3-(1h-indazol-3-yl)isoquinoline derivatives as map4k1 (HPK1) inhibitors and use thereof in therapy

Abstract

The invention relates to a compound of Formula (I), or a salt, solvate and / or N-oxide thereof, wherein Y1 to Y5, R6, R7, V1, V2 are as defined in claim 1. The compounds of formula (I) are useful as drug, in particular with an MAP4K1 inhibiting activity, and for treating or preventing cancer or neoplastic diseases. The invention further relates to methods for preparing the compounds of formula (I), as well as to pharmaceutical compositions comprising same.

Description

[0001] MAP4K1 INHIBITORS AND USE THEREOF IN THERAPY FIELD OF THE INVENTION The present invention relates to pharmaceutical compounds useful for therapy and / or 5 prophylaxis in a mammal, pharmaceutical composition comprising such compounds, and their use as MAP4K1 inhibitors, useful for treating diseases such as cancer, as well as other diseases or conditions in which MAP4K1 activity is involved. BACKGROUND OF THE INVENTION 10 Hematopoietic Progenitor Kinase 1 (HPK1), also designated as mitogen activated protein kinase 1 (MAP4K1), is a serine / threonine kinase that is a member of the Ste20-related kinase family. Predominantly expressed in hematopoietic cells, including T cells, B cells, macrophages, dendritic cells, neutrophils, and mast cells, HPK1 has been established as a key regulatory molecule in the immune signaling cascade. 15 HPK1 orchestrates a critical balance in the immune system by acting as a negative regulator of T cell and B cell signaling. Upon activation through T cell receptors (TCR) or B cell receptors (BCR), HPK1 has been shown to phosphorylate substrates such as SLP76, leading to a cascade of interactions that ultimately attenuates TCR signaling and limits levels of pro- inflammatory cytokines such as IL-2, TNF-ɑ, and IFN-γ (Hernandez et al., 2018, Cell Reports 20 25, 80–94). This modulation affects the proliferation and production of T cells, which are essential for an effective immune response against malignancies. The kinase activity of HPK1, particularly its ability to negatively influence immune cell activity, is augmented by various mediators within the tumor microenvironment (TME), such as adenosine, prostaglandin E2 (PGE2), and transforming growth factor-beta (TGFβ). These mediators can induce an 25 immunosuppressive environment that hampers the immune system's ability to combat tumor cells. In the context of immuno-oncology, HPK1’s role is twofold. On one hand, it serves as a naturalcheckpoint that prevents autoimmunity by tempering immune responses. On the other hand, its inhibitory effect on immune cells can be co-opted by tumors to evade immune surveillance. 30 The inactivation of HPK1's kinase domain has been shown to elicit robust anti-tumor immune responses (Sawasdikosol, S. et al., 2012, Immunol Res 54, 262–265), HPK1 knockout and kinase-dead models have revealed enhanced T cell function and antitumor efficacy, substantiating the hypothesis that HPK1 inhibition could potentiate immunotherapeutic outcomes (Liu et al., 2019, PLoS ONE 14(3): e0212670).35 There is thus a need for novel compounds able to inhibit HPK1 (i.e. MAP4K1), useful inparticular for treating cancer. 1

[0002] SUMMARY OF THE INVENTION In a first aspect, the invention thus relates to a compound of Formula (I), (I) or a salt, solvate and / or N-oxide thereof, wherein 5o V1 and V2 are independently N or CH,o Y1 is N or C-R1,o Y2 is N or C-R2,o Y3 is N or C-R3,o Y4 is N or C-R4,10 o Y5 is N or C-R5,provided that no more than two of Y1 to Y5 are N, oR1, R2, R3, and R4 are each independently hydrogen, hydroxy, halo, cyano, NRaRb, S-(C1-6alkyl), S(O)-(C1-6 alkyl), S(O)2-(C1-6 alkyl), S(=O)(=NRb)Rc, P(=O)RdRe, C(=O)-(C1-6 alkyl), C(=O)O-(C1-6 alkyl), NRb-C(=O)-Rf, O-C(=O)-Rf, C(=O)NRhR , 1-6 alky , 1-6 alkoxy, C3-615 cycloalkyl, or 3- to 6-membered heterocyclyl,each of said C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, or 3- to 6-membered heterocyclyl beingoptionally substituted by one or more substituents selected from cyano, hydroxy, halo, C1-4 alkoxy, C1-4 alkyl, 3- to 6-membered heterocyclyl, C3-6 cycloalkyl, and O-(C3-6 cycloalkyl),said 3- to 6-membered heterocyclyl being optionally substituted by one or more C1-4 alkyl;20 o R5 is hydrogen, halo or cyano,o R6 is hydrogen, C1-6 alkyl , 1-6 alkoxy, NRg-(C1-6 alkyl), C3-8 cycloalkyl, 3- to 10-memberedheterocyclyl, O-(C3-8 cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-8 cycloalkyl),or NRg-(3- to 10-membered heterocyclyl),each of said C1-6 alkyl, C1-6 alkoxy, NRg-(C1-6 alkyl), C3-8 cycloalkyl, 3- to 10-membered25 heterocyclyl, O-(C3-8 cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-8 cycloalkyl),or NRg-(3- to 10-membered heterocyclyl) being optionally substituted by one or moresubstituents selected from hydroxy, halo, cyano, N=OH, NRaRb, C(=O)-(C1-6 alkyl), C(=O)O- (C1-6 alkyl), C(=O)NRhRi, SO2-(C1-6 alkyl), C1-4 alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4aminoalkyl, C3-6 cycloalkyl, and 3- to 6-membered heterocyclyl, said C3-6 cycloalkyl or 3- to30 6-membered heterocyclyl being optionally substituted by one or more C1-4 alkyl; oR7 is hydrogen, halo, cyano, C1-6 alkyl, C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl,2

[0003] each of said C1-6 alkyl, C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl being optionally substituted by one or more substituents selected from hydroxy, halo, cyano, oxo, S(O)-(C1-6alkyl), S(O)2-(C1-6alkyl), C(=O)-(C1-6alkyl), C(=O)O-(C1-6 alkyl), NRaRb, C(=O)NRhRi, C1-4 alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, C1-45 aminoalkyl, C3-6 cycloalkyl, and 3- to 6-membered heterocyclyl, said C3-6 cycloalkyl or 3- to6-membered heterocyclyl being optionally substituted by one or more C1-4 alkyl;o Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh and Ri are each independently a hydrogen, or a C1-6 alkyloptionally substituted by one or more substituents selected from hydroxy, halo, C1-4alkoxy, and C3-6cycloalkyl. 10 In another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined herein, and a pharmaceutically acceptable carrier. In another aspect, the invention relates to a compound of formula (I) as defined herein, or a composition comprising a compound of formula (I) as described herein, for use as a drug, in15 particular with a MAP4K1 inhibiting activity.The present invention also concerns the use of a compound of formula (I) as defined herein, or a composition comprising a compound of formula (I) as described herein, for inhibiting MAP4K1. The present invention also concerns the use of a compound of formula (I) as defined herein, 20 or a composition comprising a compound of formula (I) as described herein, for the manufacture of a drug intended to inhibit MAP4K1.The present invention also concerns a method for inhibiting MAP4K1, comprising theadministration to a patient in need thereof of an effective amount of a compound of formula (I)as defined herein, or a composition comprising a compound of formula (I) as described herein. 25 In another aspect, the invention relates to a compound of formula (I) as defined herein, or a composition comprising a compound of formula (I) as described herein, for use in the treatment or prevention of a cancer. The present invention also concerns the use of a compound of formula (I) as defined herein, or a composition comprising a compound of formula (I) as described herein, for the treatment30 or prevention of a cancer. The present invention also concerns the use of a compound of formula (I) as defined herein, or a composition comprising a compound of formula (I) as described herein, for the manufacture of a medicine intended to treat or prevent a cancer.The present invention also concerns a method for treating or preventing a cancer, comprising35 the administration to a patient in need thereof of an effective amount of a compound of formula(I) as defined herein, or a composition comprising a compound of formula (I) as described herein. 3

[0004] It is understood that the present invention encompasses only stable compounds. The person of skill in the art knows how to segregate definitions which would lead to unstable compounds from definitions which would lead to stable compounds. 5 DEFINITIONS In the present specification, the word “comprise” and any variation thereof, such as “comprising” and “comprises”, is not intended to exclude other components or steps. As used herein, the term “hydrogen” includes any isotope of hydrogen such as deuterium. As used herein, the term “hydroxy” denotes -OH, the term “cyano” denotes -CN, and the term10 “oxo” denotes =O. The term “halogen”, as used in the present invention, refers to a fluorine, bromine, chlorine or iodine atom, preferably a chlorine or fluorine atom. The term “halo”, as used in the present invention, refers to a fluoro, bromo, chloro or iodo moiety, preferably a chloro or fluoro moiety. 15 The term “ ”, as used in the present invention, refers to a straight or branched monovalent saturated hydrocarbon chain containing from 1 to x carbon atoms. Thus, a C1-6 alkyl contains 1 to 6 carbon atoms and includes, without being limited to, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like. The term “C1-x hydroxyalkyl”, as used in the present invention, refers to a C1-x alkyl group as20 defined above substituted by one hydroxy group. The term “C1-x aminoalkyl”, as used in the present invention, refers to a C1-x alkyl group as defined above substituted by one amino group (-NH2).The term ”, as used in the present invention, refers to a C1-x alkyl group as defined above bound to the molecule via an oxygen atom, including, but not limited to, methoxy,25 ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and the like. The term “C2-x alkenyl”, as used in the present invention, refers to a straight or branched monovalent unsaturated hydrocarbon chain containing from 2 to x carbon atoms Thus, a C2-6alkenyl contains 2 to 6 carbon atoms and includes, without being limited to, ethenyl, propenyl,butenyl, pentenyl, hexenyl and the like.30 The term “C3-x cycloalkyl” or “3- to x-membered cycloalkyl”, as used in the present invention,refers to a monovalent monocyclic or polycyclic hydrocarbon group having 3 to x carbon atoms.Thus, a C3-6 cycloalkyl contains 3 to 6 carbon atoms and includes, but are not limited to,cyclopropyl, cyclopentyl, cyclohexyl and the like. A cycloalkyl group may be monocyclic orpolycyclic, in particular monocyclic or bicyclic. Polycyclic cycloalkyl groups comprise two or35 more joined rings. This includes spirocyclic compounds, fused polycyclic (in particular bicyclic)compounds, and bridged polycyclic compounds. Polycyclic cycloalkyl groups generallycomprise at least 5 carbon atoms. 4

[0005] The term “heterocyclyl”, as used in the present invention, refers to a saturated or unsaturated, but not aromatic, monocyclic or polycyclic (in particular bicyclic) group, advantageously having 3to 12 (preferably 3 to 10) ring atoms, containing at least one heteroatom, preferably 1, 2, 3or 4 heteratoms, in the ring(s), the remaining ring atoms being carbon atoms. The rings of 5polycyclic heterocyclyl may be fused, bridged or spirocyclic. Preferably, each ring of theheterocyclyl comprises 3 to 6 ring atoms. The heteroatom is preferably selected from O, N and S, and the S atom may be mono or dioxidized, i.e. the sulphur atom may be S, S(O) or SO2,preferably S. The “x- to y-membered heterocyclyl” is a heterocyclyl group having x to y ringatoms. Heterocyclyls include, but are not limited to, epoxidyl, aziridinyl, oxetanyl, pyrrolidinyl,10 tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl, dihydrothiophenyl, dihydropyranyl, tetrahydropyridinyl, dihydrooxazinyl, benzothiazinyl, benzothiazinonyl, indolinyle, isoindolinyle. The term “aryl”, as used in the present invention, refers to an aromatic hydrocarbon group comprising one or more fused rings and preferably comprising 6 to 10 carbon atoms, such as,15 for example, a phenyl or naphthyl group. Advantageously, it will be a phenyl group. The “C6-10aryl” is an aryl comprising 6 to 10 carbon atoms.The term “aryl-(C1-6 alkyl)”, as used in the present invention, refers to a C1-6 alkyl group asdefined above substituted with an aryl group as defined above. In particular, it can be a benzyl group. 20 The term “heteroaryl”, as used in the present invention, refers to an aromatic group comprising one or several, notably 1 or 2, fused hydrocarbon cycles in which one or several, notably 1, 2, 3 or 4, carbon atoms each have been replaced with a heteroatom selected from a N, O and S, preferably selected from N and O. It advantageously comprises 5 to 12 (preferably 5 to 10)ring atoms. The “x- to y-membered heteroaryl” is a heteroaryl group having x to y ring atoms.25 It can be a furyl, thienyl, pyrrolyl, pyridyl, oxazolyl, isoxazolyl, thiazolyle, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, quinoxalyl or indyl. The term “N-protecting group”, as used in the present invention, refers to groups intended to 30 protect an amine function (notably a primary amine function) against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in “Greene’s Protective Groups In Organic Synthesis”, 4th edition, 2007, John Wiley & Sons, Hoboken, New Jersey. An amine function protected by a N-protecting group can be a carbamate, an amide, a sulfonamide, an N-alkyl derivative, an amino acetal derivative, a N-benzyl derivative, an35 imine derivative, an enamine derivative or a N-heteroatom derivative. In particular, N- protecting groups can be formyl; an aryl, such as a phenyl, optionally substituted with one or several methoxy groups such as p-methoxyphenyl (PMP); an aryl-(C1-6alkyl), such as a 5

[0006] benzyl, the aryl moiety being optionally substituted with one or several methoxy groups, such as benzyl (Bn), p-methoxybenzyl (PMB) or 3,4-dimethoxybenzyl (DMPM); -CO-RPG1such as acetyl (Ac), pivaloyl (Piv or Pv), benzoyl (Bz) or p-methoxybenzylcarbonyl (Moz); -CO2-RPG1such as tbutyloxycarbonyl (Boc), trichloroethoxycarbonyl (Troc), allyloxycarbonyl (Alloc), 5 benzyloxycarbonyl (Cbz or Z) or 9-fluorenylmethyloxycarbonyl (Fmoc); -SO2-RPG1such as phenylsulfonyl, tosyl (Ts or Tos) or 2 nitrobenzenesulfonyl (also called nosyl - Nos or Ns); andthe like, with RPG1representing a C1-6alkyl optionally substituted with one or several halogen atoms such as F or Cl; a C2-6alkenyl such as an allyl; an aryl, such as a phenyl, optionally substituted 10 with one or several groups chosen among OMe (methoxy) and NO2(nitro); an aryl-(C1-6alkyl), such as a benzyl, the aryl moiety being optionally substituted with one or several methoxy groups; or a 9-fluorenylmethyl group. In particular, it may be an amino acetal protecting group, preferabl wherein the wavyline indicates the point of attachment to the rest of the molecule. 15 The person of skill in the art is familiar with Lewis and Brønsted acids. Examples of Lewis acids include aluminium chloride, zinc chloride, silver chloride. Examples of Brønsted acids include hydrochloric acid, trifluoroacetic acid, acetic acid. The person of skill in the art will choose suitable Lewis or Brønsted acids depending on the nature of the starting molecule and desired result, and to this end may refer to “Greene’s Protective Groups In Organic Synthesis”, 4th20 edition, 2007, John Wiley & Sons, Hoboken, New Jersey. Also, in the present invention, Me stands for methyl, Et stands for Ethyl, Ac stands for acetyl. More generally, the abbreviations used refer to chemical groups having the meaning commonly known in the art. 25 For the purpose of the invention, the term “pharmaceutically acceptable” is intended to mean what is useful to the preparation of a pharmaceutical composition, and what is generally safe and non-toxic, for a pharmaceutical use. 6

[0007] DETAILED DESCRIPTION OF THE INVENTION 1- Compounds of formula (I)V1, and V25 Advantageously, at most one of V1 and V2 is N. Preferably V1 is N and V2 is CH, or V1 and V2are both CH. Y1to Y5Preferably, Y1is C-R1and Y4is C-R4. 10 In some embodiments, at most one of Y1to Y4is N, in particular at most one of Y1to Y5is N. In some particular embodiments, Y2 is N and preferably Y1 is C-R1, Y3 is C-R3 and Y4 is C-R4. In some particular embodiments, Y3 is N and preferably Y1 is C-R1, Y2 is C-R2 and Y4 is C-R4. In other particular embodiments, Y1 is C-R1, Y2 is C-R2, Y3 is C-R3 and Y4 is C-R4. In these above embodiments, Y5 is advantageously C-R5, even more preferably CH. 15 In other particular embodiments, Y5 is N and preferably, Y1 is C-R1, Y2 is C-R2, Y3 is C-R3 and Y4 is C-R4. In some embodiments, Y1 and Y4 are advantageously CH or CF, preferably CH. Inthese embodiments, Y5 is advantageously C-R5, even more preferably CH. Y5 is advantageously C-R5, even more preferably CH. In some particular embodiments, Y1 is CH, Y2 is N, Y3 is C-R3 and Y4 is CH or CF, preferably20 CH. In these embodiments, Y5 is advantageously C-R5, even more preferably CH.In some particular embodiments, Y1 is CH, Y2 is C-R2, Y3 is N and Y4 is CH or CF, preferablyCH. In these embodiments, Y5 is advantageously C-R5, even more preferably CH. In other particular embodiments, Y1 is CH, Y2 is C-R2, Y3 is C-R3 and Y4 is CH. In theseembodiments, Y5 is advantageously C-R5, even more preferably CH.25 According to a preferred embodiment, Y1 is C-R1, preferably CH; Y2 is N or C-R2; Y3 is C-R3and Y4 is C-R4, preferably CH. In this embodiment, Y5 is advantageously C-R5, even morepreferably CH. R1 to R4 30 Advantageously, R1, R2, R3, and R4 are each independently hydrogen, hydroxy, halo, cyano, S-(C1-C6alkyl), S(O)2-(C1-C6alkyl), S(=O)(=NRb)Rc, P(=O)RdRe, C(=O)-(C1-6alkyl), C(=O)O- (C1-6 alkyl), C(=O)NRhRi, NRaRb, NH-C(=O)-Rf, C1-6 alkyl, C1-6 alkoxy, or 3- to 6-memberedheterocyclyl, each of said C1-6 alkyl, C1-6 alkoxy, or 3- to 6-membered heterocyclyl being optionally35 substituted by one or more substituents selected from hydroxy, halo, C1-4alkoxy, C1-4alkyl, and 3- to 6-membered heterocyclyl.7

[0008] Preferably, the 3- to 6-membered heterocyclyl is a 4-, 5- or 6-membered heterocyclyl which ismonocyclic and in which 1 or 2 carbon atoms are each replaced by a nitrogen or oxygen atom.Preferably, the 3- to 6-membered heterocyclyl is a saturated 4-, 5- or 6-membered heterocyclylwhich is monocyclic and in which 1 or 2 carbon atoms are each replaced by a nitrogen or 5 oxygen atom. According to a particular embodiment, R1, R2, R3, and R4are each independently hydrogen, hydroxy, halo, cyano, C(=O)-(C1-6 alkyl), C(=O)O-(C1-6 alkyl), C(=O)NRhRi, NRaRb, NH-C(=O)-Rf, C1-6 alkyl, C1-6 alkoxy, or 3- to 6-membered heterocyclyl,each of said C1-6 alkyl, C1-6 alkoxy, or 3- to 6-membered heterocyclyl being optionally10 substituted by one or more substituents selected from hydroxy, halo, C1-4alkoxy, and C1-4alkyl. According to another particular embodiment, R1, R2, R3, and R4 are each independently hydrogen, hydroxy, halo, cyano, NRaRb, C1-6 alkyl, C1-6 alkoxy, or 3- to 6-memberedheterocyclyl, each of said C1-6 alkyl, C1-6 alkoxy, or 3- to 6-membered heterocyclyl being optionally15 substituted by one or more substituents selected from hydroxy, halo, C1-4 alkoxy, and C1-4 alkyl. In some embodiments, R1, R2, R3 and R4 are each independently H, CN, F, methyl, OH, OMe, , , , , , , ,wherein the wavy line indicates the point of attachment to the rest of the molecule. 20 In some embodiment, R1 and R4 are each independently hydrogen, halo or C1-6 alkyl, said C1- 6 alkyl being optionally substituted by one or more substituents selected from cyano, hydroxy, halo, C1-4 alkoxy, C3-6cycloalkyl and O-(C3-6 cycloalkyl), preferably from cyano, hydroxy, halo, C1-4 alkoxy. Preferably, R1 and R4 are each independently hydrogen, halo or C1-6 alkyl, in particular hydrogen or halo. In particular, R1 and R4 are H or F, preferably H.25 In some embodiments, R1 and R4 are H or halo, preferably H, and R2 and R3 are eachindependently hydrogen, hydroxy, halo, cyano, S-(C1-C6alkyl), S(O)2-(C1-C6alkyl), S(=O)(=NRb)Rc, P(=O)RdRe, C(=O)-(C1-6 alkyl), C(=O)O-(C1-6 alkyl), C(=O)NRhRi, NRaRb, NH-C(=O)-Rf, C1-6 alkyl, C1-6 alkoxy, or 3- to 6-membered heterocyclyl,each of said C1-6 alkyl, C1-6 alkoxy, or 3- to 6-membered heterocyclyl being optionally30 substituted by one or more substituents selected from hydroxy, halo, C1-4alkoxy, C1-4alkyl, 8

[0009] and 3- to 6-membered heterocyclyl, said 3- to 6-membered heterocyclyl being optionallysubstituted by one or more C1-4alkyl. Advantageously, in some embodiments, R1 and R4 are H or F, preferably H, and R2 and R3 areeach independently H, CN, F, methyl 5, wherein the wavy line indicates the point of attachment to the rest of the molecule. R5 10 R5 is hydrogen, halo or cyano, advantageously H. R6 Advantageously, R6 is C1-6 alkyl, C1-6 alkoxy, NRg-(C1-6 alkyl), C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, O-(C3-8 cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-815 cycloalkyl), or NRg-(3- to 10-membered heterocyclyl),each of said C1-6 alkyl, C1-6 alkoxy, NRg-(C1-6 alkyl), C3-8 cycloalkyl, 3- to 10-memberedheterocyclyl, O-(C3-8 cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-8 cycloalkyl), orNRg-(3- to 10-membered heterocyclyl) being optionally substituted by one or more substituentsselected from hydroxy, halo, cyano, N=OH, NRaRb, C(=O)-(C1-6 alkyl), C(=O)O-(C1-6 alkyl),20 C(=O)NRhRi, SO2-(C1-6 alkyl), C1-4 alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 aminoalkyl, C3-6cycloalkyl, and 3- to 6-membered heterocyclyl, said C3-6 cycloalkyl or 3- to 6-memberedheterocyclyl being optionally substituted by one or more C1-4 alkyl. Preferably, R6 is hydrogen, C1-4 alkyl, C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, O-(C3-8cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-8 cycloalkyl), or NRg-(3- to 10-25 membered heterocyclyl), more preferably R6 is C1-4 alkyl, C3-8 cycloalkyl, 3- to 10-memberedheterocyclyl, O-(C3-8 cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-8 cycloalkyl), orNRg-(3- to 10-membered heterocyclyl),each of said C1-6 alkyl, C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, O-(C3-8 cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-8 cycloalkyl), or NRg-(3- to 10-membered9

[0010] heterocyclyl) being optionally substituted by one or more substituents selected from hydroxy, halo, NRaRb, C(=O)NRhRi, C1-4 alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 aminoalkyl and 3- to 6-membered heterocyclyl, said 3- to 6-membered heterocyclyl being optionally substituted byone or more C1-4alkyl. 5According to a particular embodiment, R6 is C3-8 cycloalkyl, 3- to 10-membered heterocyclyl,O-(C3-8 cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-8 cycloalkyl), or NRg-(3- to 10-membered heterocyclyl), each of said C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, O-(C3-8 cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-8 cycloalkyl), or NRg-(3- to 10-membered heterocyclyl) being10 optionally substituted by one or more substituents selected from hydroxy, halo, NRaRb, C(=O)NRhRi, C1-4 alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 aminoalkyl and 3- to 6-memberedheterocyclyl, said 3- to 6-membered heterocyclyl being optionally substituted by one or moreC1-4 alkyl, preferably each of said C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, O-(C3-8cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-8 cycloalkyl), or NRg-(3- to 10-15 membered heterocyclyl) being optionally substituted by one or more substituents selected from hydroxy, halo, NRaRb, CC1-4 alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, and C1-4 aminoalkyl. According to another particular embodiment, R6 is 3- to 10-membered heterocyclyl, O-(3- to10-membered heterocyclyl), or NRg-(3- to 10-membered heterocyclyl),each of said C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, O-(C3-8 cycloalkyl), O-(3- to 10-20 membered heterocyclyl), NRg-(C3-8 cycloalkyl), or NRg-(3- to 10-membered heterocyclyl) beingoptionally substituted by one or more substituents selected from hydroxy, halo, NRaRb, C(=O)NRhRi, C1-4 alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 aminoalkyl and 3- to 6-memberedheterocyclyl, said 3- to 6-membered heterocyclyl being optionally substituted by one or moreC1-4 alkyl, preferably each of said C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, O-(C3-825 cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-8 cycloalkyl), or NRg-(3- to 10-membered heterocyclyl) being optionally substituted by one or more substituents selected from hydroxy, halo, NRaRb, CC1-4 alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, and C1-4 aminoalkyl. Preferably, the C3-8 cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl, and the 3- to 10-membered heterocyclyl is monocyclic or bicyclic, each cycle having 4, 5, 6 or 7 ring atom,30 provided that there is 3 to 10, in particular 4 to 9 ring atoms, in which 1 or 2 carbon atoms areeach replaced by a nitrogen or oxygen atom, and which is preferably saturated. 10

[0011] , , , , 5 , ee e ay e caes e po o a ac e o e es o e oecue. 10 R7Advantageously, R7 is hydrogen, halo, cyano , C1-6 alkyl, C3-8 cycloalkyl, or 3- to 10-memberedheterocyclyl, each of said C1-6 alkyl, C3-8 cycloalkyl, or 3- to 10-membered heterocyclyl, being optionallysubstituted by one or more substituents selected from hydroxy, halo, cyano, oxo, S(O)-(C1-615 alkyl), S(O)2-(C1-6 alkyl), C(=O)-(C1-6 alkyl), C(=O)O-(C1-6 alkyl), NRaRb, C(=O)NRhRi, C1-4alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 aminoalkyl, C3-6 cycloalkyl, and 3- to 6-membered11

[0012] heterocyclyl, said C3-6 cycloalkyl or 3- to 6-membered heterocyclyl being optionally substitutedby one or more C1-4alkyl. In some embodiments, R7 is hydrogen, cyano, C1-6 alkyl, C3-8 cycloalkyl, 3- to 10-memberedheterocyclyl, or C6-10 aryl, preferably R7 is hydrogen, cyano, C1-6 alkyl, C3-8 cycloalkyl, or 3- to5 10-membered heterocyclyl, each of said C1-6 alkyl, C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, C6-10 aryl beingoptionally substituted by one or more substituents selected from hydroxy, halo, cyano, oxo, S(O)2-(C1-6alkyl), C(=O)-(C1-6alkyl), NRaRb, C1-4alkoxy, C1-4alkyl, C1-4hydroxyalkyl, C1-4aminoalkyl, C3-6 cycloalkyl and 3- to 6-membered heterocyclyl.10 Preferably, R7 is hydrogen, cyano, C1-6 alkyl, C3-8 cycloalkyl, 3- to 10-membered heterocyclyl,or C6-10 aryl, preferably R7 is hydrogen, cyano, C1-6 alkyl, C3-8 cycloalkyl, or 3- to 10-memberedheterocyclyl, each of said C1-6 alkyl, C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, C6-10 aryl beingoptionally substituted by one or more substituents selected from hydroxy, halo, cyano, oxo,15 S(O)2-(C1-6 alkyl), C(=O)-(C1-6 alkyl), C1-4 alkoxy, C1-4 alkyl, C3-6 cycloalkyl, and 3- to 6-membered heterocyclyl, said C3-6 cycloalkyl or 3- to 6-membered heterocyclyl being optionallysubstituted by one or more C1-4 alkyl. According to a particular embodiment, R7 is hydrogen, cyano, C1-6 alkyl, or 3- to 10-memberedheterocyclyl,20 each of said C1-6 alkyl, 3- to 10-membered heterocyclyl being optionally substituted by one ormore substituents selected from hydroxy, halo, cyano, C1-4 alkoxy, or C1-4 alkyl. Preferably, the C3-8 cycloalkyl is cyclopropyl, cyclopentyl, cyclohexyl, or spiro[2.2]pentane, andthe 3- to 10-membered heterocyclyl is monocyclic or bicyclic, each cycle having 3, 4, 5, 6, or7 ring atom, provided that there is 3 to 10, in particular 6 to 9 ring atoms, in which 1 or 2 carbon25 atoms are each replaced by a sulfur, nitrogen or oxygen atom, wherein the sulfur atom maybe mono or dioxidized, preferably dioxidized. ,, , , , , , , , , , , , 12

[0013] , wherein the wavy line indicates the point of attachment to the rest of the molecule. 5 Rato RiAdvantageously, Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh and Ri are each independently a hydrogen C1-6 alkyl optionally substituted by one or more substituents selected from hydroxy, halo, C1-4 alkoxy. Advantageously, Rb, Rc, Rd, Re, Rf, Rg, Rh and Ri are each independently a hydrogen or C1-410 alkyl. Combinations In particular embodiments, in formula (I), oV1 and V2 are independently N or CH,15 o Y1 is N or C-R1,o Y2 is N or C-R2,o Y3 is N or C-R3,o Y4 is N or C-R4,o Y5 is N or C-R5,20 provided that no more than two of Y1 to Y5 are N, oR1, R2, R3, and R4 are each independently hydrogen, hydroxy, halo, cyano, NRaRb, S-(C1-6alkyl), S(O)-(C1-6 alkyl), S(O)2-(C1-6 alkyl), S(=O)(=NRb)Rc, P(=O)RdRe, C(=O)-(C1-6 alkyl), C(=O)O-(C1-6 alkyl), NRb-C(=O)-Rf, O-C(=O)-Rf, C(=O)NRhR i, 1-6 alky , C1-6 alkoxy, C3-6cycloalkyl, or 3- to 6-membered heterocyclyl,25 each of said 1-6 alkyl , 1-6 alkoxy, C3-6 cycloalkyl, or 3- to 6-membered heterocyclyl beingoptionally substituted by one or more substituents selected from cyano, hydroxy, halo, C1-4alkoxy, C1-4 alkyl, 3- to 6-membered heterocyclyl, C3-6 cycloalkyl, and O-(C3-6 cycloalkyl),said 3- to 6-membered heterocyclyl being optionally substituted by one or more C1-4 alkyl;o R5 is hydrogen, halo or cyano,30 o R6 is C1-6 alkyl, C1-6 alkoxy, NRg-(C1-6 alkyl), C3-8 cycloalkyl, 3- to 10-membered heterocyclyl,O-(C3-8 cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-8 cycloalkyl), or NRg-(3- to10-membered heterocyclyl), 13

[0014] each of said C1-6 alkyl, C1-6 alkoxy, NRg-(C1-6 alkyl), C3-8 cycloalkyl, 3- to 10-memberedheterocyclyl, O-(C3-8 cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-8 cycloalkyl),or NRg-(3- to 10-membered heterocyclyl) being optionally substituted by one or moresubstituents selected from hydroxy, halo, cyano, N=OH, NRaRb, C(=O)-(C1-6 alkyl), C(=O)O- 5(C1-6 alkyl), C(=O)NRhRi, SO2-(C1-6 alkyl), C1-4 alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4aminoalkyl, C3-6 cycloalkyl, and 3- to 6-membered heterocyclyl, said C3-6 cycloalkyl or 3- to6-membered heterocyclyl being optionally substituted by one or more C1-4alkyl; oR7 is hydrogen, halo, cyano, C1-6 alkyl, C3-8 cycloalkyl, or 3- to 10-membered heterocyclyl,each of said C1-6 alkyl, C3-8 cycloalkyl, or 3- to 10-membered heterocyclyl being optionally10 substituted by one or more substituents selected from hydroxy, halo, cyano, oxo, S(O)-(C1- 6alkyl), S(O)2-(C1-6 alkyl), C(=O)-(C1-6 alkyl), C(=O)O-(C1-6 alkyl), NRaRb, C(=O)NRhRi, C1-4alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 aminoalkyl, C3-6 cycloalkyl, and 3- to 6-memberedheterocyclyl, said C3-6 cycloalkyl or 3- to 6-membered heterocyclyl being optionallysubstituted by one or more C1-4alkyl;15 o Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh and Ri are each independently a hydrogen, or a C1-6 alkyloptionally substituted by one or more substituents selected from hydroxy, halo, C1-4 alkoxy, and C3-6 cycloalkyl. In particular embodiments, in formula (I),20 o at most one of V1 and V2 is N,o Y1 is C-R1, preferably CH,o Y2 is N or C-R2,o Y3 is N or C-R3,o Y4 is C-R4, preferably CH or CF, preferably CH,25 o Y5 is C-R5.Preferably, in these embodiments, Y2 and Y3 are not N at the same time. In these embodiments, R1, R2, R3, and R4 are each independently hydrogen, hydroxy, halo, cyano, S-(C1-6 alkyl), S(O)2-(C1-6 alkyl), S(=O)(=NRb)Rc, P(=O)RdRe, C(=O)-(C1-6 alkyl), C(=O)O-(C1-6 alkyl), C(=O)NRhRi, -NRaRb, NH-C(=O)-Rf, C1-6 alkyl, C1-6 alkoxy, or 3- to 6-30 membered heterocyclyl, each of said C1-6 alkyl, C1-6 alkoxy, or 3- to 6-membered heterocyclyl being optionallysubstituted by one or more substituents selected from hydroxy, halo, C1-4 alkoxy, C1-4 alkyl, and 3- to 6-membered heterocyclyl, said or 3- to 6-membered heterocyclyl being optionallysubstituted by one or more C1-4 alkyl, 14

[0015] preferably R1, R2, R3 and R4 are each independently H, CN, F, methyl, OH, OMe, NHAc,, wherein the wavy line indicates the point of attachment to the rest of the molecule. 5In the definition of R1, R2, R3, and R4, the 3- to 6-membered heterocyclyl is preferably a 4-, 5-or 6-membered heterocyclyl which is monocyclic and in which 1 or 2 carbon atoms are each replaced by a nitrogen or oxygen atom. Preferably, the 3- to 6-membered heterocyclyl is asaturated 4-, 5- or 6-membered heterocyclyl which is monocyclic and in which 1 or 2 carbonatoms are each replaced by a nitrogen or oxygen atom. 10 In these embodiments, R5is preferably H. In these embodiments, R6 is advantageously hydrogen, C1-4 alkyl, C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, O-(C3-8 cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-8cycloalkyl), or NRg-(3- to 10-membered heterocyclyl), even more preferably R6 i C1-4 alkyl, C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, O-(C3-8 cycloalkyl), O-(3- to 10-membered15 heterocyclyl), NRg-(C3-8 cycloalkyl), or NRg-(3- to 10-membered heterocyclyl),each of said C1-6 alkyl, -6 alkoxy, C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, O-(C3-8cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-8 cycloalkyl), or NRg-(3- to 10-membered heterocyclyl) being optionally substituted by one or more substituents selected from hydroxy, halo, NRaRb, C(=O)NRhRi, C1-4 alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 aminoalkyl20 and 3- to 6-membered heterocyclyl, said 3- to 6-membered heterocyclyl being optionallysubstituted by one or more C1-4 alkyl, , , , , , , , 15

[0016] , , ,5 wherein the wavy line indicates the point of attachment to the rest of the molecule. Advantageously, in the definition of R6, the C3-8 cycloalkyl is cyclopentyl or cyclohexyl, and the3- to 10-membered heterocyclyl is monocyclic or bicyclic, each cycle having 4, 5, 6 or 7 ringatom, provided that there is 3 to 10, in particular 4 to 9 ring atoms, in which 1 or 2 carbon atoms10 are each replaced by a nitrogen or oxygen atom, and which is preferably saturated. In these embodiments, R7 is hydrogen, halo, cyano, C1-6 alkyl, C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl,R7 is hydrogen, cyano, C1-6 alkyl, C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, or C6-10 aryl,preferably R7 is hydrogen, cyano, C1-6 alkyl, C3-8 cycloalkyl, or 3- to 10-membered heterocyclyl,15 each of said C1-6 alkyl, C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, C6-10 aryl beingoptionally substituted by one or more substituents selected from hydroxy, halo, cyano, oxo, S(O)2-(C1-6 alkyl), C(=O)-(C1-6 alkyl), NRaRb, C1-4 alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4aminoalkyl, C3-6 cycloalkyl and 3- to 6-membered heterocyclyl, said C3-6 cycloalkyl or 3- to 6-membered heterocyclyl being optionally substituted by one or more C1-4 alkyl,16

[0017] , , , 5 wherein the wavy line indicates the point of attachment to the rest of the molecule. Advantageously, in the definition of R7, the C3-8 cycloalkyl is cyclopropyl, cyclopentyl orcyclohexyl, and the 3- to 10-membered heterocyclyl is monocyclic or bicyclic, each cyclehaving 3, 4, 5, or 6 ring atom, provided that there is 3 to 10, in particular 6 to 9 ring atoms, in 10 which 1 or 2 carbon atoms are each replaced by a sulfur, nitrogen or oxygen atom, wherein the sulfur atom may be mono or dioxidized, preferably dioxidized. Preferably, in formula (I), oat most one of V1 and V2 is N, preferably V2 and V1 are both CH,15 o Y1 is C-R1, preferably CH,o Y2 is N or C-R2,o Y3 is N or C-R3, provided that Y3 is not N when Y2 is N,o Y4 is C-R4, preferably CH or CF, preferably CH,o Y5 is C-R5,20 o R1, R2, R3, and R4 are each independently hydrogen, hydroxy, halo, cyano, C(=O)-(C1-6alkyl), C(=O)O-(C1-6 alkyl), C(=O)NRhRi, NRaRb, NH-C(=O)-Rf, C1-6 alkyl, C1-6 alkoxy, or 3-to 6-membered heterocyclyl, each of said C1-6 alkyl, C1-6 alkoxy, or 3- to 6-membered heterocyclyl being optionallysubstituted by one or more substituents selected from hydroxy, halo, C1-4 alkoxy, and C1-425 alkyl, 17

[0018] o R6 is C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, O-(C3-8 cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-8 cycloalkyl), or NRg-(3- to 10-membered heterocyclyl),each of said C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, O-(C3-8 cycloalkyl), O-(3- to10-membered heterocyclyl), NRg-(C3-8 cycloalkyl), or NRg-(3- to 10-membered heterocyclyl)5 being optionally substituted by one or more substituents selected from hydroxy, halo, NRaRb, C(=O)NRhRi, C1-4 alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 aminoalkyl and 3- to 6-membered heterocyclyl, said 3- to 6-membered heterocyclyl being optionally substituted byone or more C1-4 alkyl, preferably each of said C3-8 cycloalkyl, 3- to 10-memberedheterocyclyl, O-(C3-8 cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-8 cycloalkyl),10 or NRg-(3- to 10-membered heterocyclyl) being optionally substituted by one or moresubstituents selected from hydroxy, halo, NRaRb, CC1-4 alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, and C1-4 aminoalkyl, ando R7 is hydrogen, cyano, C1-6 alkyl, or 3- to 10-membered heterocyclyl,each of said C1-6 alkyl, 3- to 10-membered heterocyclyl being optionally substituted by one15 or more substituents selected from hydroxy, halo, cyano, C1-4 alkoxy, or C1-4 alkyl. Preferably, in formula (I), oat most one of V1 and V2 is N, preferably V2 and V1 are both CH,o Y1 is C-R1, preferably CH,20 o Y2 is N or C-R2,o Y3 is N or C-R3, provided that Y3 is not N when Y2 is N,o Y4 is C-R4, preferably CH or CF, preferably CH,o Y5 is C-R5,o R1, R2, R3, and R4 are each independently hydrogen, hydroxy, halo, cyano, NRaRb, C1-625 alkyl, C1-6 alkoxy, or 3- to 6-membered heterocyclyl,each of said C1-6 alkyl, C1-6 alkoxy, or 3- to 6-membered heterocyclyl being optionallysubstituted by one or more substituents selected from hydroxy, halo, C1-4 alkoxy, and C1-4 alkyl. oR6 is 3- to 10-membered heterocyclyl, O-(3- to 10-membered heterocyclyl), or NRg-(3- to30 10-membered heterocyclyl), each of said C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, O-(C3-8 cycloalkyl), O-(3- to10-membered heterocyclyl), NRg-(C3-8 cycloalkyl), or NRg-(3- to 10-membered heterocyclyl)being optionally substituted by one or more substituents selected from hydroxy, halo, NRaRb, C(=O)NRhRi, C1-4 alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 aminoalkyl and 3- to 6-35 membered heterocyclyl, said 3- to 6-membered heterocyclyl being optionally substituted byone or more C1-4 alkyl, preferably each of said C3-8 cycloalkyl, 3- to 10-memberedheterocyclyl, O-(C3-8 cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-8 cycloalkyl),18

[0019] or NRg-(3- to 10-membered heterocyclyl) being optionally substituted by one or moresubstituents selected from hydroxy, halo, NRaRb, CC1-4alkoxy, C1-4alkyl, C1-4hydroxyalkyl, and C1-4 aminoalkyl, ando R7 is hydrogen, cyano, C1-6 alkyl, or 3- to 10-membered heterocyclyl,5 each of said C1-6 alkyl, 3- to 10-membered heterocyclyl being optionally substituted by oneor more substituents selected from hydroxy, halo, cyano, C1-4alkoxy, or C1-4alkyl. Preferably, the compound of formula (I) is selected from the group consisting of compounds 1to 148, and salts, solvates and / or N-oxides thereof, preferably it is compound 1, 2, 6, 16, 18,10 20, 23, 26, 30 or 39 or a salt, solvate and / or N-oxide thereof.Tautomers, stereoisomers, salts, solvates and N-oxides The compounds of formula (I) as described herein may exist in tautomeric form or steroisomeric form, i.e. in diastereomeric or enantiomeric forms. The present invention15 contemplates all such compounds, including cis- and trans-diastereomers, E- and Z-stereomers, R- and S-enantiomers, diastereomers, d-isomers, l-isomers, racemic mixturesthereof and other mixtures thereof. The term “tautomer” used in this invention refers to structural isomers of chemical compounds that readily interconvert. As an example, compounds comprising respectively an amide group 20 (-C(=O)-NH-) and an imidic acid group (-C(OH)=N-) are tautomers such as in the following structures: . The same is true of the following two indazoles: and .The term “stereoisomers” used in this invention refers to configurational stereoisomers and 25 includes geometric isomers and optical isomers. The “geometric isomers”, also called E / Z isomers or cis-trans isomers, result from the different position of substituents on a double C=C bond which can have a Z or E configuration, also called cis or trans configuration. The “optical isomers” result from the different position in space of substituents or lone pair of electrons onan atom (such as a carbon or sulfur atom) comprising four different substituents (including 30 potentially a lone pair of electron). This atom thus represents a chiral or asymmetric center. Optical isomers which are not mirror images of one another are thus designated as 19

[0020] “diastereoisomers” and optical isomers which are non-superimposable mirror images are designated as “enantiomers”. The compounds of the present invention may be in the form of free bases or pharmaceutically acceptable acid addition salts thereof. In some embodiments, the compounds of formula (I) 5 comprise an acidic proton. In such cases, the compounds of formula (I) may be in the form of free acids or pharmaceutically acceptable bases addition salts thereof.As used herein, a “pharmaceutically acceptable salt or solvate” designates a salt or solvate of a compound which is pharmaceutically acceptable, as defined above, and which possesses the pharmacological activity of the corresponding compound. 10 The nature of the salt may vary, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of compounds for use in the present methods may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, 15 heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, 20 stearic, algenic, hydroxybutyric, salicylic, galactaric and galacturonic acid. All of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid with any of the compounds of the invention. Examples of pharmaceutically acceptable bases addition salts include salts formed when anacidic proton present in the compound is either replaced by a metal ion, such as an alkali metal25 ion, an alkaline-earth metal ion, or an aluminium ion; or coordinated with an organic or inorganic base. Acceptable organic bases comprise diethanolamine, ethanolamine, N- methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases comprise aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. 30 Acceptable solvates for the therapeutic use of the compounds of the present invention include conventional solvates such as those formed during the last step of the preparation of the compounds of the invention due to the presence of solvents. As an example, mention may be made of solvates due to the presence of water (these solvates are also called hydrates) or ethanol.35 The compounds of the present invention may also be in the form of N-oxides, i.e. a nitrogenatom of said compounds may be in an oxidized form. 20

[0021] 2 – Methods for preparing the compounds of formula (I)The compounds of the invention may be obtained by a process comprising the following successive steps: a) Subjecting a compound of the following formula (II):5 II) with V2, V1, Y5 and R7 as defined above, and PGn represents a N-protecting group, preferablyan amino acetal protecting group, to a borylation with a boronic of formula (III), II) 10 with RB1, RB2each independently being a C1-6alkyl, or RB1and RB2together form a hydrocarbon divalent chain linking together the two oxygens borne by a same boron (in order to form a cyclewith the two oxygens and the boron), to obtain a boronic ester of formula (C): C) 15 with V2, V1, Y5, R7, RB1, RB2 and PGn as defined above, b) Subjecting the boronic ester of formula (C) to a Suzuki coupling with the compound offormula (B): (B), with Y1, Y2, Y3, Y4and R6as defined above, and X representing a leaving group such as 20 halo or O-S(O)2-(C1-6alkyl) or O-S(O)2-(C1-6haloalkyl), preferably a chloro, bromo, iodo, mesylate or triflate, preferably chloro or bromo such as chloro,to obtain an intermediate of formula (D) 21

[0022] D) with V2, V1, Y1, Y2, Y3, Y4, Y5, R6, R7 and PGn as defined above,c) Subjecting the compound of formula (D) to a nitrogen deprotection reaction, to obtainthe compound of formula (I) as defined herein .5 Preferably, PGn represents an amino acetal protecting group, more preferablywherein the wavy line indicates the point of attachment to the rest of the molecule. In step a), the borylation is preferably an iridium-catalyzed borylation. Suitable iridium catalysts are for instance (Ir[dF(CF3)ppy]2(dtbpy))PF6, [Ir(OMe)COD]2.Reaction conditions for Suzuki couplings of step b) are known in the art. In particular, palladium10 catalysts may be used such as Pd(PPh)3, XantPhos Pd G4 (CAS No.: 1621274-19-8),BrettPhos Pd G3 (CAS No.:1470372-59-8).The conditions of deprotection step c) will depend on the nature of the N-protecting group, the skilled person being able to determine these conditions. If PGn represents an amino acetal protecting group, deprotection can be performed in the presence of an acid such as HCl or15 trifluoroacetic acid (TFA). The compound of formula (B) may be prepared by a process comprising subjecting the compound of formula (IV): V) with Y1, Y2, Y3 and Y4 as defined above,20 to a Suzuki coupling with a compound of formula or , with R6, RB1 and RB2 as defined above, to obtain the compound of formula (BCl): (BCl) with Y1, Y2, Y3 and Y4 as defined above.22

[0023] Alternatively, especially when R6is linked to the rest of the molecule by a nitrogen or oxygen atom, the compound of formula (B) may be prepared by a process comprising subjecting the compound of formula (IV) as defined above, to a nucleophilic aromatic substitution with a compound of formula R6H, to obtain a compound of formula (BCl) as defined above. The 5nucleophilic aromatic substitution is preferably carried out in a polar protic solvent such asDimethylacetamide. The compound of formula (BCl) may be transformed into a compound of formula (BOS), which corresponds to a compound of formula (B) wherein X is O-S(O)2-(C1-6 alkyl) or O-S(O)2-(C1-6haloalkyl), by subjecting the compound of formula (BCl) to a palladium-catalyzed hydroxylation10 followed by a reaction with a compound of formula Cl-S(O)2-(C1-6alkyl) or Cl-S(O)2-(C1-6haloalkyl). Preferred palladium catalysts for the palladium-catalyzed hydroxylation are Pd(dba)2 or solvate thereof, such as CHCl3.Pd(dba)2. The compound of formula (BOS) may be transformed into a compound of formula (BI), which corresponds to a compound of formula (B) wherein X is iodo, by subjecting the compound of15 formula (BOS) to an iodination reaction. The compound of formula (BOS) may be transformed into a compound of formula (BBr), which corresponds to a compound of formula (B) wherein X is bromo, by subjecting the compound of formula (BOS) a bromination reaction. Especially when R6 is linked to the rest of the molecule by a nitrogen or oxygen atom, the20 process for preparing compounds of formula (I) comprises: a) Subjecting the compound of formula (IV) as defined above to a nucleophilic aromaticsubstitution with NaSMe, to obtain a compound of formula (V): V) with Y1, Y2, Y3 and Y4 as defined above,25 b) Subjecting the compound of formula (V) to a Suzuki coupling with the boronic ester offormula (C) as defined above, to obtain an intermediate of formula (D1) (D1) with V2, V1, Y1, Y2, Y3, Y4 Y5, R7 and PGn as defined above, c) Oxidizing the sulfur of the compound of formula (D1), preferably in the presence of30 oxone (dipotassium peroxymonosulfate), to obtain a compound of formula (D2): 23

[0024] 2), with V2, V1, Y1, Y2, Y3, Y4 Y5, R7 and PGn as defined above, d) Subjecting the compound of formula (D2) to a nucleophilic aromatic substitution with acompound of formula R6H in the presence of a base, such as NaH or N,N- 5 diisopropylethylamine (DIPEA), to obtain a compound of formula (D) as defined above, e) Subjecting the compound of formula (D) to a nitrogen deprotecting reaction, to obtainthe compound of formula (I) as defined herein .Preferably, PGn represents an amino acetal protecting group, preferabl wherein thewavy line indicates the point of attachment to the rest of the molecule. 10 In step d, the base is preferably NaH or N,N-diisopropylethylamine (DIPEA). 3– Pharmaceutical CompositionThe present invention further concerns a pharmaceutical composition comprising a compound15 of formula (I) as defined above, and a pharmaceutically acceptable carrier. Said pharmaceutically acceptable carrier is selected, according to the dosage form and mode of administration desired, from the typical excipients known to persons skilled in the art. The pharmaceutical compositions of the invention can be intended to enteral (e.g. oral, sublingual, buccal, rectal, vaginal, etc.), parenteral (e.g. subcutaneous, intramuscular,20 intravenous, intraocular, intraperitoneal, intracranial, intrathecal, etc.) or topical (e.g.transdermal) administration, preferably oral or intravenous administration. The active ingredient can be administered in unit forms for administration, mixed with conventional pharmaceutical carriers, to animals, preferably mammals including humans. For oral administration, the pharmaceutical composition can be in a solid or liquid (solution or25 suspension) form. A solid composition can be in the form of tablets, capsules, powders, granules and the like. In tablets, the active ingredient can be mixed with pharmaceutical vehicle(s) such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like before being compressed. The tablets may be further coated, notably with sucrose or with other suitable materials, or 30 they may be treated in such a way that they have a sustained or delayed activity. In powders 24

[0025] or granules, the active ingredient can be mixed or granulated with dispersing agents, wetting agents or suspending agents and with flavor correctors or sweeteners. In capsules, the active ingredient can be introduced into soft or hard capsules in the form of a powder or granules such as mentioned previously or in the form of a liquid composition such as mentioned below. 5 A liquid composition (including a gel) can contain the active ingredient together with a sweetener, a taste enhancer or a suitable coloring agent in a solvent such as water. The liquid composition can also be obtained by suspending or dissolving a powder or granules, as mentioned above, in a liquid such as water, juice, milk, etc. It can be for example a syrup or an elixir. 10 For sublingual (under the tongue) or buccal (between the gums and the cheek) administration, the pharmaceutical composition can be in a solid or liquid (solution or suspension) form. A solid composition can be notably in the form of tablets, gelatin capsules, powders or granules as defined above for oral administration. It can be also in the form of a film. A liquid composition can be as defined previously for oral administration. It can be administered15 in the form of a spray or drops. For rectal or vaginal administration, suppositories or ovules can be prepared with binders which melt at rectal or vaginal temperature, for example cocoa butter or polyethylene glycols. For parenteral administration, the composition can be in the form of an aqueous suspension or solution which may contain dispersing agents, wetting agents or suspending agents. The20 composition is advantageously sterile. It can be in the form of an isotonic solution.The amount of the compound of the invention that may be combined with the carrier materials to produce a single dosage of the composition will vary depending upon the subject and the particular mode of administration, as known in the art. 25 The pharmaceutical composition may further comprise another therapeutic compound, preferably another anticancer agent (or chemotherapeutic agents). The compounds according to the present invention or pharmaceutical compositions thereof, may also have therapeutic applications in combination with immune modulatory agents, such as inhibitors of the PD-1 / PD-L1 immune checkpoint axis, for example antibodies (or peptides)30 that bind to and / or inhibit the activity of PD-1 (like Nivolumab, Pembrolizumab, Cemiplimab,Dostartimab) or the activity of PD-L1 (like Atezolizumab, Avelumab, Durvalumab). Thecompounds according to the present invention or pharmaceutical compositions thereof, may also be combined with radiotherapy or chemotherapeutic agents as standard of care. The compounds may also be combined with BCL2 inhibitors (like Venetoclax).35 The compounds according to the present invention or pharmaceutical compositions thereof,may also be combined with other agents that stimulate or enhance the immune response, such as vaccines. 25

[0026] 4 – Therapeutic UseThe invention further concerns a compound or a pharmaceutical composition of the invention, for use as a drug, in particular with a MAP4K1 inhibiting activity. 5 The present invention also concerns the use of a compound of formula (I) as defined herein, or a composition comprising a compound of formula (I) as described herein, for inhibiting MAP4K1. The present invention also concerns the use of a compound of formula (I) as defined herein, or a composition comprising a compound of formula (I) as described herein, for the10 manufacture of a drug intended to inhibit MAP4K1.The drug is in particular useful in the treatment or prevention of a cancer, or neoplasticdiseases such as benign papillomatosis, gestational trophoblastic diseases including hydatidiform moles and gestational trophoblastic neoplasia (e.g., invasive moles, choriocarcinomas), and benign neoplastic diseases like skin papilloma (warts) and genital15 papilloma are also treatable with the compounds of the present disclosure. Typically the drugis useful in the treatment or prevention of a cancer. The compounds or pharmaceutical compositions of the invention may be used as drug in a combination therapy with radiotherapy, or with immune-stimulating agents such as vaccines. 20 The invention further relates to a kit comprising: -a composition according to the invention;- a second composition comprising at least another therapeutic compound, and- preferably instructions for using said kit,as a combination product for simultaneous, separate and staggered use as drug, in particular 25 with a MAP4K1 inhibiting activity, in particular useful in the treatment or prevention of a cancer, or neoplastic diseases such as benign papillomatosis, gestational trophoblastic diseases including hydatidiform moles and gestational trophoblastic neoplasia (e.g., invasive moles, choriocarcinomas), and benign neoplastic diseases like skin papilloma (warts) and genital papilloma are also treatable with the compounds of the present disclosure, typically a cancer. 30 The present invention also concerns a method for inhibiting MAP4K1, comprising theadministration to a patient in need thereof of an effective amount of a compound of formula (I)as defined herein, or a composition comprising a compound of formula (I) as described herein. The present invention further relates to a method for preventing or treating a pathology35 associated with MAP4K1 oncogenic activity, comprising administering to a patient in needthereof an effective dose of the compound or the composition or the kit of the invention. 26

[0027] In particular, said pathology is a cancer, or neoplastic diseases such as benign papillomatosis, gestational trophoblastic diseases including hydatidiform moles and gestational trophoblastic neoplasia (e.g., invasive moles, choriocarcinomas), and benign neoplastic diseases like skin papilloma (warts) and genital papilloma are also treatable with the compounds of the present 5 disclosure, typically a cancer. The method may further comprise combination with radiotherapy, or with immune-stimulating agents such as vaccines. The “effective dose” of a compound of the invention varies as a function of numerous 10 parameters such as, for example, the route of administration and the weight, the age, the sex, the advancement of the pathology to be treated and the sensitivity of the subject or patient to be treated. As used herein, “patient” or “subject” includes any mammal, and is preferably a human being.In some embodiments, the inhibition of MAP4K1 by a provided compound may be useful in15 treating or preventing, in particular treating, the following non-limiting list of cancers: gastrointestinal cancers, genitourinary cancers, respiratory tract cancers, skin cancers, head and neck cancers, hematological malignancies, brain and central nervous system cancers, bone cancers, sarcomas. Examples of cancers which may be treated or prevented, in particular treated, include, but are20 not limited to, gastrointestinal cancers, genitourinary cancers, respiratory tract cancers, skincancers, head and neck cancers, hematological malignancies, brain and central nervous system cancers, bone cancers, sarcomas. Examples of gastrointestinal cancers include colorectal cancer, gastric cancer, pancreaticcancer, esophageal cancer, anal region cancer, and gastroesophageal junction carcinoma. 25 Liver cancers including hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, biliary tract cancer, and hemangioma, as well as gallbladder cancer, are also encompassed. Furthermore, specific gastrointestinal malignancies such as leiomyosarcoma and gastrointestinal lymphomas are also encompassed within the treatable conditions.30 Examples of genitourinary cancers include renal cell carcinoma, Wilms tumor, urothelialcarcinoma, bladder cancer (urothelial carcinoma, squamous cell carcinoma, adenocarcinoma), prostate cancer, testicular cancer, urethral cancer, cervical cancer, ovarian cancer, uterine cancer, vulvar cancer, renal cancer (as well as rare types such as renal oncocytoma and Bellini duct carcinoma), and vaginal cancer.35 Examples of respiratory tract cancers include non-small cell lung cancer, small cell lungcancer, and mesothelioma are treatable, emphasizing the method's efficacy against both primary and advanced stages of these malignancies. 27

[0028] Examples of skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma,and Merkel cell carcinoma, with a specific mention of their utility in treating metastatic and refractory / recurrent forms. Examples of head and neck cancers include oral cancer, laryngeal cancer, pharyngeal cancer,5 nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, and salivary gland cancer, encompassing both localized tumors and metastatic disease. Examples of hematological malignancies treatable with the compounds include leukemias such as acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, and acute promyelocytic leukemia. Lymphomas including Hodgkin 10 lymphoma and non-Hodgkin lymphoma, Burkitt's lymphoma, and angioimmunoblastic lymphoma, as well as myelomas and other plasma cell neoplasms like multiple myeloma and plasmacytomas, are also included. Myeloproliferative neoplasms, myelodysplastic syndromes, and related disorders like myeloproliferative neoplasm, post-MPN AML, post-MDS AML,Del(5q) associated high-risk MDS or AML, blast-phase chronic myelogenous leukemia, and15 Langerhans cell histiocytosis are treatable as well. Examples of brain and central nervous system cancers treatable with the compounds include various gliomas, oligodendroglioma, ependymoma, primitive neuroectodermal tumors, medulloblastoma, specific brain stem glioma variants, and pituitary adenoma. In some embodiments, bone cancers including osteosarcoma, chondrosarcoma, Ewing20 sarcoma, and malignant fibrous histiocytoma of bone are treatable. Examples of sarcomas that are treatable include Kaposi’s sarcoma, soft tissue sarcomas like fibrosarcoma and liposarcoma, clear cell sarcoma of tendon sheaths, central chondrosarcoma, central and periosteal chondroma, and specific fibrosarcomas. Furthermore, in some embodiments, unique conditions and neoplastic diseases such as 25 benign papillomatosis, gestational trophoblastic diseases including hydatidiform moles and gestational trophoblastic neoplasia (e.g., invasive moles, choriocarcinomas), and benign neoplastic diseases like skin papilloma (warts) and genital papilloma are also treatable with the compounds of the present disclosure. Specific cancers treatable with these compounds or their acceptable salts include various 30 carcinomas, lymphomas, melanomas, and leukemia forms, with examples ranging from ER+ / HER2- breast cancer to advanced non-small cell lung cancer and head and neck squamouscell cancer, even in contexts of prior resistance or partial responses to other treatments. The therapeutic approach may also address MAP4K1-dependent disorders, potentially including certain viral infections, highlighting a multifaceted strategy against a diverse set of pathologies. 35 28

[0029] EXAMPLES All the examples below are given purely for illustrative purposes and should not be construedas limiting the scope of the invention in any way. Materials and Methods 5 Several methods for preparing the compounds of this invention are illustrated in the following examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification, or alternatively can be synthesized by a skilled person by using well-known methods. LCMS 10 Hereinafter, “MSD” means Mass Selective Detector, “DAD” Diode Array Detector Table: LCMS Method codes (Flow expressed in mL / min; column temperature (Col T) in °C; Run Time in minutes). e 29

[0030] 30

[0031] SFC-MS General procedure for SFC-MS methods (Analysis methods coupled with MSD)The SFC measurement was performed using an Analytical Supercritical fluid 5 chromatography (SFC) system composed by a binary pump for delivering carbon dioxide (CO2) and modifier, an autosampler, a column oven, a diode array detector equipped with a high-pressure flow cell standing up to 400 bars. Configured with a Mass Spectrometer (MS), ESI mode, the flow from the column was brought to the (MS). MS range is set from 200 to1000 in order to obtain ions allowing the identification of the compound’s nominal 10 monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software. Table: SFC-MS Method codes (Flow expressed in mL / min; column temperature (Col T) in °C;Run Time in minutes). r) 31

[0032] NMR NMR Analytical method (RMN400, BF1:400.13MHz): All final compounds were characterized by1H NMR.1H Nuclear Magnetic Resonance spectra were recorded on a 5Bruker Ascend AVNEO400 MHz spectrometer, with a Bruker 5mm PI HR- BBO 400S1BBF-H-D-05-Z SP probe, using a SampleXpress sample changer, and registered with Bruker Topspin 4.1.1 software. For the1H spectra, all chemical shifts are reported in part per million (δ) units, and are relative to the residual signal at 7.26 and 2.50 ppm for CDCl3and DMSO, respectively, at 25ºC. 10 Abbreviations “(Ir[dF(CF3)ppy]2(dtbpy))PF6“ refers to [Ir{dF(CF3)ppy}2(dtbpy)]PF6, [4,4′-Bis(1,1- dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl- N]phenyl-C]Iridium(III) hexafluorophosphate; "°C" refers to degrees Celsius; "B2PiN2" refers to bis(pinacolato)diboron; "BBBPY" refers to 4,4′-Di-tert-butyl-2,2′-dipyridyl; "Boc" refers to15 tert-butoxycarbonyl; “BrettPhos Pd G3” refers to [(2-Di-cyclohexylphosphino-3,6-dimethoxy- 2′,4′,6′- triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′ -biphenyl)]palladium(II) methanesulfonatemethanesulfonate; “Celite®” refers to diatomaceous earth; “CHCl3” refers to chloroform; “Cmpd” refers to compound; “CsF” refers to cesium fluoride; “DCM” refers to dichloromethane; “D2O” refers to deuteriulm oxide; “DIPEA” refers to N,N-Diisopropylethylamine; “DMA” refers20 to N,N-Dimethylacetamide; “DMAP” refers to 4-Dimethylaminopyridine; “DME” refers to 1,2- Dimethoxyethane; “DMF” refers to N,N-Diméthylformamide; “DMSO” refers to dimethyl sulfoxide; “dppf” refers to 1,1′-Ferrocenediyl-bis(diphenylphosphine); “dppp” refers to 3- diphenylphosphanylpropyl(diphenyl)phosphane; “EtOAc “ refers to ethyl acetate; “EtOH”refers to ethanol; “GCMS” refers to gas chromatography-mass spectrometry; “H” refers to25 hour(s); “H2” refers to dihydrogen; “HCl” refers to hydrogen chloride; “HPLC” refers to high- performance liquid chromatography; “iPrOH” refers to iso-propoanol; “K2CO3” refers to potassium carbonate; “K3PO4” refers to tripotassium phosphate; “KOAc” refers to potassium acetate; “LAH” refers to lithium aluminum hydride; “LCMS” refers to liquid chromatography– mass spectrometry; “M” refers to molar concentration; “mCPBA” refers to 3-chloroperbenzoic 32

[0033] acid; “MeCN” refers to acetonitrile; “MeI” refers to iodomethane; “MeOD-d4”” refers to methanol-d4; “MeOH“ refers to methanol; “MgSO4” refers to magnesium sulfate; “Min” refers to minute(s); “MTBE” refers to tert-Butyl methyl ether; “N” refers to normal; “N2” refers to nitrogen; “Na2CO3” refers to sodium carbonate; “NaH” refers to sodium hydride; “NaHCO3” 5refers to sodium bicarbonate; “NaOH refers to sodium hydroxide; “NH4Cl” refers toammonium chloride; “Pd(dba)2” refers to palladium(0) bis(dibenzylideneacetone); “Pd(dppf)Cl2” refers to [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II); “Pd(OAc)2” refers to diacetoxypalladium(II); “RT” refers to room temperature; “SFC” refers to supercritical fluid chromatography; “SPhos” refers to dicyclohexyl-[2-(2,6- 10 dimethoxyphenyl)phenyl]phosphane; “TEA” refers to triethylamine; “Tf2O” refers to trifluoromethanesulfonic anhydride; “TFA” refers to trifluoroacetic acid; “THF” refers to tetrahydrofuran; “THP” refers to oxan-2-yl; “XantPhos” refers to (5-diphenylphosphanyl-9,9- dimethyl-xanthen-4-yl)-diphenyl-phosphine; “XPhos” or “XantPhos” refers to 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl; “XPhos Pd G4” refers to (SP-4-3)-15 [Dicyclohexyl[2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]phosphine](methanesulfonato- κO)[2′-(methylamino-κN)[1,1′-biphenyl]-2-yl-κC]palladium; “MOPS” refers to 3-(N- morpholino)propanesulfonic acid; “EDTA” refers to Ethylenediaminetetraacetic acid; “ATP” refers to Adenosine triphosphate; “FBS” stands for Fetal Bovine Serum.20 Synthesis of Intermediate A-1: (a) O1-Tert-butyl O3-methyl 2-(3-methoxycarbonyl-4-pyridyl)propanedioate To a solution of methyl 4-chloropyridine-3-carboxylate (4.5 g, 26.23 mmol) in DMF (60 mL), O3-tert-butyl O1-methyl propanedioate (6.85 g, 39.34 mmol, 6.65 mL) and cesium carbonate 25 (17.09 g, 52.45 mmol) were added. The resultant mixture was heated at 40 °C for 16 h. The reaction medium was diluted with water and extracted with DCM (x 3). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography using heptane / EtOAc (100:0 to 50:50) to afford O1-tert-butyl O3-methyl 2-(3-methoxycarbonyl-4-pyridyl)propanedioate (4.9 g, 15.21 30 mmol, 58% yield) as a yellow oil. LCMS (Method 4) m / z: 310.1 [M+H]+, Purity (254 nm): 96 %, rt.: 0.87 min. 33

[0034] (b) Methyl 4-(2-methoxy-2-oxo-ethyl)pyridine-3-carboxylate O1-Tert-butyl O3-methyl 2-(3-methoxycarbonyl-4-pyridyl)propanedioate (4.3 g, 13.90 mmol) was dissolved in a mixture of DCM (50 mL) and TFA (21 mL). The resultant mixture was stirred for 2h at RT. The reaction medium was concentrated under reduced pressure to dryness and 5 the residue was co-evaporated under reduced pressure with MeCN to afford methyl 4-(2- methoxy-2-oxo-ethyl)pyridine-3-carboxylate (2.9 g, 13.45 mmol, 97% yield) as a yellow oil. LCMS (Method 4) m / z: 210.0 [M+H]+, Purity (254 nm): 97%, rt.: 0.40 min. (c) 4H-2,7-Naphthyridine-1,3-dione Methyl 4-(2-methoxy-2-oxo-ethyl)pyridine-3-carboxylate (4 g, 19.12 mmol) was dissolved in 10 25% aqueous ammonium hydroxide (191.21 mmol, 30 mL) and the mixture was stirred for 3 h at 120 °C. he reaction mixture was subsequently concentrated under reduced pressure to dryness to afford a green oil. Concentrated aqueous HCl and EtOH were added to the residue and the precipitate was filtered and washed with cold water to afford 3-hydroxy-2H-2,7- naphthyridin-1-one (2.7 g) as a gray solid which was used in the next step without further15 purification. LCMS (Method 4) m / z: 162.9 [M+H]+, Purity (254 nm): 99%, rt: 0.16 min. (d) 1,3-Dichloro-2,7-naphthyridine To a solution of 4H-2,7-naphthyridine-1,3-dione (2.7 g, 16.65 mmol) in phosphoryl trichloride (76.60 g, 499.55 mmol, 46.56 mL) at 0 °C, was added portion wise DMAP (6.10 g, 49.96 mmol). The resultant mixture was heated at 120 °C for 2 h. The reaction medium was poured into an 20 ice-water bath at 0 °C. The mixture was stirred at this temperature for 15 min and extracted with EtOAc. The pH of the aqueous layer adjusted to pH 7 by addition of 5 N aqueous NaOH and the mixture was extracted with DCM (x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel using a gradient of heptane / EtOAc (100:0 to 25 60:40) to afford 1,3-dichloro-2,7-naphthyridine (200 mg, 813.92 μmol, 5% yield) as a white solid. LCMS (Method 4) m / z: 198.8 [M+H]+, Purity (254 nm): 81%, rt.: 0.74 min. Synthesis of Intermediate A-2: (a) Ethyl 2-cyano-2-(4-cyano-3-pyridyl)acetate To a solution of 3-bromopyridine-4-carbonitrile (2 g, 10.93 mmol) benzyl(triethyl)ammonium 30 chloride (49.79 mg, 218.57 μmol) and potassium carbonate (4.53 g, 32.79 mmol) in DMSO (20 mL), ethyl 2-cyanoacetate (1.24 g, 10.93 mmol, 1.16 mL) was added at RT. The resultant mixture was heated at 120 °C for 8 h. The reaction medium was cooled down to RT and acidified until pH = 1 with 2 N aqueous HCl solution. The resultant mixture was extracted with 34

[0035] EtOAc (x 3) and with CHCl3 / iPrOH (1:1) (x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using heptane / EtOAc (100:0 to 50:50) to afford ethyl 2-cyano-2-(4-cyano-3-pyridyl)acetate (1.1 g, 5.06 mmol, 46% yield) as a red oil. LCMS 5 (Method 4) m / z: 216.0 [M+H]+, Purity (254 nm): 99%, rt: 0.47 min. (b) 3-(Cyanomethyl)pyridine-4-carbonitrile To a solution of ethyl 2-cyano-2-(4-cyano-3-pyridyl)acetate (1.1 g, 5.11 mmol) in DMSO (35 mL), brine (12 mL) was added and the reaction mixture was stirred at 120 °C for 16 h. The reaction medium was diluted with EtOAc and aqueous Na2CO3solution and extracted with 10 EtOAc (x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel using a gradient of heptane / EtOAc (100:0 to 80:20) to afford 3-(cyanomethyl)pyridine- 4-carbonitrile (400 mg, 2.68 mmol, 52% yield) as a yellow oil. LCMS (Method 5) m / z: 144.0 [M+H]+, Purity (254 nm): 96 %, rt: 0.24 min. 15 (c) 4H-2,6-Naphthyridine-1,3-dione A solution of 3-(cyanomethyl)pyridine-4-carbonitrile (350 mg, 2.45 mmol) in 37 % aqueous HCl solution (8 mL) was stirred at 70 °C for 3 h. The reaction medium was concentrated under reduced pressure and the residue was co-evaporated under reduced pressure with MeCN (5 x 5 mL) to afford 4H-2,6-naphthyridine-1,3-dione (330 mg) as a brown solid which was used in 20 the next step without further purification. LCMS (Method 4) m / z: 163.0 [M+H]+, Purity (254 nm): 99 %, rt: 0.12 min. (d)1,3-Dichloro-2,6-naphthyridine – Intermediate A-2To 4H-2,6-naphthyridine-1,3-dione (330 mg, 2.04 mmol) was added phosphoryl trichloride (30.53 mmol, 2.84 mL) at 0 °C. The resultant mixture was heated at 110 °C for 1 h and then at 25 90 °C for 16 h. The reaction medium was poured into a water / ice bath very slowly. The mixture was extracted with EtOAc (3x 10 mL). Saturated aqueous solution of NaHCO3 was added to the aqueous phase and the mixture was extracted carefully with CHCl3 / iPrOH (3:1) (x 3). The combined organic layers were dried on MgSO4, filtered, and evaporated under reduced pressure to afford 1,3-dichloro-2,6-naphthyridine (400 mg, 1.99 mmol, 98% yield) as a brown30 solid. LCMS (Method 4) m / z: 199.0 [M+H]+, Purity (254 nm): 99%, rt.: 0.74 min. 35

[0036] Synthesis of Intermediate B-1: A solution of tert-butyl N-[(3S)-3-piperidyl]carbamate (404.50 mg, 2.02 mmol) in DMA (12 mL) under N2 atmosphere was cooled to 0 °C. After the slow addition of TEA (613.12 mg, 6.06 mmol, 844.52 μL), the mixture was stirred at 0 °C for 30 min and 1,3-dichloroisoquinoline (400 5 mg, 2.02 mmol) was added. The reaction medium was allowed to warm to RT and was stirred at this temperature for 1 h. The mixture was diluted with EtOAc and water and extracted with EtOAc (3x 50 mL). The resultant combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel using a gradient of heptane / EtOAc (100:0 to 0:100). The desired10 fractions were collected and concentrated under reduced pressure to afford tert-butyl N-[(3S)- 1-(3-chloro-1-isoquinolyl)-3-piperidyl]carbamate (720 mg, 1.97 mmol, 98% yield) as a colorless oil. LCMS (Method 4) m / z: 362.1 [M+H]+; Purity (254 nm): 99 %; rt: 1.37 min. Synthesis of Intermediate B-2: To a solution of 1,3-dichloroisoquinoline (800 mg, 4.04 mmol) in DMA (20 mL) were added 1- 15 N-Boc-cis-1,4-cyclohexyldiamine (1.73 g, 8.08 mmol) and TEA (1.23 g, 12.12 mmol, 1.69 mL). The mixture was stirred at 160 °C for 18 h and then the reaction medium was diluted with water and extracted with EtOAc (x 3). The combined organic phases were washed with saturated aqueous NaHCO3 solution (x 3) and brine then dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was co-evaporated under reduced pressure with xylene. 20 The crude material was purified by flash column chromatography on silica gel using a gradient of heptane / EtOAc (100:0 to 80:20). The desired fractions were collected and concentrated under reduced pressure to afford tert-butyl N-cis-[4-[(3-chloro-1- isoquinolyl)amino]cyclohexyl]carbamate (1.26 g, 3.32 mmol, 82% yield) as white solid. LCMS (Method 4) m / z: 376.2 [M+H]+; Purity (254 nm): 99%. Rt: 1.38 min.25 The following intermediates were prepared via an analogous procedure: 36

[0037] 37

[0038] 38

[0039] 39

[0040] 40

[0041] 41

[0042] 42

[0043] To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (290.69 mg, 1.40 mmol) in DMF (10 mL) at 0 °C and under N2atmosphere, NaH (60% dispersion in mineral oil, 100.86 mg, 4.20 mmol) was added slowly and the mixture was stirred at 0 °C for 1 h. After addition of 5 7-bromo-1,3-dichloro-isoquinoline (10 mg, 0.04 mmol), the reaction medium was stirred at RT for 16 h, quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel using a gradient of heptane / EtOAc 100:0 to 8:2 to afford tert-butyl 4-[(7-bromo-3- 10 chloro-1-isoquinolyl)oxy]piperidine-1-carboxylate (518 mg, 1.16 mmol, 83% yield) as a colorless oil. LCMS (Method 4) m / z: 463.1 [M+Na]+; Purity (254 nm): 99%; Rt: 1.63 min. The following intermediates were prepared via an analogous procedure: 43

[0044] 44

[0045] Synthesis of Intermediate B-46: A sealed tube was charged with tert-butyl 4-[(7-bromo-3-chloro-1-isoquinolyl)oxy]piperidine-1- carboxylate – Intermediate B-38 (0.410 g, 0.93 mmol), morpholine (64.69 mg, 0.74 mmol,64.95 μL), Cs2CO3 (907.21 mg, 2.78 mmol), Xantphos (107.41 mg, 0.19 mmol), Pd(OAc)25 (20.84 mg, 0.09 mmol) and 1,4-dioxane (12 mL). The resultant mixture was bubbled with N2 and then heated at 100 °C for 16 h. The reaction medium was diluted with EtOAc and water and extracted with EtOAc (x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel using a gradient of heptane / EtOAc (100:0 to 86:14) to afford tert- 10 butyl 4-[(3-chloro-7-morpholino-1-isoquinolyl)oxy]piperidine-1-carboxylate (320.5 mg, 0.70 mmol, 76% yield) as a light yellow solid. LCMS (Method 4) m / z: 448.0 [M+H]+; Purity (254 nm): 98 %; rt: 1.49 min. The following intermediates were prepared via an analogous procedure: 45

[0046] 46

[0047] Synthesis of Intermediate B-54: (a) 3-Chloroisoquinoline-1-carbonitrile A sealed tube was charged with 1,3-dichloroisoquinoline (600 mg, 3.03 mmol), cyanopotassium (171.63 mg, 2.64 mmol), SPhos (1.03 g, 2.42 mmol), Pd(OAc)2 (27.21 mg, 5 121.18 μmol) and toluene (12 mL). The resultant mixture was degassed with N2for 2 min then N,N,N',N'-tetramethylethane-1,2-diamine (105.61 mg, 908.87 μmol, 136.28 μL) was added. The mixture was stirred at 150 °C for 16 h, cooled and filtered on a Celite® pad. The cake was washed with EtOAc and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using a gradient of 10 heptane / EtOAc from 100:0 to 90:10. The desired fractions were collected and concentrated under reduced pressure to afford 3-chloroisoquinoline-1-carbonitrile (570 mg, 2.96 mmol, 98% yield) as a light-yellow solid. LCMS (Method 4) m / z: 188.9 [M+H]+; Purity (254 nm): 98%; rt: 0.9 min (b) Tert-butyl N-[(3-chloro-1-isoquinolyl)methyl]carbamate 15 In a round bottom flask, to a solution of 3-chloroisoquinoline-1-carbonitrile (570 mg, 3.02 mmol) in MeOH (33 mL) at 0 °C, were added tert-butoxycarbonyl tert-butyl carbonate (1.65 g, 7.56 mmol, 1.73 mL), dichloronickel hexahydrate (718.32 mg, 3.02 mmol) and sodium borohydride (228.66 mg, 6.04 mmol). The mixture was stirred at RT for 16 h. As LCMS showed partial conversion of starting material to desired product, the reaction medium was recharged with 20 tert-butoxycarbonyl tert-butyl carbonate (824.44 mg, 3.78 mmol, 866.92 μL), dichloronickel hexahydrate (359.16 mg, 1.51 mmol) and sodium borohydride (114.33 mg, 3.02 mmol), and it was stirred at RT for another 3 h. The mixture was diluted with EtOAc, quenched with water, and extracted with EtOAc (x 3). The combined organic layers were dried over MgSO4, filtered,and concentrated under reduced pressure. The crude product was purified by flash column 25 chromatography on silica gel using a gradient of heptane / EtOAc from 100:0 to 90:10. The desired fractions were collected and concentrated under reduced pressure to afford tert-butyl N-[(3-chloro-1-isoquinolyl)methyl]carbamate (274 mg, 917.20 μmol, 30% yield) as a yellow solid. LCMS (Method 4) m / z: 293.1 [M+H]+, Purity (254 nm): 98%, rt.: 1.11 min. 47

[0048] Synthesis of Intermediate B-55: To a solution 1,3-dichloroisoquinoline (3 g, 15.15 mmol) in DMF (150 mL) in a round bottom flask, was added sodium methanethiolate (1.27 g, 18.18 mmol) and the resultant solution was stirred at RT for 16 h. The mixture was bubbled with N2for 1 h, and then diluted with EtOAc 5 and water, and extracted with EtOAc (x 3). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel using a gradient of heptane / EtOAc from 100:0 to 90:10 to afford 3-chloro-1-methylsulfanyl-isoquinoline (1.30 g, 6.14 mmol, 41% yield) as awhite solid. LCMS (Method 5) m / z: 210.0 [M+H]+, Purity (254 nm): 99%, rt.:1.46 min. 10 Synthesis of Intermediate B-56: Intermediate B-56 was prepared according to the procedure described for intermediate B-2starting from 6-bromo-1,3-dichloro-isoquinoline (400 mg, 1.44 mmol) and tert-butyl N-[(3S)- azepan-3-yl]carbamate (340.48 mg, 1.59 mmol) to afford tert-butyl N-[(3S)-1-(6-bromo-3- chloro-1-isoquinolyl)azepan-3-yl]carbamate (600 mg, 1.29 mmol, 89% yield) as a colorless oil. 15 LCMS (Method 4) m / z: 454.1 [M+H]+, Purity (254 nm): 97.8 %, rt.: 1.600 min. Synthesis of Intermediate B-57: A pressure flask was charged with tert-butyl N-[(3S)-1-(6-bromo-3-chloro-1- isoquinolyl)azepan-3-yl]carbamate – Intermediate B-56 (200 mg, 439.77 μmol), zinc dicyanide(51.64 mg, 439.77 μmol), zinc (46.01 mg, 703.63 μmol), Pd(dba)2(40.27 mg, 43.98 μmol), 20 dppf (12.19 mg, 21.99 μmol) and DMA (2 mL). The mixture was degassed for 1 min by bubbling N2and stirred at 80 °C for 1.5 h. The reaction medium was then filtered over a pad of Celite® and the cake was washed with EtOAc. Aqueous saturated solution of NaHCO3was added to the filtrate and the mixture was extracted with EtOAc (x 3). The combined organic layers were 48

[0049] dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica, heptane / EtOAc from 100:0 to 85:15). The desired fractions were collected and concentrated under reduced pressure to afford tert-butyl N-[(3S)-1-(3-chloro-6-cyano-1-isoquinolyl)azepan-3-yl]carbamate (110 mg, 271.64 μmol, 62% 5 yield) as a yellow gum. LCMS (Method 4) m / z: 401.2 [M+H]+, Purity (254 nm): 99%, rt.: 1.32 min. Synthesis of Intermediate B-58: In a sealed tube, tert-butyl N-[(3S)-1-(6-bromo-3-chloro-1-isoquinolyl)azepan-3-yl]carbamate –Intermediate B-56 (160 mg, 351.81 μmol), acetamide (8.31 mg, 140.73 μmol), BrettPhos Pd10 G3 (31.89 mg, 35.18 μmol) and sodium tert-butoxide (101.43 mg, 1.06 mmol) were dissolved in 1,4-dioxane (15 mL). The mixture was bubbled with N2for 3 min and the resultant solution was stirred at 120 °C for 2 h. The reaction medium was filtered through a Celite® pad and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using heptane / EtOAc (100:0 to 50:50) to afford tert-butyl N- 15 [(3S)-1-(6-acetamido-3-chloro-1-isoquinolyl)azepan-3-yl]carbamate (24 mg, 35.48 μmol, 10% yield) as a pale yellow solid. LCMS (Method 4): m / z: 433.1 [M+H]+, Purity (254 nm): 64%, rt.: 1.47 min. Synthesis of Intermediate B-59: A sealed tube was charged with tert-butyl N-[(3S)-1-(6-bromo-3-chloro-1-isoquinolyl)azepan-20 3-yl]carbamate– Intermediate B-56 (150 mg, 329.82 μmol), 1-amino-2-methyl-propan-2-ol(23.52 mg, 263.86 μmol, 12.28 μL), BrettPhos Pd G3 (29.90 mg, 32.98 μmol), sodium tert- butoxide (95.09 mg, 989.47 μmol) and 1,4-dioxane (7.5 mL). The mixture was bubbled with N2 for 3 min and the resultant mixture was stirred at 90 °C for 16 h. The reaction medium was filtered and the filtrate was concentrated under reduced pressure The residue was purified by 25 flash column chromatography on silica gel using heptanes / EtOAc (100:0 to 60:40) to obtain tert-butyl N-[(3S)-1-[3-chloro-6-[(2-hydroxy-2-methyl-propyl)amino]-1-isoquinolyl]azepan-3- 49

[0050] yl]carbamate (62 mg, 87.04 μmol, 26% yield) as a colorless gum. LCMS (Method 4) m / z: 463.2 [M+H]+, Purity (254 nm): 65% rt.: 1.32 min. Synthesis of Intermediate B-60: To a solution of tert-butyl N-[(3S)-1-(6-bromo-3-chloro-1-isoquinolyl)azepan-3-yl]carbamate – 5Intermediate B-56 (340 mg, 747.60 μmol) and B2PiN2 (199.34 mg, 784.98 μmol) in 1,4-dioxane(10 mL), KOAc (220.11 mg, 2.24 mmol) and Pd(dppf)Cl2 (54.70 mg, 74.76 μmol) were added at RT. The resultant mixture was bubbled with N2and heated at 100 °C for 3 h. The reaction medium was diluted with EtOAc and water and extracted with EtOAc (x 3). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The 10 residue was solubilized in acetone (11 mL) and a solution of oxone (KHSO5 · 0.5KHSO4 · 0.5K2SO4) (459.60 mg, 1.50 mmol) in water (2 mL) was added. The mixture was stirred at RT for 10 min. The reaction medium was diluted with DCM and aqueous solution of NaHCO3and extracted with DCM (x 3). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column15 chromatography on silica gel using a gradient of heptane / EtOAc (100:0 to 80:20) to afford tert- butyl N-[(3S)-1-(3-chloro-6-hydroxy-1-isoquinolyl)azepan-3-yl]carbamate (183 mg, 420.27 μmol, 56% yield) as a light-yellow oil. LCMS (Method 4) m / z: 392.2 [M+H]+, Purity (254 nm): 90%, rt.: 1.21 min. Synthesis of Intermediate B-61: 20 In a sealed tube, tert-butyl N-[(3S)-1-(6-bromo-3-chloro-1-isoquinolyl)azepan-3-yl]carbamate –Intermediate B-56 (200 mg, 439.77 μmol) and [amino(methylsulfanyl)methylene]ammoniumsulfate (60.99 mg, 219.88 μmol) were dissolved in DMSO (11 mL), then Cs2CO3 (573.14 mg, 1.76 mmol) was added and the resultant mixture was stirred at 80 °C for 16 h. The reaction medium was poured into water and the mixture was extracted with DCM (x 3). The combined 25 organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The yellow residue was purified by flash column chromatography on silica gel using a gradient of 50

[0051] heptane / EtOAc (100:0 to 80:20) to afford tert-butyl N-[(3S)-1-(3-chloro-6-methylsulfanyl-1- isoquinolyl)azepan-3-yl]carbamate (75 mg, 175.96 μmol, 40% yield) as a yellow oil. LCMS (Method 5) m / z: 422.3 [M+H]+, Purity (254 nm): 99 %, rt.: 1.70 and 1.74 min. Synthesis of Intermediate B-62: 5(a) The procedure described for intermediate B-2 was applied starting from 6-bromo-1,3-dichloro-isoquinoline (250 mg, 902.71 μmol) and tert-butyl N-[(3S,5R)-5-hydroxy-3- piperidyl]carbamate (195.23 mg, 902.71 μmol) to afford tert-butyl N-[(3S,5R)-1-(6-bromo-3- chloro-1-isoquinolyl)-5-hydroxy-3-piperidyl]carbamate (400 mg, 858.22 μmol, 95% yield) as a light-yellow solid. LCMS (Method 4) m / z: 456.0 [M+H]+, Purity (254 nm): 98%, rt: 1.23 min.10 (b) Tert-butyl N-[(3S,5R)-1-(3-chloro-6-hydroxy-1-isoquinolyl)-5-hydroxy-3- piperidyl]carbamate was prepared according to the procedure described for intermediate B-60starting from tert-butyl N-[(3S,5R)-1-(6-bromo-3-chloro-1-isoquinolyl)-5-hydroxy-3- piperidyl]carbamate (200 mg, 437.87 μmol) to afford tert-butyl N-[(3S,5R)-1-(3-chloro-6- hydroxy-1-isoquinolyl)-5-hydroxy-3-piperidyl]carbamate (89 mg, 221.45 μmol, 51% yield) as a15 light-yellow solid. LCMS (Method 4) m / z: 394.2 [M+H]+, Purity (254 nm): 98%, rt.: 0.89 min. y (a) The procedure described for intermediate B-2 was applied starting from 6-bromo-1,3-dichloro-isoquinoline (300 mg, 1.08 mmol) and tert-butyl N-[(3R,5S)-5-methyl-3- piperidyl]carbamate (232.14 mg, 1.08 mmol) to afford tert-butyl N-[(3R,5S)-1-(6-bromo-3- 20 chloro-1-isoquinolyl)-5-methyl-3-piperidyl]carbamate (455 mg, 990.46 μmol, 91% yield) as a pale yellow oil. LCMS (Method 4) m / z: 454.1 [M+H]+, Purity (254 nm): 99%, rt.: 1.61 min. (b) Tert-butyl N-[(3R,5S)-1-[3-chloro-6-(3-hydroxyazetidin-1-yl)-1-isoquinolyl]-5-methyl-3- piperidyl]carbamate was prepared according to the procedure described for intermediate B-46starting from tert-butyl N-[(3R,5S)-1-(6-bromo-3-chloro-1-isoquinolyl)-5-methyl-3- 25 piperidyl]carbamate (200 mg, 439.77 μmol) and azetidin-3-ol (32.14 mg, 439.77 μmol) were dissolved in 1,4-dioxane (8 mL), then Cs2CO3 (429.85 mg, 1.32 mmol), Xantphos (50.89 mg, 87.95 μmol) and Pd(OAc)2 (9.87 mg, 43.98 μmol) were added and the resultant mixture was 51

[0052] bubbled with N2for 3 min and stirred at 100 °C for 2 h. The reaction medium was diluted with EtOAc and water and extracted with EtOAc (x 3). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel using a gradient of heptane / EtOAc 5 (100:0 to 70:30) to afford tert-butyl N-[(3R,5S)-1-[3-chloro-6-(3-hydroxyazetidin-1-yl)-1- isoquinolyl]-5-methyl-3-piperidyl]carbamate (81.4 mg, 180.29 μmol, 41% yield) as a yellow solid. LCMS (Method 4) m / z: 447.2 [M+H]+, Purity (254 nm): 99%, rt.: 1.26 min. Synthesis of Intermediate B-64: (a) The procedure described for intermediate B-2 starting from 6-bromo-1,3-dichloro-10 isoquinoline (180 mg, 649.95 μmol) and tert-butyl N-[(6R)-1,4-oxazepan-6-yl]carbamate (154.63 mg, 714.94 μmol) to afford tert-butyl N-[(6R)-4-(6-bromo-3-chloro-1-isoquinolyl)-1,4- oxazepan-6-yl]carbamate (223 mg, 473.57 μmol, 73% yield) as a yellow gum. LCMS (Method 4) m / z: 456.0 [M+H]+, Purity (254 nm): 97%, rt: 1.35 min. (b) Tert-butyl N-[(6R)-4-(3-chloro-6-hydroxy-1-isoquinolyl)-1,4-oxazepan-6-yl]carbamate was15 prepared according to the procedure described for intermediate B-60 starting from tert-butylN-[(6R)-4-(6-bromo-3-chloro-1-isoquinolyl)-1,4-oxazepan-6-yl]carbamate (220 mg, 481.65 μmol) to afford tert-butyl N-[(6R)-4-(3-chloro-6-hydroxy-1-isoquinolyl)-1,4-oxazepan-6- yl]carbamate (100 mg, 236.12 μmol, 49% yield) as a light-yellow solid.LCMS (Method 4) m / z:394.2 [M+H]+, Purity (254 nm): 93%, rt.: 1.02 min. 20 Synthesis of Intermediate B-65: (a) Tert-butyl N-[(3S)-1-(7-bromo-3-chloro-1-isoquinolyl)azepan-3-yl]carbamate was preparedaccording to the procedure described for intermediate B-2 starting from 7-bromo-1,3-dichloro-isoquinoline (587.41 mg, 2.12 mmol) and tert-butyl N-[(3S)-azepan-3-yl]carbamate (500 mg, 2.33 mmol) to afford tert-butyl N-[(3S)-1-(7-bromo-3-chloro-1-isoquinolyl)azepan-3- 25 yl]carbamate (751 mg, 1.63 mmol, 77% yield) as a yellow oil. LCMS (Method 4) m / z: 454.1 [M+H]+, Purity (254nm): 99%, rt.:1.57 min. (b) In a pressure flask, a mixture of tert-butyl N-[(3S)-1-(7-bromo-3-chloro-1- isoquinolyl)azepan-3-yl]carbamate (280 mg, 615.67 μmol), potassium trifluoro(morpholinomethyl)boranuide (101.98 mg, 492.54 μmol), Pd(OAc)2 (28.00 mg, 124.72 52

[0053] μmol), Cs2CO3 (601.79 mg, 1.85 mmol) and dicyclohexyl-[2-(2,6- dimethoxyphenyl)phenyl]phosphane (50.55 mg, 123.13 μmol) in 1,4-dioxane / H2O (4:1) (7 mL) was bubbled with N2during 2 min. The stirred medium was then heated at 140 °C for 2 h. The mixture was diluted with EtOAc and water and extracted with EtOAc (x 3). The combined 5 organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica, heptane / EtOAc from 100:0 to 50:50). The desired fractions were collected and concentrated under reduced pressure, to afford tert-butyl N-[(3S)-1-[3-chloro-7-(morpholinomethyl)-1-isoquinolyl]azepan-3- yl]carbamate (76 mg, 143.99 μmol, 23% yield) as a beige solid. LCMS (Method 4) m / z: 475.210 [M+H]+, Purity (254 nm): 90%, rt.: 0.93min. Synthesis of Intermediate B-66: Intermediate B-66 was prepared according to the procedure described for intermediate B-46starting from tert-butyl N-[(3S)-1-(7-bromo-3-chloro-1-isoquinolyl)azepan-3-yl]carbamate (250 mg, 549.71 μmol) and morpholine (38.31 mg, 439.77 μmol, 38.47 μL) to afford tert-butyl N- 15 [(3S)-1-(3-chloro-7-morpholino-1-isoquinolyl)azepan-3-yl]carbamate (82 mg, 176.10 μmol, 32% yield) as an orange gum. LCMS (Method 4) m / z: 461.2 [M+H]+, Purity (254 nm): 99%, rt.: 1.41 min. Synthesis of Intermediate B-67: In a sealed tube, to a solution of tert-butyl N-[(3S)-1-(7-bromo-3-chloro-1-isoquinolyl)azepan- 20 3-yl]carbamate (93.6 mg, 205.81 μmol) and methylphosphonoylmethane (6.43 mg, 82.32 μmol) in DMSO (8 mL), were added DIPEA (106.40 mg, 823.24 μmol, 143.39 μL), dppp (16.98 mg, 41.16 μmol) and Pd(OAc)2 (9.24 mg, 41.16 μmol). The resultant solution was bubbled with N2 for 3 min and stirred at 100 °C for 5 h. The mixture was diluted with EtOAc and water and extracted with EtOAc (x 3). The organic layers were combined, dried over MgSO4, and 25 concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using heptane / EtOAc (100:0 to 0:100) to afford tert-butyl N-[(3S)- 1-(3-chloro-7-dimethylphosphoryl-1-isoquinolyl)azepan-3-yl]carbamate (83 mg, 176.31 μmol, 86% yield) as a brown oil. LCMS (Method 4) m / z: 452.2 [M+H]+, Purity (254 nm): 96 %, rt.: 1.103 min. 53

[0054] Synthesis of Intermediate B-68: Intermediate B-68 was prepared according to the procedure described for intermediate B-61starting from tert-butyl N-[(3S)-1-(7-bromo-3-chloro-1-isoquinolyl)azepan-3-yl]carbamate (200 mg, 439.77 μmol) to afford tert-butyl N-[(3S)-1-(3-chloro-7-methylsulfanyl-1- 5 isoquinolyl)azepan-3-yl]carbamate (80 mg, 177.45 μmol, 40% yield, 93.6% purity) as a yellow oil. LCMS (Method 6): m / z: 422.3 [M+H]+, Purity (254nm): 93.6 %, rt.: 1.70 and 1.74 min. Synthesis of Intermediate B-69: (a) Tert-butyl N-[(3S)-1-(3-chloro-7-hydroxy-1-isoquinolyl)azepan-3-yl]carbamate was10 prepared according to the procedure described for intermediate B-60 starting from tert-butylN-[(3S)-1-(7-bromo-3-chloro-1-isoquinolyl)azepan-3-yl]carbamate (150 mg, 329.82 μmol) to afford tert-butyl N-[(3S)-1-(3-chloro-7-hydroxy-1-isoquinolyl)azepan-3-yl]carbamate (67 mg, 136.77 μmol, 41% yield) as a light-yellow oil. LCMS (Method 4) m / z: 392.2 [M+H]+, Purity (254 nm): 80%, rt.:1.27 min. 15 (b) Tert-butyl N-[(3S)-1-(7-acetonyloxy-3-chloro-1-isoquinolyl)azepan-3-yl]carbamate To a solution of tert-butyl N-[(3S)-1-(3-chloro-7-hydroxy-1-isoquinolyl)azepan-3-yl]carbamate (114 mg, 290.90 μmol) and 1-chloropropan-2-one (29.61 mg, 319.99 μmol, 25.50 μL) in acetone (6 mL), were added potassium iodide (48.29 mg, 290.90 μmol) and K2CO3 (80.41 mg, 581.79 μmol). The mixture was stirred at 50 °C for 2 h. The reaction medium was diluted with 20 EtOAc and saturated aqueous NaHCO3solution and extracted with EtOAc (x 3). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel using heptane / EtOAc (100:0 to 80:20) to afford tert-butyl N-[(3S)-1-(7-acetonyloxy-3-chloro-1- isoquinolyl)azepan-3-yl]carbamate (106 mg, 224.80 μmol, 77% yield) as a yellow solid. LCMS25 (Method 4) m / z: 448.2 [M+H]+, Purity (254 nm): 95%, rt.: 1.34 min. 54

[0055] Synthesis of Intermediate B-70: (a) Tert-butyl cis-N-[4-[(7-bromo-3-chloro-1-isoquinolyl)amino]cyclohexyl]carbamate wasprepared according to the procedure described for intermediate B-2 starting from 7-bromo-1,3-dichloro-isoquinoline (3 g, 10.51 mmol) and tert-butyl cis-N-(4-aminocyclohexyl)carbamate 5 (4.74 g, 21.02 mmol) to afford tert-butyl cis-N-[4-[(7-bromo-3-chloro-1- isoquinolyl)amino]cyclohexyl]carbamate (4.25 g, 9.25 mmol, 88% yield) as a white solid. LCMS (Method 4) m / z: 454.1 [M+H]+; Purity (254 nm): 70%; Rt: 1.50 min. (b) Tert-butyl cis-N-[4-[(3-chloro-7-morpholino-1-isoquinolyl)amino]cyclohexyl]carbamate wasprepared according to the procedure described for intermediate B-46 starting from tert-butyl10 cis-N-[4-[(7-bromo-3-chloro-1-isoquinolyl)amino]cyclohexyl]carbamate (2 g, 4.35 mmol) and morpholine (421.44 mg, 4.79 mmol, 423.13 μL), to afford tert-butyl cis-N-[4-[(3-chloro-7- morpholino-1-isoquinolyl)amino]cyclohexyl]carbamate (1.79 g, 3.72 mmol, 85% yield) as off- white solid. LCMS (Method 5) m / z: 461.3 / [M+H]+; Purity (254 nm): 99%; Rt: 1.51 min Synthesis of Intermediate B-71:15 (a) Tert-butyl N-[(3S)-1-(7-bromo-3-chloro-1-isoquinolyl)-3-piperidyl]carbamate was preparedaccording to the procedure described for intermediate B-2 starting from6-bromo-1,3-dichloro-isoquinoline (350 mg, 1.26 mmol) and tert-butyl N-[(3S)-3- piperidyl]carbamate (278.42 mg, 1.39 mmol) to afford tert-butyl N-[(3S)-1-(7-bromo-3-chloro- 1-isoquinolyl)-3-piperidyl]carbamate (515 mg, 1.16 mmol, 92% yield) as a yellow oil. LCMS20 (Method 4) m / z: 440.1 [M+H]+, Purity (254 nm): 99%, rt.:1.51 min. (b) Tert-butyl N-[(3S)-1-(3-chloro-7-morpholino-1-isoquinolyl)-3-piperidyl]carbamate wasprepared according to the procedure described for intermediate B-46 starting from tert-butylN-[(3S)-1-(7-bromo-3-chloro-1-isoquinolyl)-3-piperidyl]carbamate (550 mg, 1.25 mmol) and morpholine (86.97 mg, 998.27 μmol, 87.32 μL) to afford tert-butyl N-[(3S)-1-(3-chloro-7- 25 morpholino-1-isoquinolyl)-3-piperidyl]carbamate (314 mg, 695.48 μmol, 56% yield) as a light yellow solid. LCMS (Method 4) m / z: 447.3 [M+H]+, Purity (254 nm): 99 %; rt: 1.39 min. 55

[0056] Synthesis of Intermediate B-72: (a) Tert-butyl N-[(3R,5S)-1-(7-bromo-3-chloro-1-isoquinolyl)-5-methyl-3-piperidyl]carbamate was prepared according to the procedure described for intermediate B-2 starting from7-bromo-1,3-dichloro-isoquinoline (230 mg, 830.49 μmol) and tert-butyl N-[(3R,5S)-5-methyl- 5 3-piperidyl]carbamate (195.78 mg, 913.54 μmol) to afford tert-butyl N-[(3R,5S)-1-(7-bromo-3- chloro-1-isoquinolyl)-5-methyl-3-piperidyl]carbamate (330.0 mg, 718.36 μmol, 86% yield) as a yellow solid. LCMS (Method 4) m / z: 454.1 [M+H]+, Purity (254 nm): 99%, rt.: 1.51 min. (b) Tert-butyl N-[(3R,5S)-1-(3-chloro-7-morpholino-1-isoquinolyl)-5-methyl-3- piperidyl]carbamate was prepared according to the procedure described for intermediate B-4610 starting from N-[(3R,5S)-1-(7-bromo-3-chloro-1-isoquinolyl)-5-methyl-3-piperidyl]carbamate (330 mg, 725.61 μmol) and morpholine (50.57 mg, 580.49 μmol, 50.78 μL) to afford tert-butyl N-[(3R,5S)-1-(3-chloro-7-morpholino-1-isoquinolyl)-5-methyl-3-piperidyl]carbamate (153 mg, 325.25 μmol, 45% yield) as a yellow foam. LCMS (Method 4) m / z: 461.2 [M+H]+, Purity (254 nm): 98%, rt.: 1.40 min. 15 Synthesis of Intermediate B-73: Tert-butyl N-[(3R,5S)-1-(3-chloro-7-cyano-1-isoquinolyl)-5-methyl-3-piperidyl]carbamate wasprepared according to the procedure described for intermediate B-57 starting from N-[(3R,5S)-1-(7-bromo-3-chloro-1-isoquinolyl)-5-methyl-3-piperidyl]carbamate (500 mg, 1.10 mmol) to afford tert-butyl N-[(3R,5S)-1-(3-chloro-7-cyano-1-isoquinolyl)-5-methyl-3- 20 piperidyl]carbamate (94 mg, 199.30 μmol, 18% yield) as a yellow solid. LCMS (Method 7) m / z: 401.3 [M+H]+, Purity (254 nm): 85%, rt.: 1.59 min. 56

[0057] Synthesis of Intermediate B-74: Intermediate B-74 was prepared according to the procedure described for intermediate B-2starting from 1,3-dichloroisoquinoline (200 mg, 1.01 mmol) and tert-butyl N-[(6R)-1,4- oxazepan-6-yl]carbamate (218.41 mg, 1.01 mmol) to afford tert-butyl N-[(6R)-4-(3-chloro-1- 5 isoquinolyl)-1,4-oxazepan-6-yl]carbamate (360 mg, 943.20 μmol, 93% yield, 99% purity) as a colorless oil. LCMS-19 (Method 4): m / z: 378.1 [M+H] +, Purity (254nm): 99 %, rt.: 1.299 min. Synthesis of Intermediate B-75: Amixture of tert-butyl 4-[(3-chloro-1-isoquinolyl)oxy]piperidine-1-carboxylate - Intermediate B-40 (596 mg, 1.64 mmol) and sodium iodide (738.63 mg, 4.93 mmol, 201.43 μL) in CH3CN (18 10 mL) was degassed for 3 min by bubbling N2. Then, acetyl chloride (1.29 mg, 16.43 μmol, 1.00 μL) and the solution was stirred for 48 h at 80 °C. The reaction medium was diluted with EtOAc and water, and treated with saturated aqueous NaHCO3 solution. The aqueous layer was decanted and extracted with EtOAc (x 3). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash15 column chromatography on silica gel using a gradient of DCM / [DCM / MeOH (95:5)] to afford 3- iodoisoquinolin-1-ol (120 mg, 431.87 μmol, 26% yield) as an orange solid. LCMS (Method 4) m / z: 271.9 [M+H]+, Purity (254 nm): 98%, rt.: 0.68 min. Synthesis of Intermediate B-76: To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (66.83 mg, 332.04 μmol) and 3- 20 iodoisoquinolin-1-ol (90 mg, 332.04 μmol) in THF (1 mL) at 0 °C, were added triphenylphosphine (104.51 mg, 398.44 μmol) and then, slowly, diisopropyl azodicarboxylate (80.57 mg, 398.44 μmol, 78.45 μL). The mixture was stirred for 4 h at 60 °C. The reaction 57

[0058] medium was diluted with EtOAc and water, and extracted with EtOAc (x 3). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford tert-butyl 4-[(3-iodo-1-isoquinolyl)oxy]piperidine-1-carboxylate (150 mg, 323.57 μmol, 97% yield, 98% purity) as a brown gum. LCMS (Method 4) m / z: 455.1 [M+H]+, Purity (254 nm): 5 98%, rt: 1.61 min. In a sealed tube, tert-butyl N-[(3S)-1-(3-chloro-7-morpholino-1-isoquinolyl)-3- piperidyl]carbamate (486 mg, 1.09 mmol), CHCl3 Pd(dba)2 (112.55 mg, 108.73 μmol), di-tert- butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (92.34 mg, 217.46 μmol) and potassium 10 hydroxide (244.02 mg, 4.35 mmol) were dissolved in 1,4-dioxane (18 mL) and water (9.5 mL). The mixture was bubbled with N2 for 3 min and the resultant solution was stirred at 100 °C for 16 h. The reaction medium was diluted with EtOAc and brine and extracted with EtOAc (x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel using15 a gradient of heptane / AcOEt (100:0 to 60:40) to afford tert-butyl N-[(3S)-1-(3-hydroxy-7- morpholino-1-isoquinolyl)-3-piperidyl]carbamate (175.3 mg, 339.54 μmol, 31% yield) as a orange solid. LCMS (Method 4) m / z: 429.2 [M+H]+, Purity (254nm): 83%, rt.:0.95 min. y ess o e e ae Tert-butyl N-[(3S)-1-(3-hydroxy-7-morpholino-1-isoquinolyl)-3-piperidyl]carbamate (175 mg, 20 408.38 μmol) and N-Phenyl-bis(trifluoromethanesulfonimide) (175.07 mg, 490.06 μmol) were dissolved in DCM (9 mL). Then, TEA (61.99 mg, 612.57 μmol, 85.38 μL) was added and the mixture was stirred at RT for 16 h. The reaction medium was concentrated under reduced pressure and the crude material was purified by flash column chromatography on silica gel using a gradient of heptane / EOAct (100:0 to 80:20) to afford [1-[(3S)-3-(tert- 25 butoxycarbonylamino)-1-piperidyl]-7-morpholino-3-isoquinolyl] trifluoromethanesulfonate (92 mg, 162.47 μmol, 40% yield) as a yellow oil LCMS (Method 4) m / z: 561.2 [M+H]+, Purity (254 nm):99%, rt: 1.44 min. 58

[0059] Synthesis of Intermediate B-79: A mixture of [1-[(3S)-3-(tert-butoxycarbonylamino)-1-piperidyl]-7-morpholino-3-isoquinolyl] trifluoromethanesulfonate - Intermediate B-78 (67 mg, 119.52 μmol), sodium iodide (53.75 mg,358.55 μmol) and acetyl chloride (9.38 mg, 119.52 μmol, 7.25 μL) in MeCN (2 mL) was bubbled 5 with N2for 5 min and stirred for 16 h at 80 °C. LCMC revealed the presence of remaining starting material. The reaction mixture was recharged with sodium iodide (53.75 mg, 358.55 μmol) and was stirred at 80 °C for 4 h more. The reaction medium was concentrated under reduced pressure to afford (3S)-1-(3-iodo-7-morpholino-1-isoquinolyl)piperidin-3-amine hydroiodide (62 mg) which was used in the next step without further purification. LCMS10 (Method 4) m / z: 439.2 [M+H]+, Purity (254 nm): 45.68 %, rt: 0.82 min. Synthesis of Intermediate B-80: To a solution of (3S)-1-(3-iodo-7-morpholino-1-isoquinolyl)piperidin-3-amine hydroiodide (62 mg, 50.38 μmol) and TEA (26.34 mg, 260.28 μmol, 36.28 μL) in DMF (3 mL), was added tert- butoxycarbonyl tert-butyl carbonate (21.30 mg, 97.60 μmol, 22.40 μL). The solution was stirred 15 at RT for 48 h. Water (10 mL) was added to the reaction medium and the mixture was extracted with EtOAc (x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using a gradient of heptane / EtOAc (100:0 to 80:20) to afford tert- butyl N-[(3S)-1-(3-iodo-7-morpholino-1-isoquinolyl)-3-piperidyl]carbamate (52 mg, 51.19 μmol, 20 99% yield, 53% purity)) as a yellow oil. LCMS (Method 4) m / z: 539.2 [M+H]+, Purity (254 nm): 53%, rt.:1.47 min. 59

[0060] Synthesis of Intermediate B-81: To a stirred solution of tert-butyl N-[(3S,5R)-1-(3-chloro-1-isoquinolyl)-5-hydroxy-3- piperidyl]carbamate – Intermediate B-3 (100 mg, 264.65 μmol) in THF (6 mL) under N2atmosphere, was added NaH (60% dispersion in mineral oil, 15.21 mg, 380.30 μmol) at 0 °C. 5 After 30 min at 0 °C, MeI (60.10 mg, 423.43 μmol, 26.36 μL) was added, the mixture was then allowed to warm to RT and was stirred for 3h at this temperature. The reaction medium was diluted with EtOAc and water and extracted with EtOAc (x 3). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel using a gradient of10 heptane / EtOAc (100:0 to 30:70) to afford tert-butyl N-[(3S,5R)-1-(3-chloro-1-isoquinolyl)-5- methoxy-3-piperidyl]carbamate (72 mg, 176.38 μmol, 67% yield) as a yellow oil. LCMS (Method 4) m / z: 392.2 [M+H]+, Purity (254 nm): 96 %, rt.: 1.34 min. Synthesis of Intermediate C-1: o a solution of 2-(1H-indazol-5-yl)acetonitrile (201 mg, 1.27 mmol) in DCM (5 mL) was added 15 4-methylbenzenesulfonic acid hydrate (24.33 mg, 0.13 mmol) and 3,4-dihydro-2H-pyran (159.75 mg, 1.90 mmol, 172.51 μL) and the resultant mixture was stirred at RT for 2 h. The reaction medium was neutralized with saturated aqueous NaHCO3 solution (50 mL) and extracted with EtOAc (3x 20 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material20 was purified by flash column chromatography on silica gel using a gradient of DCM / (DCM- MeOH 9:1) from 100:0 to 95:5) to afford 2-(1-Tetrahydropyran-2-ylindazol-5-yl)acetonitrile (300.5 mg, 1.18 mmol, 93% yield)as a yellow oil. GCMS (Method 8) m / z: 241.1 [M+H]+; Purity (254 nm): 99 %; rt: 12.74 min. The following intermediates were prepared via an analogous procedure: 25 60

[0061] 61

[0062] Synthesis of Intermediate C-7: In a pressure flask, were introduced 2-(3,6-dihydro-2H-pyran-5-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (404.15 mg, 1.87 mmol), 5-bromo-1-tetrahydropyran-2-yl-pyrazolo[3,4- c]pyridine (350 mg, 1.24 mmol), CsF (580.14 mg, 3.82 mmol, 140.98 μL), Pd(dppf)Cl2 (104.84 5 mg, 0.13 mmol) and 1,4-dioxane / H2O (4:1) (5 mL). The mixture was degassed by bubbling N2for 5 min and stirred at 100 °C for 16 h. The mixture was then diluted with EtOAc and water and extracted with EtOAc (3x50 mL). The resultant combined organic layers were dried with MgSO4, filtered, and concentrated under reduced pressure. The mixture was purified by flash column chromatography on silica gel using DCM / MeOH(100:0 to 95:5). The desired fractions10 were collected and concentrated under reduced pressure to afford 5-(3,6-dihydro-2H-pyran-5- yl)-1-tetrahydropyran-2-yl-pyrazolo[3,4-c]pyridine (130 mg, 0.45 mmol, 36% yield) as a colorless oil. LCMS (Method 4) m / z: 286.1 [M+H]+, Purity (254 nm): 99%, rt.: 0.79 min. Synthesis of Intermediate C-8: To a solution of 5-(3,6-dihydro-2H-pyran-5-yl)-1-tetrahydropyran-2-yl-pyrazolo[3,4-c]pyridine 15 (130 mg, 0.46 mmol) in MeOH (5 mL) under N2was added 10% Pd / C (135.76 mg, 0.13 mmol). The inert atmosphere was replaced by H2gas through 10 vacuum-H2cycles. The reaction medium was stirred at RT for 16 h. The medium was filtered over a Celite® pad, the cake was washed with EtOAc, and the filtrate was concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel using heptane / EtOAc20 (100:0 to 70:30) to afford 1-tetrahydropyran-2-yl-5-tetrahydropyran-3-yl-pyrazolo[3,4- c]pyridine (96.2 mg, 331.43 μmol, 73% yield) as a colorless oil. LCMS (Method 4) m / z: 288.1 [M+H]+; Purity (254 nm): 99 %; rt: 1.28 min. 62

[0063] Synthesis of Intermediate C-9: Intermediate C-9 was prepared according to the procedure described for intermediate C-7starting from 5-bromo-1-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyridine (400 mg, 1.42 mmol) to afford 5-(3,6-dihydro-2H-pyran-5-yl)-1-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyridine (300 mg, 5 1.02 mmol, 72% yield) as a yellow oil. LCMS (Method 4) m / z: 286.1 [M+H]+, Purity (254 nm): 98%, rt.:0.84 min. Synthesis of Intermediate C-10: Intermediate C-10 was prepared according to the procedure described for intermediate C-8starting from 5-(3,6-dihydro-2H-pyran-5-yl)-1-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyridine10 (300 mg, 1.05 mmol) to afford 1-tetrahydropyran-2-yl-5-tetrahydropyran-3-yl-pyrazolo[3,4- b]pyridine (200 mg, 668.16 μmol, 64% yield) as a colorless oil. LCMS (Method 5) m / z: 288.2 [M+H]+, Purity (254 nm): 96%, rt.: 0.91 min. Synthesis of Intermediate C-11: Intermediate C-11 was prepared according to the procedure described for intermediate C-715 starting from 5-bromo-1-tetrahydropyran-2-yl-indazole (1.69 g, 6.02 mmol) to afford 5-(3,6- dihydro-2H-pyran-5-yl)-1-tetrahydropyran-2-yl-indazole (691 mg, 2.41 mmol, 40% yield) as a light-yellow oil. LCMS (Method 5) m / z: 285.1 [M+H]+, Purity (254 nm): 99%, rt.: 1.16 min. 63

[0064] Synthesis of Intermediate C-12: Intermediate C-12 was prepared according to the procedure described for intermediate C-8starting from 5-(3,6-dihydro-2H-pyran-5-yl)-1-tetrahydropyran-2-yl-indazole (1.63 g, 5.73 mmol) to afford 1-tetrahydropyran-2-yl-5-tetrahydropyran-3-yl-indazole (1.15 g, 3.98 mmol, 5 69% yield) as a colorless oil. LCMS (Method 5) m / z: 287.1 [M+H]+, Purity (254 nm): 99%, rt.: 1.18 min. To a solution of 5-(3,6-dihydro-2H-pyran-5-yl)-1-tetrahydropyran-2-yl-indazole (238 mg, 836.99 μmol) in toluene (5 mL) under N2at -50 °C, was added at -50 °C a solution 1 M of 10 diethylzinc in hexane (2.93 mmol, 2.93 mL) and then diiodomethane (1.12 g, 4.18 mmol, 337.11 μL). The reaction mixture was allowed to warm to RT for 16 h. LCMS showed the presence of the desired starting material. The mixture was recharged with more diethyl zinc solution 1 M in hexanes (2.93 mmol, 2.93 mL) and diiodomethane (1.12 g, 4.18 mmol, 337.11 μL) at -50 °C. Then the mixture was allowed to warm to RT and stirred for 16 h more. Starting 15 material was still present, so the reaction medium was recharged with more solution of diethyl zinc 1 M in hexane (2.93 mmol, 2.93 mL) and diiodomethane (1.12 g, 4.18 mmol, 337.11 μL) at -50 °C. Then the mixture was allowed to warm to RT and stirred for 48 h more. The reaction mixture was quenched with NH4Cl and diluted with EtOAc, extracted with EtOAc (x 3), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was 20 purified by flash column chromatography on silica gel using a gradient of heptane / EtOAc (100:0 to 90:10) to afford 5-(3-oxabicyclo[4.1.0]heptan-1-yl)-1-tetrahydropyran-2-yl-indazole (64 mg, 205.91 μmol, 25% yield) as a light yellow oil. LCMS (Method 4) m / z: 299.4 [M+H]+, Purity (254 nm): 96%, rt.: 1.04 min. 64

[0065] Intermediate C-14 was prepared according to a procedure similar to the one described forintermediate C-7 starting from 5-bromo-1-tetrahydropyran-2-yl-indazole (486.66 mg, 1.73mmol) and 2-(3,4-dihydro-2H-pyran-5-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (400 mg,5 1.90 mmol) to afford 5-(3,4-dihydro-2H-pyran-5-yl)-1-tetrahydropyran-2-yl-indazole (400 mg, 1.39 mmol, 80% yield) as an orange oil. LCMS (Method 4) m / z: 285.0 [M+H]+, Purity (254 nm): 99 %, rt.: 1.121 min. Intermediate C-15 was prepared according to a procedure similar to the one described for10 intermediate C-13 starting from 5-(3,4-dihydro-2H-pyran-5-yl)-1-tetrahydropyran-2-yl-indazole(380 mg, 1.34 mmol) to afford 5-(2-oxabicyclo[4.1.0]heptan-6-yl)-1-tetrahydropyran-2-yl- indazole (198 mg, 656.95 μmol, 49% yield) as a pale-yellow oil. LCMS (Method 4) m / z: 299.1 [M+H]+, Purity (24 nm): 99% rt.: 1.095 min. 15 Synt ess o ntermedate C- 6: In a round bottom flask, to a solution of 1,4-dioxepan-6-one (300 mg, 2.58 mmol) and 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (900.00 mg, 2.98 mmol, 514.29 μL) in DMF (5 mL), was added dropwise at 0 °C tert-butylimino(tripyrrolidin-1-yl)-phosphane (930.00 mg, 2.98 mmol, 909.98 μL). The mixture was stirred at RT for 1 h. The reaction medium was 20 quenched with saturated aqueous NH4Cl solution and extracted with heptane (x 3). The 65

[0066] combined organic layers were washed with water and brine, dried over Mg2SO4, and concentrated under reduced pressure to afford 3,5-dihydro-2H-1,4-dioxepin-6- yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (435 mg) as a yellow oil which was used in the next step without further purification. GCMS (Method 8) m / z: 398.0 [M+H]+, Purity (254nm): 5 98%, rt.:6.29 min. Synthesis of Intermediate C-17: In a pressure flask, to a solution of 3,5-dihydro-2H-1,4-dioxepin-6-yl1,1,2,2,3,3,4,4,4- nonafluorobutane-1-sulfonate (430 mg, 1.08 mmol) in dimethoxyethane (5 mL), were added B2PiN2 (301.00 mg, 1.19 mmol), KOAc (317.94 mg, 3.24 mmol), Pd(dppf)Cl2 (39.77 mg, 54.36 10 μmol) and dppf (30.10 mg, 54.30 μmol). The resultant mixture was bubbled with N2 and heated at 80 °C for 16 h. The reaction medium was filtered through a Celite® pad and the cake was washed with EtOAc (200 mL). The filtrate was concentrated under reduced pressure to afford 2-(3,5-dihydro-2H-1,4-dioxepin-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (900 mg) as a black solid which was used in the next step without further purification. GCMS (Method 8) m / z:15 226.0 [M+H]+, Purity (254 nm): 63%, rt.: 8.2min. Synthesis of Intermediate C-18: Intermediate C-18 was prepared according to a procedure similar to the one described forintermediate C-7 starting from 5-bromo-1-tetrahydropyran-2-yl-indazole (500 mg, 1.78 mmol)20 and 2-(3,5-dihydro-2H-1,4-dioxepin-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (884.53 mg, 1.96 mmol) afford 5-(3,5-dihydro-2H-1,4-dioxepin-6-yl)-1-tetrahydropyran-2-yl-indazole (173 mg, 512.63 μmol, 29% yield) as an orange oil. LCMS (Method 4) m / z: 301.2 [M+H]+, Purity (254 nm): 89%, rt.: 0.89 min. 66

[0067] Synthesis of Intermediate C-19: Intermediate C-19 was prepared according to a procedure like the one described forintermediate C-8 starting from 5-(3,5-dihydro-2H-1,4-dioxepin-6-yl)-1-tetrahydropyran-2-yl-indazole (170 mg, 566.00 μmol) to afford 5-(1,4-dioxepan-6-yl)-1-tetrahydropyran-2-yl- 5 indazole (106 mg, 66.43 μmol, 47% yield) as a colorless oil. LCMS (Method 4) m / z: 303.1 [M+H]+, Purity (254 nm): 76%, rt.: 0.82min. Synthesis of Intermediate C-20: To a solution of methyl 1-tetrahydropyran-2-ylindazole-5-carboxylate (1.05 g, 3.80 mmol) in THF (20 mL), was added LAH (433.08 mg, 11.41 mmol) portion wise over 10 min at 0 °C and 10 the reaction mixture was allowed to warm to RT. After 1 h, AcOEt was added, and the mixture was cooled to 0 °C. Water (0.5 mL) was added slowly, then 0.5 mL of a 15 % aqueous solution of NaOH (0.5 mL) and water (2 mL) again. The mixture was allowed to warm to RT stirred for 15 min. MgSO4was added. The mixture was stirred for 15 min, filtered and concentrated under reduced pressure to afford (1-tetrahydropyran-2-ylindazol-5-yl)methanol (956 mg) as a yellow 15 oil. This was used in the next step without further purification. LCMS (Method 4); m / z: 233.1 [M+H]+. Purity (254 nm): 87%; Rt: 0.59 min. Synthesis of Intermediate C-21: To a solution of (1-tetrahydropyran-2-ylindazol-5-yl)methanol (945 mg, 3.54mmol) in THF (10 mL) was added was added slowly NaH (60% dispersion in mineral oil, 283.13 mg, 7.08 mmol) 20 at 0 °C. After 30 min, iodomethane (1.26 g, 8.85mmol, 550.87 μL) was added at 0 °C and the reaction mixture was allowed to warm to RT. After 30 min, a saturated aqueous solution of 67

[0068] NH4Cl and AcOEt were added and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel using a gradient of heptane / EtOAc 100:0 to 80:20) to afford 5-(methoxymethyl)-1-tetrahydropyran-2-yl-indazole 5 (620 mg, 2.44mmol, 69% yield, 97% purity) as a yellow oil. LCMS (Method 4); m / z: 247.1 [M+H]+. Purity (254 nm): 99%; Rt: 0.87 min. Synthesis of Intermediate C-22: 5-(Chloromethyl)-1-tetrahydropyran-2-yl-indazole In a round bottom flask, to solution of (1-tetrahydropyran-2-ylindazol-5-yl)methanol (2.1 g, 9.04 10 mmol) in DCM (80 mL) was added TEA (1.37 g, 13.56 mmol, 1.89 mL) and methanesulfonyl chloride (1.24 g, 10.85 mmol, 841.42 μL). The mixture was stirred at RT for 3 h and then concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel using heptane / EtOAc (100:0 to 90:10) to afford 5-(chloromethyl)- 1-tetrahydropyran-2-yl-indazole (1.8 g, 5.96 mmol, 66% yield) as a colorless oil. LCMS15 (Method 5) m / z: 351.1 [M+H]+, Purity (254nm): 83%, rt.: 1.09 min. Synthesis of Intermediate C-23: To a solution of 5-(chloromethyl)-1-tetrahydropyran-2-yl-indazole (600 mg, 2.39 mmol) in 1,4- dioxane (20 mL) was added sodium methanethiolate (503.19 mg, 7.18 mmol) and the mixture was stirred at 23 °C for 1 h. The reaction medium was diluted with EtOAc and water and 20 extracted with EtOAc (x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to afford 5-(methylsulfanylmethyl)-1-tetrahydropyran-2- yl-indazole (620 mg, 2.34 mmol, 98% yield) as a colorless oil. LCMS (Method 5) m / z: 263.1 [M+H]+, Purity (254 nm): 99 %, rt.: 1.12 min. 68

[0069] Synthesis of Intermediate C-24: To a solution of 5-(methylsulfanylmethyl)-1-tetrahydropyran-2-yl-indazole (620 mg, 2.36 mmol) in DCM (50 mL) was added mCPBA (1.02 g, 4.55 mmol, 77 %) and the mixture was stirred at RT for 1 h. The reaction medium was diluted with DCM (10 mL) and washed with saturated 5 aqueous NaHCO3solution (3x 10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford 5-(methylsulfonylmethyl)-1-tetrahydropyran-2-yl-indazole (640 mg, 2.15 mmol, 91% yield) as a white solid. LCMS (Method 4) m / z: 395.1 [M+H]+, Purity (254 nm): 99%, rt.: 0.63 min. Synthesis of Intermediate C-25: 10 In a sealed tube, 5-bromo-1-tetrahydropyran-2-yl-indazole (800 mg, 2.85 mmol), (Ir[dF(CF3)ppy]2(dtbpy))PF6 (63.85 mg, 56.91 μmol), BBBPY (15.27 mg, 56.91 μmol) and 2,6-lutidine (1.83 g, 17.07 mmol, 1.98 mL) were dissolved in DME (50 mL). In a separated vial, a solution of NiCl2 glyme (31.26 mg, 142.27 μmol) and BBBPY (15.27 mg, 56.91 μmol) in DME (50 mL) was stirred for 5 min. The latter nickel solution was syringed to the previous sealed15 reaction vial and the final reaction mixture was degassed for 5 min. Then, 3- (bromomethyl)oxetane (1.93 g, 12.80 mmol, 1.29 mL) and 1 M solution of hexamethyldisilazane in THF (459.24 mg, 2.85 mmol, 593.34 μL) were added subsequently and the resultant mixture was irradiated by 18 W blue lamp for 16 h. The reaction medium was concentrated under reduced pressure. The crude material was purified using heptane / EtOAc 20 (100:0 to 40:60) to afford 5-(oxetan-3-ylmethyl)-1-tetrahydropyran-2-yl-indazole (100 mg, 293.75 μmol, 10% yield) as a pale-yellow oil. LCMS (Method 4) m / z: 273.1 [M+H]+, Purity (254 nm): 80%, r.t.: 0.86 min. 69

[0070] Synthesis of Intermediate C-26: o an ice-cooled solution of 3-amino-4-methyl-benzonitrile (2.0 g, 15.13 mmol) in DMF (80 mL) was added 1-bromopyrrolidine-2,5-dione (2.96 g, 16.65 mmol, 1.41 mL) portionwise. The mixture was stirred at the same temperature for 30min, and it was then allowed to warm to RT 5 over 2 h. The reaction medium was quenched with water at 0 °C and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel using heptane / EtOAc (100:0 to 97:3) to afford 5-amino-2-bromo-4-methyl-benzonitrile (2.80 g, 13.11 mmol, 87% yield) as a cream solid. LCMS (Method 5) m / z: 211.0 [M+H]+, Purity (254 nm):10 99%, rt.: 0.92 min. Synthesis of Intermediate C-27: To a solution of boron trifluoride diethyl etherate (2.66 g, 18.76 mmol, 2.32 mL) in DCM (65 mL) under N2at -78 °C was added 5-amino-2-bromo-4-methyl-benzonitrile (2.64 g, 12.51 mmol) in DCM (65 mL). After the dropwise addition of tert-butyl nitrite (1.42 g, 13.76 mmol,15 1.64 mL), the reaction medium was allowed to warm to RT, and it was stirred overnight. To theresultant mixture was added KOAc (2.46 g, 25.02 mmol) and 18-crown-6 (165.31 mg, 0.63 mmol, 140.69 μL). After stirring at RT for 1 h, the mixture was filtered and the solid washed with DCM. The solid was solubilized in EtOAc and the organic phase was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The crude residue 20 was purified by flash column chromatography on silica using a gradient of heptane / EtOAc (100:0 to 75:25) to afford 5-bromo-1H-indazole-6-carbonitrile (1.34 g, 5.92 mmol, 47% yield) as a cream solid. LCMS (Method 5) m / z: 223.9 [M+H]+, Purity (254 nm): 98%, rt.: 0.82 min Synthesis of Intermediate C-28: Intermediate C-28 was prepared according to the procedure described for intermediate C-125 starting from 70

[0071] 5-bromo-1H-indazole-6-carbonitrile (1.34 g, 6.03 mmol) to afford 5-bromo-1-tetrahydropyran- 2-yl-indazole-6-carbonitrile (1.45 g, 4.65 mmol, 77% yield) as a light-yellow solid. LCMS (Method 5) m / z: 307.9 [M+H]+, Purity (254 nm): 98%, rt.: 1.31 min. Synthesis of Intermediate C-29: 5Intermediate C-29 was prepared according to the procedure described for intermediate C-7starting from 5-bromo-1-tetrahydropyran-2-yl-indazole-6-carbonitrile (0.400 g, 1.31 mmol) and 2-(3,6- dihydro-2H-pyran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (274.47 mg, 1.31 mmol) to afford 5-(3,6-dihydro-2H-pyran-5-yl)-1-tetrahydropyran-2-yl-indazole-6-carbonitrile (0.160 g, 10 506.85 μmol, 39% yield) as a white solid. LCMS (Method 5) m / z: 310.2 [M+H]+, Purity (254 nm): 98%, rt.: 1.26 min. Synthesis of Intermediate C-30: idem Intermediate C-30 was prepared according to the procedure described for intermediate C-815 starting from To a solution of 5-(3,6-dihydro-2H-pyran-5-yl)-1-tetrahydropyran-2-yl-indazole-6-carbonitrile (0.120 g, 387.90 μmol) in THF (5 mL) under N2 was added 10% Pd / C (12.38 mg, 116.37 μmol). The inert atmosphere was replaced by H2 gas through 10 vacuum-H2 cycles. The mixture was stirred at 23°C for 16 h. The reaction medium was filtered on a syringe filter to remove 20 palladium on carbon and the filter washed with MeCN and CHCl3 / iPrOH (3:1). The filtrate concentrated under reduced pressure to afford 1-tetrahydropyran-2-yl-5-tetrahydropyran-3-yl- indazole-6-carbonitrile (115 mg) as a white solid. The crude material was used without further purification in the next step. LCMS (Method 4) m / z: 312.2 [M+H]+; Purity (254 nm): 77%; rt: 1.00 min. 71

[0072] Synthesis of Intermediate C-31: TEA (1.06 g, 10.48 mmol, 1.46 mL) and di-tert-butyl dicarbonate (2.29 g, 10.48 mmol, 2.40 mL) were added to a solution of 1H-indazole-6-carbonitrile (1 g, 6.99 mmol) in DCM (30 mL). The resultant mixture was stirred at RT for 2 h and then concentrated under reduced pressure. 5 The crude product was purified by flash column chromatography using a gradient of heptane / EtOAc (100:0 to 80:20). The desired fractions were collected and concentrated under reduced pressure to afford tert-butyl 6-cyanoindazole-1-carboxylate (1.6 g, 6.51 mmol, 93% yield) as a white solid. LCMS (Method 4) m / z: 244.2 [M+H]+, Purity (254 nm): 99%, rt.: 0.97 min. 10 Synthesis of Intermediate C-32: Lithium bis(trimethylsilyl)amide (1.0 M, 1.37 mmol, 1.37 mL) was added dropwise to a stirred solution of 2-(1-tetrahydropyran-2-ylindazol-5-yl)acetonitrile (150 mg, 621.66 μmol) in THF (10 mL) at -78 °C under N2atmosphere. The anion was allowed to form over 30 min, then iodomethane (247.07 mg, 1.74 mmol, 108.36 μL) was added dropwise and the reaction was 15 stirred for 1 h at a temperature close to room temperature. The reaction medium was then treated with another equivalent of lithium bis(trimethylsilyl)amide (1.0 M, 1.37 mmol, 1.37 mL) at -78 °C and after 30 min, iodomethane (247.07 mg, 1.74 mmol, 108.36 μL) was added. The mixture was allowed to stir 16 h more at RT, it was then quenched by addition of saturated aqueous NH4Cl solution and extracted with EtOAc. The organic layers were combined, dried20 with MgSO4, filtered and concentrated under reduced pressure to afford 2-(1-tetrahydropyran- 2-ylindazol-5-yl)propanenitrile (130 mg). This was used in the next steps without further purification LCMS (Method 4) m / z: 256.1 [M+H]+, Rt.: 0.90 min. 72

[0073] Synthesis of Intermediate C-33: To a stirred solution of 2-(1-tetrahydropyran-2-ylindazol-5-yl)propanenitrile (130 mg, 538.78 μmol) in DMSO (6 mL) at RT under N2 atmosphere, was added portionwise NaH (60%dispersion in mineral oil, 43.10 mg, 1.08 mmol). After the anion was allowed to form over 15 5 min, iodomethane (214.12 mg, 1.51 mmol, 93.91 μL) was added dropwise and the reaction mixture was stirred for 3h at RT. The reaction medium was then quenched by addition of saturated aqueous NH4Cl solution and extracted with EtOAc. The organic layers were combined, dried with MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel using a gradient of10 heptane / EtOAc (100:0 to 70:30) to afford 2-methyl-2-(1-tetrahydropyran-2-ylindazol-5- yl)propanenitrile (122 mg, 448.43 μmol, 83% yield) as a colorless oil. LCMS (Method 4) m / z: 270.1 [M+H]+, Purity (254 nm): 99%, rt.: 0.99 min. Synthesis of Intermediate C-34: A sealed tube was charged with 5-bromo-1-tetrahydropyran-2-yl-indazole (200 mg, 711.37 15 μmol), spiro[2.2]pentane-2-carbonitrile (66.25 mg, 711.37 μmol), N-XantPhos Pd G4 (66.61 mg, 71.14 μmol), MTBE (10 mL) and 1 M LiHDMS solution in THF (1 M, 1.78 mmol, 1.78 mL). The mixture was bubbled with N2 for 3 min and stirred at 100 °C for 3 h. The reaction medium was diluted with EtOAc (5 mL), washed with saturated aqueous NaHCO3 solution (3x 5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced 20 pressure. The crude product was purified by flash column chromatography on silica gel using heptane / EtOAc (100:0 to 80:20) to afford 2-(1-tetrahydropyran-2-ylindazol-5- yl)spiro[2.2]pentane-2-carbonitrile (135 mg, 441.77 μmol, 62% yield) as a colorless gum. LCMS (Method 4) m / z: 294.2 [M+H]+, Purity (254nm): 96%, rt.: 1.01 min. 73

[0074] Synthesis of Intermediate C-35: In a sealed tube, to a solution of 5-bromo-1-tetrahydropyran-2-yl-indazole (200 mg, 711.37 μmol), cyclopropanecarbonitrile (47.73 mg, 711.37 μmol, 52.73 μL) and N-XantPhos Pd G4 (66.61 mg, 71.14 μmol) in tert-butyl methyl ether (10 mL), was added 1 M lithium 5 bis(trimethylsilyl)amide solution in THF (1.78 mmol, 1.78 mL). The mixture was bubbled with N2 for 3 min and stirred at 100 °C for 2 h. The reaction medium was diluted with EtOAc and saturated aqueous NaHCO3 solution and extracted with EtOAc (x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel using heptane / EtOAc (from 10 100:0 to 80:20) to afford 1-(1-tetrahydropyran-2-ylindazol-5-yl)cyclopropanecarbonitrile (116 mg, 416.57 μmol, 59% yield) as a light-yellow oil. LCMS (Method 4) m / z: 268.1 [M+H]+, Purity (254 nm): 96%, rt.: 0.89 min. Synthesis of Intermediate C-36: Intermediate C-36 was prepared according to the procedure described for intermediate C-3315 starting from 2-(1-tetrahydropyran-2-ylindazol-5-yl)acetonitrile (506 mg, 2.10 mmol) and 1-chloro-2-(2- chloroethylsulfanyl)ethane (400.32 mg, 2.52 mmol) to afford 4-(1-tetrahydropyran-2-ylindazol- 5-yl)tetrahydrothiopyran-4-carbonitrile (510.9 mg, 1.54 mmol, 74% yield) as a colorless gum. LCMS (Method 4) m / z: 328.3 [M+H]+, Purity (254 nm): 99%, 25 °C.: 1.09 min. 20 Synthesis of Intermediate C-37: Intermediate C-37 was prepared according to the procedure described for intermediate C-24starting from 74

[0075] 4-(1-tetrahydropyran-2-ylindazol-5-yl)tetrahydrothiopyran-4-carbonitrile (510 mg, 1.56 mmol) to afford 1,1-dioxo-4-(1-tetrahydropyran-2-ylindazol-5-yl)thiane-4-carbonitrile (337 mg, 928.19 μmol, 60% yield) as a white gum. LCMS (Method 4) m / z: 360.1 [M+H]+, Purity (254 nm): 99%, 25 °C.: 0.74 min. 5 Synthesis of Intermediate C-38: Intermediate C-38 was prepared according to the procedure described for intermediate C-33starting from 2-(1-tetrahydropyran-2-ylindazol-5-yl)acetonitrile (300 mg, 1.24 mmol) and 1-chloro-2-(2- chloroethoxy)ethane (1.49 mmol, 175.04 μL) to afford 4-(1-tetrahydropyran-2-ylindazol-5- 10 yl)tetrahydropyran-4-carbonitrile (187 mg, 582.54 μmol, 47% yield) as a pale yellow gum. LCMS (Method 4) m / z: 312.2 [M+H]+, Purity (254 nm): 97%, rt.: 0.90 min. Synthesis of Intermediate C-39: Intermediate C-39 was prepared according to the procedure described for intermediate C-33starting from 2-(1-tetrahydropyran-2-ylindazol-5-yl)acetonitrile (200 mg, 580.22 μmol) and15 benzyl N,N-bis(2-chloroethyl)carbamate (192.28 mg, 696.26 μmol, 160.23 μL) afford benzyl 4- cyano-4-(1-tetrahydropyran-2-ylindazol-5-yl)piperidine-1-carboxylate (123 mg, 265.63 μmol, 46% yield) as a colorless gum. LCMS (Method 4) m / z: 445.2 [M+H]+, Purity (254 nm): 96%, rt: 1.17 min. Synthesis of Intermediate C-41: 75

[0076] In a pressure flask, a mixture of 5-bromo-1-tetrahydropyran-2-yl-indazole (300 mg, 1.07 mmol), thiazinane 1,1-dioxide (216.37 mg, 1.60 mmol), di-tert-butyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane methanesulfonic acid palladium 2-phenylaniline (169.74 mg, 213.41 μmol), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (181.25 mg, 5 426.82 μmol) and potassium tert-butoxide (359.21 mg, 3.20 mmol) in 1,4-dioxane (30 mL) was degassed by bubbling N2for 2 min and the mixture was stirred for 2 h at 120 °C. The mixture was diluted with EtOAc and saturated aqueous solution of NaHCO3, and extracted with EtOAc (x 3). The organic layers were combined, dried over MgSO4, and concentrated under reduced pressure. The crude material was further purified by flash column chromatography on silica10 gel using a gradient of heptane / EtOAc (100:0 to 50:50) to afford 2-(1-tetrahydropyran-2- ylindazol-5-yl)thiazinane 1,1-dioxide (254 mg, 689.11 μmol, 65% yield) as a brown gum. LCMS (Method 4) m / z: 336.1 [M+H]+, Purity (254 nm): 91 %, rt: 0.78 min. Synthesis of Intermediate C-42: In a sealed tube, a mixture of 5-bromo-1-tetrahydropyran-2-yl-indazole (486.32 mg, 1.73 15 mmol) 5-bromo-1-tetrahydropyran-2-yl-indazole (486.32 mg, 1.73 mmol), tBuXPhos Pd G3 (137.58 mg, 0.17 mmol) and potassium tert-butoxide (582.31 mg, 5.19 mmol) in 1,4-dioxane (25 mL) was degassed by bubbling N2 and heated at 85 °C for 16 h. Saturated aqueous NaHCO3 solution was added, and the mixture was extracted with EtOAc (3x50 mL). The combined organic layers were dried over Mg2SO4 and concentrated under reduced pressure. 20 The crude material was further purified by flash column chromatography on silica gel using a gradient of DCM / MeOH (100:0 to 90:10) to afford 8-(1-tetrahydropyran-2-ylindazol-5-yl)-2-oxa- 8-azaspiro[3.5]nonane (88 mg, 0.19 mmol, 11% yield, 70% purity) as a light yellow oil. LCMS (Method 5) m / z: 328.2 [M+H]+, Purity (254 nm): 30 %; rt: 0.79 min. Synthesis of Intermediate C-43: 76

[0077] To a solution of 1-tetrahydropyran-2-yl-5-tetrahydropyran-3-yl-pyrazolo[3,4-c]pyridine (95 mg, 290.15 μmol) in MTBE (3 mL) was added B2PiN2(95.78 mg, 377.19 μmol), BBBPY (778.74 μg, 2.90 μmol) and (1,5-cyclooctadiene)(methoxy)iridium(Ι)dimer (3.85 mg, 5.80 μmol). The mixture was stirred at 90 °C for 16 h and then, it was filtered over a Celite® pad. The cake was 5 washed with EtOAc, and the filtrate was concentrated under reduced pressure to afford 1- tetrahydropyran-2-yl-5-tetrahydropyran-3-yl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazolo[3,4-c]pyridine (102 mg) as a yellow solid. This product was used in the next step without further purification. LCMS (Method 4) m / z: 332.2 [M-84+H]+, Purity (254 nm): 99%, rt.: 0.48 min. 10 The following intermediates were prepared via an analogous procedure: 77

[0078] Synthesis of Intermediate D-1: A microwave vial was charged with tert-butyl N-[(3S)-1-(3-chloro-1-isoquinolyl)-3- piperidyl]carbamate - Intermediate B-1 (60 mg, 165.81 μmol), XPhos (9.49 mg, 19.90 μmol),5 1-tetrahydropyran-2-yl-5-tetrahydropyran-3-yl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)indazole - Intermediate C-46 (68.37 mg, 165.81 μmol), Xphos Pd G4 (8.56 mg, 9.95 μmol),K3PO4(105.59 mg, 497.42 μmol) and 1,4-dioxane (0.5 mL). The resultant mixture was degassed with N2and heated at 140 °C under microwave irradiation for 30 min. The reaction 82

[0079] medium was allowed to cool down to RT, diluted with EtOAc and water, and extracted with EtOAc (x 3). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using heptane / EtOAc (100:0 to 30:70) to afford tert-butyl N-[(3S)-1-[3-(1- 5 tetrahydropyran-2-yl-5-tetrahydropyran-3-yl-indazol-3-yl)-1-isoquinolyl]-3-piperidyl]carbamate (59.2 mg, 95.80 μmol, 58% yield) as a yellow solid. LCMS (Method 2) m / z: 612.3 [M+H]+; Purity (254 nm): 99%; rt.: 5.66 min. The following intermediates were prepared via an analogous procedure: d 83

[0080] 84

[0081] 85

[0082] 86

[0083] 87

[0084] 88

[0085] 89

[0086] 90

[0087] 91

[0088] % 92

[0089] 93

[0090] 94

[0091] 95

[0092] 96

[0093] 97

[0094] 98

[0095] 99

[0096] 100

[0097] 101

[0098] 102

[0099] 103

[0100] 104

[0101] 105

[0102] Synthesis of Intermediate D-116: To a solution of 1-methylsulfanyl-3-(1-tetrahydropyran-2-yl-5-tetrahydropyran-3-yl-indazol-3- yl)isoquinoline - Intermediate D-114 (814 mg, 1.77 mmol) in DCM (30 mL) was added mCPBA(992.31 mg, 4.43 mmol, 77% purity) and the mixture was stirred at RT for 3 h. The reaction 5 medium was diluted with EtOAc and saturated aqueous NaHCO3 solution and extracted with EtOAc (x 3). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to afford 1-methylsulfonyl-3-(1-tetrahydropyran-2-yl-5- tetrahydropyran-3-yl-indazol-3-yl)isoquinoline (1.15 g) as a yellow solid. The crude material was used in the next step without further purification. LCMS (Method 4) m / z: 492.2 [M+H]+,10 Purity (254 nm): 71%, rt.:1.35 min.. 106

[0103] Synthesis of Intermediate D-117: A solution of tert-butyl N-[(3S)-1-[7-methylsulfanyl-3-(1-tetrahydropyran-2-yl-5- tetrahydropyran-3-yl-indazol-3-yl)-1-isoquinolyl]azepan-3-yl]carbamate - Intermediate D-40(50 mg, 74.42 μmol) 5dissolved in MeCN (0.8 mL) was added to a solution of oxone (114.37 mg, 186.04 μmol) inwater (0.4 mL) at RT. The reaction mixture was stirred at RT for 2 h. A saturated aqueous solution of NaHCO3and a mixture of CHCl3:i-PrOH (3:1) were added. After separation, the aqueous layer was extracted with a mixture of CHCl3:i-PrOH (3:1). The organic layers were combined and dried over MgSO4, filtered and concentrated under vacuum10 to afford tert-butyl N-[(3S)-1-[7-methylsulfonyl-3-(1-tetrahydropyran-2-yl-5-tetrahydropyran-3- yl- indazol-3-yl)-1-isoquinolyl]azepan-3-yl]carbamate (50 mg, 65.64 μmol, 88% yield, 92.4% purity) as a yellow solid. This product was used in the next step without further purification. LCMS (Method 5): m / z: 704.5 [M+H]+; Purity (254 nm): 90 %; Rt: 3.41 min. 15 Synthesis of Intermediate D-118: A solution of tert-butyl N-[(3S)-1-[3-[5-(4-cyano-4-piperidyl)-1-tetrahydropyran-2-yl-indazol-3- yl]-1-isoquinolyl]azepan-3-yl]carbamate - Intermediate D-63 (40 mg, 61.56 μmol), TEA (9.34mg, 92.33 μmol, 12.87 μL) and acetic anhydride (9.43 mg, 92.33 μmol, 8.71 μL) in THF (0.8 mL) was stirred at 23 °C for 3 h. The reaction medium was concentrated under reduced20 pressure. The crude product was purified by flash column chromatography (silica,heptane / EtOAc from 100:0 to 0:100). The desired fractions were collected and concentrated under reduced pressure, to afford tert-butyl N-[(3S)-1-[3-[5-(1-acetyl-4-cyano-4-piperidyl)-1- 107

[0104] tetrahydropyran-2-yl-indazol-3-yl]-1-isoquinolyl]azepan-3-yl]carbamate (35 mg, 49.07 μmol, 80% yield) as a brown gum. LCMS (Method 5) m / z: 692.5 [M+H]+, Purity (254 nm): 97%, rt: 1.70 min. Synthesis of Intermediate D-119: 5 To a solution of tert-butyl N-[(3S)-1-[6-methylsulfanyl-3-(1-tetrahydropyran-2-yl-5- tetrahydropyran-3-yl-indazol-3-yl)-1-isoquinolyl]azepan-3-yl]carbamate - Intermediate D-40(74 mg, 110.14 μmol) in ethanol (4 mL) were added [acetoxy(phenyl)-iodanyl] acetate (106.42 mg, 330.41 μmol) and ammonium acetate (135.83 mg, 1.76 mmol). The mixture was stirred at RT for 2 h and then concentrated under reduced pressure. The crude material was purified by10 flash column chromatography on silica gel using a gradient of heptane / EtOAc to afford tert- butyl N-[(3S)-1-[6-(methylsulfonimidoyl)-3-(1-tetrahydropyran-2-yl-5-tetrahydropyran-3-yl- indazol-3-yl)-1-isoquinolyl]azepan-3-yl]carbamate (42.4 mg, 52.24 μmol, 47% yield). LCMS (Method 4) m / z: 703.3 [M+H]+, Purity (254 nm): 86.6 %, Rt: 3.399 min. Synthesis of Intermediate D-120: 15 A 35% solution of hydrogen peroxide in water (107.52 mg, 1.11 mmol, 97.74 μL) was added to a mixture of tert-butyl N-[(3S)-1-[6-cyano-3-(1-tetrahydropyran-2-yl-5-tetrahydropyran-3-yl- indazol-3-yl)-1-isoquinolyl]azepan-3-yl]carbamate (48 mg, 73.75 μmol) - Intermediate D-41and potassium carbonate (40.77 mg, 295.02 μmol) in DMSO (3 mL). The mixture was stirred at RT for 16 h. The reaction medium was diluted with EtOAc and water, and extracted with 20 EtOAc (x 3). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica, heptane / EtOAc from 100:0 to 25:75). The desired fractions were collected and 108

[0105] concentrated under reduced pressure to afford tert-butyl N-[(3S)-1-[6-carbamoyl-3-(1- tetrahydropyran-2-yl-5-tetrahydropyran-3-yl-indazol-3-yl)-1- isoquinolyl]azepan-3-yl]carbamate (28 mg, 40.61 μmol, 55% yield, 97%) as a yellow solid. LCMS (Method 5): m / z: 669.5 [M+H]+, purity (254 nm): 97%, rt.: 1.52 min. 5 Synthesis of Intermediate D-121: A solution of methylmagnesium bromide 3M in diethyl ether (275.13 μmol, 91.71 μL) was added to a solution of tert-butyl N-[(3S)-1-[7-acetonyloxy-3-(1-tetrahydropyran-2-yl-5- tetrahydropyran-3-yl-indazol-3-yl)-1-isoquinolyl]azepan-3-yl]carbamate - Intermediate D-43(48 mg, 68.78 μmol) in THF (3 mL) at RT. The mixture was stirred for 3 h at RT. The reaction 10 medium was diluted with EtOAc and H2O, and extracted with EtOAc (x 3). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel using a gradient of heptane / EtOAc (100:0 to 60:40) to afford tert-butyl N-[(3S)-1-[7-(2-hydroxy-2-methyl-propoxy)- 3-(1-tetrahydropyran-2-yl-5-tetrahydropyran-3-yl-indazol-3-yl)-1-isoquinolyl]azepan-3-15 yl]carbamate (14 mg, 19.41 μmol, 28% yield) as a yellow oil. LCMS (Method 4) m / z: 714.0 [M+H]+, Purity (254 nm): 99%, rt.:1.62 min. Synthesis of Intermediate D-122: A solution of methylmagnesium bromide 3 M in diethyl ether (179.14 μmol, 59.71 μL) was added to a solution of methyl 1-[(3S)-3-(tert-butoxycarbonylamino)azepan-1-yl]-3-(1-20 tetrahydropyran-2-yl-5-tetrahydropyran-3-yl-indazol-3-yl)isoquinoline-6-carboxylate - Intermediate D-59 (35 mg, 51.18 μmol) in THF (1.5 mL) at 0 °C. The mixture was stirred for 1h at this temperature. The reaction medium was cooled in a bath of ice / water, diluted with 109

[0106] EtOAc, then water was added and the mixture was extracted with EtOAc (x 3). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford tert-butyl N-[(3S)-1-[6-(1-hydroxy-1-methyl-ethyl)-3-(1-tetrahydropyran-2-yl-5- tetrahydropyran-3-yl-indazol-3-yl)-1-isoquinolyl]azepan-3-yl]carbamate (22 mg) as an orange 5 oil. The crude material was used in the next step without further purification. LCMS (Method 3) m / z: 684.4 [M+H]+, Purity (254 nm): 99%, rt.: 4.53 min. Synthesis of Intermediate D-123: A solution 1 N of lithium bis(trimethylsilyl)amide in THF (175.17 μmol, 175.17 μL) was added dropwise to a stirred solution of tert-butyl 4-[[3-[5-(cyanomethyl)-1-tetrahydropyran-2-yl-10 indazol-3-yl]-1-isoquinolyl]oxy]piperidine-1-carboxylate - Intermediate D-94 (45.20 mg, 79.62μmol) in THF (1 mL) at -78 °C under N2atmosphere. The anion was allowed to form over 30 min, then iodomethane (31.64 mg, 222.94 μmol, 13.88 μL) was added dropwise and the reaction was stirred for 1 h before being slowly warmed to room temperature and stirred until completion (approximately 3 h). The reaction mixture was then quenched by addition of 15 saturated aqueous NH4Cl solution and extracted with EtOAc. The organic layers were combined, dried with MgSO4, filtered and concentrated under reduced pressure to afford the crude product. The crude residue was purified by flash column chromatography on silica using a gradient of heptane / EtOAc (100:0 to 70:30) to afford tert-butyl 4-[[3-[5-(1-cyano-1-methyl- ethyl)-1-tetrahydropyran-2-yl-indazol-3-yl]-1-isoquinolyl]oxy]piperidine-1-carboxylate (0.012520 g, 19.93 μmol, 25% yield) as a light-yellow oil. LCMS (Method 7) m / z: No ionization, Purity (254 nm): 95%, rt.: 2.12 min. Synthesis of Intermediate D-124: 110

[0107] A microwave vial was charged with tert-butyl 4-[(3-chloro-1-isoquinolyl)oxy]piperidine-1- carboxylate (220.00 mg, 606.31 μmol), 1-tetrahydropyran-2-yl-5-tetrahydropyran-3-yl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole - Intermediate C-46 (250 mg, 606.31μmol), K3PO4(386.10 mg, 1.82 mmol), XPhos (57.81 mg, 121.26 μmol), XPhos Pd G4 (52.17 5 mg, 60.63 μmol) and 1,4-dioxane (15 mL). The mixture was degassed with N2and stirred for 30 min at 140°C under microwave irradiation. The reaction medium was diluted with EtOAc and saturated aqueous solution of NaHCO, and was extracted with EtOAc (x 3). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by SFC (Isoc.55% 2 isopropyl alcohol + 0.11% DEA) to afford 10 two fractions F1 and F2 representing the different THP diastereoisomers. Each of these diastereoisomers was then separated into enantiomers by SFC using for F1 (Isoc.45% EtOH + 0.11% DEA) and for F2 (Isoc. 25% 2 MeOH + 11% DEA) to afford four enantiomers of unknown absolute configuration: Diastereomer 1: tert-butyl 4-[[3-(1-tetrahydropyran-2-yl-5-tetrahydropyran-3-yl-indazol-3-yl)- 15 1-isoquinolyl]oxy]piperidine-1-carboxylate (20 mg, 32.31 μmol, 5% yield, 99% purity) as a colorless oil. LCMS (Method 2) m / z: 613.3 [M+H]+, Purity (254 nm): 99%, rt.: 5.99 min. SFC (Method 9): rt.: 7.133 min. %ee=99% Diastereomer 2: tert-butyl 4-[[3-(1-tetrahydropyran-2-yl-5-tetrahydropyran-3-yl-indazol-3-yl)- 20 1-isoquinolyl]oxy]piperidine-1-carboxylate (23 mg, 37.16 μmol, 6% yield, 99% purity) as a colorless oil. LCMS (Method 2) m / z: 613.3 [M+H]+, Purity (254 nm): 99%, rt.: 5.99 min. SFC (Method 9): rt: 7.687 min. %ee=99% Diastereomer 3: tert-butyl 4-[[3-(1-tetrahydropyran-2-yl-5-tetrahydropyran-3-yl-indazol-3-yl)- 25 1-isoquinolyl]oxy]piperidine-1-carboxylate (20 mg, 31.01 μmol, 5% yield, 95% purity) as a colorless oil. LCMS (Method 2) m / z: 613.3 [M+H]+, Purity (254 nm): 95%, rt.: 5.95 min. SFC (Method 10): rt: 5.337 min. %ee=99% Diastereomer 4: tert-butyl 4-[[3-(1-tetrahydropyran-2-yl-5-tetrahydropyran-3-yl-indazol-3-yl)- 30 1-isoquinolyl]oxy]piperidine-1-carboxylate (17 mg, 27.47 μmol, 5% yield, 99% purity) as a colorless oil. LCMS (Method 2) m / z: 613.3 [M+H]+, Purity (254 nm): 99%, rt.: 5.96 min. SFC (Method 10): rt: 5.540 min. %ee=99% 111

[0108] Synthesis of Intermediate D-125: In a round bottom flask, tert-butyl 4-hydroxy-3,3-dimethyl-piperidine-1-carboxylate (93.29 mg, 406.83 μmol) was dissolved in THF (2 mL). Then, NaH (60% dispersion in mineral oil, 12.20 mg, 305.13 μmol) was added at 0 °C. After 15 min at 0 °C, 1-methylsulfonyl-3-(1- 5 tetrahydropyran-2-yl-5-tetrahydropyran-3-yl-indazol-3-yl)isoquinoline (100 mg, 203.42 μmol) - Intermediate D-116 was added. The mixture was allowed to reach a temperature close to RTand was stirred for 16 h at this temperature. The reaction medium was quenched with water, diluted with EtOAc and extracted with EtOAc (x 3). The organic layers were combined, dried over MgSO4,and concentrated under reduced pressure. The crude material was further 10 purified by flash column chromatography on silica gel in heptane / EtOAc (100:0 to 80:20) to afford tert-butyl 3,3-dimethyl-4-[[3-(1-tetrahydropyran-2-yl-5-tetrahydropyran-3-yl-indazol-3- yl)-1-isoquinolyl]oxy]piperidine-1-carboxylate (40 mg, 61.80 μmol, 30% yield) as a colorless oil. LCMS (Method 3) m / z: 641.4 [M+H]+, Purity (254 nm): 99.75%, rt.: 6.25 min. 15 The following intermediates were prepared via an analogous procedure: 112

[0109] 113

[0110] 114

[0111] Synthesis of Intermediate D-140: A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (300 mg, 1.43 mmol), TEA (217.78 mg, 2.15 mmol, 299.97 μL), acetic anhydride (219.71 mg, 2.15 mmol, 203.06 μL) in THF (20 mL) was stirred at 25°C for 16 h under N2atmosphere. The 5 reaction medium was diluted with EtOAc and water and extracted with EtOAc (x 3). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1- 115

[0112] yl]ethanone (356 mg, crude) as a white solid. The crude was used as such in the next step. LCMS (Method 4) m / z: 252.2 [M+H]+; No UV absorption; rt: 0.796 min Synthesis of Intermediate D-141: A solution of tert-butyl N-[(3S)-1-[3-(5-benzyloxy-1-tetrahydropyran-2-yl-indazol-3-yl)-1- 5isoquinolyl]azepan-3-yl]carbamate - Intermediate D-112 (502 mg, 774.93 μmol) in methanol(10 mL) was placed under N2 atmosphere through 10 vacuum-N2 cycles. Then, 10% Pd / C (82.47 mg, 77.49 μmol) was added, and the inert atmosphere was replaced by H2 gas through 10 vacuum-H2 cycles. The mixture was stirred at RT for 24 h. The reaction medium was filtered through a short pad of Celite® and the filtrate was evaporated under reduced pressure. The 10 crude material was purified by flash column chromatography on silica gel using a gradient of heptane / EtOAc (100:0 to 50:50) to afford tert-butyl N-[(3S)-1-[3-(5-hydroxy-1-tetrahydropyran- 2-yl-indazol-3-yl)-1-isoquinolyl]azepan-3-yl]carbamate (292 mg, 455.53 μmol, 59% yield) as a white solid. LCMS (Method 4) m / z: 558.4 [M+H]+, Purity (254 nm): 87%, rt.: 1.38 min. Synthesis of Intermediate D-142:15 Intermediate D-142 was prepared according to the procedure described for intermediate D-141 starting from tert-butyl 4-[[3-(5-benzyloxy-1-tetrahydropyran-2-yl-indazol-3-yl)-1-isoquinolyl]oxy]piperidine-1-carboxylate - Intermediate D-114 to afford tert-butyl 4-[[3-(5-hydroxy-1-tetrahydropyran-2-yl-indazol-3-yl)-1-isoquinolyl]oxy]piperidine-1-carboxylate (1.1 g, 1.85 mmol, 36% yield) as a white solid. LCMS (Method 4) m / z: 545.2 [M+H]+, Purity (254 nm):20 91.5 %, rt.: 1.544 min. 116

[0113] Synthesis of Intermediate D-143: To a solution of tert-butyl N-[(3S)-1-[3-(5-hydroxy-1-tetrahydropyran-2-yl-indazol-3-yl)-1- isoquinolyl]azepan-3-yl]carbamate - Intermediate D-141 (234 mg, 419.59 μmol) and N-Phenyl-bis(trifluoromethanesulfonimide) (179.88 mg, 503.51 μmol) in DCM (6 mL) was added TEA 5 (63.69 mg, 629.39 μmol, 87.72 μL). The mixture was stirred at RT for 16 h and then concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel using a gradient of heptane / EtOAc (100:0 to 90:10) to afford [3- [1-[(3S)-3-(tert-butoxycarbonylamino)azepan-1-yl]-3-isoquinolyl]-1-tetrahydropyran-2-yl- indazol-5-yl] trifluoromethanesulfonate (268 mg, 365.24 μmol, 87% yield) as a light-yellow10 solid. LCMS (Method 4) m / z: 690.3 [M+H]+, Purity (254 nm): 94%, rt.: 1.77 min. Synthesis of Intermediate D-144: Intermediate D-144 was prepared according to the procedure described for intermediate D-143 starting from tert-butyl 4-[[3-(5-hydroxy-1-tetrahydropyran-2-yl-indazol-3-yl)-1-isoquinolyl]oxy]piperidine-1-carboxylate (900 mg, 1.65 mmol) - Intermediate D-142 to afford15 tert-butyl 4-[[3-[1-tetrahydropyran-2-yl-5-(trifluoromethylsulfonyloxy)indazol-3-yl]-1- isoquinolyl]oxy]piperidine-1-carboxylate (1.06 g, 1.55 mmol, 94% yield) as a white solid. LCMS (Method 4) m / z: 677.4 [M+H]+, Purity (254 nm): 99 %, rt: 1.84 min. Synthesis of Intermediate D-145: 117

[0114] In a sealed tube, [3-[1-[(3S)-3-(tert-butoxycarbonylamino)azepan-1-yl]-3-isoquinolyl]-1- tetrahydropyran-2-yl-indazol-5-yl]-trifluoromethanesulfonate - Intermediate D-143 (120 mg,173.98 μmol), (4S)-4-methyloxazolidin-2-one (17.59 mg, 173.98 μmol), BrettPhos Pd G4 (15.77 mg, 17.11 μmol) and potassium tert-butoxide (58.57 mg, 521.93 μmol) were dissolved 5 in 1,4-dioxane (2.40 mL). The mixture was bubbled with N2for 2 min and stirred at 100 °C for 3 h. The reaction medium was diluted with EtOAc and water and extracted with EtOAc (x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica, heptane / EtOAc from 100:0 to 80:20). The desired fractions were collected, and the solvents10 evaporated under reduced pressure, to afford tert-butyl N-[(3S)-1-[3-[5-[(4S)-4-methyl-2-oxo- oxazolidin-3-yl]-1-tetrahydropyran-2-yl-indazol-3-yl]-1- Isoquinolyl]azepan-3-yl]carbamate (19 mg, 27.58 μmol, 16% yield) as a yellow gum. LCMS (Method 5) m / z: 641.2 [M+H]+, Purity (254 nm): 93%, rt.: 3.5min. 15 The following intermediates were synthesized via an analogous protocol: 118

[0115] Synthesis of Intermediate D-153: 119

[0116] To a solution of tert-butyl 4-[[3-[5-(3,6-dihydro-2H-thiopyran-5-yl)-1-tetrahydropyran-2-yl- indazol-3-yl]-1-isoquinolyl]oxy]piperidine-1-carboxylate - Intermediate D-151 (35 mg, 55.84μmol) in DCM (1 mL) was added m-chloroperoxybenzoic acid (77%, 24.09 mg, 139.60 μmol) and the mixture was stirred at a temperature close to RT for 1 h. The reaction medium was 5 diluted with EtOAc (5 mL), washed with saturated aqueous NaHCO3solution (3x 5 mL), dried with MgSO4, filtered and concentrated reduced pressure. The crude product was purified by flash column chromatography using heptane / EtOAc (100:0 to 80:20) to afford tert-butyl 4-[[3- [5-(1,1-dioxo-3,6-dihydro-2H-thiopyran-5-yl)-1-tetrahydropyran-2-yl-indazol-3-yl]-1- isoquinolyl]oxy]piperidine-1-carboxylate (15 mg, 20.72 μmol, 37% yield) as a white solid. 10 LCMS (Method 4) m / z: 559.232 [M-Boc+H]+, Purity (254 nm): 91%, rt.: 5.39 min. Synthesis of Intermediate D-154: Intermediate D-154 was prepared according to the procedure described for intermediate C-8starting from tert-butyl 4-[[3-[5-(3,6-dihydro-2H-pyran-4-yl)-1-tetrahydropyran-2-yl-indazol-3-15 yl]-1-isoquinolyl]oxy]piperidine-1-carboxylate - Intermediate D-148 (90 mg, 147.36 μmol) affordtert-butyl 4-[[3-(1-tetrahydropyran-2-yl-5-tetrahydropyran-4-yl-indazol-3-yl)-1- isoquinolyl]oxy]piperidine-1-carboxylate (72 mg, 109.28 μmol, 74% yield) as an off-white solid. LCMS (Method 4) m / z: 613.3 [M+H]+, Purity (254 nm): 93%, rt.: 5.22 min. The following intermediates were synthesized via an analogous protocol: 120

[0117] Synthesis of Intermediate D-159: A solution of tert-butyl 4-[[3-[1-tetrahydropyran-2-yl-5-(trifluoromethylsulfonyloxy)indazol-3-yl]- 1-isoquinolyl]oxy]piperidine-1-carboxylate - Intermediate D-144 (51 mg, 75.37 μmol), piperidin-3-ol (9.15 mg, 90.44 μmol), RuPhos (14.07 mg, 30.15 μmol) and Pd(dba)2 (13.80 mg, 15.07 5 μmol) in 1,4-dioxane (901.45 μL) was degassed with N2 for 5 min. Then, 1 N lithium bis(trimethylsilyl)azanide solution in THF (452.19 μL, 452.19 μmol) was added and the mixture was stirred for 16 h at 120 °C. A saturated aqueous NaHCO3 solution (5 mL) was added, and the mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried with MgSO4, 10 filtered, and concentrated under reduced pressure. The crude material was purified by flash 121

[0118] column chromatography using heptane / EtOAc (1:1). The desired fractions were collected and concentrated under reduced pressure to afford tert-butyl 4-[[3-[5-(3-hydroxy-1-piperidyl)-1- tetrahydropyran-2-yl-indazol-3-yl]-1-isoquinolyl]oxy]piperidine-1-carboxylate (31 mg, 49.38 μmol, 66% yield) as an orange solid. LCMS (Method 3) m / z: 628.4 [M+H]+, Purity (254 nm): 5 99 %, rt: 5.192 min. Synthesis of Intermediate D-160: Intermediate D-160 was prepared according to the procedure described for intermediate D-159 starting from 4-[[3-[1-tetrahydropyran-2-yl-5-(trifluoromethylsulfonyloxy)indazol-3-yl]-1-isoquinolyl]oxy]piperidine-1-carboxylate - Intermediate D-144 (100 mg, 147.78 μmol) and10 piperazin-2-one (17.75 mg, 177.33 μmol) to afford tert-butyl 4-[[3-[5-(3-oxopiperazin-1-yl)-1- tetrahydropyran-2-yl-indazol-3-yl]-1-isoquinolyl]oxy]piperidine-1-carboxylate (60 mg, 93.82 μmol, 63% yield) as a yellow solid. LCMS (Method 3) m / z: 627.3 [M+H]+, Purity (254 nm): 98%, rt: 5.189 min. Synthesis of Intermediate D-161: 15 A solution of tert-butyl 4-[[3-[1-tetrahydropyran-2-yl-5-(trifluoromethylsulfonyloxy)indazol-3-yl]- 1-isoquinolyl]oxy]piperidine-1-carboxylate - Intermediate D-144 (500 mg, 738.88 μmol) and3,4,7,8-tetramethyl-1,10-phenanthroline (87.30 mg, 369.44 μmol) in 1,4-dioxane (7 mL) was degassed for 3 min by bubbling N2 and 3.0 M ethylmagnesium bromide solution in diethyl ether (2.22 mmol, 738.88 μL) was added. The mixture was stirred at 120 °C for 72 h. Then, the 20 reaction medium was diluted with EtOAc (2x 10 mL) and washed with water (3x 10 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel using heptane / EtOAc (3:1) to afford tert-butyl 4-[[3-(5-bromo-1-tetrahydropyran-2-yl-indazol-3-yl)-1- isoquinolyl]oxy]piperidine-1-carboxylate (197 mg, 230.22 μmol, 31% yield) as a colorless oil. 25 LCMS (Method 4) m / z: 607.1 [M+H]+, Purity (254 nm): 71 %, rt: 1.880 min. 122

[0119] Synthesis of Intermediate D-162: A mixture of tert-butyl 4-[[3-(5-bromo-1-tetrahydropyran-2-yl-indazol-3-yl)-1- isoquinolyl]oxy]piperidine-1-carboxylate - Intermediate D-161 (55 mg, 90.53 μmol), thiazinane1,1-dioxide (18.36 mg, 135.79 μmol), di-tert-butyl-[2-(2,4,6- 5 triisopropylphenyl)phenyl]phosphane methanesulfonic acid palladium 2- phenylaniline (14.40 mg, 18.11 μmol), di-tert-butyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane (15.38 mg, 36.21 μmol), potassium tert-butoxide (30.48 mg, 271.59 μmol) and 1,4-dioxane (2.5 mL) was degassed by bubbling N2 for 5 min and then stirred for 2 h at 120 °C. The reaction medium was diluted with EtOAc and saturated aqueous 10 NaHCO3 solution, and extracted with EtOAc (x 3). The combined organic layers were dried MgSO4, filtered and concentrated under reduced pressure. The crude material was further purified by flash column chromatography on silica gel using a gradient of heptane / EtOAc (100:0 to 60:40) to afford tert-butyl 4-({3-[5-(1,1-dioxo-1lambda6,2- thiazinan-2-yl)-1-(oxan-2-yl)-1H-indazol-3-yl]isoquinolin-1-yl}oxy)piperidine-1-carboxylate 15 (42 mg, 62.83 μmol, 69% yield) as a colorless oil. LCMS (Method 3) m / z: 662.4 [M+H]+, Purity (254 nm): 99 %, rt: 5.52 min. Synthesis of Intermediate D-163: A solution of 3-methylazetidine-3-carboxylic acid (500 mg, 4.34 mmol), TEA (659.19 mg, 6.51 mmol, 907.97 μL), acetic anhydride (615 μL, 6.51 mmol) in THF (20 mL) was stirred at 25°C 20 for 16 h. The reaction medium was concentrated under reduced pressure and co-evaporated under reduced pressure with heptane (x 3) to afford 1-acetyl-3-methyl-azetidine-3-carboxylate, triethylammonium (1.3 g) as a yellow oil, which was used without further purification in the next step. LCMS (Method 4) m / z: 158.1 [M+H]+; Purity (254 nm): No UV absorption; rt: 0.178 min 123

[0120] Synthesis of Intermediate D-164: To a solution of 1-acetyl-3-methyl-azetidine-3-carboxylate;triethylammonium (682 mg, 4.34 mmol) in DCM (40 mL) were added N-hydroxyphthalimide (778.67 mg, 4.77 mmol), DMAP (53.01 mg, 433.93 μmol) and then, N,N'-diisopropylcarbodiimide (602.38 mg, 4.77 mmol,5 743.68 μL). The mixture was stirred 16 h at RT. The reaction medium was diluted with water, and extracted with EtOAc (3x 10 mL). The resultant combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using heptane / EtOAc (from 100:0 to 80:20) to afford (1,3-dioxoisoindolin-2-yl)1-acetyl-3-methyl-azetidine-3-carboxylate (90 mg, 238.19 μmol, 5% yield)10 as a white solid. LCMS (Method 4) m / z: 303.2 [M+H]+, Purity (254 nm): 80%, r.t.: 0.682 min. Synthesis of Intermediate D-165: A solution of (1,3-dioxoisoindolin-2-yl) 1-acetyl-3-methyl-azetidine-3-carboxylate - Intermediate D-164 (20 mg, 66.16 μmol) and tert-butyl 4-[[3-(5-bromo-1-tetrahydropyran-2-yl-indazol-3-yl)-1-isoquinolyl]oxy]piperidine-1-carboxylate - Intermediate D-161 (63.17 mg, 72.7815 μmol) in DMA (3 mL) under N2was stirred for 10 min at RT. On the other hand, nickel(II) chloride hexahydrate (6.60 mg, 27.77 μmol) and BBBPY (7.46 mg, 27.79 μmol) were dissolved in DMA (1.5 mL) under N2and the mixture was stirred for 10 min at RT. Then, the first solution was added dropwise to the latter one. After bubbling N2for 5 min into the mixture, Zn (8.65 mg, 132.33 μmol) was added, and the reaction medium was stirred at RT for 16 h. The mixture 20 was filtered through a Celite® pad, the cake was washed with EtOAc (20 mL), and the filtrate was evaporated under reduced pressure. The crude material was purified by flash column chromatography on silica gel using heptane / AcOEt (50:50 to 10:90) and then DCM / MeOH (90:10) to afford tert-butyl 4-[[3-[5-(1-acetyl-3-methyl-azetidin-3-yl)-1-tetrahydropyran-2-yl- indazol-3-yl]-1-isoquinolyl]oxy]piperidine-1-carboxylate (2 mg, 2.98 μmol, 5% yield) as a white25 solid. LCMS (Metod 3) m / z: 640.377 [M+H]+; Purity (254 nm): 95.31%; rt: 5.47 min. 124

[0121] Synthesis of final compounds:Synthesis of Compound 9: from A mixture of tert-butyl N-[(3S)-1-[3-(1-tetrahydropyran-2-yl-5-tetrahydropyran-3-yl- indazol-3-yl)-1-isoquinolyl]-3-piperidyl]carbamate - Intermediate D-1 (15 mg, 24.52 μmol) in 45 N HCl in 1,4-dioxane (1 mL) was stirred at RT for 16 h. After addition of MeOH, the reaction medium was concentrated under reduced pressure and the residue was co-evaporated under reduced pressure with MeOH (x2) and water (x 2) to afford (3S)-1-[3-(5-tetrahydropyran-3-yl- 1H-indazol-3-yl)-1-isoquinolyl]piperidin-3-amine, dihydrochloride (5.9 mg, 11.67 μmol, 48% yield) as a yellow solid. LCMS (Method 2): m / z: 428.2 [M+H]+, Purity (254nm): 99 %, rt.: 2.5710 min The following final compounds were prepared via an analogous procedure: 125

[0122] 126

[0123] 127

[0124] 128

[0125] 129

[0126] 130

[0127] 131

[0128] 132

[0129] 133

[0130] 134

[0131] Synthesis of Compound 94: A mixture of tert-butyl N-[(3S)-1-[3-[5-(1-cyano-1-methyl-ethyl)-1-tetrahydropyran-2-yl-indazol- 3-yl]-7-morpholino-1-isoquinolyl]-3-piperidyl]carbamate – Intermediate D-4 (65 mg, 95.61μmol) and 4 N HCl solution in 1,4-dioxane (2 mL) was stirred for 6h at RT. The reaction medium 5 was concentrated under a stream of N2,and the residue was solubilized in chloroform / isopropanol (3:1) (2 mL). The solution was washed with aqueous NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using dichloromethane / 7 N NH3 in MeOH (100:0:0 to 90:10) to afford 10 2-[3-[1-[(3S)-3-amino-1-piperidyl]-7-morpholino-3-isoquinolyl]-1H-indazol-5-yl]-2-methyl- propanenitrile (10.6 mg, 20.32 μmol, 21% yield) as a white solid. LCMS (Method 3): m / z: 495.3 [M+H]+, Purity (254nm): 95 %, rt.: 2.74min. The following final compounds were prepared via an analogous procedure: 135

[0132] 136

[0133] 137

[0134] Synthesis of Compound 24: To a solution of tert-butyl 8-[3-(1-tetrahydropyran-2-yl-5-tetrahydropyran-3-yl-indazol-3-yl)-1- isoquinolyl]-2,8- diazaspiro[3.5]nonane-2-carboxylate – Intermediate D-33 (20 mg, 31.365 μmol) in DCM (1 mL) was added TFA (10.25 mmol, 789.31 μL). The mixture was stirred at RT for 72 h. The resultant solution was concentrated under reduced pressure and the residue was co-evaporated under reduced pressure with Milli-Q® water and dried under high vacuum to 138

[0135] provide 1-(2,6-diazaspiro[3.5]nonan-6-yl)-3-(5-tetrahydropyran-3-yl-1H-indazol-3-yl)isoquinoline, 2,2,2-trifluoroacetic acid (10 mg, 14.23 μmol, 45% yield) as a yellow oil. LCMS (Method 2) m / z: 454.2 [M+H]+, Purity (254 nm): 97%, rt.: 2.65 min. The following final compounds were prepared via an analogous procedure: 139

[0136] A solution of tert-butyl N-[(3S,5R)-5-hydroxy-1-[6-hydroxy-3-(1-tetrahydropyran-2-yl-5- tetrahydropyran-3-yl-indazol-3-yl)-1-isoquinolyl]-3-piperidyl]carbamate – Intermediate D-10(70 mg, 108.73 μmol) in DCM / TFA (1:1) (6 mL) was stirred at RT for 16 h. The reaction medium 5 was concentrated under a stream of N2. The residue was diluted with CHCl3 / iPrOH (3:1) and saturated aqueous solution of NaHCO3. The mixture was extracted with CHCl3 / iPrOH (3:1) and the combined organic layers were dried over MgSO4, filtered and the concentrated under reduced pressure. The crude product was triturated with DCM / MeOH (9:1) (x1) and MeCN (x 3). The solid was dried under reduced pressure and finally it was lyophilized to afford 1-10 [(3S,5R)-3-amino-5-hydroxy-1-piperidyl]-3-(5-tetrahydropyran-3-yl-1H-indazol-3- yl)isoquinolin-6-ol (13.8 mg, 28.83 μmol, 27% yield) as a beige solid. LCMS (Method 3): m / z: 460.2 [M+H]+, Purity (254 nm): 96%, rt.: 2.27 min. The following final compounds were prepared via an analogous procedure 140

[0137] 141

[0138] 142

[0139] 143

[0140] 144

[0141] 145

[0142] 146

[0143] 147

[0144] 148

[0145] 149

[0146] 150

[0147] Table: Retention time (Rt) in min., [M+H]+peak (protonated molecule), LC / MS method and1H NMR ),),0th-16 151

[0148] -36- 8-83in),1m,-),),),7),(t,3ind,1 ),br 152

[0149] d, 7 br ). d,), z,96m,1 ),),in0,),),-),ez,3m,),2 153

[0150] ), ),35m),),),m,2s,), z, -24),3),92 0 72), 0 154

[0151] 163),-0793),s,m,m,-mz,53),z,5 377),8 9155

[0152] 59126 ),17-92d, br- 1in-707t.-707t.48 7156

[0153] 24in),d,),1.m,m,),),-7 6),ins, 251),7),).),0 0157

[0154] 97th624m,d, ), 42d,3),6128re), 111n), 2 - 158

[0155] ),),d, 67eC. ),-1s,1(t,),),).),662),),3-76 ),159

[0156] 13d,-),1m,811 2ly8 5 d, 15),5d, ),-961 7),ns 160

[0157] 09d,1 m,),),),52 d, s, ),13 ),92),m,061 1 ),),), 161

[0158] ),),-5d, 1-5m,d,z,m,).at 1 1m,3a51 70m),4 3162

[0159] 6d,37 2911 ),0 11br-), 1),s,d, m,m,-1 1m,m,m, 163

[0160] ), d,7 ),),).5z, z, m,9),148th- 1z,1,m),d,1-7),), ),164

[0161] 10d, 20z,63m,8m,m,-),),),),),brd,),),),), ),165

[0162] ),),).16 8),31-1),3).-83m,m,),2 br),m,m8 ), d,166

[0163] ),3e 2 z, 2 ),37),),),52), 3 m,0 m,al. 8040), 34 0167

[0164] 5,22912d,386e), 1),697z,m,m,ns1 m,d,- 1168

[0165] 3s,), ), 631),z,),d, ),br4th-458),),),1), 4 169

[0166] 34m,d, ), 5),).m,),5),),32m,-6-7-42 m,),), al.170

[0167] -4487d,),4),d,331z,m,m,31m,m,e5892 171

[0168] m,1m,2), z,81m,in),),),).),6 84d,1), d,),),2), ),172

[0169] ),22238t.), z,2m,e),),-2), 7 -m,m,91 1 d,), 173

[0170] ),-010z, 7 8),0re 9),m,),H)d, ),07-5),13d,),), m,174

[0171] hez, ),-3),),),d,),8 8),m,),),),),inm,1d,ns),), ),175

[0172] ),in1m,m,m,), z, 1 d,),0 3s,m, 176

[0173] II – Biological AssaysHPK1 Enzymatic Assay HPK1(h) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.33 mg / mL myelin basic protein, 10 mM Magnesium acetate and [γ-33P]-ATP (specific activity and concentration as 5 required). The reaction is initiated by the addition of the Mg / ATP mix. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of phosphoric acid to a concentration of 0.5%. An aliquot of the reaction is then spotted onto a filter and washed four times for 4 minutes in 0.425% phosphoric acid and once in ethanol prior to drying and scintillation counting. 10 Phosphorylation Assay In the cellular HPK1 phosphorylation assay the human T cell leukemia cell line Jurkat is used, which expresses the T-cell receptor complex including co-receptor CD3 and co-stimulatory receptor CD28. Stimulation of these cells with a CD3 / CD28 antibody complex results in activation of T-cell receptor signaling. This leads to HPK1 activation and phosphorylation of its15 target SLP76 at Ser376. Jurkat cells were plated in RPMI supplemented with 0.5% FBS in multiwell cell culture plates. After serum-starvation overnight cells were incubated with compounds (4 h at 37°C) in presence of 0.5 % FBS. For stimulation, cells were treated with 1:40 CD3 / CD28 antibody complex for 30 min at 37°C. After cell lysis quantification of SLP76 phosphorylation was 20 assessed in 96-well plates via sandwich-ELISA using a SLP76 specific capture antibody and an anti-phospho SLP76 (Ser376) detection antibody. Raw data were converted into percent substrate phosphorylation relative to solvent control (high control), which was set to 100%. The basal level (0%) was defined by the phosphorylation level of cells treated with the low control. The values for high and low control were calculated 25 by the median value of the corresponding 8 single data points. IC50 values were determined using GraphPad Prism software with constraints of bottom to 0 and top to 100 using a nonlinear regression curve fit with variable hill slope. Cytokine measurement Jurkat cells were plated in RPMI supplemented with 0.5% FBS in multiwell cell culture plates. 30 After serum-starvation overnight cells were incubated with compounds (4 h at 37°C) in presence of 0.5 % FBS. Cells treated with 1,0E-05 M Staurosporine served as low control for the cell viability assay. For stimulation, cells were then treated with 1:40 CD3 / CD28 antibody complex for 24 hours at 37°C in the presence of 10% FBS in the culture medium. Subsequently, the cell culture supernatants were collected and analyzed in the Il-2 secretion 35 assay using the Mesoscale V-PLEX Human IL-2 Kit. The IL-2 assay was performed using 1:5 diluted cell culture supernatants. An IL-2 calibrator solution provided with the kit was measured in a 1:2 dilution on each assay plate. 177

[0174] 0.003 0. 3 -178

[0175] 42 2 4 85 0.0008 - -179

[0176] 9 0.0 - -180

[0177] 1 1 - : not measured.181

Claims

CLAIMS 1. A compound of general formula (I):(I) 5 or a salt, solvate and / or N-oxide thereof, wherein oV1 and V2 are independently N or CH,o Y1 is N or C-R1o Y2 is N or C-R2o Y3 is N or C-R310 o Y4 is N or C-R4o Y5 is N or C-R5provided that no more than two of Y1to Y5are N, oR1, R2, R3, and R4 are each independently hydrogen, hydroxy, halo, cyano, NRaRb, S-(C1-6alkyl), S(O)-(C1-6alkyl), S(O)2-(C1-6alkyl), S(=O)(=NRb)Rc, P(=O)RdRe, C(=O)-15 (C1-6alkyl), C(=O)O-(C1-6alkyl), NRb-C(=O)-Rf, O-C(=O)-Rf, C(=O)NRhR,C1-6alkyl, C1-6 alkoxy, C3-6 cycloalkyl, or 3- to 6-membered heterocyclyl,each of said C1-6 alkyl,1-6 alkoxy, C3-6 cycloalkyl, or 3- to 6-membered heterocyclylbeing optionally substituted by one or more substituents selected from cyano, hydroxy, halo, C1-4 alkoxy, C1-4 alkyl, 3- to 6-membered heterocyclyl, C3-6 cycloalkyl,20 and O-(C3-6 cycloalkyl); oR5 is hydrogen, halo or cyano;o R6 is C1-6 alkyl, C1-6 alkoxy, NRg-(C1-6 alkyl), C3-8 cycloalkyl, 3- to 10-memberedheterocyclyl, O-(C3-8 cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-8cycloalkyl), or NRg-(3- to 10-membered heterocyclyl),25 each of saidC1-6 alkyl, C1-6 alkoxy, NRg-(C1-6 alkyl), C3-8 cycloalkyl, 3- to 10-memberedheterocyclyl, O-(C3-8 cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-8cycloalkyl), or NRg-(3- to 10-membered heterocyclyl) being optionally substituted byone or more substituents selected from hydroxy, halo, cyano, N=OH, NRaRb, C(=O)-(C1-6 alkyl), C(=O)O-(C1-6 alkyl), C(=O)NRhRi, SO2-(C1-6 alkyl), C1-4 alkoxy, C1-4 alkyl,30 C1-4 hydroxyalkyl, C1-4 aminoalkyl, C3-6 cycloalkyl, and 3- to 6-membered heterocyclyl,said C3-6 cycloalkyl or 3- to 6-membered heterocyclyl being optionally substituted byone or more C1-4 alkyl; 182o R7 is hydrogen, halo, cyano, C1-6 alkyl, C3-8 cycloalkyl or 3- to 10-memberedheterocyclyl, each of said C1-6 alkyl, C3-8 cycloalkyl, or 3- to 10-membered heterocyclyl beingoptionally substituted by one or more substituents selected from hydroxy, halo, cyano, 5 oxo, S(O)-(C1-6alkyl), S(O)2-(C1-6alkyl), C(=O)-(C1-6alkyl), C(=O)O-(C1-6alkyl), NRaRb, C(=O)NRhRi, C1-4 alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 aminoalkyl, C3-6cycloalkyl, and 3- to 6-membered heterocyclyl, said C3-6 cycloalkyl or 3- to 6-membered heterocyclyl being optionally substituted by one or more C1-4 alkyl;o Ra, Rb, Rc, Rd, Re, Rf, Rg, Rh and Ri are each independently a hydrogen or C1-6 alkyl10 optionally substituted by one or more substituents selected from hydroxy, halo, C1-4alkoxy, C1-4 alkyl, C3-6 cycloalkyl.

2. The compound of claim 1, wherein at most one of V1 and V2 is N.15 3. The compound of claim 1 or 2, wherein Y1 is C-R1 and Y4 is C-R4.

4. The compound of any of claims 1 to 3, wherein R1, R2, R3 and R4 are each independently ,or20 , wherein the wavy line indicates the point of attachment to the rest of the molecule.

5. The compound of any of claims 1 to 3, wherein R1 and R4 are each independently hydrogen, halo or C1-6 alkyl, said C1-6 alkyl being optionally substituted by one or more substituents 25 selected from cyano, hydroxy, halo, C1-4alkoxy, C3-6cycloalkyl and O-(C3-6cycloalkyl), preferably R1and R4are each independently hydrogen, halo or C1-6alkyl. 1836. The compound of any of claims 1 to 5, wherein R6 is C1-4 alkyl, C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, O-(C3-8 cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-8cycloalkyl), or NRg-(3- to 10-membered heterocyclyl),each of said C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, 3- to 10-membered heterocyclyl, O-(C3-85 cycloalkyl), O-(3- to 10-membered heterocyclyl), NRg-(C3-8 cycloalkyl), or NRg-(3- to 10-membered heterocyclyl) being optionally substituted by one or more substituents selected from hydroxy, halo, NRaRb, C(=O)NRhRi, C1-4 alkoxy, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 aminoalkyland 3- to 6-membered heterocyclyl, said 3- to 6-membered heterocyclyl being optionallysubstituted by one or more C1-4alkyl. 10 H27. The compound of any of claims 1 to 5, wherein R6is -CH2NH2, , , , H , H215, , , , , or 184,wherein the wavy line indicates the point of attachment to the rest of the molecule. 5 8. The compound of any of claims 1 to 7, wherein R7 is hydrogen, cyano, C1-6 alkyl, C3-8 cycloalkyl, or 3- to 10-membered heterocyclyl,each of said C1-6 alkyl, C3-8 cycloalkyl, or 3- to 10-membered heterocyclyl being optionallysubstituted by one or more substituents selected from hydroxy, halo, cyano, oxo, S(O)2-(C1-6 alkyl), C(=O)(C1-6alkyl), NRaRb, C1-4alkoxy, C1-4alkyl, C1-4hydroxyalkyl, C1-4aminoalkyl, C3-610 cycloalkyl, and 3- to 6-membered heterocyclyl, said C3-6 cycloalkyl or 3- to 6-memberedheterocyclyl being optionally substituted by one or more C1-4alkyl, ,,15 ,or , wherein the wavy line indicates the point of attachment to the rest of the molecule. 1859. The compound of any of claims 1 to 8, wherein Rb, Rc, Rd, Re, Rf, Rg, Rhand Riare each independently a hydrogen or C1-4alkyl.

10. The compound of any one of claims 1 to 9, wherein the compound of formula (I) is selected from the group consisting of:5, , , 186, ,, and salts, solvates and / or N-oxides thereof.

11. A pharmaceutical composition comprising a compound of formula (I) as defined in any one 5 of claims 1 to 10, and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition of claim 11, further comprising another anticancer agent.

13. A compound of any one of claims 1 to 10 or a composition of claim 11 or 12, for use as a10 drug, in particular with an MAP4K1 inhibiting activity.

14. A compound of any one of claims 1 to 10 or a composition of claim 11 or 12, for use in the treatment or prevention of a cancer, or neoplastic diseases such as benign papillomatosis, gestational trophoblastic diseases including hydatidiform moles and gestational trophoblastic 15 neoplasia (e.g., invasive moles, choriocarcinomas), skin papilloma (warts) and genital papilloma.

15. The compound or composition for use of claims 13 or 14, in a combination therapy with radiotherapy, or with immuno-stimulating agents such as vaccines. 20 16. A method for preparing a compound of formula (I) as defined in any of claims 1 to 10, comprising the following successive steps: 198a) Subjecting a compound of the following formula (II):II) ith V V1, Y5 and R7 as defined in any of claims 1 to 10, and PGn represents a N-5 protecting group, to a borylation with a boronic of formula (III),II) with RB1, RB2each independently being-6alkyl, or RB1and RB2together form a hydrocarbon divalent chain linking together the two oxygens borne by a same boron (in10 order to form a cycle with the two oxygens and the boron), to obtain a boronic ester of formula (C):C) with V2, V1, Y5, R7, as defined in any of claims 1 to 10, and with RB1, RB2 and PGn asdefined above,15 b) Subjecting the boronic ester of formula (C) to a Suzuki coupling with the compound offormula (B):(B), with Y1, Y2, Y3, Y4and R6as defined in any of claims 1 to 10, and X representing a leaving group such as halo or O-S(O)2-( C1-6 alkyl) or O-S(O)2-( C1-6 haloalkyl),20 preferably a chloro, bromo, iodo, mesylate or triflate, to obtain an intermediate of formula (D) 199D)with V2, V1, Y1, Y2, Y3, Y4Y5, R6, R7as defined above in any of claims 1 to 10, and PGn as defined above,c) Subjecting the compound of formula (D) to a nitrogen deprotection reaction, to obtain5 the compound of formula (I) as defined in any of claims 1 to 10. 200

Images