Heterobifunctional compounds for the degradation of HPK1

Abstract

Heterobifunctional compounds of the formula 1 are provided that are potent degraders or inhibitors of hematopoietic progenitor kinase 1 (HPK1). The compounds are useful to treat or prevent cancer and / or inflammatory and / or autoimmune diseases or symptoms thereof in mammals, particularly humans.

Description

TITLE OF THE INVENTIONHETEROBIFUNCTIONAL COMPOUNDS FOR THE DEGRADATION OF HPK1BACKGROUND OF THE INVENTIONCROSS-REFERENCE TO RELATED APPLICATIONSThis application claims the benefit of priority to U.S. Provisional Application No. 63 / 626,203 filed January 29, 2024 and 63 / 655,474 filed June 3, 2024, both of which are incorporated by reference herein for all purposes.Field of the Invention

[0001] Heterobifunctional compounds are provided that are potent degraders or inhibitors of hematopoietic progenitor kinase 1 (HPKI). The compounds are useful to treat or prevent cancer and / or inflammatory and / or autoimmune diseases or symptoms thereof in mammals, particularly humans. The compounds have a chemical structure of the general formula I or a prodrug or pharmaceutically acceptable salt of any of the foregoing including mixtures thereof in all ratios.Description of Related Art

[0002] Hematopoietic progenitor kinase 1 (HPKI) is a serine / threonine kinase expressed in T cells, B-cells, and dendritic cells (Shui et al.. Nature Immunology, 2007, vol.8, pp. 84-91). In T cells, HPKI acts as a rheostat of T cell activation by regulating the molecular circuits of the T cell receptor (TCR) signaling pathway. Upon recruitment of HPKI to the TCR complex, HPKI phosphorylates SLP76 protein, which leads to SLP76 degradation and down-modulation of TCR signal strength. Genetic ablation of HPKI results in T cell activation, lower TCR threshold, increased proliferation, and elevated levels of pro- inflammatory cytokines such as IL -2, TNF-a, and IFN-y. Loss of HPKI expression enhances dendritic cell activation and antigen presentation. (Hernandez et al.. Cell Reports, 2018, vol. 25. pp. 80-94). HPKI kinase activity is believed to be critical in conferring suppressive functions of HPKI in a wide range of immune cells, such as CD8+, CD4+, DC, andNK to regulatory T cells (Tregs). Inactivation of the kinase domain of HPKI was sufficient to elicit robust anti-tumor immune responses (Liu et al., PLoS One, March 26, 2019). HPKI knockout (KO) and kinase dead (KD) mice show enhanced T cell function and antitumor efficacy (You et al., J. Immunother. Cancer, 2021). Therefore, pharmacological inhibition ofHPK1 has the potential to enhance effector T cell function and antitumor activity.Furthermore, HPK1 is believed to possess a scaffolding role in addition to its kinase function (Wu et al., Structure, 2019, vol. 27, pp. 125-133).

[0003] Small molecule degraders are increasingly utilized as tools to examine the functional roles of proteins and emerged as a novel therapeutic modality. Operating at the post-translational level, these molecules provide the potential for differentiated biological responses in comparison to classical inhibitors and expand the repertoire of methods for protein knock down beyond genetic approaches (e.g.: knock-out, siRNA). Priority text P21- 195 EP-EPA-3-5 10 15 20 25 30 Degrader molecules provide an example of a chemical genetic technique capable of more generally targeting the proteome. These chimeric molecules are designed to induce the degradation of their target proteins via the ubiquitin proteasome system (UPS), thereby eliminating pre-existing proteins. The UPS is the major intracellular pathway for protein degradation in which a series of enzymes known as Els (ubiquitin activating enzymes), E2s (ubiquitin conjugating enzymes) and E3s (ubiquitin ligases) carry out covalent linkage of the 9kDa, 76 amino acid protein ubiquitin to a target protein. Subsequent enzymatic reactions result in the formation of a polyubiquitin chain, which targets the protein for degradation by the 26S proteasome. Bifunctional degraders (sometimes also referred to as “heterobifunctional degraders”) comprise an E3 ligase-binding motif that is linked to a target protein binding moiety. Consequently, these molecules hijack the cell’s own degradation machinery by recruiting an E3 ligase in vicinity of the target protein. The spatial proximity enables ubiquiti nation of the protein and subsequent recognition and depletion by the UPS through the formation of a stable ternary complex. Specificity for a particular target protein is associated with the E3 ligase (Li W, et al. PLoS One. 2008; 3:el487) that facilitates the final step of ubiquitin attachment to the target protein. While the first-generation degraders were successfully developed using peptides as an E3 ubiquitin ligase-recognizing motif, they were either not cell-permeable or made cell- permeable by adding a cell-permeating motif such as the TAT peptide (Sakamoto KM, et al Proc Natl Acad Sei U S A. 2001; 98:8554-8559; Zhang D, et al. Bioorg Med Chem Lett. 2004; 14:645-648; Schneekloth JS Jr. et al. J Am Chem Soc. 2004; 126:3748- 3754.). The poor cell permeability of the first generation of bifunctional degraders was significantly improved by the discovery of small molecules that bind to E3 ligases such as the Von Hippel Lindau (VHL) ligand binding to VHL ligase (Buckley et al, J. Am. Chem. Soc., 2012, 134 (10), pp 4465-4468) or Priority text P21-195 EP-EPA - 4 - 5 10 15 20 25 30 thalidomidederivatives binding to the CRBN or Cereblon E3 Ligase (Winter et al, Science 19 Jun 2015: Vol. 348. Issue 6241, pp. 1376-1381). Thus, one type of targeted therapy involves bifunctional degrader molecules that utilize the intracellular UPS to selectively degrade target proteins by forming a ternary complex between the target protein, the bifunctional degrader molecule, and the E3 (ubiquitin) ligase which ultimately provides for the degradation of the target protein by a proteasome.

[0004] As such, small molecule therapeutic agents that leverage E3 ligase mediated protein degradation to target HPK1 hold promise as therapeutic agents.

[0005] Additionally, an HPK1 degrader or inhibitor might enable investigation of the scaffolding effect and address any scaffolding role on immune function and might lead to enhanced immune response.SUMMARY OF THE INVENTION

[0006] In an embodiment, a compound of Formula I or a prodrug or pharmaceutically acceptable salt thereof,wherein:R1is selected from the group consisting of C1-C6alkyl, C1-C6haloalky 1, hydrogen, OH, -O- C1-C6alkyl, halogen, -NR’R” and -CN;R’ and R” are independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl;R2is selected from the group consisting of C1-C6alkyl, C1-C6haloalky 1, hydrogen and halogen;X’ and Y’ are each independently selected from CH and N with the proviso that at least oneof X’ and Y’ is N;C’ is selected from the group consisting ofR3, R4, R5, R6, R7, R8. R9and R10are each independently selected from the group consisting of C1-C6alkyl, hydrogen and halogen;W is selected from the group consisting of N and CH;Z is selected from the group consisting of CH, CR11and N; R11selected from the group consisting of C1-C6alkyl and halogen; xx is selected independently for each occurrence from the group consisting of 1, 2, 3 and 4; yy is selected independently for each occurrence from the group consisting of 1, 2, 3 and 4;D is selected from the group consisting ofR12is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6, alkyl and C1-C6haloalkyl;R13is hydrogen or C1-C6alkyl;X is selected from the group consisting of-CH2-, -NR14- and -O-;R14is hydrogen or C1-C6alkyl; rr is 1, 2, 3 or 4;Ar is selected from the group consisting ofR15is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6alkyl, -O-C1-C6alkyl and C1-C6, haloalkyl;A is either absent or selected from the group consisting of (-CH2-)n, -O-,R16is hydrogen or C1-C6alkyl;R17is hydrogen or C1-C6alkyl;R18is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6, alkyl and C1-C6haloalkyl; n is selected from the group consisting of 0, 1. 2, 3 and 4; q is selected from the group consisting of 0, 1, 2, 3 and 4; r is selected from the group consisting of 0, 1, 2, 3 and 4 with the proviso that r cannot be 0 when W is N; s is selected from the group consisting of 0, 1, 2, 3 and 4; t is selected from the group consisting of 0, 1, 2, 3 and 4; u is selected from the group consisting of 0, 1, 2, 3 and 4; v is selected from the group consisting of 0, 1, 2, 3 and 4; w is selected from the group consisting of 0. 1, 2, 3 and 4; x is selected from the group consisting of 0, 1 , 2, 3 and 4; y is selected from the group consisting of 0, 1, 2, 3 and 4; z is selected from the group consisting of 0, 1, 2, 3 and 4;B is absent or selected from the group consisting of (-CH2-)OO,R19is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6alkyl and C1-C6haloalky 1; mm is 0, 1, 2, 3, 4, 5 or 6; mt is 0, 1, 2, 3, 4, 5 or 6; oo is 0, 1, 2, 3 or 4; pp is 0, 1, 2, 3, 4, 5 or 6; qq is 0, 1, 2, 3, 4, 5 or 6:x’ is independently chosen for each occurrence from the group consisting of 1, 2 and 3; and y’ is independently chosen for each occurrence from the group consisting of 1 , 2 and 3.

[0007] In an embodiment a compound of formula I wherein X’ and Y’ are N is provided.

[0008] In an embodiment a compound of formula I wherein X’ is N and Y ’ is CH is provided.

[0009] In an embodiment a compound of formula I wherein X’ is CH and Y’ is N is provided.

[0010] In an embodiment a compound of formula I wherein R1is selected from the group consisting of hydrogen, -CN, -OCH3and -CH3is provided. Preferably R1is -CH3.

[0011] In an embodiment a compound of formula I wherein R2 is selected from the group consisting of hydrogen and -F is provided. Preferably R2is hydrogen.

[0012] In an embodiment a compound of formula I wherein R3, R5, R6, R7. R9and R10are hydrogen and R4and R8are -CH3.

[0013] In an embodiment a compound of formula I wherein R3, R4, R7, R8, R9and R10are hydrogen and R5and R6- are -F.

[0014] In an embodiment a compound of formula I wherein R3, R4, R5, R6, R9and R10are hydrogen and R7and R8are -F is provided.

[0015] In an embodiment a compound of formula I wherein R3, R4, R5, R6, R7, R8, R9and R10are hydrogen is provided.

[0016] In an embodiment a compound of formula I wherein xx is 1 and yy is 1 is provided.

[0017] In an embodiment a compound of formula I wherein R11is selected from hydrogen, -F and -CH3, is provided.

[0018] In an embodiment a compound of formula I wherein R12is independently selected for each occurrence from the group consisting of hydrogen and halogen with the proviso that only one occurrence is halogen is provided. Preferably the halogen is -F.Preferably R12is hydrogen.

[0019] In an embodiment a compound of formula I wherein R13, is hydrogen or -CH3is provided. Preferably R13is -CH3.

[0020] In an embodiment a compound of formula I wherein X is selected from the group consisting of -CH2-, -NH-, -NCH3- and -O- is provided,

[0021] In an embodiment a compound of formula I wherein Ar is provided.

[0022] In an embodiment a compound of formula I wherein Ar is is provided.

[0023] In an embodiment a compound of formula I wherein Ar is

[0024] In an embodiment a compound of formula I wherein R15is hydrogen is provided.

[0025] In an embodiment a compound of formula I wherein R15is halogen. Preferably R15is -F.

[0026] In an embodiment a compound of formula I wherein A is absent is provided.

[0027] In an embodiment a compound of formula I wherein A is

[0028] In an embodiment a compound of formula I wherein A is -CH2- is provided.

[0029] In an embodiment a compound of formula I wherein A is -CH2-CH2- is provided.

[0030] In an embodiment a compound of formula I wherein A is provided.

[0031] In an embodiment a compound of formula I wherein A is provided.

[0032] In an embodiment a compound of formula I wherein W is N and Z is N isprovided.

[0033] In an embodiment a compound of formula I wherein W is N and Z is CH is provided.

[0034] In an embodiment a compound of formula I wherein W is CH and Z is N is provided.

[0035] In an embodiment a compound of formula I wherein D is selected from the group consisting ofis provided.

[0036] In an embodiment a compound of fonnula I wherein R12is hydrogen is provided.

[0037] In an embodiment a compound of formula I wherein R13, is hydr ogen or CH; is provided.

[0038] In an embodiment a compound selected from the group consisting of:

[0039] or a prodrug or pharmaceutically acceptable salt thereof is provided.

[0040] In an embodiment, a pharmaceutical composition contains a compound of formula I, or a combination thereof, as defined above and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

[0041] In an embodiment, a method is provided in which a therapeutically effective amount of the compound having the structure of formula I, or a combination thereof, or a physiologically acceptable salt thereof as defined above is administered to a patient having or suspected of having an HPK1 -mediated disorder. The HPK1 -mediated disorder may be cancer or an autoimmune and / or inflammatory disease.

[0042] In an embodiment, a method is provided in which a therapeutically effective amount of the pharmaceutical composition that contains a compound of formula I, or a combination thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle, is administered to a patient having or suspected of having an HPK1 -mediated disorder.

[0043] In an embodiment the HPK1 -mediated disorder may be cancer or an autoimmune and / or inflammatory disease.

[0044] In an embodiment he HPK1 -mediated disorder may be a cancer.

[0045] In an embodiment the cancer may be one or more of cancer of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands, esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, ovaiy, pancreas, prostate, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina, and vulva.

[0046] In an embodiment the HPK1 -mediated disorder may be an autoimmune disease.

[0047] In an embodiment the autoimmune disease may be one or more of rheumatoid arthritis (RA), autoimmune pancreatitis (AIP), systemic lupus erythematosus (SLE), type Idiabetes mellitus, multiple sclerosis (MS), antiphospholipid syndrome (APS), sclerosing cholangitis, systemic onset arthritis, irritable bowel disease (IBD), scleroderma, Sjogren's disease, vitiligo, polymyositis, pemphigus vulgaris, pemphigus foliaceus, inflammatory bowel disease including Crohn's disease and ulcerative colitis, autoimmune hepatitis, hypopituitarism, graft-versus-host disease (GvHD), autoimmune skin diseases, uveitis, pernicious anemia, and hypoparathyroidism. Autoimmune diseases may also include, without limitation, polyangiitis overlap syndrome, Kawasaki's disease, sarcoidosis, glomerulonephritis, and cryopathy.

[0048] In an embodiment the compound of formula I, or a combination thereof, or pharmaceutical composition thereof may be used to treat an inflammatory disorder and or the immune response is associated with an inflammatory disorder.

[0049] In an embodiment the inflammatory’ disorder may be one or more of non- rheumatoid arthritis, kidney fibrosis, and liver fibrosis.

[0050] In an embodiment the inflammatory disorder may be an interface dermatitis.

[0051] In an embodiment the inflammatory disorder may be a skin disorder such as atopic dermatitis (eczema); a sterile inflammatory condition such as drug-induced liver and / or pancreas inflammation; an inflammatory liver disorder; and / or an inflammatory pancreatic disorder.

[0052] In an embodiment the therapeutically effective amount of the compound of formula I or pharmaceutical composition may be in a range of 0.1 to 100 mg / kg of body weight of the patient, 0. 1 to 50 mg / kg of body weight of the patient, 0.5 to 50 mg / kg of bodyweight of the patient, 1 to 20 mg / kg of body weight of the patient, 5 to 20 mg / kg of body weight of the patient, 10 to 20 mg / kg of body weight of the patient, 10 to 50 mg / kg of bodyweight of the patient, and 10 to 100 mg / kg of body weight of the patient.

[0053] In another embodiment the compound of formula I or pharmaceutical composition may be administered to the patient continuously, multiple times daily, once daily, once every other day, weekly, bi-weekly, monthly, or bi-monthly.

[0054] In another embodiment the compound may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir.

[0055] In another embodiment the compound may be administered subcutaneously, intravenously, intramuscularly, intra-articularly, intra-synovially, intrasternally, intrathecally, intrahepaticly, intralesionally, and by intracranial injection or infusion technique.

[0056] In an embodiment, a kit is provided that includes a therapeutically effective amount of the compound of formula I, or a combination thereof as defined above or a physiologically acceptable salt or prodrug thereof; and instructions for use of the compound.

[0057] Additional features, advantages, and embodiments of the disclosed subject matter may be set forth or apparent from consideration of the following detailed description and claims. Moreover, it is to be understood that both the foregoing summary and the following detailed description are exemplary' and are intended to provide further explanation without limiting the scope of the claims. All cited references are incorporated by reference in their entirety.DETAILED DESCRIPTION OF THE INVENTION

[0058] Provided herein is the chemical structure of the general formula I, or a prodrug or pharmaceutically acceptable salt of any of the foregoing including mixtures thereof in all ratios, preferably for use in the treatment and / or prevention of cancer and / or inflammatory and / or autoimmune diseases. The compounds can degrade or inhibit HPK1 activity. The compounds disclosed herein have the general formula I or a prodrug or pharmaceutically acceptable salt thereofwherein;R1is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, hydrogen, OH, -O- C1-C6alkyl, halogen, -NR’R” and -CN;R’ and R' ' are independently selected for each occurrence from the group consisting of hydrogen and C1-C6, alkyl;R2is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, hydrogen and halogen;X’ and Y’ are each independently selected from CH and N with the proviso that at least one of X’ and Y’ is N;C’ is selected from the group consisting ofR3, R4, R5, R6. R7, R8, R9and R10are each independently selected from the group consisting of C1-C6 alkyl, hydrogen and halogen;W is selected from the group consisting of N and CH;Z is selected from the group consisting of CH, CR11and N;R11 selected from the group consisting of C1-C6, alkyl and halogen; xx is selected independently for each occurrence from the group consisting of 1 , 2, 3 and 4; yy is selected independently for each occurrence from the group consisting of 1 , 2, 3 and 4;D is selected from the group consisting ofR12is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen. C1-C6, alkyl and C1-C6haloalkyl;R13is hydrogen or C1-C6, alkyl;X is selected from the group consisting of -CH;-, -NR14- and -0-;R14is hydrogen or C1-C6, alkyl; rr is 1, 2, 3 or 4;Ar is selected from the group consisting ofR15is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6alkyl, -O-C1-C6, alkyl and C1-C6haloalkyl;A is either absent or selected from the group consisting of (-CH2-)n, -O-,R16is hydrogen or C1-C6alkyl;R17is hydrogen or C1-C6alkyl;R18is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6, alkyl and C1-C6haloalkyl; n is selected from the group consisting of 0, 1, 2, 3 and 4; q is selected from the group consisting of 0, 1, 2, 3 and 4; r is selected from the group consisting of 0, 1, 2, 3 and 4 with the proviso that r cannot be 0 when W is N; s is selected from the group consisting of 0, 1 , 2, 3 and 4; t is selected from the group consisting of 0, 1, 2, 3 and 4; u is selected from the group consisting of 0, 1, 2, 3 and 4; v is selected from the group consisting of 0, 1, 2, 3 and 4; w is selected from the group consisting of 0, 1, 2, 3 and 4; x is selected from the group consisting of 0, 1, 2, 3 and 4; y is selected from the group consisting of 0, 1, 2, 3 and 4; z is selected from the group consisting of 0, 1, 2, 3 and 4;B is absent or selected from the group consisting of (-CH2-)oo;R19is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6alkyl and C1-C6haloalkyl; mm is 0, 1, 2, 3, 4, 5 or 6; nn is 0, 1, 2, 3, 4, 5 or 6; oo is 0, 1, 2, 3 or 4;pp is 0, 1, 2, 3, 4, 5 or 6; qq is 0, 1, 2, 3, 4, 5 or 6; x’ is independently chosen for each occurrence from the group consisting of 1, 2 and 3; and y is independently chosen for each occurrence from the group consisting of 1. 2 and 3.

[0059] A compound or composition may include a combination of one or more of formula I, including any pharmaceutically acceptable salt or prodrug of one or more of formula I.

[0060] An alkyl can be a straight, branched or cyclic alkyl group. Exemplary alkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. The number of carbon atoms in the alkyl is not particularly limited. In some embodiments, an alkyl may have a specified number of carbon atoms such as 1-6. An alkyl group may be optionally substituted by one or more groups, preferably 1-4, selected from C1-C6 alkyl, NH2, NHR’, NR’R”, halo C1-C6 alkyl, - O-C1-C6 alkyl. -OH, halogen. (=0), and -OH. R’ and R” are independently selected for each occurrence from the group consisting of C1-C6 alkyl and H.

[0061] A halogen may refer to F, Cl, Br. or I. A haloalkyl may refer to a halogen bonded to an alkyl. An example of a haloalkyl may include CF3.

[0062] A sigma bond may refer to a covalent bond formed by overlap between atomic orbitals. It is symmetrical regarding rotation about the bond axis.

[0063] A heterocyclyl is a univalent group formed by removing a hydrogen atom from any ring atom of a heterocyclic compound. It may include one or more heteroatoms. A heteroatom may refer to one or more of oxygen, sulfur, nitrogen, phosphorous, or any oxidized form thereof. A heterocycle, heterocyclyl, and heterocyclic ring may be used interchangeably and refer to a stable 3 to 7-membered monocyclic or 6 to 14-membered bicyclic heterocyclic moiety’ that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of saturated or partially unsaturated heterocyclic rings include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl,piperazinyl, dioxanyl, oxazepinyl, thiazepinyl, and morpholinyl. A heterocyclyl may include groups in a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be a mono- or bicyclic. A heterocyclyl group may be optionally substituted by one or more groups, preferably 1-4, selected from C1-C6alkyd, NH2, NHR’, NR’R”, C1-C6haloalkyl, -O-C1-C6, alkyl, -OH, halogen, (=0), and -OH. R’ and R” are independently selected for each occurrence from the group consisting of C1-C6alkyl and H.

[0064] Partially unsaturated may refer to a ring moiety that includes at least one double or triple bond. It may encompass rings that have multiple sites of unsaturation, but it not intended to include aryl or heteroaryl moieties. The term unsaturated may refer to a moiety that has one or more units of unsaturation.

[0065] An aryl may refer to an aryl alone or a larger moiety such as an aralkyl, aralkoxy, and / or aryloxyalkyl. It may refer to monocyclic and bicyclic rings. At least one ring in the system may be aromatic. Each ring in the system may contain 3-7 members.Exemplary ary l groups include, without limitation, phenyl, biphenyl, naphthyl, anthracyl, and the like, which optionally includes one or more substituents. An aryl may also refer to a group in which an aromatic ring is fused to one or more non-aromatic rings such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, tetrahydronaphthyl., and the like. An aryl group may be optionally' substituted by one or more groups, preferably 1-4, selected from C1-C6alkyl, NH2, NHR’, NR’R”, C1-C6haloalkyl, -O-C1-C6alkyl, halogen, (=0) and -OH. R’ and R” are independently selected for each occurrence from the group consisting of C1-C6alkyl and H.

[0066] A heteroaryl may refer to a heteroaryl alone or as a part of a larger moiety such as heteroaralkyl or heteroaralkoxy. It may refer to a group having 4- 14 ring atoms, preferably 4, 5. or 6 ring atoms. In addition to carbon atoms, the heteroaryl may include 1 to 5 heteroatoms as provided above. Heieroary! groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. Heteroaryl may also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, and / or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofiiranyl, dibenzofuranyl, indazolyl,benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl. acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin- 3(4H)-one. A heteroaryl group is optionally mono- or bicyclic. A heteroaryl group may be optionally substituted by one or more groups, preferably 1-4, selected from C1-C6alkyl. NH2, NHR’, NR'R". C1-C6haloalkyl, -O-C1-C6alkyl, halogen, (=0) and -OH. R’ and R” are independently selected for each occurrence from the group consisting of C1-C6alkyl and H.

[0067] The term optionally substituted may refer to one or more hydrogens of the designated moiety being replaced with a suitable substituent. Unless otherwise indicated, optionally substituted group has suitable substituent at each substitutable position of the group and when more than one position in any given structure is substituted with more than one substituent selected from the specified group, the substituent is either the same or different at every position.

[0068] The term stable may refer to compounds that are not substantially altered when subjected to conditions to allow for their production or synthesis, detection, recovery, purification, and / or use as disclosed herein. A pharmaceutically acceptable salt may refer to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio.Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2 -naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0069] Salts may be derived from appropriate bases include alkali metal, alkaline earth metal, and ammonium salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate, and aryl sulfonate.

[0070] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g, enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure. For example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. In some instances, the enantiomeric excess is at least 50%, at least 60%, at least 70%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100%. Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention. Since the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomer. In these cases, the end product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or even employed as such in the synthesis.

[0071] Where tautomerism, e.g., keto-enol tautomerism, of compounds disclosed herein or their prodrugs may occur, the individual forms, e.g., the keto or the enol form, are claimed separately and together as mixtures in any ratio. The same applies for stereoisomers, e.g., enantiomers, cis / trans isomers, conformers, and the like. If desired, isomers can be separated by methods well known in the art, e.g., by liquid chromatography. The same applies for enantiomers, e.g., by using chiral stationary phases. Additionally, an enantiomer may be isolated by converting it into a diastereomer, i.e., coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomer and cleavage ofthe auxiliary residue. Alternatively, any enantiomer of a compound disclosed herein may be obtained from stereoselective synthesis using optically pure starting materials.

[0072] It is also contemplated that compounds disclosed herein may include isotope- labeled forms thereof. An isotope-labeled form of a compound disclosed herein is identical to this compound apart from the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the atom which usually occurs naturally. Examples of isotopes which are readily commercially available and can be incorporated into a compound of the formula I by well-known methods include, without limitation, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example2H,3H,13C,14C,15N,1SO,!7O,31P,32P,35S,18F, and36C1, respectively. It is also contemplated that a compound of the formula I, a prodrug thereof, or a pharmaceutically acceptable salt of either which contains one or more of the above-mentioned isotopes and / or other isotopes of other atoms are embodiments of the present disclosure. An isotope-labeled compound of the formula I can be used in a number of beneficial ways. For example, an isotope-labeled compound of the formula I into which, for example, a radioisotope, such as3H or14C, has been incorporated, is suitable for medicament and / or substrate tissue distribution assays.These radioisotopes are particularly preferred due to their ease of preparation and excellent detectability. Incorporation of heavier isotopes, for example, deuterium (2H), into a compound of the formula I may have therapeutic advantages due to the higher metabolic stability of this isotope-labeled compound. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages. An isotope-labeled compound of the formula I can be adapted to the procedures disclosed in the synthesis schemes and the related description, in the example part and in the preparation part, disclosed herein, replacing a non- isotope-labeled reactant by a readily available isotope-labeled reactant.

[0073] The compounds disclosed herein can be in the form of a prodrug compound. A prodrug compound may refer to a derivative that is converted into a biologically active compound under physiological conditions in the living body, e.g. , by oxidation, reduction, hydrolysis, or the like, each of which is carried out enzymatically, or wi thout enzyme involvement. Examples of prodrugs are compounds, wherein the amino group in a compound is acylated, alkylated, or phosphorylated; wherein the hydroxyl group is acylated, alkylated, phosphorylated, or converted into borate; wherein the carboxyl group is esterified or amidated; or wherein a sulfhydryl group forms a disulfide bridge with a carrier molecule,e.g., a peptide, that delivers the drug selectively to a target and / or to the cytosol of a cell. These compounds can be produced from compounds disclosed herein according to well- known methods. Other examples of prodrugs are compounds, wherein the carboxylate in a compound is for example converted into an alkyl-, aryl-, choline-, amino, acyloxyme thy tester, or linolenoyl-ester.

[0074] According to an embodiment, a composition comprising a compound disclosed herein or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions disclosed herein may be effective to measurably degrade or inhibit HPK1, or a mutant thereof, in a biological sample or in a patient. A therapeutically effective amount of the compound may be administered to a patient in need thereof. A patient or subject may refer to an animal, preferably a mammal, and even more preferably, a human. A biological sample may refer to. without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0075] A pharmaceutically acceptable carrier, adjuvant, or vehicle may refer to a nontoxic carrier, an adjuvant, or a vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that are used in the compositions disclosed herein include, without limitation, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. A pharmaceutically acceptable derivative means any nontoxic salt, ester, salt of an ester or other derivative of a compound disclosed herein that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound disclosed herein.

[0076] Compositions disclosed herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. Parenteral administration may refer to subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the composition may be administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions disclosed herein include aqueous or oleaginous suspension. These suspensions are formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils may be conventionally employed as a solvent or suspending medium.

[0077] Pharmaceutically acceptable compositions disclosed herein may be orally administered in any orally acceptable dosage form. Exemplary oral dosage forms are capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn star ch. When aqueous suspensions are required for oral use, the active ingredient may be combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, and / or coloring agents may be optionally added. Most preferably, pharmaceutically acceptable compositions disclosed herein are formulated for oral administration. Such formulations may be administered with or without food.

[0078] An amount of the compounds disclosed herein that may be combined with the carrier materials to produce a composition in a single dosage form may vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions may be formulated so that a dosage of between 0.01 - 100 mg / kg body weight / day of the compound can be administered to a patient receiving these compositions. In some instances, the dosage is between 0.1 to 100 mg / kg, 0.1 to 50 mg / kg, 0.5 to 50 mg / kg, 1 to 50 mg / kg, 1 to 20 mg / kg, 5 to 20 mg / kg, 10 to 20 mg / kg, 10-50 mg / kg of body weight of the patient, or 10-100 mg / kg of body weight of the patient or any other dosing range disclosed herein. In some instances, the compounds or compositions herein are administered continuously, multiple times daily, once daily, once every other day, weekly, bi-weekly, monthly, or bi- monthly. A therapeutically effective amount of a compound or composition herein may vary according to factors known in the art, but a dose of about 0.1 to 100 mg / kg, 0.1 to 50 mg / kg, 0.5-50 mg / kg, 1 to 50 mg / kg, 1 to 20 mg / kg, 5 to 20 mg / kg, 10 to 20 mg / kg, or 10-50 mg / kgof body weight of the patient, or 10-100 mg / kg of body weight of the patient or any other dosing range disclosed herein, may be therapeutically effective. A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound disclosed herein in the composition will also depend upon the particular compound in the composition.

[0079] The compounds of formula I disclosed herein can be administered before or following an onset of disease once or several times acting as therapy. The aforementioned compounds and medical products of the inventive use are particularly used for the therapeutic treatment. A therapeutically relevant effect relieves to some extent one or more symptoms of a disorder, or returns to normality, either partially or completely, one or more physiological or biochemical parameters associated with or causative of a disease or pathological condition. Monitoring is considered as a kind of treatment provided that the compounds are administered in distinct intervals, e.g., in order to boost the response and eradicate symptoms of the disease completely. Either the identical compound or different compounds can be applied. The methods disclosed herein can also be used to reduce the likelihood of developing a disorder or even prevent the initiation of disorders associated with HPK1 activity in advance or to treat the arising and continuing symptoms.

[0080] The host or patient can belong to any mammalian species, for example a primate species, particularly humans; rodents, including mice, rats, and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of interest for experimental investigations, providing a model for treatmen t of human disease.

[0081] The compounds disclosed herein may be usefill as anticancer agents for cancers that are responsive to HPK1 degradation or inhibition. In certain embodiments, the cancer may include, without limitation, cancer of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands, esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina, and vulva. In some instances, the cancer is a mesothelioma, sarcoma, retinoblastoma. Wilms tumor, leukemia, lymphoma, non-Hodgkin disease, chronic and acute myeloid leukemia, acutelymphoblastic leukemia, Hodgkin disease, multiple myeloma, T-cell lymphoma, myelodysplastic syndrome, plasma cell neoplasia, and paraneoplastic syndromes.

[0082] The compounds of formula I may be used in a method for ameliorating symptoms associated with and / or treating unwanted immune activation, including, but not limited to, symptoms associated with and / or treatment of autoimmunity. The disclosed compounds may be useful to inhibit the immune response and thereby prevent or delay development of the autoimmune disease. The autoimmune disease may be characterized by joint pain, antinuclear antibody positivity, malar rash, or discoid rash. The autoimmune disease may be associated with the skin, muscle tissue, and / or connective tissue. In some embodiments, the autoimmune disease is not evidenced in the individual by skin, muscle tissue, and / or connective tissue symptoms. In some embodiments, the autoimmune disease is systemic. Autoimmune diseases include, without limitation, rheumatoid arthritis (RA), autoimmune pancreatitis (AIP), systemic lupus erythematosus (SLE), type I diabetes mellitus, multiple sclerosis (MS), antiphospholipid syndrome (APS), sclerosing cholangitis, systemic onset arthritis, irritable bowel disease (IBD), scleroderma, Sjogren's disease, vitiligo, polymyositis, pemphigus vulgaris, pemphigus foliaceus, inflammatory bowel disease including Crohn's disease and ulcerative colitis, autoimmune hepatitis, hypopituitarism, graft- versus-host disease (GvHD), autoimmune skin diseases, uveitis, pernicious anemia, and hypoparathyroidism. Autoimmune diseases may also include, without limitation, polyangiitis overlap syndrome, Kawasaki's disease, sarcoidosis, glomerulonephritis, and cryopathy.

[0083] In some embodiments, the disclosed compounds may be used to treat an inflammatory disorder and / or the immune response is associated with an inflammatory disorder. As used herein, the term “inflammatory disorder” may encompass autoimmune diseases, as well as inflammatory conditions without a known autoimmune component (e.g., atherosclerosis, asthma, etc.). In further aspects, inhibiting the immune response may alleviate or mitigate one or more symptoms of the inflammatory disorder. Inhibiting the immune response may be useful to treat the inflammatory disorder and / or prevent or delay development of the inflammatory disorder. The inflammatory disorder may include, without limitation, non-rheumatoid arthritis, kidney fibrosis, and liver fibrosis. The inflammatory' disorder may be an interface dermatitis. The interface dermatitis may be one or more of lichen planus, lichenoid eruption, lichen planus-like keratosis, lichen striatus, keratosis lichenoides chronica, erythema multiforme, fixed drug eruption, pityriasis lichenoides, phototoxic dermatitis, radiation dermatitis, viral exanthems, dermatomyositis, secondarysyphilis, lichen sclerosus et atrophicus, mycosis fungoides, bullous pemphigoid, lichen aureus, porokeratosis, acrodermatitis chronicus atrophicans, and regressing melanoma. The inflammatory disorder may be a skin disorder such as atopic dermatitis (eczema); a sterile inflammatory condition such as drug-induced liver and / or pancreas inflammation; an inflammatory liver disorder; and / or an inflammatory pancreatic disorder.

[0084] Sensitivity of a given cancer to HPK1 degradation or inhibition can be assessed by, without limitation, measurement of a decrease in primary or metastatic tumor load (minor, partial, or complete regression), alterations in the hemogram, altered hormone or cytokine concentrations in the blood, inhibition of further increase of tumor load, stabilization of the disease in the patient, assessment of biomarkers or surrogate markers relevant for the disease, prolonged overall survival of a patient, prolonged time to disease progression of a patient, prolonged progression-free survival of a patient, prolonged disease- free survival of a patient, improved quality of life of a patient, or modulation of the co-morbidity of the disease (for example, but not limited to, pain, cachexia, mobilization, hospitalization, altered hemogram, weight loss, wound healing, fever). Significant improvements in the pharmacokinetic profiles of compounds of the formula I may thereby be obtained and can be expressed quantitatively in terms of increases in the in vivo half-life ( t / 2), concentration at maximum therapeutic effect (Crnax) and area under the dose response curve (AUC).

[0085] In various embodiments, compounds of formula I and related formulae, exhibit an IC50for inhibiting HPK1 of less than about 1000 nW. less than about 500 nM, less than 100 nM, less than 500 nM, or less than 1000 nM. In some embodiments, the compounds of formula I, and related formulae exhibit an IC50for inhibiting HPK1 of at least 1 nM, at least 10 nM, at least 100 nM, or at least 500 nM. In some embodiments, the range is a combination of these values.

[0086] Compounds of formula I and / or a physiologically acceptable salt thereof can be employed as an intermediate for the preparation of further medicament active ingredients. The medicament is preferably prepared in a non-chemical manner, e.g., by combining the active ingredient with at least one solid, fluid and'or semi-fluid carrier or excipient, and optionally in conjunction with a single or more other active substances in an appropriate dosage form.

[0087] A medicament is provided herein that can include at least one compound disclosed herein or a prodrug or pharmaceutically acceptable salt thereof including mixturesthereof in all ratios. A medicament may refer to any agent in the field of medicine, which comprises one or more compounds of formula I or preparations thereof (e.g., a pharmaceutical composition or pharmaceutical formulation) and can be used in prophylaxis, therapy, follow-up or aftercare of patients who suffer from diseases, which are associated with HPK1 activity, in such a way that a pathogenic modification of their overall condition or of the condition of particular regions of the organism could establish al least temporarily.[00881 In various embodiments, the active ingredient may be administered alone or in combination with other treatments. A synergistic effect may be achieved by using more than one compound in the pharmaceutical composition, i.e. the compound of formula I may be combined with at least another agent as active ingredient, which is either another compound of formula I or a compound of different structural scaffold. The active ingredients can be used either simultaneously or sequentially, hi some embodiments, the HPK1 degrader or inhibitor compounds disclosed herein is administered simultaneously with one or more additional therapeutic agents. In some embodiments, sequential administration includes administering the HPK1 degrader or inhibitor or additional therapeutic agent followed within about any of one minute, five minutes, 30 minutes, one hour, five hours, 24 hours, 48 hours, or a week. In some embodiments, the HPK1 degrader or inhibitor is administered by the same route of administration as the additional therapeutic agent. In some embodiments, the HPK1 or degrader inhibitor may be administered by a different route of administration than the additional therapeutic agent.

[0089] A therapeutic agent may include, without limitation, an anti-inflammatory drug and / or one or more anti-tumor agents conventionally used in chemotherapy or targeted therapy. The compounds or compositions disclosed herein may be used as a monotherapy or may be combined with therapeutic agents. Examples of anti-tumor agents include, without limitation, platinum compounds such as carboplatin, cisplatin, picoplatm, and the like; alkylating agents such as altretamine, carmustine, chlorambucil, mitobromtol, apaziquone, palifosfamide, and the like; DNA altering agents such as bisantrene, decitabine, mitoxantrone, procarbazine, and the like; microtubule modifiers such as docetaxel, eribulin, paclitaxel, vinblastine, and the like; topoisomerase inhibitor such as etoposide, razoxane, topotecan, and the like; anticancer antibodies such as bleomycin, mitomycin C, and the like; antimetabolites such as capecitabine, cladribine, and the like; hormones or antagonists such as tamoxifen, dexamethasone, and the like; cytokines such as interferon and the like; antibodies such as pembrolizumab, nivolumab, ipilimumab, cetuximab, and the like.

[0090] A method for inhibiting abnormal cell growth in a mammal, preferably a human, or treating a cancer may include administering to the mammal an amount of a compound of formula I disclosed herein, or a prodrug or a pharmaceutically acceptable salt thereof, in combination with radiation therapy, wherein the amounts of the compound , salt, or prodrug, is in combination with the radiation therapy effective in inhibiting abnormal cell growth or treating the cancer or symptoms thereof in the mammal. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein.

[0091] As used herein, the terms “treatment”, “treat”, and “treating” may refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment is administered after one or more symptoms have developed. In other embodiments, treatment is administered in the absence of symptoms. For example, treatment is administered to a susceptible individual prior to the onset of symptoms (e.g. , in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment is also continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0092] Disclosed herein is a kit that includes separate packs of a therapeutically effective amount of a compound disclosed herein or a physiologically acceptable salt, or prodrug thereof, and optionally, a therapeutically effective amount of a therapeutic agent. The kit may include suitable containers, such as boxes, individual bottles, bags, or ampoules as well as instructions for using or applying the kit. The kit may, for example, contain separate ampoules, each containing a therapeutically effective amount of a compound disclosed herein and / or pharmaceutically usable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and an effective amount of a further therapeutic agent in dissolved or lyophilized form.Experimental procedures

[0093] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds, the following general methods, and other methods known to one of ordinary skill in the art, can be appliedto all compounds and subclasses and species of each of these compounds, as described herein.

[0094] The symbols and conventions used in the following descriptions of processes, schemes, and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry.

[0095] Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade).

[0096] All solvents used were commercially available and were used without further purification. Reactions were typically run using anhydrous solvents under an inert atmosphere of nitrogen. Flash column chromatography was generally carried out using Silica gel 60 (0.035-0.070 mm particle size).

[0097] All NMR experiments were recorded either on Bruker Mercury Plus 400 NMR Spectrometer equipped with a Bruker 400 BBFO probe at 400 MHz for proton NMR, or on Bruker Mercury Plus 300 NMR Spectrometer equipped with a Bruker 300 BBFO probe at 300 MHz for proton NMR, or on a Bruker Avance III 400 NMR Spectrometer equipped with a Bruker PABBO BB-1H / D Z GRD probe at 400 MHz for proton NMR. Most deuterated solvents contained typically 0.03% to 0.05% v / v tetramethylsilane, which was used as the reference signal (set at d 0.00 for both 1H and 13C). In cases where the deuterated solvents did not contain tetramethylsilane, the residual non- deuterated solvent peaks were used as a reference signal, as per published guidelines (J. Org. Chem., vol. 62, No. 21, 1997).LC-MS analyses were performed one either one of the two following instruments:

[0098] In general, the compounds according to formula I and related formulae described herein can be prepared from readily availabl e starting materials. If such starting materials are not commercially available, they may be prepared by standard synthetic techniques. In general, the synthesis pathways for any individual compound of formula I and related formulae will depend on the specific substituents of each molecule, such factors being appreciated by those of ordinary skilled in the art. The following general methods and procedures described hereinafter in the examples may be employed to prepare compounds of formula I and related formulae. Reaction conditions depicted in the following schemes, such as temperatures, solvents, or co-reagents, are given as examples only and are not restrictive. Itwill be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solven ts etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimization procedures. For all the protection and deprotection methods, see Philip J. Kocienski, “Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greene and Peter G. M. Wuts, “Protective Groups in Organic Synthesis”, Wiley Interscience, 3rd Edition 1999.Experimental procedures

[0099] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

[0100] The symbols and conventions used in the following descriptions of processes, schemes, and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry.

[0101] Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade).

[0102] All solvents used were commercially available and were used without further purification. Reactions were typically run using anhydrous solvents under an inert atmosphere of nitrogen. Flash column chromatography was generally carried out using Silica gel 60 (0.035-0.070 mm particle size).

[0103] All NMR experiments were recorded either on Bruker Mercury Plus 400 NMR Spectrometer equipped with a Bruker 400 BBFO probe at 400 MHz for proton NMR, or on Bruker Mercury Plus 300 NMR Spectrometer equipped with a Bruker 300 BBFO probe at 300 MHz for proton NMR, or on a Bruker A vance III 400 NMR Spectrometer equipped with a Bruker PABBO BB-1H / D Z GRD probe at 400 MHz for proton NMR. Mostdeuterated solvents contained typically 0.03% to 0.05% v / v tetramethylsilane, which was used as the reference signal (set at d 0.00 for both 1H and 13C). In cases where the deuterated solvents did not contain tetramethylsilane, the residual non- deuterated solvent peaks were used as a reference signal, as per published guidelines (J. O. rg. Chem., vol. 62, No. 21, 1997).

[0104] LC-MS analyses were performed one either one of the two following instruments:

[0105] LC-MS analyses were performed one either one of the two following instruments or by the methods below:

[0106] SHIMADZU LC-MS machine consisting of an UFLC 20-AD system and LCMS 2020 MS detector. The column used was a Shim-pack XR-ODS, 2.2 μm, 3.0 x 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% trifluoroacetic acid (TFA) in water) and ending at 100% B (B: 0.05% TFA in acetonitrile (ACN)) over 2.2 min. with a total run time of 3.6 min. The column temperature was at 40 °C with the flow rate at 1.0 mL / min. The Diode Array detector was scanned from 200-400 nm. The mass spectrometer was equipped with an electro spray ion source (ES) operated in a positive or negative mode. The mass spectrometer was scanned between m / z 90-900 with a scan time of 0.6 s.

[0107] Agilent 1200 Series mass spectrometers from Agilent Technologies, using either Atmospheric Chemical Ionization (APCI) or Electrospray Ionization (ESI). Diode Array detector was scanned from 200-400 nm. The mass spectrometer was scanned between m / z 90-900 with a scan time of 0.6 s. Column: XBridge C8, 3.5 μm, 4.6 x 50 mm; Solvent A: water + 0.1 % TFA; Solvent B: ACN + 0.1 % TFA; Flow: 2 ml / min.; Gradient: 0 min.: 5 % B, 8 min.: 100 % B, 8.1 min.: 100 % B, 8.5 min.: 5% B, 10 min. 5% B or a LC / MS Waters ZMD (ESI).

[0108] HPLC data were either obtained from the SHIMAZU LC-MS machine or using Agilent 1 100 series HPLC from Agilent technologies using a column (XBridge C8, 3.5 μm, 4.6 x 50 mm) and two mobile phases (mobile phase A: water + 0.1 % TFA; mobile phase B: ACN + 0.1 % TFA). The flow rate was 2 ml / min. The gradient method was: 0 min.: 5 % B; 8 min.: 100 % B; 8.1 min.: 100 % B; 8.5 min.: 5% B; 10 min. 5% B, unless otherwise indicated.LC-MS MethodsMethod A: Chromolith SpeedRod RP-18e 5 μm 4.6-50 mm; flow: 3.3 mL / min; T: 40 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 1-99 % B (0 - 2.0 min); 99% B (2 - 2.5 min).Method AU: Waters Acquity BEHC8 1.7μm; 2.1-50mm; gradient A: water + CHOOH (0.1%) B: acetonitrile + CHOOH (0.1%) gradient: 10 % B - 90 % B in 2 minMethod B: HALO CIS 2 μm 3.0-30 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B - 95 % B in 2.0 min.Method C: HALO CIS 2 μm 3.0-30 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 5 % B - 95 % B in 2.0 min.Method D: HALO CIS 2 μm 3.0-30 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B - 100 % B in 1.2 min.Method E: HALO C18 2 μm 3.0-30 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B - 95 % B in 1.5 min.Method F: HALO C18 2 μm 3.0-30 mm; flow: 1.2 mL / min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0. 1 % TFA; gradient: 5 % B - 95 % B in 3.0 min.Method G: HALO C18 2 μm 3.0-30 mm; flow: 1.0 mL / min; T: 45 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 10 % B - 100 % B in 1.5 min.Method H: Kinetex XB-C18 100A 2 μm 2.1-30 mm; flow: 1.0 mL / min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B - 95 % B in 1.5 mm.Method I: XSelect CSH 2.5 μm 3.0-50 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 5 % B - 95 % B in 2.0 min.Method J: Poroshell HPH-C18 2.7 μm 3.0-50 mm; flow: 1.2 mL / min; T: 40 °C; buffer A: 6.5mM NH4HCO3+NH4OH(pH=10); buffer B: Acetonitrile; gradient: 10 % B - 95 % B in 3.0 min.Method K: Kinetex EVO C18 1.7 μm 2.1 - 50 mm; flow 0.9 mL / min; T: 40 °C; buffer A: water + 0.05% HCOOH; buffer B: Acetonitrile + 0.04% HCOOH; gradient: 1 % B - 99 % B in 1.3 min.Method L: Kinetex EVO C18 5.0 μm 4.6 - 50 mm; flow: 3.3 mL / min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 1 % B - 99 % B in 2.1 min.Method M: Kinetex EVO C18 5.0 μm 4.6 - 50 mm; flow: 3.3 mL / min; T: 40 °C; buffer A: water + 0.05% HCOOH; buffer B: Acetonitrile + 0.04% HCOOH; gradient: 0 % B - 100 % B in 2.1 min.Method N: Shim-Pack C18 3.0 μm 3.0-33 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: 5 mM NH4HCO3in water; buffer B: Acetonitrile; gradient: 10 % B - 95 % B in 1.5 min.Method O: HALO C18 2 μm 3.0-30 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B - 100 % B in 2.0 min.Method P: Chromolith SpeedRod RP-18e 5 μm 4.6-50 mm; flow: 3.3 mL / min; T: 40 °C: buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 1 - 99 % B in 2 min - 99 % B from 2 - 2.5 min.Method Q: HALO C18 2 μm 3.0-30 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 5 % B - 100 % B in 1.2 min.Method R: HALO C18 2 μm 3.0-30 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile; gradient: 5 % B - 100 % B in 25 min.Method S: HALO CIS 2 μm 3.0-30 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile; gradient: 5 % B - 100 % B in 35 min.Method T: F-phenyl Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 25% B in 10 mmMethod U: Kinetex XB-C 18 100A 1.7 μm 2.1-30 mm; flow: 1.0 mL / min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B - 95 % B in 2 min.Method V: HALO C18 2 μm 3.0-30 mm; flow: 1.0 mL / min; T: 45 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 0 % B - 100 % B in 1.2 min.Method W: HALO C18 2 μm 3.0-30 mm; flow: 1.0 mL / min; T: 45 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 0 % B - 100 % B in 1.5 min.Method X: HALO C 18 2 μm 3.0-30 nun; flow: 1.2 mL / min; T: 40 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 0 % B - 100 % B in 2.0 min.Method Y: HALO C18 2 μm 3.0-30 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 0 % B - 100 % B in 2.0 min.Method Z: HALO C18 2 μm 3.0-30 mm; flow: 1.2 mL / min; T : 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 0 % B - 100 % B in 2.0 min.Method AA: Kinetex EVO C18 1.7 μm 2.1 - 50 mm; flow: 0.9 mL / min; T: 40 °C; buffer A: water + 0.05% HCOOH; buffer B: Acetonitrile + 0.04% HCOOH; gradient: 0 % B - 100 % B in 1.3 min.Method AB: HALO C18 2 μm 3.0-30 mm; flow: 1.2 mL / min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B - 100 % B in 1.2 min.Method AC = Method C-MM:: Cortecs T3 2.7 μm 4.6-50 mm; flow: 3.5 mL / min; T: 45 °C; buffer A: water + 0.05 % HCOOH; buffer B: Acetonitrile + 0.04 % HCOOH; gradient: 1 % B - 99 % B in 2.5 min; 99% B from 2.5 - 2.9 min.Method AD: Kinetex XB-C18 1.7 μm 2.1-30 mm; flow: 1.0 mL / min; T: 40 °C; buffer A:water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B - 95 % B in 1.5 min.Method AE = Method D-MM: Chromolith HR RP-18e 50-4,6 mm; flow-: 3.3mL / min; T: 45°C; buffer A: H2O + 0.05% HCOOH; buffer B: MeCN + 0.04% HCOOH; gradient: 1% -> 99% B: 0 -> 2,0 min 99% B: 2,0 -> 2,5 minMethod AF: HALO C18 2 μm 3.0-30 mm; flow: 1.5 mL / min; T: 45 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 5 % B - 95 % B in 1.5 min.Method AG: HALO C18 2 μm 3.0-30 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B - 95 % B in 3 min.Method AH: HALO C18 2 μm 3.0-30 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B - 100 % B in 1.00 min.Method Al: CORTLCS T3 1.6 gM 2.1-50 mm; flow 0.9 ml / min; T: 45°C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile +0.1 % FA; 2 % B - 99 % B (0- 2 min), 99 % B (2-2.31 min)Method AJ: HALO C18 2 μm 3.0-30 mm; flow: 1.2 mL / min; T: 40 °C; buffer A: w ater + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5 % B - 95 % B in 1.0 min, 95 %B 1-1.4 min.Method AK: Shim-Pack C18 3.0 μm 3.0-33 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: 0.1 % TFA in water; buffer B: 0.1 % TFA in Acetonitrile; gradient: 5 % B - 95 % B in 1.5 min.Method AL: XSelect CSH Fluoro 2.5 μm 3.0-50 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 5 % B - 95 % B in 1.5 min.Method AM: HALO C18 2 μm 3.0-30 mm; flow: 1.2 mL / min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 0 % B - 100 % B in 2.0 min.Method AN: CORTECS C18 2.7 μm 2.1-30 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5-100 % B in 2 minMethod AO: CORTECS C182.7 μm 2.1-30 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 5-100 % B in 1.2 minMethod AP: XSelect CSH Fluoro 2.5 μm 3.0-50 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 5 % B - 95 % B in 1.5 min.Method AQ: Shim-Pack C18 3.0 μm 3.0-33 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: 5 mM TFA in water; buffer B: Acetonitrile; gradient: 5 % B - 100 % B in 1.2 min.Method AR: HALO C18 2.7 μm 4.6-100 mm: How: 1.5 mL / min; T: 60 °C; buffer A: water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient: 10 % B - 100 % B in 10 min.Method AS: Kinetex XB-C18 1.7 μm 2.1-30 mm; flow: 1.5 mL / min; T; 40 °C; buffer A; water + 0.1 % TFA; buffer B: Acetonitrile + 0.1 % TFA; gradient; 5 %B - 95 % B in 1.5 min.Method AT: SunFire C18 5,0 μm 100-3 mm; flow: 1.4mL / min; T: 40°C; buffer A: H2O + 0.05% HCOOH; buffer B: MeCN + 0.04% HCOOH + 1% H2O; gradient: 1% -> 99% B: 0 -> 2.0 min ] 99% B: 2.0 -> 2.7 minGeneral ProceduresGeneral procedure A for nucleophilic aromatic substitution

[0109] To a stirred solution of the desired halogenated aromatic compound (1.0 eq.) the aniline (1.0 eq.) was added in n-BuOH (0.13 M). TFA (3.0 eq.) was then added. The reaction mixture was stirred at 90 °C for 3h. The reaction mixture was concentrated under reduced pressure and directly purified by prep-HPLC to obtain the desired products in pure form.General procedure B for reductive amination

[0110] To a solution of the desired amine (1.0 eq.) and aldehyde ( 1 .0 - 2.0 eq.) in DCM: MeOH 1: 1 mixture (0.14 M- 0.35 M) sodium acetate (2.7 - 5.0 eq.) was added. After 1h, and sodium cyanoborohydride (1 .6 - 4.0 eq.) was added. In some reactions, acetic acid (1.0 eq.) was also added. The reaction mixture was stirred at room temperature for 2 - 12 h. The reaction mixture was concentrated under reduced pressure, or a work up was performed with EtOAc or DCM, and directly purified by flash column chromatography to afford the desired product in pure form.General procedure C for reduction with iron and ammonium chloride

[0111] The desired nitro or phenyl protected compound (1 .0 eq) was dissolved in MeOH (0.04 - 0.06 M), EtOH and water (1.5 / 1 mixture; 0.2 M) or THF and water (1.5 / 1 mixture; 0.2 M) . Fe (4.1 - 5.0 eq.) and a 2.4 M ammonium chloride (4.0 - 5.2 eq.) solution in water were then added. The reaction mixture was stirred at 80 - 100 °C for 3 - 12 h. The reaction mixture was filtered and concentrated. Water was added to the residue, and the formed precipitate was filtered and dried under vacuum to afford the desired product.Alternatively, the residue was purified by prep-HPLC or flash column chromatography.General procedure D for Suzuki coupling

[0112] To a stirred solution of the corresponding boronic ester (1 .0 - 1.7 eq.) and aryl halide (1.0 - 1.1 eq.) in DMF: H2O 4: 1 mixture (0.17 M), dioxane H2O mixture 5: 1 or 6:1 (0.16 - 0.27 M) or THF: H2O 5: 1 mixture (0.25 M) were added Pd(dppf)Cl2DCM (0.1 eq.) and NagCO3(3.0 eq.), K2CO3(2.0 - 2.7 eq.) or CS2CO3(3.0 eq.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1-12 h at 70 - 1 10 °C, The reaction mixture was extracted with EtOAc three times. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography affording thedesired coupled products in pure form. Alternatively, the reaction mixture was concentrated under reduced pressure and directly purified by flash column chromatography.General procedure E for hydrogenation

[0113] The desired nitro, alkene or benzyl protected compound ( 1.0 eq) was dissolved in MeOH (0.15 M), dioxane (0.10 - 0.57 M), EtOH:EtOAc 1:1 mixture (0.08 M) or DMF (0.16 M) and Pd / C or Pd(OH)2 / C (0.1 - 0.5 eq.) was then added. The reaction mixture was stirred at room temperature or 50 °C for 2 - 16 h under hydrogen atmosphere. The reaction mixture was filtered over celite, washed with DCM, MeOH or EtOAc and concentrated under reduced pressure to afford the desired product. If needed, the obtained products were then purified by flash column chromatography.General procedure F for Boc deprotection

[0114] The Boc protected amine or aniline (1 .0 eq.) was dissolved in 2-4 M HC1 in EtOAc (6.7 - 75.5 eq.) or dioxane (7.5 - 16.2 eq.) and in some cases DCM (0.13 M). The reaction mixture was stirred at room temperature for 2-5 h. The reaction mixture was concentrated under reduced pressure and used without farther purification. Alternatively, the reaction was diluted with water and the pH brought to 7 by the addition of aqueous NaHCO3. The mixture was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and was concentrated under reduced pressure.General procedure G for Suzuki coupling

[0115] To a stirred solution of the corresponding boronic acid or ester ( 1 .0 eq.) and aryl halide (1.0 - 2.0 eq.) in dioxane: H2O 5: 1 mixture (0.12 - 0.33 M) were added Pd(dppf)Cl2(0.1 eq.) and K2CO3(1.4 - 2.0 eq.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 50 - 80 °C. The reaction mixture was concentrated under reduced pressure, or a workup with water and EtOAc w as performed, and directly purified by flash chromatography to afford the coupled products in pure form.General procedure H for Buchwald coupling

[0116] To a mixture of the aryl halide (1.0 - 1.1 eq.) and the desired aniline (1.0 - 1.5 eq.) in dioxane (0.03 - 0.12 M), Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (0.03 - 0.1 eq.) or Pd-PEPPSI-IPent (0.04 - 0.2 eq.) and CS2CO3(3.0 eq.) were added at roomtemperature. The mixture was stirred for 12 - 17 h at 90 - 110 °C under argon atmosphere. The resulting mixture was concentrated under reduced pressure and purified by prep-HPLC, silica gel column chromatography or prep-TLC to afford the desired product. In some cases, a work-up with EtOAc was performed.General procedure I for amide coupling

[0117] To a solution of the desired amine ( 1.0 - 1.2 eq.) and the acid (1.0 - 1.2 eq.) in DMF (0.06 - 0.2 M), TCFH (1.3 - 2.0 eq.) and NMI (3.5 - 7.2 eq.) were added. The reaction mixture was stirred at room temperature for 1- 35h. The reaction mixture was concentrated under reduced pressure and directly purified by prep HPLC or flash column chromatography to afford the desired amides in pure form.General procedure J for Boc / acetyl deprotection, tertbutyl ester or acetal cleavage

[0118] The starting material (1.0 eq.) was dissolved in DCM (0.01 - 0.43 M) and TFA (8.6 - 659.4 eq) was slowly added at room temperature. The reaction mixture was stirred for 2 - 21 h at room temperature or at 40 °C. The reaction mixture was diluted with water and the pH adjusted to 8 by the addition of aqueous NaHCO3. It was extracted with EtOAc three times. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. In some cases, the reaction mixture was concentrated under reduced pressure and directly purified by prep-HPLC or flash column chromatography (or continued without further purification).General procedure K for Buchwald coupling

[0119] To a mixture of the aryl halide (1.0 eq.) and the desired aniline (1.2 eq.) in dioxane (0.08 M), Ephos Pd G4 (0.10 eq.) and CS2CO3(2.0 eq.) were added at room temperature. The mixture was stirred for 12 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by prep-HPLC or silica gel column chromatography to afford the desired product.General procedure L for Boc deprotection

[0120] The Boc protected compound (1.0 eq.) was dissolved in 2,2,2-trifluoroethanol (0.01 - 0.05 M) and the reaction mixture was heated at 120 °C for 6 h under nitrogen atmosphere in a microwave. It was then concentrated under reduced pressure and directlypurified by prep HPLC to obtain the desired product in pure form.General procedure M for reduction with tetrahydroxydiboron and 4,4 -bipyridine

[0121] To a stirred solution of nitro compound (l.OOeq) and 4,4 '-bipyridine (O.leq) in DMF was added tetrahydroxy diboron (3.00eq) in portions at 0°C. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography to afford the desired product.General procedure N for nitro reduction

[0122] The corresponding nitro compound (1.0 eq.) and tetrahydroxydiboron (3.0 eq.) were dissolved in DMF (0.42 M) and 4,4’-bipyridine (0.1 eq.) was added in portions at room temperature. The reaction mixture was stirred at room temperature for 1h. The reaction mixture was concentrated under reduced pressure and directly purified by flash column chromatography to afford the desired anilines.General procedure O for amide coupling with HATU

[0123] The carboxylic acid (1.0 eq) and amine (1.0 eq) were dissolved in DMF (5.00 mL). To the solution was added HATU (2.00 eq.) and DIEA (5.00 eq) at room temperature. The reaction mixture was stirred at room temperature or 50 °C for 2-20 h. Then, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography. Sometimes water was added to the reaction mixture and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography.General procedure P for Buchwald coupling

[0124] To a mixture of the desired aryl halide (1.0 - 2.2 eq.) and aniline (1.0 - 1.2 eq.) in dioxane (0.18 - 0.27 M) or DMF (0.36 M), XPhos (0.1 - 0.2 eq.), K2CO3(2.0 eq.) or CS2CO3(2.0 eq.) and XPhos Pd G3 (0. 1 eq.) were added at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 2 - 16 h at 100 °C. The reaction mixture was then concentrated under reduced pressure, or a work up was done with wnter and EtOAc. The residue was then directly purified by silica gel column chromatography to afford the coupled product in pure form.Synthesis of IntermediatesIntermediate 1: 2-chloro-7-{8-methyl-1H,2H,3H-pyrido[2,3-b] [1,4]oxazin-7- yl} quin azoline

[0125] 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b] [1,4]oxazine (5.0 g; 21.61 mmol;1.0 eq.) and bis(pinacolato)diboron (6.0 g; 23.77 mmol; 1.1 eq.) were suspended in dioxane (100 ml) and KOAc (6.4 g; 64.83 mmol; 3.0 eq.) was added. The reaction mixture was degassed with nitrogen and Pd(ddpf)Cl2DCM (893 mg; 1.1 mmol; 0.05 eq.) was added. The reaction mixture was stirred at 110°C for 30 h.

[0126] To the reaction mixture was added K2CO3(8.96 g; 64.83 mmol; 3.0 eq.), 7- bromo-2-chloroquinazoline (5.6 g; 23.77 mmol; 1.1 eq.) and demineralized water (25 ml) at room temperature. The vial was purged with nitrogen and Pdlddpf)Cl2DCM (893 mg; 1.1 mmol; 0.05 eq.) was added. The mixture was stirred at 100°C for 2 h.

[0127] The dark brown reaction mixture was evaporated. The residue was diluted with waler and ethyl acetate and stirred for 1 h. The undissolved solid was filtered off and rinsed with water and ethyl acetate. The solid was suspended in dichloromethane and filtered again. The solid was diluted with DMF, heated to 60°C, filtered off and rinsed with DMF and petrol ether to obtain the desired product (2.3 g; 7.22 mmol; 33 % yield).

[0128] LC-MS method A: [M+H]+313.1; Rt: 1.10 minIntermediate 2: 3-[4-(piperidin-4-yl)phenyI]piperidine-2, 6-dionetert-butyl 4-[4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yI)phenyI]-1, 2,3,6- tetrahydropyridine-1-carboxylate

[0129] To a stirred solution of tert-butyl 4-(4-bromophenyl)- 1.2,3.6- tetrahydropyridine-1 -carboxylate (2.0 g; 5.09 mmol; 1.0 eq.) and BPD (2.0 g; 7.64 mmol; 1.5 eq.) in dioxane (20 ml) Pd(dppf)Cl2CH2Cl2(438 mg; 0.51 mmol; 0.1 eq.) and KOAc (1.0 g;10.18 mmol; 2.0 eq.) were added at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE:EtOAc (20: 1), to afford the desired product (2.0 g;4.18 mmol; 82 % yield).

[0130] LC-MS method D; [M - Boc +H]+286.2; Rt: 0.95 min tert-butyl 4-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}-1, 2,3,6-tetrahydropyridine-1- carboxylate

[0131] Starting from tert-butyl 4-[4-(4,4,5,5-tetramethyl-1, 3,2- dioxaborolan-2-yl)phenyl]-1,2,3,6-tetrahydropyridine-1-carboxylate (2.0 g;4.14 mmol; 1.0 eq.) and commercially available 2,6-bis(benzyloxy)-3- bromopyridine (1.8 g; 4.56 mmol; 1.1 eq.) the general procedure D for Suzuki Coupling was followed in the presence of DMF: H2O 4: 1 mixture (0.17 M). Pd(dppf)Cl2DCM (0.1 eq.) and CS2CO3(3.0 eq.) to afford the desired product (1.70 g; 3.02 mmol; 73% yield).

[0132] LC-MS method D: [M +H]+549.2; Rt: 1.03 mm tert-butyl 4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperidine-1-carboxylate

[0133] Starting from tert-butyl 4- {4-[2,6-bis(benzyloxy)pyridin-3- yl]phenyl} -1,2,3,6-tetrahydropyridine-1-carboxylate (1.70 g; 3.02 mmol; 1.0 eq.) the general procedure E for reduction was followed in the presence of MeOH (0.15 M) and Pd / C (0.5 eq.) to afford the desired product (1.1 g; 2.72 mmol; 90% yield) as an off-white solid.

[0134] LC-MS method D: [M +Na]+395. 1 ; Rt: 0.72 min3- [4-(piperidin-4-yl)phenyl]piperidine-2, 6-dione

[0135] Starting from tert-butyl 4-[4-(2,6-dioxopiperidin-3- yl)phenyl]piperidine-1-carboxylate (1.1 g; 2.72 mmol; 1.0 eq.) the general procedure B for Boc deprotection was followed in the presence of 4M HC1 in EtOAc (14.7 eq.) to afford the desired product (750 mg; 2.63 mmol; 97 % yield) as a white solid.

[0136] LC-MS method D: [ M-H ] 273. 1 ; Rt; 0.43 minIntermediate 3: 1-(4-nitrophenyl)piperidine-4-carbaIdehyde[1-(4-nitrophenyl)piperidin-4-yl]methanol

[0137] To a stirred solution of 1-fluoro-4-nitrobenzene (5.0 g; 33.66 mmol; 1.0 eq.) and (piperidin-4-yl)methanol (8.2 g; 67.33 mmol; 2.0 eq.) in ACN (50 ml) K2CO3(9.4 g;67.33 mmol; 2.0 eq.) was added in portions at room temperature. The resulting mixture was stirred for 2h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10: 1) to afford [ 1 -(4-nitrophenyl)piperidin-4-yl]methanol (7.4 g;31.28 mmol; 93 % yield) as a yellow solid.

[0138] LC-MS method D: [M+H]+237.2; Rt: 0.70 min 1-(4-nitrophenyl)piperidine-4-carbaldehyde

[0139] To a stirred solution of [1-(4-nitrophenyl)piperidin-4-yl]methanol (2.0 g; 8.46 mmol; 1.0 eq.) in DCM (10 ml) was added Dess-Martin periodinane (7.6 g; 16.91 mmol: 2.0 eq.) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was slimed for 1h at room temperature. The resulting mixture was quenched with water at room temperature and extracted with DCM three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EtOAc (3:1) to afford 1- (4-nitrophenyl)piperidine-4-carbaldehyde (1.2 g; 5.08 mmol; 60 % yield) as an orange yellow solid.

[0140] LC-MS method D: [M+H]+235.1 ; Rt: 0.66 minIntermediate 4: 3-[4-(1-{[1-(4-aminophenyl)piperidin-4-yl]methyl}piperidin-4- yl)phenyl] piperidine-2, 6-dione3-[4-(1-{[1-(4-nitrophenyl)piperidin-4-yl]methyl}piperidin-4-yl)phenyl]piperidine-2,6- dione

[0141] Starting from Intermediate 2 (400 mg; 1 .4 mmol; 1.0 eq.) and Intermediate 3 (331 mg; 1.4 mmol; 1.0 eq.) the general procedure B for reductive amination was followed in the presence of DCM: MeOH 1 :1 mixture (0.35 M) sodium acetate trihydrate (3.0 eq.) and sodium cyanoborohydride (3.0 eq.) to afford the desired product (500 mg; 0.88 mmol; 63 % yield) as a yellow solid.

[0142] LC-MS method D: [M+H]+491 .2; Rt: 0.61 min3-[4-(1-{[1-(4-aminophenyI)piperidin-4-yI]methyl}piperidin-4-yl)phenyl]piperidine-2,6- dione

[0143] Starting from 3-[4-(1-{[1-(4-nitrophenyl)piperidin-4-yl]methyl}piperidin-4- yl)phenyl]piperidine-2, 6-dione (480 mg; 0.85 mmol; 1.0 eq.) the general procedure C for reduction with iron and ammonium chloride was followed in the presence of a EtOH: H2O 5:1 mixture (0.14 M), Fe (5.0 eq.) and ammonium chloride (6.0 eq.) to afford the desired product (400 mg; 0.82 mmol; 97% yield) as a yellow solid.

[0144] LC-MS method D: [M+H] ]++461 .2: Rt: 0.47 minIntermediate 5: 2-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperidin-1-yl)acetic acidtert-butyl 4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperidine-1-carboxyIate

[0145] To a solution of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (20.0 g; 71 .08 mmol; 1 .0 eq.) and 3-bromopiperidine-2, 6-dione (64.2 g; 284.34 mmol; 4.0 eq.) in DMF (180 ml) DIEA (29.01 g; 213.25 mmol; 3.0 eq.) was added. The reaction mixture was stirred for 2 h at 80 °C. The reaction mixture was diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. filtered and concentrated under reduced pressure to obtain the desired product (28.0 g; 68.36 mmol; 96 % yield) as a green solid.

[0146] LC-MS method E: [M+Na]+410.2; Rt: 0.81 min3-{[4-(piperidin-4-yl)phenyl]amino}piperidine-2, 6-dione

[0147] Starting from tert-butyl 4-{4-[(2,6-dioxopiperidin-3- yl)amino]phenyl(piperidine-1-carboxylate (41.4 g; 106.72 mmol; 1.0 eq.) the general procedure F for Boc deprotection was followed in the presence of 4M HCI in dioxane (7.5 eq.) to afford the desired product (28.0 g; 89.64 mmol; 84% yield).

[0148] LC-MS method E; [M+H]+288.1; Rt; 0.40 min tert-butyl 2-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl]piperidin-1-yl)acetate

[0149] To a stirred mixture of 3- {[4-(piperidin-4-yl)phenyl]amino}piperidine-2,6- dione (28.0 g; 95.30 mmol; 1.0 eq.)and D1EA (80.1 ml; 476.48 mmol; 5.0 eq.) in DMF (200 ml) was added tert-butyl 2 -bromoacetate (22.8 g; 114.36 mmol; 1.2 eq.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature. The reaction mixture was then extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA:PE=1;1, to afford tert-butyl 2-(4-{4-[(2,6-dioxopiperidin-3- yl)amino]phenyl)piperidin-1-yl)acetate (20.00 g; 48.55 mmol; 51 % yield) as a white solid.

[0150] LC-MS method E: [M+H]+402.2; Rt: 0.56 min2-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl(piperidin-1-yl)acetic acid

[0151] To a stirred mixture of tert-butyl 2-(4-{4-[(2,6-dioxopiperidm-3-yl)amino]phenyl}piperidin-1-yl)acetate (10.0 g; 21.17 mmol; 1.0 eq.) in DCM (150 ml) was added TFA (38 ml) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 4h at room temperature. The reaction mixture was concentrated under reduced pressure and directly used in the next step without further purification.

[0152] LC-MS method B: [M+H]+346.0; Rt; 0.36 minIntermediate 6: tert-butyl 7-(2-aminoquinazolin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3- b] [1,4]oxazine-1-carboxylate

[0153] To a stirred solution of tert -butyl 7-(2-chloroquinazolin-7-yl)-8- methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate Intermediate 1 (2.0 g; 4.68 mmol; 1.0 eq.) in dioxane (8.0 ml) NH3.H2O (8.0 ml; 58.16 mmol;12.4 eq.) was added in portions at room temperature under nitrogenatmosphere. The reaction mixture was stirred in a sealed tube for 4h at 90°C. The reaction mixture was concentrated under reduced pressure to obtain the desired product (1 .8 g; 4.23 mmol; 91 % yield) as a yellow solid which was used without further purification.

[0154] LC-MS method G: [M+H]+394.3 ; Rt: 0.61 minIntermediate 7: 3-(4-bromophenyI)azetidinetert-butyl 3-(4-bromophenyl)azetidine-1-carboxyIate

[0155] A solution of tert-butyl 3-iodoazetidine-1-carboxylate (4.0 g; 13.42 mmol; 0.7 eq.), (4-bromophenyl)boronic acid (4.2 g; 20.06 mmol; 1.0 eq.), ( 1R,2R)-2- aminocyclohexan-1-ol (163 mg; 1.34 mmol; 0.07 eq.), NaHMDS (6.8 ml; 13.60 mmol; 0.7 eq.), NiI2 (440 mg; 1.34 mmol; 0.07 eq.) in iPrOH (40 ml) was stirred for 30 min at room temperature. The reaction mixture was stirred in a microwave for 2h at 80 °C under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column, eluted with 70% EtOAc in PE, to afford tert-butyl 3-(4-bromophenyl)azetidine- 1-carboxylate (2.9 g; 7.55 mmol; 38 % yield) as a white solid.

[0156] LC-MS method C: [M+H] ]+ +255.9; Rt: 1 .17 min3-(4-bromophenyl)azetidine

[0157] Starting from tert-butyl 3-(4-bromophenyl)azetidine-1-carboxylate (1.5 g; 3.90 mmol; 1 .0 eq.) the general procedure J for Boc deprotection was followed in the presence of DCM (0.43 M) and TFA ( 10.1 eq) to obtain the desired product (640 mg; 2.53 mmol; 65 % yield) as a yellow solid.

[0158] LC-MS method B; [M+H]+212.0; Rt: 0.54 minIntermediate 8: 2,6-bis(benzyIoxy)-3-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2- yl)pyridine

[0159] To a stirred solution of 2,6-bis(benzyloxy)-3-bromopyridine (34.0 g; 87.24 mmol; 1 .0 eq.) and BPD ( 1 16.6 g; 436.20 mmol; 5.0 eq.) in dioxane (340 ml) 1 , 1'- bis(diphenylphosphmo)ferrocene-palladium(II)dichloride dichloromethane complex (7.5 g;8.72 mmol; 0. 1 eq.) and KOAc (18.0 g; 174.48 mmol; 2.0 eq.) were added in portions at room temperatine. The reaction mixture was stirred for 3 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the residue directly purified by silica gel column chromatography, eluted with PE / EA(5: 1), to afford2,6- bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)pyridine (36.0 g; 80.22 mmol; 92 % yield) as a white solid.

[0160] LC-MS method B; [M+H]+418.2; Rt: 1 .41 mmIntermediate 9: 1-[4-(2,6-dioxopiperidin-3-yl)phenyI]piperidine-4-carbaldebyde1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine

[0161] To a stirred solution of 1-bromo-4-iodobenzene (3.0 g; 10.07 mmol; 1.0 eq.) and 4-(dimethoxymethyl)piperidine (1.4 g; 8.35 mmol; 0.8 eq.) in toluene (40 ml) Pd2(dba)3(812 mg; 0.80 mmol; 0.08 eq.), Xantphos (1.0 g; 1.67 mmol; 0.2 eq.) and CS2CO3(578 mg; 1.69 mmol; 0.2 eq.) were added in portions at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 12h at 100 °C under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc three times.The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column, eluted with 75% EtOAc in PE, to afford 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (2.0 g; 4.56 mmol; 45 % yield) as a yellow solid.

[0162] LC-MS method C: [M+H]+316.1; Rt: 0.75 min2.6-bis(benzjdoxy)-3-{4-[4-(dimethoxymethyl)piperidin-1-yl]phenyl}pyridme

[0163] Starting from 1-(4-bromophenyl)-4-(dimethoxymethyl)piperidine (4.0 g; 9.08 mmol; 2.0 eq.) and Intermediate 8 (2.0 g; 4.46 mmol; 1.0 eq.) the general procedure G for Suzuki coupling was followed in the presence of dioxane: H2O 5: 1 mixture (0.12 M), Pd(dppf)Cl2(0.1 eq.) and K2CO3(1.4 eq.) to afford the desired product (1.7 g; 3.24 mmol; 36 % yield) as a white solid.

[0164] LC-MS method E: [M+H]+525.3; Rt: 0.90 min3-{4-[4-(dimethoxymethyl)piperidin-1-yI]phenyI}piperidine-2, 6-dione

[0165] Starting from 2,6-bis(benzyloxy)-3- { 4-[4-(dimethoxymethyl)piperidin- 1 - yl]phenyl [pyridine (1.5 g; 2.86 mmol; 1.0 eq.) the general procedure E for hydrogenation was followed in the presence of dioxane (0.57 M) and Pd / C (0.2 eq.) to afford the desired product (1.0 g; 2.80 mmol; 98 % yield) as a yellow solid.

[0166] LC-MS method E: [M+H]+347.2; Rt: 0.36 min 1-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperidine-4-carbaldehyde

[0167] Starting from 3-{4-[4-(dimethoxymethyl)piperidin-1-yl]phenyl}piperidine-2.6-dione (500 mg; 1 .40 mmol; 1.0 eq.) the general procedure J was followed in the presence of DCM (0. 16 M) and TFA (28.0 eq.) to afford the desired product (410 mg; 1 .24 mmol; 88% yield) as a yellow solid.

[0168] LC-MS method H: [M+H]+301 .2; Rt: 0.20 minIntermediate 10: 1- (4- 1b-romo-2-methylphenyl)-1, 3-diazinane-2, 4-dione

[0169] To a solution of 4-bromo-2 -methylaniline (25.0 g; 133.03 mmol; 1 .0 eq.) and prop-2 -enoic acid (40.4 g; 532.59 mmol; 4.0 eq.) was stirred at 110 °C for 3 h. Then urea (53.80 g; 851 .05 mmol; 6.4 eq.) and AcOH (200 ml) was added and the reaction mixture was stirred at 120 °C for 12 h under a nitrogen atmosphere. Water was added into the reaction mixture at 0°C. The solid was filtered, and the filter cake was washed with water to give 1-(4- bromo-2-methylphenyl)-1, 3-diazinane-2 ,4-dione (32.0 g; 103.93 mmol; 78 % yield) as a light yellow solid.

[0170] LC-MS method E: [M+H]+283.0; Rt: 0.64 mmIntermediate 11: tert-butyl 3-{4-[4-(2,4-dioxo-1, 3-diazinan-1-yI)-3-methylphenyl]- 1, 2, 3, 6-tetrahydropyridin-1-yl}azetidine-1-carboxylatetert-butyl 4-[4-(2,4-dioxo-1, 3-diazinan-1-yl)-3-methyIphenyI]-1, 2,3,6- tetra hyd ropyridine- 1 -carboxylate

[0171] Starting from Intermediate 10 (3.0 g; 9.74 mmol; 1.0 eq.) and tert-butyl 4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1, 2,3, 6-tetrahydropyridine-1-carboxylate (3.6 g; 9.75 mmol; 1.0 eq.) the general procedure D for Suzuki coupling was followed in the presence of dioxane. H2O mixture 5.1 (0.27 M), Pd(dppf)Cl2DCM (0. 1 eq.) and K2CO3(2.0 eq.) to obtain the desired product (3.5 g; 9.01 mmol; 93% yield) as a pink solid.

[0172] LC-MS method E: [M-tBu+H]+286. 1 ; Rt: 0.78 min1-[2-methyl-4-(1,2, 3,6-tetrahydropyridin-4-yl)phenyl]-1, 3-diazinane-2, 4-dione hydrochloride

[0173] Starting from tert-butyl 4-[4-(2,4-dioxo-1, 3-diazinan-1-yl)-3-methylphenyl]- 1 , 2, 3, 6-tetrahydropyridine-1-carboxylate (3.5 g; 9.01 mmol; 1.0 eq.) the general procedure F for Boc deprotection was followed in the presence of 2M HC1 in EtOAc (6.7 eq.) to afford the desired product (3.1 g; 8.76 mmol; 97% yield) as a yellow solid.

[0174] LC-MS method E; [M+H]+286.0; Rt; 0.40 minIntermediate 12: 7-{8-methyl-1H,2H,3H-pyrido[2,3-b] [1,4]oxazin-7-yl}-N-(4-{1- [(piperidin-4-yl)methyl]piperidin-4-yl}phenyI)quinazolin-2-amine; trifluoroacetic acidtert-butyl 4-{[4-(4-aminophenyl)piperidin-1-yl]methyl}piperidine-1-carboxylate

[0175] 4-(piperidin-4-yl)aniline (140 mg; 0.77 mmol; 1.0 eq.), K2CO3(215 mg; 1.54 mmol; 2.0 eq.) and Nal (58 mg; 0.39 mmol; 0.5 eq. ) were suspended in acetonitrile (2.8 ml) and tert-butyl 4-(bromomethyT)piperidine- 1 -carboxylate (226 mg; 0.77 mmol; 1 .0 eq.) was added in a vial. The vial was crimped, inertised with argon and stirred at 60°C for 61 h.

[0176] The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was then purified by flash column chromatography to obtain tert- butyl 4- {[4-(4-aminophenyl)piperidin-1-yl]methyl}piperidine-1-carboxylate (240 mg; 0.64 mmol; 78 % yield) as a white solid.

[0177] LC-MS method K: [M+H]+374.4; Rt; 0.37 min tert-butyl 4-[(4-[4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyI-1H,2H,3H-pyrido[2,3- b][1,4]oxazin-7-yl}quinazolin-2-yl)amino]phenyl}piperidin-1-yl)methyI]piperidine-1- carboxylate

[0178] Starting from Intermediate 1 (80 mg; 0. 19 mmol; 1 .0 eq.) and tert-butyl 4- {[4-(4-aminophenyl)piperidin-1-yl]methyI}piperidine- 1 -carboxylate (72 mg; 0.19 mmol; 1.0eq.) the general procedure H for Buchwald coupling was used in the presence of dioxane (0.12 M), Pd-PEPPSI-IPentCl 2 -methylpyridine (o-picoline) (0.03 eq.) and CS2CO3(2.0 eq.) to afford the desired product (124 mg; 0. 14 mmol; 63% yield) as a yellow solid.

[0179] LC-MS method L: [M+H]+750.3; Rt: 1 .38 min7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-N-(4-{1-[(piperidin-4- yl)methyl]piperidin-4-yl}phenyI)qumazolin-2-amine; trifluoroacetic acid

[0180] Starting from tert-butyl 4-[(4-{4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl- 1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}quinazolin-2-yl)amino]phenyl}piperidin-1- yl)methyl]piperidine-1-carboxylate (124 mg; 0.14 mmol; 1.0 eq.) the general procedure J for Boc deprotection was followed in the presence of DCM (0.06 M) and TFA (20.0 eq.) to afford the desired product (90 mg; 0.14 mmol; 99% yield).

[0181] LC-MS method M: [M+H]+550.3; Rt: 0.75 minIntermediate 13: 4-[(2,6-dioxopiperidin-3-yI)oxy]benzoic acidtert-butyl 4-[(2,6-dioxopiperidin-3-yl)oxy]benzoate

[0182] Tert-butyl 4-hydroxybenzoate (1 .0 g; 4.89 mmol; 1.0 eq.) was dissolved in THF (16 ml). The reaction was cooled down under argon atmosphere to 0°C and NaH 60 % dispersion in mineral oil (489 mg; 12.23 mmol; 2.50 eq.) was added in portions. The reaction mixture was stirred at 0°C for 0.5 h and 3-bromopiperidine-2, 6-dione (1.48 g; 7.34 mmol; 1.50 eq.) was added in portions. The reaction was then heated at 50 °C for 1 h. The reaction mixture was quenched by the addition of ice and saturated NH4CI solution and extracted with EtOAc three times. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained pale beige solid was triturated with MTB ether, filtered off, washed with ice-cold MTB ether and dried at 2mbar and 55°C to give to give tert-butyl 4-[(2,6-dioxopiperidin-3-yl)oxy]benzoate (1.27 g; 4.15 mmol; 85 % yield) as a white solid.

[0183] LC-MS method K: [M-‘Bu+H]+250.1 ; Rt: 0.72 min4-[(2,6-dioxopiperidin-3-yl)oxy]benzoic acid

[0184] Starting from tert-butyl 4-[(2,6-dioxopiperidin-3-yl)oxy]benzoate (250 mg;0.82 mmol; 1.0 eq.) the general procedure J was followed in the presence of DCM (0.16 M) and TFA (40.0 eq.) to give the desired product (209 mg; 0.82 mmol; 100 % yield) as a gray solid.

[0185] LC-MS method K: [M+H]+250. 1 ; Rt: 0.46 minIntermediate 14: (az 1e-tidin-3-yl)-4-(4-nitrophenyl)piperidinetert-butyl 3-[4-(4-nitrophenyl)piperidin-1-yl]azetidine-1-carboxylate

[0186] Starting from 4-(4-nitrophenyl)piperidine (1.3 g; 5.99 mmol; 1.0 eq.) and tert- butyl 3 -oxoazetidine- 1 -carboxylate ( 1.2 g; 6.59 mmol; 1.1 eq.) the general procedure B for reductive amination was followed in the presence of DCM: MeOH 1 :1 mixture (0.30 M) sodium acetate (5.0 eq.) and sodium cyanoborohydride (4.0 eq.) was added to afford the desired product (2.0 g; 5.48 mmol; 92% yield) as a yellow oil.

[0187] LC-MS method E: [M+H]+362.2; Rt: 0.59 min 1-(azetidin-3-yl)-4-(4-nitrophenyl)piperidine

[0188] Starting from tert-butyl 3-[4-(4-nitrophenyl)pipeiidin-1-yl]azetidine-1- carboxylate (2.0 g; 5.48 mmol; 1.0 eq.) the general procedure J for Boc deprotection was followed in the presence of DCM (0.27 M) and TFA (1 1.9 eq) to afford the desired product (1.0 g; 3.71 mmol; 68% yield) as a yellow solid.

[0189] LC-MS method E: [M+H]+262. 1 ; Rt: 0.18 minIntermediate 15: 3-[4-(piperidin-4-yI)phenoxy]piperidine-2, 6-dione hydrochloridetert-butyl 4-{4-[(2,6-dioxopiperidin-3-yl)oxy]phenyl]piperidine-1-carboxylate

[0190] Tert-butyl 4-(4-hydroxyphenyl)piperidine-1-carboxylate (7.0 g; 23.98 mmol;1.0 eq.) was filled into the flask and dissolved in DMF (112 ml). It was cooled down to 0°C and sodium hydride, 60 % dispersion in mineral oil (2.4 g; 59.94 mmol; 2.5 eq.) was added portion wise and stirred at 0 - 5°C for 0.5 hrs. Thereafter 3-bromopiperidine-2, 6-dione (7.3 g; 35.96 mmol; 1.50 eq.) was added portion 'wise and the reaction mixture was stirred for 1h at 0-5°C. Additionally sodium hydride, 60 % dispersion in mineral oil (250 mg; 6.25 mmol;0.26 eq.) was added and stirring was continued for 1 h. Sodium hydride, 60 % dispersion in mineral oil (150 mg; 3.75 mmol; 0.16 eq.) was added and stirring was continued for 1 h.

[0191] The reaction mixture w as poured into a mixture of saturated ammonium chloride solution and icew ater and stirred for 15 min to form a grey blueish suspension, which was filtered off. The filtered off solid was washed three times with ice cold water and dried (approx. 3 mbar ; 50°C ; 16 h) to give 9.83 g erode product (105.5% yield). The solid was triturated with MTB ether and dried (approx. 3 mbar ;50°C; 16 h) to give tert-butyl 4-{4- [(2,6-dioxopiperidin-3-yl)oxy]phenyl}piperidine-1-carboxylate (7.36 g; 18.95 mmol; 79 % yield) as a beige brownish solid.

[0192] LC-MS method K; [ M-H-tBu]+333.2; Rt; 0.78 min3-[4-(piperidin-4-yI)phenoxy]piperidine-2, 6-dione hydrochloride

[0193] Starting from tert-butyl 4-{4-[(2,6-dioxopiperidin-3-yl)oxy]phenyl}piperidine- 1 -carboxylate (750 mg; 1.93 mmol; 1.0 eq.) the general procedure F for Boc deprotection was followed in the presence of DMC (0.13 M) and 4 M HC1 in dioxane (16.2 eq.) to obtain the desired product (663 mg; 1.93 mmol; 100 % yield) as a beige solid.

[0194] LC-MS method K: [M+H]+289.2; Rt: 0.32 minIntermediate 16: 7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-N-{4- ](piperazin-1-y])methyl]phenyl]quinazoIin-2-amine; trifluoroacetic acidtert-butyl 4-({4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3- b] [ 1 ,4] oxazin-7-yl] quinazolin-2-yl)amino] phenyl] methyl)piperazine-1-carboxy late

[0195] Starting from Intermediate 1 (250 mg; 0.61 mmol; 1.0 eq.) and tert- butyl 4-[(4-aminophenyl)methyl]piperazine- 1 -carboxylate (186 mg; 0.61 mmol; 1.0 eq.) the general procedure H for Buchwald coupling was followed in the presence ofdioxane (0.12 M), Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (0.03 eq.) and CS2CO3(2.0 eq.) to obtain the desired product (322 mg; 0.40 mmol; 63 % yield) as a yellow solid.

[0196] LC-MS method L: [M+H]+668.3; Rt: 1 .34 min7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-N-{4-[(piperazin-1- yl)methyl] phenyl] quinazolin-2-amine; trifluoroacetic acid

[0197] Starting from 7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-N-{4-[(piperazin-1-yl)methyl]phenyl}quinazolin-2-amine; trifluoroacetic acid (322 mg; 0.40 mmol; 1.0 eq.) the general procedure J for Boc deprotection was followed in the presence of DCM (0.06 M) and TFA (20.0 eq.) to afford the desired product (188 mg; 0.32 mmol; 82% yield) as a yellow oil.

[0198] LC-MS method M: [M+Hty 468.2; Rt; 0.76 minIntermediate 17: 3-[4-(piperazin-1-yl)phenoxy]piperidine-2, 6-dione dihydrochloridetert-butyl 4-{4-[(2,6-dioxopiperidin-3-yI)oxy]phenyl]piperazine-1-carboxyIateUNZ014 / 430

[0199] tert-butyl 4-(4-hydroxyphenyI)piperazine-1-carboxylate (8.0 g;27.88 mmol; 1 .0 eq.) was dissolved into DMF ( 128 ml). The mixture was cooled down to 0°C and sodium hydride, 60 % dispersion in mineral oil (2.8 g; 69.70 mmol; 2.5 eq.) was added portion wise. After 5 min, 3- bromopiperidine-2, 6-dione (8.45 g; 41.82 mmol; 1.5 eq.) was added portion wise and the reaction mixture was stirred for 1 h at 0-5°C.

[0200] The reaction mixture was poured into a mixture of saturated ammonium chloride solution and icewater. It was stirred for 15 min to form a grey blueish suspension, which was filtered off. The filtered off solid was washed three times with ice cold water and dried (approx. 3 mbar; 50°C; 16 h). The solid was triturated with MTB ether, filtered off with suction, washed two times with MTB ether and dried (approx. 3 mbar; 50°C; 22 h) to give tert-butyl 4-{4-[(2,6-dioxopiperidin-3-yl)oxy]phenyI]piperazine-1-carboxylate (10.10 g; 25.93 mmol; 93 % yield) as a beige brownish solid.

[0201] LC-MS method K; [M+H]+390.3; Rt: 0.66 min3-[4-(piperazin-1-yl)phenoxy]piperidine-2, 6-dione dihydrochloride

[0202] Starting from tert-butyl 4-{4-[(2,6-dioxopiperidin-3- yl)oxy]phenyl}piperazine-1-carboxylate (1.0 g; 2.57 mmol; 1.0 eq.) the general procedure F for Boc deprotection was followed in the presence of DCM (0.13 M) and 4 M HC1 in dioxane (16.2 eq.) to obtain the desired product (980 mg; 2.57 mmol; 100 % yield) as a grey- solid.

[0203] LC-MS method K: [M+H]+290.2; Rt: 0.30 minIntermediate 18: 3-[2,6-bis(benzyloxy)pyridin-3-yl]-7-bronio-1-methyl-1H-indazole7-bromo-3-iodo-1H-indazole

[0204] To a stirred solution of 7-bromo-1H-indazole (49.0 g; 236.26 mmol; 1.0 eq.) and I2(94.7 g; 354.38 mmol; 1.5 eq.) in DMF (800 ml) was added KOH (20.9 g; 354.38 mmol; 1 .5 eq.) at 0 °C. The resulting mixture was stirred for 12h at room temperature under nitrogen atmosphere. The reaction was quenched with water at 0°C, followed by the addition of a saturated sodium sulfite aqueous solution. The resulting mixture was filtered and the filter cake was dissolved in with washed with water and EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. This resulted 7-bromo-3-iodo-1H-indazole (77.0 g; 232.93 mmol; 99 % yield) as a white solid.

[0205] LC-MS method N: [M+H]+320.8; Rt: 1 .03 min7-bromo-3-iodo-1-methyI-1H-mdazole

[0206] To a stirred solution of 7-bromo-3-iodo-1H-indazole (77.0 g; 238.44 mmol; 1.0 eq.) and KOH (35.2 g; 596.1 1 mmol; 2.5 eq.) in acetone (500 ml) CH3I (37.5 ml; 596.11 mmol; 2.5 eq.) was added at 0 º C. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere.

[0207] The resulting mixture was filtered, and the filter cake was washed with DCM. The filtrate was concentrated under reduced pressure. The residue was purified by silica gelcolumn chromatography, eluted with petroleum ether / EtOAc (20: 1) to afford 7-bromo-3- iodo-1 -methyl- 1H-indazole (62.0 g; 173.59 mmol; 73 % yield) as a white solid.

[0208] LC-MS method O: [M+H]+336.9; Rt: 1.14 min3-[2,6-bis(benzyloxy)pyridin-3-yl]-7-bromo-1-methyl-1H-indazole

[0209] To a stirred solution of 7-bromo-3 -iodo- 1 -methyl- 1H-indazole (50.0 g; 139.99 mmol; l.OOeq.) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2- yl)pyridine Intermediate 8 (102.0 g; 181.99 mmol; 1.3 eq.) in 1,4-dioxane (1800 ml) and H2O (600 ml) K3PO4(259.61 g; 1161 .91 mmol; 8.30 eq.) and Pd(PPh3)4(17.03 g; 14.00 mmol;0.10 eq.) were added. The resulting mixture was stirred for 2 h at 85 °C under nitrogen atmosphere.

[0210] The mixture was allowed to cool down to room temperature. The aqueous layer was extracted with EtOAc twoce. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / EtOAc (50:1), to afford 21b (24.0 g; 39.42 mmol; 28 % yield) as a white solid.

[0211] LC-MS method G: [M+H]+500.1 ; Rt: 1 .50 minIntermediate 19: 3-[1-methyl-7-(piperazin-1-yl)-1H-indazoI-3-yl]piperidine-2, 6-dione; trifluoroacetic acidtert-butyl 4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyl-1H-indazol-7-yl}piperazine-1- carboxylate

[0212] Starting from Intermediate 18 (4.1 g; 7.49 mmol; 1.0 eq.) and tert-butyl piperazine- 1 -carboxylate (2.2 g; 1 1.23 mmol; 1.5 eq.) the general procedure H for Buchwald coupling was followed in the presence of dioxane(0.12 M), Pd-PEPPSI-IPent (0.04 eq.) and CS2CO3(2.0 eq.) to obtain the desired product (3.2 g; 5.26 mmol; 70% yield) as a yellow solid.

[0213] LC-MS method N: [M+H]+606.4; Rt: 1 .58 min tert-butyl 4-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yI]piperazine-1- carboxylate

[0214] Starting from tert-butyl 4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]- 1-methyl-1H-indazol-7-yl}piperazine-1-carboxylate (1.0 g; 1.46 mmol; 1.0 eq.) the general procedure E for hydrogenation was followed in the presence of dioxane (0.10 M) and Pd / C (0.32 eq.) to afford the desired product (600 mg; 1 .08 mmol; 74% yield) as a yellow oil.

[0215] LC-MS method O: [M+H]+428.2 ; Rt: 1 .02 min3-[1-methyl-7-(piperazin-1-yI)-1H-indazol-3-yI]piperidine-2, 6-dione; trifluoroacetic acid

[0216] Starting from tert-butyl 4-[3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-7-yl]piperazine-1-carboxylate (1.0 g; 2.33 mmol; 1.0 eq.) the general procedure J for Boc deprotection was followed in the presence of DCM (0.23 M) and TFA (19.6 eq.) to afford the desired product ( 1.1 g; 2.15 mmol; 92% yield) as a brown solid.

[0217] LC-MS method H: [M+H]+328.2; Rt: 0.46 minIntermediate 20: tert-butyl N-(4-{[4-(2-bronioacetyI)piperazin-1- yl] methyl}phenyl)carbamatetert-butyl N-{4-[(piperazin-1-yI)methyl]phenyl}carbamate

[0218] Piperazine (2.1 g; 24.90 mmol; 5.0 eq.) was dissolved in DCM (100 ml) and N-boc-4-(bromomethyl)aniline (1.5 g; 4.98 mmol; 1.0 eq.) dissolved in DCM (10 ml) was added dropwise. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was washed with water twice and the combined water layers were re-extracted with dichloromethane once. The combined organic layers were washed with brine once, dried overNa2SO4, filtered and evaporated to obtain the desired product (1.6 g; 4.75 mmol; 95 % yield) which was used in the next step without further purification.

[0219] LC-MS method P: [M+H]+292.2; Rt: 1 .08 min tert-butyl N-(4-{[4-(2-bromoacetyl)piperazin-1-yI]methyl}phenyl)carbamate

[0220] tert-Butyl N- {4-[(piperazin-1-yl)methyl]phenyl}carbamate (1.60 g; 4.75 mmol; 1 .0 eq.) was suspended in DCM (30 ml) and DIPEA (1.6 ml; 9.49 mmol; 2.0 eq.) was added. The solution was cooled with an ice water bath and bromoacetyl chloride (499 [M;+H]+5.70 mmol; 1.2 eq.) dissolved in DCM (5 ml) was added dropwise and stirred for 1 h at 5°C. The reaction mixture was diluted with water and extracted with DCM three times. The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by flash column chromatography (DCM:MeOH; 95:5 as eluent) to obtain the desired product (687 mg; 1.58 mmol; 33% yield) as a yellow oil.

[0221] LC-MS method P: [M+Na]+436.0; Rt: 1 .25 minIntermediate 21: 3-[1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl]piperidine-2, 6-dione: trifluoroacetic acidtert-butyl 4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyI-1H-indazol-6-yl]-1, 2,3,6- tetrahydropyridine-1-carboxylate

[0222] Starting from Intermediate 18 (4.5 g; 8.35 mmol; 1.0 eq.) and tert-butyl 4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1, 2,3,6-tetrahydropyridine-1- carboxylate (4.4 g; 13.52 mmol; 1.6 eq.) the general procedure D for Suzuki coupling was followed in the presence of dioxane:H2O mixture 6: 1 (0.16 M), Pd(dppf)Cl2DCM (0.1 eq.) and K2CO3(2.7 eq.) to obtain the desired product (6.0 g; 9.34 mmol; quantitative yield) as a yellow solid.

[0223] LC-MS method O: [M+H]+603.3 ; Rt: 1 .50 mintert-butyl 4-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yI]piperidine-1- carboxylate

[0224] Starting from tert-butyl 4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1- methyl-1H-indazol-6-yl} -1, 2,3,6-tetrahydropyridine-1-carboxylate (5.5 g; 8.48 mmol; 1.0 eq.) the general procedure E for hydrogenation was followed in the presence of EtOH:EtOAc 1 : 1 mixture (0.08 M) and Pd / C (0.3 eq.) to afford the desired product (4.5 g; 9.70 mmol; quantitative yield) as a brown oil.

[0225] LC-MS method B: [M+H]+427. 1 ; Rt: 0.89 min3-[1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yI]piperidine-2, 6-dione; trifluoroacetic acid

[0226] Starting from tert-butyl 4-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H- indazol-6-yl]piperidine-1-carboxylate (4.4 g; 9.48 mmol; 1.0 eq.) the general procedure J for Boc deprotection was followed in the presence of DCM (0. 19 M) and TFA (13.8 eq.) to afford the desired product (2.1 g; 4.77 mmol; 50 % yield) as a light brown solid.

[0227] LC-MS method N: [M+H]+327.1 ; Rt; 0.88 minIntermediate 22: 3-[2,6-bis(benzyloxy)pyridin-3-yI]-6-bromo-1-methyl-1H- indazole6-bromo-3-iodo-1H-indazole

[0228] To a solution of 6-bromo-1H-indazole (94.0 g; 453.23 mmol; I.OOeq.) in DMF (1000 ml) were added K2CO3(200 g; 1374.76 mmol; 3.0 eq.) and L (181.0 g; 711 .71 mmol;1.6 eq.) at room temperature. The mixture was stirred for overnight at room temperature under nitrogen atmosphere. The resulting mixture was dropwise added into an aqueous solution of Na2S2O3and filtered to afford 6-bromo-3-iodo-1H-indazole (145.0 g; 436.44 mmol; 96 % yield) as a light orange solid.

[0229] LC-MS method O: [M+H]+324.9; Rt: 0.95 min6-bromo-3-iodo-1-methyl-1H-indazole

[0230] To a solution of 6-bromo-3-iodo-1H-indazole (70.0 g; 212.65 mmol; 1.0 eq.) in acetone (700 ml) KOH (31.50 g; 533.33 mmol; 2.5 eq.) and Mel (34.00 ml; 546. 15 mmol;2.6 eq.) were added. The resulting mixture was stirred for 3h at room temperature under nitrogen atmosphere.

[0231] The resulting mixture was added water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EtOAc (5:1) to afford 6-bromo-3-iodo-1-methyl- 1H- indazole (51.0 g; 144.09 mmol; 68 % yield) as a yellow solid.

[0232] LC-MS method O: [M+H]+336.9; Rt: 1.08 min3-[2,6-bis(benzyloxy)pyridin-3-yl]-6-bromo-1-methyl-1H-indazoIe

[0233] Starting from 6-bromo-3 -iodo- 1 -methyl -1H-indazole (1.0 g; 2.96 mmol; 1.0 eq.) and intermediate 10 (2.5 g; 5.14 mmol; 1.7 eq.) the general procedure D for Suzuki coupling was followed in the presence of THF: H2O 5: 1 mixture (0.25 M), Pd(dppf)Cl2DCM (0. 1 eq.) and CS2CO3(3.0 eq.) to obtain the desired product (700 mg; 1 .22 mmol; 41% yield) as a yellow oil.

[0234] LC-MS method O: [M+H]+500.1 ; Rt: 1 .38 minIntermediate 23: 3-[1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl]piperidine-2,6-dione; trifluoroacetic acidtert-butyl 4-{3-[2,6-bis(benzyloxy)pyridin-3-yI]-1-methyl-1H-indazoI-6-yl}piperazine-1- carboxylate

[0235] A solution of 3 -[2,6-bis(benzyloxy)pyndin-3-yl]-6-bromo-1-methyl- 1H- indazole (5.6 g; 10.59 mmol; 1.0 eq.) and 1 -Boc -piperazine (4.5 g; 15.48 mmol; 1.46 eq.) and CS2CO3(11.2 g; 30.99 mmol; 2.9 eq.) and X-Phos (1 .0 g; 1 .99 mmol; 0.2 eq.) and Pd2(dba)3(1.00 g; 0.98 mmol; 0.1 eq.) in 1,4-dioxane (60ml) was stirred for 2h at 100 °C under nitrogen atmosphere.

[0236] The resulting mixture was added water and extracted with EtOAc (3 x 300mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE.ElOAc (3: 1) to afford tert-butyl 4-{3-[2,6- bis(benzyloxy)pyridin-3-yl]-1-methyl-1H-indazol-6-yl}piperazine-1-carboxylate (6.3 g; 9. 15 mmol; 86 % yield) as a light orange solid.

[0237] LC-MS method E: [M+H]+606.4; Rt: 1 .22 min tert-butyl 4-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yI]piperazine-1- carboxylate

[0238] Starting from tert-butyl 4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyl-1H- indazol-6-yl}piperazine-1-carboxylate (5.0 g; 7.26 mmol; 1.0 eq.) the general procedure E for hydrogenation was followed in the presence of dioxane (0.15 M) and Pd(OH)2. / C (0.5 eq.) to obtain the desired product (4.1 g; 8.13 mmol; quantitative yield) as a brown oil .

[0239] LC-MS method E: [M+H]+428.3; Rt: 0.78 min3-[1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl]piperidine-2,6-dione; trifluoroacetic acid

[0240] Starting from tert-butyl 4-[3-(2,6-dioxopiperidin-3-yl)-1-methyl- 1H-indazol-6- yl]piperazine-1-carboxylate (3.5 g; 5.24 mmol; 1.0 eq.) the general procedure J for Boc deprotection was followed in the presence of DCM (0.17 M) and TFA (24.9 eq.) to afford the desired product (850 mg; 1.87 mmol; 36% yield) as an off-white solid.

[0241] LC-MS method O: [M+H]+328.2; Rt: 0.48 minIntermediate 24: 7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl]-N-{1- [(piperidin-4-yl)methyl]-1H-pyrazol-4-yl}quinazolin-2-ainine hydrochloridetert-butyl 4-[(4-nitro-1H-pyrazol-1-yl)methyl]piperidine-1-carboxylate

[0242] To a mixture of 4-nitro-1H-pyrazole (2.00 g; 17.51 mmol; 1.00 eq.) and tert- butyl 4-(bromomethyl)piperidine-1-carboxylate (5.64 g; 19.26 mmol; 1.10 eq.) in MeCN (50.00 ml), CS2CO3(12.01 g; 35.02 mmol; 2.00 eq.) was added. The mixture was stirred for 2h at 80°C under an argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :4) to afford tert-butyl 4-[(4-nitro-1H-pyrazol- 1 -yl)methyl]piperidine- 1 -carboxylate (5.000 g; 15.88 mmol; 90.7 %) as a white solid.

[0243] LC-MS method H: [M+H]+333; Rt: 0.89 min tert-butyl 4-[(4-amino-1H-pyrazol-1-yI)methyl]piperidine-1-carboxylate

[0244] Starting from tert-butyl 4-[(4-nitro-1H-pyrazol- 1 -yl)methyl]piperidine- 1 - carboxylate (2.00 g; 6.35 mmol; 1.00 eq.) the general procedure E for hydrogenation was followed in the presence of DMF (20.00 ml) was added Pd / C (670.00 mg; 0.63 mmol; 0.10 eq.) to afford the desired product tert-butyl 4-[(4-amino-1H-pyrazol- 1-yl )methyl]piperidine- 1 -carboxylate (1.800 g; 6.12 mmol; 96.4 %) as a purple solid.

[0245] LC-MS method H: [M+H]+281 ; Rt: 0.59 min tert-butyl 4-({4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazin-7-yl}quinazolin-2-yl)amino]-1H-pyrazol-1-yl}methyl)piperidine-1- carboxylate

[0246] Starting from Intermediate 1 (1.00 g; 2.31 mmol; 1.00 eq.) and tert-butyl 4- [(4-amino-1H-pyraz.ol-1-yl)methyl]piperidine-1-carboxylate (680.00 mg; 2.31 mmol; 1.00 eq.) the general procedure H for Buchwald coupling was followed in the presence of in Dioxane- 1,4 (10.00 ml) were added Pd-PEPPSI-IPentCl 2 -methylpyridine (o-picoline) (205.00 mg; 0.23 mmol; 0.10 eq.) and Cs2CO3(1.59 g; 4.64 mmol; 2.00 eq.) to afford the desired product tert-butyl 4-( {4-[(7-{1-[(lert-butoxy)carbonyl]-8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazin-7-yl}quinazolin-2-yl)amino]-1H-pyrazol-1-yl}methyl)piperidine-1- carboxylate (750.00 mg; 1.07 mmol; 46.3 %) as a yellow solid.

[0247] LC-MS method H; [M+H]+657; Rt; 0.97 min7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-N-{1-[(piperidin-4-yl)methyI]-1H- pyrazol-4-yl] quinazoIin-2-amine hydrochloride

[0248] To tert-butyl 4-({4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H- pyrido[2,3-b][ 1 ,4]oxazin-7-yl } quinazolin-2-yl)amino]-1H-pyrazol-1 -yI}methyl)piperidine-1- carboxylate (730.00 mg; 1.04 mmol; 1.00 eq.), hydrochloric acid (2.0 M Solution In Ethyl Acetate) (7.00 ml; 14.00 mmol; 13.42 eq.) was added and stirred for 5h at RT under N2 atmosphere. The resulting mixture was concentrated under reduced pressure to afford 7-{8- methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-N-{1-[(piperidin-4-yI)methyl]-1H-pyrazol- 4-yl}quinazolin-2-amine hydrochloride (600.000 mg; 0.99 mmol; 94.6 %; yellow solid;Crude Product)

[0249] LC-MS method H; [M+H]+457; Rt; 0.56 minIntermediate 25: 2-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl] piperidin-1-yl)acetic acid hydrochloridetert-butyl 4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperidine-1-carboxyIate

[0250] To tert-butyl 4-(4-aminophenyl)piperidine- 1 -carboxylate (5.00 g; 17.77 mmol; 1.00 eq.) and 3-bromopiperidine-2,6-dione (5.38 g; 26.62 mmol; 1.50 eq.) in DMF (50.00 ml), DIEA (7.25 g; 53.29 mmol; 3.00 eq.) was added. The mixture was stirred for overnight at 60°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 : 1) to afford terl-butyl 4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperidine-1-carboxylate (4.600 g; 11.36 mmol; 63.9 %) as a green solid.

[0251] LC-MS method H: [M+H]+388; Rt: 0.65 min3-{[4-(piperidin-4-yl)phenyl]amino]piperidine-2, 6-dione hydrochloride

[0252] To tert-butyl 4- {4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperidine- 1 - carboxylate (3.40 g; 8.40 mmol; 1.00 eq.), hydrochloric acid (2.0 M Solution In Ethyl Acetate) (34.00 ml; 68.00 mmol; 8.10 eq.) was added portion wise at 0 °C under a N2atmosphere. The resulting mixture was stirred for 5h at room temperature under N2atmosphere. The resulting mixture was concentrated under vacuum to afford 3-{[4-(piperidin-4-yI)phenyl]amino}piperidine-2, 6-dione hydrochloride (2.800 g; 8.38 mmol; 99.7 %) as a brown solid.

[0253] LC-MS method H: [M+H]+288; Rt: 0.42 min tert-butyl 2-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyI}piperidin-1-yI)acetate

[0254] To 3-{[4-(piperidin-4-yl)phenyl]amino}piperidine-2, 6-dione hydrochloride(500.00 mg; 1.50 mmol; 1.00 eq.) and DIEA (1.26 ml; 7.48 mmol; 5.00 eq.) in DMF (10.00 ml), tert-butyl 2 -bromoacetate (595.00 mg; 2.99 mmol; 2.00 eq.) was added portion wise under a nitrogen atmosphere. The resulting mixture was stirred for 2h at 25 °C under nitrogen atmosphere. The resulting mixture was diluted with water (20ml), extracted with EtOAc (3 x 15ml). The combined organic layers were washed with brine (20ml), dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :4) to afford tert-butyl 2-(4-{4-[(2,6- dioxopiperidin-3-yl)amino]phenyl}piperidin-1-yl)acetate (310.000 mg; 0.72 mmol; 48.1 %) as a yellow solid.

[0255] LC-MS method H; [M+H]+402; Rt: 0.63 min2-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperidin-1-yl)acetic acid hydrochloride

[0256] To tert-butyl 2-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperidin-1- yl)acetate (300.00 mg; 0.72 mmol; 1.00 eq.), Hydrochloric acid (2.0 M Solution In Ethyl Acetate) (3.00 ml; 6.00 mmol; 8.34 eq.) was added. The mixture was stirred for 5h at room temperature under a N2atmosphere. The resulting mixture was concentrated under reduced pressure to afford 2-(4- {4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperidin-1-yl)acetic acid hydrochloride (300.000 mg; 0.64 mmol; 88.5 %) as a yellow solid.

[0257] LC-MS method H: [M+H]+346; Rt: 0.46 minIntermediate 26: [(4-b-romophenyI)methyl]-3-[(4-methoxyphenyl)methyl]-1, 3- diazinane-2, 4-dione3-[(4-methoxyphenyl)methyl]-1, 3-diazinane-2, 4-dione

[0258] To 1, 3 -diazinane-2 ,4-dione (10.00 g; 83.26 mmol; 1.00 eq.) and CS2CO3(42.83 g; 124.89 mmol; 1,50 eq.) in DMF (100.00 ml), (chloromethyl)- 14--methoxybenzene (13.73 g; 83.26 mmol; 1 .00 eq.) was added. The resulting mixture was stirred for 12h at RT under a nitrogen atmosphere. The reaction was diluted with H2O. The resulting mixture was extracted with EA (3 x 100mL). The combined organic layers were washed w ith brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The obtained solid was washed with EA:PE=1:1 to obtain 3-[(4-methoxyphenyl)methyl]-1, 3-diazinane-2,4- dione (10.00g; 42.69 mmol; 51.3%).

[0259] LC-MS method D: [M+H]+235. 10; Rt: 0.63 min1-[(4-bromophenyl)methyl]-3-[(4-methoxyphenyi)methyl]-1, 3-diazinane-2, 4-dione

[0260] To a stirred mixture of 3-[(4-methoxyphenyl)methyl]-1 ,3-diazinane-2, 4-dione (5.00 g; 20.28 mmol; 1.00 eq.) and bromo-4-(b 1r-omomethyl)benzene (5.33 g; 20.28 mmol; 1.00 eq.) in ACN (40.00 ml), CS2CO3(21.99 g; 60.83 mmol; 3.00 eq.) was added. The mixture was stirred for 2h at 100°C. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (1:1) to afford [ 1(4--bromophenyl)methyl]-3-[(4-methoxyphenyl)methyl]-1, 3-diazinane-2, 4-dione (4.20 g; 8.78 mmol; 43.3 %) as a white solid.

[0261] LC-MS method D: [M+H]+403.10; Rt: 0.69 minIntermediate 27: {[41-(-4-{2-[4-(4-aminophenyl)piperazin-1-yl]ethyl}piperazin-1- yl)phenyl]methyl]-1, 3-diazinane-2, 4-dione1 -(2-chloroethyl)-4-(4-nitrophenyl)piperazine

[0262] A solution of (4- 1n-itrophenyl)piperazine (2.00 g; 8.69 mmol; 1.00 eq.), DIEA (5.90 g; 43.38 mmol; 4.99 eq.), and bromo-2-chloro 1et-hane (1 1.10 g; 69.66 mmol; 8.02 eq.) in DMF (20.00 ml) was stirred for overnight at RT under an argon atmosphere. The reaction was quenched with H2O at RT. The resulting mixture was extracted with DCM. The combined organic layers were washed with NaCl (aq.), dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (7: 1 ) to afford 1 -(2- chloroethyl)-4-(4-nitrophenyl)piperazine (2.00 g; 6.75 mmol; 77.7 %).

[0263] LC-MS method E: [M+H]+270.00; Rt: 0.49 min tert-butyl 4-{2-[4-(4-nitrophenyl)piperazin-1-yl]ethyl}piperazine-1-carboxylate

[0264] A mixture of (2- 1c-hloroethyl)-4-(4-nitrophenyl)piperazine (1.00 g; 3.37 mmol; 1.00 eq.), tert-butyl piperazine-1 -carboxylate (926.00 mg; 4.72 mmol; 1.40 eq.), KI(1.10 g; 6.30 mmol; 1.87 eq.), DIEA (1.75 ml; 9.56 mmol; 2.83 eq.) in MeCN (10.00 ml) was stirred for 3h at 85°C under an argon atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (3: 1 ) to afford tert-butyl 4-{2-[4-(4-nitrophenyl)piperazin-1-yl]ethyl}piperazine-1- carboxylate (1.40 g; 3.30 mmol; 97.8 %) as a yellow solid.

[0265] LC-MS method D: [M+H]+420.00; Rt: 0.49 min1-(4-nitrophenyl)-4-[2-(piperazin-1-yI)ethyl]piperazine

[0266] To tert-butyl 4-{2-[4-(4-nitrophenyI)piperazin-1-yl]ethyI}piperazine-1- carboxylate (1.20 g; 2.72 mmol; 1.00 eq.), HC1 (12.00 ml, 4M in EtOAc) was added portion wise. The resulting mixture was stirred for 4h at RT under a nitrogen atmosphere. The mixture was basified to pH 9 with saturated NaHCO3(aq.) and extracted with DCM. The combined organic layers were washed with NaCl (aq.), dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure to afford (4-nitrophenyi)-4-[2- 1(p-iperazin- l-yl)ethyl]piperazine (800.00 mg; 2.40 mmol; 88.4 %) as a yellow solid.

[0267] LC-MS method D: [M+H]+320; Rt: 0.37 min3-[(4-methoxyphenyl)methyl]-1-{[4-(4-{2-[4-(4-nitrophenyl)piperazin-1- yl]ethyl]piperazin-1-yl)phenyl]methyl}-1, 3-diazinane-2, 4-dione

[0268] To a mixture of Intermediate 26 [(4-bromo 1p-henyl)methyl]-3-[(4- methoxyphenyl)methyl]-1,3-diazinane-2, 4-dione (780.00 mg; 1.62 mmol; 1.00 eq.) and l-(4- nitrophenyl)-4-[2-(piperazin-1-yl)ethyl]piperazine (540.00 mg: 1.62 mmol; 1.00 eq.) in Dioxane-1,4 (15.00 ml), Xphos (163.00 mg: 0.32 mmol; 0.2 eq.), Pd2(dba)3(149.00 mg; 0.16 mmol; 0.1 eq.) and Cesium carbonate (1.11 g; 3.24 mmol; 2 eq.) were added. The mixture was stirred for 2h at 100 °C under an argon atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10: 1 ) to afford 3-[(4-methoxyphenyl)methyl]-1-{[4-(4-{2-[4-(4- nitrophenyl)piperazin- 1 -yl]ethyl] piperazin- 1 -yl)phenyl]methyl} - 1 ,3-diazinane-2,4-dione (600.00 mg; 0.90 mmol; 55.5 %) as a yellow solid.

[0269] LC-MS method E: [M+H]+642; Rt: 0.74 min1-{[4-(4-{2-[4-(4-nitrophenyI)piperazin-1-yl]ethyl]piperazin-1-yl)phenyl]methyl}-1, 3- diazinane-2, 4-dione

[0270] To 3-[(4-methoxyphenyl)methyl]-1-{[4-(4-{2-[4-(4-nitrophenyl)piperazin-1- yl]ethyl}piperazin-1-yl)phenyl]methyl}- 1,3-diazinane-2,4-dione (600.00 mg; 0.90 mmol;1.00 eq.) in TFA (10.00 ml), CF3SO3H (1.00 ml; 10.74 mmol; 1 1.91 eq.) was added. The resulting mixture was stirred for 1h at 60°C under a nitrogen atmosphere. The mixture was basified to pH 7 with saturated DIEA (aq.). The resulting mixture was extracted with DCM. The combined organic layers were washed with NaCl (aq.), dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (11:1) to afford {[4-(4-{2-[4-(4- 1- nitrophenyl)piperazin- 1 -yl] ethyl } piperazin-1-yl)phenyl] methyl} 1 -- 1 ,3-diazinane-2, 4-dione (450.00 mg; 0.83 mmol; 91 .6 %) as a yellow solid.

[0271] LC-MS method E: [M+H]+522; Rt: 0.61 min1-{[4-(4-{2-[4-(4-aminophenyl)piperazin-1-yl]ethyl}piperazin-1-yl)pbenyl]methyl]-1, 3- diazinane-2,4-dione

[0272] To a mixture of { [4 -(4- {2-[4-(4-nitrophenyl)piperazin-1-yl]ethyl}piperazin- 1-yI)phenyI]methyl}-1, 3-diazinane-2, 4-dione (400.00 mg; 0.73 mmol; 1.00 eq.) and Tetrahydroxydiboron (208.00 mg; 2.20 mmol; 3.00 eq.) in DMF (6.00 ml), 4,4'-bipyridine (6.00 mg; 0.04 mmol; 0.05 eq.) was added portion wise. The resulting mixture was stirred for 0. 1h at RT under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with MeOH:DCM= 1 :4 to afford 1 - {[4-(4- {2-[4-(4-aminophenyl)piperazin- 1 -yl]ethyl}piperazin- 1 - yl)phenyl]methyl} -1, 3-diazinane-2, 4-dione (220.00 mg; 0.44 mmol; 59.8%) as a yellow solid.

[0273] LC-MS method D: [M+H]+49 [M2;+ RHt:]+0.33 minIntermediate 28: Synthesis of 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6- dione.tert-butyl 4-(2-(2,6-dioxopiperidin-3-yI)-1-oxoisoindoIin-5-yl)piperazine-1-carboxylate.

[0274] A suspension of 4-bromolenalidomide (400.0 mg; 1.2 mmol;1.0 eq.), 1-Boc-piperazine (345.8 mg; 1.8 mmol; 1.5 eq.), 3 -chloropyridine;{ 1,3-bis[2,6-bis(heptan-4-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazol-2-ylidene} dichloropalladium (61.4 mg; 0.06 mmol; 0.05 eq.), CS2CO3(1.2 g; 3.7 mmol; 3.0 eq.) and anhydrous 1,4-dioxane (8.0 ml; 20.0 V) was heated to 90 °C under nitrogen overnight. The reaction mixture was washed with brine, dried ( Na2SO4) , concentrated using rotary evaporation, and purified using reverse-phase column chromatography using acetonitrile and water (15-100%) under acidic conditions to afford tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)piperazine-1-carboxylate (422.5 mg (72.5%) as a beige solid.3-(1-oxo-5-(piperazin-1-yl)isoindoIin-2-yl)piperidine-2,6-dione.

[0275] A suspension of tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1- oxo-2, 3-dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate (422.50 mg; 0.90 mmol; 1.00 eq.) in DCM (4.22 ml; 10.00 V) and TFA (3.88 ml; 44.86 mmol; 50.00 eq.) was stirred at room temperature for 2h. The reaction mixture was dried using rotary' evaporation, chased with DCM, purified using reverse- phase column chromatography using acetonitrile and water (5-60%) under acidic conditions to afford 206.50mg (68.0%) of 3-(1-oxo-5-(piperazin-1- yl)isoindolin-2-yl)piperidine-2, 6-dione.Intermediate 29: Synthesis of 3-[1-oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-isoindol-2- yl] piperidine-2, 6-dione3-(5-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2, 6-dione.

[0276] To a solution of methyl 4-bromo-2-(bromomethyl)benzoate(50.00 g; 160.73 mmol; 1.00 eq.) in ACN (300.00 ml) were added DIEA(65.53 g; 482.19 mmol; 3.00 eq.) and 3-aminopiperidine-2, 6-dione hydrochloride (55.69 g; 321.46 mmol; 2.00 eq.) at 25 °C. The resulting mixture was stirred for overnight at 80 °C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake purified by silica gel column chromatography, eluted with DCM:MeOH (24: 1) and trituration with VEtOAc:VH2O=1 : 1 (50mL:50mL) to afford 3-(5-bromo-1-oxo-2,3-dihydro-1H- isoindol-2-yl)piperidine-2, 6-dione (53.00 g; 98.4 %) as a crude product. tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-1, 2,3,6- tetra hyd ropyridine- 1 -carb oxyla te.

[0277] To a solution of 3-(5-bromo-1-oxo-2,3-dihydro-1H-isomdol-2- yl)piperidine-2,6-dione (50.00 g; 149.24 mmol; 1.00 eq.) and tert-butyl 4- (4,4,5,5-tetramethyl-1, 3,2-dioxaboroian-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate (58.29 g; 179.09 mmol; 1 .20 eq.) in Dioxane (500.00 ml) and Water (150.00 ml) were added Pd(dtbpf)Cl2(10.24 g; 14.92 mmol; 0.10 eq.) and CsF (71.59 g; 447.71 mmol; 3.00 eq.). The resulting mixture was stirred for 2h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purifi ed by silica gel column chromatography, eluted with DCM:MeOH (50: 1) to afford tert-butyl 4-[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]-1, 2,3,6- tetrahydropyridine-1 -carboxylate (60.00 g; 93.6 %) as an off-white solid. tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindoI-5-yl]piperidine- 1-carboxylate.

[0278] To a stirred solution of tert-butyl 4-[2-(2,6-dioxopiperidin-3- yl)-1-oxo-2, 3-dihydro-1H-isoindol-5-yl]-1, 2,3, 6-tetrahydropyridine-1- carboxylate (10.00 g; 23.29 mmol; 1.00 eq.) in DMF (150.00 ml) was added Pd / C (4.96 g; 4.66 mmol; 0.20 eq.). The resulting mixture was stirred for 2h at 25 °C under H2atmosphere. The resulting mixture was filtrated and added water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperidine-1- carboxylate (9.50 g; 94.8%) as a crude product.3-[1-oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2, 6-dione.

[0279] To a stirred solution of tert-butyl 4-[2-(2,6-dioxopiperidin-3- yl)- 1 -oxo-2, 3-dihydro-1H-isoindol-5-yl]piperidine- 1 -carboxylate (6.00 g;13.94 mmol; 1.00 eq.) in dichloromethane (60.00 ml) was added TFA (20.00 ml; 261 .36 mmol; 18.75 eq.) at 0 °C. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in TFA, 20% to 50% gradient in 25 min; detector, UV 254 nm. This result is 3-[1-oxo- 5-(piperidin-4-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione (4.87 g;77.6 %) as an off-white solid.Intermediate 30: Synthesis of 3-(1-oxo-5-{1-[(piperidin-4-yI)methyl]piperidin-4-yl}-2,3- dihydro-1H-isoindol-2-yl)piperidine-2,6-dionetert-butyl 4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5- yl] piperidin- 1-yl} methyl)piperidine-1-carboxylate.

[0280] To a solution of Intermediate 29, 3-[ 1 -oxo-5-(piperidin-4-yl)- 2, 3-dihydro-1H-isoindol-2-yl]piperidine-2, 6-dione; trifluoroacetic acid, (6.00 g; 13.46 mmol; 1.00 eq.) and benzyl piperazine-1 -carboxylate (4.68 g; 20.18 mmol; 1 .50 eq.) in DCM (200.00 ml) was added NaBH(OAc)3(14.85 g; 67.28 mmol; 5.00 eq.) at 25 °C. The resulting mixture was stirred for overnight at 25 °C. The resulting mixture was added aqueous solution of NaHCO3adjust Ph to neutral and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM:MeOH (9:1) to afford the crude. The crude was purified by reverse flash chromatography with thefollowing conditions: column, C 18 silica gel; mobile phase, Acetonitrile in water(0.05% Trifluoroacetic acid), 10% to 100% gradient in 30 min; detector, UV 254 nm to afford tert-butyl 4-({4-[2-(2,6-dioxopiperi din-3-yl)-1-oxo-2,3- dihydro-1H-isoindol-5-yl]piperidin- 1 -yl }methyl)piperidine- 1 -carboxylate (5.50 g; 70.0 %) as a white solid.3-(1-oxo-5-{1-[(piperidin-4-yl)methyl]piperidin-4-yl]-2,3-dihydro-1H-isoindol-2- yl)piperidine-2, 6-dione.

[0281] To a stirred solution of tert-butyl 4-({4-[2-(2,6-dioxoptperidin- 3-yl)-1-oxo-2, 3-dihydro- 1H-isoindol-5-yl]piperidin-1-yl}methyl)piperidine-1- carboxylate (5.00 g; 9.42 mmol; 1.00 eq.) in DCM (50.00 ml) was added TFA (20.00 ml; 255.79 mmol; 27.16 eq.) at 0 °C. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in TFA, 50% to 30% gradient in 50 min; detector, UV 254 nm to give 3 -( 1 -oxo-5 - { 11- -[(piperidin-4-y l)methyl]piperidin-4-yl }-2,3 -dihydro- 1H- isoindol-2-yl)piperidine-2, 6-dione (4.90 g; 95.4 %) as a yellow solid.Intermediate 31: Synthesis of 2-(2.6-dioxopiperidin-3-yI)-5-{3-[(piperazin-1- yl) methyl]azetidin-1-yl}-2,3-dihydro-1H-isoindole-1, 3-dione.benzyl 4-({1-[(tert-butoxy)carbonyI]azetidin-3-yl}methyl)piperazine-1-carboxylate.

[0282] To a stirred solution of benzyl piperazine- 1 -carboxylate (8.15 g; 35.15 mmol; 1.00 eq.) and tert-butyl 3-formylazetidine-1-carboxylate (6.85 g; 35.15 mmol; 1.00 eq.) in DCE (100.00 ml) was added CH3COOH (0.50 ml) dropwise under nitrogen atmosphere. The resulting mixture was stirred for 4h at room temperature under nitrogen atmosphere. Then to the reation added NaBH(OAc)3(7.85 g; 35.56 mmol; 1.01 eq.) The residue was purified by reverse flash chromatography with the following conditions: column. C18 silica gel, mobile phase, MeCN in water, 10% to 60% gradient in 30min;detrctor, UV 254nm. This resulted in benzyl 4-({ 1-1-[(t 1e-rt-butoxy)carbonyl]azetidin-3-yl}methyl)piperazine-1-carboxylate (7.60 g;46.7 %) as a colorless oil. benzyl 4-[(azetidin-3-yl)methyl]piperazine-1-carboxylate.

[0283] To a stirred solution of benzyl 4-( { 11- -[(tert-butoxy)carbonyl]azetidin-3- yl] methyl )piperazine-1-carboxylate (6.00 g; 12.96 mmol; 1.00 eq.) in DCM (70.00 ml) was added trimethylsilyl trifluoromethanesulfonate (7.40 ml; 38.87 mmol; 3.00 eq.) dropwiseunder nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The reaction was quenched with water at room temperature. This resulted in benzyl 4-[(azetidin-3-yl)methyl]piperazine-1-carboxylate (4.30 g; 92.8 %) as a crude product. benzyl 4-({1-[2-(2,6-dioxopiperidin-3-yl)-1, 3-dioxo-2,3-dihydro-1H-isoindol-5- yl] azetidin-3-yI} methyl)piperazine-1-carboxylate.

[0284] To a stirred solution of benzyl 4-[(azetidin-3-yl)methyl]piperazine- 1 - carboxylate (3.00 g; 8.39 mmol; 1.00 eq.)and 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3- dihydro-1H-isoindole- 1,3-dione (2.50 g; 8.60 mmol; 1.03 eq.) in DMSO (20.00 ml) was added DIEA (5.00 ml; 27.27 mmol; 3.25 eq.) dropwise under nitrogen atmosphere .The resulting mixture was stirred for 4h at room temperature under nitrogen atmosphere. The residue was purified by reverse flash chromatography with the follow ing : column, C 18 silica gel, mobile phase, MeCN in w ater, 10% to 65% gradient in 30min; detector, UV 254nm. This resulted in benzyl 4-({1-[2-(2,6-dioxopiperidin-3-yl)-1, 3-dioxo-2,3-dihydro-1H- isoindol-5-yl]azetidin-3-yl}methyl)piperazine-1-carboxylate (3.60 g; 78.3 %) as a green solid.2-(2,6-dioxopiperidin-3-yl)-5-{3-[(piperazin-1-yl)methyl]azetidin-1-yl}-2,3-dihydro-1H- isoindole-1, 3-dione.

[0285] To a stirred solution of benzyl 4-({1-[2-(2,6-dio 1x-opiperidin-3-yl)-1 ,3-dioxo- 2, 3-dihydro-1H-isoindol-5-yl]azetidin-3-yl}methyl)piperazine-1-carboxylate (3.60 g; 6.57 mmol; 1.00 eq.) and Pd / C (2.00 g; 1.88 mmol; 0.29 eq.)inEthyl acetate (100.00 ml) dropwise under nitrogen atmosphere. The resulting mixture was stirred for 24h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 X 30ml). The filtrate was concentrated under reduced pressure. The result in 2-(2,6-dioxopiperidin-3-yl)-5-{3-[(piperazin-1-yl)methyl]azetidin-1-yl}-2,3- dihydro-1H-isoindole- 1,3 -dione (1.53 g; 53.1 %) as a yellow solid.Intermediate 32: Synthesis of 3-[1-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-isoindol-2- y 1] piperidine-2 ,6-dione.methyl 3-bromo-2-(bromomethyl).

[0286] To a stirred solution of methyl 3-bromo-2 -methylbenzoate (48.00 g; 206.06 mmol; 1.00 eq.) and NBS (45.00 g; 240.19 mmol; 1.17 eq.) in was added AIBN (3.45 g;19.96 mmol; 0.10 eq.). The resulting mixture was stirred for 12h at 70 °C under nitrogen atmosphere. The resulting mixture was added water and extracted with DCM (3 x 1000rnL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EtOAc (8: 1) to afford methyl 3-bromo-2- (bromomethyl)benzoate (60.00 g; 93.4 %) as a yellow solid.3-(4-bromo-1-oxo-2,3-dihydro-1H-isoindoI-2-yl)piperidine-2, 6-dione.

[0287] To a solution of methyl 3-bromo-2-(bromomethyl)benzoate (50.00 g; 160.41 mmol; 1.00 eq.) in ACN (500.00 ml) were added DIEA (75.00 g; 551.90 mmol; 3.44 eq.) and 3-aminopiperidine-2, 6-dione hydrochloride (53.50 g; 308.80 mmol; 1.93 eq.) at 25 °C. The resulting mixture was stirred for overnight at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by trituration with water andEtOAc (V1 :V2=1: 1 ), The residue was filtrated to afford 3-(4-bromo-1-oxo-2,3-dihydro-1H- isoindol-2-yl)piperidine-2, 6-dione (50.00 g; 96.0 %) as a brown solid. tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-1, 2,3,6- tetr a hyd ropyridine-1 -carboxylate.

[0288] To a solution of 2-[(2S)-1-[(tert-butoxy)carbonyl]pyrrolidin-2-yl]-1 ,3-thiazole- 4-carboxylic acid (50.00 g; 167.42 mmol; 1.00 eq.) and N,O-Dimethylhydroxylamine hydrochloride (24.66 g; 240.18 mmol; 1.43 eq.) in DMF (500.00 ml) were added N,N diisopropyl ethylamine (54.11 g; 398.48 mmol; 2.38 eq.) and HATU (63.79 g; 159.38 mmol; 0.95 eq.). The resulting mixture was stirred for 2h at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with DCM:MeOH (20: 1) to afford tert-butyl 4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2, 3-dihydro-1H-isoindol-4-yl]-1, 2,3, 6-tetrahydropyridine-1- carboxylate (60.00 g; 91 .2 %) as an orange solid. tert-butyl 4-[2-(2,6-dioxopiperidin-3-yI)-1-oxo-2,3-dihydro-1H-isoindoI-4-yl]piperidine- 1-carboxylate

[0289] To a stirred solution of tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2, 3- dihydro-1H-isoindol-4-yl]-1,2,3.6-tetrahydropyTidine-1-carboxylate (20.00 g; 46.86 mmol; 1.00 eq.) in DMF (200.00 ml) were added and Pd / C (10.00 g: 9.40 mmol; 0.20 eq.). The resulting mixture was stirred for 2h at 25 °C under H2atmosphere. The resulting mixture was filtrated and added water and extracted with EtOAc (3 x 200mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1- oxo-2, 3-dihydro-1H-isoindol-4-yl]piperidine-1-carboxylate (16.50 g; 82.2 %) as an orange solid.3-[1-oxo-4-(piperidm-4-yl)-2,3-dihydro-1H-isoindol-2-yI]piperidine-2, 6-dione.

[0290] To a solution of tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro- 1H-isoindol-4-yl]piperidine-1-carboxylate (10.00 g; 23.35 mmol; 1.00 eq.) in DCM (100.00 ml) were added trifluoroacetic acid (30.00 ml; 372.42 mmol; 15.95 eq.). The resulting mixture was stirred for 2h at 25 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by C 18 silica gel with the following conditions (0.05 TFA in water: ACN=9: 1) to afford 3-[1-oxo-4-(piperidin-4-yl)-2,3-dihydro- 1H-isoindol-2-yl]piperidine-2,6-dione (8.50 g; 19.22 mmol; 82.3 %) as a white solid.Intermediate 33: Synthesis of 3-(1-oxo-4-{1-[(piperidin-4-yl)methyI]piperidin-4-yl}-2,3- dihydro-1H-isoindol-2-yl)piperidine-2, 6-dionetert-butyl 4-({4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl]piperidin-1-yl}methyl)piperidine-1-carboxylate.

[0291] To a solution of Intermediate 32, 3-[1-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2, 6-dione; trifluoroacetic acid, (4.00 g; 9.04 mmol; 1.00 eq.) in DCE (40.00 ml) were added tert-butyl 4-formylpiperidine- 1 -carboxylate (4.00 g; 17.82 mmol; 1.97 eq.) and Sodium triacetoxyborohydride (4.00 g; 18.01 mmol; 1.99 eq.) and acetic acid (0.05 ml; 0.79 mmol; 0.09 eq.) at 25 °C. The resulting mixture was stirred for 2h at 25 °C under nitrogen atmosphere. The resulting mixture was added aqueous solution of NaHCO3adjust pH to neutral and extracted with EtOAc (3 x 200mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM:MeOH (81) to afford tert-butyl 4-({4-[2-(2,6- dioxopiperidin-3-yl)-1-oxo-2, 3-dihydro-1H-isoindol-4-yl]piperidin-1-yl}methyl)piperidine- 1 -carboxylate (4.80 g; 100.0 %) as a white solid.3-(1-oxo-4-{1-[(piperidin-4-yl)methyl]piperidin-4-yl]-2,3-dihydro-1H-isoindoI-2- yl)piperidine-2,6-dione.

[0292] To a solution of tert-butyl 4-( {4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3- dihydro-1H-isoindol-4-yl]piperidm-1-yl}methyl)piperidine-1-carboxylate (4.50 g; 7.77 mmol: 1.00 eq.) in DCM (45.00 ml) were added trifluoroacetic acid (15.00 ml; 186.21 mmol;23.95 eq.). The resulting mixture was stirred for 2h at 25 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by C 18 column with following condition (water+0.05%FA:ACN=9:1) to afford 3-(1-oxo-4-{1-[(piperidin-4- yl)methyl]piperidin-4-yl}-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (2.81 g; 84.4 %) as a white solid.Intermediate 34: Synthesis of 3-[(3-fluoro-4-{4-[(piperidin-4-yl)methyI]piperazin-1- yl}phenyl)amino]piperidine-2, 6-dionetert-butyl 4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazine-1- carboxylate.

[0293] A solution of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate (22.00 g; 74.49 mmol; 1.00 eq.) and 3-bromopiperidine-2,6-dione (29.00 g; 143.48 mmol;1.93 eq.) and NaHCO3(20.00 g: 226.17 mmol; 3.04 eq.) in MeCN (250.00 ml) was stirred for 2d at 85 °C under nitrogen atmosphere. The resulting mixture was added water and extracted with EtOAc (3 x 500mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EtOAc (1 : 1) to afford tert-butyl 4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2- fluorophenyl } piperazine- 1 -carboxylate (23.00 g; 75.2 %) as a blue solid.-{[3-fluoro-4-(piperazin-1-yl)phenyl]amino}piperidine-2, 6-dione.

[0294] A solution of tert-butyl 4- {4-[(2.6-dioxopiperidin-3-yl )amino]-2- fluorophenyl}piperazine-1-carboxylate (22.00 g; 53.53 mmol; 1.00 eq.) in TFA (50.00 ml) and DCM (250.00 ml) was stirred for 2h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford 3-{[3-fluoro-4- (piperazin-1-yl)phenyl]amino}piperidine-2, 6-dione as a crude product. tert-butyl 4-[(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1-yl)methyl] piperidine-1 -carboxylate.

[0295] To a stirred solution of 3-{[3-fluoro-4-(piperazin-1- yl)phenyl]amino}piperidine-2, 6-dione; trifluoroacetic acid (5.00 g; 11.57 mmol; 1.00 eq.) and tert-butyl 4-formylpiperidine-1-carboxylate (5.00 g; 22.27 mmol; 1.92 eq.) in DCE (100.00 ml) was added DIEA ( 10.00 g; 73.53 mmol; 6.35 eq.) and Sodium triaceloxyborohydride (8.50 g; 24.06 mmol; 2.08 eq.). The resulting mixture was stirred for 5 h at 25 °C under nitrogen atmosphere. The resulting mixture was added water and extracted with EtOAc (3 x 1000mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EtOAc (3: 1) to afford tert-butyl 4-[(4- {4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl } piperazin- 1 - yl)methyl]piperidine-1-carboxylate (5.00 g; 85.1 %) as a blue solid.3-[(3-fluoro-4-{4-[(piperidin-4-yl)methyl]piperazin-1-yl]phenyl)amino]piperidine-2,6- dione.

[0296] To a solution of tert-butyl 4-[(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2- fluorophenyl}piperazin-1-yl)methyl]piperidine-1-carboxylate (5.00 g; 9.85 mmol; 1.00 eq.) in DCM (60.00 ml) were added trifluoroacetic acid (8.00 ml; 99.31 mmol; 10.08 eq.). The resulting mixture was stirred for 2h at 25 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by C 18 column chromatography, eluted with water(0.05%TFA):ACN (10:1 ) to afford 3-[(3-fluoro-4-{4- [(piperidin-4-yl)methyl]piperazin-1-yl}phenyl)ammo]piperidine-2, 6-dione (4.32 g; 82.2 %) as a green solid.Intermediate 35: Synthesis of 4-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H- isoindol-5-yl]methyl]piperidin-1-ium chloride.tert-butyl 4-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5- yl] methyl] piperidine-1-carboxylate.

[0297] To a suspension of 3-(5-bromo-1-oxo-2,3-dihydro-1H-isoindol-2- yl)piperidine-2, 6-dione (950.00 mg; 2.94 mmol; 1.00 eq.), Boc-4- 1- bromomethylpiperidine (2.04 g; 7.35 mmol; 2.50 eq.), (Ir[dF(CF3)ppy]2(dtbpy))PF6(28.78 mg; 29.40 μmol; 0.01 eq.) and Sodium carbonate (778.98 mg; 7.349 mmol; 2.50 eq.) in 1 ,2-Dimethoxyethane (14.00 mi) (20 mL Microwave vial) was added Tris(trimethylsilyl)silane, (1.58 ml; 5.144 mmol; 1.75 eq.) and the vial was degassed for 10min using a constant nitrogen flow in an ultra sound bath. In parallel, Nickel(II) chloride ethylene glycol dimethyl ether complex, 98% (6.46 mg; 29.40 μmol; 0.01 eq.) and 4,4[' ]- Di-tert-butyl-2,2[']-dipyridyl, 98% (7.89 mg; 29.40 μmol; 0.01 eq.) were dissolved in 1 ,2- Dimethoxyethane (4.00 ml) and stirred for 10 min. 2mL of these mixture was added to the reaction suspension the vial was degassed for 10min using a constant nitrogen flow in an ultra sound bath. The vial was than placed in the photobox and irradiated for 24h (fan on, 254 nm). The crude mixture was evapurated on isolute and purified by NP column chromatography to give tert-butyl 4-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H- isoindol-5-yl]methyl}piperidine-1-carboxylate (1.22 g; 2.062 mmol) as a pale yellow solid.4-{]2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]methyI]piperidin- 1-ium chloride.

[0298] To a solution of terl-butyl 4- {[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3- dihydro-1H-isoindol-5-yl]methyl} piperidine- 1 -carboxylate (1.22 g; 2.76 mmol; 1.00 eq.) in DCM (20.00 ml) was added HC1 in 4.0 M in dioxane (2.00 ml) and the mixture was stirred for 4h at room temperature. All volatile incredients were removed under reduced pressure to deliver crude 4-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5- yl]methyl}piperidin-1-ium chloride (1.20 g; 1.905 mmol) as a beige solid.Intermediate 36: Synthesis of 3-(4-{1-[(piperidin-4-yl)methyl]piperidin-4- yl}phenyl)piperidine-2, 6-dione.tert-butyl 4-[4-(2,6-dioxopiperidin-3-yl)phenyl]-1, 2,3,6-tetrahydropyridine-1- carboxylate.

[0299] 3-(4-bromophenyl)-2,6-piperidinedione (500.0 mg; 1.865 mmol; 1.0 eq. ). N- Boc-1, 2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (692.0 mg; 2.238 mmol; 1.2 eq.), [1,1 [']-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (138.3 mg; 0.186 mmol; 0.1 eq.), potassium carbonate, (773.2 mg; 5.595 mmol; 3.0 eq.), 1 ,4-Dioxane (5.0 ml; 10.00 V), and water (1.0 ml; 2.00 V) were combined in a 20 mL septum vial. Air was removed from the vial by vacuum and the vail was back filled with N2. The mixture was heated to 80 °C and stirred for 1h. The mixture was cooled to room temperature and diluted with water (30 mL). The solution was extracted with EtOAc (3 times, 30 mL each). Organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude residue. The crude was purified using normal phase chromatography (10g silica sfar column) using a ethyl acetate / hexanes 0-100% gradient over 12 column volumes to give tert-butyl 4-[4-(2,6-dioxopiperidin-3-yl)phenyl]- 1 ,2,3,6-tetrahydropyridine- 1 -carboxylate as a yellow solid.3-[4-(piperidin-4-yI)phenyl]piperidine-2, 6-dione.

[0300] To a 20 mi vial with a magnetic stirbar, tert-butyl 4-[4-(2,6-dioxopiperidin-3- yl)phenyl]piperidine-1-carboxylate (400.0 mg; 1.074 mmol; 1.0 eq.) was dissolved in DCM (8.0 ml; 20.00 V) and added TFA (0.8 ml; 10.739 mmol; 10.0 eq.). The reaction mixture wasstirred at room temperature. The reaction mixture was concentrated and azeotroped with DCM (x3) to give 3-[4-(piperidin-4-yl)phenyl]piperidine-2,6-dione as a crude product.

[0301] tert-butyl 4-({4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperidin-1- yl}methyl)piperidine-1-carboxylate, 3-[4-(piperidin-4-yl)phenyl]piperidine-2, 6-dione (292.0 mg; 1.072 mmol; 1.0 eq.), 1 -Boc-4-Bromomethylpiperidine (298.3 mg; 1.072 mmol; 1.0 eq.), potassium carbonate (222.3 mg; 1.608 mmol; 1.5 eq.) and Nal (80.4 mg; 0.536 mmol; 0.5 eq.) were combined in acetonitrile (5.8 ml; 20.00 V) in a 20 ml microwave vial. The vial was capped and purged with nitrogen, and the reaction was stirred at 60 °C. The mixture was cooled to RT then filtered through celite and washed with DCM. The resulting filtrated was concentrated under rotary evaporation to give tert-butyl 4-( {4-[4-(2,6- dioxopiperidin-3-yl)phenyl]piperidin-1-yl}methyl)piperidine-1-carboxylate as a crude product.3-(4-[1-[(piperidin-4-yI)methyl]piperidin-4-yI}phenyI)piperidine-2, 6-dione.

[0302] To a 20 ml vial with a magnetic stirbar, tert-butyl 4-({4-[4-(2,6- dioxopiperidin-3 -yl)phenyl]piperidin- 1 -yl } methyl)piperidine- 1 -carboxylate (500.0 mg; 0.852 mmol; 1.0 eq.) was dissolved in DCM (8.0 ml; 20.00 V) and added TFA (0.6 ml; 8.518 mmol; 10.0 eq.). The reaction mixture was stirred at room temperature. The reaction mixture was concentrated and azeotroped with DCM (x3) to give 3-(4-{1-[(piperidin-4- yl)methyl]piperidin-4-yl}phenyl)piperidine-2, 6-dione as a crude product.Intermediate 37: Synthesis of 3-[(4-{1-[(piperidin-4-yl)methyl]piperidin-4- yl} phenyl)amino] piperidine-2, 6-dione.tert-butyl 4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperidine-1-carboxylate.

[0303] To a vial containing 3-bromo-2,6-piperidinedione (1,250.6 mg; 6.513 mmol;1.8 eq.) tert-Butyl 4-(4-aminophenyl)-1-piperidinecarboxylate (1,000.0 mg; 3.618 mmol; 1.0 eq.) was added DIPEA (1.2 ml; 7.237 mmol; 2.0 eq.) dioxane (25.0 ml; 25.00 V). The vial was sealed and purged with nitrogen. The reaction mixture was then stirred at 90 °Covernight. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with ethyl acetate, washed with water then brine, dried over MgSCO4filtered, and concentrated to give tert-butyl 4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperidme-1- carboxylate as a crude product.3-{[4-(piperidin-4-yl)phenyl]amino}piperidine-2,6-dione.

[0304] To a round bottomed flask containing tert-butyl 4-{4-[(2,6-dioxopiperidin-3- yl)amino]phenyl}piperidine-1-carboxylate (1,400.0 mg; 3.613 mmol; 1.0 eq.) in DCM (28.0 ml; 20.00 V) was added TFA (2.7 ml; 36.132 mmol; 10.0 eq.). The reaction mixture was stirred at room temperature until complete. The mixture was concentrated under reduced pressure and azetroped with DCM (3x), then kept under high vacuum overnight to give crude product. The crude residue was purified by reverse phase chromatography (55g C18 column, Interchim, 0.1% formic acid in water / MeCN. 10-100% gradient over 18 minutes to give 3- {[4-(piperidin-4-yl)phenyl]amino}piperidine-2, 6-dione (898.000 mg; 86.5 %) as a beige solid. tert-butyl 4-[(4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperidin-1- yl)methyl]piperidine-1-carboxylate.

[0305] 3- {[4-(piperidin-4-yl)phenyl]amino}piperidine-2, 6-dione (494.8 mg; 1.722 mmol; 1.0 eq.)l-Boc-4-Bromomethylpiperidine (479.0 mg; 1.722 mmol; 1.0 eq.), potassium carbonate (357.0 mg; 2.583 mmol; 1.5 eq.) and Nal (129.1 mg; 0.861 mmol; 0.5 eq.) were combined in acetonitrile (9.9 ml; 20.00 V) in a 5 mL septum vial. The solution was heated to 60 °C and stirred overnight. The mixture was cooled to room temperature then filtered through celite and washed with DCM. The resulting filtrated was concentrated under rotary evaporation to give tert-butyl 4-[(4-{4-[(2.6-dioxopiperidin-3-yl)amino]phenyl}piperidin-1- yl)methyl]piperidine-1-carboxylate as a crude product.3-](4-{1-[(piperidin-4-yl)methyI]piperidin-4-yl}phenyl)amino]piperidine-2, 6-dione.

[0306] To a 20 ml vial with a magnetic stirbar, tert-butyl 4-[(4- {4-[(2,6- dioxopiperidin-3-yl)amino]phenyl}piperidin-1-yl)methyl]piperidine-1-carboxylate (834.0 mg; 1.721 mmol; 1.0 eq.) was dissolved in DCM (16.7 ml; 20.00 V) and added TFA (1.3 ml; 17.209 mmol; 10.0 eq.). The reaction mixture was stirred for 1 hour al room temperature. The reaction mixture was concentrated and azeotroped with DCM (x3). The crude residue was then diluted with DMSO and purified using reverse phase chromatography under acidicconditions with a gradient of 0-60 % over 18 minutes (55g C18 column, 0.1% formic acid in water / MeCN solvents to give 3-[(4-{1-[(piperidin-4-yl)methyl]piperidin-4- yl}phenyl)amino]piperidine-2, 6-dione (640.00 mg; 96.7 %) as a brown solid.Intermediate 38: Synthesis of 3-[(4-{4-[(piperidin-4-yl)methyl]piperazin-1- yl}phenyl)amino ]piperidine-2,6-dione.tert-butyl 4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperazine-1-carboxylate.

[0307] To a 20 ml vial containing tert-butyl 4-(4-aminophenyl)piperazine- 1 - carboxylate (1,000.0 mg; 3.605 mmol; 1.0 eq.) and 3-bromo-2,6-piperidinedione (1,070.5 mg; 5.408 mmol; 1.5 eq.) were added dioxane (25.0 ml; 25.00 V) and DIPEA (1.2 ml; 7.211 mmol; 2.0 eq.) under nitrogen and then stirred at 90 °C overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give tert-butyl 4- {4- [(2,6-dioxopiperidin-3-yl)amino]phenyl}piperazine-1-carboxylate as a crude product.3-{[4-(piperazin-1-yI)phenyl]amino}piperidine-2, 6-dione.

[0308] To a 20 ml vial with a magnetic stirbar, crude tert-butyl 4- {4-[(2,6- dioxopiperidin-3-yl)amino]phenyl} piperazine- 1 -carboxylate (1,400.0 mg: 3.604 mmol; 1.0 eq.) was dissolved in DCM (28.0 ml; 20.00 V) was added TFA (2.7 ml; 36.040 mmol; 10.0 eq.). The LCMS shows the reaction was completed in 1 hour at room temperature. The reaction mixture was concentrated and azeotroped with DCM (x3) then kept under high vacuum overnight to give 3-{[4-(piperazin-1-yl)phenyl]amino}piperidine-2, 6-dione as a crude product. tert-butyl 4-[(4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperazin-1- yl)methyl]piperidine-1-carboxylate.

[0309] 3-{[4-(piperazin-1-yl)phenyl]amino}piperidine-2,6-dione (500.0 mg; 1.734 mmol; 1.0 eq.)l-Boc-4-Bromomethylpiperidine (482.4 mg; 1.734 mmol; 1.0 eq.), potassium carbonate (359.5 mg; 2.601 mmol; 1.5 eq.) and Nal (130.0 mg; 0.867 mmol; 0.5 eq.) were combined in acetonitrile (10.0 ml; 20.00 V) in a 5 mL septum vial. The solution was heatedto 60 °C and stirred overnight. The mixture was cooled to room temperature diluted with water (5 mL) and extracted 3 times with EtOAc (5 mL each). Organic layers were pooled washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude solid was purified by Biotage Isolera flash chromatography (100% hexane to 100% EtOAc, normal phase 10 g KP-NH silica gel column) to give tert-butyl 4-[(4-{4-[(2,6-dioxopiperidin- 3-yl)amino]phenyl) piperazin-1 -yl)methyl]piperidine-1-carboxylate (442.400 mg; 52.5 %) as a dark blue solid.3-[(4-{4-[(piperidin-4-yl)methyl]piperazin-1-yl}phenyl)amino]piperidine-2, 6-dione.

[0310] To a 20 ml vial with a magnetic stirbar, tert-butyl 4-[(4-{4-[(2,6- dioxopiperidin-3-yl)amino]phenyl}piperazin-1-yl)methyl]piperidine-1-carboxylate (442.0 mg; 0.910 mmol; 1.0 eq.) was dissolved in DCM (8.8 ml; 20.00 V) was added TFA (0.7 ml;9. 102 mmol; 10.0 eq.). The reaction was stirred for 1 hour at room temperature. The reaction mixture was concentrated and azeotroped with DCM (x3) then kept under high vacuum overnight to give 3-[(4- { 4-[(piperidin-4-yl)methyl]piperazin- 1 -yl} phenyl)amino]piperidine- 2, 6-dione as a crude product.Intermediate 39: Synthesis of 3-[1-oxo-4-({1-[(piperidin-4-yl)methyl]azetidin-3- yl}methyl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2, 6-dione.tert-butyl 3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl]methyl}azetidine-1-carboxylate.

[0311] To a suspension of 3-(4-bromo-1-oxo-2,3-dihydro-1H-isoindol-2- yl)piperidine-2, 6-dione (484.71 mg; 1,50 mmol; 1.00 eq.), tert-butyl 3- (bromomethyl)azetidine-1-carboxylate (938.00 mg; 3,75 mmol; 2.50 eq.), (Ir[dF(CF3)ppy]2(dtbpy))PF6 (14.68 mg; 15.00 μmol; 0,01 eq.) and sodium carbonate (397.46 mg; 3.750 mmol; 2,50 eq.) in 1 ,2-Dimethoxyethane (7,00 ml) was added Tris(trimethylsilyl)silane, 97% (809.85 [M;+ 2H.6]2+5 mmol; 1,75 eq.) and the vial was degassed for 10min using a constant nitrogen flow in an ultra sound bath. In parallel Nickel(II) chloride ethylene glycol dimethyl ether complex, 98% (3.30 mg; 15.00 μmol ; 0.01 eq.) and 4,4[']-Di- tert-butyl-2,2[']-dipyridyl, 98% (4.03 mg; 15,00 μmol; 0,01 eq.) were dissolved in 1 ,2- Dimethoxyethane (2,00 ml) and stirred for 10 min. 1mL of these mixture was added to the reaction suspension the vial was degassed for 10min using a constant nitrogen flow in an ultra sound bath. The vial was than placed in the photobox and irradiated for 24h (fan on, 254 nm). The crude mixture was evaporated on isolute and purified by NP column chromatography to give tert-butyl 3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H- isoindol-4-yl]methyl} azetidine- 1 -carboxylate (650,00 mg; 1 .414 mmol) as a pale yellow solid.3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindoI-4-yl]methyl]azetidin-1- ium trifluoroacetate.

[0312] To a solution of tert-butyl 3-{[2-(2.6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro- 1H-isoindol-4-yl]methy]}azetidine-1-carboxylate (650.00 mg; 1.57 mmol; 1.00 eq.) in DCM (10,00 ml) was added TFA (2,00 ml) and the reaction mixture was stirred for 4h at room temperature. Evaporation of all volatile ingredients furnished 3-{[2-(2,6-dioxopiperidin-3-yl)- l-oxo-2,3-dihydro-1H-isoindol-4-yl]methyl}azetidin-1-ium trifluoroacetate (710.00 mg; 1.66 mmol) as a yellow oil. tert-butyl 4-[(3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl] methyl] azetidin- 1 -yl) methyl] pip eridine-1 -carboxylate.

[0313] 3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindoI-4- yl] methyl] azetidin- 1 -ium (150.0 mg0.479 mmol; 1.0 eq.), Boc-4-Bromomethylp 1-iperidine (133.2 mg; 0.479 mmol; 1.0 eq.), potassium carbonate (99.2 mg; 0.718 mmol; 1.5 eq.) and Nal (35.9 mg; 0.239 mmol; 0.5 eq.) were combined in Acetonitrile (3.0 ml; 20.00 V) in a 20 ml microwave vial. The vial was capped and purged with nitrogen. The solution was heated to 60 °C and stirred overnight. The mixture was cooled to RT then filtered through celite andwashed with DCM. The resulting filtrated was concentrated under rotary evaporation to give tert-butyl 4-[(3-{ [2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl]methyl}azetidin-1-yl)methyl]piperidine-1-carboxylate as a crude product.3-[1-oxo-4-({1-[(piperidin-4-yl)methyI]azetidin-3-yl}methyI)-2,3-dihydro-1H-isoindoI-2- yl]piperidine-2, 6-dione.

[0314] To a 20 ml vial with a magnetic stirbar, tert-butyl 4-[(3-{[2-(2,6- dioxopiperidm-3 -y 1)- 1 -oxo-2, 3 -dihydro-1H-isoindol-4-yl]methyl } azetidin- 1 - yl)methyl]piperidine-1-carboxylate (244.4 mg; 0.479 mmol; 1.0 eq.) was dissolved in DCM (4.9 ml; 20.00 V) and was added TFA (355.5 pl; 4.786 mmol; 10.0 eq.). The reaction mixture was stirred at room temperature. Then, the reaction mixture was concentrated and azeotroped with DCM (x3) to give 3-[1-oxo-4-({ 1-[(piperid 1in--4-yl)methyl]azetidin-3-yl}methyl)-2,3- dihydro-1H-isoindol-2-yl]piperidine-2, 6-dione as a crude product.Intermediate 40: 3-(1-oxo-5-(piperazin-1-yl)isoindoIin-2-yl)piperidine-2, 6-dionetert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yI]piperazine- 1-carboxylate:

[0315] To a stirred mixture of 3-(5-bromo-1-oxo-2,3-dihydro-1H-isoindol-2- yl)piperidine-2, 6-dione (1.5 g; 4.41 mmol.) and tert-butyl piperazine- 1 -carboxylate ( 1037.48 mg; 5.29 mmol) in DMF (25 ml), Pd-PEPPSI-IPentCl 2 -methylpyridine (o-picoline) (195 mg; 0.22 mmol) and CS2CO3(3024.85 mg; 8.82 mmol) were added in portions at 25 °C. The resulting mixture was stirred for 3 h at 100 ºC under nitrogen atmosphere. The resulting mixture was quenched by ice water and extracted with EA. The combined organic layers were washed with brine and dried over anhydrous Mg2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with EA:PE=90:10 to afford tert-butyl 4-[2-(2,6-dioxopiperidin- 3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate as an off-white solid (1.96 mg; 0.1 %).3-(1-oxo-5-(piperazin-1-yl)isoindoiin-2-yI)piperidine-2, 6-dione :

[0316] To a stirred solution of tert-butyl 4-[ 2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3- dihydro-1H-isoindol-5-yl]piperazine-1-carboxylate (1.46 g; 3.29 mmol.) in 1,4-dioxane (10 ml), HCl(gas) was added in 1,4-dioxane (10 ml). The resulting mixture was stirred for 4 at 25 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum to afford 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2, 6-dione as an off-white solid (1 g, crude product).Intermediate 41: {[11-(-4-nitrophenyI)piperidin-4-yl]methyl}piperazinetert-butyl 4-{[1-(4-nitrophenyl)piperidin-4-yI]methyl}piperazine-1-carboxylate

[0317] To a stirred mixture of fluoro 1-4--nitrobenzene (2.68 g; 18.07 mmol; 2.00 eq.) and tert-butyl 4-[(piperidin-4-yl)methyl]piperazine-1-carboxylate (3.20 g; 9.03 mmol; 1.00 eq.) in DMF (60.00 ml) was added K2CO3(2.63 g; 18.07 mmol; 2.00 eq.) at room temperature. The mixture was stirred for 2 h at 85°C. The resulting mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrousThe resulting mixture was filtered and concentrated under reduced. The crude material was purified by silica gel column chromatography, eluted with PE / EtOAc (1 :1) to afford tert-butyl 4-{[1-(4-nitrophenyl)piperidin-4-yl]methyl}piperazine-1- carboxylate (3.60 g; 8.77 mmol).

[0318] LC-MS method U: [M+H]+ 405; Rt: 0.78 mm1- { [1-(4-nitrophenyl)piperidin-4-yl] methyl}piperazine

[0319] tert-butyl 4- { [ 1 -(4-nitrophenyl)piperidin-4-yl]methyl} piperazine- 1 - carboxylate (4.00 g; 9.74 mmol; 1.00 eq.) was added in 4M HC1 in Ethylacetate (25.00 ml; 100.00 mmol; 10.27 eq.) at room temperature. The resulting mixture was stirred for 2h at 25 °C under nitrogen atmosphere. The mixture was basified to pH=9 with sat. NaHCO3(aq.). The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (1: 1) to afford { [1-(4- 1- nitrophenyl)piperidin-4-yl]methyl}piperazine (2.90 g; 9.42 mmol).

[0320] LC-MS Method U: [M+H]+ 305; Rt: 0.66 minIntermediate 42: 3-[7-(4-{[1-(4-aminophenyI)piperidin-4-yl]methyl}piperazin-1-yl)-2- oxo-2, 3-diliydro-1, 3-benzoxazol-3-yl]piperidine-2, 6-dione1-[(4-methoxyphenyl)methyl]-3-[7-(4-{[1-(4-nitrophenyI)piperidin-4- yl]methyl}piperazin-1-yI)-2-oxo-2,3-dihydro-1, 3-benzoxazoI-3-yl]piperidine-2, 6-dione

[0321] To a stirred mixture of 3-(7-bromo-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl)-1- [(4-methoxyphenyl)methyl]piperidine-2, 6-dione Intermediate 63 (500.00 mg; 1.09 mmol;1.00 eq.) and {[11--(4-nitrophenyl)piperidin-4-yl]methyI}piperazine Intermediate 41 (380.00 mg; 1.23 mmol; 1.13 eq.) in 1,4-dioxane (20.00 ml) and Pd2(dba)3(118.00 mg; 0.12 mmol;0.1 1 eq.) were added Xphos (61.00 mg; 0.12 mmol; 0.11 eq.) and Cs2CO3(837.00 mg; 2.44 mmol; 2.23 eq.) at room temperature. The mixture was stirred for 16 h at 100°C. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10: 1) to afford [(4- 1- methoxyphenyl)methyl]-3-[7-(4- {[1-(4-nitrophenyi)piperidin-4-yl]methyl}piperazin-1-yl)-2- oxo-2, 3-dihydro-1,3-benzoxazol-3-yl]piperidine-2, 6-dione (550.00 mg; 0.53 mmol;).

[0322] LC-MS Method V: [M+H]+669; Rt: 0.78 mm3-[7-(4-{[1-(4-nitrophenyl)piperidin-4-yl]methyl}piperazin-1-yl)-2-oxo-2,3-dihydro-1, 3- benzoxazol-3-yl]piperidine- 2, 6-dione

[0323] 1- [(4-methoxyphenyl)methyl]-3-[7-(4-{[1-(4-nitrophenyl)piperidin-4- yl]methyl}piperazin-1-yl)-2-oxo-2,3-dihydro-1, 3-benzoxazol-3-yl]piperidine-2,6-dione (540.00 mg; 0.52 mmol; 1.00 eq.) was added in the mixture of TfOH (2.00 ml; 21.52 mmol; 41.32 eq.) and TFA (10.00 ml) at 0 °C. The mixture was stirred for 4 h at 0 °C.

[0324] The resulting mixture was quenched by water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3-[7-(4-{[1- (4-nitrophenyl)piperidin-4-yl]methyl}piperazin-1-yl)-2-oxo-2,3-dihydro-1, 3-benzoxazol-3- yl]piperidine-2, 6-dione (350.00 mg; 0.51 mmol; 97.9 %; yellow solid; Crude Product).

[0325] LC-MS method E: [M+H]+ 549; Rt; 0.62 min3-[7-(4-{[1-(4-aminophenyI)piperidin-4-yI]methyl}piperazin-1-yI)-2-oxo-2,3-dihydro-1, 3- benzoxazol-3-yl]piperidine- 2, 6-dione

[0326] To a stirred mixture of 3-[7-(4-{[1-(4-nitrophenyl)piperidin-4- yl]methyl} piperazin-1-yl)-2-oxo-2,3-dihydro-1.3-benzoxazol-3-yI]piperidine-2, 6-dione (460.00 mg; 0.67 mmol; 1.00 eq.) and Tetrahydroxy diboron (190.00 mg; 2.01 mmol; 3.01 eq.) in DMF (6.00 ml) was added 4,4'-bipyridine (1 1 .00 mg; 0.07 mmol; 0.10 eq.) in portions at 25°C. The resulting mixture was stirred for 1h at 25°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (1:1 ) to afford 3-[7-(4-{[1-(4- aminophenyl)piperidin-4-yl]methyl)piperazin-1-yl)-2-oxo-2,3-dihydro-1, 3-benzoxazol-3- yl]piperidine-2, 6-dione (110.00 mg; 0.16 mmol).

[0327] LC-MS Method U; [M+H] ]+ +519; Rl; 0.83 mmIntermediate 43: 3-[4-(4-{[1-(4-aminophenyI)piperidin-4-yI]methyl}piperazin-1-yl)-3- methyl-2-oxo- 2, 3-dihydro-1H-1, 3-benzodiazol-1-yl]piperidine-2, 6-dione; trifluoromethanesulfonic acid1- [(4-methoxyp henyl)methyl] -3- [3-methyl-4-(4- { [ 1 -(4-nitrophenyl)piperidin-4- yl]methyl}piperazin-1-yl)-2-oxo-2,3-dihydro-1H-1, 3-benzodiazol-1-yl]piperidine-2,6- dione

[0328] 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1 H-1,3-benzodiazol-1-yl)-1-[(4- methoxyphenyl)methyl]piperidine-2, 6-dione Intermediate 64 (250.00 mg; 1.00 eq.; 0.484 mmol), Cesium carbonate (473.48 mg; 3.00 eq.; 1.453 mmol) and {[1-(4- 1- nitrophenyl)piperidin-4-yl]methyl}piperazine Intermediate 41 (227.77 mg; 1.50 eq.; 0.727 mmol) were added to a vial and suspended in 1 ,4-Dioxane (6.25 ml). The vial was sealed and placed under vacuum, sonicated for 1 minute and refilled with argon. This procedure was repeated two times, followed by addition of Pd-PEPPSI-IPentCl 2 -methylpyridine (42.84 mg; 0.10 eq.; 0.048 mmol) to give a beige suspension. The vial was reopened and the procedure described above was repeated, followed by stirring at 100°C for 3 hrs to give a brown suspension. The reaction mixture was filtered through kieselguhr, rinsed with additional dichloromethane (approx. 30 ml) and concentrated. The crude product was purified by Isco CombiFlash Rf®and concentrated to give [(4-methoxyp 1h-enyl)methyl]-3-[3-methyl-4-(4- { [ 1 -(4-nitrophenyl)piperidin-4-yl]methyl} piperazin- 1 -yl)-2-oxo-2, 3-dihydro-1H- 1 ,3- benzodiazol-1-yl]piperidine-2, 6-dione (203.60 mg; 0.30 mmol; 61.7 %)

[0329] LC-MS method K: [M+H]+682.6; Rt: 0.58 min3-[3-methyl-4-(4-{[1-(4-nitrophenyl)piperidin-4-yl]methyl}piperazin-1-yl)-2-oxo-2,3- dihydro-1H-1, 3-benzodiazol-1-yl]piperidine-2, 6-dione; trifluoromethanesulfonic acid

[0330] 1- [(4-methoxyphenyl)methyl]-3-[3-methyl-4-(4-{[1-(4-nitrophenyl)piperidin-4-yl]methyl } piperazin- 1 -yl)-2-oxo-2 ,3 -dihydro-1H- 1 ,3-benzodiazol- 1 -yl]piperidine-2,6- dione (193.60 mg; 1.00 eq.; 0.284 mmol) was dissolved in Trifluoroacetic acid (4.03 ml) and Trifluoromethanesulfonic acid (418.69 pl; 16.80 eq.; 4.771 mmol) was added. The vial was sealed, flushed with argon and stirred at 50°C for 20 h. The reaction mixture was concentrated in vacuo. To the crude product MTB ether (approx. 20 ml) was added and sonicated to form a solid precipitate, which was stirred vigorously for 2 hrs. Subsequently this solid was filtered off, washed twice with additional MTB ether (approx. 10 ml each time) and dried. The crude product was purified by Isco CombiFlash Rf®to give 3-[3-methyl-4-(4- { [ 1 -(4-nitrophenyl)piperidin-4-yl]methyl}piperazin- 1 -yl)-2-oxo-2,3-dihydro-1H- 1 ,3- benzodiazol- yl]p 1i-peridine-2, 6-dione; trifluoromethanesulfonic acid (190.70 mg; 0.24 mmol; 79.3 %).

[0331] LC / MS Method K: [M+H]+562.5; Rt: 0.48 min3-[4-(4-{[1-(4-aminophenyI)piperidin-4-yl]methyl]piperazin-1-yl)-3-methyl-2-oxo-2,3- dihydro-1H-1, 3-benzodiazol-1-yl]piperidine-2, 6-dione; trifluoromethanesulfonic acid

[0332] 3-[3-methyl-4-(4- { [ 1 -(4-nitrophenyl)piperidin-4-yl]methyl }piperazin- 1 -yl)-2- oxo-2,3-dihydro-1H-1 ,3-benzodiazol- yl]piperidine 1--2, 6-dione; trifluoromethanesulfonic acid (190.70 mg; 1.00 eq.; 0.237 mmol) was dissolved in N,N-Dimethylformamide (1.91 ml) in a vial. To this Tetrahydroxydiboron (134.12 mg; 6.00 eq.; 1 .421 mmol) was added, followed by 4,4[’][-]Dipyridyl (3.77 mg; 0.10 eq.; 0.024 mmol). The reaction mixture was stirred at RT for 1.5 h. The mixture was concentrated and then added dichloromethane (approx. 8 ml). The formed precipitate was stirred for 0.25 hrs followed by filtration, washing the solid with dichloromethane and MTB ether (approx. 4 ml of both) and drying. The crude solid was purified by Isco CombiFlash Rf*’ to give 3-[4-(4-{[1-(4-aminophenyl)piperidin-4- yl]methyl }piperazin- 1 -yl)-3-methyl-2-oxo-2,3-dihydro-1H- 1 ,3-benzodiazol- 1 -yl]piperidine- 2, 6-dione; trifluoromethanesulfonic acid (107.50 mg; 0.14 mmol; 60.8 %).

[0333] LC / MS Method K: [M+H]+532.4; Rt: 0.31 minIntermediate 44: [2-c 1h-loro-4-(piperazin-1-yl)phenyI]-1, 3-diazinane-2, 4-dione; bis(trifluoroacetic acid)1-(4-bromo-2-chlorophenyl)-1, 3-diazinane-2,4-dione

[0334] To 4-bromo-2-chloroaniline (5,50 g) was added acrylic acid anhydrous (7,23 ml) and stirred at 110°C for 3 h. To the mixture urea (10,17 g) and acetic acid (glacial) (45,00 ml) were added at 30°C to the reaction mixture and stirred 12 h at 120°C. Further urea (3,50 g) and acetic acid (glacial) (20,00 ml) was added and stirred at 120°C for 16 h. The reaction solution was poured into 200 ml water / ice. The formed solid was filtered off, rinsed with water and dried at 60°C under vacuo. The solid was suspended in 20 ml ethanol, treated 5 min in an ultrasonic bath. The solid was filtered off, rinsed with ethanol and dried at 60°C under vacuo to yield (4-bro 1m- o-2-chlorophenyl)-1.3-diazinane-2, 4-dione (4.66g; 59%)

[0335] LC / MS Method P: [M+H]+304.9; Rt: 1 .29 min tert-butyl 4-[3-chloro-4-(2,4-dioxo-1, 3-diazinan-1-yl)phenyI]piperazine-1-carboxylate

[0336] 1- (4-bromo-2-chlorophenyl)-1, 3-diazinane-2,4-dione (500 mg), 1-Boc- piperazine, (407 mg) and Sodium tert-butylate (317 mg) were suspended in 1,4-Dioxane (15 ml) at room temperature. The reaction mixture was purged with nitrogen and then Xantphos (96,28 mg) and tris(dibenzylidenaceton)-dipalladium(0) (45,25 mg) were added. The reactionwas stirred at 100°C for 17 h. The reaction suspension was filtered over diatomaceous earth. It was rinsed with dioxane, dichloromethane and methanol. All layers were combined and evaporated, crude mixture was purified by column chromatography with a gradient of 0- 100% EtOAc in DCM to yield tert-butyl 4-[3-chloro-4-(2,4-dioxo-1, 3-diazinan-1- yl)phenyl]piperazine- 1 -carboxylate (285 mg; 42%).

[0337] LC / MS Method P: [M+Na]+431 ; Rt: 1.49 min 1-[2-chloro-4-(piperazin-1-yI)phenyI]-1, 3-diazinane-2, 4-dione; bis(trifluoroacetic acid)

[0338] Tert-butyl 4-[3-chloro-4-(2,4-dioxo-1, 3-diazinan-1-yl)phenyl]piperazine-1- carboxylate (285 mg) was dissolved in Dichloromethane (10 ml) and Trifluoroacetic acid (1 ml) was added. The reaction solution was stirred at room temperature for 4h. The reaction solution was evaporated, diluted with acetonitrile and evaporated to dryness to give l-[2- chloro-4-(piperazin-1-yl)phenyl]-1 ,3-diazinane-2, 4-dione; bis(trifluoroacetic acid) (370 mg; 95.6%)

[0339] LC / MS Method P: [M+H]+309; Rt: 0.85 minIntermediate 45 : [4-( 14--{[1-(4-aminophenyI)piperidin-4-yI]methyl}piperazin-1-yl)-2- chIorophenyl]-1, 3-diazinane-2, 4-dione1-[2-chloro-4-(4-{[1-(4-nitrophenyl)piperidin-4-yl]methyl}piperazin-1-yI)phenyl]-1, 3- diazinane-2.4-dione

[0340] 1- (4-nitrophenyl)piperidine-4-carbaldehyde Intermediate 3 (67 mg) and 1-[2- chloro-4-(piperazin-1-yl)phenyl]-1 ,3-diazinane-2, 4-dione; bis(trifluoroacetic acid)Intermediate 44 (150 mg) were dissolved in Dichloromethane (5 ml) and Methanol (0.5 ml). To the mixture, N-Ethyldiisopropylamine ( 91 [M)+ aHnd]+Sodium triacetoxyborohydride (234mg) were added. The reaction mixture was stirred for 2h at room temperature. The reaction mixture was quenched with water and the layers were separated. The water layer wasextracted with dichloromethane twice. The dichloromethane layers were combined, washed once with brine, dried over Na2SO4, filtered and evaporated. To the residue solid was added diethyl ether and stirred 1h. The solid was filtered off, rinsed with ether and the solid was dried to yield 1 -[2-chloro-4-(4- { [ 1 -(4-nitrophenyl)piperidin-4-yl]methyl] piperazin- 1 - yl)phenyI]-1, 3-diazinane-2, 4-dione (134 mg; 95%)

[0341] LC / MS Method P; [M+H]+528; Rt: 1.28 min 1-[4-(4-{[1-(4-aminophenyI)piperidin-4-yI]methyl]piperazin-1-yI)-2-chlorophenyl]-1, 3- diazinane-2, 4-dione

[0342] 1- [2-chloro-4-(4-{[1-(4-nitrophenyl)piperidin-4-yl]methyl}piperazin-1- yl)phenyl]-1, 3-diazinane-2, 4-dione (134 mg) was dissolved in N.N-Dimethylformamide (3 ml) and 4,4 ’-Dipyridyl (2 mg) was added. To the mixture tetrahydroxydiboron (68 mg) was added. The reaction solution was stirred at room temperature for 1h. To the reaction mixture was added 4,4 ’-Dipyridyl (2 mg) and tetrahydroxydiboron (68 mg) and stirred for a further 1h at room temperature. The reaction mixture was evaporated. The residue was diluted with 5% NaHCO3-solution and extracted with dichloromethane three times. The combined organic layers were washed once with brine, dried over Na2SO4, filtered and evaporated. The crude mixture was purified by flash chromatography with a gradient of 0-100% DCM:Methanol (9: 1) in DCM and concentrated to give [4-(4-{[1-(41--aminophenyl)piperidin-4- yl]methyl}piperazin-1-yl)-2-chlorophenyl]-1, 3-diazinane-2, 4-dione (85 mg; 67%).

[0343] LC / MS Method P: [M+H]+498; Rt: 0.91 minIntermediate 46: [7- 1(4--{[1-(4-aminophenyl)piperidin-4-yI]methyl]piperazin-1-yl)-1- methyl-1H-indazol-3-yl]-1, 3-diazinane-2, 4-dione; trifluoromethanesulfonic acid3-[(4-methoxyphenyl)methyl]-1-[1-methyl-7-(4-{[1-(4-nitrophenyl)piperidin-4- yl]methyI]piperazin-1-yl)-1H-indazol-3-yl]-1, 3-diazinane-2, 4-dione

[0344] 1- (7-bromo-1-methyl-1H-indazol-3-yl)-3-[(4-methoxyphenyl)methyl]-1, 3- diazinane-2,4-dione Intermediate 65 (225.00 mg; 1.00 eq.; 0.493 mmol), cesium carbonate (481.69 mg; 3.00 eq.; 1.478 mmol) and {[1-(4-nitrop 1h-enyl)piperidin-4- yl ]methyl } piperazine Intermediate 41 (231.72 mg; 1.50 eq.; 0.739 mmol) were filled into the vial and suspended in 1 ,4-Dioxane (5.63 ml). Next the vial was sealed, placed under vacuum, sonicated for 1 minute and refilled with argon. The vial was purged a further two times, followed by addition of Pd-PEPPSI-IPentCl 2-methylpyridine (43.58 mg; 0.10 eq.; 0.049 mmol). Subsequently the vial was resealed and purged. The mixture was stirred at 100°C for 3 h. The reaction mixture was filtered through kieselguhr, rinsed with dichloromethane (approx. 30 ml) and concentrated. The crude product was adsorbed onto Isolute HM-N®and purified by Isco CombiFlash Rf®(Redisep Rf Silica 12 g column; cyclohexane -> ethyl acetate to dichloromethane -> ethanol). The pure fractions were combined and concentrated to give 3-[(4-methoxyphenyl)methyl]- 1 -[ 1 -methyl-7-(4- { [ 1 -(4-nitrophenyl)piperidin-4- yl]methyl}piperazin-1-yl)-1H-indazol-3-yl]-1, 3-diazinane-2, 4-dione (266.80 mg; 0.39 mmol;78.9 %; intensive yellow foamed oil; Purified Product)

[0345] LC / MS method K: [M+H ]+667.6; Rt 0.581-[1-methyl-7-(4-{[1-(4-nitrophenyl)piperidin-4-yl]methyl}piperazin-1-yl)-1H-indazoI-3- yl]-1, 3-diazinane-2, 4-dione; trifluoromethanesulfonic arid

[0346] 3-[(4-methoxyphenyl)methyl]-1-[ 1 -methyl-7-(4- { [ 1 -(4-nitrophenyl)piperidin-4-yl]methyl}piperazin-1-yl)-1H-indazol-3-yl]-1, 3-diazinane-2, 4-dione (256.80 mg; 1.00 eq.; 0.374 mmol) was dissolved in Trifluoroacetic acid (5.34 ml) and Trifluoromethanesulfonic acid for synthesis (551.97 pl; 16.80 eq.; 6.289 mmol) was added. The vial was sealed, flushed with argon and stirred at 50°C for 4.5h. The reaction mixture was concentrated in vacuo. The crude product was suspended in dichloromethane (approx. 30 ml), and saturated sodium bicarbonate solution (approx. 15 ml). The mixture was filtered and the filtrate extracted with dichloromethane (20 ml x 2). The filtered solid was treated once more with dichloromethane and saturated sodium bicarbonate solution and extracted with DCM (20 ml x 2). The combined organic phases were washed with saturated sodium bicarbonate solution (approx. 5 ml), dried over sodium sulfate, filtered and concentrated. The crude product was adsorbed onto Isolute HM-N® and purified by Isco CombiFlash Rf® (Redisep Rf Silica 4 g column; A: Dichloromethane B: Ethanol ; 0% B: 0->8.0 min ; 0% ->100% B: 8.0->16.5 min ; Flow; 18 ml / min). The pure fractions were combined and concentrated to give 1-[1-methyl-7-(4-{[1- (4-nitrophenyl)piperidin-4-yl]methyl}piperazin-1-yl)-1H-indazol-3-yl]-1, 3-diazinane-2,4- dione; trifluoromethanesulfonic acid (172.30 mg; 0.22 mmol; 56.3 %).

[0347] LC / MS Method K: [M+H]+547.4; Rt 0.48 1-[7-(4-{[1-(4-aminophenyl)piperidin-4-y]]methyl}piperazin-1-yl)-1-methyl-1H-indazol- 3-yl]-1, 3-diazinane-2,4-dione; trifluoromethanesidfonic acid

[0348] 1- [1-methyl-7-(4- {[1-(4-nitrophenyl)piperidin-4-yl]methyl] piperazin-1 -yl)- 1H-indazol-3-yl]-1, 3-diazinane-2,4-dione; trifluoromethanesulfonic acid (172.30 mg; 1.00 eq.; 0.219 mmol) was dissolved in N,N-Dimethylformamide (1.72 ml) and filled into the vial. To this Tetrahydroxy diboron (124.21 mg; 6.00 eq.; 1.316 mmol) was added, followed by 4,4 ’-Dipyridyl (2.45 mg; 0.07 eq.; 0.015 mmol) and stirring was continued at rt for 1.5h. The mixture was concentrated and the residue was treated with dichloromethane (approx. 8 ml), which caused a precipitation. This precipitate was stirred for 0.25h followed by filtration, additional dichloromethane and MTB ether were rinsed over the solid (approx. 4 ml of both) and the solid was dried. The solid was adsorbed onto Isolute HM-N® and purified by Isco CombiFlash Rf®(Redisep Rf Silica 4 g column; A: Dichloromethane B: Ethanol ; 0% B: 0- >2.2 min ; 0% ->97% B; 2.2->12.7 min ; Flow; 18 ml / min). The pure fractions were combined and concentrated to give [7-(4-{[1-(41-a-minophenyl)piperidin-4-yl]methyl}piperazin-1-yl)-1-methyl-1H-indazol-3-yl]-1, 3-diazinane-2, 4-dione; trifluoromethanesulfonic acid (116.30 mg; 0.17 mmol; 79.5 %).

[0349] LC / MS Method K; [M+H]+= 517.4; Rt 0.34Intermediate 47 ; [2-m 1-ethyl-4-(piperazin-1-yl)phenyl]-1, 3-diazinane-2, 4-dione; trifluoroacetic acidtert-butyl 4-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1, 3-diazinan-1-yl}-3- methylphenyl)piperazine-1-carboxylate

[0350] To a stirred solution of 1 -(4-bromo-2-methylphenyl)-3-[(4- methoxyphenyl)methyl]- 1 , 3 -diazinane-2 ,4-dione Intermediate 67 (1.50 g; 3.14 mmol; 1.00 eq.) and tert-butyl piperazine- 1 -carboxylate (1.05 g; 5.62 mmol; 1.79 eq.) in Dioxane-1,4 (15 ml) were added tris(dibenzylideneacetone)dipalladium (O) (320 mg; 0.31 mmol; 0.10 eq.), X- PHOS (315 mg; 0.63 mmol; 0.20 eq.) and CS2CO3(2.15 g; 6.27 mmol; 2.00 eq.) in portions at room temperature under N2atmosphere. The resulting mixture was stirred for overnight at 100°C under N2atmosphere. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column, eluted with 40% EtOAc in PE to afford tert-butyl 4-(4- {3-[(4- methoxyphenyl)methyl]-2 ,4-dioxo- 1 ,3 -diazinan- 1 -yl } -3-methylphenyl)piperazine- 1 - carboxylate (650 mg; 1.17 mmol; 37.2 %)

[0351] LC / MS method H: [M+Na]+531 ; Rt 0.99 1-[2-methyl-4-(piperazin-1-yl)phenyl]-1, 3-diazinane-2, 4-dione; trifluoroacetic acid

[0352] To a solution of tert-butyl 4-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1, 3- diazinan-1-yl}-3-methylphenyl)piperazine-1-carboxylate (630 mg; 1.13 mmol; 1.00 eq.) in TFA (6 ml) were added CF3SO3 H (0.60 ml; 6.44 mmol; 5.70 eq.), The resulting mixture was stimed for 1h at 60°C under nitrogen atmosphere. A slurry was formed in TBME. Thenthe solid was filtered, and the filter cake was washed with TBME (30 mL) and the filter cake was dried under reduced pressure to afford [2-methyI-4-( 1p-iperazin-1-yl)phenyl]-1, 3- diazinane-2, 4-dione; trifluoroacetic acid (500 mg; 1.13 mmol; 99.9 %; yellow solid; Crude Product)

[0353] LC / MS method H: [M+H]+289; Rt 0.54Intermediate 48 : {4- 1[(-7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazin-7-yl}quinazolin-2-yl)amino]phenyl]piperidine-4-carboxylic acidmethyl 1{4- [(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazin-7-yI]quinazolin-2-yl)amino]phenyl]piperidine-4-carboxylate

[0354] To a stirred mixture of methyl (4-amino 1p-henyl)piperidine-4-carboxylate (471938-27-9) (250 mg; 0.96 mmol; 1.00 eq.) and tert-butyl 7-(2-chloroquinazolin-7-yl)-8- methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate Intermediate 1 (408 mg; 0.96 mmol; 1 .00 eq.) in Dioxane- 1 ,4 (6 ml) were added Pd-PEPPSI-IPentCl 2-methylpyridine (o- picoline) (85.00 mg; 0.10 mmol; 0.10 eq.) and CS2CO3(660 mg; 1.92 mmol; 2.00 eq.) at room temperature. The mixture was stirred for 3 h at 100 °C under argon atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10: 1) to afford methyl 1 - {4-[(7- { 11- -[(tert- butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}quinazoIin-2- yl)amino]phenyl}piperidine-4-carboxylate (420 mg; 0.66 mmol; 69.1 %).

[0355] LC / MS method H: [M+H]+611; Rt 0.881-{4-[(7-{1-[(tert-butoxy)carbonyI]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7- yl}quinazolin-2-yl)amino]phenyl}piperidine-4-carboxyIic acid

[0356] To a stirred solution of methyl 1 - {4-[(7- { 1-[(tert-butoxy)ca 1r-bonyl]-8-methyl- 1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}quinazolm-2-yl)amino]phenyl}piperidine-4- carboxylate (400 mg; 0.63 mmol; 1 .00 eq.) in oxolane (4 ml), MeOH (4 ml)and H2O (2 ml) were added NaOH (106 mg; 2.52 mmol; 3.99 eq.) in portions at room temperature under N2atmosphere. The resulting mixture was stirred for 2h at 25 °C under N2atmosphere. Theresulting mixture was diluted with H2O, the pH of the solution was adjusted to 3 with HC1 (2 M). Then extracted with MeOH / DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 1-{4-[( 17--{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazin-7-y}j quinazolin-2-yl)amino]phenyl}piperidine-4-carboxylic acid (300 mg; 0.50 mmol; 79.2 %)

[0357] LC / MS method H: [M+H]+597; Rt 0.85Intermediate 49 : tert-butyl 4-[(2-oxopiperazin-1-yl)methyl]piperidine-1-carboxyIatebenzyl 4-({1-[(tert-butoxy)carbonyl]piperidin-4-yl]methyl)-3-oxopiperazine-1- carboxylate

[0358] To a stirred solution of benzyl 3 -oxopiperazine- 1 -carboxylate (3 g; 12.17 mmol; 1 .00 eq.) in DMF (30 ml) was added NaH (0.97 g; 24.33 mmol; 2.00 eq.) in portion at 0°C, the mixture was stirred for 30 mins at 0°C and then warmed to room temperature and stirred for 30 mins at room temperature. To the mixture tert-butyl 4-(iodomethyl)piperidine- 1 -carboxylate (4.58 g; 13.38 mmol; 1.10 eq.) was added in portion at room temperature, the resulting mixture was stirred for 16h at room temperature.

[0359] The resulting mixture was quenched by ice / water, extracted by EtOAc, the organic layer was combined and washed by brine, dried under Na2SO4, concentrated under vacuum, the residue was purified by silica gel column chromatography, eluted with DCM / MeOH(10:l) to afford benzyl 4-({1-[(tert-butoxy)carbonyl]piperidm-4-yl}methyl)-3- oxopiperazine-1 -carboxylate (1.40 g; 3.06 mmol; 25.15 %)

[0360] LC / MS method G. [M+H]+376.2; Rt 0.77 tert-butyl 4-[(2-oxopiperazin-1-yl)methyl]piperidine-1-carboxylate

[0361] benzyl 4-( { 1 (leri-butoxy)carbonyl ]piperidin-4-yl } methyl)-3-oxopiperazine-1-carboxylate (1.35 g; 3.12 mmol; 1.00 eq.) and Pd / C (332 mg; 0.31 mmol; 0.10 eq.) was added in MeOH (1 ml) at room temperature. The resulting mixture was stirred for 16h at 25°C under hydrogen atmosphere. The solid was filtered out and the filter cake was washed by MeOH, the filtrate was concentrated under vacuum, this was afford crude product tert- butyl 4-[(2-oxopiperazin-1-yl)methyl]piperidine- 1-carboxylate (680 mg; 1.83 mmol; 58.71 %; yellow solid; Crude Product) used in the next step without any purification.

[0362] LC / MS method G: [M+H]+298.2; Rt 0.46Intermediate 50 : [4-( 14--{[1-(4-aminophenyl)piperidin-4-yl]methyl}-3-oxopiperazin-1- yl)-2-methylphenyl]-3-[(4-methoxyphenyl)methyl]-1, 3-diazinane-2, 4-dionetert-butyl 4-{[4-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1, 3-diazinan-1-yl}-3- methylphenyl)-2-oxopiperazin-1-yl]methyl}piperidine-1-carboxylate

[0363] To a stirred solution of 1 -(4-bromo-2-methylphenyl)-3-[(4- methoxyphenyl)methyl]-1,3-diazinane-2, 4-dione Intermediate 67 (600 mg; 1.46 mmol; 1.00 eq.) and tert-butyl 4-[(2-oxopiperazin-1-yl)methyl]piperidine- 1-carboxylate Intermediate 49 (670 mg; 1.80 mmol; 1.24 eq.) in Dioxane-1,4 (10 ml) was added Pd-PEPPSI-IPentCl 2- methylpyridine (o-picoline) ( 129 mg; 0.15 mmol; 0.10 eq.) and Cs2CO3 (960.00 mg; 2.92 mmol; 2.00 eq.) in portion at room temperature. The resulting mixture was stirred for 2 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum.the residue was purified by silica gel column chromatography, eluted withDCM / MeOH( 10:1 ) to afford tert-butyl 4- {[4-(4-{3--[(4-melhoxyphetiyI)methyl ]-2,4-dioxo- l ,3-diazinan-1-yl}-3-methylphenyl)-2-oxopiperazin-1-yl]methyl}piperidine-1-carboxylate (730 mg; 1.06 mmol; 72.71 %)

[0364] LC / MS method G: [M+H]+620.5 ; Rt 0.753-[(4-methoxyphenyl)methyl]-1-(2-methyl-4-{3-oxo-4-[(piperidin-4-yI)methyl]piperazin- 1-yl}phenyI)-1, 3-diazinane-2, 4-dione hydrochloride

[0365] tert-butyl 4- {[4-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1, 3-diazinan-1- yl} -3-methylphenyl)-2-oxopiperazin-1-yl ]methyl] piperidine- 1 -carboxylate (720 mg; 1.05 mmol; 1 .00 eq.) was added in 4M HC1 in EA (20 ml; 80.00 mmol; 76.51 eq.) at room temperature. The resulting mixture was stirred for 1h at 25°C. The solid was collected by filtration and filter cake was dried under reduced pressure. To yield 3-[(4- methoxyphenyl)methyl]- 1 -(2-methyl-4- { 3-oxo-4-[(piperidin-4-yl)methyl]piperazin- 1 - yl} phenyl)-1,3-diazinane-2, 4-dione hydrochloride (580 mg; 0.87 mmol; 83.39 %).

[0366] LC / MS Method U; [M+H]+520.3; Rt 0.763-[(4-methoxyphenyl)methyl]-1-[2-methyl-4-(4-{[1-(4-nitrophenyl)piperidin-4- yl]methyI)-3-oxopiperazin-1-yl)phenyl]-1, 3-diazinane-2, 4-dione

[0367] To a stirred solution of 3-[(4-methoxyphenyl)methyl]-1-(2-methyl-4- {3-oxo-4-[(piperidin-4-yl)methyl]piperazin- 1 -yI}phenyl)- 1 ,3-diazinane-2, 4-dione hydrochloride (570 mg; 0.86 mmol; 1.00 eq.) and 1 -fluoro-4-nitrobenzene (0.1 1 ml; 1.03 mmol; 1.20 eq.) in ACN (10 ml) was added DIEA (0.47 ml; 2.57 mmol; 3.00 eq.) in dropwise at room temperature. The resulting mixture was stirred for 3h at 80°C under nitrogen atmosphere. The solid was filtered out and the filtrate was concentrated under vacuum, the residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10: 1) to afford 3- [(4-methoxyphenyl)methyl]-1-[2-methyl-4-(4- { [ 1 -(4-nitrophenyl)piperidin-4-yl]methyl } -3- oxopiperazin-1-yl)phenyl]-1, 3-diazinane-2, 4-dione (605 mg; 0.75 mmol; 87.82 %)

[0368] LC / MS Method U: [M+H]+641.3; Rt 0.97 1-[4-(4-{[1-(4-aminophenyI)piperidin-4-yl]methyl]-3-oxopiperazin-1-yl)-2- methylphenyl] -3- [(4-methoxyphenyl)methyl] -1 ,3-diazinane-2, 4-dione

[0369] To a solution of 3-[(4-methoxyphenyl)methyl]-1-[2-methyl-4-(4- {[1-(4- nitrophenyl)piperidin-4-yl]methyl}-3-oxopiperazin-1-yl)phenyl]-1, 3-diazinane-2, 4-dione(595 mg; 0.74 mmol; 1.00 eq.) in DMF (10 ml), Pd / C (80 mg; 0.08 mmol; 0.10 eq.) was added at room temperature. The reaction mixture was stirred for 16h at room temperature under H2atmosphere. The resulting mixture was filtered, the filter cake was washed with DMF (150ml). The filtrate was concentrated under reduced pressure and a slurry formed with MTBE, filtered and dried under vacuum to afford [4-(4-{[1-(4-am 1-inophenyl)piperidin-4- yl]methyl}-3-oxopiperazin-1-yl)-2-methylphenyl]-3-[(4-methoxyphenyl)methyl]-1, 3- diazinane-2, 4-dione (280 mg; 0.44 mmol; 59.34 %)

[0370] LC / MS Method U: [M+H]+61 1.3; Rt 0.82Intermediate 51 : 3-[7-(4-{[1-(4-aminophenyI)piperidin-4-yl]methyl}piperazin-1-yl)-1- methyl-1H-indazol-3-yl]piperidine-2,6-dione3-[1-methyI-7-(4-{[1-(4-nitrophenyl)piperidin-4-yI]methyl}piperazin-1-yl)-1H-indazol-3- yl] piperidine-2, 6-dione

[0371] 1- (4-nitrophenyl)piperidine-4-carbaldehyde Intermediate 3 (47 mg) and3-[1- methyl-7-(piperazin-1-yl)-1H-indazol-3-yl]piperidine-2, 6-dione; trifluoroacetic acid Intermediate 19 (80 mg) were dissolved in Dichloromethane (2 ml), Methanol (0.50 ml) and N-Ethyldiisopropylamine for synthesis (56.5 [M)+. THh]+en Sodium triacetoxyborohydride (145 mg) was added. The reaction mixture was stirred 1h at room temperature. The reaction solution was quenched with water and 5% NaHCO3solution and the layers were separated. The water layer was extracted with dichloromethane twice. The dichloromethane layers were combined, washed once with brine, dried over Na2SO4, filtered and evaporated to yield 3-[1-methyl-7 -(4- { [ 1 -(4-nitrophenyl)piperidin-4-yl ]methyl} piperazin- 1 -y 1)- 1H-indazol-3- yl]piperidine-2, 6-dione (99 mg; 0.18 mmol; quant.)

[0372] LC / MS method A: [M+H]+546.2; Rt 1 .303-[7-(4-{[1-(4-aminophenyl)piperidin-4-yl]methyl]piperazin-1-yl)-1-methyl-1H-indazol- 3-yl] piperidine-2,6-dione

[0373] 3-[ 1 -methyl-7-(4- { [ 1 -(4-nitrophenyl)piperidin-4-yl]methyl}piperazin- 1 -yl)-1H-indazol-3-yl ]piperidine-2, 6-dione (99 mg) was dissolved in N,N-Dimethylformamide (3 ml) and cooled with an ice water bath. After 10 mins, tetrahydroxydiboron (95 mg) and 4,4’- Dipyridyl (3 mg) were added. The reaction mixture was stirred 10 mins with ice cooling and 25 mins at room temperature. The reaction solution was diluted with water and 5% NaHCO3- solution and extracted with dichloromethane three times. The combined organic layers were washed once with brine, dried over Na2SO4, filtered and evaporated to yield 3-[7-(4-{[1-(4- aminophenyl)piperidin-4-yl] methyl } piperazin- 1 -yl)- 1 -methyl-1H-indazol- 3 -yl]piperidine- 2, 6-dione (98 mg; 0.18 mmol; quant.)

[0374] LC / MS method A: [M+H]+516.3; Rt 0.96Intermediate 52 : 3-[4-(4-{[1-(4-aminophenyI)piperidin-4-yl]methyl}piperazin-1-yl)-2-methylphenyl]piperidine-2,6-dione1-{4-[2,6-bis(benzyIoxy)pyridin-3-yl]-3-methylphenyl}-4-{[1-(4-nitrophenyI)piperidin-4- yl]methyl}piperazine

[0375] To a stirred mixture of [(4-br 1o-mophenyl)methyl]-3-[(4- methoxyphenyl)methyl]-1, 3-diazinane-2,4-dione Intermediate 68 (1.63 g; 3.54 mmol; 1.00 eq.) and (41--nitrophenyl)-4-[(piperidin-4-yl)methyl]piperazine Intermediate 41 (1.10 g; 3.54 mmol; 1.00 eq.) in Dioxane-1,4 (15 ml) were added Xphos (0.36 g; 0.71 mmol; 0.20 eq.) and Pd2(dba)3 (0.36 g; 0.35 mmol; 0. 10 eq.) and CS2CO3(2.43 g; 7.08 mmol; 2.00 eq.) at room temperature. The mixture was stirred for 12 h at 100°C under argon atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with PE / EtOAc (1 : 1) to afford 3-[(4-methoxyphenyl)methyl]-1-{[4- (4- { [4-(4-nitrophenyl)piperazin- 1 -yl] methyI}piperidin- 1 -yl)phenyl]methyl ) - 1 ,3-diazinane- 2, 4-dione (1.75 g; 2.52 mmol; 71.0 %).

[0376] LC / MS method E: [M+H]+684.5; Rt 0.94

[0377] 3-[4-(4-{[1-(4-aminophenyl)piperidin-4-yl]methyl}piperazin-1-yl)-2- methylphenyl]piperidine-2,6-dione

[0378] To a stirred solution of 1 -{4-[2,6-bis(benzyloxy)pyridin-3-yl]-3- methylphenyl}-4-{[1-(4-nitrophenyl)piperidin-4-yl]methyl}piperazine (500 mg; 0.73 mmol; 1.00 eq.) in Dioxane- 1,4 (20.00 ml) was added Pd / C (1 g; 0.94 mmol; 1.29 eq.) in portions at room temperature under N2atmosphere. The mixture was stirred for 2 days at 60°C under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with dioxane. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH ( 1 :1 ) to afford 3-[4-(4-{[1-(4- aminophenyl)piperidin-4-yl]methyl}piperazin-1-yl)-2-methylphenyI]piperidine-2, 6-dione (220.00 mg; 0.38 mmol; 52.3 %).

[0379] LC / MS method E: [M+H]+476.5 ; Rt 0.50Intermediate 53 : 3-[4-(4-{[1-(4-aminophenyl)piperidin-4-yl]methyl}piperazin-1-yl)-6- oxo-1 ,6-dihydropyridazin- 1-yl] piperidine-2, 6-dione4-chloro-5-(piperazin-1-yl)-2,3-dihydropyridazin-3-one hydrochloride

[0380] To a stirred solution of 4,5-dichloro-2,3-dihydropyridazin-3-one (5 g; 28.79 mmol; 1.00 eq.) in EtOH (50 ml) was added piperazine (2.74 g; 30.23 mmol; 1.05 eq.) in portion at room temperature. The resulting mixture was stirred for 16 h at 80°C. The solid was collected by filtration and the filter cake was washed by EtOH, cold MeOH, dried under vacuum to afford 4-chloro-5-(piperazm-1-yl)-2,3-dihydropyridazin-3-one hydrochloride (4.20 g; 15.10 mmol; 52.46 %).

[0381] LC / MS method G: [M+H]+215. 1 ; Rt 0.165-(piperazin-1-yl)-2,3-dihydropyridazin-3-one

[0382] To a stirred solution of 4-chloro-5-(piperazin-1-yl)-2,3-dihydropyridazin-3- one hydrochloride (4.20 g; 15.10 mmol; 1.00 eq.) in EtOH (100 ml) was added N2H4H2O (8 ml; 205.68 mmol; 13.62 eq.) in portion, Pd / C (2 g; 1.88 mmol; 0.12 eq.) was added at room temperature. The resulting mixture was stirred for 16h at 80°C under argon atmosphere. Thesolid was filtered out and the filter cake was washed by MeOH, the filtrate was concentrated under vacuum, this was afford crude product 5-(piperazm-1-yI)-2,3-dihydropyridazin-3-one (2.20 g; 12.01 mmol; 79.54 %).

[0383] LC / MS Method U: [M+H]+181.2; Rt 0. 11 tert-butyl 4-{[4-(6-oxo-1, 6-dihydropyridazin-4-yl)piperazin-1-yl]methyl}piperidine-1- carboxylate

[0384] To a stirred solution of 5-(piperazin-1-yl)-2,3-dihydropyridazin-3-one (2.10 g; 11.47 mmol; 1.00 eq.) and tert-butyl 4-formylpiperidine-1-carboxylate (5.15 g; 22.93 mmol; 2.00 eq.) in the mixture of DCM (20 ml) and MeOH (20 ml) was added NaOAc (4.95 g; 57.33 mmol; 5.00 eq.) and AcOH (0.72 g; 11 .47 mmol; 1.00 eq.) in portions at room temperature. The mixture was stirred for 4h at room temperature, NaBH3CN (2.25 g; 34.40 mmol; 3.00 eq.) was added, the resulting mixture was stirred for 16 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH(10:l) to afford tert-butyl 4- {[4-(6-oxo- 1 ,6-dihydropyridazin-4-yl)piperazin- 1 -yl]methyl } piperidine- 1 - carboxylate (3.20 g; 8.30 mmol; 72.38 %)

[0385] LC / MS Method U: [M+H]+378.2; Rt 0.69 tert-butyl 4-({4-[1-(2,6-dioxopiperidin-3-yl)-6-oxo-1, 6-dihydropyridazin-4-yl]piperazin- 1 -yl} methyl)piperidine- 1 -carboxylate

[0386] tert-butyl 4- { [4-(6-oxo- 1 ,6-dihydropyridazin-4-yl)piperazin-1- yl]methyl} piperidine- 1 -carboxylate (3.10 g; 7.80 mmol; 1.00 eq.) was added in THF (50 ml), then LiHMDS (15.6 ml; 15.60 mmol; 2.00 eq.) was added in dropwise at -30°C under argon atmosphere, the resulting mixture was stirred for 1 hour at -30°C. To the mixture, 3- bromopiperidine-2, 6-dione (3.15 g; 15.60 mmol; 2.00 eq.) was added in portion at -30°C. the resulting mixture was wanned to room temperature and stirred for 16 hours at reflux. The mixture was quenched by saturated NH4CI (aq), extracted by EtOAc, combined the organic layers, and washed by brine, dried by Na2SO4, concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH(10;l) to afford tert- butyl 4-( {4-[ 1 -(2,6-dioxopiperidin-3-yl)-6-oxo- 1 ,6-dihydropyridazin-4-yl]piperazin-1- yl} methyl (piperidine-! -carboxylate (2.50 g; 4.85 mmol; 62.1 1 %).

[0387] LC / MS Method U; [M+H]+489.3; Rt 0.733-(6-oxo-4-{4-[(piperidin-4-yl)methyl]piperazin-1-yl]-1, 6-dihydropyridazin-1- yl)piperidine-2 ,6-dione hydrochloride

[0388] tert-butyl 4-( {4-[ 1 -(2,6-dioxopiperidin-3-yl)-6-oxo-1,6-dihydropyridazin-4- yl]piperazin-1-yl}methyl)piperidine-1-carboxylate (2.40 g; 4.65 mmol; 1.00 eq.) was added in 4M HC1 in EA (30 ml; 120.00 mmol; 25.80 eq.) at room temperature. The resulting mixture was stirred for 1h at 25°C. The solid was collected by filtration and the filler cake was washed with EtOAc and slurry formed with MTBE to afford 3-(6-oxo-4-{4-[(piperidin-4-yl)methyl]piperazin- 1 -yl} - 1 ,6-dihydropyridazin- 1 -yl)piperidine-2, 6-dione hydrochloride (1.80 g; 4.22 mmol; 90.79 %).

[0389] LC / MS method G: [M+H]+389.3; Rt 0.163-[4-(4-{[1-(4-nitrophenyl)piperidin-4-yl]methyl}piperazin-1-yl)-6-oxo-1, 6- dihydropyridazin-1-yl]piperidine-2, 6-dione

[0390] To a stirred solution of 3-(6-oxo-4-{4-[(piperidin-4-yl)methyl]piperazin-1-yl} - l,6-dihydropyridazin-1-yl)piperidine-2, 6-dione hydrochloride (800 mg; 1.88 mmol; 1.00 eq.) and 1 -fluoro-4-nitrobenzene (0.41 ml; 3.76 mmol; 2.00 eq.) in ACN (20 ml) was added DIEA (1 .03 ml; 5.63 mmol; 3.00 eq.) in dropwise at room temperature. The resulting mixture was stirred for 3h at 80°C under nitrogen atmosphere. The solid was filtered out and the filtrate was concentrated under vacuum, the residue was purified by silica gel column chromatography, eluted with DCM / MeOH(20:l) to afford 3-[4-(4- {[1-(4- nitrophenyl)piperidin-4-yl]methyl [piperazin- 1 -yl)-6-oxo-1,6-dihydropyridazin-] - yl]piperidine-2, 6-dione (330 mg; 0.64 mmol; 34.26 %).

[0391] LC / MS method D: [M+H]+510.5; Rt 0.503-[4-(4-{[1-(4-aminophenyI)piperidin-4-yl]methyl}piperazin-1-yl)-6-oxo-1, 6- dihydropyridazin-1-yl]piperidine-2, 6-dione

[0392] 3- [4 - (4 - { [ 1 -(4-nitrophenyl)piperidin-4-yl]methyl} piperazin- 1 -yl)-6-oxo- 1 ,6- dihydropyridazin- yl]pi 1p-eridine-2, 6-dione (320 mg; 0.62 mmol; 1.00 eq.)\vas added in DMF (10 ml), Pd / C (50 mg; 0.05 mmol; 0.08 eq.) was added in portion at room temperature. The resulting mixture was stirred for 16h at room temperature under hydrogen atmosphere. The solid was filtered out and the filtrate was concentrated under vacuum, a slurry formed with MTBE, filtered and dried to afford 3-[4-(4-{[1-(4-aminophenyf)piperidin-4-yl]methyl}piperazin-1-yl)-6-oxo- 1 ,6-dihydropyridazin- 1 -yl]piperidine-2,6-dione (280 mg;0.54 mmol; 86.88 %).

[0393] LC / MS method C: [M+H]+480.2; Rt 0.36Intermediate 54 : 2-chIoro-7-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)quinazoline2-chloro-7-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)quinazoline

[0394] To a stirred solution of 7-bromo-2-chloroquinazoline (1 g; 4.02 mmol; 1.00 eq.) and BPD (2.06 g; 8.05 mmol; 2.00 eq.) in 1,4-Dioxane (15 ml), Pd(dppf)Cl2,CH2Cl2(0.33 g; 0.40 mmol; 0.10 eq.) and KOAc (1.20 g; 12.07 mmol; 3.00 eq.) were added in portions at room temperature. The resulting mixture was stirred for 2h at 100ºC. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 2-chloro-7-(4, 4,5, 5-tetramethyl- 1,3,2- dioxaborolan-2-yl)quinazoline (1.20 g; 3.82 mmol; 94.81 %).

[0395] LC / MS method N: [M+H] ]+ :291.1 ; Rt 0.92Intermediate 55 : tert-butyl 7-bromo-8-methoxy-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1- carboxylate5-bromo-4-chloro-3-nitropyridin-2-ol

[0396] To a stirred solution of 4-chloro-3-nitropyridin-2-ol (20 g; 108.86 mmol; 1.00 eq.) in THF (400 ml) was added NBS (39.95 g; 217.71 mmol; 2.00 eq.) in portions at room temperature. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was diluted with water ( 1000mL), extracted with EtOAc (3x500mL). The combined organic layers were washed with brine(500mL), dried over anhydrous Na2SO4. The resulting mixture was concentrated under. A slurry was formed with EA / PE=20 / l and stirred for 30 min. After filtration, the filter cake was washed with PE, the filter cake was reduced pressure to afford 5-bromo-4-chloro-3-nitropyridin-2-ol (30.00 g; 99.1 1 mmol; 91.05 %).

[0397] LC / MS method O: [M+H]+254.9; Rt 0.695-bromo-4-methoxy-3-nitropyridin-2-ol

[0398] To a solution of 5-bromo-4-chloro-3-nitropyridin-2-ol (29 g; 95.81 mmol;1.00 eq.) in MeOH (500 ml) was added MeONa in MeOH (30%) (75 ml) at room temperature. The mixture was stirred at room temperature for 16 h at 60°C .The resulting mixture was filtered, the filter cake was washed with MeOH (100ml). Then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (1:1 ) and combined with the previously filtered solid to afford 5-bromo-4-methoxy-3-nitropyridin-2-ol (25.00 g; 98.67 mmol; Quant.).

[0399] LC / MS method O: [M+H] ' 250.9; Rt 0.613-amino-5-bromo-4-methoxypyridin-2-ol

[0400] To a stirred solution of 5-bromo-4-methoxy-3-nitropyridin-2-ol (16 g; 63.15 mmol; 1.00 eq.) and NH4Cl (14.22 g; 252.59 mmol; 4.00 eq.) in water (140 ml) and THF (210 ml), Fe (18.61 g; 315.73 mmol; 5.00 eq.) was added in portions at room temperature. The resulting mixture was stirred for 1 h at 80°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10: 1) to afford 3-amino-5-bromo-4-methoxypyridin-2-ol (6.00 g; 23.14 mmol; 36.65 %).

[0401] LC / MS method O: [M+H]+220.9; Rt 0.507-bromo-8-methoxy-1 H,2H,3H-pyrido[2,3-b][L4]oxazin-2-one (PH-MS-PMC611 / 017 / 996)

[0402] To a stirred solution of 3-amino-5-bromo-4-methoxypyridin-2-ol (6 g; 23. 14 mmol; 1.00 eq.) and K2CO3(10 g; 69.42 mmol; 3.00 eq.) m DMF (50 ml) was added 2- chloroacetyl chloride (2.32 ml; 27.77 mmol; 1 .20 eq.) in portions at 0 °C under argon atmosphere. The resulting mixture was stirred for 1 day at 50°C under argon atmosphere. The resulting mixture was diluted with water (300mL), extracted with EtOAc (3x150mL). The combined organic layers were washed with brine (150mL), dried over anhydrous Na2SO4.The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column, eluted with 70% EtOAc in PE to afford 7-bromo-8-methoxy-1H,2H,3H- pyrido[2,3-b][1,4]oxazin-2-one (5.30 g; 20.00 mmol; 86.42 %)

[0403] LC / MS method B: [M+H]+260.8; Rt 0.567-bromo-8-methoxy-1H,2H,3H-pyrido[2,3-b][1,4]oxazine

[0404] A solution of 7-bromo-8-methoxy-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-2-one (5.30 g; 20.00 mmol; 1.00 eq.) in THF (150 ml), and was added BH3, in THF (80 ml; 79.99 mmol; 4.00 eq.) at 5-10°C.The mixture was stirred for 16h at 40°C under N2atmosphere. The reaction was then quenched with MeOH (30ml) and water (30ml) at 0°C. The mixture was basified to pH = 8 with Na2CO3. The resulting mixture was extracted with EtOAc (3x50mL). The combined organic layers were washed with brine (50mL), dried over Na2SO4. After nitration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (11 : 1) to afford 7-bromo-8- methoxy-1H,2H,3H-pyrido[2,3-b][1,4]oxazine (2.30 g; 8.81 mmol: 44.06 %).

[0405] LC / MS method O: [M+H]+247; Rt 0.56 tert-butyl 7-bromo-8-methoxy-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

[0406] To a stirred solution of 7-bromo-8-methoxy-1H,2H,3H-pyrido[2,3- b][1,4]oxazine (2.30 g; 8.81 mmol; 1.00 eq.) and Di-tert-butyl dicarbonate (6.07 g; 26.43 mmol; 3.00 eq.) in Dichloromethane (100 ml), Triethylamine (3.87 ml; 26.43 mmol; 3.00 eq.) and N,N-dimethylpyridin-4-amine (0.23 g; 1 .76 mmol; 0.20 eq.) were added in portions at room temperature. The resulting mixture was stirred for 1 day at 30 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (4:1 ) to afford tert-butyl 7-bromo-8-methoxy- 1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (2.40 g; 6.93 mmol; 78.60 %).

[0407] LC / MS method B: [M+H]+346.9; Rt 0.91Intermediate 56 : tert-butyl 7-(2-chIoroquinazoIin-7-yl)-8-methoxy-1H,2H,3H- pyrido[2,3-b][1,4]oxazine-1-carboxylatetert-butyl 7-(2-chloroquinazolin-7-yl)-8-methoxy-1H,2H,3H-pyrido[2,3-b][1,4]oxazine- 1-carboxylate

[0408] To a stirred solution of 2-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboroIan-2- yl)quinazoline Intermediate 54 and tert-butyl 7-bromo-8-methoxy-1H,2H,3H-pyrido[2,3- b][1,4]oxazine-1-carboxylate Intermediate 55 (623.65 mg; 1.78 mmol; 0.80 eq.) in 1,4- Dioxane (10 ml) and H2O (I ml), PdAMPHOS ( 166 mg; 0.22 mmol; 0.10 eq.) and Na2CO3(745 mg; 6.68 mmol; 3.00 eq.) were added portionwise at room temperature. The resulting mixture was stirred for 2h at 80°C. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 :3) to afford tert-butyl 7-(2-chloroquinazolin-7-yl)-8-methoxy-1H,2H,3H-pyrido[2,3- b][1,4]oxazine-1-carboxylate (460 mg; 0.98 mmol; 44.08 %).

[0409] LC / MS method O: [M+H]+429. 1 ; Rt 0.94Intermediate 57 : tert-butyl 7-(3-chIoroisoquinolm-6-yl)-8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazine-1-carboxylate

[0410] tert-butyl 7-(3-chloroisoquinolin-6-yl)-8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazine-1-carboxylate

[0411] To a stirred solution of tert-butyl 8-methyl-7-(4,4,5,5-teframethyl-1 ,3,2-dioxaborolan-2-yl)- 1 H,2H,3H-pyrido[2,3-b] [ 1 ,4]oxazine- 1 -carboxylate (40 g; 21.09 mmol; 1.00 eq.), 6-bromo-3-chloroisoquinoline (5.38 g; 21.09 mmol; 1.00 eq.) and K2CO3(5.89 g; 42.18 mmol; 2.00 eq.) in Dioxane-1,4 (200 ml) / H20 (20 ml) was added Pd(PPh3)4(2.57 g; 2. 11 mmol; 0.10 eq.) under nitrogen atmosphere. The resulting mixture was stirred for 16h at 100°C under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with PE / EtOAc=1 / 1 to afford tert-butyl 7-(3- chloroisoquinolin-6-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (7.50 g; 17.78 mmol; 84.3%).

[0412] LC / MS Method U: [M+H]+412.2; Rt 1 .00Intermediate 58 : 3-[4-(4-{[1-(4-aminophenyl)-4-fluoropiperidin-4-yI]methyl}piperazin- 1-yl)phenyl]piperidine-2, 6-dionetert-butyl 4-{4-[2,6-bis(benzyloxy)pyridin-3-yI]phenyl]piperazine-1-carboxyIate

[0413] To a solution of 2,6-bis(benzyloxy)-3-bromopyridine (2.60 g; 6.99 mmol; 1.00 eq.) and tert-butyl 4- [4-(4,4.5,5-telramethyl-1,3,2-dioxaborolan-2- yl)phenyl]piperazine- 1 -carboxylate (3.14 g; 7.68 mmol; 1.10 eq.) in dioxane-1,4 (40 ml) and Water (10 ml) were added Pd(dppf)Cl2(597 mg; 0.70 mmol; 0.10 eq.) and K2CO3(3.05 g; 20.97 mmol; 3.00 eq.). The resulting mixture was stirred for 2h at 90 °C under nitrogen atmosphere. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (6:1) to afford tert-butyl 4-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}piperazine-1- carboxylate (3.50 g; 5.46 mmol; 78.1 %).

[0414] LC / MM method E: [M+H]+552.0; Rt 1. 151-{4-[2,6-bis(benzyioxy)pyridin-3-yl]phenyl} piperazine

[0415] To a stirred solution of tert-butyl 4-{4-[2,6-bis(benzyloxy)pyridin-3- yl]phenyl} piperazine- 1 -carboxylate (3.50 g; 5.46 mmol; 1.00 eq.) was added TFE (20 ml) at room temperature. The resulting mixture was microwave radiation for 9h at 120°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (6: 1) to afford 1{-4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}piperazine (2.00 g; 4.27 mmol; 78.1 %).

[0416] LC / MS method E: [M+H]+452.0; Rt 0.92 tert-butyl 4-[(4-{4-[2,6-bis(benzyIoxy)pyridin-3-yl]phenyl}piperazin-1- yl)methyl]-4-hydroxypiperidine-1-carboxylate

[0417] To a solution of {4- 1[2-,6-bis(benzyloxy)pyridin-3- yl]phenyl] piperazine (1 g; 2.13 mmol; 1.00 eq.) andtert-butyl 1-oxa-6- azaspiro[2.5]octane-6-carboxylate (719 mg; 3.20 mmol; 1.50 eq.) in EtOH (10 ml), Et.rN (720 mg; 6.40 mmol; 3.00 eq.) was added. The resulting mixture was stirred for overnight at at 80°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-bulyl 4-[(4-{4-[2,6- bis(benzyloxy)pyridin-3-yl]phenyl}piperazin- 1 -yl)methyl]-4-hydroxypiperidine- 1 - carboxylate (1 . 10 g; 1 .60 mmol; 75.0 %).

[0418] LC / MS method E: [M+H]+665.0; Rt 0.97 tert-butyl 4-[(4-{4-[2,6-bis(benzyIoxy)pyridin-3-yl]phenyl}piperazin-1-yl)methyl]-4- fluoropiperidine-1-carboxylate

[0419] To a stirred solution of tert-butyl 4-[(4-{4-[2,6-bis(benzyloxy)pyridin-3- yl]phenyl}piperazin-1-yl)methyl]-4-hydroxypiperidine-1-carboxylate (500 mg; 0.73 mmol;1.00 eq.) in dichloromethane (10 ml), DAST (247 mg; 1.46 mmol; 2.00 eq.) was added dropwise at -78°C under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature. The reaction was quenched by the addition of H2O at room temperature and extracted by 3x30ml of DCM, The combined organic layers were washed with 3x30ml brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted withPE / EA (5:1) to afford tert-butyl 4-[(4- {4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}piperazin- 1-yl)methyl]-4- fluoropiperidine- 1 -carboxylate (300.00 mg; 0.42 mmol: 58.3 %)

[0420] LC / MS method E: [M+H]+667.0; Rt 1.00 tert-butyl 4-({4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin-1-yl}methyl)-4- fluoropiperidine-1-carboxylate

[0421] A solution of tert-butyl 4-[(4- {4-[2,6-bis(benzyloxy)pyridin-3- yl]phenyl}piperazin-1-yl)methyl]-4-fluoropiperidine-1-carboxylate (300 mg; 0.42 mmol;1.00 eq.), Pd / C (20 mg; 0.02 mmol; 0.04 eq.) in EtOH (8 ml) was stirred for 2h at 25°C under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with 40 mL of EtOH. The filtrate was concentrated under reduced pressure. The filtrate was concentrated under reduced pressure to afford tert-butyl 4-( {4-[4-(2,6-dioxopiperidin-3- yl)phenyl]piperazin- 1 -yl } methyl)-4-fluoropiperidine- 1 -carboxylate (200.00 mg; 0.35 mmol; 83.4 %)

[0422] LC / MS method E; [M+H]+489.4; Rt 0.673-(4-{4-[(4-fluoropiperidin-4-yl)methyl]piperazin-1-yI]phenyl)piperidine-2,6-dione

[0423] A mixture of tert-butyl 4-( {4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin- 1 - yl}methyl)-4-fluoropiperidine-1-carboxylate (200 mg; 0.35 mmol; 1.00 eq.) and HC1 in EA (5 ml) was stirred at 25°C. The resulting mixture was stirred for 4h at 25°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford 3-(4- {4-[(4-fluoropiperidin-4-yl)methyl]piperazin- 1 -yl }phenyl)piperidine-2, 6-dione (200 mg; 0.40 mmol; 1 12.0 %)

[0424] LC / MS method E: [M+Hf 389.2; Rt 0.333-[4-(4-{[4-fluoro-1-(4-nitrophenyl)piperidin-4-yl]methyl}piperazin-1- yl)phenyl] piperidine-2, 6-dione

[0425] To a solution of 3-(4- {4-[(4-fluoropiperidin-4-yl)methyl]piperazin- 1 - yl}phenyl)piperidine-2, 6-dione (110 mg; 0.24 mmol; 0.38 eq.) ,3-(4-{4-[(4-fluoropiperidin-4- yl)methyl]piperazin-1-yl}phenyl)piperidine-2, 6-dione (200 mg; 0.40 mmol; 0.62 eq.) and 1 - fluoro-4-nitrobenzene (90 mg; 0.64 mmol; 1.00 eq.) in ACN (10 ml) was added DIEA (870 mg; 6.40 mmol; 10.00 eq.) at room temperature. The mixture was stirred for 12h at 80°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH(6 :1 ) to afford 3- [4-(4- { [4- fluoro- 1 -(4-nitrophenyl)piperidin-4-yl]methyl} piperazin- 1 - yl)phenyl]piperidine-2, 6-dione (200 mg; 0.25 mmol; 39.1 %)

[0426] LC / MS method E: [M+Na]+532.3; Rt 0.663-[4-(4-{[1-(4-aminophenyl)-4-fluoropiperidin-4-yl]methyl}piperazin-1- yl)phenyl] piperidine-2,6-dione

[0427] To a stirred mixture of 3-[4-(4-{[4-fluoro-1-(4-nitrophenyl)piperidin-4- yl]methyl}piperazin-1-yl)phenyl]piperidine-2,6-dione (150 mg; 0.28 mmol; 1.00 eq.) and Tetrahydroxydiboron (78 mg; 0.83 mmol; 2.99 eq.) in DMF (4 ml), 4, 4' -bipyridine (3.00 mg; 0.02 mmol; 0.07 eq.) was added in portions at 25°C. The resulting mixture was stirred for O.lh at 25°C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted withMeOH:DCM (1:4) to afford 3-[4-(4-{[1-(4-aminophenyl)-4-fluoropiperidin-4- yl]methyl}piperazin-1-yl)phenyl]piperidine-2, 6-dione (90.00 mg; 0.18 mmol; 66.2 %).

[0428] LC / MS method D: [M+H]]+ :480. 1 ; Rt 0.38Intermediate 59 : tert-butyl 7-{2-[(4-formylphenyI)amino]quinazoIin-7-yl}-8-methyl- 1H,2H,3H-pyrido [2,3-b] [ 1 ,4] oxazine-1-carboxylate

[0429] To a stirred solution of tert-butyl 7-(2-chloroquinazolin-7-yl)-8-methyl- 1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate Intermediate 1 (2.00 g; 4.84 mmol; 1.00 eq.) and 4-aminobenzaldehyde (0.80 g; 6.30 mmol; 1.30 eq.) in Dioxane-1 ,4 (20 ml), Pd- PEPPSI-IPr (0.31 g; 0.48 mmol; 0.10 eq.) and CS2CO3(3.32 g; 9.69 mmol; 2.00 eq.) was added in portions at room temperature under N2atmosphere. The resulting mixture was stirred for 12h at 100°C under N2atmosphere. The resulting mixture was extracted with DCM and concentrated under reduced pressure. A slurry was formed with EA, filtered and dried to afford tert-butyl 7-{2-[(4-formylphenyl)amino]quinazolin-7-yl}-8-methyl- 1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (2.00 g; 3.86 mmol; 79.59 %)

[0430] LC / MS method D; [M+H]+498.2; Rt 0.76Intermediate 60 : 3-({3-fluoro-4-[4-(piperidin-4-yl)piperazin-1- yl] phenyl} amino)piperidine-2, 6-dione; formic acidtert-butyl 4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazine-1- carboxylate

[0431] To a stirred mixture of tert-butyl 4-(4-amino-2- fluorophenyl)piperazine-1-carboxylate (3.00 g; 9.65 mmol; 1.00 eq.) and 3- bromopiperidine-2, 6-dione (3.90 g; 19.30 mmol; 2.00 eq.) in MeCN (40 ml) , NaHCO3(2.56 g; 28.95 mmol; 3.00 eq.) was added in portions at 25 °C under nitrogen atmosphere. The resulting mixture was stirred for 2d at 85 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA:PE=5():50 to afford tert-butyl 4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazine- 1 -carboxylate (3.00 g; 7.38 mmol; 76.5 %)

[0432] LC / MS method X; [M+H]+407.2; Rt 0.833-{[3-fluoro-4-(piperazin-1-yl)phenyl]amino]piperidine-2, 6-dione; trifluoroacetic acid

[0433] To a stirred mixture of tert-butyl 4-{4-[(2,6-dioxopiperidin-3- yl)ammo]-2-fluorophenyl}piperazine-1-carboxylate (3.00 g; 7.38 mmol; 1.00 eq.) in DCM (40 ml), TFA (TO ml; 127.89 mmol; 17.33 eq.) was added in portions at 25 °C under nitrogen atmosphere. The resulting mixture was stirred for 2h at 25 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to yield 3- {[3-fluoro-4-(piperazin- 1 -yl)phenyl]amino}piperidine-2,6-dione; trifluoroacetic acid (2.00 g; 4.70 mmol; 63.7%).

[0434] LC / MS Method Z: [M+H]+307. 1 ; Rt 0.46 tert-butyl 4-(4-{4-[(2,6-dioxopiperidin-3-yI)amino]-2-fluorophenyl}piperazin-1- yl)piperidine-1-carboxylate

[0435] A mixture of 3-{[3-fluoro-4-(piperazin-1-yl)phenyl]amino}piperidine- 2, 6-dione; trifluoroacetic acid (1.00 g; 2.35 mmol; 1.00 eq.), tert-butyl 4- oxopiperidine-1 -carboxylate (739.58 mg; 3.53 mmol; 1.50 eq.) and DIEA (4.31 ml; 23.51 mmol; 10.00 eq.) in DCE (20 ml) was stirred for 14h at 25 °C under nitrogen atmosphere. Then added NaBH(AcO)3 (1.05 g; 4.70 mmol; 2.00 eq.) in portions at 25 °C under nitrogen atmosphere. The resulting mixture was stirred for 2h at 25 °C under nitrogen atmosphere. The mixture was basified to pH =8 with NaHCO3. The resulting mixture was extracted with EA (3 x 50 ml). The combined organic layers were washed with brine, dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA:PE=85:15 to afford tert-butyl 4-(4-{4-[(2,6- dioxopiperidin-3 -yl)amino] -2-fluorophenyl } piperazin- 1 -yl)piperidine- 1 -carboxylate (700 mg; 1.43 mmol; 60.8 %).

[0436] LC / MS method G: [M+H]+490.3 ; Rt 0.583-({3-fluoro-4-[4-(piperidin-4-yl)piperazin-1-yl]phenyI}a) mino )piperidine-2,6- dione; formic acid

[0437] To a stirred mixture of tert-butyl 4-(4-{4-[(2,6-dioxopiperidin-3- yl)amino]-2-fluorophenyl}piperazin-1-yI)piperidine-1-carboxylate (700 mg; 1.43 mmol; 1.00 eq.) in DCM (8 ml; 125.28 mmol; 87.62 eq.), TFA (2 ml) was added in portions at 25 °C under nitrogen atmosphere. The resulting mixture was stirred for 2hat 25 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by column chromatography, eluted with ACN:H2O (2:98) to afford 3-({3-fluoro-4-[4-(piperidin-4-yl)piperazin-1- yl]phenyl} amino )piperidine-2 ,6-dione; formic acid (400 mg; 0.92 mmol; 64.2 %).

[0438] LC / MS method G: [M+H]+390.2; Rt 0.20Intermediate 61: (4- 1{7-[1-(4-aminophenyl)azetidin-3-yI]-2,7-diazaspiro[3.5]nonan-2- yl]-2-methylphenyl)-1, 3-diazinane-2, 4-dionetert-butyl 7-{1-[(beiizyloxy)carbonyl]]zetidin-3-yI]-2,7-diazaspiro[3.5]nonane-2- carboxylate

[0439] benzyl 3-oxoazetidine- 1 -carboxylate (1.06 g; 4.93 mmol; 1.15 eq.) and tert- butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (1.00 g; 4.29 mmol; 1.00 eq.) inDichloromethane, anhydrous, (20.00 ml). To the mixture, N-Ethyldiisopropylamine (2.58 ml;15.00 mmol; 3.50 eq.) was added followed by the addition of sodiumbis(acetyloxy)boranuidyl acetate (3.75 g; 17.14 mmol; 4.00 eq.). The suspension was stirred for 18h at rt under Argon atmosphere. The reaction mixtures were treated with saturated ammonium chloride solution, diluted with deionized water and extracted twice with dichloromethane. The combined organic phases were washed once with deionized water, once with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography eluting with 0-100% EtOAc in Heptane. The pure fractions were combined and concentrated to give tert-butyl 7-{ 1- [(benzyloxy)carbonyl]azetidin-3-yl}-2,7-diazaspiro[3.5]nonane-2-carboxylate (1.35 g; 3.25 mmol; 68.5 %).

[0440] LC / MS Method AA: [M+H]+416.4; Rt 0.50 tert-butyl 7-(azetidin-3-yI)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0441] tert-butyl 7-{1-[(benzyloxy)carbonyl]azetidin-3-yl}-2,7- diazaspiro[3.5]nonane-2-carboxylate (1.17 g; 2.82 mmol; 1.00 eq.) was subjected to the conditions in General procedure E to give tert-butyl 7-(azetidin-3-yl)-2,7- diazaspiro[3.5]nonane-2-carboxylate (762.40 mg; 2.71 mmol; 96.2 %).

[0442] LC / MS Method AA: [M+H]+282.2; Rt 0.33 tert-butyl 7-[1-(4-nitrophenyl)azetidin-3-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0443] tert-butyl 7-(azetidin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (762.40 mg; 2.71 mmol; 1 .00 eq.) was filled into the vial and dissolved in Dimethyl sulfoxide (9. 15 ml). To the mixture, 1 -Fluoro-4-nitrobenzene (287.44 pl; 2.71 mmol; 1 .00 eq.) w as added, the vial was sealed and stirred at 85 °C for 1h. The reaction mixture was cooled to room temperature and poured into deionized water. The precipitate was filtered and washed with deionized water. The solid was dried to give tert-butyl 7-[1-(4-nitropheny)lazetidin-3-yl]-2,7- diazaspiro[3.5]nonane-2-carboxylate (658.20 mg; 1.62 mmol; 59.8 %).

[0444] LC / MS Method AA: [M+H]+403.3 ; Rt 0.497-[1-(4-nitrophenyl)azetidin-3-yl]-2,7-diazaspiro[3.5]nonane; bis(trifluoroacetic acid)

[0445] tert-butyl 7-[1-(4-nitrophenyl)azetidin-3-yl]-2,7-diazaspiro[3.5]nonane-2- carboxylate (658.20 mg; 1 .62 mmol; 1 .00 eq.) in dichloromethane (18.16 ml), Trifluoroacetic acid (1.24 ml; 16.19 mmol; 10.00 eq.) was added to the mixture. The reaction mixture was stirred at RT for 19h. The reaction mixture was evaporated in vacuo. The residue was treated with MTB ether and stirred over the weekend. The resulting suspension was filtered off.washed with MTB ether and dried to give 7-[1-(4-nitrophenyl)azetidin-3-yl]-2,7- diazaspiro[3.5]nonane; bis( trifluoroacetic acid) (790.20 mg: 1.43 mmol; 88.3 %).

[0446] LC / MS Method AA: [M+H]+303.2; Rt 0.203-[(4-methoxyphenyl)methyl]-1-(2-methyl-4-{7-[1-(4-nitrophenyl)azetidin-3-yl]-2,7- diazaspiro[3.5]nonan-2-yl}phenyI)-1, 3-diazinane-2, 4-dione

[0447] 7-[1-(4-nitrophenyl)azetidin-3-yl]-2,7-diazaspiro[3.5]nonane; bis(trifluoroacetic acid) (400 mg; 0.72 mmol; 1.00 eq.), (4-bromo-2-methy 1-lphenyl)-3-[(4- methoxyphenyl)methyl]-1, 3-diazinane-2,4-dione Intermediate 67 (295 mg; 0.72 mmol; 1.00 eq.) and Cesium carbonate (708 mg; 2.17 mmol; 3.00 eq.) were filled into the flask and suspended in 1,4-dioxane (8 ml). The vial was sealed, placed under vacuum, sonicated for 2 minutes and refilled with argon. This procedure was repeated two times, followed by addition of Pd-PEPPSI-IPentCl 2 -methylpyridine (o-picoline) (64 mg; 0.07 mmol; 0.10 eq.). The vial was resealed and purged again. The mixture was stirred at 115°C for 20 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc and deionized water. The mixture was filtered over Celite and the phases were separated. The aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated to dryness. The mixture was purified by column. The pure fractions (15-45) were combined and evaporated to dryness to give 3-[(4- methoxyphenyl)methyl]]-1-(2-methyl-4-{7-[1-(4-nitropheny 1-l)azetidin-3-yl]-2,7- diazaspiro[3.5]nonan-2-yl}phenyl)-1,3-diazinane-2, 4-dione (297.00 mg; 0.48 mmol; 65.7 %).

[0448] LC / MS Method AA: [M+H]+625.4; Rt 0.58 1-(2-methyl-4-{7-[1-(4-nitrophenyl)azetidin-3-yl]-2,7-diazaspiro[3.5]nonan-2-yI}phenyl)- l,3-diazinane-2,4-dione; trifluoromethanesulfonic acid

[0449] To a solution of 3-[(4-methoxyphenyl)methyl]-1-(2-methyl-4-{7-[1-(4- nitrophenyl)azetidin-3-yl]-2,7-diazaspiro[3.5]nonan-2-yl}phenyl)-1, 3-diazinane-2, 4-dione (290 mg; 0.46 mmol; 1.00 eq.) in Trifluoroacetic acid (2.68 ml; 34.82 mmol; 75.00 eq.), trifluoromethanesulfonic acid (270 pi; 3.02 mmol; 6.50 eq.) was added dropwise. The reaction mixture was stirred for 20 hours at RT. The reaction mixture was evaporated to dryness. The residue was treated with MTBE and stirred overnight. The mixture was evaporated to dryness and the crude product was purified by Column chromatography (DCM / EtOH+0.1% TEA). The pure fractions were combined and evaporated to dryness. The solid was treated with MTBE and stirred overnight. The resulting suspension was filtered,washed with MTB ether and dried to give (2-methyl-4- 1{-7-[1-(4-nitrophenyl)azetidin-3-yl]-2,7-diazaspiro[3.5]nonan-2-yl (phenyl)-1, 3-diazinane-2, 4-dione; trifluoromethanesulfonic acid (258.1 mg; 0.39 mmol; 85%)

[0450] LC / MS Method AA: [M+H]+505.3; Rt 0.431-(4-{7-[1-(4-aminophenyl)azetidin-3-yl]-2,7-diazaspiro[3.5]nonan-2-yl}-2- methylphenyl)-1, 3-diazinane-2,4-dione

[0451] 1- (2-methyl-4-{7-[1-(4-nitrophenyl)azetidin-3-yl]-2,7-diazaspiro[3.5]nonan-2 -yl] phenyl)-1, 3-diazinane-2, 4-dione; trifluoromethanesulfonic acid (200 mg; 0.31 mmol; 1.00 eq.) and 4,4' -Dipyridyl (4.77 mg; 0.03 mmol; 0.10 eq.) in N,N -Dimethylformamide (10 ml), Tetrahydroxy diboron ( 172.98 mg; 1 .83 mmol; 6.00 eq.) was added. The reaction mixture stirred for 10 mins at RT. The reaction mixture was basified using a saturated sodium bicarbonate solution, diluted with deionized water and DCM and filtered. The liquid was extracted twice with DCM. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated with heptane. The resultant product was purified by column chromatography eluting with 0-30% EtOH in DCM. The pure fractions were combined and evaporated to dryness to yield (4-{7-[1-(4-amino 1p-henyl)azetidin-3-yl]- 2, 7-diazaspiro[3.5]nonan-2-yl}-2-methylphenyl)-1, 3-diazinane-2, 4-dione (40.8 mg; 0.08 mmol; 25.9%).

[0452] LC / MS Method AA; [M / 2+H] 238.2; Rt 0.31Intermediate 62 : [(4- 1m- ethoxyphenyl)methyl]-2,6-dioxopiperidin-3-yl trifl uoroniethan esulfonate

[0453] To a stirred solution of 3-hydroxy-1-[(4-methoxyphenyl)methyl]piperidine- 2, 6-dione (10.00 g; 38.1 1 mmol; 1.00 eq.) and DCM (100.00 ml) was added Pyridine (6.21 ml; 76.22 mmol; 2.00 eq.) at 0 °C under nitrogen atmosphere. The resulting mixture wasstirred for 10 min at 0 °C under nitrogen atmosphere. Trifluoromethanesulfonyl trifluoromethanesulfonate (16.98 g; 57. 17 mmol; 1 .50 eq.) was then added at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for additional 3h at room temperature and then concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography, eluted with PE / EA (1 : 1) to afford 1-[(4- methoxyphenyl)methyl]-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (14.00 g; 34.64 mmol; 90.9 %)

[0454] LC-MS method AD: 404 [M+Na]; Rt: 0.93 minIntermediate 63 : 3-(7-bromo-2-oxo-2,3-dihydro-1, 3-benzoxazol-3-yl)-1-[(4- methoxyphenyl)methyl]piperidine-2, 6-dione

[0455] To a solution of 7-bromo-2,3-dihydro-1,3-benzoxazol-2-one (1.00 g; 4.44 mmol; 1.00 eq.) in THF (10.00 ml) were added t-BuOK (0.63 g; 5.33 mmol; 1.20 eq.) at 0 °C. The resulting mixture was stirred for 0.5h at 0 °C under nitrogen atmosphere and then 1-[(4-nielhoxyphenyl)methyl]-2,6-dioxopiperidin-3-yI trifluoromethanesulfonate Intermediate 62 (2.50 g; 5.05 mmol; 1.14 eq.) was added at 0 °C. The reaction mixture was stirred for 1 h at 25 °C under nitrogen atmosphere and then concentrated under reduced pressure. The crude material was purified by silica gel column chromatography, eluted with PE / EA (1 : 1) to afford 3-(7-bromo-2-oxo-2,3-dihydro-1, 3-benzoxazol-3-yl)-1-[(4- methoxyphenyl)methyl]piperidine-2, 6-dione (1.00 g; 2.16 mmol; 48.6 %).

[0456] LC-MS method U: 445 [M+H]; Rt; 1 .03 minIntermediate 64: 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-1, 3-benzodiazol-1-yI)-1- [(4-methoxyphenyl)methyl]piperidine-2, 6-dione

[0457] To a solution of 7-bromo-1-methyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (3.00 g; 12.55 mmol; 1.00 eq.) in THF (30.00 ml) at 0 °C t-BuOK (1.78 g; 15.07 mmol; 1.20 eq.) was added. The resulting mixture was stirred for 0.5h at 0 °C under nitrogen atmosphere and 1 -[(4-melhoxyphenyl)methyl]-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate Intermediate 62 (7.10 g; 17.57 mmol; 1.40 eq.) at 0 °C was added, the reaction was stirred for 1h at 25 °C under nitrogen atmosphere and then concentrated under reduced pressure. The crude material was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 3-(4-bromo-3-methyl-2-oxo-2,3- dihydro-1H- 1 ,3-benzodiazol- 1-yl)- 1 -[(4-methoxyphenyl)methyl]piperidine-2, 6-dione (4.300 g; 8.52 mmol; 67.9 %)

[0458] LC-MS method AD: 458 [M+H]; Rt: 0.94 minIntermediate 65 : (7-b 1-romo-1-methyl-1H-indazol-3-yl)-3-[(4-methoxyphenyl)methyl]- 1,3-diazinane-2, 4-dione3-[(7-bromo-1-methyl-1H-indazoI-3-yl)amino]propanoicacid

[0459] 7 -bromo-1-methyl-1H-indazol-3-amine (3651.6 mg; 1.140 mmol; 1.00 eq.) was suspended in 2N HC1 (63.90 mi; 17.50 V). Tetra-n-butylammonium bromide (484.731 mg; 1.489 mmol; 0.10 eq.) was added under stirring. Acrylic acid (2062.000 pl; 29.772 mmol; 2.00 eq.) was added and the reaction mixture was stirred at 125°C for 6h. The reaction mixture was cooled down to room temperature, placed in an ice bath and neutralized to pH=5 under Stirling by adding 13.03mL sodium hydroxide solution (NaOH, w=32%). The beige suspension was stirred at room temperature for 1h, filtered with suction, washed three times with deionized water (50mL each) and dried in a vacuum drying oven at 50°C and 10- 20mbar for 71h to afford 3-[(7-bromo-1-methyl-1H-indazol-3-yl)amino]propanoic acid (4361.100 mg; 12.750 mmol; 85.65 % yield) as a beige solid.

[0460] LC MS Method A: [M+H]+298-300; Rt: 1,34 min 1-(7-bromo-1-methyl-1H-indazol-3-yI)-1, 3-diazinane-2, 4-dione

[0461] 3-[(7-bromo-1-methyl-1H-indazol-3-yl)amino]propanoic acid (4361.100 mg; 12.750 mmol; 1.00 eq.) was suspended in Acetic acid (glacial) (43.611 ml; 10.00 V) and Sodium cyanate (1480.031 mg; 22.312 mmol; 1.75 eq.) was added. The reaction mixture was stirred at 75°C for 3,5h. The reaction mixture was cooled down and Hydrochloric acid 25% (13.282 ml; 101.997 mmol; 8.00 eq.) was added and the reaction mixture was stirred again at 75°C for 3,5h. The beige suspension was cooled down to room temperature, diluted with 80mL deionized water and stirred at room temperature for 2.25h. Then the suspension was filtered with suction, washed twice with deionized water (20mL each) and dried in a vacuum drying oven at 50°C and 10-20mbar for 69.5h and lyophilisated for 23h to afford 1-(77 bromo- 1-methyl-1H-indazol-3-yl)-1, 3-diazinane-2, 4-dione (2925.400 mg; 9.053 mmol;71.01 %) as a pale beige solid.

[0462] LC MS Method A: [M+H]+ 323-325; Rt: 1,34 mm 1-(7-bronio-1-methyl-1H-indazol-3-yI)-3-[(4-methoxyphenyl)methyl]-1, 3-diazinane-2,4- dione

[0463] 1- (7-bromo-1-methyl-1H-indazol-3-yl)-1,3-diazinane-2,4-dione (1.00 g; 1.00 eq.; 3.057 mmol) was dissolved in N.N-Dimethylformamide (10.00 ml; 10.00 V). Cesium carbonate (1.20 g; 1.20 eq.; 3.669 mmol) and 4-Methoxybenzyl chloride (589.68 pl; 1.40 eq.; 4.280 mmol) were added and the reaction mixture was intertied with argon and stirred at rt for 16,5h. The reaction mixture was poured into deionized water (approx. 250 ml) and satiated ammonium chloride solution (approx. 40 ml) was added and extraction carried outthree times with ethyl acetate (approx. 60 ml each time). The combined organic phases were washed twice with deionized water (approx. 20 ml each time), once with brine (approx. 20 ml), dried over sodium sulfate, filtered with suction and concentrated. Next the crude product was purified by Isco CombiFlash Rf® to afford (7-bromo-1-m 1-ethyl-1H-indazol-3-yl)-3- [(4-methoxyphenyl)methyl]-1, 3-diazinane-2, 4-dione (927.50 mg; 2.03 mmol; 64.9 % yield) as a pale beige resin.

[0464] LC MS Method A: [M+H]+ 443-445; Rt: 1 ,68 minIntermediate 66 : (4-b 1-romo-2-methylphenyl)-1, 3-diazinane-2,4-dione4-bromo-2-methylaniline (25.00 g; 133.03 mmol; 1.00 eq.) was suspended in prop-2-enoic acid (40.40 g; 532.59 mmol; 4.00 eq.) and stirred at 1 10 °C for 3 h. Then urea (53.80 g; 851.05 mmol; 6.40 eq.) and AcOH (200.00 ml) were added and the reaction mixture was stirred at 120 ºC for 12 h under nitrogen atmosphere. The reaction was poured into water (1000 mL) at 0°C. Then the solid was filtered, washed with water (500 mL) and concentrated under reduced pressure to afford (4-bromo-21--methylphenyl)-1,3-diazinane-2, 4-dione (32.000 g; 103.93 mmol; 78.1 % yield) as a light yellow solid.

[0465] LC MS Method C: [M+H]+283,0; Rt: 0.64 minIntermediate 67 : (4-b 1r-omo-2-methyIphenyl)-3-[(4-methoxyphenyl)methyl]-1, 3- diazinane-2, 4-dione

[0466] To a stirred solution of (4-bro 1m-o-2 -methylphenyl)- 1 ,3 -diazinane-2, 4-dione Intermediate 66 (10.00 g; 32.48 mmol; 1.00 eq.) and (chloromethyl)-4- 1m-ethoxybenzene (10.71 g; 64.95 mmol; 2.00 eq.) in DMF (150.00 ml) was added K2CO3(14.17 g; 97.43 mmol; 3.00 eq.) in portions at room temperature. The rection mixture was stirred at room temperature for 48h. The resulting mixture was diluted with water (200ml) and extracted with EtOAc (3x150ml). The combined organic layers were washed with brine (200ml) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (2:1) to afford to afford (4-bromo 1--2-methylphenyl)-3-[(4- methoxyphenyl)methyl]-1, 3-diazinane-2, 4-dione (8.000 g; 19.06 mmol; 58.7 % yield) as a colorless oil.

[0467] LC MS Method AD: [M+H]+403,0; Rt: 0.94 minIntermediate 68 : 2,6-bis(benzyloxy)-3-(4-bromo-2-methyIphenyl)pyridine

[0468] Starting from 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2- yl)pyridine Intermediate 8 (6,60 mmol; 100,00 mol%; 2.810,79 mg) and 5-bromo-2- iodotoluene 9 (6.60 mmol; 100,00 mol%; 2.000,00 mg; 935,02 [M)+ thHe]+general procedure D for Suzuki coupling was followed in the presence of 1,4-Dioxane (50,00 ml), water (5,00 ml), Potassium carbonate (19,80 mmol; 300,00 mol%; 2,74 g; 1,13 ml) and [1,1- Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0,66 mmol; 10,00 mol%; 545,70 mg) to afford 2,6-bis(benzyloxy)-3-(4-bromo-2- methylphenyl)pyridine (2,120 g; 4,421 mmol; 66,974 % yield) as a white solid.

[0469] LC MS Method A: [M+H]+460; Rt: 2,287 minIntermediate 69 : (2-m 1-ethyl-4-{4-[(piperidin-4-yl)methyl]piperazin-1-yl}phenyl)-1, 3- diazinane-2, 4-dionetert-butyl 4-{[4-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1, 3-diazinan-1-yl}-3- methylphenyl)piperazin-1-yl]methyl]piperidine-1-carboxylate

[0470] Starting from -1-( 4-bromo-2-methylphenyl)-3-[(4-methoxyphenyl)methyl]-1, 3- diazinane-2, 4-dione Intermediate 67 (300 g; 1,00 eq.; 73,65 mmol) and tert-butyl 4- [(piperazin-1-yl)methyl]piperidine-1-carboxylate (22,0 g; 1 ,00 eq.; 73,65 mmol) the general procedure H for Buchwald coupling was followed with 1,4-Dioxane (300,0 ml; 10,00 V), Cs2CO3 (29,1 g; 1,20 eq.; 88,38 mmol) and XPhos Pd G3, 95% (1.246,8 mg; 0,02 eq.; 1,47 mmol) to afford terl-butyl 4-{[4-(4-{3-[(4-methoxyphenyl)melhyl]-2.4-dioxo-1, 3-diazinan-1- yl}-3-methylphenyl)piperazin-1-yl]methyl}piperidine-1-carboxylate (44,00 g; 0,069 mol; 93,7 % yield) as a beige amorphous solid.

[0471] LC MS Method AC: [M-boc+H]+506,2; Rt: l,493min 1-(2-methyl-4-{4-[(piperidin-4-yl)methyl]piperazin-1-yl} phenyl)-1, 3-diazinane-2, 4-dione

[0472] To a stirred mixture of tert-butyl 4- { [4-(4- (3-[(4-methoxyphenyl)methyl]-2,4- dioxo- 1 ,3-diazinan- 1 -yl } -3-methylphenyl)piperazin-1-yl]methyl}piperidine- 1 -carboxylate (40.0 g; 1.0 eq.; 59,43 mmol) in Dichloromethane (532.0 g; 400.0 ml; 10.00 V) were added Trifluoroacetic acid (135.5 g; 91,6 ml; 20,0 eq.; 1.188, 57 mmol) and TfOH ( 53,51 g; 31,29 ml; 6,00 eq.) in portions at 25 °C. The resulting mixture was stirred for 5h at room temperature. The reaction mixture was slow poured in 21 MTBE and stirred over night at room temperature. The solid was filtered, washed with MTBE and dried under vacuo at 50°C to afford 1 -(2-methyl-4- {4-[(piperidin-4-yl)melhyl]piperazin- 1 -yl}phenyl)- 1 ,3-diazinane-2,4- dione (65,00 g; 0,059 mol; 99,3% yield) as a light beige powder.

[0473] LC MS Method E: [M+H]+ 386,25; Rt: 0,34minIntermediate 70 : 1-[4-(4-{[1-(4-amino-2-methoxyphenyl)piperidin-4- yl]methyI}piperazin-1-yl)-2 -methylphenyl]-1, 3-diazinane-2, 4-dione1-[4-(4-{[1-(2-methoxy-4-nitrophenyl)piperidin-4-yl]methyl}piperazin-1-yl)-2- methylphenyl]-1, 3-diazinane-2, 4-dione

[0474] To a solution of (2-m 1-ethyl-4-{4-[(piperidin-4-yl)methyl]piperazin-1- yl) phenyl)-1 , 3-diazinane-2, 4-dione; bis( trifluoromethanesulfonic acid) Intermediate 69 (2,000 g; 2,917 mmol; 100,00 mol%) and 2-Fluoro-5-nitroanisole (61 1.214 mg; 3.500 mmol;120.00 mol%) in N,N-Dimethylformamide (30.000 ml) was added Cesium carbonate extra pure (0.701 ml; 8,751 mmol; 300.00 mol%) under Argon. The reaction mixture was stirred for 2 h al 80°C. The reaction mixture was evaporated. The residue was diluted with water and extracted with DCM. The combined organic layers were washed with water, dried over sodium sulfate, filtered and purified by silica gel column chromatography to afford the desired product (950.00 mg; 1.735 mmol; 59.5 % yield).

[0475] LC MS Method AE: [M+H]+537.3; Rt: 1.193 min 1-[4-(4-{[1-(4-amino-2-methoxyphenyI)piperidin-4-yl]methyl}piperazin-1-yl)-2- methylphenyl]-1, 3-diazinane-2, 4-dione

[0476] Starting from [4- 1(-4-{[1-(2-methoxy-4-nitrophenyl)piperidin-4- yl]methyl}piperazin-1-yl)-2-methylphenyl]-1,3-diazinane-2, 4-dione (950,000 mg; 1 ,735 mmol; 100,00 mol%) the general procedure N for nitro reduction was followed in the presence of DMF (30,000 ml). Tetrahydroxydiboron (466,613 mg; 5,205 mmol; 300,00 mol% )) and 4,4-Dipyridyl (27,650 mg; 0,173 mmol; 10,00 mol%) to afford the desired product (660,00 mg; 1,277 mmol; 73,6 % yield).

[0477] LC MS Method AE: [M+H] ' 507,3; Rt: 0,784 minIntermediate 71: 3-[4-(piperazin-1-yl)phenyl]piperidine-2, 6-dione hydrochloridetert-butyl 4-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}piperazine-1-carboxyIate

[0478] To a stirred solution of tert-butyl 4-[4-(4,4,5,5-tetramethyl-1, 3,2- dioxaborolan-2-yl)phenyl]piperazine-1-carboxylate (12.0 g; 29.36 mmol; 1.0 eq.) and 2,6-bis(benzyloxy)-3-bromopyridine (10.0 g; 25.66 mmol; 0.9 eq.) in dioxane (140 ml) and water (28 ml) Pd(dppf)Cl2.DCM (2.2 g; 2.56 mmol; 0.1 eq.) and K2CO3(8.2 g; 56.36 mmol; 1.9 eq.) were added. The resulting mixture was stirred for 3h at 80 °C under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EtOAc (20: 1) to afford tert-butyl 4-{4-[2,6- bis(benzyloxy)pyridin-3-yl]phenyl}piperazine-1-carboxylate (17.2 g; 29.24 mmol; quantitative yield) as a yellow solid.

[0479] LC-MS method Y: [M+H]+552.3 ; Rt: 1 .37 min tert-butyl 4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazine-1-carboxylate

[0480] To a stirred solution of tert-butyl 4-{4-[2,6-bis(benzyloxy)pyridin-3- yl]phenyl] piperazine- 1 -carboxylate (8.5 g; 15.17 mmol; 1.0 eq.) in dioxane (85 ml) Pd(OH)2 / C (4.8 g; 6.76 mmol; 0.5 eq.) was added. The reaction mixture was stirred for 12 h at room temperature under hydrogen atmosphere. The reaction mixture was filtered over celite and the filter cake was washed with dioxane. The filtrate was concentrated under reduced pressure resulting in tert-butyl 4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazine-1- carboxylale (5.5 g; 14.26 mmol; 94% yield) as a -white solid.

[0481] LC-MS method AF: [M+H]1374.3; Rt: 0.74 min3-[4-(piperazin-1-yl)phenyl]piperidine-2,6-dione hydrochloride

[0482] To a stirred solution of tert-butyl 4-[4-(2,6-dioxopiperidin-3- yl)phenyl]piperazine- 1 -carboxylate (1.5 g; 3.96 mmol; 1.0 eq.) 4M HC1 in EtOAc (10 mL) was added . It was stirred for 1 h at room temperature. The reaction was then filtered and the filter cake washed with dioxane. The organic phase was concentrated under reduced pressure to afford 3-[4-(piperazin-1-yl)phenyl]piperidine-2, 6-dione hydrochloride (1.1 g; 3.24 mmol; 82 % yield) as a white solid.

[0483] LC-MS method N: [M+H]+274.1 ; Rt: 0.51 minIntermediate 72 : 3-[4-(4-{[1-(4-aminophenyI)piperidin-4-yl]methyl}piperazin-1- yl)phenyl] piperidine-2, 6-dione1-(4-nitrophenyl)piperidine-4-carbaldehyde

[0484] To a stirred solution of [ 1 -(4-nitrophenyl)piperidin-4-yl]methanol (2.00 g;8.46 mmol; 1.00 eq.) in DCM (20.00 ml) was added Dess-Martin periodinane (7.55 g; 16.91 mmol; 2.00 eq.) in portions at 0 °C under N2atmosphere. The resulting mixture was stirred for 1h at room temperature under N2atmosphere. The reaction mixture was quenched with water, extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EtOAc (3: 1) to afford 1(4--nitrophenyl)piperidine-4-carbaldehyde (1.00 g; 4.10 mmol; 48.49 % yield) as a yellow solid.

[0485] LC MS Method O: [M+H]+235,15; Rt: 0,81 min3- [4-(4-{ [1 -(4-nitrophenyl)piperidin-4-yl] methyl} piperazin-1-yl)phenyl]piperidine-2,6- dione

[0486] To a stirred solution of 3-[4-(piperazin-1-yl)phenyl]piperidine-2, 6-dione hydrochloride Intermediate 71 (737.22 mg; 2.05 mmol; 1.00 eq.) and 1-(4- nitrophenyl)piperidine-4-carbaldehyde (500.00 mg; 2.05 mmol; 1.00 eq.) in DCM (2.50 ml) and MeOH (2.50 ml) were added Sodium acetate trihydrate (845.41 mg; 6.15 mmol; 3.00 eq.) and Sodium cyanoborohydride (542.45 mg; 8.20 mmol; 4.00 eq.) al room temperature under N2atmosphere. The reaction mixture was stirred for 2h at room temperature under N2atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with DCM:MeOH (20:1) to afford 3-[4-(4-{[1-(4- nitrophenyl)piperidin-4 4-yl]methyl}piperazin- 1 -yl)phenyl]piperidine-2, 6-dione (620.00 mg; 1.26 mmol; 61.32 % yield) as a yellow solid.

[0487] LC MS Method O: [M+H]+492,3; Rt: 0,84 min3-[4-(4-{[1-(4-aminophenyi)piperidin-4-yl]methyl}piperazin-1-yl)phenyi]piperidine-2,6- dione

[0488] 3-[4-(4- { [ 1 -(4-nitrophenyl)piperidin-4-yl]methyl} piperazin- 1 - yl)phenyl]piperidine-2,6-dione (150.00 mg; 0.30 mmol: 1.00 eq.) was dissolved in DMF (10.00 ml) and Raney-Ni (54.86 mg; 0.61 mmol; 2.00 eq.) was added at room temperature. The reaction mixture was stirred for 2 h at room temperature under H2atmosphere. The resulting mixture was filtered, washed with DMF (10 mL). The filtrate was quenched with water (100 mL) and filtered and washed with water (50 mL). The solids were concentrated under reduced pressure to afford 3-[4-(4-{[1-(4-aminophenyl)piperidin-4- yl]methyl} piperazin-1-yl)phen 1y-l]piperidine-2, 6-dione (90.00 mg; 0.19 mmol; 62.49 % yield) as a grey solid.

[0489] LC MS Method O: [ M-H ] 462,3; Rt: 0,46 minIntermediate 73 : [4-( 1p-iperazin-1-yl)phenyI]-1, 3-diazinane-2, 4-dionetert-butyl 4-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1, 3-diazinan-1- yl}phenyl)piperazine-1-carboxylate

[0490] A solution of 3-[(4-methoxyphenyl)methyl]-1, 3-diazinane-2, 4-dione (6.00 g;24.97 mmol; 1.00 eq.) and tert-butyl 4-(4-bromophenyl)piperazine-1-carboxylate (9.00 g; 25.06 mmol; 1.00 eq.) in in 1,4-dioxane (50.00 ml) were added Pd2(dba)3(5.00 g; 5.19 mmol; 0.21 eq.), Xphos (1.30 g; 2.59 mmol; 0.10 eq.) and CS2CO3(17.00 g; 49.57 mmol;1 .98 eq.). The reaction was stirred for 16 h at 100 °C. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (1 :1) to afford tert-butyl 4-(4-{3-[(4-methoxyphenyl)mefhyl]-2, 4-dioxo-1, 3-diazinan-1-yl}phenyl)piperazine-1-carboxylate (7.00 g; 13.60 mmol; 54.5 % yield) as a yellow solid; Purified Product.

[0491] LC MS Method U: [M+H]+495,25; Rt: 1 ,17 min1 - [4-(piperazin-1 -yl)ph enyl] -1 ,3-diazinane-2, 4-dione

[0492] To a stirred mixture of terl-butyi 4-(4-{3-[(4-methoxyphenyl)melhyl]-2,4- dioxo-1,3-diazinan-1-yl}phenyl)piperazine-1-carboxylate (7.00 g; 12.94 mmol; 1.00 eq.) in TFA (30.00 ml) was added CF3SO3H ( 1.30 ml; 13.96 mmol; 1.08 eq.) at room temperature. The mixture was stirred for 12 h at 70 °C. The mixture was basified to pH=9 with sat.NaHCO3(aq.).The resulting mixture was quenched with ice / water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH ( 1 : 1 ) to afford 1[4--(piperazin-1-yl)phenyl]-1, 3-diazinane-2, 4-dione (4.00 g; 8.53 mmol; 65.9 % yield) as a brown solid; Crude Product.

[0493] LC MS Method U: [M+H]+275.2; Rt: 0.24 minIntermediate 74 : 1-[4-(4-{[1-(4-aminophenyI)piperidin-4-yl]methyl}piperazin-1- yl)phenyl] -1 ,3-diazinane-2, 4-dione1-[4-(4-{[1-(4-nitrophenyl)piperidin-4-yl]methyl]piperazin-1-yl)phenyI]-1, 3-diazinane- 2, 4-dione

[0494] To a stirred mixture of [4-(pip 1-erazin-1-yl)phenyl]-1, 3-diazinane-2,4-dione Intermediate 73 (1.00 g; 3.61 mmol; 1.00 eq.) and (4-nitrophenyl)p piperidine-4- carbaldehyde (0.95 g; 3.97 mmol; 1.10 eq.) in DCM (10.00 ml) and MeOH (10.00 ml) was added NaOAc (1.56 g; 18.04 mmol; 5.00 eq.) at room temperature. The mixture was stirredfor 1 h at room temperature. Then NaBH3CN (0.94 g; 14.44 mmol; 4.00 eq.) was added and the mixture was stirred for 12 h at room temperature. The resulting mixture was quenched by ice / water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (1:1) to afford the desired product (750.00 mg; 1.11 mmol; 30.8 % yield) as a yellow solid.

[0495] LC MS Method E: [M+H]+493,3; Rt: 0,71 min 1-[4-(4-{[1-(4-aminophenyI)piperidin-4-yl]methyl}piperazin-1-yl)phenyl]-1, 3-diazinane- 2, 4-dione

[0001] Starting from [4- 1(-4-{[1-(4-nitrophenyl)piperidin-4-yl]methyl}piperazin-1- yl)phenyl]-1, 3-diazinane-2, 4-dione (710.00 mg; 1.05 mmol; 1.00 eq.) the general procedure N for nitro reduction was followed in the presence of DMF (3.00 mL), Tetrahydroxydiboron (298.31 mg; 3.16 mmol; 3.00 eq.) and 4,4'-bipyridine (17.32 mg;0.11 mmol; 0. 10 eq.) to afford the desired product (500.00 mg; 1 .01 mmol; 96.3 % yield) as a yellow solid.

[0496] LC MS Method E: [M+H]+463,3; Rt: 0,41 minIntermediate 75 : 1-[4-(4-{[1-(4-amino-2-methylphenyl)piperidin-4-yl]methyl]piperazin- 1-yl)-2-methylphenyl]-1, 3-diazinane-2, 4-dione1-[2-methyl-4-(4-{[1-(2-methyl-4-nitrophenyl)piperidin-4-yl[methyI] piperazin-1- yl)phenyl] -1 ,3-diazinane-2, 4-dione

[0497] To a solution of (2-m 1-ethyl-4-{4-[(piperidin-4-yl)methyl]piperazin-1- yl}phenyl)-1, 3-diazinane-2,4-dione Intermediate 69 (3,000 g; 7,782 mmol; 1,00 eq.) and 2-Fluoro-5 -nitrotoluene 99% (1585,207 mg; 10,117 mmol; 1,30 eq.) in N,N-Dimethylformamide (30,000 ml) was added Cesium carbonate ( 1 ,869 ml; 23,346 mmol;3,00 eq.) under Argon. Then the mixture was stirred for 6 h at 80°C. The reaction mixture was evaporated. The residue was diluted with water and extracted with CF2Cl2. The combined organic layers were washed with water, dried over sodium sulfate, filtered and purified by silica gel column chromatography to afford [2-methyl-4-(4-{[1-((-methyl-4- nitrophenyl)piperidin-4-yl]methyl} piperazin- 1 -yl)phenyl]- 1 ,3-diazinane-2,4-dione (1,00 g; 1,748 mmol; 22,5 % yield).

[0498] LC MS Method AE: [M+H]+521,2-522,3; Rt: 1.275min 1-[4-(4-{[1-(4-amino-2-methyIphenyI)piperidin-4-yl]methyI}piperazin-1-yl)-2- methylphenyl] -1 ,3-diazinane-2, 4-dione

[0499] Starting from [2- 1m- ethyl-4-(4-{[1-(2-methyl-4-nitrophenyl)piperidin-4- yl]methyl}piperazin-1-yl)phenyl]-1, 3-diazinane-2, 4-dione (1,000 g; 1,748 mmol; 1,00 eq.) the general procedure N for nitro reduction was followed in the presence of DMF (30.00 ml), 4,4'-bipyridine (27,86 mg; 0,175 mmol; 0.1 eq.) and tetrahydroxydiboron (470,10 mg; 5,244 mmol; 3.00 eq.) to afford [4-(4-{[1- 1(-4-amino-2-methylphenyl)piperidin-4- yl]methyl}piperazin-1-yl)-2-methylphenyl]-1, 3-diazinane-2,4-dione (745,00 mg; 1,382 mmol; 79,1 % yield)

[0500] LC MS Method AE: [M+H]+491,3-492,3; Rt: 0,818 minIntermediate 76 : [4-( 14--{[1-(4-aminophenyl)piperidin-4-yl]methyl}piperazin-1-yl)-2- methylphenyl]-1, 3-diazinane-2, 4-dione1-[2-methyl-4-(4-{[1-(4-nitrophenyl)piperidin-4-yl]methyl]piperazin-1-yl)phenyl]-1, 3- diazinane-2, 4-dione

[0501] To a solution of (2-m 1-ethyl-4- {4-[(piperidin-4-yl)methyl]piperazin-1- yl}phenyl)-1, 3-diazinane-2, 4-dione; bis(trifluoromethanesulfonic acid) Intermediate 69 (4,00 g; 5,83 mmol; 100,00 mol%) and Fluoro-4-ni 1tr-obenzene (1,24 g; 8,75 mmol; 150,00 mol%) in N,N-Dimethylformamide (40,00 ml) was added Cesium carbonate (1,40 ml; 17,50 mmol; 300,00 mol%) under Argon. The reaction mix true was stirred for 2 h at80°C. The reaction mixture was evaporated. The residue was diluted with water and extracted with CH2Cl2. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the desired product (1,90 g; 3,60 mmol; 61,7 % yield).

[0502] LC MS Method AE: [M+H]+507,3; Rt: 1 ,06 min l-[4-(4-{[1-(4-aminophenyI)piperidin-4-yI]methyl]piperazin-1-yI)-2-methylphenyl]- l,3-diazinane-2, 4-dione

[0503] Starting from [2- 1m- ethyl-4-(4-{[1-(4-nitrophenyl)piperidin-4- yl]methyl] piperazin- 1- yl)phenyI]-1, 3-diazinane-2, 4-dione (1,80 g; 3,41 mmol; 100,00 mol%) the general procedure N for nitro reduction was followed in the presence of DMF (30.00 ml), 4,4'-bipyridine (54,36 mg; 0,341 mmol; 0.10 eq.) and tetrahydroxydiboron (917,40 mg; 10,23 mmol; 3.00 eq.) to afford the desired product (1,25 g; 2,439 mmol; 71 ,5 % yield).

[0504] LC MS Method AE: [M+H]+477,4; Rt: 0,66 minIntermediate 77 : 3-(7-{2,7-diazaspiro[3.5]nonan-2-yl]-1-methyl-1H-indazol-3- yl)piperidine-2, 6-dione; bis(trifluoroacetic acid)tert-butyl 2-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyl-1H-indazol-7-yl}-2,7- diazaspiro[3.5]nonane-7-carboxylate

[0505] Starting from 3-[6-(benzyloxy)-2-(phenoxymethyl)pyridin-3-yl ]-7- bromo- 1- methyl-1H-indazole Intermediate 18 (300,00 mg; 1,00 eq.) and tert-Butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (130,80 mg; 1,00 eq.) the general procedure H for Buchwald coupling was followed with 1,4-Dioxane (10,00 ml), Cesium carbonate (564,92 mg; 3,00 eq.), Pd-PEPPSI-IPentCl 2-methylpyridine (51,1 1 mg; 1,00 eq.) to afford the desired product (263,00 mg; 69,6 % yield) as a light orange oil.

[0506] LC MS Method A: [M+H]+646-647; Rt: 2,28 min tert-butyl 2-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl]-2,7- diazaspiro [3.5] nonane-7-carboxylate

[0507] Starting from tert-butyl 2-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyl-1H- indazol-7-yl}-2,7-diazaspiro[3.5]nonane-7-carboxylate (263,00 mg; 1,00 eq.) the general procedure E for reduction under hydrogen was followed in the presence of 1,4-Dioxane (10,00 ml) and Pd / C (263,00 mg; 4,65 eq.) to afford the desired product (75,00 mg; 34,4 % yield) as a colorless oil.

[0508] LC MS Method A: [M+H]+468-469; Rt: 1,62 min3-(7-{2,7-diazaspiro[3.5]nonan-2-yl}-1-methyI-1H-indazol-3-yI)piperidine-2, 6-dione; bis(trifluoroaceticacid)

[0509] Starting from tert-butyl 2-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol- 7-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylale (75,00 mg; 1,00 eq.) the general procedure J for Boc deprotection was followed in the presence of DCM (3.00 ml) and TFA (1.00 ml) to afford the desired product (69,00 mg; 74,9 % yield) as a colorless oil.

[0510] LC MS Method A: [M+H]+368-369; Rt: 1,01 minIntermediate 78 : 2-{4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazin-7-yl}quinazolin-2-yI)amino]-2-fluorophenyl}acetic acidTert-butyl 7-(2-{[3-fluoro-4-(2-metboxy-2-oxoethyl)phenyl]amino }quinazolin-7-yl)-8- methyl-1H,2H,3H-pyrido[2,3-b] (l,4]oxazine-1 -carboxylate

[0511] Starting from Intermediate I (1.00 g; 2.34 mmol; 1.00 eq.) and methyl 2-(4- amino-2-fluorophenyl)acetate (452.0 mg; 2.34 mmol; 1.00 eq.) general procedure K for Buchwald coupling was followed to afford tert-butyl 7-(2-{[3-fluoro-4-(2-methoxy-2- oxoethyl)phenyl]amino}quinazolin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine- I -carboxylate (700.0 mg; 1.20 mmol; 51.3 %) as brown solid.

[0512] LC-MS method E; [M+H]+520.6; Rt; 0.93 min.2-{4-[(7-{1-[(tert-butoxy)carbonyI]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7- yl] quin azo!in-2-yl)amino] -2 -fluorophenyl] acetic acid

[0513] A solution of tert-butyl 7-(2-{[3-fluoro-4-(2-methoxy-2- oxoethyl)phenyl]amino}quinazolin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine- 1 -carboxylate (650.0 mg; 0.96 mmol; 1.00 eq.), NaOH (161.0 mg; 3.82 mmol; 4.00 eq.), MeOH (10 mL) and H2O (3 mL) was stirred for 3 h at 50 °C under air atmosphere. The resulting mixture was concentrated under reduced pressure and was neutralized to pH 7 with HC1. The resulting mixture was filtered, the filter cake was washed with water (50 mL). The filter cake was dried under reduced pressure to afford 2-{4-[(7-{1-[(tert- butoxy)carbonyl]-8-methyl1H ,2H,3H-pyrido[2,3-b][ 1 ,4]oxazin-7-yl } quinazolin-2- yl)amino]-2-fluorophenyl}acetic acid (550.0 mg; 0.93 mmol; 97.7 %) as brown solid.

[0514] LC-MS method U: [M+H]+546.2; Rt; 0.93 min.Intermediate 79 : 2-{4-[(7-{1-[(tert-butoxy)carbonyI]-8-methyl-1H,2H,3H-pyrido[2,3- b] [1,4]oxazin-7-yl]quinazolin-2-yl)amino]phenyl] acetic acidTert-butyl 7-(2-{[4-(2-methoxy-2-oxoethyI)phenyl]amino}quinazolin-7-yI)-8-methyl- 1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

[0515] Starting from Intermediate I (292.00 mg; 0.69 mmol; 1 .00 eq.) and methyl 2-(4-aminophenyl)acetate (120.0 mg; 0.69 mmol; 1.00 eq.) general procedure H for Buchwald coupling was followed to afford tert-butyl 7-(2-{[4-(2-methoxy-2-oxoethyl)phenyl]amino}quinazolm-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine- 1 -carboxylate (230.0 mg; 0.41 mmol; 59.1 %) as yellow solid.

[0516] LC-MS method U: [M+H]+542.0; Rt: 0.94 min.2-{4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7- yl}quinazolin-2-yl)amino]phenyl}acetic acid

[0517] To a solution of tert-butyl 7-(2- { [4-(2-methoxy-2- oxoethyl)phenyl]amino}quinazolin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine- 1 -carboxylate (210.0 mg; 0.37 mmol; 1 .00 eq.) in oxolane (4 ml), MeOH (2 mL) and H2O (4 mL) was added NaOH (63.00 mg; 1.50 mmol; 4.0 eq.) in portions at room temperature under N2atmosphere. The resulting mixture was stirred for 2h at 25 °C under N2atmosphere. The resulting mixture was diluted with H2O. The pH was adjusted to 3 with 2N HC1. Then, the aqueous layer was extracted with MeOH / DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2- {4-[(7- { [(tert-butoxy)carbonyl]-81-- methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl)quinazolin-2-yl)amino]phenyl} acetic acid (210.0 mg; 0.36 mmol; 96.2 %) as yellow solid. The product was used in the next step without further purification.

[0518] LC-MS method U: [M+H]+528.0; Rt; 0.88 min.Intermediate 80 : tert-butyl 7-(3-chIoroisoquinolin-6-yl)-8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazine-1-carboxylatetert-butyl 8-methyl-7-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-1H,2H,3H- pyrido[2,3-b][1,4]oxazine-1-carboxylate

[0519] To a stirred solution of tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazine-1-carboxylate (10 g; 24.67 mmol; 1.00 eq.), BPD (6.92 g; 25.90 mmol; 1.05 eq.) and Pd(dppf)Cl●CH2Cl2(1.01 g; 1.23 mmol; 0.05 eq.) in 1,4-Dioxane (200 mL) was added KO Ac (2.93 g; 29.60 mmol; 1.20 eq.) under nitrogen atmosphere. The resultingmixture was stirred for 16 h at 100 °C under nitrogen atmosphere. The reaction mixture was cooled down to room temperature and concentrated under reduced pressure to afford tert-butyl 8-methyl-7-(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H,2H,3H-pyrido[2,3- b][1,4]oxazine-1-carboxylate (40.00 g; 21.09 mmol; 85.5 %) as brown liquid). The crude product used in the next step without further purification.

[0520] LC-MS method E; [M+H]+377.2; Rt; 0.94 min. tert-butyl 7-(3-chloroisoquinoIin-6-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine- 1-carboxylate

[0521] To a stirred solution of tert-butyl 8-methyl-7-(4,4,5,5-tetramethyl-1, 3,2- dioxaborolan-2-yl)-1H,2H,3H-pyrido[2.3-b][1,4]oxazme-1-carboxylate (40.0 g; 21.09 mmol; 1.00 eq.), 6-bromo-3 -chloroisoquinoline (5.38 g; 21.09 mmol; 1.00 eq.) and K2CO3(5.89 g; 42.18 mmol; 2.00 eq.) in 1,4-Dioxane (200 mL)H2O (20 mL) was added Pd(PPh3)4(2.57 g; 2.11 mmol; 0.10 eq.) under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 100 °C under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with PE / EtOAc (1 : 1) to afford tert-butyl 7-(3-chloroisoquinolin-6-yl)-8-methyl- 1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (7.50 g; 17.8 mmol; 84.3) as green solid.

[0522] LC-MS method U: [M+H] ]+412.2; Rt: 1 .00 min. tert-butyl 7-(3-{[3-fluoro-4-(2-methoxy-2-oxoethyI)phenyl]amino]isoquinolin-6-yl)-8- methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

[0523] To a stirred mixture of methyl 2-(4-amino-2-fluorophenyl)acetate (1 .00 g; 5.14 mmol; 1.00 eq.) and tert-butyl 7-(3-chloroisoquinolin-6-yl)-8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazine-1-carboxylate (2.17 g; 5.15 mmol; 1.00 eq.) in 1 ,4-Dioxane (10 mL) were added Xphos (515.00 mg; 1.03 mmol; 0.20 eq.) and Pd2(dba)3(522.00 mg;0.51 mmol; 0.10 eq.) and CS2CO3(3.71 g; 10.27 mmol; 2.00 eq.) at room temperature. The mixture was stirred overnight at 100 °C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (15: 1) to afford tert-butyl 7-(3-{[3-fluoro-4-(2- methoxy-2-oxoethyl)phenyl]amino}isoquinolin-6-yl)-8-methyl-1H,2H,3H-pyrido[2,3- b] [1,4] oxazine- 1 -carboxy late (1.20 g; 1.73 mmol; 33.6 %) as yellow solid.

[0524] LC-MS method E: [M+H]+559.0; Rt; 0.97 min.2-{4-[(6-{1-[(tert-butoxy)carbonyl]-8-metmhyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7- yl]isoquinolin-3-yl)amino ]-2-fluorophenyl}acetic acid

[0525] To a stirred solution of tert-butyl 7-(3-{[3-fluoro-4-(2-methoxy-2- oxoethyl)phenyl ]amino}isoquinolin-6-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][ 1,4]oxazine- 1-carboxylate (800.00 mg; 1.15 mmol; 1.00 eq.) in oxolane (4 mL), MeOH (2 mL)and H2O (4 mL) were added NaOH (194.0 mg; 4.61 mmol; 4.01 eq.) in portions at room temperature under N2atmosphere. The resulting mixture was stirred for 2h at 25 °C under N2atmosphere. The resulting mixture was diluted with H2O. The pH was adjusted to 3 with 2N HC1. Then the aqueous layer was extracted with MeOH / DCM. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2- {4-[(6-{1-[(tert- butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}isoquinolin-3- yl)amino]-2-fluorophenyl}acetic acid (800.0 mg; 1.13 mmol; 98.5 %) as yellow solid.

[0526] LC-MS method U: [M+H]+545.0; Rt: 0.94 min.Intermediate 81: 2-{5-[(7-fl -[( tert--butoxy )carbonyl ]-8-methyl-1 H,2H,3H-pyrido[2, 3- b][1,4]oxazin-7-yl}quinazolin-2-yl)amino]pyridin-2-yl]acetic acid1- tert-butyl 3-methyl 2-(5-nitropyridin-2-yl)propanedioate

[0527] To a stirred solution of 1 - tert-butyl 3-methyl propanedioate (6.80 g; 37.09 mmol; 1.20 eq.) and THF (50 mL) was added NaH (2.80 g; 70.00 mmol; 2.26 eq.) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 20 min at 0 °C under nitrogen atmosphere. Then, 2-chloro-5-nitropyridine (5.00 g; 30.91 mmol; 1.00 eq.) was added at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 12h at room temperature. The reaction was quenched by the addition of H2O (200 mL) at room temperature. The aqueous layer was extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 1- tert-butyl 3-methyl 2-(5-nitropyridin-2-yl)propanedioate (9.00 g; 28.25 mmol; 91.4 %; yellow liquid. The crude product was used in the next step without further purification.

[0528] LC-MS method U: [M+H]+297.0; Rt; 1 .01 min.Methyl 2-(5-nitropyridin-2-yl)acetate

[0529] To a solution of tert- bulyl 3-methyl 2-(5-nitropyridin-2-yl)propanedioate (8.90 g; 27.93 mmol; 1.00 eq.) in DCM (89 mL) was added TFA (22.00 ml; 295.21 mmol; 10.57 eq.) at room temperature. The mixture was stirred for 3 h at room temperature. The mixture was diluted to pH 9 with 1.5 M potassium phosphate solution. The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 2-(5-nitropyridin-2-yl)acetate (5.30 g; 26.24 mmol; 93.9 %) as yellow liquid. The crude product was used in the next step without further purification.

[0530] LC-MS method U: [M+H]+197.0; Rt: 1 .0 min.Methyl 2-(5-aminopyridin-2-yl)acetate

[0531] To a solution of methyl 2-(5-nitropyridin-2-yl)acetate (5.20 g; 25.74 mmol; 1.00 eq.) in DMF (52 mL) was added Pd / C (2.70 g; 2.54 mmol; 0.10 eq.). The mixture was stirred for 16 h at 25 °C under hydrogen atmosphere. The resulting mixture was filtered over celite and the filter cake was washed with 200 mL of DCM. The filtrate was diluted with H2O at room temperature and the aqueous layer was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (3 x 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 2-(5-aminopyridin-2-yl)acetate (3.00 g; 16.98 mmol; 66.0 %) as yellow solid.

[0532] LC-MS method U: [M+H]+167.0; Rt; 0.2 min. tert-butyl 7-(2-{[6-(2-methoxy-2-oxoethyl)pyridin-3-yl]amino}quinazolin-7-yl)-8- methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

[0533] Starting from Intermediate 1 (504.00 mg; 1.19 mmol; 1 .00 eq.) and methyl 2-(5-aminpyridin2-yl)acetate (210.00 mg; 01.19 mmol; 1.00 eq.) general procedure H for Buchwald coupling was followed to afford tert-butyl 7-(2-{[6-(2-methoxy-2- oxoethyl)pyridin-3-yl]amino}quinazolin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b ][ 1 ,4 ]oxazine-1 -carboxylate (500.00 mg; 0.84 mmol; 71.1 %) as yellow solid.

[0534] LC-MS method U: [M+H]+543.0; Rt: 0.84 min.2-{5- [(7-{1 - [( tert-butoxy)carbonyl] -8-methyl-1H,2H,3H-pyrido [2,3-b] [1,4] oxazin-7- yl}quinazolin-2-yl)amino]pyridin-2-yl}acetic acid

[0535] To a stirred solution of tert-butyl 7-(2-{[6-(2-methoxy-2-oxoethyl)pyridin-3-yl ]amino} quinazolin-7-yl)-8-methyl- 1 H,2H,3H-pyrido| 2,3-b ] [ 1 ,4 ]oxazin - 1 -carboxylate (480.00 mg; 0.81 mmol; 1 .00 eq.) in oxolane (4 mL), MeOH (4 mL) and H2O (2 mL) were added NaOH (137.00 mg; 3.25 mmol; 4.01 eq.) in portions at room temperature under N2atmosphere. The resulting mixture was stirred for 2h at 25 °C under N2atmosphere. The resulting mixture was diluted with H2O. The pH was adjusted to 3 with 2N HC1. The aqueous layer was extracted with MeOH / DCM. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-{5-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H- pyrido[2,3-b][ l,4]oxazin-7-yl} quinazolin-2-yl)amino]pyridin-2-yl}acetic acid (350.0 mg; 0.55 mmol; 67.8 %) as yellow solid.

[0536] LC-MS method U: [M+H]T529.0; Rt: 0.81 min.Intermediate 82 : 2-{6-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3- b][1.4]oxazin-7-yl}quinazolin-2-yl)amino]pyridin-3-yl} acetic acidtert-butyl 7-(2-{[5-(2-ethoxy-2-oxoethyl)pyridin-2-yl]amino}quinazoIin-7-yl)-8-methyl- 1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

[0537] Starting from Intermediate I (500.0 mg; 1.18 mmol; 1.00 eq.) and ethyl 2- (6-aminpyridin-3-yl)acetate (2180. mg; 1.15 mmol; 1.00 eq.) general procedure H for Buchwald coupling was followed to afford tert-butyl 7-(2-{[5-(2-ethoxy-2-oxoethyl)pyridin-2-yl]amino} quinazolin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazine-1-carboxylate (510.0 mg; 0.90 mmol; 78.6 %) as brown solid.

[0538] LC-MS method U: [M+H]+557.4; Rt; 0.87 min.2-{6-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7- yl}quinazolin-2-yI)amino]pyridin-3-yl} acetic acid

[0539] To a stirred mixture of tert-butyl 7-(2- { [5-(2-ethoxy-2-oxoethyl)pyridin-2- yl]amino}quinazolin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (510.0 mg; 0.73 mmol; 1.00 eq.) in MeOH (15 mL) and H2O (7 mL) was added NaOH (123.0 mg; 2.92 mmol; 4.01 eq.) at room temperature. The mixture was stirred for 16h at 50 °C under argon atmosphere. The mixture was acidified to pH 4 with 2N HC1. The resulting mixture was diluted by ice / water and extracted with DCM / MeOH (10: 1). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 2-{6-[(7-{1-[( / err- butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}quinazolin-2- yl)amino]pyridin-3-yl} acetic acid (450.0 mg; 0.69 mmol; 95.4 %) as yellow solid.

[0540] LC-MS method U: [M+H]T529.3; Rt: 0.81 min.Intermediate 83 : 2-{2-fluoro-4-[(7-{8-methyl-2H,3H-[1,4]dioxino[2,3-b]pyridin-7- yl}quinazolin-2-yI)amino]phenyl}acetic acid2-Chloro-7-{8-methyl-2H,3H-[1,4]dioxino[2,3-b]pyridin-7-yl}quinazolme (LOU040 / 399)

[0541] 7-Chloro-8-methyl-2,3-dihydro-[1.4]dioxino[2,3-b]pyridine (400.0 mg; 2.07 mmol; 1.00 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-L3,2- dioxaborolane (718.9 mg; 2.69 mmol; 1.30 eq.) and KOAc (406.1 mg; 4,. 14 mmol; 2.00 eq.) were filled into the vial and dissolved in 1 ,4-Dioxane. The vial was set under vacuum, placed into an ultrasonic bath and thereafter filled with argon. Then XPhos Pd G3 (87.56 mg; 0.10 mmol; 0. 05 eq.) was added to the mixture and the degassing procedure was repeated. Next the reaction mixture was stirred at 100°C for 2 h. Subsequently, 7-bromo-2- chloroquinazoline (503.8 mg; 2.07 mmol; 1.00 eq.), K2CO3(571.9 mg; 4.14 mmol; 2.00eq.) and water (800.0 pl) were added to the mixture and the stirring was continued at 100°C for 3h. The reaction mixture was diluted with water and extracted with EtOAc (3 x 150 mL). The combined organic phases were dried over sodium sulfate, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography, eluting with 0-20% DCM / MeOH to afford 2-chloro-7-{8-methyl-2H,3H-[1,4]dioxino[2,3-b]pyridin-7- yl}quinazoline (82.46 mg; 0.32 mmol, 12.7 %) as yellow solid.

[0542] LC-MS method K: [M+H]+314.1 ; Rt: 0.71 min.Methyl 2-{2-fluoro-4-[(7-{8-methyl-2H,3H-[1,4]dioxmo[2,3-b]pyridin-7-yl}quinazolin- 2-yI)amino]phenyl} acetate; trifluoroacetic acid

[0543] 2-chloro-7-{8-methyl-2H,3H-[ L4]dioxino[2,3-b]pyridin-7-yl}quinazoline (61.00 mg; 0.18 mmol; 1.00 eq.) and methyl 2-(4-amino-2-fluorophenyI)acetate (38.37 mg;0.20 mmol; 1.10 eq.) were filled into the vial and dissolved in 1 -butanol (1.22 ml). Then TFA (71.2 pl; 0.92 mmol; 5.00 eq.) was added to the reaction mixture. The reaction mixture was stirred at 80°C for 2 h. The reaction mixture was evaporated in vacuo to afford methyl 2-{2-fluoro-4-[(7- {8-methyl-2H,3H-[1,4]dioxino[2,3-b]pyridin-7-yl }quinazolin-2- yl)amino]phenyI}acetate trifluoroacetic acid (151.8 mg; 0.20 mmol, 100 %) as yellow residue. The crude product was used in the next step without further purification.

[0544] LC-MS method K: [M+H]+461 .3 ; Rt: 0.82 min.2-{2-fliioro-4-[(7-{8-methy]-2H,3H-[1,4]dioxino[2,3-b]pyridin-7-yl}quinazolin-2- yl)amino]phenyl] acetic acid

[0545] Methyl 2- {2-fluoro-4-[(7- {8-methyl-2H,3H-[1,4]dioxino[2,3-b]pyridin-7- yl(quinazolin-2-yl)amino]phenyl( acetate; trifluoroacetic acid (151.8 mg; 0.20 mmol; 1.00 eq.) was filled into the vial and dissolved in THF (2.28 mL). Then 2N NaOH (0.50 mL;1 .00 mmol; 5.00 eq.) was added to the reaction mixture. The reaction mixture was stirred at 50°C for 2 h. THF was evaporated under reduced pressure, followed by acidification to pH 2 with 2N HC1 solution, which caused precipitation. The precipitate was filtered off, rinsed twice with water and dried under reduced pressure to afford 2-{2-fluoro-4-[(7-{8-methyl- 2H,3H-[1,4]dioxino[2,3-b]pyridin-7-yl} quinazolin-2-yl)amino]phenyl} acetic acid (62.60 mg; 0.14 mmol; 70.0 %).

[0546] LC-MS method K: [M / 2+H]+224.2; Rt: 0.73 min.Intermediate 84 : 3-{6-[3-(piperazin-1-yl)azetidin-1-yl]pyridin-3-yl}piperidine-2,6- dione hydrochloridetert-butyl 4-[ (5- 1io-dopyridin-2-yl)azetidin-3-yl]piperazme-1-carboxylate

[0547] To a stirred solution of 2-fluoro-5-iodopyridine (1.00 g; 4.26 mmol; 1.00 eq.) and tert-butyl 4-(azetidin-3-yl)piperazine-1-carboxylate hydrochloride (1.22 g; 4.26 mmol; 1.00 eq.) in N,N-dimethyIformamide (15 mL) was added K2CO3(1.86 g; 12.78 mmol; 3.00 eq.) in portions at room temperature under N2atmosphere. The resulting mixture was stirred for 5 h at 90 °C under N2atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography, eluted with PE / ElOAc (1 : 1) to afford tert-butyl 4-[1-(5-iodopyridin-2- yl)azetidin-3-yl]piperazine-1-carboxylate (900.0 mg; 2.00 mmol; 47.0 %) as yellow solid.

[0548] LC-MS Method AH: [M+H]+445. 1 ; Rt: 0.72 min. tert-butyl 4-{1-[2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yI]azetidin-3-yl}piperazine-1- carboxylate

[0549] To a solution of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1, 3,2- dioxaborolan-2-yl)pyridine Intermediate 8 (747.0 mg; 1.78 mmol: 1.00 eq.) and tert-butyl 4-[1-(5-iodopyridin-2-yl)azetidin-3-yl]piperazine-1-carboxylate (800.0 mg; 1.78 mmoi; 1.00 eq.) in 1 ,4-dioxane (15 mL) and water (5 mL) were added Pd(dppf)Cl2●CH2Cl2(145.0 mg; 0.18 mmol; 0.10 eq.) and Na2CO3(596.0 mg; 5.34 mmol; 3.00 eq.) at room temperature. The resulting mixture was stirred for 3 h at 100 °C under argon atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (6: 1) to afford tert-butyl 4-{1-[2',6'-bis(benzyloxy)-[3,3'-bipyridin]-6-yl]azetidin-3-yl}piperazine-1-carboxylate (1.00 g; 1.50 mmol; 84.4 %) as yellow solid.

[0550] LC-MS method E: [M+H]+608.3; Rt: 0.98 min. tert-butyl 4-{1-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]azetidin-3-yl}piperazine-1- carboxylate

[0551] A solution of tert-butyl 4- { 1 -[2',6’-bis(benzyloxy)-[3,3'-bipyridin]-6- yl]azetidin-3-yl}piperazine-1-carboxylate (920.0 mg; 1.44 mmol; 1.00 eq.) and Pd / C (200.0 mg; 0.19 mmol; 0.13 eq.) in DMF (20 mL) was stirred for 16 h at room temperature under H2 atmosphere. The reaction mixture was filtered and the filter cake was washed with DMF. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10: 1 ) to afford tert-butyl 4- {1-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]azetidin-3-yl}piperazine-1-carboxylate (450.0 mg; 0.94 mmol; 64.9 %) as brown solid.

[0552] LC-MS method E: [ M+H ] 430.2; Rt: 0.45 min.3-{6-[3-(piperazin-1-yl)azetidin-1-yI]pyridin-3-yl]piperidine-2, 6-dione hydrochloride

[0553] Tert-butyl 4-{1-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]azetidin-3- yl } piperazine- 1 -carboxylate (430.0 mg; 0.89 mmol; 1.00 eq.) was dissolved in 4N HC1 in EtOAc (10 mL) at room temperature. The reaction mixture was stirred for 1 h at room temperature. The mixture was concentrated under reduced pressure to afford 3-{6-[3- (piperazin- 1 -yl)azetidin- 1 -yl]pyridin-3-yl] piperidine-2, 6-dione hydrochloride (340.0 mg; 0.88 mmol; 98.4 %) as light yellow solid.

[0554] LC-MS Method AB: [M+H]+330.2; Rt: 0.34 mm.Intermediate 85 : 2-{5-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazin-7-yl}quinazolin-2-yl)amino]pyrazin-2-yl}acetic acidtert-butyl 7-(2-{[5-(2-ethoxy-2-oxoethyl)pyrazin-2-yl]amino}quinazoIin-7-yl)-8- methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

[0555] Starting from Intermediate 1 (950.0 mg; 2.39 mmol; 1.00 eq.) and Ethyl 2- (5-bromopyrazin-2-yl)acetate (585.8 mg; 2.39 mmol; 1.00 eq.) general procedure H for Buchwald coupling was followed to afford tert-butyl 7-(2-{[5-(2-elhoxy-2- oxoethyl)pyrazin-2-yl]amino}quinazolin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazine-1-carboxylate (1,00 g ; 1,04 mmol; 43,5 %) as a white solid.

[0556] LC-MS method A; [M+H]+558.6; Rt; 1 .68 min.2-{5-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7- yl}quinazolin-2-yl)amino]pyrazin-2-yl] acetic acid

[0557] To a solution of tert-butyl 7-(2-{[5-(2-ethoxy-2-oxoethyl)pyrazin-2- y 1] amino } quinazolin-7-yl)-8-methyl- 1H,2H,3H-pyrido [2 ,3 -b] [ 1 ,4]oxazine- 1 -carboxylate (1.00 g; 1.63 mmol; 1.00 eq.) in THF (20 mL) and water (20 mL) was added NaOH (195.82 mg; 4,90 mmol; 3.00 eq.) and the mixture was stirred at 50°C for 20 h. The reaction mixture was acidified with 1N HC1 and extracted with DCM. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduce pressure. The aqueous layer w as filtered with suction to afford 2- {5-[(7- { 1 -[(tert-butoxy)carbonyl]-8-methyl- 1H.2H,3H-pyrido[2,3-b] [ 1 ,4]oxazin-7- yl}quinazolin-2-yl)amino]pyrazin-2-yl} acetic acid (630.0 mg; 1 .09 mmol; 67.1 %).

[0558] LC-MS method A; [M+H]+530.2; Rt; 1 .52 min.Intermediate 86 : 3-{3-[3-(piperazin-1-yl)azetidin-1-yl]phenyl}piperidine-2,6-dione2,6-bis(benzyIoxy)-3-(3-bromophenyl)pyridine

[0560] Starting from 1 ,3-Dibromobenzene (2.90 ml; 23.96 mmol; 1.00 eq.) and 2,6- dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine ( 10.00 g; 23.96mmol; 1.00 eq.) general procedure G for Suzuki coupling was followed to afford 2,6- bis(benzyloxy)-3-(3-bromophenyl)pyridine (3.95 g; 7.94 mmol; 33.1 %) as colorless resin.

[0561] LC-MS method A: [M+H]+448.0; Rt: 2.24 min. tert-butyl 4-(1-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl]azetidin-3-yl)piperazine-1- carboxyiate

[0562] Starting from 2,6-bis(benzyloxy)-3-(3-bromophenyl)pyridine (2.00 g; 4.02 mmol; 1.00 eq.) and N-Bo 1c--4-azetidin-3-yl-piperazine (1.00 g; 4.02 mmol; 1.00 eq.) general procedure H for Buchwald coupling was followed to afford tert-butyl 4-( 1- {3-[2,6- bis(benzyloxy)pyridin-3-yl]phenyl}azetidin-3-yl)piperazine-1-carboxylate (1.95 g; 3.22 mmol; 80.0 %) as beige solid.

[0563] LC-MS method A: [M+H]+607.3; Rt: 1.86 min. tert-butyl 4-{1-[3-(2,6-dioxopiperidin-3-yl)phenyl]azetidin-3-yl]piperazine-1- carboxylate

[0564] Starting from tert-butyl 4-(1-{3-[2,6-bis(benzyIoxy)pyridin-3- yl]phenyl}azetidin-3-yl)piperazine-1-carboxylate (1.95 g; 3.22 mmol, 1.00 eq.) general procedure E for hydrogenation was followed to afford tert-butyl 4-{ 1-[3-(2,6- dioxopiperidin-3-yl)phenyl]azetidin-3-yl}piperazine-1-carboxylale (1.39 g; 2.55 mmol; 79.3 %) as a brown solid.

[0565] LC-MS method A: [M+H]+373.2; Rt: 1 .10-1 . 13 min.3-{3-[3-(piperazin-1-yl)azetidin-1-yl]phenyl}piperidine-2, 6-dione

[0566] Starting from tert-butyl 4- { 1 -[3-(2,6-dioxopiperidin-3-yl)phenyl]azetidin-3- yl}piperazine-1-carboxylate (1.39 g; 2.55 mmol; 1.00 eq) general procedure J for Boc deprotection was followed to afford 3-{3-[3-(piperazin-1-yl)azetidin-1- yl]phenyl}piperidine-2, 6-dione (1.29 g; 3.90 mmol; 152.9 %) as light yellow resin.

[0567] LC-MS method A: [M+H]+329.2; Rt: 0.85min.Intermediate 87 : {3- 1[3--(piperazin-1-yl)azetidin-1-yl]phenyl}-1, 3-diazinane-2, 4-dione; trifluoroacetic acid1-(3-bromophenyl)-1, 3-diazinane-2,4-dione

[0568] To 3-Bromoaniline (4.49 mL; 0.04 mol; 1.00 eq.) was added anhydrous acrylic acid (11 .30 mL; 0.16 mol; 4.00 eq.) and the reaction mixture was stirred at 110°C for 3 h. Then, urea ( 15.85 g; 0.26 mol; 6.42 eq.) and AcOH (glacial) (140.3 mL; 2.45 mol; 60.00 eq.) was added to the reaction mixture and stirred 12 h at 120°C. The reaction mixture was poured into 200 mL water / ice mixture. The formed solid was filtered off, rinsed with water and dried at 60°C in vacuo to afford (3-bromoph 1e-nyl)-1, 3-diazinane-2, 4-dione (2.87 g;10.42 mmol; 25.6 %) as beige solid.

[0569] LC-MS method A: [M+H]+271 .1 ; Rt: 1 .81 min. tert-butyl 4-{1-[3-(2,4-dioxo-1, 3-diazinan-1-yl)phenyl]azetidin-3-yl]piperazine-1- carboxylate

[0570] Starting from (3- 1b-romophenyl)-1, 3-diazinane-2, 4-dione (500.0 mg; 1.67 mmol; 1.00 eq.) and N-Bo 1c--4-azetidin-3-yl-piperazine (415.0 mg; 1.67 mmol; 1.00 eq.) general procedure H for Buchwald coupling was followed to afford tert-butyl 4- { 1-[3-(2,4- dioxo-1,3-diazinan-1-yl)phenyl]azetidin-3-yl]piperazine-1-carboxylate (221.7 mg; 0.42 mmol; 25.1 %) as yellow oil.

[0571] LC-MS method A: [M+H]+374.0; Rt: 1.09 min. 1-[3-[3-(piperazin-1-yl)azetidin-1-yl]phenyl}-1, 3-diazinane-2, 4-dione; trifluoroacetic acid

[0572] Starting from tert-butyl 4-{ [3-(2,4-di 1o-xo-1, 3-diazinan-1-yl)phenyl]azetidin- 3-yl } piperazine- 1 -carboxylate (221.7 mg; 0.52 mmol; 1.00 eq.) general procedure J for Bocdeprotection was followed to afford {3-[3-(piperazin-1-yl)azetidm-1-yl]phenyl}-1, 3- diazinane-2, 4-dione; trifluoroacetic acid (219.2 mg; 0.49 mmol; 95.8 %) as yellow solid.

[0573] LC-MS method A: [M+H]+330.0; Rt: 0.82 min.Intermediate 88 : [4-( 13--{4-[2-(4-amino-1H-pyrazol-1-yl)acetyl]piperazin-1-yl}azetidin- 1 -yl)phenyi] -1 ,3-diazinane-2 ,4-dione1-(4-{3-[4-(2-chioroacetyI)piperazin-1-yl]azetidin-1-yl]phenyI)-1, 3-diazinane-2, 4-dione

[0574] To a stirred mixture of 1- {4-[3-(piperazin-1-yl)azetidin-1-yl]phenyl}-1, 3- diazinane-2, 4-dione; trifluoroacetic acid ( 1.50 g; 3.17 mmol; 1.00 eq.) and TFA (0.60 g; 5.00 mmol; 1.58 eq.) in DCM (20 mL) was added 2-chloroacetyl chloride (14.00 g; 19.34 mmol;6. 1 eq. ) at room temperature. The mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with DCM / MeOH (10: 1) to afford (4-{3-[4-(2- 1- chloroacetyl)piperazin-1-yl]azetidin-1-yl}phenyl)-1, 3-diazinane-2, 4-dione (725.0 mg; 1.33 mmol; 42.1 %) as yellow solid.

[0575] LC-MS method H: [M+H]+406.2; Rt: 0.59 min.1- [4-(3-{4- [2-(4-nitro- 1H-pyrazol-1-yl)acetyl]piperazin-1-yl} azetidin-1-yl)ph enyl] -1 ,3- diazinane-2, 4-dione

[0576] To a stirred solution of (4- (3- 1[-4-(2-chloroacetyl)piperazin-1-yl]azetidin-1- yl} phenyl)-1, 3 -diazinane-2, 4-dione (625.0 mg; 1.15 mmol; 1.00 eq.) and DIEA (0.40 mL;2.29 mmol; 2.00 eq.) in DMF (6.00 mL) was added 4-nitro-1H-pyrazole (205.0 mg; 1.72 mmol; 1 .50 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (93:7) to afford [4-(3-{4-[2-(4-nitro- 1- 1H-pyrazol-1-yl)acetyl]piperazin- 1 -yl } azetidin- 1 -yl)phenyl]-1,3-diazinane-2, 4-dione (520.0 mg; 1 .02 mmol; 89.0 %) as yellow solid.

[0577] LC-MS method H: [M+H]+483.3; Rt: 0.64 min. 1-[4-(3-{4-[2-(4-amino-1H-pyrazol-1-yl)acetyl]piperazin-1-yl}azetidin-1-yl)phenyI]-1, 3- diazinane-2, 4-dione

[0578] To a stirred mixture of [4-(3- 1){-4-[2-(4-nitro-1H-pyrazol-1- yl)acetyl]piperazin-1-yl}azetidin-1-yl)phenyl]-1,3-diazinane-2, 4-dione (490.0 mg; 0.96 mmol; 1.00 eq.) and Tetrahydroxydiboron (365.0 mg; 3.87 mmol; 4.01 eq.) in DMF (6.00 mL) was added 4,4'-bipyridine (16.00 mg; 0.10 mmol; 0.10 eq.) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with DCM / MeOH (1: 1 ) to afford 1-[4-(3-{4-[2-(4- amino-1H-pyrazol- 1 -yl)acetyl]piperazin-1-yl] azetidin- 1 -yl)phenyl]-1,3-diazinane-2, 4-dione (80.00 mg; 0.17 mmol; 17.5 %) as yellow solid.

[0579] LC-MS method H: [M+H]+453.3; Rt; 0.46 min.Intermediate 89: 3-[4-(3-{4-[2-(4-aminophenyl)-2-oxoethyl]piperazin-1-yl]azetidin-1- yl)phenyl]piperidine-2, 6-dione3-[4-(3-{4-[2-(4-nitrophenyl)-2-oxoethyl]piperazin-1-yl}azetidin-1-yl)phenyl]piperidine- 2,6-dione

[0580] To a solution of 4-Nitrophenacylbromid (280.0 mg; 1.90 mmol; 1.00 eq.) and 3- {4-[3-(piperazin-1-yl)azetidin-1-yl]phenyl}piperidine-2, 6-dione; trifluoroacetic acid (622.3 mg; 1.31 mmol; 1.20 eq.) in DCM (20 mL) was added N-Ethyldiisopropylamine (0.61 mL;3.59 mmol; 3.30 eq.) at rt under argon atmosphere. The reaction mixture was stirred for 20 h at room temperature. Then the reaction mixture was concentrated to dryness under reduced pressure and the residue was purified by silica flash column chromatography, eluted withDCM / MeOH (1 : 1) to afford 3-[4-(3-{4-[2-(4-nitrophenyl)-2-oxoethyl]piperazin-1- yl) azetidin-1-yl)p 1-henyl]piperidine-2, 6-dione (410.00 mg; 0.81 mmol; 74.2 %).

[0581] LC-MS method A: [M+H]+492.1 ; Rt: 1 .11 min.3-[4-(3-{4-[2-(4-aminophenyl)-2-oxoethyl]piperazin-1-yl}azetidin-1- yl)phenyl]piperidine-2, 6-dione

[0582] To a solution of 3-[4-(3-{4-[2-(4-nitrophenyl)-2-oxoethyl]piperazin-1- yl} azetidin-1-yl)p 1h-enyl]piperidine-2, 6-dione (410.0 mg; 0.81 mmol; 1.00 eq.) and Tetrahydroxydiboron (217.6 mg; 2.43 mmol; 3.00 eq.) in DMF (10 mL) was added 4,4’- Dipyridine (12.9 mg; 0.08 mmol; 0.1 eq.) under argon atmosphere. Then the mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by column chromatography, eluted with DCM / MeOH (1:1) to afford 3-[4-(3-{4-[2-(4-aminophenyI)-2-oxoethyl]piperazin-1-yl] azetidin-1- yl)phenyl]piperidine-2, 6-dione (290.00 mg; 0.62 mmol; 76.9 %).

[0583] LC-MS method A: [M+H]+462.1 ; Rt: 1 .04 min.Intermediate 90 : 3-[4-(3-{4-[(4-aminophenyI)methyl]piperazin-1-yI]azetidin-1- yl)phenyl]piperidine-2, 6-dione3-[4-(3-{4-[(4-nitrophenyl)methyl]piperazin-1-yl]azetidin-1-yl)phenyl]piperidine-2,6- dione

[0584] To a stirred mixture of 3- {4-[3 -(piperazin-1-yl)azetidin-1- 1- yl]phenyl}piperidine-2, 6-dione (8.00 g; 16.82 mmol; 1.00 eq.) in ACN (10 mL) were added 1 -(bromomethyl)-4-nitrobenzene (3.70 g; 16.82 mmol; 1.00 eq.) and DIEA (15.42 mL; 84.12 mmol; 5.00 eq.) in portions at room temperature. The resulting mixture was stirred for 2h at room temperature under nitrogen atmosphere. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (95:5) to afford 3-[4-(3-{4-[(4- nitrophenyl)methyl]piperazin- 1 -yl } azetidin- 1 -yl)phenyl]piperidine-2 ,6-dione (7.50 g; 15.9mmol; 94.3 %) as yellow solid.

[0585] LC-MS method Q: [M+H]+464.2; Rt: 0.59 min.3-[4-(3-{4-[(4-aminophenyI)methyl]piperazin-1-yl}azetidin-1-yl)phenyl]piperidine-2,6- dione

[0586] To a stirred mixture of 3-[ 4-(3- {4-[(4-nitrophenyI)methyl]piperazin-1- yl}azetidin-1-yl)phenyl]piperidine-2,6-dione (3.50 g; 7.40 mmol; 1.00 eq.) and Tetrahydroxy diboron (2.09 g; 22.20 mmol; 3.00 eq.) in DMF (20 mL) was added 4.4'- bipyridine (0.61 g; 3.70 mmol; 0.50 eq.) in portions at room temperahire. The resulting mixture was stirred for 0.1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (93:7) to afford 3-[4-(3-{4-[(4- aminophenyl)methyl]piperazin- 1 -yl } azetidin- 1 -yl)phenyl]piperidine-2, 6-dione (3.00 g; 6.16 mmol; 83.3 %) as yellow solid.

[0587] LC-MS method V: [M+H]+434.3; Rt: 0.44 min.Intermediate 91 : 3-[4-(3-{4-[2-(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)acetyl]piperazin- 1-yl}azetidin-1-yl)phenyl]pip zeridine-2, 6-dione3-[4-(3-{4-[2-(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)acetyl]piperazin-1-yl}azetidin-1- yl)phenyl] piperidine-2, 6-dione

[0588] Starting from (3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)-acetic acid (100.00 mg; 0.48 mmol; 1.00 eq.)) and 3- {4-[3-(piperazin-1-yl)azetidm-1-yl]phenyl}piperidine-2, 6-dione; trifluoroacetic acid (216.0 mg; 0.48 mmol; 1.00 eq.) General procedure O was followed to afford - [4-(3 - {4-[2-(3,5-dimethyl-4-nitro-1H-pyrazol- 1 -yl)acetyl]piperazin- 1 -yl} azetidin- 1 - yl)phenyl]piperidine-2, 6-dione (204.0 mg; 0.40 mmol; 83.9 %)

[0589] LC-MS method A: [M+H]+511.0; Rt: 1.09 min.3-[4-(3-{4-[2-(4-amino-3,5-dimethyl-1H-pyrazol-1-yl)acetyl]piperazin-1-yl}azetidin-1- yl)phenyl] piperidine-2, 6-dione

[0590] 3-[4-(3-{4-[2-(3,5-dimethyl-4-nitro-1H-pyrazol-1-yl)acetyl]piperazin-1- yl}azetidin-1-yl)phenyl]piperidine-2, 6-dione (204.0 mg; 0.40 mmol; 1.00 eq.) was suspended in N,N-Dimethylformamide (3 ml) and Tetrahydroxydiboron (215.4 mg; 2.40 mmol; 6.00 eq.) was added. Under ice cooling 4, 4‘ -Dipyridine (6.38 mg; 0.04 mmol; 0.10 eq.) was added. The reaction solution was stirred 30 min under ice cooling and I h at room temperature. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed once with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford 3-[4-(3-{4-[2-(4-amino-3,5-dimethyl-1H-pyrazol-1- yl)acetyl]piperazin-1-yl}azetidin-1-yl)phenyl]piperidine-2, 6-dione (164.00 mg; 0.34 mmol; 85.4 %) as yellow oil.

[0591] LC-MS method A; [M+H]+480.0; Rt; 0.78-0.85 min.Intermediate 92 : 3-[7-(4-{1-[(4-aminophenyl)methyl]azetidin-3-yl}piperazin-1-yl)-1- methyl-1H-indazol-3-yl]piperidin e-2, 6-dione

[0592] 3-[1-methyl-7-(4-{1-[(4-nitrophenyl)methyl]-azetidine-3-yl}piperazin-1- yl)-1H-indazol-3-yl]piperidine-2, 6-dione

[0593] Intermediate 103 (600.0 mg; 0.89 mmol; 1.00 eq.) and 4-nitrobenzaldehyde (426.0 mg; 2.68 mmol; 3.00 eq.) general procedure A for reductive amination was followed to afford 3- [ 1 -methyl-7-(4- { 1 - [( 4-nitrophenyl)methyl] azetidin-3 -yl} piperazin-1 -yl)- 1H- indazol-3-yl]piperidine-2, 6-dione (410.0 mg; 0.69 mmol; 77.4 %) as yellow solid.

[0594] LC-MS Method AB; [M+H]+518.2; Rt; 0.77 min.3-[7-(4-{1-[(4-aminophenyI)methyl ]azetidin-3-yl}piperazin-1-yl)-1-methyl-1H-indazol-3- yl] piperidine-2 ,6-dione

[0595] A mixture of 3-[1-methyl-7-(4-{ 1-[(4-nitrop 1h-enyl)methyl]azetidin-3-yl}piperazin-1-yl)-1H-indazol-3-yl]piperidine-2,6-dione (400.00 mg; 0.67 mmol; 1.00 eq.) and Raney-Ni (122.0 mg; 1.35 mmol; 2.01 eq.) in DMF (5 mL) was stirred at room temperature for 4 h under H2atmosphere. The resulting mixture was filtered, the filter cake was washed with DMF (10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford 3 -[7-(4- { 1 -[(4-aminophenyl)methy l]azetidin-3-yl } piperazin- 1 -yl)-1-methyl-1H- indazol-3-yl]piperidine-2, 6-dione (320.00 mg; 0.53 mmol; 78.4 %) as gray solid.

[0596] LC-MS Method AB: [M+H]+488.2; Rt: 0.44 min.Intermediate 93 : 5-{3-[(3R,5S)-4-(4-aminophenyl)-3,5-dimethylpiperazin-1-yl]azetidin- 1-yI}-2-(2,6-dioxopiperidin-3-yI)-2,3-dihydro-1H-isoindole-1, 3-dionetert-butyl N,N-bis(2-hydroxypropyl)carbamate

[0597] To a stirred solution of [(2-hy 1d-roxypropyl)amino]propan-2-ol (20.00 g;147.2 mmol; 1 .00 eq.) and BOC2O (34.06 g; 154.5 mmol; 1 .05 eq.) in DCM (200 mL) was added TEA (64.6 mL; 441.5 mmol; 3.00 eq.) at room temperature. The resulting mixture was stirred 40 °C for 4 h under nitrogen atmosphere. The reaction was diluted with water (400 mL) at room temperature. The resulting mixture was extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (30:1 ) to afford tert-butyl N,N-bis(2-hydroxypropyl)carbamate (30.00 g; 115.7 mmol; 78.6 %) as white solid.

[0598] TLC Rf (DCM / MeOH 30: 1): 0.4 tert-butyl N,N-bis(2-oxopropyl)carbamate

[0599] To a stirred solution of oxalyl dichloride (15.46 g; 1 15.7 mmol; 3.00 eq.) in DCM (100 mL) was added a solution of DMSO (12.06 g; 154.3 mmol; 4.00 eq.) in DCM(100 mL) dropwise at -70 °C under argon atmosphere. The mixture was stirred at -70 °C for 0.5 h. A solution of tert-butyl N,N-bis(2-hydroxypropyl)carbamate (10.00 g; 38.58 mmol; 1 .00 eq.) in DCM (100 mL) was added into to the mixture dropwise and the mixture was stirred at -70 °C for 0.5 h under argon atmosphere. Then TEA (28.22 mL; 192.88 mmol; 5.00 eq.) was added to the reaction mixture at -70 °C. The mixture was allowed warm to 15 °C and stirred at 15 °C for 2 h under argon atmosphere. The reaction was quenched with water (500 mL) at room temperature. The resulting mixture was extracted with DCM (3 x 300 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (3:2) to afford tert- butyl N,N-bis(2-oxopropyl)carbamate (7.00 g; 27.48 mmol; 71.2 %) as colorless oil.

[0600] TLC Rf (PE / EtOAc 2: 1): 0.3 tert-butyl 3,5-dimethyl-4-(4-nitrophenyl)piperazine-1-carboxylate

[0601] To a stirred solution of tert-butyl N,N-bis(2-oxopropyl)carbamate (7.06 g; 24.63 mmol; 1.05 eq.) and 4-nitroaniline (3.60 g; 23.46 mmol; 1.00 eq.) in MeOH (70 mL) was added AcOH (7 mL). The mixture was stirred at 15 °C for 0.5 h. (2-methylpyridin-1- ium-1-yl)boranuide (5.07 g; 46.91 mmol; 2.00 eq.) was added. T hen the mixture was stirred at 15 °C for 2 h under argon atmosphere. The reaction was quenched with water (150 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 90 mL). The combined organic layers were washed with brine (2 x 150 mL), dried over anhydrous Na2SO4After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (5:1). to afford tert-butyl 3,5-dimethyl-4-(4-nitrophenyl)piperazine-1-carboxylate (3.60 g; 3.77 mmol; 16.1 %) as colorless oil.

[0602] LC-MS method E: [M+H]I336.3; Rt: 1 .04 min.2,6-dimethyl-1-(4-nitrophenyl)piperazine

[0603] To a stirred solution of tert-butyl 3,5-dimethyl-4-(4-nitrophenyl)piperazine- 1- carboxylate (3.60 g; 3.77 mmol; 1 .00 eq.) in 4N HC1 in EtOAc (30 mL). The reaction mixture was stirred for 1 h at 25 °C. The resulting mixture was concentrated under reduced pressure. Then water (15 mL) was added. The mixture was basified to pH 8 with aq. Na2CO3solution. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (9: 1) to afford 2,6-dimethyl-1-(4-nitrophenyI)piperazine (0.90 g; 3.68 mmol; 97.7 %) as white solid.

[0604] LC-MS method E: [M+H]+236.2; Rt: 0.63 min. tert-butyl 3-[3,5-dimethyl-4-(4-nitrophenyl)piperazin-1-yl]azetidine-1-carboxylate

[0605] To a stirred solution of tert-butyl 3-oxoazetidine-1-carboxylate and 2,6- dimethyl-1-(4-nitrophenyl)piperazine (890.0 mg; 3.70 mmol; 1.00 eq.) in DCM (10 mL) and MeOH (10 mL) were added sodium acetate trihydrate ( 1.52 g; 11.09 mmol; 3.00 eq.) and sodium cyanoborohydride (733.6 mg; 11 .09 mmol; 3.00 eq.) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting mixture was extracted with DCM (3 x 100 mL) and quenched with water (150 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (15: 1) to afford tert-butyl 3-[3,5- dimethyl-4-(4-nitrophenyl)piperazin-1-yl] azetidine- 1 -carboxylate (1.10 g; 2.82 mmol; 76.2 %) as brown solid.

[0606] LC-MS method E: [M+H]+391.2; Rt: 0.78 min. tert-butyl 3-[(3S,5S)-3,5-dimethyl-4-(4-nitrophenyl)piperazin-1-yl]azetidine-1- carboxylate

[0607] The product tert-butyl 3-[3,5-dimelhyl-4-(4-nitrophenyl)piperazin-1- yl]azetidine-1-carboxylate (1.10 g; 2.82 mmol; 1.00 eq.) was purified by Prep-Chiral-HPLC (Column: GreenSep Basic 3* 15 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.1% 2M NH3-MeOH); Flow rate: 75 mL / min; Gradient: isocratic 20% B; Column Temperature 35 °C; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 1.92; RT2 (min): 2.73) to afford tert-butyl 3-[(3S,5S)-3,5-dimethyl-4-(4-nitrophenyl)piperazin-1- yl]azetidine-1-carboxylate (260.00 mg; 0.64 mmol; 22.75 %) as orange solid and tert-butyl 3- [(3R,5S)-3,5-dimethyl-4-(4-nitrophenyl)piperazin-1-yl]azetidine-1-carboxylate (620.0 mg; 1.57 mmol; 55.8 %) as yellow solid.

[0608] LC-MS method E: [M+H]+391.2; Rt: 0.78 min.(2S,6S)-4-(azetidin-3-yl)-2,6-dimethyl-1-(4-nitrophenyl)piperazine hydrochloride

[0609] To a stirred solution of tert-butyl 3-[(3S,5S)-3,5-dimethyl-4-(4- nitrophenyl)piperazin- 1 -yl]azetidine- 1 -carboxylate (250.0 mg; 0.62 mmol; 1.00 eq.) in 4N HC1 in EtOAc (10 mL). The reaction mixture was stirred for 1 h at 25 °C. The mixture wasconcentrated under reduced pressure to afford (2S,6S)-4-(azetidin-3-yl)-2,6-dimethyl-1-(4- nitrophenyl)piperazine hydrochloride (190.0 mg; 0.57 mmol; 92.74 %) as yellow solid.

[0610] LC-MS method E: [M+H]+291 .2; Rt: 0.61 min.5-{3-[(3R,5S)-3,5-dimethyI-4-(4-nitrophenyl)piperazin-1-yl]azetidin-1-yl}-2-(2,6- dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1, 3-dione

[0611] A mixture of (2R,6S)-4-(azetidin-3-yl)-2,6-dimethyl- 1-(4- nitrophenyl)piperazine hydrochloride (470.0 mg; 1.42 mmol; 1.00 eq.), 2-(2,6- dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole- 1,3-dione (539.91 mg; 1.56 mmol;1.10 eq.) and DIEA (966.9 mg; 7.1 1 mmol; 5.00 eq.) in DMF (15 mL) at room temperature. The reaction mixture was stirred at 90 °C for 4 h. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (2: 1) to afford 5-{3-[(3R,5S)-3,5-dimethyl-4-(4- nitrophenyl)piperazin- 1 -yl]azetidin- 1 -yl } -2-(2 ,6-dioxopiperidin-3-yl)-2,3-dihydro-1H- isoindole-1,3-dione (620.0 mg; 1.09 mmol; 76.9 %) as yellow solid.

[0612] LC-MS method E: [M+H]+547.4; Rt: 0.74 min.5-{3-[(3R,5S)-4-(4-aminophenyI)-3,5-dimethylpiperazin-1-yl]azetidin-1-yI}-2-(2,6- dioxopiperidin-3-yI)-2,3-dihydro-1H-isoindole-1, 3-dione

[0613] To a stirred mixture of 5- {3-[(3R,5S)-3,5-dimethyl-4-(4- nitrophenyl)piperazin-1-yl]azetidin-1-yl}-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H- isoindoie- 1,3-dione (620.0 mg; 1.09 mmol; 1.00 eq.) and Tetrahydroxydiboron (307.3 mg;3.26 mmol; 3.00 eq.) in DMF (3 mL) was added 4,4'-bipyridine (17.9 mg; 0.11 mmol; 0.10 eq.) in portions at room temperature. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with DCM / MeOH (1 : 1) to afford 5-{3-[(3R,5S)-4-(4-aminophenyl)-3,5-dimethyIpiperazin-1-yl]azetidin-1-yl}-2-(2,6- dioxopiperidm-3-yl)-2.3-dihydro-1H-isoindole- 1,3-dione (450.0 mg; 0.84 mmol; 77.2 %) as yellow solid.

[0614] LC-MS method E: [M+H]+517.4; Rt: 0.52 min.Intermediate 94 : 3-({4-[4-(azetidin-3-yl)piperazin-1-yI]phenyi}methyl)piperidine-2,6- dione hydrochloride2,6-bis(benzyloxy)-3-[(4-chlorophenyl)methyl]pyridine (PH-MS-PMC046 / 002 / 423)

[0615] A solution of 1 -(bromomethyl)-4-chlorobenzene (2.00 g; 9.25 mmol; 1.00 eq.), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)pyridine Intermediate 8 (4.10 g; 9.33 mmol; 1.01 eq.), Pd(PPh3)4(1.10 g; 0.90 mmol; 0.10 eq.), K2CO3(2.70 g; 18.56 mmol; 2.01 eq.), H2O (5 mL) and 1,4-Dioxane (15 mL) was stirred for 3 h at 100 °C. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (10: 1) to afford 2,6- bis(benzyloxy)-3-[(4-chiorophenyl)methyl]pyridine (4.00 g; 8.90 mmol; 96.2 %) as brown solid.

[0616] LC-MS method U: [M+H]+416.0; Rt: 1 .21 min. tert-butyl 3-[4-(4-{ [2, 6-bis(benzyIoxy)pyridin-3-yl] methyl }phenyl)piperazin-1- yl] azetidine-1-carboxylate

[0617] A solution of 2,6-bis(benzyloxy)-3-[(4-chlorophenyl)methyl]pyridine (4.00 g;8.94 mmol; 1.00 eq.), tert-butyl 3 -(piperazin-1-yl)azetidine-1-c 1a-rboxylate (2.27 g; 8.94 mmol; 1.00 eq.), Pd2(dba)3(862.0 mg; 0.89 mmol; 0.10 eq.), Xphos (898.0 mg; 1.79 mmol;0.20 eq.), CS2CO3(6.13 g; 17.87 mmol; 2.00 eq.) and 1,4-dioxane (40 mL) was stirred for 3 h at 100 °C. The resulting mixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with PE / EtOAc (5:1) to afford tert- butyl 3-[4-(4-{ [2,6-bis(benzyloxy)pyridin-3 -yl]methyl} phenyl)piperazin- 1 -y 1] azetidine- 1 - carboxylate (5.00 g; 7.77 mmol: 86.8 %;) as yellow solid.

[0618] LC-MS method E: [M+H]+621.0; Rt: 0.93 min. tert-butyl 3-(4-{4-[(2,6-dioxopiperidin-3-yl)methyl]phenyl}piperazin-1-yl)azetidine-1- carboxylate

[0619] Starting from tert -butyl 3-[4-(4-{[2,6-bis(benzyloxy)pyridin-3- yl]methyl}phenyl)piperazin-1-yl]azetidine-1-carboxylate (5.00 g; 7.77 mmol; 1.00 eq.) general procedure E for hydrogenation was followed to afford tert-butyl 3-(4- {4-[(2,6- dioxopiperidin-3-yl)methyl]phenyl}piperazin-1-yl)azetidine-1-carboxylate (3.50 g; 7.40 mmol; 95.3 %) as gray solid.

[0620] LC-MS method U: [M+H]+443.0; Rt: 0.95 min.3-({4-[4-(azetidin-3-yl)piperazin-1-yl]phenyI}methyl)piperidine-2, 6-dione hydrochloride

[0621] tert-butyl 3-(4-{4-[(2,6-dioxopiperidin-3-yl)methyl]phenyl}piperazin-1- yl)azetidine-1-carboxylate (3.40 g; 7.19 mmol; 1.00 eq.) and 4N HC1 in EtOAc (34.00 mL; 136.00 mmol; 18.9 eq.) was stirred at room temperature for 2 h under N2atmosphere. A slurry with MTBE was formed. Then the solid was filtered and the filter cake was washed with MTBE (30 mL) and the filter cake was dried under reduced pressure to afford 3-({4-[4- (azetidin-3-yl)piperazin-1-yl]phenyl}methyl)piperidine-2, 6-dione hydrochloride (2.90 g; 7.00 mmol; 97.3 %) as purple solid.

[0622] LC-MS method D: [M+...

Claims

CLAIMSWhat is claimed:

1. A compound of formula I or a prodrug or pharmaceutically acceptable salt thereof,wherein:R1is selected from the group consisting of C1-C6, alkyl, C1-C6haloalkyl, hydrogen, OH, -O-C1-C6alkyl, halogen, -NR’R” and -CN;R’ and R” are independently selected for each occurrence from the group consisting of hydrogen and C1-C6alkyl;R2 is selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, hydrogen and halogen;X’ and Y’ are each independently selected from CH and N with the proviso that at least one of X’ and Y’ is N;C’ is selected from the group consisting ofR.3, R4, R5, R6, R7, R8, R9and R10are each independently selected from the group consisting of C1-C6alkyl, hydrogen and halogen;W is selected from the group consisting of N and CH;Z is selected from the group consisting of CH, CR11and N; R11selected from the group consisting of Ci -Co alkyl and halogen; xx is selected independently for each occurrence from the group consisting of 1, 2, 3 and 4; yy is selected independently for each occurrence from the group consisting of 1, 2, 3 and 4;D is selected from the group consisting ofR12is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6alkyl and C1-C6haloalkyl;R13is hydrogen or C1-C6alkyd;X is selected from the group consisting of -CH2-, -NR14- and -O-; R14is hydrogen or C1-C6alkyl;rr is 1, 2, 3 or 4;Ar is selected from the group consisting ofR15is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6alkyd, -O- C1-C6alkyl and C1-C6haloalkyl;A is either absent or selected from the group consisting of (-CH2-)n, -O-,R16is hydrogen or C1-C6alkyl;R17is hydrogen or C1-C6, alkyl;R18is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6alkyl and C1-C6haloalkyl; n is selected from the group consisting of 0, 1, 2, 3 and 4; q is selected from the group consisting of 0, 1, 2, 3 and 4; r is selected from the group consisting of 0, 1 , 2, 3 and 4 with the proviso that r cannot be 0 when W is N; s is selected from the group consisting of 0, 1, 2, 3 and 4; t is selected from the group consisting of 0, 1, 2, 3 and 4;u is selected from the group consisting of 0, 1 , 2, 3 and 4; v is selected from the group consisting of 0, 1, 2, 3 and 4; w is selected from die group consisting of 0, 1, 2, 3 and 4; x is selected from the group consisting of 0, 1, 2, 3 and 4; y is selected from the group consisting of 0, 1, 2, 3 and 4; z is selected from the group consisting of 0, 1, 2, 3 and 4;B is absent or selected from the group consisting of (-CH2-)oo,R19is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6alkyl and C1-C6haloalkyl; mm is 0, 1, 2, 3, 4, 5 or 6; nn is 0, 1, 2, 3, 4, 5 or 6; oo is 0, 1 , 2, 3 or 4; pp is 0, 1, 2, 3, 4, 5 or 6; qq is 0, 1, 2, 3, 4, 5 or 6; x’ is independently chosen for each occurrence from the group consisting of 1, 2 and 3; and y’ is independently chosen for each occurrence from the group consisting of 1, 2 and3.

2. The compound according to claim 1 wherein X’ and Y’ are N.

3. The compound according to claim 1 wherein X’ is N and Y’ is CH.

4. The compound according to claim 1 wherein X’ is CH and Y’ is N.

5. The compound according to claim 1 wherein R1is selected from the group consisting of hydrogen, -CN, -OCH3, and -CH3,.

6. The compound according to claim 5 wherein R1is -CH3.

7. The compound according to claim 1 wherein R2is selected from the group consisting of hydrogen and -F.

8. The compound according to claim 7 wherein R2is hydrogen.

9. The compound according to claim 1 wherein R3, R5, R6, R7, R9and R10are hydrogen and R4and R8are -CHu10. The compound according to claim 1 wherein R3, R4, R7, R8, R9and R10are hydrogen and R5and R6are -F.

11. The compound according to claim 1 wherein R3, R4, R5, R6, R9and R10are hydrogen and R7and R8are -F.

12. The compound according to claim 1 wherein R3, R4. R5, R6, R7, R8, R9and R10are hydrogen.

13. The compound according to claim 1 wherein xx is 1 and yy is 1.

14. The compound according to claim 1 wherein R11 is selected from hydrogen, -F and -CH3.

15. The compound according to claim 1 wherein R12is independently selected for each occurrence from the group consisting of hydrogen and halogen with the proviso that only one occurrence is halogen.

16. The compound according to claim 15 wherein the halogen is -F.

17. The compound according to claim 1 wherein R12is hydrogen.

18. The compound according to claim 1 wherein R13is hydrogen or -CH3.

19. The compound according to claim 1 wherein R13is -CH3.

20. The compound according to claim 1 wherein X is selected from the group consisting of-CH2-, -NH-, -NCH3- and -O-22. The compound according to claim 1 wherein Ar is22. The compound according to claim 1 wherein Ar is23. The compound according to claim 15 wherein Ar is24. The compound according to claim 23 wherein R15is hydrogen.

25. The compound according to claim 23 wherein R15is halogen.

26. The compound according to claim 25 wherein R15is -F.

27. The compound according to claim 1 wherein A is absent.

28. The compound according to claim 1 wherein A is29. The compound according to claim 1 wherein A is -CH2-.

30. The compound according to claim 1 wherein A is -CH2-CH2-.

31. The compound according to claim 1 wherein A is32. The compound according to claim 1 wherein A is33. The compound according to claim 1 wherein W is N and Z is N.

34. The compound according to claim 1 wherein W is N and Z is CH.

35. The compound according to claim 1 wherein W is CH and Z is N.

36. The compound according to claim 1 wherein D is selected from the group consisting of37. The compound according to claim 36 wherein R12is hydrogen.

38. The compound according to claim 36 wherein R13is hydrogen or CH3.

39. A compound selected from the group consisting of:or a prodrug or pharmaceutically acceptable salt thereof.

40. A pharmaceutical composition comprising a compound of claim 1 or 39 and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

41. A method, comprising: administering to a patient having an HPK1 -mediated disorder a therapeutically effective amount of the compound of claim 1 or 39 or a pharmaceutically acceptable salt thereof.

42. The method of claim 41, wherein the HPK1 -mediated disorder is a cancer.

43. The method of claim 42, wherein the cancer is selected from the group consisting of cancer of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands, esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina, and vulva.

44. The method of claim 41, wherein the therapeutically effective amount of the compound is selected from a range consisting of 0.1 to 100 mg / kg of body weight of the patient, 0.1 to 50 mg / kg of body weight of the patient, 0.5 to 50 mg / kg of body weight of the patient, 1 to 20 mg / kg of body weight of the patient, 5 to 20 mg / kg of body weight of the patient, 10 to 20 mg / kgof body weight of the patient, 10 to 50 mg / kg of body weight of the patient, and 10 to 100 mg / kg of body weight of the patient.

45. The method of claim 41, wherein the compound is administered to the patient continuously, multiple times daily, once daily, once every other day, weekly, bi-weekly, monthly, or bi-monthly.

46. The method of claim 41, wherein the compound is administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir.

47. The method of claim 41, wherein the compound is administered subcutaneously, intravenously, intramuscularly, intra-articularly, intra-synovially, intrasternally, intrathecally, intrahepaticly, intralesionally, and by intracranial injection or infusion technique.

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