. In addition, the skilled person will understand that general sequence of reactions outlined below is applicable to all tautomeric forms even if only one tautomer form is drawn.

The necessary starting materials for the synthetic methods as described herein, if not commercially available, may be made by procedures which are described in the scientific literature, or may be made from commercially available compounds using adaptations of processes reported in the scientific literature. The reader is further referred to March J., Smith M., Advanced Organic Chemistry, 7th Edition, Publisher: John Wiley & Sons, 2013 for general guidance on reaction conditions and reagents.

The compounds according to the present invention, pharmaceutically acceptable salts, solvates, and hydrates thereof can be prepared according to the general sequence of reactions outlined below, followed, if necessary, by: manipulation of substituents to give a new final product. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, substitution, coupling including transition-metal catalyzed coupling and hydrolysis reactions which are commonly known by those skilled in the art; removing any protecting groups; forming a pharmaceutically acceptable salt; or forming a pharmaceutically acceptable solvate or hydrate.

Scheme 1

Generally, compounds of formula (I) are obtained following Scheme 1, as described below.

Compounds of formula (s-1), compounds of formula (r-1), compounds of formula (r-2) and compounds of formula (r-3) can be obtained from commercial sources, or are prepared following procedures described in literature, or by procedures known by a person skilled in the art.

Compounds of formula (Int-I), wherein PG is hydrogen are generally obtained from compounds of formula (s-1), wherein El is a halogen or a leaving group such as a triflate, and a compound of formula (r-1), wherein E2 is an amino group, via a transition-metal catalyst reaction coupling. Typical catalysts include palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0) or alike. The reaction is typically run at a temperature from 0°C to 150°C, more frequently from 60°C to 110°C. Usually the reaction is performed in the presence of a ligand such as di-tert-butyl-[3,6-dimethoxy-2-(2,4,6- triisopropylphenyl)phenyl]phosphane, di-/ -butyl-| 2.3.4.5-tctramcthyl-6-(2.4.6- triisopropylphenyl)phenyl]phosphane, 2-(dicyclohexylphosphino)biphenyl, 4,5-bis(diphenylphospheno)- 9,9-dimethylxanthene or the like and a base such as sodium tert-butylate, cesium carbonate or potassium carbonate, more frequently cesium carbonate, and may be performed in a large variety of inert solvents such as toluene, tetrahydrofuran, dioxane, 1,2-dichloroethane, N, JV-dimethyl formamide, dimethylsulfoxide, water and acetonitrile, or a mixture of solvents, more frequently in dioxane. Preferably, compounds of formula (Int-I), wherein PG is hydrogen are prepared from compounds of formula (s-1), wherein El is a chloro atom, and compounds of formula (r- 1), wherein E2 is an amino group in presence of palladium(II) acetate, 4,5-bis(diphenylphospheno)-9,9-dimethylxanthene and cesium carbonate in dioxane at a temperature of 60°C.

Compounds of formula (Int-I), wherein PG is a protecting group can be obtained from compounds of formula (Int-2) wherein PG is hydrogen using classical methods for the introduction of an amino protecting group. Usually, when PG is a BOC group, the compound of formula (Int-I) is prepared from a compound of formula (Int-I), wherein PG is hydrogen and (BOC)2O in an aprotic solvent such as dicloromethane, ethyl acetate, tetrahydrofuran, '. '-dimcthylformamidc. dimethylsulfoxide or the like, in the presence of an organic base such as triethylamine, /V,/V-diisopropylethylamine, pyridine or 4- (dimethylamino)pyridine or an inorganic base such as sodium hydroxide, potassium carbonate or sodium hydrogen carbonate. Reactions are typically run from -20 to 100°C, preferably at temperature ranging from 0°C to 40°C. Further general methods to introduce amino protecting groups have been described in Greene T.W., Wuts P.G.M., Protective Groups in Organic Synthesis, 5th Edition, Publisher: John Wiley & Sons, 2014.

Compounds of formula (Int-II) can be generated from compounds of formula (Int-I) and compounds of formula (r-2) via aromatic substitution reaction. The nucleophilic aromatic substitution can be performed in a large variety of solvents such as methanol, ethanol, iso -propanol, '. '-dimcthylformamidc. dimethyl sulfoxide or tetrahydrofuran, more frequently in '. '-dimcthylformamidc. and in presence of an organic base, such as triethylamine, /V,/V-diisopropylethylamine, pyridine or potassium /c/V-butoxidc. or an inorganic base such as sodium hydroxide, potassium carbonate or sodium hydrogen carbonate, more frequently using sodium hydride. Reactions are typically run from -20 to 140°C, using classical heating devices or using microwave devices.

For compounds of formula (r-2), compounds of formula (Int-II), compounds of formula (Int-III) and compounds of formula (Int-IV), Rl’ is as defined by the claims for R1 but also includes moieties bearing any convenient protecting groups or any suitable functional groups, enabling the formation of Rl using standard practice in medicinal chemistry. For example, when Rl is -CH2CH2OH, the free hydroxyl group can be protected with a / -biityldi methyl silyl group. It is understood that such deprotection steps or reactions of functional groups of Rl’ to form Rl can be executed at any convenient stage during the synthesis of compounds of formula (I).

Compounds of formula (Int-III) are generally obtained from a condensation reaction between compounds of formula (Int-II) and a hydroxylamine solution or a hydroxylamine salt (generally hydroxylamine hydrochloride). The reaction is typically run in alcoholic solvents such as methanol, ethanol, /.so-propanol or tert-butanol (more frequently /.so-propanol) in a presence or absence of an inorganic base such as sodium carbonate, more frequently sodium hydrogen carbonate, or in the presence or absence of an organic base such as sodium tert-butoxide, triethylamine, pyridine or alike at a temperature typically ranging from 20°C to 90°C.

Generally, compounds of formula (Int-IV) can be obtained by a coupling reaction of a compound of formula (Int-III) and a compound of formula (r-3), wherein E3 and E4 are leaving groups, such as chlorine, imidazole, phenol, 4-nitrophenol, 2,2,2-trifluoro-ethanol, methanol, ethanol or 1- hydroxypyrrolidine-2, 5-dione, followed by intra-molecular cyclization. The coupling reaction and the cyclization reaction can be performed sequentially but are generally simultaneously performed in situ. Depending on the reactivity of compound of formula (r-3), different reaction conditions can be applied, which would be readily apparent to a skilled chemist. For example, when a compound of formula (r-3) is phosgene, or more frequently a phosgene analogue (such as bis(trichloromethyl) carbonate or trichloromethyl chloroformate), the reaction is typically performed in aprotic and inert solvents such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran or ethyl acetate (more frequently dichloromethane) in presence or absence of a base such as triethylamine, 4-(dimethylamino)pyridine or '.A'-diisopropylcthylaminc. Reactions are typically run from -40°C to 50°C, generally 0 °C.

When a compound of formula (r-3) is l,l'-carbonyldiimidazole (which can be activated by methylation prior to the reaction), methyl chloroformate, phenyl chloroformate, 4-nitrophenyl chloroformate, 2,2,2- trifluoroethyl chloroformate or A'.A"-disuccinimidyl carbonate, the reaction can be performed in absence or in presence of a base, such as sodium hydride, triethylamine, pyridine (diluted or neat), 4- (dimethylamino)pyridine, or l,8-diazabicyclo[5.4.0]undec-7-ene in aprotic solvents such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, ethyl acetate or A'.A'-dimcthylformamidc. Reactions are typically run from -10°C to 150°C. More frequently, compounds of formula (Int-6) are prepared from the reaction between a compound of formula (Int-5) and 1. 1 '-carbonyldi imidazole in tetrahydrofuran at a temperature of 60°C. Alternatively, when a compound of formula (r-3) is dimethylcarbonate, the reaction is typically performed in aprotic solvents such as N.N- dimethylformamide or dimethyl sulfoxide in the presence of an inorganic base such as sodium hydroxide, sodium carbonate or an organic base such as triethylamine or pyridine. Reactions are generally run from - 10°C to 120°C, more frequently at room temperature.

Generally, compounds of formula (I) can be obtained from compounds of formula (Int-IV) after removal of any protecting groups using conventional techniques well known in the art. For example, when PG is a BOC group, the cleavage of the tert-butyl carbamate bond is usually performed under acidic conditions. Strong acid, such as trifluoroacetic acid or hydrochlorid acid, can be employed in an inert solvent such as dichloromethane, ethyl acetate, chloroform, diethylether or dioxane at a wide range of temperatures (e.g. - 10°C to 100°C), more frequently at 20°C. Further general methods to remove amino protecting groups are described in Greene T.W., Wuts P.G.M., Protective Groups in Organic Synthesis, 5th Edition, Publisher: John Wiley & Sons, 2014.

The schemes and processes described herein are not intended to present an exhaustive list of methods for preparing the compounds of formula (I); rather, additional techniques of which the skilled chemist is aware of may be also used for the compound synthesis.

All aspects and embodiments of the invention described herein may be combined in any combination where possible.

A number of publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

Particular embodiments of the invention are described in the following Examples, which serve to illustrate the invention in more detail and should not be construed as limiting the invention in any way.

Examples

Preparation of Examples

All reagents and solvents are generally used as received from the commercial supplier; reactions are routinely performed with anhydrous solvents in well -dried glassware under nitrogen atmosphere, unless otherwise specified; evaporations are carried out by rotary evaporation under reduced pressure and work-up procedures are carried out after removal of residual solids by filtration; all temperatures are given in degree Celsius (°C) and are approximate temperatures; unless otherwise noted, operations are carried out at room temperature (rt), that is typically in the range 18°C - 25°C; column chromatography (by the flash procedure) is used to purify compounds and is performed using Merck silica gel 60 (70-230 mesh ASTM) unless otherwise stated; classical flash chromatography is often replaced by automated systems. This does not change the separation process per se. A person skilled in the art will be able to replace a classical flash chromatography process by an automated one, and vice versa. Typical automated systems can be used, as they are provided by Btichi or Isco (combiflash) for instance; reaction mixture can often be separated by preparative HPLC using water and acetonitrile as system of eluents, unless otherwise stated. A person skilled in the art will find suitable conditions for each separation; in some cases the compounds are isolated after purification in a form of the corresponding trifluoroacetic acid (TFA) salt (*1), or the respective formic acid salt (*2); such compounds are marked accordingly; reactions, which required higher temperature, are usually performed using classical heating instruments; but can also be performed using microwave apparatus (CEM Explorer) at a power of 250 W, unless otherwise noted; hydrogenation or hydrogenolysis reactions can be performed using hydrogen gas in balloon or using Parrapparatus system or other suitable hydrogenation equipment; concentration of solutions and drying of solids are performed under reduced pressure unless otherwise stated; in general, the course of reactions is followed by TLC, HPLC, or LC/MS and reaction times are given for illustration only; yields are given for illustration only and are not necessarily the maximum attainable; the structure of the final products of the invention is generally confirmed by NMR and mass spectral techniques.

Proton NMR spectra are recorded on a Brucker 400 MHz spectrometer. Chemical shifts (5) are reported in ppm relative to Me4Si as internal standard, and NMR coupling constants (J values) are in Hertz (Hz). Each peak is denoted as a broad singlet (br), singlet (s), doublet (d), triplet (t), quadruplet (q), doublet of doublets (dd), triplet of doublets (td) or multiplet (m). Mass spectra are generated using a q-Tof Ultima (Waters AG or Thermo Scientific MSQ Plus) mass spectrometer in the positive or negative ESI mode. The system is equipped with the standard Lockspray interface; each intermediate is purified to the standard required for the subsequent stage and is characterized in sufficient detail to confirm that the assigned structure is correct; analytical and preparative HPLC on non-chiral phases are performed using RP-C18 based columns.

The following abbreviations may be used (reference can also be made to The Journal of Organic Chemistry Guidelines for Authors, 2017 for a comprehensive list of standard abbreviations): ACN Acetonitrile

(BOC) ₂ O Di -tert-butyl dicarbonate

BOC tert-butoxy carbonyl group

Cat. no. Catalog number

CDCE Deuterated chloroform

CDI 1 , T -Carbonyldiimidazole

DBU l,8-Diazabicyclo[5.4.0]undec-7-ene

DCM Dichloromethane

DIPEA '. '-Diisopropylcthylaminc

DMAP 4-Dimethylaminopyridine DMF Dimethylformamide

DMSO Dimethyl sulfoxide

DMSO-d6 Deuterated dimethyl sulfoxide

EA Ethyl acetate

ELSD Evaporative light scattering detection

EtOH Ethanol

Ex. Example c-Hex Cyclohexane w-Hex w-Hexane z-PrOH /.so-propanol

LC/MS Liquid chromatography coupled to mass spectroscopy

Me4Si Tetramethylsilane

MeOH Methanol nt Not Tested

PBS Phosphate-Buffered Saline

PCR Polymerase Chain Reaction

Pd(OAc)2 Palladium (II) acetate

PE Petroleum Ether qd quaque die

RNA ribonucleic acid

SEM Standard Error of the Measurement

TBDMS tert-butyldimethylsilyl

TEA Triethylamine

THF Tetrahydrofuran

Tol Toluene

W Watt

XantPhos 4,5-bis(diphenylphospheno)-9,9-dimethylxanthene

The following Examples refer to the compounds of formula (I) as indicated in Table 1.

The Examples listed in the following table can be prepared using procedures described above, and detailed synthesis methodology is described in detail below. The Example numbers used in the leftmost column are used in the application text for identifying the respective compounds. Table 1: Exemplified compounds

Preparation of Example 1:

Step 1: Preparation of A-cyclohexyl-4-hydroxy-5.6-dimethyl-2-oxo-lH-pyridine-3-carb oxamide: To a solution of ethyl 4-hydroxy-5,6-dimethyl-2-oxo-lH-pyridine-3-carboxylate (2 g; 7.58 mmol) in Tol (20 mL) was added cyclohexylamine (1.75 mL; 15.15 mmol). The suspension was heated to 110°C and stirred for 8 h. The reaction was concentrated to dryness and the residue was triturated in EA. The suspension was fdtrated to afford /V-cyclohexyl-4-hydroxy-5,6-dimethyl-2-oxo- lH-pyridine-3- carboxamide (1.6 g) as a brown solid, used in the next step without further purification. MS m/z (+ESI): 265.2 [M+H] ⁺ . Step 2: Preparation of 2.4-dichloro-5.6-dimethyl-pyridine-3-carbonitrile:

A solution of A-cyclohexyl-4-hydroxy-5,6-dimethyl-2-oxo-lTT-pyridine-3-car boxamide (0.19 g; 0.65 mmol) in POCL (1.90 mL; 20.1 mmol) was heated to 90°C and stirred for 18 h. The mixture was concentrated and the residue was purified by column chromatography (silica gel; PE:EA; 9: 1 to 1: 1; v/v) to afford 2,4-dichloro-5,6-dimethyl-pyridine-3-carbonitrile (0.07 g) as a white solid.

MS m/z (+ESI): 201.0 [M+H] ⁺ .

’H-NMR (400 MHz, CDC1 ₃ ) 5 ppm: 2.63 (s, 3H), 2.40 (s, 3H).

Step 3: Preparation of 4-chloro-5.6-dimethyl-2-[4-(trifluoromethyl)anilino]pyridine -3-carbonitrile: To a solution of 2,4-dichloro-5,6-dimethyl-pyridine-3-carbonitrile (0.04 g; 0.18 mmol) and 4- (trifluoromethyl)aniline (0.023 mL; 0.18 mmol) in dioxane (2 mL) were added CS2CO3 (0.12 g; 0.36 mmol), XantPhos (0.021 g; 0.036 mmol) and Pd(OAc)2 (0.008 g; 0.036 mmol). The suspension was heated to 60°C and stirred for 1 h. The suspension was filtrated and the filtrate was concentrated. The residue was purified by column chromatography (silica gel; PE:EA; 1 :0 to 1: 1; v/v) to afford 4-chloro-

5.6-dimethyl-2-[4-(trifhioromethyl)anilino]pyridine-3-car bonitrile (0.03 g) as a white solid.

MS m/z (+ESI): 326.1 [M+H] ⁺ .

’H-NMR (400 MHz, DMSO- 4) 5 ppm: 9.51 (s, 1H), 7.77 (d, J= 8.8 Hz, 2H), 7.64 (d, J= 8.8 Hz, 2H), 2.48 (s, 3H), 2.26 (s, 3H).

Step 4: Preparation of tert-butyl A-(4-chloro-3-cvano-5.6-dimethyl-2-pyridyl)-A-[4- (trifluoromethyl)phenyll carbamate :

To a solution of 4-chloro-5,6-dimethyl-2-[4-(trifluoromethyl)anilino]pyridine -3-carbonitrile (0.33 g; 0.81 mmol), TEA (0.23 mL; 1.62 mmol) and DMAP (0.010 g; 0.08 mmol) in DCM (5 mL) was added (BOC)2O (0.81 g; 3.65 mmol) in three portions at 0°C. The ice-bath was removed and the solution was stirred for 3 h. The solution was washed with water and brine, dried over Na2SC>4 and concentrated to afford tert-butyl A-(4-chloro-3-cyano-5,6-dimethyl-2-pyridyl)-/V-[4-(trifluoro methyl)phenyl ]carbamate (0.33 g) as a yellow oil, used in next step without further purification.

MS m/z (+ESI): 426.1 [M+H] ⁺ .

Step 5: Preparation of tert-butyl A-[4-[2-[tert-butyl(dimethyl)silyl1oxyethoxy|-3-cyano-5.6-di methyl-2- pyridyl1-A-[4-(trifluoromethyl)phenyllcarbamate:

To a solution of 2-((tert-butyldimethylsilyl)oxy)ethanol (0.65 g; 3.57 mmol) in DML (3 mL) was added NaH (0.14 g; 3.57 mmol) at 0°C and the mixture was stirred for 10 min. Tert-butyl A-(4-chloro-3-cyano-

5.6-dimethyl-2-pyridyl)-A-[4-(trifluoromethyl)phenyl]carb amate (0.32 g; 0.71 mmol) was added and the suspension was for 2 h. The reaction was deactivaed by addition of NH4CI aqueous solution and the product was extracted with EA (twice). The combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated. The residue was purified by column chromatography (silica gel; PE:EA; 1:0 to 1: 1; v/v) to afford tert-butyl A-[4-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-3-cyano-5,6- dimethyl-2-pyridyl]-/V-[4-(trifluoromethyl)phenyl]carbamate (0.55 g) as a yellow oil.

MS m/z (+ESI): 566.3 [M+H] ⁺ .

Step 6: Preparation of tert-butyl A-|4-|2-|tcrt-biityl(dimethyl)silyl |oxyethoxy|-3-| A'- hydroxycarbamimidoyl1-5.6-dimethyl-2-pyridyl1-/V-[4-(trifluo romethyl)phenyl]carbamate:

To a solution of tert-butyl A-[4-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-3-cyano-5,6-di methyl-2- pyridyl |-A-|4-(trifhioromcthyl)phcnyl |carbamatc (1.8 g; 2.86 mmol) in EtOH (6 mL) was added NH2OH solution, 50% in H2O (2.42 mL; 41.2 mmol). The solution was heated at 90°C and stirred for 4 h. The solution was concentrated. The residue was purified by column chromatography (silica gel; PE:EA; 1:0 to 1: 1; v/v) to afford tert-butyl A-|4-|2-|tcrt-butyl(dimcthyl)silyl |oxycthoxy |-3-| A'-hydroxycarbamimidoyl ]- 5,6-dimethyl-2-pyridyl]-A-[4-(trifluoromethyl)phenyl]carbama te (0.95 g) as yellow oil.

MS m/z (+ESI): 599.4 [M+H] ⁺ .

‘H-NMR (400 MHz, CDC1 ₃ ) 5 ppm: 7.51 - 7.45 (m, 4H), 5.06 (br, 2H), 4.14 (t, J= 4.8 Hz, 2H), 3.89 (t, J = 4.8 Hz, 2H), 2.48 (s, 3H), 2.24 (s, 3H), 1.46 (s, 9H), 0.90 (s, 9H), 0.08 (s, 6H).

Step 7: Preparation of tert-butyl A-|4-|2-|tcrt-biityl(dimcthyl)silyl|oxycthoxy|-5.6-dimethyl- 3-(5-oxo-4//-

1.2.4-oxadiazol-3-yl)-2-pyridyl1-A-[4-(trifluoromethyl)ph enyl1carbamate:

To a solution of tert-butyl A-[4-[2-[tert-butyl(dimethyl)silyl |oxycthoxy ]-3-[ A'-hydroxycarbamimidoyl ]- 5,6-dimethyl-2-pyridyl]-A-[4-(trifluoromethyl)phenyl]carbama te (0.85 g; 1.35 mmol) in THF (15 mL) was added CDI (0.45 g; 2.70 mmol). The solution was heated to 60°C and stirred for 18 h. The solution was concentrated. The residue was purified by column chromatography (silica gel; PE:EA; 1:0 to 0: 1; v/v) to afford tert-butyl A-| 4-| 2-[ tcrt-bntyl (dimethyl )silyl |oxycthoxy ]-5,6-dimethyl-3-(5-oxo-4H- 1 ,2,4- oxadiazol-3-yl)-2-pyridyl]-A-[4-(trifluoromethyl)phenyl]carb amate (0.58 g) as a yellow oil.

MS m/z (+ESI): 625.3 [M+H] ⁺ .

Step 8: Preparation of 3-|4-(2-hvdroxycthoxy)-5.6-dimcthyl-2-|4-(trifliioromethyl)a nilino |-3-pyridyl I-4A-

1.2.4-oxadiazol-5-one:

A solution of tert-butyl A-[4-[2-[tert-butyl(dimethyl)silyl]oxyethoxy]-5,6-dimethyl-3 -(5-oxo-4H-l,2,4- oxadiazol-3-yl)-2-pyridyl]-/V-[4-(trifluoromethyl)phenyl]car bamate (0.14 g; 0.22 mmol) in HC1 solution, 4N in dioxane (2.8 mL; 11.2 mmol) was stirred for 1 h. The solution was concentrated and the product was purified by preparative HPLC to afford 3-[4-(2-hydroxyethoxy)-5,6-dimethyl-2-[4- (trifluoromethyl)anilino]-3-pyridyl]-4H-l,2,4-oxadiazol-5-on e (0.031 g) as a white solid.

MS m/z (+ESI): 411.6 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-t/ ₆ ) 5 ppm: 12.42 (br, 1H), 8.81 (s, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.59 (d, J= 8.8 Hz, 2H), 5.05 (br, 1H), 3.87 (t, J= 4.8 Hz, 2H), 3.63 (t, J= 4.8 Hz, 2H), 2.43 (s, 3H), 2.15 (s, 3H). Biological Examples

In Vitro assay studies

Thermal shift assay

The thermal shift assay (TSA) was utilized to characterize target engagement in vitro based on liganddependent thermal stabilization of the protein. N-terminally His-tagged human TEAD2 (amino acids 217- 447) expressed and purified from E. coli was purchased from Proteros biostructures (cat no. PR-0365). The melting reactions were performed in white, 96 well qPCR plates (Roche Diagnostics, cat. no. 04 729 692 001) in 20 mM HEPES pH 7, 100 mM NaCl in the presence of 4x SYPRO orange (Sigma, cat. no. S5692). Each well contained 3 pM recombinant TEAD2 and either DMSO (control) or experimental compounds at a final concentration of 14 pM. The total volume was 20 pL and the final DMSO concentration was 1%. The plate was sealed and analyzed in a LightCycler 480 II (Roche Diagnostics) by continuously reading the fluorescence using the 465-580 nm filter set while heating from 25°C to 95°C using a linear gradient of l°C/min. Melting temperatures were determined by numerical differentiation using the LightCycler Thermal Shift Analysis software (Roche Diagnostics). The shifts in melting temperature caused by experimental compounds compared to the control are expressed as ATm (Table 2).

TEAD reporter gene assay (RGA)

A TEAD reporter cell line was purchased from BPS Bioscience (cat. no. 60618). It contains the firefly luciferase gene under control of TEAD responsive elements stably integrated into the human breast cancer MCF7 cells. In proliferating cells, a basal level of unphosphorylated YAP/TAZ resides in the nucleus and drives the TEAD-dependent expression of the luciferase reporter. The cells were cultivated as recommended by the supplier. Inhibition of TEAD reporter gene activity by experimental compounds was measured using white, clear-bottom, 96 well cell culture plates (Greiner Bio-One, cat. no. 655098). The cells were seeded at a density of 20,000 cells per well in 100 pL growth medium and the plates were incubated overnight at 37°C with 5% CO2 prior to treatment. Experimental compounds were serially diluted in DMSO to 200x the desired final concentrations. 0.5 pL aliquots of DMSO or the test samples were then mixed into the wells and the cells were further incubated for 24 hours. Luminescence was then measured on a Synergy 4 reader (BioTek) using the ONE-Glo Luciferase Assay System (Promega, cat. no. E6120) according to the manufacturer's instructions. Relative inhibition values were calculated by normalizing the raw data using DMSO-treated cells (0% inhibition) and wells devoid of cells (100% inhibition). IC50 values were calculated by fitting concentration-response data to a sigmoidal 4-parameter logistic model.

Compounds of formula (I) inhibit TEAD reporter gene activity and bind to TEAD as reported in Table 2: Table 2

Example IC50 TEAD ATm (°C)

RGA (nM) TSA

1 31 15.1