INHIBITORS OF THE YAP/TAZ-TEAD INTERACTION AND

THEIR USE IN THE TREATMENT OF CANCER

Field of the invention

The present invention concerns new compounds inhibitors of the YAP/TAZ-TEAD interaction, and their use in therapy, particularly in the treatment of cancer such as malignant mesothelioma, non-small cell lung cancer, uveal melanoma, renal cancer.

The hippo pathway regulates cell proliferation, cell death and cell differentiation in multicellular organisms to ensure normal tissue development (Tumaneng K et al., Curr. Biol., 2013, 22, R368-379; Yu Fx.et al., Genes Dev. 2013, 27, 355-371 , Moon S etal. Cell Mol Life Science, 2018, 13, 2303-2319). Over the past years, various genetic and biochemical studies in Drosophila and mammals have defined a highly conserved core hippo signaling module (Huang et al., Cell, 2005, 122, 421-434; Zeng et al., Cancer Cell, 208, 13, 188-192; Badouel et al., Curr. Opin. Cell. Biol., 2009, 21 , 837-843).

Essentially, the core hippo signaling module is composed of members of Ste20-like kinase, (MST1/2) and a large tumor suppressor 1/2 (LATS1/2), together with MOB activator 1A (MOB1A) and MOB1B and the AGC (protein kinase A(PKA)/PKG/PKC-like) kinase families (Hong W et al., Cell. Dev. Biol., 2012, 23, 785-793).

Latsl and 2, AGC kinases (homologous to Drosophila Warts), are activated by association with Mob1 (Mps one binder kinase activator-like 1A and 1 B) (Mats in Drosophila) and also by phosphorylation by the STE20 family protein kinases MST1 and 2 (Hippo in Drosophila).

The final output of hippo signaling is the inhibition of the transcriptional co-activators YAP (Yes-associated protein; Yorkie in drosophila)/ TAZ (transcriptional co-activator with PDZ-binding motif) by phosphorylation by the complex Lats/Mob, in flies and mammals (Hong W et al., Cell. Dev. Biol., 2012, 23, 785-793; Zhao et al., Cancer Res., 2009, 69, 1089-98; Lei et al., Mol. Cell. Biol., 2008, 28, 2426-2436).

Functionally, when the hippo pathway is activated, YAP and TAZ are sequestered in the cytoplasm and degraded. Conversely, when the Hippo pathway is deactivated, YAP and TAZ translocate into the nucleus and promote transcription of downstream genes by forming complexes with transcription factors, such as transcriptional enhancer factors (TEF; also referred to as TEAD) and others. TEADs seem to be the key mediators of the growth and the tumorigenic potential of YAP/TAZ. (Zhao et al., Genes Dev., 2008, 22, 1962-1971 ; Harvey et al., Nat. Rev. Cancer, 2013,13, 246-257; Lin K et al., Trends Biochem Science, 2017, 42, 862-872; Pobbati A, Cancer Biol therapy, 2013, 390-398) by inducing the expression of target genes, such as CTGF, Cyr61, FGF1 (Wang L et al., Tumor Biol., 2014, 14, 463-468).

Hyperactivation of YAP and TAZ subsequent to a deregulation of the hippo pathway is widespread in cancer, indeed, the levels and nuclear localization of YAP/TAZ are elevated in many tumors such as lung, thyroid, skin, ovarian, colorectal, prostate, pancreas, esophagus, liver and breast cancer (Harvey et al., Nat. Rev. Cancer, 2013,13, 246-257; Avruch et al., Cell Cycle, 2012, 1090-1096; De Christofaro T, Eur. J. Cancer, 2011, 926-933; Zhou et al., Oncogene, 2011 , 30, 2181-2186; Wang et al., Cancer Sci., 2010, 101, 1279-85; Chad et al., Cancer Res., 2010, 70, 8517-25; Steinhardt et al., Hum.. Pathol., 2008, 39, 1582-9, Zhao et al. Genes Dev., 2007, 21: 2747-2761; Dong et al. Cell, 2007, 130: 1120-1133; Holden J, Cancers, 2018, 10, ASAP).

Although hippo signaling is clearly altered in human cancer, only few germline and somatic mutation of hippo signaling components have been described so far, this is especially true of the core hippo pathway genes. Only neurofibromin 2 (NF2 or merlin in Drosophila) an upstream component of the hippo pathway core component has been linked to a heritable cancer syndrome and classified as a tumor suppressor gene. Hundreds of somatically acquired mutation have been reported in NF2, predominantly in meningiomas, mesotheliomas and peripheral nerve sheath tumors, but also in other cancer types. (Harvey et al., Nat. Rev. Cancer, 2013, 13, 246-257; Bianchi et al., Nat. Genet., 1994, 6, 185-192; Ruttledge et al., Nat. Genet., 1994, 6, 180-184).

Malignant pleural mesothelioma (MPM) is an aggressive human malignancy, mostly associated with asbestos exposure (Carbone et al., Clin. Cancer Res., 2012, 18, 598-604). About 3 out of 4 mesotheliomas are pleural mesotheliomas. MPM is a rare disease with a 15-year cumulative frequency during 1994-2008 in the 56 countries reporting MPM to be 174300 cases (Park et al., Environ. Health Perspect., 2011, 119, 514-518). However, the real incidence of MPM is unknown, since there are countries for which MPM mortality is not reported, including asbestos producers. Despite treatment with chemotherapy, radiation therapy or surgery, the prognosis is poor; the median survival time of patients after diagnosis is only 7-12 months. (Bianchi et al. Natl. Acad.. Sci., USA, 1995, 92, 10854-10858; Sekido et al., Cancer Res., 1995, 55, 1227; Deguen et al., Int. J. Cancer, 1998, 77, 554-560).

Malignant pleural mesothelioma shows frequent inactivation of the NF2-tumor suppressor gene, indeed data mining of the catalogue of somatic mutations in cancers shows that the genes that are mostly mutated in MPM are cyclin-dependent kinase activator (CDKN2A), neurofibromatosis type 2 and BRCA-associated protein 1 (BAP1) (Forbe et al., Nucleic Acids Res., 2011, 39, D945-950).

Recently, besides the NF2 mutation, genetic alterations in the components of the hippo-signaling pathway have also been identified, including inactivating mutations of Lats1/2 and amplification of YAP. Together with NF2 mutation, MPM shows frequent Merlin-Hippo

pathway inactivation, which leads to YAP activation over 70% of MPM cases (Bott et al., Nat. Genet., 2011 , 43, 668-672; Murakami et al., Cancer Res., 2011 , 71 , 873-883; Yokoyama et al., Carcinogenesis, 2008, 29, 2139-2146; Sekido et al., Pathol. Int, 2011, 61 , 331-344; Woodward et a/.,Transl. Lung Res. ,2017,6,335-342; Sekido et al., Cancers, 2018, ASAP).

Inhibition of the activity of Hippo pathway effectors YAP and TAZ is likely to represent a valuable approach for the treatment of several cancers since the Hippo pathway deregulation is largely observed in many cancers, leading to YAP/TAZ nuclear translocation.

Therefore, disruption of hippo pathway downstream YAP/TAZ-TEAD interaction is believed to abrogate the oncogenic property of YAP/TAZ. The compounds of invention are designed to block this interaction upon binding to TEAD and can be further developed into drugs for cancers especially for the treatment of malignant mesothelioma.

WO 2004/087153 and WO 2013/123071 disclose hundreds of small molecules susceptible to be used generally in relation with cancer treatments. Two hydrozobenzothiazole derivatives, different from the one disclosed in the present application, are disclosed but no YAP/TAZ-TEAD interaction inhibiting activity is reported, not to mention specific anticancer activity.

The invention provides new compounds identified as inhibitors of the YAP/TAZ-TEAD interaction, and particularly new hydrazoboroaryl derivatives inhibiting YAP/TAZ-TEAD interaction.

Brief disclosure of the invention

The present invention concerns a compound of formula (I):

wherein:

is a substituted or unsubstituted N-containing monocyclic, bicyclic or tricyclic heteroraryl;

R1 is H, an alkyl optionally substituted with one or two groups R6 or an aryl optionally substituted with one or more groups R6;

R2 is H or alkyl; or

R1 and R2 are bound together to form a 5- or 6-membered heterocycle;

R3 and R4 independently are H, an alkyl optionally substituted with one or two groups R6; or

R3 and R4 are bound together to form a 5- to 8-membered heterocycle;

R5 is H, a halogen, an alkyl optionally substituted with 1 or 2 groups R6, an alkoxy optionally substituted with 1 or 2 groups R6; or

R4 and R5 are bound together to form a 5- to 7-membered heterocycle;

R6 is hydroxy, alkoxy, -NR15R16, ‒CO-Y-R17, -CN, -CF3, aryl;

R15 and R16 are independently H, alkyl, -CO-alkyl or form together with the nitrogen atom a 3- to 6-membered cyclic group;

Y is ‒O- or -NR18-;

R17 is H or alkyl;

R18 is H, alkyl or hydroxyalkyl;

or pharmaceutically acceptable salts thereof.

The invention also concerns a compound of formula (Ib):

wherein:

R3 is H or an alkyl optionally substituted with one or two groups R6;

Each R14 is independently H, an alkyl optionally substituted with one or two groups R6, an aryl, -NR15R16, or -CO-Y-R17; and

n is 1 , 2 or 3;

or pharmaceutically acceptable salts thereof;

with R1, R2, R15, R16 and R17 being as defined above and below.

The invention also concerns a compound of formula (I) or (Ib), for use as a medicament, particularly for use in the treatment of a cancer indication where YAP is localized in the nucleus of the tumor cells, such as lung, thyroid, ovarian, colorectal, prostate, pancreas, esophagus, liver, breast and skin cancer, more particularly in the treatment of malignant mesothelioma

The invention also concerns a pharmaceutical composition comprising a compound of formula (I) or (Ib) and a pharmaceutically acceptable vehicle or excipient.

Brief disclosure of the figure

Figure 1 represents the anti-proliferative activity of representative compounds of the invention as inhibitors of the YAP/TAZ-TEAD interaction in mesothelioma cells NCI-H2052 (×) and Met5A (■)

Detailed disclosure of the invention

The compounds of formula (I) described herein and their pharmaceutically acceptable salts are representatives of this new class of compounds, inhibitors of the YAP/TAZ-TEAD interaction.

According to the present invention, the term “alkyl” of the prefix "alk” means a linear or branched C1-C6 alkyl or alkylene moiety, particularly a C1-C4 alkyl or alkylene moiety, more particularly C1, C2, C3 or C4 alkyl or alkylene moieties, including the groups methyl or methylene, ethyl or ethylene, propyl or propylene, isopropyl or isopropylene, butyl or butylene, isobutyl or isobutylene and tertiobutyl or tertiobutylene. In particular embodiments, the alkyl moieties are selected among methyl or methylene, ethyl or ethylene, propyl or propylene.

According to the invention, the term "cycloalkyl” means a 3- to 6-membered hydrocarbon cycle, which can be bridged particularly cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

According to the present invention, the “halo” group is selected among F, Cl, Br or I, particularly F or Cl.

According to the present invention, “aryl” means an aromatic (hetero)cycle comprising 1 or 2 rings, including phenyl, naphthyl, pyrazolyl, pyridyl, indolyl, isoindolyl, thienyl, thiazolyl, benzimidazolyl, benzotriazolyl, and derivatives thereof. The aryl groups are optionally substituted by one or more substituents selected from alkyl, alkoxy and halo groups.

In one embodiment, when R3 is H and R4 and R5 are bound together to form a 5-membered heterocycle, then R1 is not H.

In one embodiment, R1 is an alkyl optionally substituted with one or two groups R6 or an aryl optionally substituted with one or more groups R6. R, is preferably an alkyl, particularly selected among methyl, ethyl, n-propyl, i-propyl, sec-butyl, optionally substituted with an alkoxy (R6 is alkoxy), particularly methoxy.

R2 is preferably H.

When R1 and R2 are bound together to form a 5- or 6-membered heterocycle, they particularly represent a moiety selected from -C(R19)2-C(R20)2-, -C(R19)2-C(R20)2-C(R21)2-

and -C(R19)2-C(R20)2-O- wherein R19, R20 and R21 are each independently H or alkyl. Independently means that both R19, both R20 and both R21 respectively can be the same or different. In one embodiment, all R19, R20 and R21 are the same. In another embodiment, at least one of R19, R20 and R21 is different from the other R19, R20 or R21. In a particular embodiment, at least one R19 is H and at least one R20 is alkyl. In another embodiment, at least one R19 is H and at least one R20 is H and one of the other R19 or R20 is alkyl, particularly one R19 is alkyl and both R20 are H. In another embodiment, at least one R19 is H and at least one R20 is alkyl and one of the other R19 or R20 is alkyl, particularly both R19 are H and both R20 are alkyl. In preferred embodiments, both R21 are H.

In one embodiment, R3 and R4 are independently H or alkyl. In another embodiment, both R3 and R4 are H or an alkyl, particularly the same alkyl. The alkyl group for R3 and R4 is preferably methyl or ethyl, more preferably methyl.

In another embodiment, R3 and R4 are bound together form a 5- to 8-membered heterocycle. Such heterocycle is particularly 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, 5,5-dimethyl-1,3,2-dioxaborinan-2-yl or 1,3,6,2-dioxazaborocane-4,8-dione.

In one embodiment, R5 is selected among H, alkoxy, particularly methoxy or ethoxy, optionally substituted with one methoxy or ethoxy, such as methoxyethoxy, and -F or Cl, preferably Cl.

In one embodiment R4 and R5 are bound together to form a 5- to 7-membered heterocycle which is optionally substituted with one or more groups selected from alkyl and alkoxy.

In one embodiment, R3 is H, R4 and R5 are bound together to form a 5-membered heterocycle, and R1 is an alkyl optionally substituted with one or two groups R6 or an aryl optionally substituted with one or more groups R6.

In one embodiment, R6 is hydroxy, alkoxy, -NR15R16, ‒CO-Y-R17, -CN, -CF3, or aryl.

R15 and R16 are independently H, alkyl, -CO-alkyl or form together with the nitrogen atom a 3- to 6-membered cyclic group.

In one embodiment, Y is ‒O- or -NR18-.

In one embodiment, R17 is H or alkyl.

In one embodiment, R18 is H, alkyl or hydroxyalkyl or R17 and R18 are bound together to form a 4- to 7-membered cyclic group.

When R15 and R16 together with the nitrogen atom form a 3- to 6-membered cyclic group, including 3-, 4-, 5- or 6-membered cycles, said group is preferably selected from aziridinyl, azetidinyl, diazetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolidinyl, imidazolyl, pyrazolidinyl, pyrazolyl, piperidinyl, piperazinyl, pyrazinyl, triazinyl, morphonlinyl, oxazinyl, thiomorpholinyl, thiazinyl. A prefered cyclic group is morpholinyl. The 3- to 6-membered cyclic group may be substituted by one or more groups selected from alkyl and halo.

The same definition applies when R17 and R18 are bound together to form a 4- to 7- membered cyclic group, in case X is ‒NR18-. Preferably, the cyclic group is selected among azetidine, pyrrolidine, piperidine, morpholine, azepane and oxazepane.

In preferred embodiments, R6 is an alkoxy, particularly methoxy or ethoxy.

In particular embodiments, R3 is H or an alkyl optionally substituted with one or two groups R6, and R4 and R5 are bound together to form a 5- to 7-membered heterocycle. Said compounds of the invention are more particularly compounds of formula (Ib):

wherein:

each R14 is independently H, an alkyl optionally substituted with one or two groups R6, an aryl, -NR15R16, or -CO-Y-R17;

n is 1 , 2 or 3; and

R1, R2, R3, R15, R16 and R17 are as defined above and below;

and pharmaceutically acceptable salts thereof.

In some embodiments, R3 and ail R14 are H. In another embodiment R3 is H, one R14 is an alkyl, particularly methyl, and the other R14 are H.

In a particular embodiment, n is 1 and both R14 are H or one R14 is H and the other is methyl.

In one embodiment
is a N-containing monocyclic or bicyclic heteroraryl. Said heteroaryls are known, such as derivatives of saccharine, including tetrahydrosaccharine, derivatives of pyridazine, derivatives of quinazoline, derivatives of thieno-pyrimidine, derivatives of pyrrolo-pyrimidine, derivatives of pyrrolo-pyrimidinone, derivatives of dihydro pyrrolo-pyrimidine, derivatives of pyrazolo-pyrimidine, derivatives of furano-pyrimidine, derivatives of dihydro furano-pyrimidine, derivatives of thiazolo-pyrimidine, derivatives of purinone, derivatives of dihydro pyrido-pyrimidinone, derivatives of tetrahydrobenzothieno- pyrimidine. In one aspect of this embodiment the N-containing monocyclic or bicyclic heteroraryl is selected from derivatives of saccharine, including tetrahydrosaccharine,

derivatives of pyrizadine, derivatives of quinazoline, derivatives of thieno-pyrimidine, derivatives of pyrrolo-pyrimidine, derivatives of pyrazolo-pyrimidine, and derivatives of furano-pyrimidine.

More particularly, the N-containing monocyclic or bicyclic heteroraryl is selected among the groups of formulae (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) (X), (XI) , (XII), (XIII), (XIV), (XV), (XVI), (XVII) and (XVIII).

wherein:

R7, R8, R9 and R10 are each independently H, a halogen, an alkyl optionally substituted with 1 or 2 groups R6, a perfluoroalkyl, an alkoxy optionally substituted with 1 or 2 groups R6, or a cyano group.

R10 can also represent a cycloalkyl, an aryl, -NR15R16 where R15 and R16 are as defined above, or ‒CO-Y-R22 where Y is as defined above and R22 is H, alkyl optionally substituted with hydroxy or alkoxy, or -NR15R16 where R15 and R16 are as defined above.

R10 can also be bound together with R12 to form a 6-membered carbocycle.

R11, R12, and R13 are each independently H, an alkyl optionally substituted with 1 or 2 groups R6, a perfluoroalkyl.

R12 can also represent an alkylthio or a group -NR15R16 where R15 and R16 are as defined above.

R13 can also represent a cycloalkyl optionally substituted with hydroxy or alkoxyalkyl. R7 is particularly H, an alkyl, such as methyl, ethyl, n-propyl or i-propyl, optionally substituted with one R6, with R6 being particularly selected among hydroxyl, alkoxy (e.g. methoxy, ethoxy) and a halide, particularly F.

R8 is particularly H, an alkyl, such as methyl or ethyl, a halogen, particularly F, or a cyano group.

Rg and R10 are particularly each independently H, an alkyl, such as methyl or ethyl, or an alkoxy, such as methoxy or ethoxy.

In one embodiment, R10 is -CO-Y-R22 or -NR15R16 wherein Y, R15, R16, R22 are as defined above. Particularly Y is -NR18- wherein R18 is as defined above.

R11 and R12 are particularly each independently H, an alkyl, such as methyl or ethyl, or a perfluoroalkyl such as trifluoromethyl. In particular R11 and R12 are both H.

R,3 is particularly H or an alkyl, such as methyl or ethyl.

In one embodiment, in the groups of formula (II) and (V), R8 is H when one of R7 or R9 is not H.

In one embodiment, R8, R9 and R10 are H and R7 is particularly H, an alkyl, such as methyl, ethyl, n-propyl or i-propyl, optionally substituted with one R6, R6 being particularly selected among hydroxyl, alkoxy (e.g. methoxy, ethoxy) and a halogen, particularly F. In another embodiment, R8 and R10 are H and R7 and R9 are not H as defined above.

In one embodiment, the N-containing monocyclic or bicyclic heteroraryl is a group of formula (II) or a group of formula (VI).

In one embodiment, R1, R2, R3, R4 and R5 are as defined in priority application

EP18306294.2.

In a particular embodiment, compounds of formula (I) where R4 and R5 are not bound together are selected from:

- [4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-isobutyl-hydrazono]methyl]-2-methoxy- phenyl]boronic acid

- [4-[(E)-[isobutyl-(5-methoxy-1,1-dioxo-1,2-benzothiazol-3-yl)hydrazono]methyl]-2- methoxy-phenyl]boronic acid

- [4-[(E)-[(5,7-dimethoxy-1,1-dioxo-1,2-benzothiazol-3-yl)-isobutyl-hydrazono]methyl]-2- methoxy-phenyl]boronic acid

- [4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-ethyl-hydrazono]methyl]-2-methoxy- phenyl]boronic acid

- [4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-(2-methoxyethyl)hydrazono]methyl]-2- methoxy-phenyl]boronic acid

- [2-chloro-4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-isobutyl- hydrazono] methyl] phenyl] boronic acid

- [4-[(E)-[isobutyl-(5-methyl-1,1-dioxo-1,2-benzothiazol-3-yl)hydrazono]methyl]-2- methoxy-phenyl]boronic acid

- [4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-isobutyl-hydrazono]methyl]phenyl]boronic acid

- [4-[(E)-[isobutyl-[5-(2-methoxyethoxy)-1,1-dioxo-1,2-benzothiazol-3- yl]hydrazono]methyl]-2-methoxy-phenyl]boronic acid

- [4-[(E)-[(6-cyano-1,1-dioxo-1,2-benzothiazol-3-yl)-isobutyl-hydrazono]methyl]-2- methoxy-phenyl]boronic acid

- [4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-isobutyl-hydrazono]methyl]-2-(2- methoxyethoxy) phenyl] boronic acid

- [4-[(E)-[[5-(3-hydroxypropoxy)-1,1-dioxo-1,2-benzothiazol-3-yl]-isobutyl- hydrazono]methyl]-2-methoxy-phenyl]boronic acid

- [4-[(E)-[isobutyl-(8-methoxyquinazolin-4-yl)hydrazono]methyl]-2-methoxy- phenyl]boronic acid

- [4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-isobutyl-hydrazono]methyl]-2-ethoxy- phenyl]boronic acid

- [2-chloro-4-[(E)-[(5,7-dimethoxy-1,1-dioxo-1,2-benzothiazol-3-yl)-isobutyl- hydrazono]methyl]phenyl]boronic acid

- [4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-sec-butyl-hydrazono]methyl]-2-methoxy- phenyl]boronic acid

- [4-[(E)-[(6,8-dimethoxyquinazolin-4-yl)-isobutyl-hydrazono]methyl]-2-methoxy- phenyl]boronic acid

- [4-[(E)-[(7-fluoroquinazolin-4-yl)-isobutyl-hydrazono]methyl]-2-methoxy-phenyl]boronic acid

- [4-[(E)-[isobutyl-(6-methoxyquinazolin-4-yl)hydrazono]methyl]-2-methoxy- phenyl]boronic acid

- [4-[(E)-[isobutyl(thieno[3,2-d]pyrimidin-4-yl)hydrazono]methyl]-2-methoxy- phenyl] boronic acid

- [4-[(E)-[ethyl-(8-methoxyquinazolin-4-yl)hydrazono]methyl]-2-methoxy-phenyl]boronic acid

- [2-methoxy-4-[(E)-[(8-methoxyquinazolin-4-yl)-methyl- hydrazono]methyl]phenyl]boronic acid

- [4-[2-(1,1-dioxo-1,2-benzothiazol-3-yl)-3-methyl-4,5-dihydro-3H-pyridazin-6-yl]-2- methoxy-phenyl]boronic acid

- [4-[2-(5,7-dimethoxy-1,1-dioxo-1,2-benzothiazol-3-yl)-3-methyl-4,5-dihydro-3H- pyridazin-6-yl]-2-methoxy-ph6nyl]boronic acid

- [2-methoxy-4-[2-(8-methoxyquinazolin-4-yl)-3-methyl-4,5-dihydro-3H-pyridazin-6- yl] phenyl] boronic acid

- [4-[2-(1,1-dioxo-1,2-benzothiazol-3-yl)-4,4-dimethyl-3,5-dihydropyridazin-6-yl]-2- methoxy-phenyl]boronic acid

- [4-[4-(1,1-dioxo-1,2-benzothiazol-3-yl)-6-methyl-5,6-dihydro-1,3,4-oxadiazin-2-yl]-2- methoxy-phenyl]boronic acid

- [2-methoxy-4-[(E)-[methyl-(5-methylpyridazin-3-yl)hydrazono]methyl]phenyl]boronic acid

- 2-[4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-isobutyl-hydrazono]methyl]-2-methoxy- phenyl]-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

- [4-[(E)-[ethyl-(7-methylthieno[3,2-d]pyrimidin-4-yl)hydrazono]methyl]-2-methoxy- phenyl]boronic acid

- [4-[(E)-[ethyl(thieno[3,2-d]pyrimidin-4-yl)hydrazono]methyl]-2-methoxy-phenyl]boronic acid

- [4-[(E)-[ethyl(thiazolo[4,5-d]pyrimidin-7-yl)hydrazono]methyl]-2-methoxy- phenyl] boronic acid

- [4-[(E)-[ethyl(furo[2,3-d]pyrimidin-4-yl)hydrazono]methyl]-2-methoxy-phenyl]boronic acid

- [4-[(E)-[ethyl-(7-methylpyrrolo[2,3-d]pyrimidin-4-yl)hydrazono]methyl]-2-methoxy- phenyl] boronic acid

- [4-[(E)-[isobutyl-(7-methylthieno[3,2-d]pyrimidin-4-yl)hydrazono]methyl]-2-methoxy- phenyl]boronic acid

- [4-[(E)-[isobutyl-(2-methylthieno[3,2-d]pyrimidin-4-yl)hydrazono]methyl]-2-methoxy- phenyl]boronic acid

- [4-[(E)-[isobutyl-(6-methylthieno[3,2-d]pyrimidin-4-yl)hydrazono]methyl]-2-methoxy- phenyl]boronic acid

- [2-methoxy-4-[(E)-[2-methoxyethyl(thieno[3,2-d]pyrimidin-4-yl)hydrazono]methyl]- phenyl]boronic acid

- [2-methoxy-4-[(E)-[methyl-(7-methylthieno[3,2-d]pyrimidin-4-yl)hydrazono]methyl]- phenyl]boronic acid

- [2-methoxy-4-(3-methyl-2-thieno[3,2-d]pyrimidin-4-yl-4,5-dihydro-3H-pyridazin-6- yl)phenyl]boronic acid

- [2-methoxy-4-[3-methyl-2-(7-methylpyrrolo[2,3-d]pyrimidin-4-yl)-4,5-dihydro-3H- pyridazin-6-yl] phenyl] boronic acid

- [4-[4-(7-fluoroquinazolin-4-yl)-6-methyl-5,6-dihydro-1,3,4-oxadiazin-2-yl]-2-methoxy- phenyl]boronic acid

and pharmaceutically acceptable salts thereof.

In another particular embodiment, compounds of formula (Ib) are selected from:

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl-1,1-dioxo- 1,2-benzothiazol-3-amine

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-(2-methoxyethyl)-1,1- dioxo-1,2-benzothiazol-3-amine

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-(3-methoxypropyl)- 1,1-dioxo-1,2-benzothiazol-3-amine

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-methyl-1,1-dioxo-1,2- benzothiazol-3-amine

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-1,1-dioxo-1,2- benzothiazol-3-amine

- 5-fluoro-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl-1,1- dioxo-1,2-benzothiazol-3-amine

- N-[(E)-(1-hydroxy-3 H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl-5-methyl-1,1- dioxo-1,2-benzothiazol-3-amine

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl-6-methoxy- 1,1-dioxo-1,2-benzothiazol-3-amine

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl-6-methyl-1,1- dioxo-1,2-benzothiazol-3-amine

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl-8-methoxy- quinazolin-4-amine

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-8-methoxy-N-methyl- quinazolin-4-amine

- - N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-8-methoxy- quinazolin-4-amine

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl-thieno[3,2- d]pyrimidin-4-amine

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N,5-dimethyl-1,1-dioxo- 1,2-benzothiazol-3-amine

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-5-methoxy-N-methyl- 1,1-dioxo-1,2-benzothiazol-3-amine

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]thieno[3,2- d]pyrimidin-4-amine

- N-ethyl- N-[(E) -(1-hydroxy-3 H-2, 1-benzoxaborol-5-yl) methyleneamino]-7H-pyrrolo[2,3- d]pyrimidin-4-amine

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]thieno[2,3- d]pyrimidin-4-amine

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-1-methyl- pyrazolo[3 ,4-d] pyrimid in-4-amine

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-7-methyl- thieno[3,2-d]pyrimidin-4-amine

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]furo[2,3- d]pyrimidin-4-amine

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-7-methyl- pyrrolo[2,3-d]pyrimidin-4-amine

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-2-methyl- thieno[3,2-d]pyrimidin-4-amine

- N-[(E)-(1-hydroxy-3,4-dihydro-2,1-benzoxaborinin-6-yl)methyleneamino]-N-isobutyl- 1,1-dioxo-1,2-benzothiazol-3-amine;

- N-[(E)-(1-hydroxy-4, 5-dihydro-3H-2,1-benzoxaborepin-7-yl)methyleneamino]-N- isobutyl-1,1-dioxo-1,2-benzothiazol-3-amine

- N-[(E)-(1-hydroxy-7-methoxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl- 1,1-dioxo-1,2-benzothiazol-3-amine

- N-[(E)-(1-hydroxy-3-methyl-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl-1,1- dioxo-1,2-benzothiazol-3-amine

- N-[(E)-(1-hydroxy-3-methyl-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-methyl-1,1- dioxo-1,2-benzothiazol-3-amine

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-methyl-1,1-dioxo- 4,5,6,7-tetrahydro-1,2-benzothiazol-3-amine

- 3-[6-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-3-methyl-4,5-dihydro-3H-pyridazin-2-yl]- 1,2-benzothiazole 1,1-dioxide

- 4-[6-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-3-methyl-4,5-dihydro-3H-pyridazin-2-yl]-8- methoxy-quinazoline

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-5-methoxy-N-methyl- pyridazin-3-amine

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-methyl-2- methylsulfanyl-thiazolo[4,5-d]pyrimidin-7-amine

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N,1-dimethyl- pyrazolo[3,4-d]pyrimidin-4-amine

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yi)methyleneamino]-N,7-dimethyl-thieno[3,2- d]pyrimidin-4-amine

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-1H- pyrazolo[4,3-d]pyrimidin-7-amine

- N7-ethyl-N7-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N2,N2- dimethyl-thiazolo[4,5-d]pyrimidine-2,7-diamine

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-3-methyl-1H- pyrazolo[4,3-d]pyrimidin-7-amine

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-5H-pyrrolo[3,2- d]pyrimidin-4-amine

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-2-morpholino- thiazolo[4,5-d]pyrimidin-7-amine

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-2- methylsulfanyl-thiazolo[4,5-d]pyrimidin-7-amine hydrochloride

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-7-propyl- pyrrolo[2,3-d]pyrimidin-4-amine

- N,7-diethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl) methylene amino]pyrrolo[2,3- d] pyrimidin-4-amine

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-1H- pyrazolo[3,4-d]pyrimidin-4-amine

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]thiazolo[4,5- d]pyrimidin-7-amine

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-2,7-dimethyl- thieno[3,2-d]pyrimidin-4-amine

- N-ethyl-7-fluoro-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]- quinazolin-4-amine

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-6-methyl- thieno[3,2-d]pyrimidin-4-amine

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-6,7,8,9- tetrahydrobenzothiopheno[3,2-d]pyrimidin-4-amine

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl-2- methylsulfanyl-thiazolo[4,5-d]pyrimidin-7-amine

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl-7-methyl- thieno[3,2-d]pyrimidin-4-amine

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-(2-methoxyethyl)-7- methyl-thieno[3,2-d]pyrimidin-4-amine

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-(2-methoxyethyl)-2- methylsulfanyl-thiazolo[4,5-d]pyrimidin-7-amine, hydrochloride

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-(3-methoxypropyl)-2- methylsulfanyl-thiazolo[4,5-d]pyrimidin-7-amine

- 2-[[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl) methyleneamino]-(7-methylthieno[3,2- d]pyrimidin-4-yl) amino]ethanol

- 6-[[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-methyl-amino]-9- methyl-7H-purin-8-one

- 4-[[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-methyl-amino]-7- methyl-5H-pyrrolo[2,3-d]pyrimidin-6-one

- Example 100: 4-[[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-methyl- amino]-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-methyl-5,6- dihydrofuro[2,3-d]pyrimidin-4-amine

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-methyl-7-phenyl- thieno[3,2-d]pyrimidin-4-amine

- 7-cyclopropyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-methyl- thieno[3,2-d]pyrimidin-4-amine

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-methyl-7-morpholino- thieno[3,2-d]pyrimidin-4-amine

- 7-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-methyl- th ieno[3, 2-d] pyrimidin-4-ami ne

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N,7-dimethyl-5,6- dihydropyrrolo[2,3-d]pyrimidin-4-amine

- 9-cyclobutyl-6-[[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-methyl- amino]-7H-purin-8-one

- 6-[[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-methyl-amino]-9-[3- (methoxymethyl)cyclobutyl]-7H-purin-8-one

- 6-[[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-methyl-amino]-9-(3- hydroxycyclobutyl)-7H-purin-8-one hydrochloride

- 9-(3-bicyclo[1.1.1]pentanyl)-6-[[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5- yl)methyleneamino]-methyl-amino]-7H-purin-8-one

- 7-cyclobutyl-4-[[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-methyl- amino]-5H-pyrrolo[2,3-d]pyrimidin-6-one

- 4-[ethyl-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]amino]-N-propyl- thieno[3,2-d]pyrimidine-7-carboxamide

- 4-[ethyl-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]amino]-N,N- dimethyl-thieno[3,2-d]pyrimidine-7-carboxamide

- N,N-dibutyl-4-[ethyl-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]- amino]thieno[3,2-d]pyrimidine-7-carboxamide

- 4-[ethyl-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino] amino]-N-(oxetan- 3-yl)thieno[3,2-d]pyrimidine-7-carboxamide

- 4-[ethyl-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]amino]-N-(4- methoxybutyl)thieno[3,2-d]pyrimidine-7-carboxamide

- 4-[6-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-3-methyl-4,5-dihydro-3H-pyridazin-2- yl]furo[2,3-d]pyrimidine

- 4-[6-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-3-methyl-4,5-dihydro-3H-pyridazin-2-yl]-7- methyl-thieno[3,2-d] pyrimidine

- (+) 4-[6-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-3-methyl-4,5-dihydro-3H-pyridazin-2-yl]- 7-methyl-thieno[3,2-d]pyrimidine

- (-) 4-[6-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-3-methyl-4,5-dihydro-3H-pyridazin-2-yl]- 7-methyl-thieno[3,2-d]pyrimidine

- 4-[6-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-3-methyl-4,5-dihydro-3H-pyridazin-2- yl]thieno[3,2-d] pyrimidine

- 4-[6-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-3-methyl-4,5-dihydro-3H-pyridazin-2-yl]- 6,7,8,9-tetrahydrobenzothiopheno[3,2-d]pyrimidine

- 7-[6-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-3-methyl-4,5-dihydro-3H-pyridazin-2-yl]-2- methylsulfanyl-thiazolo[4,5-d]pyrimidine

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-7-(methoxymethyl)-N- methyl-thieno[3,2-d]pyrimidin-4-amine

and pharmaceutically acceptable salts thereof.

According to the invention, pharmaceutically acceptable salts are salts of acids or bases, known for their use in the preparation of active principles for use in therapy. Examples of pharmaceutically acceptable acids suitable as source of anions are those disclosed in the Handbook of Pharmaceutical Salts: Properties, Selection and Use (P. H. Stahl and C. G. Wermuth, Weinheim/Zürich:Wiley-VCH/VHCA, 2002).

The present invention also concerns a pharmaceutical composition comprising at least one compound of formula (I) as described herein or one of its pharmaceutically acceptable salts as the active principle. Pharmaceutical compositions and method for their preparation are well known in the art. Particularly, the composition comprises at least the compound of general formula (I) or one of its pharmaceutically acceptable salts as the active principle and at least one pharmaceutically acceptable excipient.

The pharmaceutical composition of the invention is formulated for administration by usual routes particularly the oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal routes. The form of the pharmaceutical composition is particularly chosen among the group consisting of tablets, capsules, powders, granules and oral solutions or suspensions, sublingual forms of administration, subcutaneous, topical, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration.

Such forms, excipients and methods for their preparation are well known in the art, such as described in the art (Handbook of pharmaceutical Excipients, Rowe et al, seventh edition, June 2012; Rules and Guidance For Pharma Manufacturers and distributors 205, Medecines and Healthcare products Regulatory Agency, London UK).

Pharmaceutical compositions are designed for their intended use in therapy. The choice of components, their form and composition are governed by rules of the pharmacopeia. As such, they differ structurally from other compositions such as reactants used in laboratory experiments or compositions for applications on plants or non-living material. Therefore, the present invention also concerns the compounds of formula (I) as described herein, for use in therapy, particularly in the treatment of any cancer indication where YAP is localized in the nucleus of the tumor cells, such as lung, thyroid, ovarian, colorectal, prostate, pancreas, esophagus, liver, breast and skin cancer, more particularly in the treatment of malignant mesothelioma.

The invention also concerns a method for treating cancer in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I) as described herein, wherein the cancer is any cancer indication where YAP is localized in the nucleus of the tumor cells, such as lung, thyroid, ovarian, colorectal, prostate, pancreas, esophagus, liver, breast and skin cancer, particularly malignant mesothelioma. The skilled practitioner, depending on the activity of the compound of formula (I) and the body weight of the patient, shall determine the appropriate dose of compound and the administration regimen. Such a dose is generally between 5 mg and 1000 mg per day

orally for an adult. In general the doctor will determine the appropriate dosage depending on the age, weight and any other factors specific to the subject to be treated.

In a particular embodiment, the inhibitor of the YAP/TAZ-TEAD interaction, and particularly the compounds of formula (I) are used together or separately in combination with another treatment of cancer, particularly malignant mesothelioma, such as surgery, chemotherapy (with among other cisplatin, carboplatin, alimta (pemetrexed), gemcitabine and doxorubicin) and radiation.

General Synthetic Schemes

Compounds of the invention may be prepared using the synthetic transformations illustrated in schemes I, II, VII, XVIII, XIX, XX. Starting materials are commercially available or may be prepared by procedures described herein (schemes III-VI, VIII-XVII), by literature procedures, or by procedures well known to one skilled in the art of organic chemistry.

In scheme I, step a, an aldehyde (commercially available or prepared following schemes XIII-XVII) in solution in alcohol or THF is reacted with a commercially available hydrazine in the presence or not of an organic or inorganic base (such as sodium acetate, triethylamine, sodium hydrogenocarbonate, potassium carbonate.......) (see for example,

Kurian et al., Bioorg. Med. Chem. Lett., 2014, 24(17), 41764180; Loghmani-Khouzani et al., J. Chem. Res. Syn., 2001 , (2), 80-81). In step b, the hydrazono derivative (obtained in step a) and a halogeno heterocycle (commercially available or obtained following schemes XI-XII) react together in the presence or not of an organic or inorganic base (see for example, Haffner et al., Bioorg. Med. Chem. Lett., 2010, 20(23), 6989-92; Haffner et al., Bioorg. Med. Chem. Lett., 2010, 20(23), 6983-88).

Scheme I

In scheme II, step a, aromatic substitution of the halogeno heterocycle (commercially available or prepared using transformations described in schemes XI-XII) with the hydrazine can be done under similar conditions as described in scheme I step b. In step b, the heterocycle-hydrazine derivative obtained in step a is reacted with an aldehyde (commercially available or prepared following schemes XIII-XVII) under similar conditions as described in scheme I, step a.

Scheme II

In scheme III, step a, condensation of the tert-butoxycarbonyl hydrazide with an aldehyde (commercially available or prepared following schemes XIII-XVII) is done using similar conditions as described in scheme I, step a. In step b, alkylation is done using a halogeno alkylating agent with an inorganic or organic base (such as triethylamine, pyridine, potassium carbonate, cesium carbonate...) in dimethylformamide. In step c, cleavage of the tert-butylcarboxyl protecting group is carried out using hydrochloric acid in dioxane. Step d can be done under similar conditions used in Scheme I step b.

Scheme III

In scheme IV, step a, the formation of the Weinreb amide is done using classical conditions with methoxymethanamine in the presence of pyridine in dichloromethane. In step b, the ketone is obtained from the corresponding bromo derivative with the Weinreb amide using butyl lithium as base in THF (see for example WO 00/04013). In step c, cyclisation to the tetrahydropyridazine is done with hydrazine hydrate in ethanol (see for example, Gouault et al., Journal of Pharmacy and Pharmacology, 2001 , 53(7), 981-985). In step d, aromatic substitution is done using a halogeno hetero-aryl either in THF or with copper iodide in isopropanol depending of the nature of heterocycle.

Scheme IV

In scheme V, step a, succinic ring opening is done using a phenylmagnesiumbromide (prepared from the corresponding phenylbromide with magnesium turnings) in THF (see for example, Sakai et al. Chemistry Letters, 2015, 44(11), 1503-1505). In step b, cyclisation to the tetrahydropyridazine is done with hydrazine hydrate in ethanol as

described in scheme IV step c. In step c, the reduction is done using lithium aluminium hydride in THF (see for example, Winton. et al., Journal of Heterocyclic Chemistry, 1984, 21 (3), 889-91). Step d is done using similar conditions as described for Scheme IV step d.

Scheme V

In scheme VI, step a, oxidation of benzaldehyde to benzoic acid is done with iodine, potassium hydroxide in methanol (Yamada S et al., Tetrahedron Letters, 1992, 33,4 329-4332). In step b, acylhydrazine formation is performed with hydrazine hydrate in ethanol. In step c, acylation of hydrazine is done with 2-chloro-propionyl chloride in dioxane (US 6,197,766). In step d, cyclisation is done with triethylamanine in DMF under microwave irradiation at 150°C. In step e, reduction is done using borane in THF (see for example, Hudlicky Reductions in Organic Chemistry ACS monograph 188 second edition). Step f is performed using the same conditions as described in scheme IV step d.

Scheme VI

In scheme VII, step a, formation of the phenyl boronic derivative is done from the corresponding chloro analog (prepared following schemes l-VI, Vlll-X) with tetrahydroxy diboron in the presence of XPHOS palladacycle and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl in ethanol (see for example, Molander G et al., J Am Chem Soc, 2012, 134, 11667-11673).

Scheme VII

In scheme VIII, step a, aromatic substitution of the bromo derivative (prepared following scheme I) with bis pinacolborane is done in the presence of palladium catalyst (see for example, Dzhevakov et al., Adv. Synth. Catal., 2016, 358(6), 977-983; WO 2009/029998). In step b, the pinacol borane analog is hydrolyzed with hydrogen peroxide to give the corresponding phenol derivative (see for example WO 2007/038367).

Scheme VIII

In scheme IX, step a and b, alkylation of the hydroxyl group (prepared following scheme VIII) can be done either using halogeno alkylating agent with an inorganic or organic base (such as triethylamine, pyridine, potassium carbonate, cesium carbonate) or by a Mitsunobu reaction in the presence of triphenyl phosphine and azodicarboxylate reagents (such as diethyl azodicarboxylate, diisopropyl azodicarboxylate). In step c, cleavage of the protective group of R5, if needed, is done using classical methods (for example tributyl ammonium fluoride in THF for silyl group) (see for example, Green et al., Protective Group in Organic Synthesis, Wiley, third edition).

Scheme IX

In scheme X, step a, formation of the trifluoromethanesulfonate is done starting from the corresponding phenol (prepared following scheme VIII) with trifluoromethanesulfonic anhydride in the presence of di-isopropylethylamine in dichloromethane. In step b, cyanation is done using zinc cyanide and tetrakis(triphenylphosphine)palladium in DMF under microwave irradiation (see for example, Sandgren V et al Bioorganic & Medicinal Chemistry, 2012, 20(14), 4377-4389).

CLAIMS

1. A compound of formula (I):

wherein:

is a substituted or unsubstituted N-containing monocyclic, bicyclic or tricyclic heteroraryl;

R1 is H, an alkyl optionally substituted with one or two groups R6 or an aryl optionally substituted with one or more groups R6;

R2 is H or alkyl; or

R1 and R2 are bound together to form a 5- or 6-membered heterocycle;

R3 and R4 are each independently H or an alkyl optionally substituted with one or two groups R6; or

R3 and R4 are bound together to form a 5- to 8-membered heterocycle;

R5 is H, a halogen, an alkyl optionally substituted with 1 or 2 groups R6, or an alkoxy optionally substituted with 1 or 2 groups R6; or

R4 and R5 are bound together to form a 5- to 7-membered heterocyle;

R6 is hydroxy, alkoxy, -NR15R16, ‒CO-Y-R17, -CN, -CF3, or aryl;

R,5 and R16 are each independently H, alkyl, -CO-alkyl or form together with the nitrogen atom a 3- to 6-membered cyclic group;

Y is ‒O- or -NR18-;

R17 is H or alkyl; and

R18 is H, alkyl or hydroxyalkyl;

provided that when R3 is H and R4 and R5 are bound together to form a 5-membered heterocycle, then R1 is not H;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
is selected from the groups of formulae (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII) and (XVIII):

wherein:

R7, R8, R9 and R10 are each independently H, a halogen, an alkyl optionally substituted with 1 or 2 groups R6, a perfluoroalkyl, an alkoxy optionally substituted with 1 or 2 groups R6, or a cyano group;

R10 can also represent a cycloalkyl, an aryl, -NR15R16, or ‒CO-Y-R22 where R22 is H, alkyl optionally substituted with hydroxy or alkoxy, or -NR15R16;

R10 can also be bound together with R12 to form a 6-membered carbocycle;

R11, R12, and R13 are each independently H, an alkyl optionally substituted with 1 or 2 groups R6, or a perfluoroalkyl;

R12 can also represent an alkylthio or a group -NR15R16;

R13 can also represent a cycloalkyl optionally substituted with hydroxyl or alkoxyalkyl.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R1 is an alkyl optionally substituted with one or two groups R6 or an aryl optionally substituted with one or more groups R6 and R6 is as defined in claim 1.

4. The compound of one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:

R3 and R4 are each independently H or an alkyl; or

R3 and R4 are bound together to form a 5- to 8-membered heterocycle;

R5 and R6 are as defined in claim 1.

5. The compound of claim 4, which is selected from:

- [4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-isobutyl-hydrazono]methyl]-2-methoxy- phenyl]boronic acid;

- [4-[(E)-[isobutyl-(5-methoxy-1,1-dioxo-1,2-benzothiazol-3-yl)hydrazono]methyl]-2- methoxy-phenyl]boronic acid;

- [4-[(E)-[(5,7-dimethoxy-1,1-dioxo-1,2-benzothiazol-3-yl)-isobutyl-hydrazono]methyl]-2- methoxy-phenyl]boronic acid;

- [4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-ethyl-hydrazono]methyl]-2-methoxy- phenyl]boronic acid;

- [4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-(2-methoxyethyl)hydrazono]methyl]-2- methoxy-phenyl]boronic acid;

- [2-chloro-4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-isobutyl- hydrazono]methyl]phenyl]boronic acid;

- [4-[(E)-[isobutyl-(5-methyl-1,1-dioxo-1,2-benzothiazol-3-yl)hydrazono]methyl]-2- methoxy-phenyl]boronic acid;

- [4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-isobutyl-hydrazono]methyl]phenyl]boronic acid;

- [4-[(E)-[isobutyl-[5-(2-methoxyethoxy)-1,1-dioxo-1,2-benzothiazol-3- yl]hydrazono]methyl]-2-methoxy-phenyl]boronic acid;

- [4-[(E)-[(6-cyano-1,1-dioxo-1,2-benzothiazol-3-yl)-isobutyl-hydrazono]methyl]-2- methoxy-phenyl]boronic acid;

- [4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-isobutyl-hydrazono]methyl]-2-(2- methoxyethoxy)phenyl]boronic acid;

- [4-[(E)-[[5-(3-hydroxypropoxy)-1,1-dioxo-1,2-benzothiazol-3-yl]-isobutyl- hydrazono]methyl]-2-methoxy-phenyl]boronic acid;

- [4-[(E)-[isobutyl-(8-methoxyquinazolin-4-yl)hydrazono]methyl]-2-methoxy- phenyl]boronic acid;

- [4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-isobutyl-hydrazono]methyl]-2-ethoxy- phenyl]boronic acid;

- [2-chloro-4-[(E)-[(5,7-dimethoxy-1,1-dioxo-1,2-benzothiazol-3-yl)-isobutyl- hydrazono]methyl]phenyl]boronic acid;

- [4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-sec-butyl-hydrazono]methyl]-2-methoxy- phenyl]boronic acid;

- [4-[(E)-[(6,8-dimethoxyquinazoIin-4-yl)-isobutyl-hydrazono]methyl]-2-methoxy- phenyl]boronic acid;

- [4-[(E)-[(7-fluoroquinazolin-4-yl)-isobutyl-hydrazono]methyl]-2-methoxy-phenyl]boronic acid;

- [4-[(E)-[isobutyl-(6-methoxyquinazolin-4-yl)hydrazono]methyl]-2-methoxy- phenyl]boronic acid;

- [4-[(E)-[isobutyl(thieno[3,2-d]pyrimidin-4-yl)hydrazono]methyl]-2-methoxy- phenyl]boronic acid;

- [4-[(E)-[ethyl-(8-methoxyquinazolin-4-yl)hydrazono]methyl]-2-methoxy-phenyl]boronic acid;

- [2-methoxy-4-[(E)-[(8-methoxyquinazolin-4-yl)-methyl-hydrazono]methyl]phenyl]- boronic acid;

- [4-[2-(1,1-dioxo-1,2-benzothiazol-3-yl)-3-methyl-4,5-dihydro-3H-pyridazin-6-yl]-2- methoxy-phenyl]boronic acid;

- [4-[2-(5,7-dimethoxy-1,1-dioxo-1,2-benzothiazol-3-yl)-3-methyl-4,5-dihydro-3H- pyridazin-6-yl]-2-methoxy-phenyl]boronic acid;

- [2-methoxy-4-[2-(8-methoxyquinazolin-4-yl)-3-methyl-4,5-dihydro-3H-pyridazin-6- yl]phenyl]boronic acid;

- [4-[2-(1,1-dioxo-1,2-benzothiazol-3-yl)-4,4-dimethyl-3,5-dihydropyridazin-6-yl]-2- methoxy-phenyl]boronic acid;

- [4-[4-(1,1-dioxo-1,2-benzothiazol-3-yl)-6-methyl-5,6-dihydro-1,3,4-oxadiazin-2-yl]-2- methoxy-phenyl]boronic acid;

- [2-methoxy-4-[(E)-[methyl-(5-methylpyrida2in-3-yl)hydrazono]methyl]phenyl]boronic acid;

- 2-[4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-isobutyl-hydrazono]methyl]-2-methoxy- phenyl]-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione;

- [4-[(E)-[ethyl-(7-methylthieno[3,2-d]pyrimidin-4-yl)hydrazono]methyl]-2-methoxy- phenyl]boronic acid;

- [4-[(E)-[ethyl(thieno[3,2-d]pyrimidin-4-yl)hydrazono]methyl]-2-methoxy-phenyl]boranic acid;

- [4-[(E)-[ethyl(thiazolo[4,5-d]pyrimidin-7-yl)hydrazono]methyl]-2-methoxy- phenyl]boronic acid;

- [4-[(E)-[ethyl(furo[2,3-d]pyrimidin-4-yl)hydrazono]methyl]-2-methoxy-phenyl]boronic acid;

- [4-[(E)-[ethyl-(7-methylpyrrolo[2,3-d]pyrimidin-4-yl)hydrazono]methyl]-2-methoxy- phenyl]boronic acid;

- [4-[(E)-[isobutyl-(7-methylthieno[3,2-d]pyrimidin-4-yl)hydrazono]methyl]-2-methoxy- phenyl]boronic acid;

- [4-[(E)-[isobutyl-(2-methylthieno[3,2-d]pyrimidin-4-yl)hydrazono]methyl]-2-methoxy- phenyl]boronic acid;

- [4-[(E)-[isobutyl-(6-methylthieno[3,2-d]pyrimidin-4-yl)hydrazono]methyl]-2-methoxy- phenyl]boronic acid;

- [2-methoxy-4-[(E)-[2-methoxyethyl(thieno[3,2-d]pyrimidin-4-yl)hydrazono]methyl]- phenyl]boronic acid;

- [2-methoxy-4-[(E)-[methyl-(7-methylthieno[3,2-d]pyrimidin-4-yl)hydrazono]methyl]- phenyl]boronic acid;

- [2-methoxy-4-(3-methyl-2-thieno[3,2-d]pyrimidin-4-yl-4,5-dihydro-3H-pyridazin-6- yl)phenyl]boronic acid;

- [2-methoxy-4-[3-methyl-2-(7-methylpyrrolo[2,3-d]pyrimidin-4-yl)-4,5-dihydro-3H- pyridazin-6-yl]phenyl]boronic acid;

- [4-[4-(7-fluoroquinazolin-4-yl)-6-methyl-5,6-dihydro-1,3,4-oxadiazin-2-yl]-2-methoxy- phenyl]boronic acid, and

pharmaceutically acceptable salts thereof.

6. The compound of one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:

R3 is H or an alkyl optionally substituted with one or two groups R6;

R4 and R5 are bound together to form a 5- to 7-membered heterocycle;

R6 is as defined in claim 1.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, represented by formula (Ib):

wherein:

R3 is H or an alkyl optionally substituted with one or two groups R6;

Each R14 is independently H, an alkyl optionally substituted with one or two groups R6, an aryl, -NR15R16, or -CO-Y-R17;

n is 1 , 2 or 3; and

R1 , R2, R6, R15, R16 and R17 are as defined in claim 1.

8. The compound of claim 6 or claim 7, which is selected from:

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl-1,1-dioxo- 1,2-benzothiazol-3-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-(2-methoxyethyl)-1,1- dioxo-1,2-benzothiazol-3-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-(3-methoxypropyl)- 1,1-dioxo-1,2-benzothiazol-3-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-methyl-11,1-dioxo-1,2- benzothiazol-3-amine;

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-1,1-dioxo-1,2- benzothiazol-3-amine;

- 5-fluoro-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl-1,1- dioxo-1,2-benzothiazol-3-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl-5-methyl-1,1- dioxo-1,2-benzothiazol-3-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl-6-methoxy- 1,1-dioxo-1,2-benzothiazol-3-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl-6-methyl-1,1- dioxo-1,2-benzothiazol-3-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl-8-methoxy- quinazolin-4-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-8-methoxy-N-methyl- quinazolin-4-amine;

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-8-methoxy- quinazolin-4-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl-thieno[3,2- d]pyritnidin-4-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N,5-dimethyl-1,1-dioxo- 1,2-benzothiazol-3-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-5-methoxy-N-methyl- 1,1-dioxo-1,2-benzothiazol-3-amine;

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]thieno[3,2- d]pyrimidin-4-amine;

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-7H-pyrrolo[2,3- d]pyrimidin-4-amine;

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]thieno[2,3- d]pyrimidin-4-amine;

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-1-methyl- pyrazolo[3,4-d]pyrimidin-4-amine;

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-7-methyl- thieno[3,2-d]pyrimidin-4-amine;

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]furo[2,3- d]pyrimidin-4-amine;

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-7-methyl- pyrrolo[2,3-d]pyrimidin-4-amine;

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-2-methyl- thieno[3,2-d]pyrimidin-4-amine;

- N-[(E)-(1-hydroxy-3,4-dihydro-2,1-benzoxaborinin-6-yl)methyleneamino]-N-isobutyl- 1,1-dioxo-1,2-benzothiazol-3-amine;

- N-[(E)-(1-hydroxy-4,5-dihydro-3H-2,1-benzoxaborepin-7-yl)methyleneamino]-N- isobutyl-1,1-dioxo-1,2-benzothiazol-3-amine;

- N-[(E)-(1-hydroxy-7-methoxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl- 1,1-dioxo-1,2-benzothiazol-3-amine;

- N-[(E)-(1-hydroxy-3-methyl-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl-1,1- dioxo-1,2-benzothiazol-3-amine;

- N-[(E)-(1-hydroxy-3-methyl-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-methyl-1,1- dioxo-1,2-benzothiazol-3-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-methyl-1,1-dioxo- 4,5,6,7-tetrahydro-1,2-benzothiazol-3-amine;

- 3-[6-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-3-methyl-4,5-dihydro-3H-pyridazin-2-yl]- 1,2-benzothiazole 1,1-dioxide;

- 4-[6-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-3-methyl-4,5-dihydro-3H-pyridazin-2-yl]-8- methoxy-quinazoline;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-5-methoxy-N-methyl- pyridazin-3-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-methyl-2- methylsulfanyl-thiazolo[4,5-d]pyrimidin-7-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N,1-dimethyl- pyrazolo[3,4-d]pyrimidin-4-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N,7-dimethyl-thieno[3,2- d]pyrimidin-4-amine;

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-1H- pyrazolo[4,3-d]pyrimidin-7-amine;

- N7-ethyl-N7-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N2,N2- dimethyl-thiazolo[4,5-d]pyrimidine-2,7-diamine;

- N-ethyi-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-3-methyl-1H- pyrazolo[4,3-d]pyrimidin-7-amine;

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-5H-pyrrolo[3,2- d]pyrimidin-4-amine;

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-2-morpholino- thiazolo[4,5-d]pyrimidin-7-amine;

- N-ethyi-N-[(E)-(1-hydroxy-3H-2,1-benzoxaboroi-5-yl)methyleneamino]-2- methylsulfanyl-thiazo!o[4,5-d]pyrimidin-7-amine hydrochloride;

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-7-propyl- pyrrolo[2,3-d]pyrimidin-4-amine;

- N,7-diethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl) methylene amino]pyrrolo[2,3- d]pyrimidin-4-amine;

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-1H- pyrazolot3,4-d]pyrimidin-4-amine;

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]thiazolo[4,5- d]pyrimidin-7-amine;

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-2,7-dimethyl- thieno[3,2-d]pyrimidin-4-amine;

- N-ethyl-7-fluoro-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5- yl)methyleneamino]quinazolin-4-amine;

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-6-methyl- thieno[3,2-d]pyrimidin-4-amine;

- N-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-6,7,8,9- tetrahydrobenzothiopheno[3,2-d]pyrimidin-4-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl-2- methylsulfanyl-thiazolo[4,5-d]pyrimidin-7-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-isobutyl-7-methyl- thieno[3,2-d]pyrimidin-4-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-(2-methoxyethyl)-7- methyl-thieno[3,2-d]pyrimidin-4-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-(2-methoxyethyl)-2- methylsulfanyl-thiazolo[4,5-d]pyrimidin-7-amine, hydrochloride;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-{3-methoxypropyl)-2- methylsulfanyl-thiazolo[4,5-d]pyrimidin-7-amine;

- 2-[[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-(7-methylthieno[3,2- d]pyrimidin-4-yl)amino]ethanol;

- 6-[[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-methyl-amino]-9- methyl-7H-purin-8-one;

- 4-[[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-methyl-amino]-7- methyl-5H-pyrrolo[2,3-d]pyrimidin-6-one;

- Example 100: 4-[[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-methyl- amino]-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-methyl-5,6- dihydrofuro[2,3-d]pyrimidin-4-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-methyl-7-phenyl- thieno[3,2-d]pyrimidin-4-amine;

- 7-cyclopropyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-methyl- thieno[3,2-d]pyrimidin-4-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-methyl-7-morpholino- thieno[3,2-d]pyrimidin-4-amine;

- 7-ethyl-N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N-methyl- thieno[3,2-d]pyrimidin-4-amine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-N,7-dimethyl-5,6- dihydropyrrolo[2,3-d]pyrimidin-4-amine;

- 9-cyclobutyl-6-[[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-methyl- amino]-7H-purin-8-one;

- 6-[[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-methyl-amino]-9-[3- (methoxymethyl)cyclobutyl]-7H-purin-8-one;

- 6-[[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-methyl-amino]-9-(3- hydroxycyclobutyl)-7H-purin-8-one hydrochloride;

- 9-(3-bicyclo[1.1.1]pentanyl)-6-[[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5- yl)methyleneamino]-methyl-amino]-7H-purin-8-one;

- 7-cyclobutyl-4-[[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-methyl- amino]-5H-pyrrolo[2,3-d]pyrimidin-6-one;

- 4-[ethyl-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]amino]-N-propyl- thieno[3,2-d]pyrimidine-7-carboxamide;

- 4-[ethyl-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]amino]-N,N- dimethyl-thieno[3,2-d]pyrimidine-7-carboxamide;

- N,N-dibutyl-4-[ethyl-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]- amino]thieno[3,2-d]pyrimidine-7-carboxamide;

- 4-[ethyl-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]amino]-N-(oxetan- 3-yl)thieno[3,2-d]pyrimidine-7-carboxamide;

- 4-[ethyl-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]amino]-N-(4- methoxybutyl)thieno[3,2-d]pyrimidine-7-carboxamide;

- 4-[6-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-3-methyl-4,5-dihydro-3H-pyridazin-2- yl]furo[2,3-d]pyrimidine;

- 4-[6-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-3-methyl-4,5-dihydro-3H-pyridazin-2-yl]-7- methyl-thieno[3,2-d]pyrimidine;

- (+) 4-[6-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-3-methyl-4,5-dihydro-3H-pyridazin-2-yl]- 7-methyl-thieno[3,2-d]pyrimidine;

- (-) 4-[6-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-3-methyl-4,5-dihydro-3H-pyridazin-2-yl]- 7-methyl-thieno[3,2-d]pyrimidine;

- 4-[6-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-3-methyl-4,5-dihydro-3H-pyridazin-2- yl]thieno[3,2-d]pyrimidine;

- 4-[6-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-3-methyl-4,5-dihydro-3H-pyridazin-2-yl]- 6,7,8,9-tetrahydrobenzothiopheno[3,2-d]pyrimidine;

- 7-[6-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-3-methyl-4,5-dihydro-3H-pyridazin-2-yl]-2- methylsulfanyl-thiazolo[4,5-d]pyrimidine;

- N-[(E)-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyleneamino]-7-(methoxymethyl)-N- methyl-thieno[3,2-d]pyrimidin-4-amine; and

pharmaceutically acceptable salts thereof.

9. The compound of one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for use as a medicament.

10. The compound of one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of a cancer where YAP is localized in the nucleus of the tumor cells.

11. The compound for the use of claim 10, wherein the cancer is lung, thyroid, ovarian, colorectal, prostate, pancreas, esophagus, liver, breast or skin cancer.

12. The compound for the use of claim 10, wherein the cancer is malignant mesothelioma.

13. A pharmaceutical composition comprising a compound of one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

14. A method of treating a cancer where YAP is localized in the nucleus of the tumor cells, which comprises administering to a subject in need thereof a compound of one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

15. The method of claim 14, wherein the cancer is lung, thyroid, ovarian, colorectal, prostate, pancreas, esophagus, liver, breast or skin cancer.

16. The method of claim 14, wherein the cancer is malignant mesothelioma.