(7-{1h,2h,3h-pyrido [2,3-b][1,4]oxazin-7-yl}-5h,6h,7h,8h-pyrido[3,4-d]pyrimidin-2-yl)amine derivatives as bifunctional degraders of HPK1 for the treatment of cancer

Abstract

The present invention relates to compounds of the formula (I) 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.

Description

Attorney Docket No. : P24-187-WO-PCT TITLE OF THE INVENTION TETRAHYDROPYRIDINE COMPOUNDS FOR THE DEGRADATION OF HPK1 BACKGROUND OF THE INVENTION CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 572,714 filed April 1, 2024, which is incorporated by reference herein for all purposes. Field of the Invention

[0001] Tetrahydropyridine compounds 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. 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 (HPK1) 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, HPK1 acts as a rheostat of T cell activation by regulating the molecular circuits of the T cell receptor (TCR) signaling pathway. Upon recruitment of HPK1 to the TCR complex, HPK1 phosphorylates SLP76 protein, which leads to SLP76 degradation and down-modulation of TCR signal strength. Genetic ablation of HPK1 results in T cell activation, lower TCR threshold, increased proliferation, and elevated levels of pro-inflammatory cytokines such as IL- 2, TNF-α, and IFN-γ. Loss of HPK1 expression enhances dendritic cell activation and antigen presentation. (Hernandez et al., Cell Reports, 2018, vol.25, pp.80-94). HPK1 kinase activity is believed to be critical in conferring suppressive functions of HPK1 in a wide range of immune cells, such as CD8+, CD4+, DC, and NK to regulatory T cells (Tregs). Inactivation of the kinase domain of HPK1 was sufficient to elicit robust anti-tumor immune responses (Liu et al., PLoS One, March 26, 2019). HPK1 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 of HPK1 has the potential to enhance effector T cell function and antitumor activity. Furthermore, HPK1 is believed to possess a -1-Attorney Docket No. : P24-187-WO-PCT 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-3-51015202530 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 E1s (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 ubiquitination 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:e1487) 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 Sci 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 -2-Attorney Docket No. : P24-187-WO-PCT - 51015202530 thalidomide derivatives 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: R1 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, 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; R2 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, 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 of -3-Attorney Docket No. : P24-187-WO-PCTR3, R4, R5, R6, R7, R8, R9 and R10 are each independently selected from the group consisting of C1-C6alkyl, hydrogen and halogen; or R8and R9maybe taken together with the carbons to which they are attached to form a 3, 4, 5 or 6 membered carbocycle; or R7 and R10 maybe taken together with the carbons to which they are attached to form a 3, 4, 5 or 6 membered carbocycle; 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 -4-Attorney Docket No. : P24-187-WO-PCT D is selected from the group consisting of-5-Attorney Docket No. : P24-187-WO-PCT-6-Attorney Docket No. : P24-187-WO-PCTR12is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6alkyl and C1-C6haloalkyl; R13 is hydrogen or C1-C6 alkyl; X is selected from the group consisting of -CH2-, -NR14- and -O-; R14is hydrogen or C1-C6alkyl; qq 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-C6 alkyl and C1-C6 haloalkyl; -7-Attorney Docket No. : P24-187-WO-PCT A is either absent or selected from the group consisting of (-CH2-)n, -O-, ,R16 is hydrogen or C1-C6 alkyl; R17is hydrogen or C1-C6alkyl; R18 is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6 alkyl and C1-C6 haloalkyl; 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; -8-Attorney Docket No. : P24-187-WO-PCT 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,-9-Attorney Docket No. : P24-187-WO-PCT-10-Attorney Docket No. : P24-187-WO-PCT-11-Attorney Docket No. : P24-187-WO-PCT R19 is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6 alkyl and C1-C6 haloalkyl; mm is 0, 1, 2, 3 or 4; nn is 0, 1, 2, 3 or 4; oo is 0, 1, 2, 3 or 4;

[0007] 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.

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

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

[0010] In an embodiment a compound of Formula I wherein X’ is CH and Y’ is N is provided.

[0011] In an embodiment a compound of Formula I wherein R1 is selected from the group consisting of hydrogen, -CN, -OCH3and -CH3is provided.

[0012] In an embodiment a compound of Formula I wherein R1is -CH3is provided.

[0013] In an embodiment a compound of Formula I wherein R2is selected from the group consisting of hydrogen and -F is provided.

[0014] In an embodiment a compound of Formula I wherein R2 is hydrogen is provided.

[0015] In an embodiment a compound of Formula I wherein R3, R5, R6, R7, R9and R10 are hydrogen and R4 and R8 are -CH3 is provided.

[0016] In an embodiment a compound of Formula I wherein R3, R4, R7, R8, R9 and R10are hydrogen and R5and R6are -F is provided.

[0017] In an embodiment a compound of Formula I wherein R3, R4, R5, R6, R9 and R10 are hydrogen and R7 and R8 are -F is provided.

[0018] In an embodiment a compound of Formula I wherein R3, R4, R5, R6, R7, R8, R9and R10are hydrogen is provided.

[0019] In an embodiment a compound of Formula I wherein xx is 1 and yy is 1 is provided.

[0020] In an embodiment a compound of Formula I wherein R11is selected from hydrogen, -F and -CH3 is provided. -12-Attorney Docket No. : P24-187-WO-PCT

[0021] In an embodiment a compound of Formula I wherein R12 is 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 R12 is -F. Preferably R12 is hydrogen.

[0022] In an embodiment a compound of Formula I wherein R13 is hydrogen or -CH3is provided. Preferably R13is -CH3.

[0023] In an embodiment a compound of Formula I wherein X is selected from the group consisting of. -CH2-, -NH-, -NCH3- and -O- is provided.

[0024] In an embodiment a compound of Formula I wherein Ar isprovided.

[0025] In an embodiment a compound of Formula I wherein Ar isprovided.

[0026] In an embodiment a compound of Formula I wherein Ar isprovided.

[0027] In an embodiment a compound of Formula I wherein R15is hydrogen is provided.

[0028] In an embodiment a compound of Formula I wherein R15is halogen is provided. Preferably R15is -F.

[0029] In an embodiment a compound of Formula I wherein A is absent is provided.

[0030] In an embodiment a compound of Formula I wherein A is -13-Attorney Docket No. : P24-187-WO-PCT

[0031] In an embodiment a compound of Formula I wherein A is -CH2- is provided.

[0032] In an embodiment a compound of Formula I wherein A is -CH2-CH2- is provided.

[0033] In an embodiment a compound of Formula I wherein A is

[0035] In an embodiment a compound of Formula I wherein W is N and Z is N is provided.

[0036] In an embodiment a compound of Formula I wherein W is N and Z is CH is provided.

[0037] In an embodiment a compound of Formula I wherein W is CH and Z is N is provided.

[0038] In an embodiment a compound of Formula I wherein D is selected from the group consisting of -14-Attorney Docket No. : P24-187-WO-PCT-15-Attorney Docket No. : P24-187-WO-PCT-16-Attorney Docket No. : P24-187-WO-PCTPreferably R12is hydrogen. Preferably R13is hydrogen or CH3.

[0039] In an embodiment a compound selected from the group consisting of-17-Attorney Docket No. : P24-187-WO-PCT-18-Attorney Docket No. : P24-187-WO-PCT O-19-Attorney Docket No. : P24-187-WO-PCT-20-Attorney Docket No. : P24-187-WO-PCT-21-Attorney Docket No. : P24-187-WO-PCT-22-Attorney Docket No. : P24-187-WO-PCT-23-Attorney Docket No. : P24-187-WO-PCT H N-24-Attorney Docket No. : P24-187-WO-PCT-25-Attorney Docket No. : P24-187-WO-PCTNH O HN O N N O N N N N N N O N N H O NH O N N N N H N N O N N H O N -26-Attorney Docket No. : P24-187-WO-PCT-27-Attorney Docket No. : P24-187-WO-PCT-28-Attorney Docket No. : P24-187-WO-PCT-29-Attorney Docket No. : P24-187-WO-PCT-30-Attorney Docket No. : P24-187-WO-PCT-31-Attorney Docket No. : P24-187-WO-PCT O N-32-Attorney Docket No. : P24-187-WO-PCT-33-Attorney Docket No. : P24-187-WO-PCT-34-Attorney Docket No. : P24-187-WO-PCT-35-Attorney Docket No. : P24-187-WO-PCT-36-Attorney Docket No. : P24-187-WO-PCT-37-Attorney Docket No. : P24-187-WO-PCT-38-Attorney Docket No. : P24-187-WO-PCT-39-Attorney Docket No. : P24-187-WO-PCTor a prodrug or pharmaceutically acceptable salt thereof is provided. In an embodiment a compound selected from Table 3 or a prodrug or pharmaceutically acceptable salt thereof is provided. -40-Attorney Docket No. : P24-187-WO-PCT

[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, ovary, 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 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. -41-Attorney Docket No. : P24-187-WO-PCT

[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 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 / kg of 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.

[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 -42-Attorney Docket No. : P24-187-WO-PCT 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 thereof,wherein: R1 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, 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 of -43-Attorney Docket No. : P24-187-WO-PCTR3, R4, R5, R6, R7, R8, R9 and R10 are each independently selected from the group consisting of C1-C6alkyl, hydrogen and halogen; or R8and R9maybe taken together with the carbons to which they are attached to form a 3, 4, 5 or 6 membered carbocycle; or R7 and R10 maybe taken together with the carbons to which they are attached to form a 3, 4, 5 or 6 membered carbocycle; 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 of -44-Attorney Docket No. : P24-187-WO-PCT-45-Attorney Docket No. : P24-187-WO-PCT-46-Attorney Docket No. : P24-187-WO-PCTR12is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6alkyl and C1-C6haloalkyl; R13 is hydrogen or C1-C6 alkyl; X is selected from the group consisting of -CH2-, -NR14- and -O-; R14 is hydrogen or C1-C6 alkyl; qq is 1, 2, 3 or 4; Ar is selected from the group consisting of-47-Attorney Docket No. : P24-187-WO-PCT R15 is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6 alkyl and C1-C6 haloalkyl; A is either absent or selected from the group consisting of (-CH2-)n, -R16 is hydrogen or C1-C6 alkyl; R17 is hydrogen or C1-C6 alkyl; -48-Attorney Docket No. : P24-187-WO-PCT R18 is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6 alkyl and C1-C6 haloalkyl; 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,-49-Attorney Docket No. : P24-187-WO-PCT-50-Attorney Docket No. : P24-187-WO-PCT-51-Attorney Docket No. : P24-187-WO-PCTR19is 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 or 4; nn is 0, 1, 2, 3 or 4; oo is 0, 1, 2, 3 or 4; 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] The singular forms “a”, “an”, and “the” may include the plural forms as well unless the context clearly indicates otherwise.

[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-C6alkyl, NH2, NHR’, NR’R’’, halo C1-C6alkyl, -O-C1-C6alkyl, -OH, halogen, (=O), and -OH. R’ and R’’ are independently selected for each occurrence from the group consisting of C1-C6 alkyl and H.

[0061] A sigma bond may refer to a covalent bond formed by overlap between atomic orbitals. It is symmetrical regarding rotation about the bond axis.

[0062] 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 -52-Attorney Docket No. : P24-187-WO-PCT 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-C6alkyl, NH2, NHR’, NR’R’’, C1-C6haloalkyl, -O-C1-C6alkyl, -OH, halogen, (=O), and -OH. R’ and R’’ are independently selected for each occurrence from the group consisting of C1-C6alkyl and H.

[0063] 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.

[0064] 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 aryl 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- C6 haloalkyl, -O-C1-C6 alkyl, halogen, (=O) and -OH. R’ and R’’ are independently -53-Attorney Docket No. : P24-187-WO-PCT selected for each occurrence from the group consisting of C1-C6 alkyl and H.

[0065] 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, secondary syphilis, 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.

[0066] 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 -54-Attorney Docket No. : P24-187-WO-PCT maximum therapeutic effect (Cmax) and area under the dose response curve (AUC).

[0067] In various embodiments, compounds of formula I and related formulae, exhibit an IC50for inhibiting HPK1 of less than about 1000 nM, 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 IC50 for 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.

[0068] 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.

[0069] A medicament is provided herein that can include at least one compound disclosed herein or a prodrug or pharmaceutically acceptable salt thereof including mixtures thereof 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 at least temporarily.

[0070] 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. In 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 -55-Attorney Docket No. : P24-187-WO-PCT 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.

[0071] 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, picoplatin, and the like; alkylating agents such as altretamine, carmustine, chlorambucil, mitobronitol, 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.

[0072] 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.

[0073] 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 -56-Attorney Docket No. : P24-187-WO-PCT susceptibility factors). Treatment is also continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0074] 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

[0075] 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.

[0076] 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.

[0077] Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade).

[0078] 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).

[0079] 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 -57-Attorney Docket No. : P24-187-WO-PCT 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).

[0080] LC-MS analyses were performed one either one of the two following instruments: 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.

[0081] 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).

[0082] HPLC data were either obtained from the SHIMAZU LC-MS machine or using Agilent 1100 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.

[0083] In general, the compounds according to formula I and related formulae described herein can be prepared from readily available 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 -58-Attorney Docket No. : P24-187-WO-PCT 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. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents 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. Methods: LC-MS: Method A: HALO C182 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: 5 % B – 95 % B in 1.5 min. Method B: HALO C182 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 C: HALO C182 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 C182 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 2.0 min. Method E: Shim‐Pack C183 µm 3.0 – 33 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 5 mM NH4HCO3; buffer B: acetonitrile; gradient 10% B – 95% B in 1.9 min. -59-Attorney Docket No. : P24-187-WO-PCT Method F: HALO C182 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 2.0 min. Method G: Shim‐Pack C183 µm 3.0 – 33 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 5 mM NH4HCO3; buffer B: acetonitrile; gradient 10% B – 95% B in 1.5 min. Method H: HALO C182 µm 3.0-30 mm; flow: 1.2 mL / min; T: 40 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 5 % B – 100 % B in 2.0 min. Method I: HALO C182 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 J: HALO C182 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 1.2 min. Method K: HALO C182 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 3.0 min. Method L: HALO C182 µm 3.0-30 mm; flow: 1.2 mL / min; T: 40 °C; buffer A: water + 0.1 % FA; buffer B: Acetonitrile + 0.1 % FA; gradient: 5 % B – 95 % B in 3.0 min. Method M: HALO C182 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 N: HALO C182 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 O: HALO C182 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 2.0 min. Method P: HALO C182 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. -60-Attorney Docket No. : P24-187-WO-PCT Method Q: HPH C183 µm 3.0 – 50 mm; flow: 1.2 mL / min; T: 40 °C; buffer A: water + 6.5 mM NH4HCO3 + NH4OH (pH = 10); buffer B: acetonitrile; gradient 10% B – 95% B in 3.0 min. Method R: HALO C182 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 S: Cortecs T32.7 μm 30-4.6 mm; flow: 3.3 mL / min; T: 45 °C; buffer: A: H2O + 0.05% HCOOH | B: MeCN + 0.04% HCOOH; gradient: 1% -> 99% B: 0 -> 0,8 min | 99% B: 0,8 -> 1,05 min Method T: Chromolith SpeedRod RP-18e 5.0 μm 50-4.6 mm; flow: 3.3 mL / min; T: 40 °C; buffer: A: H2O + 0.1% TFA | B: MeCN + 0,1% TFA; gradient: 1% -> 99% B: 0 -> 2.0 min | 99% B: 2,0 -> 2,5 min Method U: Chromolith HR RP-18e 50-4,6 mm; flow: 3.3 mL / min; T: 45 °C; buffer: A: H2O + 0.05% HCOOH | B: MeCN + 0.04% HCOOH; gradient: 1% -> 99% B: 0 - > 2.0 min | 99% B: 2.0 -> 2.5 min Method V: Kinetex EVO C18 50-4.6 mm; flow: 3.3 mL / min; T: 40 °C; buffer: A: H2O + 0.05% HCOOH | B: MeCN + 0.04% HCOOH + 1%H2O; gradient: 0% -> 100% B: 0 -> 1.8 min |100% B: 1.8 -> 2.1 min Method W: HALO C182 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 X: HALO C182 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 Y: Shim-Pack C183.0 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 3.0 min. Method Z: Chromolith SpeedRod (RP-18e, 50-4,6mm) + Chromolith Guard (RP- 18e, 5-4,6mm); flow: 2.0 mL / min; buffer A: 100 % water + 0,1 % TFA; buffer B: 100 % ACN + 0,1 % TFA in 9.5 min Method AA: Cortecs T31.6 µm 2.1-50 mm; flow: 0.9 mL / min; T: 45 °C; buffer A: water + 0.05 % HCOOH; buffer B: Acetonitrile + 0.04 % HCOOH; gradient: 2 % B – 99 % B in 2.0 min; 99%B from 2.0 – 2.31 min. -61-Attorney Docket No. : P24-187-WO-PCT Method AB: Cortecs T32.7 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 AC: HALO C182 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 AD: Kinetex XB-C181.7 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: HPH C183 µm 3.0 – 50 mm; flow: 1.2 mL / min; T: 40 °C; buffer A: water + 6.5 mM NH4HCO3 + NH4OH (pH = 10); buffer B: acetonitrile; gradient 10% B – 95% B in 1.9 min. Method AF: Kinetex XB-C181.7 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 2.0 min. Method AG: 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 AH: 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 2.0 min. Method AI: HALO C182 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 2.0 min. Method AJ: Kinetex EV O -C 181 ,7 μm 50-2 ,1 mm; Flow: 0 ,9 mL / min; T : 40 °C, buffer A : H2O + 0 ,05% FA; buffer B: MeC N + 0,04% FA; gradient 1% -> 99% B: 0 -> 1 ,0 min | 99% B: 1 ,0 -> 1,3 min Method AK: Shim‐Pack C183 µm 3.0 – 33 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: Water + 0.05% TFA; buffer B: Acetonitrile + 0.05% TFA; gradient: 5 % B – 95 % B in 1.5 min. Method AL: SunFire C185,0 μm 100-3 mm; flow: 1,4 mL / 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 min -62-Attorney Docket No. : P24-187-WO-PCT Method AM: HALO C182µm 2.0mm-30mm; flow: 1.5mL / min; T:40°C; buffer A: H2O +0,05%TFA; Buffer B: Acetonitrile +0,05% TFA; gradient: 5%B -95%B in 1.0min 100%B for 0.4min Method AN: HALO C182.7 µm 100-4.6 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.05 % TFA; buffer B: Acetonitrile + 0.05 % TFA; gradient: 10 % B – 95 % B in 12 min Method AO: Cortecs T32.7 µm 75-4,6 mm; flow: 2.8 mL / min; T: 45 °C; buffer A: water + 0.05 % TFA; buffer B: Acetonitrile + 0.05 % TFA; gradient: 1 % B – 99 % B in 3.2 min; 99% B from 3.2 – 4.0 min. Method AP: Shim‐Pack C183 µm 3.0 – 33 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 5 mM NH4HCO3; buffer B: acetonitrile; gradient 10% B – 95% B in 1.2 min. Method AQ: Shim‐Pack C183 µm 3.0 – 33 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: 6.5 mM NH4HCO3 + NH4OH; buffer B: acetonitrile; gradient 10% B – 95% B in 2.0 min. Method AR: Shim‐Pack C183 µm 3.0 – 33 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 5 mM NH4HCO3; buffer B: acetonitrile; gradient 10% B – 95% B in 2.0 min. Method AS: HALO C182 µm 3.0-30 mm; flow: 1.5 mL / min; T: 40 °C; buffer A: water + 0.05 % TFA; buffer B: Acetonitrile + 0.05 % TFA; gradient: 5 % B – 95 % B in 3.0 min. Method AT: Cortecs C182.7 μm 30-2.1 mm; flow: 1.2 mL / min; T: 40 °C; buffer: A: H2O + 0.05% TFA| B: MeCN + 0.05% TFA; gradient: gradient: 5 % B – 95 % B in 3.0 min. Method AU: HALO C182 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 1.5 min. Method AV: Shim‐Pack C183 µm 3.0 – 33 mm; flow: 1.2 mL / min; T: 40 °C; buffer A: Water + 0.05% TFA; buffer B: Acetonitrile + 0.05% TFA; gradient: 5 % B – 95 % B in 1.5 min. Method AW: HALO C182 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 – 40 % B in 1.8 min; 40% - 95 % B in 1.2 min. -63-Attorney Docket No. : P24-187-WO-PCT Method AX: Waters Acquity BEHC81.7µm; 2.1-50mm; gradient water + CHOOH (0.1%) B acetonitrile + CHOOH (0.1%) gradient: 10 % B – 90 % B in 2 min; Method AY: 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 – 100 % B in 1.5 min. Method AZ: Cortecs C182.7 μm 30-2.1 mm; flow: 1.2 mL / min; T: 40 °C; buffer: A: H2O + 0.05% TFA| B: MeCN + 0.05% TFA; gradient: gradient: 5 % B – 100 % B in 1.80 min Method BA: Shim-pack XR-ODS 2.2 μm 50-3.0 mm; flow: 1.2 mL / min; T: 40 °C; buffer: A: H2O + 0.05% TFA| B: MeCN + 0.05% TFA; gradient: gradient: 5 % B – 100 % B in 1.35 min General procedure A for Boc deprotection The Boc protected compound (1.0 eq.) was dissolved in 2,2,2-trifluoroethanol (0.01 – 0.09 M) and the reaction mixture was heated at 120 - 130 ⁰C for 3 - 16 h under nitrogen atmosphere. It was concentrated under reduced pressure or a work-up was done with EtOAc and brine. It was then directly purified by silica gel column chromatography or prep HPLC to obtain the desired product in pure form. General procedure B for Boc deprotection or tert-butyl ester hydrolysis The Boc protected amine or aniline (1.0 eq.) was dissolved in DCM (0.01 – 0.62 M) or MeOH (0.04 – 4.3 M) and TFA (8.9 – 198.0 eq) was slowly added at room temperature. The reaction mixture was stirred for 15 min – 20 h at room temperature (at 40 ⁰C for the tert-butyl hydrolysis). It was then concentrated under reduced pressure, or a work-up with EtOAc or DCM and brine was performed (after adjusting the pH value of the water phase with NaHCO3 to 8). If required, the residue was purified by silica gel column chromatography or prep HPLC to afford the desired product in pure form. In some cases, the reaction mixture was filtered and the filter cake washed with tert-butyl methyl ether. The filtrate was then concentrated under reduced pressure and the residue used in the next step without further purification. General procedure C for Boc deprotection The Boc protected amine or aniline (1.0 eq.) was dissolved in 4M HCl in dioxane (19.4 - 50.0 eq.) or 4M HCl in EtOAc (60.9 eq.) or 4M HCl in MeOH (235.3 eq.). The reaction mixture was stirred at room temperature for 1 – 3 h. The reaction mixture was concentrated under reduced pressure and used without further purification (or -64-Attorney Docket No. : P24-187-WO-PCT purified by prep-HPLC). Alternatively, the reaction mixture was diluted with water and extracted with EtOAc three times and then with 5% NaHCO3 solution. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. General procedure D for Boc deprotection The Boc protected amine or aniline (1.0 eq.) was dissolved in 1,1,1,3,3,3- hexafluoropropan-2-ol (0.06 M). The reaction mixture was stirred at 100 ⁰C for 6h. The reaction mixture was concentrated under reduced pressure and directly purified by prep-HPLC. General procedure E for Buchwald coupling 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 ⁰C. The reaction mixture was then concentrated under reduced pressure, or a work up was done with water and EtOAc. The residue was then directly purified by silica gel column chromatography to afford the coupled product in pure form. General procedure F for Buchwald coupling To a mixture of the haryl halide (1.0 – 1.2 eq) and the desired amine (1.0 – 2.9 eq.) in dioxane (0.03 – 0.25 M) or DMF (0.10 - 0.15 M), Pd-PEPPSI-IPentCl 2- methylpyridine (o-picoline) (0.03 – 0.1 eq.) and Cs2CO3 (1.5 – 3.0 eq.) were added at room temperature. The mixture was stirred for 2- 18 h at 95 - 110 ⁰C under argon atmosphere. The resulting mixture was concentrated under reduced pressure or a work up was performed with EtOAc and brine. The residue was then purified by prep- HPLC or silica gel column chromatography to afford the desired product. General procedure G for reduction under hydrogen The desired nitro or phenyl protected compound (1.0 eq) was dissolved in dioxane (0.06 M), THF (0.10 M), MeOH (0.02 M), EtOH (0.2 M), DMF (0.10 - 0.15 M), or EtOH:EtOAc 1:1 mixture (0.08 M) and Pd / C (0.2 – 4.0 eq.) was then added. The reaction mixture was stirred at room temperature or 50 °C for 1 - 12h. The reaction mixture was filtered over celite to and concentrated under reduced pressure to afford the desired product. In some cases, the obtained residue was purified by flash column chromatography. General procedure H for amide coupling -65-Attorney Docket No. : P24-187-WO-PCT The desired carboxylic acid (1.0 – 1.2 eq) was dissolved in DMF (0.03 – 0.18 M) and Et3N or DIEA (2.0 – 5.0 eq.) and HATU (1.2 – 3.0 eq.) were added. The desired amine (1.0 – 3.5 eq.) was then added in portions at room temperature. The reaction mixture was stirred at room temperature for 30 min – 20 h. The resulting mixture was then 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 to afford the desired amides. Alternatively, the reaction mixture was diluted with water and the formed precipitate was filtered. In some cases, the reaction mixture was concentrated and directly purified by flash column chromatography. The amides were purified by flash column chromatography or prep-HPLC if required. General procedure I for nucleophilic aromatic substitution To a solution of the corresponding aryl halide (0.6 - 1.1 eq.) and the desired amine (1.0 - 1.2 eq.) in DMSO (0.03 - 0.90 M) or DMF (0.15 – 2.5 M), DIEA (3.0 – 5.0 eq.), K2CO3 (4.0 eq.) or Cs2CO3 (2.0 – 2.5 eq.) was added. The resulting mixture was stirred for 2 - 5h at 100 - 120 ⁰C under nitrogen atmosphere (DMSO) or for 2h at 90 ⁰C (DMF). The reaction mixture was diluted with water and 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 prep-HPLC or flash column chromatography to afford the desired products in pure form. Alternatively, the reaction mixture was directly concentrated under reduced pressure and the obtained residue was washed with MeOH. The filtrate was then concentrated to afford the desired product. In reactions with DMF, water can also be added to the reaction mixture, and the precipitated solid is then filtered. General procedure J for amide coupling To a solution of the desired amine (1.0 – 1.5 eq.) and the acid (1.0 – 1.2 eq.) in DMF (0.04 – 0.12 M), TCFH (1.2 - 1.7 eq.) and NMI (3.0 – 6.0 eq.) or DMI (3.0 – 6.0 eq.) were added. The reaction mixture was stirred at room temperature or 40 ⁰C for 1 h – 5 days. It 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 or prep HPLC to afford the desired amides in pure form. Alternatively, the reaction mixture was diluted with water and the form solid was filtered and dried under vacuum. -66-Attorney Docket No. : P24-187-WO-PCT General procedure K for reductive amination To a solution of the desired amine (1.0 – 1.1 eq.) and aldehyde (1.0 - 1.5 eq.) in DCE (0.05 M) or DCM (0.49 M) sodium triacetoxyborohydride (2.0 eq.) was added. In same cases, DIEA was also added (10.0 eq.) The reaction mixture was stirred at room temperature for 2-12 h. The formed precipitates were filtered off and discarded. The organic phase was concentrated and used in the next step without further purification. In same cases, the reaction mixture was basified to pH 8 by the addition of NaHCO3and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography. General procedure L for reduction with iron and ammonium chloride 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 ⁰C 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 M for Cbz deprotection A mixture of the Cbz containing compound (1.0 eq.) and Pd / C (0.2 eq.) in EtOH (0.02 – 0.05 M) equipped with a condenser was filled in with argon three times. A solution of 1,4-cyclohexadiene (10.0 eq.) in EtOH (0.84 M) was added and the reaction mixture was heated to 100 ⁰C for 3 hours. The formed precipitate was filtered off over a pad of celite and washed with MeOH. The MeOH was then concentrated and dried under vacuum to afford the desired deprotected amines. General procedure N for nitro reduction 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 Suzuki coupling -67-Attorney Docket No. : P24-187-WO-PCT To a stirred solution of the corresponding boronic ester (1.6 eq.) and aryl halide (1.0 eq.) in dioxane:H2O mixture 6:1 (0.16 M) were added Pd(dppf)Cl2DCM (0.1 eq.) and K2CO3(2.7 eq.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 12 h at 110 ⁰C. 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 the desired coupled products in pure form. General procedure P for Buchwald coupling To a mixture of the aryl halide (1.0 – 1.2 eq) and the desired amine (1.0 – 2.9 eq.) in dioxane (0.03 – 0.25 M) or DMF (0.10 - 0.15 M), EPhos (0.1 - 0.2 eq.), EPhos Pd G4 (0.1 eq.) and Cs2CO3 (1.5 – 3.0 eq.) or NaOtBu (1.5 – 3.0 eq.) were added at room temperature. The mixture was stirred for 2- 16 h at 90 - 105 ⁰C under argon atmosphere. The resulting mixture was concentrated under reduced pressure or a work up was performed with EtOAc and brine. The residue was then purified by prep- HPLC or silica gel column chromatography to afford the desired product. Intermediate 1 tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazine-1-carboxylate7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine (1150 g; 5.02 mol; 1.0 eq.) was suspended in 2-methyltetrahydrofuran (10.0 L). DIEA (1707 mL; 10.04 mol; 2.0 eq.) and 4-(dimethylamino)pyridine (45.0 g; 0.37 mol; 0.1 eq.) were added. The mixture was stirred and di-tert-butyl dicarbonate (1.720 g; 7.88 mol; 1.6 eq.) was added via a dropping funnel over 30 min. The reaction mixture was stirred for 2 h at 70 °C. The reaction mixture was cooled to room temperature and concentrated to dryness under vacuo. The residue (brown oil) was solved in tert-butylmethylether (15.0 L) washed 3 times with 5 L water, once with 5 L citric acid solution (10 %) and once with 5 L brine. The brown solution was dried over sodium sulfate (1.0 kg). The filtrate was evaporated to a thick suspension and 3 L of heptane were added. It was stored overnight in the fridge (0 °C) and the formed solid was collected by vacuum -68-Attorney Docket No. : P24-187-WO-PCT filtration, washed with 2 L heptane and dried at 2 mbar at 40 °C. Since the mother liqueur contained product it was reduced to dryness under vacuo, 200 mL heptane were added and the mixture was stirred for 3 h. The solid was filtered off and dried under vacuo to obtain a total of 1513 g (4.54 mol; 91 % yield) as a beige powder. LC MS Method Z: Rt: 4.52 min1H NMR (500 MHz, DMSO-d6): 8.13 (s, 1H), 4.53 (br, 1H), 4.31 (br, 1H), 4.19 (br, 1H), 3.16 (br, 1H), 2.19 (s, 3H), 1.43 (s, 9H). Intermediate 2: 2-{4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl)amino]phenyl}acetic acid2-{4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin- 7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}acetic acid To a stirred solution of tert-butyl 7-(2-{[4-(2-methoxy-2-oxoethyl)phenyl]amino}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazine-1-carboxylate (510.0 mg; 0.84 mmol; 1.00 eq.) in THF (4.0 mL), H2O (4.00 mL) and MeOH (2.00 mL), NaOH (142.0 mg; 3.37 mmol; 4.00 eq.) was added in portions at room temperature. The mixture was stirred for 3 h at 50 ⁰C. The reaction mixture was concentrated under reduced pressure, water was added to the residue and the pH was adjusted to pH 6-7 by the addition of concentrated HCl. The formed solid was collected by filtration, washed with water and dried under vacuum to afford 2-{4- [(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}acetic acid as a yellow solid (400.0 mg, 0.73 mmol; 87 %). LC-MS method A: [M+H]+533.3; Rt: 0.92 min -69-Attorney Docket No. : P24-187-WO-PCT tert-butyl 7-(2-{[4-(2-methoxy-2-oxoethyl)phenyl]amino}-5H,6H,7H,8H- pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1- carboxylate Starting from tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1- carboxylate (4.20 g; 12.76 mmol; 1.10 eq.) general procedure F for Buchwald coupling was followed to obtain tert-butyl 7-(2-{[4-(2-methoxy-2- oxoethyl)phenyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl- 1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (4.31 g; 5.97 mmol; 52 %) as a yellow oil. LC-MS method A: [M+H]+547.4; Rt: 1.02 min methyl 2-[4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)phenyl]acetate Starting from tert-butyl 2-{[4-(2-methoxy-2-oxoethyl)phenyl]amino}-5H,6H,7H,8H- pyrido[3,4-d]pyrimidine-7-carboxylate (5.18 g; 13.00 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford methyl 2-[4- ({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)phenyl]acetate (3.10 g; 10.22 mmol; 79 %) as a pink solid. LC-MS method B: [M+H]+299.2; Rt: 0.49 min tert-butyl 2-{[4-(2-methoxy-2-oxoethyl)phenyl]amino}-5H,6H,7H,8H-pyrido[3,4- d]pyrimidine-7-carboxylate Starting from tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7- carboxylate (5.00 g; 18.06 mmol; 1.0 eq.) and methyl 2-(4-aminophenyl)acetate (3-69 g; 21.7 mmol; 1.20 eq.) general procedure E for Buchwald coupling was followed to afford tert-butyl 2-{[4-(2-methoxy-2-oxoethyl)phenyl]amino}-5H,6H,7H,8H- pyrido[3,4-d]pyrimidine-7-carboxylate was obtained as a yellow solid (5.28 g; 12.71 mmol; 70 %). LC-MS method B: [M+H]+399.2; Rt: 0.73 min Intermediate 3: 1-(azetidin-3-yl)-4-(4-nitrophenyl)piperazine; trifluoroacetic acid -70-Attorney Docket No. : P24-187-WO-PCTtert-butyl 3-[4-(4-nitrophenyl)piperazin-1-yl]azetidine-1-carboxylate To a stirred mixture of 1-fluoro-4-nitrobenzene (11.58 g; 77.94 mmol; 1.10 eq.) and tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (18.00 g; 70.86 mmol; 1.00 eq.) in DMF (200 mL) was added K2CO3 (15.46 g; 106.29 mmol; 1.50 eq.) in portions at room temperature. The resulting mixture was stirred overnight at 80 ⁰C under nitrogen atmosphere. The resulting mixture was cooled down to room temperature and poured into water. The precipitated solid was collected by filtration to afford tert-butyl 3-[4- (4-nitrophenyl)piperazin-1-yl]azetidine-1-carboxylate as a yellow solid (25.0 g; 52.96 mmol; 75 %). LC-MS method C: [M+H]+363.1; Rt: 0.65 min 1-(azetidin-3-yl)-4-(4-nitrophenyl)piperazine; trifluoroacetic acid To tert-butyl 3-[4-(4-nitrophenyl)piperazin-1-yl]azetidine-1-carboxylate (25.00 g; 64.94 mmol; 1.00 eq.) in DCM (0.81 M) was added TFA (80.0 mL) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature. The reaction mixture was poured into ice-cold MTBE and the precipitated solid was collected by filtration to afford 1-(azetidin-3-yl)-4-(4-nitrophenyl)piperazine; trifluoroacetic acid (24.0 g; 63.77 mmol; 98 %) as a yellow solid. LC-MS method A: [M+H]+263.2; Rt: 0.51 min Intermediate 4: 3-[1-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-isoindol-2- yl]piperidine-2,6-dione hydrochloridetert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5- yl]piperazine-1-carboxylate -71-Attorney Docket No. : P24-187-WO-PCT Starting from 3-(5-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (5.00 g; 14.70 mmol; 1.00 eq.) and tert-butyl piperazine-1-carboxylate (3.46 g; 17.6 mmol; 1.20 eq.) general procedure F for Buchwald coupling to afford tert-butyl 4-[2- (2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-yl]piperazine-1- carboxylate (4.80 g; 11.04 mmol; 75 %) as an off-white solid. LC-MS method C: [M+H]+429.2; Rt: 0.79 min 3-[1-oxo-5-(piperazin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione hydrochloride Starting from tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H- isoindol-5-yl]piperazine-1-carboxylate (3.70 g; 8.26 mmol; 1.00 eq.) general procedure C for Boc deprotection was followed to afford 3-[1-oxo-5-(piperazin-1-yl)- 2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione hydrochloride (3.0 g; 8.18 mmol; 99.0 %) as a white solid. LC-MS method C: [M+H]+329.1; Rt: 0.44 min Intermediate 5: 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)-2,3-dihydro-1H- isoindole-1,3-dionetert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5- yl]piperazine-1-carboxylate Starting from 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3- dione (10.0 g; 35.82 mmol; 1.00 eq.)and tert-butyl piperazine-1-carboxylate (8.10 g; 42.98 mmol; 1.20 eq.) general procedure I for nucleophilic aromatic substitution was followed to afford tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro- 1H-isoindol-5-yl]piperazine-1-carboxylate (15.0 g; 33.90 mmol; 95 %) as a yellow solid. LC-MS method A: [M+H-tBu]+387.2; Rt: 0.83 min 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)-2,3-dihydro-1H-isoindole-1,3-dione -72-Attorney Docket No. : P24-187-WO-PCT Starting from tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H- isoindol-5-yl]piperazine-1-carboxylate (7.00 g; 15.03 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 2-(2,6-dioxopiperidin-3-yl)- 5-(piperazin-1-yl)-2,3-dihydro-1H-isoindole-1,3-dione (5.00 g; 14.46 mmol; 96.0 %) as a yellow solid. LC-MS method R: [M+H]+343.2; Rt: 0.44 min Intermediate 6: 2-(2,6-dioxopiperidin-3-yl)-5-[3-(piperazin-1-yl)azetidin-1-yl]- 2,3-dihydro-1H-isoindole-1,3-dionetert-butyl 4-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5- yl]azetidin-3-yl}piperazine-1-carboxylate Starting from 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3- dione (1.10 g; 3.94 mmol; 1.00 eq) and tert-butyl 4-(azetidin-3-yl)piperazine-1- carboxylate (1.00 g; 3.94 mmol; 1.00 eq.) general procedure I for nucleophilic aromatic substitution was followed to afford tert-butyl 4-{1-[2-(2,6-dioxopiperidin-3- yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]azetidin-3-yl}piperazine-1-carboxylate (1.80 g; 3.62 mmol; 92 %). LC-MS method G: [M+H-Boc]+398.2; Rt: 0.96 min 2-(2,6-dioxopiperidin-3-yl)-5-[3-(piperazin-1-yl)azetidin-1-yl]-2,3-dihydro-1H- isoindole-1,3-dione Starting from tert-butyl 4-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H- isoindol-5-yl]azetidin-3-yl}piperazine-1-carboxylate (1.80 g; 3.62 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 2-(2,6- dioxopiperidin-3-yl)-5-[3-(piperazin-1-yl)azetidin-1-yl]-2,3-dihydro-1H-isoindole- 1,3-dione (1.5 g; 3.77 mmol; quantitative) as yellow solid. LC-MS method F: [M+H]+398.2; Rt: 0.67 min 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)-2,3-dihydro-1H-isoindole-1,3-dione -73-Attorney Docket No. : P24-187-WO-PCT Starting from tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H- isoindol-5-yl]piperazine-1-carboxylate (7.00 g; 15.03 mmol; 1.00 eq.) general procedure B for Boc deprotection to afford 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin- 1-yl)-2,3-dihydro-1H-isoindole-1,3-dione as a yellow solid (5.00 g; 14.46 mmol; 96 %). LC-MS method B: [M+H]+343.2; Rt: 0.44 min Intermediate 7: 2-{4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl)amino]phenyl}acetic acidtert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5- yl]piperidine-1-carboxylate 5-bromo-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (5.00 g; 14.09 mmol; 1.0 eq.), tert-butyl 4-bromopiperidine-1-carboxylate (5.70 g; 21.13 mmol; 1.50 eq.), tris(trimethylsilyl)silane (3.69 g; 14.09 mmol; 1.00 eq.), Ir(dF(CF3)ppy)2(dtbpy)PF6 (22.00 mg; 0.14 mmol; 0.01 eq.) and Na2CO3 (3.14 g; 28.18 mmol; 2.00 eq.) were dissolved in DME (100 mL) under argon atmosphere. In a different flask, NiCl2-glyme (33.00 mg; 0.14 mmol; 0.01 eq.), 4,4'-di-tert-butyl-2,2'- bipyridine (40.00 mg; 0.14 mmol; 0.01 eq.) and DME (20 mL) were added under argon atmosphere. The solution was sonicated for 10 min, and 10 mL of this solution (0.5 % mol catalyst) was then transferred to the reaction. The reaction mixture was irradiated with blue LED light overnight. The reaction mixture was then diluted with water and extracted with DCM three times. The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (1:1) to afford tert-butyl 4- -74-Attorney Docket No. : P24-187-WO-PCT [2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidine-1- carboxylate as a yellow solid (18.00 g; 40.36 mmol; quantitative yield) LC-MS method D: [M+H-tBu]+386.2; Rt: 0.94 min 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)-2,3-dihydro-1H-isoindole-1,3- dione; trifluoroacetic acid Starting from tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H- isoindol-5-yl]piperidine-1-carboxylate (17.50 g; 33.69 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 2-(2,6-dioxopiperidin-3-yl)- 5-(piperidin-4-yl)-2,3-dihydro-1H-isoindole-1,3-dione; trifluoroacetic acid (15.0 g; 32.61 mmol; 97 %). as a yellow solid. LC-MS method H: [M+H]+342.1; Rt: 0.63 min tert-butyl 4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5- yl]piperidin-1-yl}methyl)piperidine-1-carboxylate To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-(piperidin-4-yl)-2,3-dihydro- 1H-isoindole-1,3-dione; trifluoroacetic acid (8.00 g; 17.55 mmol; 1.00 eq.) and benzyl piperazine-1-carboxylate (8.14 g; 35.10 mmol; 2.00 eq.) in DCM (160 mL) was added AcOH (2.11 g; 35.10 mmol; 2.00 eq.). The resulting mixture was stirred for 6 h at room temperature. To the reaction mixture NaBH(OAc)3(7.83 g; 35.10 mmol; 2.00 eq.) was added and it was stirred for 24 h at room temperature. The reaction mixture was diluted with water and extracted with EtOAc three times. The combined organic phases 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 DCM / MeOH (10:1) to afford tert-butyl 4-({4-[2-(2,6- dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-1- yl}methyl)piperidine-1-carboxylate (8.00 g; 14.70 mmol; 84 %) as a yellow solid. LC-MS method F: [M+H]+539.4; Rt: 0.78 min 2-(2,6-dioxopiperidin-3-yl)-5-{1-[(piperidin-4-yl)methyl]piperidin-4-yl}-2,3- dihydro-1H-isoindole-1,3-dione; trifluoroacetic acid Starting from tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H- isoindol-5-yl]piperidine-1-carboxylate (8.00 g; 14.70 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 2-(2,6-dioxopiperidin-3-yl)- -75-Attorney Docket No. : P24-187-WO-PCT 5-{1-[(piperidin-4-yl)methyl]piperidin-4-yl}-2,3-dihydro-1H-isoindole-1,3-dione; trifluoroacetic acid (6.10 g; 10.91 mmol; 74 %). LC-MS method D: [M+H]+439.3; Rt: 0.51 min Intermediate 8: 3-[4-(piperazin-1-yl)phenyl]piperidine-2,6-dione hydrochloridetert-butyl 4-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}piperazine-1-carboxylate To a stirred solution of tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]piperazine-1-carboxylate (12.00 g; 29.36 mmol; 1.00 eq.) and 2,6- bis(benzyloxy)-3-bromopyridine (10.00 g; 25.66 mmol; 0.90eq.) in dioxane (140 mL) and water (28 mL) were added Pd(dppf)Cl2•DCM (2.20 g; 2.56 mmol; 0.10 eq.) and K2CO3 (8.20 g; 56.36 mmol; 1.90 eq.). The resulting mixture was stirred for 3 h at 80 ⁰C 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 (17.20 g; 29.24 mmol; quantitative yield) as a yellow solid. LC-MS method D: [M+H]+552.3; Rt: 1.37 min tert-butyl 4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazine-1-carboxylate To a stirred solution of tert-butyl 4-{4-[2,6-bis(benzyloxy)pyridin-3- yl]phenyl}piperazine-1-carboxylate (8.50 g; 15.17 mmol; 1.00 eq.) in dioxane (85.0 mL) was added Pd(OH)2 / C (4.80 g; 6.76 mmol; 0.50 eq.). 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 to afford tert-butyl 4-[4-(2,6- -76-Attorney Docket No. : P24-187-WO-PCT dioxopiperidin-3-yl)phenyl]piperazine-1-carboxylate (5.50 g; 14.26 mmol; 94 %) as a white solid. LC-MS method I: [M+H]+374.3; Rt: 0.74 min 3-[4-(piperazin-1-yl)phenyl]piperidine-2,6-dione hydrochloride To a stirred solution of tert-butyl 4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazine-1- carboxylate (1.50 g; 3.96 mmol; 1.00 eq.) was added 4 M HCl in EtOAc (10 mL). 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 (1.10 g; 3.24 mmol; 82 %) as a white solid. LC-MS method G [M+H]+274.1; Rt: 0.51 min Intermediate 9: 3-[1-oxo-4-(piperazin-1-yl)-2,3-dihydro-1H-isoindol-2- yl]piperidine-2,6-dione hydrochloride3-(4-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione To a solution of methyl 3-bromo-2-(bromomethyl)benzoate (50.0 g; 160.4 mmol; 1.0 eq.) in ACN (500 mL) were added DIEA (75.0 g; 551.9 mmol; 3.40 eq.) and 3- aminopiperidine-2,6-dione hydrochloride (53.50 g; 308.8 mmol; 2.00 eq.). The resulting mixture was stirred at 80 ⁰C for 12 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and purified by trituration with water and EtOAc (1:1). The residue was filtered to afford 3-(4-bromo-1-oxo-2,3- dihydro-1H-isoindol-2-yl)piperidine-2,6-dione as a brown solid (50.00 g; 154.0 mmol; 96.0 %). LC-MS method H [M+H]+325.0; Rt: 0.79 min tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl]piperazine-1-carboxylate -77-Attorney Docket No. : P24-187-WO-PCT Starting from 3-(4-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (500.0 mg; 1.54 mmol; 1.00 eq.) and tert-butyl piperazine-1-carboxylate (867.0 mg; 4.42 mmol; 2.90 eq.) general procedure F for Buchwald coupling was followed to afford tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl]piperazine-1-carboxylate (1.20 g; 2.75 mmol; quantitative yield) as a yellow solid. LC-MS method J [M+H]+429.2; Rt: 0.67 min 3-[1-oxo-4-(piperazin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione hydrochloride Starting from tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H- isoindol-4-yl]piperazine-1-carboxylate (510.0 mg; 1.15 mmol; 1.00 eq.) general procedure C for Boc deprotection was followed to afford 3-[1-oxo-4-(piperazin-1-yl)- 2,3-dihydro-1H-isoindol-2-yl]piperidine-2,6-dione hydrochloride (quantitative). LC-MS method D [M+H]+329.2; Rt: 0.43 min Intermediate 10: 3-{4-[(3R)-3-methylpiperazin-1-yl]-1-oxo-2,3-dihydro-1H- isoindol-2-yl}piperidine-2,6-dione hydrochloridetert-butyl (2R)-4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4- yl]-2-methylpiperazine-1-carboxylate Starting from 3-(4-bromo-1-oxo-2,3-dihydro-1H-isoindol-2-yl)piperidine-2,6-dione (1.00 g; 2.94 mmol; 1.00 eq.) and tert-butyl (2R)-2-methylpiperazine-1-carboxylate (1.00 eq.) general procedure F for Buchwald coupling was followed to afford tert- butyl (2R)-4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl]-2- methylpiperazine-1-carboxylate (900.0 mg; 2.00 mmol; 69 %) as a yellow solid. LC-MS method D [M+H]+443.2; Rt: 1.01 min 3-{4-[(3R)-3-methylpiperazin-1-yl]-1-oxo-2,3-dihydro-1H-isoindol-2- yl}piperidine-2,6-dione hydrochloride Starting from tert-butyl (2R)-4-[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H- isoindol-4-yl]-2-methylpiperazine-1-carboxylate (1.60 g; 3.25 mmol; 1.00 eq.) general procedure C for Boc deprotection was followed to afford 3-{4-[(3R)-3- -78-Attorney Docket No. : P24-187-WO-PCT methylpiperazin-1-yl]-1-oxo-2,3-dihydro-1H-isoindol-2-yl}piperidine-2,6-dione hydrochloride (1.30 g; 3.18 mmol; 98 %) as a yellow solid. LC-MS method H [M+H]+343.2; Rt: 0.48 min Intermediate 11: 5-{3-[4-(4-amino-3-fluorophenyl)piperazin-1-yl]azetidin-1-yl}- 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione1-(azetidin-3-yl)-4-(3-fluoro-4-nitrophenyl)piperazine Starting from tert-butyl 3-[4-(3-fluoro-4-nitrophenyl)piperazin-1-yl]azetidine-1- carboxylate (1.20 g; 3.09 mmol; 1.00 eq.) general procedure C for Boc deprotection was followed to afford 1-(azetidin-3-yl)-4-(3-fluoro-4-nitrophenyl)piperazine (850.0 mg; 2.94 mmol; 95 %) as a brown solid. LC-MS method B [M+H]+281.2; Rt: 0.60 min 2-(2,6-dioxopiperidin-3-yl)-5-{3-[4-(3-fluoro-4-nitrophenyl)piperazin-1- yl]azetidin-1-yl}-2,3-dihydro-1H-isoindole-1,3-dione Starting from 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3- dione (410.0 mg; 1.45 mmol; 1.00 eq.) and 1-(azetidin-3-yl)-4-(3-fluoro-4- nitrophenyl)piperazine (420.0 mg; 1.45 mmol; 1.00 eq.) general procedure I for nucleophilic aromatic substitution was followed to afford 2-(2,6-dioxopiperidin-3-yl)- 5-{3-[4-(3-fluoro-4-nitrophenyl)piperazin-1-yl]azetidin-1-yl}-2,3-dihydro-1H- isoindole-1,3-dione (700.0 mg; 1.29 mmol; 89 %) as a yellow solid. LC-MS method I [M+H]+537.2; Rt: 0.63 min 5-{3-[4-(4-amino-3-fluorophenyl)piperazin-1-yl]azetidin-1-yl}-2-(2,6- dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-5-{3-[4-(3-fluoro-4- nitrophenyl)piperazin-1-yl]azetidin-1-yl}-2,3-dihydro-1H-isoindole-1,3-dione (700.0 mg; 1.29 mmol; 1.00 eq.) and NH4Cl (290.0 mg; 5.15 mmol; 4.00 eq.) in water (8.00 -79-Attorney Docket No. : P24-187-WO-PCT mL) and EtOH (12.00 mL) was added Fe (380.0 mg; 6.45 mmol; 5.00 eq.) in portions at room temperature. The resulting mixture was stirred for 2 h at 80 ⁰C. The reaction was diluted with water and the resulting mixture was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 5-{3-[4-(4-amino- 3-fluorophenyl)piperazin-1-yl]azetidin-1-yl}-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro- 1H-isoindole-1,3-dione (350.0 mg; 0.65 mmol; 50 %). LC-MS method G [M+H]+507.2; Rt: 0.95 min Intermediate 12a and 12b: 2-{2-fluoro-4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl)amino]phenyl}acetic acidtert-butyl 2-{[3-fluoro-4-(2-methoxy-2-oxoethyl)phenyl]amino}-5H,6H,7H,8H- pyrido[3,4-d]pyrimidine-7-carboxylate Starting from methyl 2-(4-amino-2-fluorophenyl)acetate (2.00 g; 10.92 mmol; 1.00 eq.) and tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (3.83 g; 14.2 mmol; 1.3 eq.) general procedure E for Buchwald coupling was followed to afford tert-butyl 2-{[3-fluoro-4-(2-methoxy-2-oxoethyl)phenyl]amino}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate as a yellow solid (2.40 g; 5.67 mmol; 52 %). LC-MS method J [M+H]+417.1; Rt: 0.76 min methyl 2-[2-fluoro-4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl}amino)phenyl]acetate Starting from tert-butyl 2-{[3-fluoro-4-(2-methoxy-2-oxoethyl)phenyl]amino}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (2.30 g; 5.57 mmol; 1.00 eq) general procedure B for Boc deprotection was followed to afford methyl 2-[2-fluoro- -80-Attorney Docket No. : P24-187-WO-PCT 4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)phenyl]acetate as a yellow solid (1.60 g; 5.12 mmol; 92 %). LC-MS method J [M+H]+317.0; Rt: 0.43 min tert-butyl 7-(2-{[3-fluoro-4-(2-methoxy-2-oxoethyl)phenyl]amino}-5H,6H,7H,8H- pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1- carboxylate Starting from methyl 2-[2-fluoro-4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl}amino)phenyl]acetate (1.60 g; 5.06 mmol; 1.00 eq.) and intermediate 1 (2.00 g; 6.07 mmol; 1.20 eq.) general procedure F for Buchwald coupling was followed to afford tert-butyl 7-(2-{[3-fluoro-4-(2-methoxy-2-oxoethyl)phenyl]amino}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazine-1-carboxylate (1.80 g; 3.15 mmol; 62 %) as a yellow solid. LC-MS method B [M+H]+565.1; Rt: 0.67 min Intermediate 12a: 2-{4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl)amino]-2-fluorophenyl}acetic acid To a solution of tert-butyl 7-(2-{[3-fluoro-4-(2-methoxy-2-oxoethyl)phenyl]amino}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazine-1-carboxylate (1.80 g; 3.12 mmol; 1.00 eq.) in THF (7.00 mL), water (21.0 mL) and NaOH (656.0 mg; 15.58 mmol; 5.00 eq.) were added at room temperature. The mixture was stirred for 16 h at 70 °C. Aqueous NaHCO3solution was then added until pH 7 was reached. The resulting mixture was filtered, the filtrate cake was washed with water and the water layer was concentrated under reduced pressure to afford 2-{4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-2- fluorophenyl}acetic acid (1.70 g; 2.81 mmol; 90 %) as a yellow solid. LC-MS method J [M+H]+551.2; Rt: 0.69 min Intermediate 12b: 2-{2-fluoro-4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl)amino]phenyl}acetic acid Starting from 2-{4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]-2- -81-Attorney Docket No. : P24-187-WO-PCT fluorophenyl}acetic acid (1.30 g; 2.21 mmol; 1.00 eq.) general procedure A for Boc deprotection was to afford 2-{2-fluoro-4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}acetic acid (700.0 mg; 1.55 mmol; 70 %) as a yellow solid LC-MS method J [M+H]+451.2; Rt: 0.50 min Intermediate 13a and 13b: 3-{4-[3-(piperazin-1-yl)azetidin-1- yl]phenyl}piperidine-2,6-dione2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine To a stirred solution of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridine (4.00 g; 8.77 mmol; 1.00 eq.) and 1-bromo-4-iodobenzene (3.10 g; 10.53 mmol; 1.20 eq.) in 1,4-dioxane (35.0 mL) and water (7.0 mL) were added Pd(PPh3)4(1.00 g; 0.88 mmol; 0.10 eq.) and Na2CO3(2.00 g; 17.72 mmol; 2.00 eq.) in portions at room temperature. The reaction mixture was stirred for 2 h at 100 ⁰C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (3.8 g; 7.02 mmol; 80.0 %) as a white solid. LC-MS method I [M+H]+448.2; Rt: 1.35 min tert-butyl 4-(1-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}azetidin-3- yl)piperazine-1-carboxylate To a stirred mixture of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (14.7 g; 26.22 mmol; 1.5 eq.) and tert-butyl 4-(azetidin-3-yl)piperazine-1-carboxylate (4.50 g; 17.71 mmol; 1.00 eq.) in 1,4-dioxane (200.0 mL) were added RuPhos Pd G3 (3.10 g; 3.54 -82-Attorney Docket No. : P24-187-WO-PCT mmol; 0.20 eq.), RuPhos (1.70 g; 3.54 mmol; 0.20 eq.) and Cs2CO3 (12.2 g; 35.43 mmol; 2.00 eq.) in portions. The resulting mixture was stirred for 16 h at 100 ⁰C under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and directly purified by silica gel column chromatography, eluted with PE / EA (60:40) to afford tert-butyl 4-(1-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}azetidin-3- yl)piperazine-1-carboxylate (9.00 g; 14.74 mmol; 83 %) as a yellow solid. LC-MS method I [M+H]+607.4; Rt: 0.99 min Intermediate 13a: tert-butyl 4-{1-[4-(2,6-dioxopiperidin-3-yl)phenyl]azetidin-3- yl}piperazine-1-carboxylate To a stirred mixture of tert-butyl 4-(1-{4-[2,6-bis(benzyloxy)pyridin-3- yl]phenyl}azetidin-3-yl)piperazine-1-carboxylate (17.00 g; 27.85 mmol; 1.00 eq.) in dioxane (200.0 mL) was added Pd(OH)2 / C (6.80 g; 9.68 mmol; 0.40 eq.) in portions. The reaction mixture was stirred at 60 ⁰C for 12 h under hydrogen atmosphere. The reaction mixture was filtered over celite and washed with DCM / MeOH (4:1). The filtrate was concentrated under reduced pressure to afford tert-butyl 4-{1-[4-(2,6- dioxopiperidin-3-yl)phenyl]azetidin-3-yl}piperazine-1-carboxylate (15.0 g; 19.40 mmol; 70 %) as a yellow solid. LC-MS method I [M+H]+429.3; Rt: 0.58 min Intermediate 13b: 3-{4-[3-(piperazin-1-yl)azetidin-1-yl]phenyl}piperidine-2,6- dione Starting from tert-butyl tert-butyl 4-{1-[4-(2,6-dioxopiperidin-3-yl)phenyl]azetidin-3- yl}piperazine-1-carboxylate (14.00 g; 18.11 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 3-{4-[3-(piperazin-1-yl)azetidin-1- yl]phenyl}piperidine-2,6-dione (8.50 g; 17.89 mmol; 99 %) as a yellow solid. LC-MS method I [M+H]+329.2; Rt: 0.43 min Intermediate 14: 1-{4-[3-(piperazin-1-yl)azetidin-1-yl]phenyl}-1,3-diazinane-2,4- dione PH-MS- -83-Attorney Docket No. : P24-187-WO-PCT3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione To a stirred solution of 1,3-diazinane-2,4-dione (10.00 g; 83.26 mmol; 1.00 eq.) and Cs2CO3(42.00 g; 122.5 mmol; 1.50 eq.) in DMF (100 mL) was added 1- (chloromethyl)-4-methoxybenzene (13.00 g; 78.86 mmol; 1.00 eq.). The resulting mixture was stirred for 12 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water and extracted with DCM 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 trituration with MeCN to afford 3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4- dione (11.00 g; 40.97 mmol; 49 %) as a white solid. LC-MS method D: [M+H]+235.0; Rt: 0.62 min 1-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione To a stirred solution of 3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (10.0 g; 37.31 mmol; 1.00 eq.) and 1-bromo-4-iodobenzene (11.1 g; 37.27 mmol; 1.00eq.) in DMF (100 mL) were added CuI (1.50 g; 7.48 mmol; 0.2 eq.), K2CO3(16.3 g; 111.9 mmol; 3.00 eq.) and glycine (572.0 mg; 7.47 mmol; 0.2 eq.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 12 h at 140 ⁰C 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)-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (11.2 g; 28.66 mmol; 77 %) as a yellow solid. LC-MS method I: [M+H]+391.1; Rt: 0.83 min -84-Attorney Docket No. : P24-187-WO-PCT tert-butyl 4-[1-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1- yl}phenyl)azetidin-3-yl]piperazine-1-carboxylate A mixture of 1-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4- dione (800.0 mg; 1.95 mmol; 1.00 eq.), tert-butyl 4-(azetidin-3-yl)piperazine-1- carboxylate (1.77 mg; 5.86 mmol; 3.00 eq.), Pd2(dba)3 (188.0 mg; 0.20 mmol; 0.10 eq.), 2-(dicyclohexylphosphino)-2'-i-propylbiphenyl (98.00 mg; 0.20 mmol; 0.10 eq.) and Cs2CO3(1.34 mg; 3.91 mmol; 2.00 eq.) in dioxane (15 mL) was stirred overnight at 90 ⁰C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column eluted with 5 % MeOH in DCM to afford tert-butyl 4- [1-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}phenyl)azetidin-3- yl]piperazine-1-carboxylate (800.0 mg; 1.46 mmol; 75 %) as a yellow solid. LC-MS method I: [M+H-Boc]+450.3; Rt: 0.74 min 1-{4-[3-(piperazin-1-yl)azetidin-1-yl]phenyl}-1,3-diazinane-2,4-dione A mixture of tert-butyl 4-[1-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3- diazinan-1-yl}phenyl)azetidin-3-yl]piperazine-1-carboxylate (780.0 mg; 1.42 mmol; 1.00 eq.) in TFA (10 mL) and CF3SO3H (2.00 mL) was stirred for 2 h at 60 ⁰C under nitrogen atmosphere. The resulting mixture was cooled down to room temperature and added dropwise to MTBE. The solid was filtered and dried under reduced pressure to afford 1-{4-[3- (piperazin-1-yl)azetidin-1-yl]phenyl}-1,3-diazinane-2,4-dione (350.0 mg; 1.04 mmol; 73 %) as a yellow solid. LC-MS method E: [M+H]+330.0; Rt: 0.51 min Intermediate 15: 5-{3-[4-(4-amino-2-fluorophenyl)piperazin-1-yl]azetidin-1-yl}- 2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione-85-Attorney Docket No. : P24-187-WO-PCT tert-butyl 3-[4-(2-fluoro-4-nitrophenyl)piperazin-1-yl]azetidine-1-carboxylate A solution of tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (1.00 g; 3.94 mmol; 1.00 eq.), 1,2-difluoro-4-nitrobenzene (0.66 g; 3.94 mmol; 1.00 eq.), DIEA (23.0 g; 169.27 mmol; 43.00 eq.) and EtOAc (10 mL) was stirred for 3 h at 60 ⁰C under argon atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 3-[4-(2-fluoro-4-nitrophenyl)piperazin-1-yl]azetidine-1-carboxylate (1.10 g; 2.61 mmol; 66 %) as a yellow solid. LC-MS method M: [M+Na]+403.2; Rt: 0.59 min 1-(azetidin-3-yl)-4-(2-fluoro-4-nitrophenyl)piperazine Starting from tert-butyl 3-[4-(2-fluoro-4-nitrophenyl)piperazin-1-yl]azetidine-1- carboxylate (1.00 g; 2.37 mmol; 1.00 eq.) general procedure C for Boc deprotection was followed in the presence of 4 M HCl in dioxane (30.6 eq.) to afford 1-(azetidin-3- yl)-4-(2-fluoro-4-nitrophenyl)piperazine (0.8 g; 2.79 mmol; quantitative) as a yellow solid. LC-MS method M: [M+H]+281.2; Rt: 0.55 min 2-(2,6-dioxopiperidin-3-yl)-5-{3-[4-(2-fluoro-4-nitrophenyl)piperazin-1- yl]azetidin-1-yl}-2,3-dihydro-1H-isoindole-1,3-dione A solution of 1-(azetidin-3-yl)-4-(2-fluoro-4-nitrophenyl)piperazine (400.0 mg; 1.39 mmol; 1.00 eq.), 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-1H-isoindole-1,3- dione (406.0 mg; 1.40 mmol; 1.00 eq.), K2CO3(609.0 mg; 4.19 mmol; 3.00 eq.) and MeCN (15 mL) was stirred for 3 h at 90 ⁰C under argon atmosphere. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with DCM / MeOH (3:1) to afford 2-(2,6- dioxopiperidin-3-yl)-5-{3-[4-(2-fluoro-4-nitrophenyl)piperazin-1-yl]azetidin-1-yl}- 2,3-dihydro-1H-isoindole-1,3-dione (540.0 mg; 1.00 mmol; 72 %) as a brown solid. LC-MS method M: [M+H]+537.2; Rt: 0.79 min 5-{3-[4-(4-amino-2-fluorophenyl)piperazin-1-yl]azetidin-1-yl}-2-(2,6- dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione Starting from 2-(2,6-dioxopiperidin-3-yl)-5-{3-[4-(2-fluoro-4-nitrophenyl)piperazin- 1-yl]azetidin-1-yl}-2,3-dihydro-1H-isoindole-1,3-dione (400.0 mg; 0.74 mmol; 1.00 eq.) general procedure G for reduction under hydrogen was followed in the presence of MeOH (0.2 M) and Pd / C (0.3 eq.) to 5-{3-[4-(4-amino-2-fluorophenyl)piperazin-1- -86-Attorney Docket No. : P24-187-WO-PCT yl]azetidin-1-yl}-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (320.0 mg; 0.53 mmol; 71 %) as a brown solid. LC-MS method M: [M+H]+507.3; Rt: 0.46 min Intermediate 16 and 17: (2R) and (2S)-2-{4-[(7-{1-[(tert-butoxy)carbonyl]-8- methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4- d]pyrimidin-2-yl)amino]phenyl}propanoic acidtert-butyl 2-{[4-(1-methoxy-1-oxopropan-2-yl)phenyl]amino}-5H,6H,7H,8H- pyrido[3,4-d]pyrimidine-7-carboxylate To a stirred solution of methyl 2-(4-aminophenyl)propanoate (4.00 g; 21.85 mmol; 1.00 eq.), tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (9.00 g; 33.37 mmol; 1.50 eq.) and t-BuBrettPhos Pd G3 (1.90 g; 2.11 mmol; 0.10 eq.), t-BuBrettPhos (2.10 g; 4.12 mmol; 0.20 eq.) in dioxane (80 mL) was added Cs2CO3 (21.9 g; 63.85 mmol; 2.90 eq.) in portions at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 16 h at 100 ⁰C under nitrogen atmosphere. It 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 PE / EA (1:3) to afford tert-butyl 2-{[4-(1-methoxy-1- oxopropan-2-yl)phenyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (4.00 g; 9.70 mmol; 44 %) as a yellow oil. LC-MS method N: [M+H]+413.3; Rt: 0.89 min -87-Attorney Docket No. : P24-187-WO-PCT methyl 2-[4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl}amino)phenyl]propanoate Starting from tert-butyl 2-{[4-(1-methoxy-1-oxopropan-2-yl)phenyl]amino}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (3.70 g; 8.97 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed in the presence of DCM (0.02 M) and TFA (14.6 eq.) to afford methyl 2-[4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin- 2-yl}amino)phenyl]propanoate (2.50 g; 8.00 mmol; 89 %). LC-MS method N: [M+H]+313.1; Rt: 0.55 min tert-butyl 7-(2-{[4-(1-methoxy-1-oxopropan-2-yl)phenyl]amino}-5H,6H,7H,8H- pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1- carboxylate Starting from methyl 2-[4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl}amino)phenyl]propanoate (1.50 g; 4.80 mmol; 1.00 eq.) and intermediate 1 (1.2 eq.) general procedure F for Buchwald coupling was followed to afford tert-butyl 7- (2-{[4-(1-methoxy-1-oxopropan-2-yl)phenyl]amino}-5H,6H,7H,8H-pyrido[3,4- d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (1.40 g; 2.46 mmol; 51 %) as a white solid. LC-MS method N: [M+H]+561.3; Rt: 0.88 min tert-butyl 7-[2-({4-[(2R)-1-methoxy-1-oxopropan-2-yl]phenyl}amino)- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazine-1-carboxylate and tert-butyl 7-[2-({4-[(2S)-1-methoxy-1- oxopropan-2-yl]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-8- methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate tert-butyl 7-(2-{[4-(1-methoxy-1-oxopropan-2-yl)phenyl]amino}-5H,6H,7H,8H- pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1- carboxylate (1.38 g; 2.46 mmol; 1.00 eq.) was purified by Prep-SFC Column in a CHIRALCEL OD-3, 3.0x100mm, 3µm; Mobile Phase A: CO2, Mobile Phase B: MeOH: ACN=1: 1 (0.1% 2M NH3-MeOH); Gradient: isocratic 50% B; to afford the two enantiomers; tert-butyl 7-[2-({4-[(2R)-1-methoxy-1-oxopropan-2- yl]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazine-1-carboxylate (600.0 mg; 1.02 mmol; 41 %) as yellow solid (Rt 0.85 min) and tert-butyl 7-[2-({4-[(2S)-1-methoxy-1-oxopropan-2- yl]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-8-methyl-1H,2H,3H- -88-Attorney Docket No. : P24-187-WO-PCT pyrido[2,3-b][1,4]oxazine-1-carboxylate (660.0 mg; 1.12 mmol; 45 %) as yellow solid (Rt 1.01 min). (2R)-2-{4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl)amino]phenyl}propanoic acid To a stirred solution of tert-butyl 7-[2-({4-[(2R)-1-methoxy-1-oxopropan-2- yl]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazine-1-carboxylate (280.0 mg; 0.47 mmol; 1.00 eq.) in THF (6.00 mL) was added NaOH (207.0 mg; 4.92 mmol; 10.4 eq.) disssolved in H2O (2 mL) dropwise at room temperature. The reaction mixture was stirred for 16 h at 60oC and directly concentrated under reduced pressure. The residue was purified by silica gel column, eluted with DCM / MeOH (9:1) to afford (2R)-2-{4-[(7-{1-[(tert- butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H- pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}propanoic acid (400.0 mg; 0.67 mmol; quantitative) as a yellow solid. LC-MS method O: [M+H]+547.2; Rt: 0.95 min (2S)-2-{4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl)amino]phenyl}propanoic acid A mixture of tert-butyl 7-[2-({4-[(2S)-1-methoxy-1-oxopropan-2-yl]phenyl}amino)- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazine-1-carboxylate (660.0 mg; 1.12 mmol; 1.00 eq.) in oxolane (6 mL) was stirred for 30 min at room temperature. NaOH (235.0 mg; 5.58 mmol; 5.00 eq.) and H2O (2.00 mL) were then added in portions at room temperature. The reaction mixture was stirred for 16 h at 60 ⁰C. It was concentrated under reduced pressure and directly purified by silica gel column, eluted with DCM / MeOH (9:1) to afford (2S)-2- {4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7- yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}propanoic acid (280.0 mg; 0.49 mmol; 44 %) as a yellow solid. LC-MS method N: [M+H]+547.3; Rt: 0.81 min Intermediate 18: 5-{3-[4-(4-aminophenyl)piperazin-1-yl]azetidin-1-yl}-2-(2,6- dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione -89-Attorney Docket No. : P24-187-WO-PCT2-(2,6-dioxopiperidin-3-yl)-5-{3-[4-(4-nitrophenyl)piperazin-1-yl]azetidin-1-yl}- 2,3-dihydro-1H-isoindole-1,3-dione Starting from intermediate 6 (45.0 g; 113.23 mmol; 1.00 eq.) general procedure I for nucleophilic aromatic substitution was followed in the presence of 1-fluoro-4- nitrobenzene (0.6 eq.) and DMF (0.25 M) and K2CO3(4.0 eq.) to afford 2-(2,6- dioxopiperidin-3-yl)-5-{3-[4-(4-nitrophenyl)piperazin-1-yl]azetidin-1-yl}-2,3- dihydro-1H-isoindole-1,3-dione as a yellow solid (27.0 g; 52.07 mmol; 46 %). LC-MS method M: [M+H]+519.2; Rt: 0.56 min 5-{3-[4-(4-aminophenyl)piperazin-1-yl]azetidin-1-yl}-2-(2,6-dioxopiperidin-3-yl)- 2,3-dihydro-1H-isoindole-1,3-dione Starting from 2-(2,6-dioxopiperidin-3-yl)-5-{3-[4-(4-nitrophenyl)piperazin-1- yl]azetidin-1-yl}-2,3-dihydro-1H-isoindole-1,3-dione (25.0 g; 48.21 mmol; 1.00 eq.) general procedure G for reduction under hydrogen was followed in the presence of THF (0.10 M) and Pd / C (0.20 eq.) to give 5-{3-[4-(4-aminophenyl)piperazin-1- yl]azetidin-1-yl}-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione (16.0 g; 32.75 mmol; 68 %) as a yellow solid. LC-MS method P: [M+H]+489.2; Rt: 0.51 min Intermediate 19: benzyl 3-(piperazin-1-yl)azetidine-1-carboxylatebenzyl 4-({1-[(tert-butoxy)carbonyl]piperidin-4-yl}methyl)piperazine-1- carboxylate Starting from benzyl piperazine-1-carboxylate (1.00 g; 4.54 mmol; 1.00 eq.) and tert- butyl 4-formylpiperidine-1-carboxylate (1.10 eq.) general procedure K for reductive amination was followed in the presence of DCE (0.05 M) and NaBH(OAc)3 (2.00 eq) to obtain benzyl 4-({1-[(tert-butoxy)carbonyl]piperidin-4-yl}methyl)piperazine-1- carboxylate (2.66 g; 6.38 mmol; 140.5 %) as a white powder. LC-MS: [M+H]+418.2; Rt: 1.80 min -90-Attorney Docket No. : P24-187-WO-PCT benzyl 3-(piperazin-1-yl)azetidine-1-carboxylate Starting from tert-butyl 4-{1-[(benzyloxy)carbonyl]azetidin-3-yl}piperazine-1- carboxylate (35.00 g; 93.22 mmol; 1.00 eq.) general procedure C for Boc deprotection was followed in the presence of 4 M HCl (50.0 eq.) to obtain benzyl 3-(piperazin-1- yl)azetidine-1-carboxylate (25.00 g; 90.79 mmol; 97 %) as an orange oil. LC-MS: [M+H]+276.1; Rt: 1.24 min Intermediate 20: tert-butyl 8-methyl-7-{7-[(4-{4-[(piperazin-1- yl)methyl]piperidin-1-yl}phenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2- yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylatebenzyl 4-{[1-(4-nitrophenyl)piperidin-4-yl]methyl}piperazine-1-carboxylate Starting from Intermediate 19 (4.00 g; 12.60 mmol; 1.00 eq.) and 1-fluoro-4- nitrobenzene (1.10 eq.) general procedure I for nucleophilic aromatic substitution was followed to afford benzyl 4-{[1-(4-nitrophenyl)piperidin-4-yl]methyl}piperazine-1- carboxylat (4.10 g; 9.35 mmol; 74 %). LC-MS: [M+H]+439.2; Rt: 1.92 min benzyl 4-{[1-(4-aminophenyl)piperidin-4-yl]methyl}piperazine-1-carboxylate Starting from benzyl 4-{[1-(4-nitrophenyl)piperidin-4-yl]methyl}piperazine-1- carboxylate (3.20 g; 7.30 mmol; 1.00 eq.) general procedure L for reduction was followed to afford benzyl 4-{[1-(4-aminophenyl)piperidin-4-yl]methyl}piperazine-1- carboxylate (2.70 g; 6.61 mmol; 91 %). LC-MS: [M+H]+409.2; Rt: 0.62 min tert-butyl 7-({4-[4-({4-[(benzyloxy)carbonyl]piperazin-1-yl}methyl)piperidin-1- yl]phenyl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate Starting from tert-butyl 7-chloro-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (1.00 g; 3.72 mmol; 1.00 eq.) and benzyl 4-{[1-(4-aminophenyl)piperidin-4- -91-Attorney Docket No. : P24-187-WO-PCT yl]methyl}piperazine-1-carboxylate (1.10 eq.) general procedure F for Buchwald coupling was followed to afford tert-butyl 7-({4-[4-({4- [(benzyloxy)carbonyl]piperazin-1-yl}methyl)piperidin-1-yl]phenyl}amino)-1,2,3,4- tetrahydro-2,6-naphthyridine-2-carboxylate (1.30 g; 2.03 mmol; 55 %). LC-MS: [M+H]+641.3; Rt: 1.77 min benzyl 4-[(1-{4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3- yl)amino]phenyl}piperidin-4-yl)methyl]piperazine-1-carboxylate Starting from tert-butyl 7-({4-[4-({4-[(benzyloxy)carbonyl]piperazin-1- yl}methyl)piperidin-1-yl]phenyl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridine-2- carboxylate (1.00 g; 1.56 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford benzyl 4-[(1-{4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3- yl)amino]phenyl}piperidin-4-yl)methyl]piperazine-1-carboxylate (610.0 mg; 1.13 mmol; 72 %). LC-MS: [M+H]+541.3; Rt: 0.25 min benzyl 4-[(1-{4-[(6-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3- yl)amino]phenyl}piperidin-4-yl)methyl]piperazine-1-carboxylate Starting from benzyl 4-[(1-{4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3- yl)amino]phenyl}piperidin-4-yl)methyl]piperazine-1-carboxylate (500.0 mg; 0.92 mmol; 1.00 eq.) and Intermediate 1 (1.20 eq.) general procedure F for Buchwald coupling was followed to afford benzyl 4-[(1-{4-[(6-{1-[(tert-butoxy)carbonyl]-8- methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6- naphthyridin-3-yl)amino]phenyl}piperidin-4-yl)methyl]piperazine-1-carboxylate (200.0 mg; 0.25 mmol; 27 %). LC-MS: [M+H]+790.4; Rt: 1.90 min tert-butyl 8-methyl-7-{7-[(4-{4-[(piperazin-1-yl)methyl]piperidin-1- yl}phenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-1H,2H,3H- pyrido[2,3-b][1,4]oxazine-1-carboxylate Starting from benzyl 4-[(1-{4-[(6-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3- yl)amino]phenyl}piperidin-4-yl)methyl]piperazine-1-carboxylate (200.0 mg; 0.25 mmol; 1.00 eq.) general procedure M for Cbz deprotection was followed to afford tert-butyl 8-methyl-7-{7-[(4-{4-[(piperazin-1-yl)methyl]piperidin-1- -92-Attorney Docket No. : P24-187-WO-PCT yl}phenyl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-1H,2H,3H-pyrido[2,3- b][1,4]oxazine-1-carboxylate (150.0 mg; 0.23 mmol; 90 %). LC-MS: [M+H]+655.3; Rt: 1.53 min Intermediate 21: benzyl 3-(piperazin-1-yl)azetidine-1-carboxylatetert-butyl 4-{1-[(benzyloxy)carbonyl]azetidin-3-yl}piperazine-1-carboxylate Starting from benzyl 3-oxoazetidine-1-carboxylate (20.00 g; 97.46 mmol; 1.00 eq.) and tert-butyl piperazine-1-carboxylate (1.10 eq.) general procedure K for reductive amination was followed to afford tert-butyl 4-{1-[(benzyloxy)carbonyl]azetidin-3- yl}piperazine-1-carboxylate (35.0 g; 93.22 mmol; 96 %) as a yellow solid. LC-MS: [M+H]+376.2; Rt: 2.42 min benzyl 3-(piperazin-1-yl)azetidine-1-carboxylate Starting from tert-butyl 4-{1-[(benzyloxy)carbonyl]azetidin-3-yl}piperazine-1- carboxylate (35.0 g; 93.22 mmol; 1.00 eq.) general procedure C for Boc deprotection was to afford benzyl 3-(piperazin-1-yl)azetidine-1-carboxylate (25.0 g; 90.79 mmol; 97 %) as an orange oil. LC-MS: [M+H]+276.1; Rt: 1.24 min Intermediate 22: tert-butyl 7-[7-({4-[4-(azetidin-3-yl)piperazin-1- yl]phenyl}amino)-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl]-8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazine-1-carboxylate-93-Attorney Docket No. : P24-187-WO-PCT benzyl 3-[4-(4-nitrophenyl)piperazin-1-yl]azetidine-1-carboxylate Starting from benzyl 3-(piperazin-1-yl)azetidine-1-carboxylate (4.0 g; 14.53 mmol; 1.0 eq.) and 1-fluoro-4-nitrobenzene (2.2 g; 15.98 mmol; 1.1 eq.) the general procedure I for nucleophilic aromatic substitution was followed in the presence of DMF (0.97 M) and Cs2CO3 (2.0 eq.) to obtain the desired product (3.2 g; 8.07 mmol; 56 % yield). LC-MS: [M+H]+397.1; Rt: 2.38 min benzyl 3-[4-(4-aminophenyl)piperazin-1-yl]azetidine-1-carboxylate Starting from benzyl 3-[4-(4-nitrophenyl)piperazin-1-yl]azetidine-1-carboxylate (2.40 g; 6.05 mmol; 1.00 eq.) general procedure L for reduction was followed to afford benzyl 3-[4-(4-aminophenyl)piperazin-1-yl]azetidine-1-carboxylate (1.60 g; 4.37 mmol; 72 %). LC-MS: [M+H]+367.2; Rt: 1.07 min tert-butyl 7-{[4-(4-{1-[(benzyloxy)carbonyl]azetidin-3-yl}piperazin-1- yl)phenyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate Starting from benzyl 3-[4-(4-aminophenyl)piperazin-1-yl]azetidine-1-carboxylate (500.0 mg; 1.36 mmol; 1.00 eq.) and tert-butyl 7-chloro-1,2,3,4-tetrahydro-2,6- naphthyridine-2-carboxylate (367.0 mg; 1.36 mmol; 1.00 eq.) general procedure E for Buchwald coupling was followed to afford tert-butyl 7-{[4-(4-{1- [(benzyloxy)carbonyl]azetidin-3-yl}piperazin-1-yl)phenyl]amino}-1,2,3,4-tetrahydro- 2,6-naphthyridine-2-carboxylate (430.0 mg; 0.72 mmol; 53 %). LC-MS: [M+H]+599.3; Rt: 1.82 min benzyl 3-(4-{4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3- yl)amino]phenyl}piperazin-1-yl)azetidine-1-carboxylate Starting from tert-butyl 7-{[4-(4-{1-[(benzyloxy)carbonyl]azetidin-3-yl}piperazin-1- yl)phenyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (600.0 mg; 1.00 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford benzyl 3-(4-{4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}piperazin-1- yl)azetidine-1-carboxylate (430.0 mg; 0.86 mmol; 86 %). LC-MS: [M+H]+499.3; Rt: 0.23 min benzyl 3-(4-{4-[(6-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3- yl)amino]phenyl}piperazin-1-yl)azetidine-1-carboxylate Starting from benzyl 3-(4-{4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3- -94-Attorney Docket No. : P24-187-WO-PCT yl)amino]phenyl}piperazin-1-yl)azetidine-1-carboxylate (300.0 mg; 0.60 mmol; 1.00 eq.) and intermediate 1 (1.2 eq.) general procedure F for Buchwald coupling was followed to afford benzyl 3-(4-{4-[(6-{1-[(tert-butoxy)carbonyl]-8-methyl- 1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3- yl)amino]phenyl}piperazin-1-yl)azetidine-1-carboxylate (160.0 mg; 0.21 mmol; 36 %). LC-MS: [M+H]+748.4; Rt: 1.99 min tert-butyl 7-[7-({4-[4-(azetidin-3-yl)piperazin-1-yl]phenyl}amino)-1,2,3,4- tetrahydro-2,6-naphthyridin-2-yl]-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazine-1-carboxylate Starting from benzyl 3-(4-{4-[(6-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3- yl)amino]phenyl}piperazin-1-yl)azetidine-1-carboxylate (600.0 mg; 0.80 mmol; 1.00 eq.) general procedure M for Cbz deprotection was followed to afford tert-butyl 7-[7- ({4-[4-(azetidin-3-yl)piperazin-1-yl]phenyl}amino)-1,2,3,4-tetrahydro-2,6- naphthyridin-2-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (460.0 mg; 0.75 mmol; 93 %). LC-MS: [M+H]+613.4; Rt: 1.49 min Intermediate 23: tert-butyl 8-methyl-7-{7-[(6-{4-[(piperazin-1- yl)methyl]piperidin-1-yl}pyridin-3-yl)amino]-1,2,3,4-tetrahydro-2,6- naphthyridin-2-yl}-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylatebenzyl 4-{[1-(5-nitropyridin-2-yl)piperidin-4-yl]methyl}piperazine-1-carboxylate Starting from intermediate 19 (8.00 g; 25.20 mmol; 1.00 eq.) and 2‐fluoro‐5‐ nitropyridine (1.20 eq.) general procedure I for nucleophilic aromatic substitution was -95-Attorney Docket No. : P24-187-WO-PCT followed to afford benzyl 4-{[1-(5-nitropyridin-2-yl)piperidin-4- yl]methyl}piperazine-1-carboxylate (6.80 g; 15.47 mmol; 61 %). LC-MS: [M+H]+440.2; Rt: 1.87 min benzyl 4-{[1-(5-aminopyridin-2-yl)piperidin-4-yl]methyl}piperazine-1- carboxylate Starting from benzyl 4-{[1-(5-nitropyridin-2-yl)piperidin-4-yl]methyl}piperazine-1- carboxylate (5.00 g; 11.38 mmol; 1.00 eq.) general procedure L for reduction was followed to afford benzyl 4-{[1-(5-aminopyridin-2-yl)piperidin-4- yl]methyl}piperazine-1-carboxylate (5.80 g; 14.16 mmol; quantitative) as a red solid. LC-MS: [M+H]+410.2; Rt: 0.65 min tert‐butyl 7‐({6‐[4‐({4‐[(benzyloxy)carbonyl]piperazin‐1‐yl}methyl)piperidin‐1‐ yl]pyridin‐3‐yl}amino)‐1,2,3,4‐tetrahydro‐2,6‐naphthyridine‐2‐carboxylate Starting from benzyl 4-{[1-(5-aminopyridin-2-yl)piperidin-4-yl]methyl}piperazine-1- carboxylate (1.30 g; 3.10 mmol; 1.00 eq.) and tert-butyl 7-chloro-1,2,3,4-tetrahydro- 2,6-naphthyridine-2-carboxylate (1.10 eq.) general procedure F for Buchwald coupling was followed to afford tert‐butyl 7‐({6‐[4‐({4‐ [(benzyloxy)carbonyl]piperazin‐1‐yl}methyl)piperidin‐1‐yl]pyridin‐3‐yl}amino)‐ 1,2,3,4‐tetrahydro‐2,6‐naphthyridine‐2‐carboxylate (1.80 g; 2.76 mmol; 89 %) as a brown solid. LC-MS: [M+H]+642.3; Rt: 1.72 min benzyl 4‐[(1‐{5‐[(5,6,7,8‐tetrahydro‐2,6‐naphthyridin‐3‐yl)amino]pyridin‐2‐ yl}piperidin‐4‐yl)methyl]piperazine‐1‐carboxylate Starting from tert‐butyl 7‐({6‐[4‐({4‐[(benzyloxy)carbonyl]piperazin‐1‐ yl}methyl)piperidin‐1‐yl]pyridin‐3‐yl}amino)‐1,2,3,4‐tetrahydro‐2,6‐naphthyridine‐2‐ carboxylate (2.80 g; 4.33 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford benzyl 4‐[(1‐{5‐[(5,6,7,8‐tetrahydro‐2,6‐naphthyridin‐3‐ yl)amino]pyridin‐2‐yl}piperidin‐4‐yl)methyl]piperazine‐1‐carboxylate (522.0 mg; 0.96 mmol; 22 %) as a yellow solid. LC-MS: [M+H]+542.30; Rt: 0.24 min benzyl 4‐[(1‐{5‐[(6‐{1‐[(tert‐butoxy)carbonyl]‐8‐methyl‐1H,2H,3H‐pyrido[2,3‐ b][1,4]oxazin‐7‐yl}‐5,6,7,8‐tetrahydro‐2,6‐naphthyridin‐3‐yl)amino]pyridin‐2‐ yl}piperidin‐4‐yl)methyl]piperazine‐1‐carboxylate Starting from benzyl 4‐[(1‐{5‐[(5,6,7,8‐tetrahydro‐2,6‐naphthyridin‐3‐ yl)amino]pyridin‐2‐yl}piperidin‐4‐yl)methyl]piperazine‐1‐carboxylate (522.0 mg; -96-Attorney Docket No. : P24-187-WO-PCT 0.96 mmol; 1.00 eq.) and intermediate 1 (1.10 eq.) general procedure F for Buchwald coupling was followed to afford benzyl 4‐[(1‐{5‐[(6‐{1‐[(tert‐butoxy)carbonyl]‐8‐ methyl‐1H,2H,3H‐pyrido[2,3‐b][1,4]oxazin‐7‐yl}‐5,6,7,8‐tetrahydro‐2,6‐ naphthyridin‐3‐yl)amino]pyridin‐2‐yl}piperidin‐4‐yl)methyl]piperazine‐1‐carboxylate (271.0 mg; 0.34 mmol; 36 %) as a brown solid. LC-MS: [M+H]+790.3; Rt: 1.86 min tert-butyl 8-methyl-7-{7-[(6-{4-[(piperazin-1-yl)methyl]piperidin-1-yl}pyridin-3- yl)amino]-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl}-1H,2H,3H-pyrido[2,3- b][1,4]oxazine-1-carboxylate Starting from benzyl 4-[(1-{5-[(6-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3- yl)amino]pyridin-2-yl}piperidin-4-yl)methyl]piperazine-1-carboxylate (270 mg; 0.34 mmol; 1.0 eq.) the general procedure M for Cbz deprotection was followed in the presence of EtOH (0.02 M), Pd / C (0.2 eq.) and 1,4 cyclohexadiene (10.0 eq.) to obtain the desired product (147 mg; 0.22 mmol; 66 % yield). LC-MS: [M+H]+656.4; Rt: 1.10 min Intermediate 24: tert-butyl 7-(7-{[4-(2-{2,7-diazaspiro[4.4]nonan-2-yl}-2- oxoethyl)phenyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl)-8-methyl- 1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylatebenzyl 7-[2-(4-{[(tert-butoxy)carbonyl]amino}phenyl)acetyl]-2,7- diazaspiro[4.4]nonane-2-carboxylate To a solution of benzyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (1.00 g; 3.84 mmol; 1.00 eq.), {4-[(tert-butoxycarbonyl)amino]phenyl}acetic acid (1.20 eq.) in DMF (20 mL), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) -97-Attorney Docket No. : P24-187-WO-PCT (2.60 g; 4.99 mmol; 1.30 eq.) and DIEA (2.50 mL) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with EtOAc three times. The combined organic phases were concentrated. The residue was dissolved in DMF (5 mL) and purified it by prep-HPLC to obtain the desired product (900.0 mg; 1.82 mmol; 48 %) as a brown solid. LC-MS: [M+H-tBu]+438.2; Rt: 2.97 min benzyl 7-[2-(4-aminophenyl)acetyl]-2,7-diazaspiro[4.4]nonane-2-carboxylate Starting from benzyl 7-[2-(4-{[(tert-butoxy)carbonyl]amino}phenyl)acetyl]-2,7- diazaspiro[4.4]nonane-2-carboxylate (900.0 mg; 1.82 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford benzyl 7-[2-(4- aminophenyl)acetyl]-2,7-diazaspiro[4.4]nonane-2-carboxylate (600.0 mg; 1.52 mmol; 84 %). LC-MS: [M+H]+394.2; Rt: 1.86 min tert-butyl 7-{[4-(2-{7-[(benzyloxy)carbonyl]-2,7-diazaspiro[4.4]nonan-2-yl}-2- oxoethyl)phenyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate Starting from benzyl 7-[2-(4-aminophenyl)acetyl]-2,7-diazaspiro[4.4]nonane-2- carboxylate (400.0 mg; 1.02 mmol; 1.00 eq.) and benzyl 7-[2-(4-aminophenyl)acetyl]- 2,7-diazaspiro[4.4]nonane-2-carboxylate (1.00 eq.) general procedure E for Buchwald coupling was followed to afford tert-butyl 7-{[4-(2-{7-[(benzyloxy)carbonyl]-2,7- diazaspiro[4.4]nonan-2-yl}-2-oxoethyl)phenyl]amino}-1,2,3,4-tetrahydro-2,6- naphthyridine-2-carboxylate (410.0 mg; 0.66 mmol; 65 %). LC-MS: [M+H]+626.4; Rt: 2.34 min benzyl 7-(2-{4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]phenyl}acetyl)- 2,7-diazaspiro[4.4]nonane-2-carboxylate Starting from tert-butyl 7-{[4-(2-{7-[(benzyloxy)carbonyl]-2,7-diazaspiro[4.4]nonan- 2-yl}-2-oxoethyl)phenyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridine-2-carboxylate (900.0 mg; 1.44 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford benzyl 7-(2-{4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3- yl)amino]phenyl}acetyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (610.0 mg; 1.16 mmol; 81 %). LC-MS: [M+H]+526.3; Rt: 1.53 min -98-Attorney Docket No. : P24-187-WO-PCT benzyl 7-(2-{4-[(6-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3- yl)amino]phenyl}acetyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate Starting from benzyl 7-(2-{4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3- yl)amino]phenyl}acetyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (360.0 mg; 0.68 mmol; 1.00 eq.) and intermediate 1 (1.20 eq.) general procedure F for Buchwald coupling was followed to afford benzyl 7-(2-{4-[(6-{1-[(tert-butoxy)carbonyl]-8- methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6- naphthyridin-3-yl)amino]phenyl}acetyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (300.0 mg; 0.39 mmol; 57 %). LC-MS: [M+H]+774.4; Rt: 2.41 min tert-butyl 7-(7-{[4-(2-{2,7-diazaspiro[4.4]nonan-2-yl}-2-oxoethyl)phenyl]amino}- 1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl)-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazine-1-carboxylate Starting from benzyl 7-(2-{4-[(6-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3- yl)amino]phenyl}acetyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (300.0 mg; 0.39 mmol; 1.00 eq.) general procedure M for Cbz deprotection was followed to afford tert-butyl 7-(7-{[4-(2-{2,7-diazaspiro[4.4]nonan-2-yl}-2-oxoethyl)phenyl]amino}- 1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl)-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazine-1-carboxylate (200.0 mg; 0.31 mmol; 81 %). Intermediate 25: 2-[4-({4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7- yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}methyl)piperazin- 1-yl]pyrimidine-5-carboxylic acid -99-Attorney Docket No. : P24-187-WO-PCTethyl 2-(4-{[4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl}amino)phenyl]methyl}piperazin-1-yl)pyrimidine-5-carboxylate Starting from ethyl 2-(4-{[4-({7-[(tert-butoxy)carbonyl]-5H,6H,7H,8H-pyrido[3,4- d]pyrimidin-2-yl}amino)phenyl]methyl}piperazin-1-yl)pyrimidine-5-carboxylate (52.00 g; 86.87 mmol) general procedure C for Boc deprotection was followed to afford ethyl 2-(4-{[4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl}amino)phenyl]methyl}piperazin-1-yl)pyrimidine-5-carboxylate (41.20 g; 86.82 mmol; 99 %) as a colorless solid. LC-MS method T: [M+2H]2+239.1; Rt: 1.07 min ethyl 2-[4-({4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}methyl)piperazin-1- yl]pyrimidine-5-carboxylate Starting from ethyl 2-(4-{[4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl}amino)phenyl]methyl}piperazin-1-yl)pyrimidine-5-carboxylate (10.00 g; 20.09 mmol; 1.00 eq.) and 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine (4.92 g; 20.09 mmol; 1.0 eq.) general procedure F for Buchwald coupling was used to afford ethyl 2-[4-({4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}methyl)piperazin-1- yl]pyrimidine-5-carboxylate (6.20 g; 9.66 mmol; 48 %) as a colorless solid. LC-MS method T: [M+H]+623.3; Rt: 1.24 min 2-[4-({4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H- pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}methyl)piperazin-1-yl]pyrimidine-5- carboxylic acid -100-Attorney Docket No. : P24-187-WO-PCT Ethyl 2-[4-({4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}methyl)piperazin-1- yl]pyrimidine-5-carboxylate (100.0 mg; 0.16 mmol; 1.00 eq.) was suspended in THF (700 µl) and water (700 µl) at room temperature. Lithium hydroxide (11.00 mg; 0.47 mmol; 3.00 eq.) was added and the reaction stirred 4 days at room temperature. The reaction mixture was diluted with water and the pH of the pale yellow solution was adjusted to 5 using 1N HCl. The precipitate was filtered off by suction, washed with water and dried under reduced pressure to afford 2-[4-({4-[(7-{8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl)amino]phenyl}methyl)piperazin-1-yl]pyrimidine-5-carboxylic acid (91.00 mg; 0.14 mmol: 91%) as pale yellow solid. LC-MS method S: [M+H]+595.2; Rt: 0.65 min Intermediate 26: 4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]benzoic acidtert-butyl 2-{[4-(methoxycarbonyl)phenyl]amino}-5H,6H,7H,8H-pyrido[3,4- d]pyrimidine-7-carboxylate Starting from tert-butyl 2-amino-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7- carboxylate (1.00 g; 3.60 mmol; 1.00 eq.) and methyl-4-brombenzoat (1.42 g; 6.47 mmol; 1.80 eq.) procedure E for Buchwald coupling was followed to afford tert-butyl 2-{[4-(methoxycarbonyl)phenyl]amino}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7- carboxylate (900.0 mg; 2.25 mmol; 63 %) as a colorless solid LC-MS method U: [M+H]+385.2; Rt: 1.80 min -101-Attorney Docket No. : P24-187-WO-PCT Methyl 4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)benzoate; trifluoroacetic acid Starting from tert-butyl 2-{[4-(methoxycarbonyl)phenyl]amino}-5H,6H,7H,8H- pyrido[3,4-d]pyrimidine-7-carboxylate (900.0 mg; 2.25 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford Methyl 4-({5H,6H,7H,8H- pyrido[3,4-d]pyrimidin-2-yl}amino)benzoate; trifluoroacetic acid (980.0 mg; 2.25 mmol; 99 %) as a TFA salt. LC-MS method U: [M+H]+ 285.1; Rt: 0.98 min tert-butyl 7-(2-{[4-(methoxycarbonyl)phenyl]amino}-5H,6H,7H,8H-pyrido[3,4- d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate Starting from tert-butyl 7-bromo-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1- carboxylate (880.0 mg; 2.54 mmol; 1.00 eq.) and methyl 4-({5H,6H,7H,8H- pyrido[3,4-d]pyrimidin-2-yl}amino)benzoate; trifluoroacetic acid (825. mg; 2.03 mmol; 0.80 eq.) general procedure F for Buchwald coupling was followed to afford tert-butyl 7-(2-{[4-(methoxycarbonyl)phenyl]amino}-5H,6H,7H,8H-pyrido[3,4- d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (580.0 mg; 1.00 mmol; 40.0 %) as a colorless solid. LC-MS method U: [M+H]+533.1; Rt: 1.87 min 4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7- yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]benzoic acid To a solution of tert-butyl 7-(2-{[4-(methoxycarbonyl)phenyl]amino}-5H,6H,7H,8H- pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1- carboxylate (580.0 mg; 1.00 mmol; 1.00 eq.) in THF (10 mL) and water (100 mL) was added NaOH pellets (120.0 mg; 3.00 mmol; 3.00 eq.) and the mixture stirred for 16 h at 50 °C. The reaction mixture was acidified with 1 N HCl and extracted with DCM three times. The combined organic layers were washed with water, dried over sodium sulfate, and filtered. Evaporation of the solvent afforded the desired product (430.0 mg; 0.77 mmol; 77 %) as a colorless solid. LC-MS method U: [M+H]+ 519.2; Rt: 1.66 min Intermediate 27: 3-({4-[5-(piperazin-1-yl)-1,3,4-oxadiazol-2- yl]phenyl}amino)piperidine-2,6-dione -102-Attorney Docket No. : P24-187-WO-PCT5-(4-nitrophenyl)-2,3-dihydro-1,3,4-oxadiazol-2-one To a stirred solution of 4-nitrobenzohydrazide (500.0 mg; 2.62 mmol; 1.00 eq.) and Et3N (419.0 mg; 3.73 mmol; 1.40 eq.) in DMF (5.00 eq.) was added CDI (448.0 mg; 2.62 mmol; 1.00 eq.) in portions at 0 ⁰C under nitrogen atmosphere. The reaction mixture was stirred for 2 h at room temperature. It was diluted with water and extracted with EA (ethyl acetate) three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtain residue was purified by flash column chromatography, eluted with PE / EA (1:1) to afford 5-(4-nitrophenyl)-2,3-dihydro-1,3,4-oxadiazol-2-one (360.0 mg; 1.74 mmol; 66 %) as a yellow solid. LC-MS method G: [M-H]- 205.9; Rt: 0.68 min tert-butyl 4-[5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl]piperazine-1-carboxylate To a stirred solution of 5-(4-nitrophenyl)-2,3-dihydro-1,3,4-oxadiazol-2-one (360.0 mg; 1.74 mmol; 1.00 eq.) and tert-butyl piperazine-1-carboxylate (512.0 mg; 2.61 mmol; 1.50 eq.) in THF (3.00 mL) were added DIEA (710.0 mg; 5.22 mmol; 3.00 eq.) and BOP reagent (2.32 g; 5.19 mmol; 3.00 eq.). The reaction mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was diluted with water and extracted with EtOAc three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography, (eluted with PE / EA (1:1) to afford tert-butyl 4-[5-(4-nitrophenyl)-1,3,4-oxadiazol-2- yl]piperazine-1-carboxylate (200.0 mg; 0.53 mmol; 31 %) as a yellow solid. LC-MS method N: [M+H]+376.2; Rt: 0.84 min tert-butyl 4-[5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl]piperazine-1-carboxylate -103-Attorney Docket No. : P24-187-WO-PCT Starting from tert-butyl 4-[5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl]piperazine-1- carboxylate (180.0 mg; 0.48 mmol; 1.00 eq.) in EtOH (3.00 mL) and water (2.00 mL) were added NH4Cl (102.0 mg; 1.81 mmol; 3.80 eq.) and Fe (135.0 mg; 2.29 mmol; 4.80 eq.) in portions at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 1 h at 80 ⁰C. The reaction mixture was diluted with water and extracted with EA three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl 4-[5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl]piperazine-1-carboxylate (210.0 mg; 0.61 mmol; quantitative), which was used in the next step without further purification. LC-MS method N: [M+H]+376.3; Rt: 0.70 min tert-butyl 4-[5-(4-{[2,6-bis(benzyloxy)pyridin-3-yl]amino}phenyl)-1,3,4- oxadiazol-2-yl]piperazine-1-carboxylate To a solution of tert-butyl 4-[5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl]piperazine-1- carboxylate (150.0 mg; 0.43 mmol; 1.00 eq.) and 2,6-bis(benzyloxy)-3-bromopyridine (193.0 mg; 0.51 mmol; 1.20 eq.) in dioxane (5.0 mL), Pd2(dba)3(40.00 mg; 0.04 mmol; 0.10 eq.), Xantphos (51.00 mg; 0.09 mmol; 0.20 eq.) and tBuONa (126.0 mg; 1.25 mmol; 2.90 eq.) were added in portions at room temperature. The reaction mixture was stirred for 2 h at 100 ⁰C under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatograph, eluted with PE / EA (1:1) to afford tert-butyl 4-[5-(4-{[2,6-bis(benzyloxy)pyridin-3- yl]amino}phenyl)-1,3,4-oxadiazol-2-yl]piperazine-1-carboxylate (210.0 mg; 0.33 mmol; 76 %) as a yellow solid. LC-MS method N: [M+H]+635.4; Rt: 1.10 min tert-butyl 4-(5-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}-1,3,4-oxadiazol-2- yl)piperazine-1-carboxylate To a solution of tert-butyl 4-[5-(4-{[2,6-bis(benzyloxy)pyridin-3-yl]amino}phenyl)- 1,3,4-oxadiazol-2-yl]piperazine-1-carboxylate (4.45 g; 7.01 mmol; 1.00 eq.) in dioxane (50 mL) was added Pd(OH)2 / C (4.00 g; 5.70 mg; 0.80 eq.). The reaction mixture was hydrogenated at 60 ⁰C overnight using a hydrogen balloon. The reaction mixture was filtered through celite and washed with MeOH. The filtrate was -104-Attorney Docket No. : P24-187-WO-PCT concentrated under reduced pressure and purified by flash column chromatography (eluted with 100% EtOAc) to afford the desired product (500.0 mg; 1.10 mmol; 16 % yield) as a green solid. LC-MS method N: [M+H]+457.2; Rt: 0.74 min 3-({4-[5-(piperazin-1-yl)-1,3,4-oxadiazol-2-yl]phenyl}amino)piperidine-2,6-dione Starting from tert-butyl 4-(5-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}-1,3,4- oxadiazol-2-yl)piperazine-1-carboxylate (300.0 mg; 0.66 mmol; 1.00 eq.) general procedure C for Boc deprotection was followed to afford 3-({4-[5-(piperazin-1-yl)- 1,3,4-oxadiazol-2-yl]phenyl}amino)piperidine-2,6-dione (190.0 mg; 0.53 mmol; 81 %) as an off-white solid. LC-MS method D: [M+H]+357.2; Rt: 0.39 min Intermediate 28: 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidineStarting from tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7- carboxylate (7.50 g; 27.56 mmol; 1.0 eq.) general procedure B for Boc deprotection was to obtain 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine (4.80 g; 27.06 mmol; 1.00 eq.) as a brown solid. LC-MS method N: [M+H]+170.2; Rt: 0.14 min Intermediate 29: 3-({3-fluoro-4-[3-(piperazin-1-yl)azetidin-1- yl]phenyl}amino)piperidine-2,6-dione -105-Attorney Docket No. : P24-187-WO-PCTtert-butyl 4-[1-(2-fluoro-4-nitrophenyl)azetidin-3-yl]piperazine-1-carboxylate To a stirred solution of tert-butyl 4-(azetidin-3-yl)piperazine-1-carboxylate (3.00 g; 11.81 mmol; 1.00 eq.) and 1,2-difluoro-4-nitrobenzene (0.90 mL; 7.78 mmol; 0.70 eq.) in DMF (30.0 mL) was added Cs2CO3 (5.00 g; 15.80 mmol; 1.30 eq.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 90 ⁰C under. The resulting mixture was filtered and the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure to afford tert-butyl 4-[1-(2-fluoro-4-nitrophenyl)azetidin-3-yl]piperazine-1-carboxylate (4.80 g; 11.64 mmol; 99 %) as a yellow oil. LC-MS method O: [M+H]+381.1; Rt: 0.78 min tert-butyl 4-[1-(4-amino-2-fluorophenyl)azetidin-3-yl]piperazine-1-carboxylate Starting from tert-butyl 4-[1-(2-fluoro-4-nitrophenyl)azetidin-3-yl]piperazine-1- carboxylate (2.00 g; 4.99 mmol; 1.00 eq.) general procedure L was followed to afford tert-butyl 4-[1-(4-amino-2-fluorophenyl)azetidin-3-yl]piperazine-1-carboxylate (1.60 g; 4.48 mmol; 90 %) as a red oil. LC-MS method N: [M+H]+351.3; Rt: 0.46 min tert-butyl 4-[1-(4-{[2,6-bis(benzyloxy)pyridin-3-yl]amino}-2- fluorophenyl)azetidin-3-yl]piperazine-1-carboxylate To a stirred solution of tert-butyl 4-[1-(4-amino-2-fluorophenyl)azetidin-3- yl]piperazine-1-carboxylate (750.0 mg; 2.14 mmol; 1.00 eq.) and 2,6-bis(benzyloxy)- 3-bromopyridine (1.00 g; 2.73 mmol; 1.30 eq.) in 1,4-dioxane (7.00 mL) were added Pd2(dba)3(197.0 mg; 0.19 mmol; 0.10 eq.), Xantphos (249.0 mg; 0.43 mmol; 0.20 -106-Attorney Docket No. : P24-187-WO-PCT eq.) and t-BuONa (618.0 mg; 6.11 mmol; 2.90 eq.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 12 h at 100 ⁰C. 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 / EA (1:3) to afford tert-butyl 4-[1-(4- {[2,6-bis(benzyloxy)pyridin-3-yl]amino}-2-fluorophenyl)azetidin-3-yl]piperazine-1- carboxylate (1.00 g; 1.56 mmol; 73 %) as a black solid. LC-MS method O: [M+H]+640.4; Rt: 1.10 min tert-butyl 4-(1-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}azetidin-3- yl)piperazine-1-carboxylate Starting from tert-butyl 4-[1-(4-{[2,6-bis(benzyloxy)pyridin-3-yl]amino}-2- fluorophenyl)azetidin-3-yl]piperazine-1-carboxylate (1.00 g; 1.56 mmol; 1.00 eq.) general procedure G for reduction was followed to afford tert-butyl 4-(1-{4-[(2,6- dioxopiperidin-3-yl)amino]-2-fluorophenyl}azetidin-3-yl)piperazine-1-carboxylate (280. mg; 0.61 mmol; 39 %) as a brown solid. LC-MS method P: [M+H]+462.2; Rt: 0.71 min 3-({3-fluoro-4-[3-(piperazin-1-yl)azetidin-1-yl]phenyl}amino)piperidine-2,6-dione Starting from tert-butyl 4-(1-{4-[(2,6-dioxopiperidin-3-yl)amino]-2- fluorophenyl}azetidin-3-yl)piperazine-1-carboxylate (1.20 g; 2.37 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 3-({3-fluoro-4-[3- (piperazin-1-yl)azetidin-1-yl]phenyl}amino)piperidine-2,6-dione (1.50 g; 4.04 mmol; quantitative) as a green solid. LC-MS method G: [M+H]+362.2; Rt: 0.18 min Intermediate 30: 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridineTo a stirred solution of 2,6-bis(benzyloxy)-3-bromopyridine (34.0 g; 87.24 mmol; 1.00 eq.) and BPD (116.6 g; 436.2 mmol; 5.00 eq.) in dioxane (340 mL) were added -107-Attorney Docket No. : P24-187-WO-PCT 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (7.50 g; 8.72 mmol; 0.10 eq.) and KOAc (18.0 g; 174.5 mmol; 2.00 eq.) in portions at room temperature. The reaction mixture was stirred for 3 h at 100 ⁰C 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 afford 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridine (36.0 g; 80.22 mmol; 92 %) as a white solid. LC-MS method X: [M+H]+418.2; Rt: 1.41 min Intermediate 31: 3-[2,6-bis(benzyloxy)pyridin-3-yl]-7-bromo-1-methyl-1H- indazole7-bromo-3-iodo-1H-indazole To a stirred solution of 7-bromo-1H-indazole (49.0 g; 236.3 mmol; 1.00 eq.) and I2(94.7 g; 354.4 mmol; 1.50 eq.) in DMF (800 mL) was added KOH (20.9 g; 354.4 mmol; 1.50 eq.) at 0 ⁰C. The resulting mixture was stirred for 12 h at room temperature under nitrogen atmosphere. The reaction was quenched with water at 0 °C, followed by the addition of a saturated aqueous sodium sulfite solution. The resulting mixture was filtered and the filter cake washed with water and EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 7-bromo-3-iodo-1H- indazole (77.0 g; 232.93 mmol; 99 %) as a white solid. LC-MS method G: [M+H]+320.8; Rt: 1.03 min 7-bromo-3-iodo-1-methyl-1H-indazole To a stirred solution of 7-bromo-3-iodo-1H-indazole (77.0 g; 238.4 mmol; 1.00 eq.) and KOH (35.2 g; 596.1 mmol; 2.50 eq.) in acetone (500 mL) was added CH3I (37.5 mL; 596.1 mmol; 2.5 eq.) at 0 ⁰ C. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated under reduced -108-Attorney Docket No. : P24-187-WO-PCT pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20:1) to afford 7-bromo-3-iodo-1-methyl-1H-indazole (62.0 g; 173.6 mmol; 73 %) as a white solid. LC-MS method P: [M+H]+336.9; Rt: 1.14 min 3-[2,6-bis(benzyloxy)pyridin-3-yl]-7-bromo-1-methyl-1H-indazole To a stirred solution of 7-bromo-3-iodo-1-methyl-1H-indazole (50.0 g; 139.99 mmol; 1.00eq.) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (102.0 g; 181.99 mmol; 1.3 eq.) in 1,4-dioxane (1800 mL) and H2O (600 mL) K3PO4(259.6 g; 1161.9 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 ⁰C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The aqueous layer was extracted with EtOAc twice. 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 3-[2,6-bis(benzyloxy)pyridin-3- yl]-7-bromo-1-methyl-1H-indazole (24.0 g; 39.42 mmol; 28 %) as a white solid. LC-MS method O: [M+H]+500.1; Rt: 1.50 min Intermediate 32: 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-methyl-1H-indazol-6-yl}- 1,2,3,6-tetrahydropyridine-1-carboxylate Starting from 31 (4.50 g; 8.35 mmol; 1.00 eq.) and tert-butyl 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (4.40 g; 13.52 mmol; 1.60 eq.) general procedure O for Suzuki coupling was followed to obtain tert- butyl 4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyl-1H-indazol-6-yl}-1,2,3,6- -109-Attorney Docket No. : P24-187-WO-PCT tetrahydropyridine-1-carboxylate (6.00 g; 9.34 mmol; quantitative) as a yellow solid. LC-MS method O: [M+H]+603.3; Rt: 1.50 min tert-butyl 4-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]piperidine-1- carboxylate 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 (5.50 g; 8.48 mmol; 1.00 eq.) general procedure G for hydrogenation was followed to afford tert-butyl 4-[3-(2,6- dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]piperidine-1-carboxylate (4.50 g; 9.70 mmol; quantitative) as a brown oil. LC-MS method X: [M+H]+427.1; Rt: 0.89 min 3-[1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl]piperidine-2,6-dione; trifluoroacetic acid Starting from tert-butyl 4-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6- yl]piperidine-1-carboxylate (4.40 g; 9.48 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 3-[1-methyl-6-(piperidin-4-yl)-1H-indazol-3- yl]piperidine-2,6-dione; trifluoroacetic acid (2.10 g; 4.77 mmol; 50 %) as a light brown solid. LC-MS method Y: [M+H]+327.1; Rt: 0.88 min Intermediate 33: 3-{[3-fluoro-4-(piperazin-1-yl)phenyl]amino}piperidine-2,6- dionetert-butyl 4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazine-1- carboxylate A solution of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate (22.0 g; 74.49 mmol; 1.00 eq.) and 3-bromopiperidine-2,6-dione (29.0 g; 143.48 mmol; 1.90 eq.) and NaHCO3 (20.0 g; 226.2 mmol; 3.00eq.) in CH3CN (250.0 mL) was stirred for 2 days at 85 ⁰C 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 -110-Attorney Docket No. : P24-187-WO-PCT reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2- fluorophenyl}piperazine-1-carboxylate (23.00 g; 55.98 mmol; 75 %) as a blue solid. LC-MS method X: [M+H]+407.0; Rt: 0.75 min 3-{[3-fluoro-4-(piperazin-1-yl)phenyl]amino}piperidine-2,6-dione Starting from tert-butyl 4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2- fluorophenyl}piperazine-1-carboxylate (500.0 mg; 1.11 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 3-{[3-fluoro-4-(piperazin-1- yl)phenyl]amino}piperidine-2,6-dione (500.0 mg; 0.62 mmol; 56 %) as a yellow solid. LC-MS method E: [M+H]+307.1; Rt: 0.29 min Intermediate 34: 3-({3-fluoro-4-[4-(piperidin-4-yl)piperazin-1- yl]phenyl}amino)piperidine-2,6-dionetert-butyl 4-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2-fluorophenyl}piperazin-1- yl)piperidine-1-carboxylate Starting from 3-{[3-fluoro-4-(piperazin-1-yl)phenyl]amino}piperidine-2,6-dione; trifluoroacetic acid (1.00 g; 2.35 mmol; 1.00 eq.) general procedure K for reductive amination was followed to tert-butyl 4-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2- fluorophenyl}piperazin-1-yl)piperidine-1-carboxylate (700.0 mg; 1.43 mmol; 61 %) as a yellow solid. LC-MS method A: [M+H]+490.3; Rt: 0.58 min 3-({3-fluoro-4-[4-(piperidin-4-yl)piperazin-1-yl]phenyl}amino)piperidine-2,6- dione Starting from tert-butyl 4-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2- fluorophenyl}piperazin-1-yl)piperidine-1-carboxylate (6.00 g; 12.13 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 3-({3-fluoro-4-[4- -111-Attorney Docket No. : P24-187-WO-PCT (piperidin-4-yl)piperazin-1-yl]phenyl}amino)piperidine-2,6-dione (5.50 g; 10.86 mmol; 90.0 % yield) as a green solid. LC-MS method O: [M+H]+390.2; Rt: 0.44 min Intermediate 35: 3-(4-{4-[2-(piperazin-1-yl)ethyl]piperazin-1- yl}phenyl)piperidine-2,6-dionetert-butyl 2-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin-1-yl}acetate The TFA salt of intermediate 8 (199.0 mg; 0.51 mmol; 1.00 eq) was dissolved in DMF (2.0 mL) and DIEA (436 µL, 2.56 mmol; 5.00 eq.) was added. The reaction mixture was stirred for 20 h at room temperature. The reaction mixture was diluted with water and extracted with EtOAc three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was then purified by flash column chromatography to afford tert-butyl 2-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin-1-yl}acetate (125.0 mg; 0.32 mmol; 63 %). LC-MS method U: [M+H]+388.1; Rt: 1.05 min 2-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin-1-yl}acetic acid; trifluoroacetic acid Starting from tert-butyl 2-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin-1- yl}acetate (125.0 mg; 0.32 mmol; 1.00 eq.) general procedure B for tert-butyl ester hydrolysis was followed to afford 2-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin- 1-yl}acetic acid; trifluoroacetic acid (180.0 mg; 0.29 mmol; 90 %). LC-MS method AB: [M+H]+332.1; Rt: 0.75 min tert-butyl 4-(2-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin-1- yl}acetyl)piperazine-1-carboxylate -112-Attorney Docket No. : P24-187-WO-PCT Starting from 2-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin-1-yl}acetic acid; trifluoroacetic acid (180.0 mg; 0.29 mmol; 1.00 eq.) general procedure H for amide coupling was followed to afford tert-butyl 4-(2-{4-[4-(2,6-dioxopiperidin-3- yl)phenyl]piperazin-1-yl}acetyl)piperazine-1-carboxylate (130.0 mg; 0.15 mmol; 50 %). LC-MS method U: [M+H]+500.3; Rt: 1.10 min 3-(4-{4-[2-oxo-2-(piperazin-1-yl)ethyl]piperazin-1-yl}phenyl)piperidine-2,6- dione; trifluoroacetic acid Starting from tert-butyl 4-(2-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin-1- yl}acetyl)piperazine-1-carboxylate (130.0 mg; 0.15 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 3-(4-{4-[2-oxo-2-(piperazin- 1-yl)ethyl]piperazin-1-yl}phenyl)piperidine-2,6-dione; trifluoroacetic (110.0 mg; 0.16 mmol; quantitative). LC-MS method U: [M+H]+400.3; Rt: 0.64 min Intermediate 36: 3-(4-{4-[2-(piperazin-1-yl)ethyl]piperazin-1- yl}phenyl)piperidine-2,6-dionetert-butyl 4-(2-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin-1- yl}ethyl)piperazine-1-carboxylate To a stirred solution of tert‐butyl 4‐(2‐chloroethyl)piperazine‐1‐carboxylate (100.0 mg; 0.40 mmol; 1.00 eq.) and the TFA salt of intermediate 8 (156.0 mg; 0.40 mmol; 1.00 eq.) in acetonitrile (2.00 mL) were added NaI (60.00mg; 0.40 mmol; 1.0 eq.) and K2CO3(111.0 mg; 0.80 mmol; 2.00 eq.) in portions at room temperature and the resulting mixture was stirred for 20 h at 80 °C. The reaction mixture was diluted with water and extracted using EtOAc. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography to afford tert- butyl 4-(2-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin-1-yl}ethyl)piperazine-1- carboxylate (90.0 mg; 0.19 mmol; 46 %). LC-MS method U: [M+H]+486.3; Rt: 1.07 min -113-Attorney Docket No. : P24-187-WO-PCT 3-(4-{4-[2-(piperazin-1-yl)ethyl]piperazin-1-yl}phenyl)piperidine-2,6-dione Starting from tert-butyl 4-(2-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin-1- yl}ethyl)piperazine-1-carboxylate (90.00 mg; 0.19 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford the desired product (95.00 mg; 0.20 mmol; quantitative). LC-MS method U: [M+H]+386.2; Rt: 0.66 min Intermediate 37: 7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-N-{4- [(piperazin-1-yl)methyl]phenyl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-aminetert-butyl 4-{[4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl}amino)phenyl]methyl}piperazine-1-carboxylate Starting form intermediate 28 (605.0 mg; 3.57 mmol; 2.20 eq.) and tert-butyl 4-[(4- aminophenyl)methyl]piperazine-1-carboxylate (500.0 mg; 1.63 mmol; 1.00 eq.) general procedure E for Buchwald coupling was followed to afford tert-butyl 4-{[4- ({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)phenyl]methyl}piperazine-1- carboxylate (220.0 mg; 0.48 mmol; 30 %) as a yellow solid. LC-MS method N: [M+H]+425.4; Rt: 0.52 min tert-butyl 4-({4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl)amino]phenyl}methyl)piperazine-1-carboxylate Starting from tert-butyl 4-{[4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl}amino)phenyl]methyl}piperazine-1-carboxylate (210.0 mg; 0.46 mmol; 1.00 eq.) and intermediate 1 (195.0 mg; 0.57 mmol; 1.20 eq.) general procedure F for Buchwald coupling was to afford tert-butyl 4-({4-[(7-{1-[(tert-butoxy)carbonyl]-8- methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4- -114-Attorney Docket No. : P24-187-WO-PCT d]pyrimidin-2-yl)amino]phenyl}methyl)piperazine-1-carboxylate (130.0 mg; 0.16 mmol; 36 %) as a yellow solid. LC-MS method N: [M+H]+673.6; Rt: 0.81 min 7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-N-{4-[(piperazin-1- yl)methyl]phenyl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine Starting from tert-butyl 4-({4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl)amino]phenyl}methyl)piperazine-1-carboxylate (120.0 mg; 0.15 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 7-{8-methyl- 1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-N-{4-[(piperazin-1-yl)methyl]phenyl}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine (60.00 mg; 0.13 mmol; 84 %). LC-MS method AB: [M+H]+473.3; Rt: 0.38 min Intermediate 38: 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-carboxylate To a solution of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (20.0 g; 71.08 mmol; 1.00 eq.) and 3-bromopiperidine-2,6-dione (64.2 g; 284.3 mmol; 4.00 eq.) in DMF (180 mL) DIEA (29.01 g; 213.3 mmol; 3.00 eq.) was added. The reaction mixture was stirred for 2 h at 80 ⁰C. 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 afford tert-butyl 4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperidine-1- carboxylate (28.00 g; 68.36 mmol; 96 %) as a green solid. LC-MS method N: [M+Na]+410.2; Rt: 0.81 min 3-{[4-(piperidin-4-yl)phenyl]amino}piperidine-2,6-dione -115-Attorney Docket No. : P24-187-WO-PCT Starting from tert-butyl 4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperidine-1- carboxylate (41.4 g; 106.7 mmol; 1.00 eq.) general procedure F for Boc deprotection was to afford 3-{[4-(piperidin-4-yl)phenyl]amino}piperidine-2,6-dione (28.0 g; 89.64 mmol; 84 %). LC-MS method N: [M+H]+288.1; Rt: 0.40 min tert-butyl 2-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperidin-1-yl)acetate To a stirred mixture of 3-{[4-(piperidin-4-yl)phenyl]amino}piperidine-2,6-dione (28.0 g; 95.30 mmol; 1.00 eq.)and DIEA (80.1 mL; 476.5 mmol; 5.00 eq.) in DMF (200 mL) was added tert-butyl 2-bromoacetate (22.8 g; 114.4 mmol; 1.02 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 PE / EA (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 %) as a white solid. LC-MS method N: [M+H]+402.2; Rt: 0.56 min 2-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}piperidin-1-yl)acetic acid To a stirred mixture of tert-butyl 2-(4-{4-[(2,6-dioxopiperidin-3- yl)amino]phenyl}piperidin-1-yl)acetate (10.0 g; 21.17 mmol; 1.00 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. LC-MS method X: [M+H]+346.0; Rt: 0.36 min Intermediate 39: 3-({4-[3-(piperazin-1-yl)azetidin-1-yl]phenyl}amino)piperidine- 2,6-dione -116-Attorney Docket No. : P24-187-WO-PCTtert-butyl 4-[1-(4-nitrophenyl)azetidin-3-yl]piperazine-1-carboxylate To a stirred solution of 1-fluoro-4-nitrobenzene (1.00 g; 6.73 mmol; 1.00 eq.) and tert-butyl 4-(azetidin-3-yl)piperazine-1-carboxylate (1.70 g; 6.73 mmol; 1.00 eq.) in DMF (20.0 mL) was added K2CO3 (2.90 g; 20.20 mmol; 3.00 eq.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 80 ⁰C under. The reaction mixture was diluted with water, filtered and the filter cake was washed with water. The filtrate cake was concentrated under reduced pressure to give tert-butyl 4-[1-(4-nitrophenyl)azetidin-3-yl]piperazine-1-carboxylate (1.90 g; 5.35 mmol; 80 %) as a yellow solid. LC-MS method N: [M+H]+363.1; Rt: 0.67 min tert-butyl 4-[1-(4-aminophenyl)azetidin-3-yl]piperazine-1-carboxylate Starting from tert-butyl 4-[1-(4-nitrophenyl)azetidin-3-yl]piperazine-1-carboxylate (1.90 g; 5.24 mmol; 1.00 eq.) general procedure L for reduction was followed to afford tert-butyl 4-[1-(4-aminophenyl)azetidin-3-yl]piperazine-1-carboxylate (1.20 g; 3.52 mmol; 67 %) as a yellow solid. LC-MS method M: [M+H]+333.1; Rt: 0.39 min tert-butyl 4-[1-(4-{[2,6-bis(benzyloxy)pyridin-3-yl]amino}phenyl)azetidin-3- yl]piperazine-1-carboxylate To a stirred solution of tert-butyl 4-[1-(4-aminophenyl)azetidin-3-yl]piperazine-1- carboxylate (1.10 g; 3.40 mmol; 1.00 eq.) and 2,6-bis(benzyloxy)-3-bromopyridine (1.50 g; 4.08 mmol; 1.20 eq.) in 1,4-dioxane (20.0 mL) were added Pd2(dba)3 (346.0 mg; 0.34 mmol; 0.10 eq.), Xantphos (397.0 mg; 0.68 mmol; 0.20 eq.) andt-BuONa (1.00 g; 10.20 mmol; 3.00 eq.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100 ⁰C under nitrogen atmosphere. The resulting mixture was diluted with water and extracted with EtOAc -117-Attorney Docket No. : P24-187-WO-PCT three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and was concentrated under reduced pressure. The residue was purified by silica gel column chromatogrpahy, eluted with PE / EA (1:1) to afford tert-butyl 4-[1-(4-{[2,6-bis(benzyloxy)pyridin-3-yl]amino}phenyl)azetidin-3- yl]piperazine-1-carboxylate (1.80 g; 2.89 mmol; 85 %) as a yellow solid. LC-MS method J: [M+H]+622.3; Rt: 0.78 min tert-butyl 4-(1-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}azetidin-3- yl)piperazine-1-carboxylate Starting from tert-butyl 4-[1-(4-{[2,6-bis(benzyloxy)pyridin-3- yl]amino}phenyl)azetidin-3-yl]piperazine-1-carboxylate (1.80 g; 2.81 mmol; 1.00 eq.) general procedure G for reduction was followed to afford tert-butyl 4-(1-{4-[(2,6- dioxopiperidin-3-yl)amino]phenyl}azetidin-3-yl)piperazine-1-carboxylate (1.20 g; 2.40 mmol; 85 %) as a green solid. LC-MS method M: [M+H]+444.2; Rt: 0.42 min 3-({4-[3-(piperazin-1-yl)azetidin-1-yl]phenyl}amino)piperidine-2,6-dione Starting from tert-butyl 4-(1-{4-[(2,6-dioxopiperidin-3-yl)amino]phenyl}azetidin-3- yl)piperazine-1-carboxylate (1.20 g; 2.36 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 3-({4-[3-(piperazin-1-yl)azetidin-1- yl]phenyl}amino)piperidine-2,6-dione (780.0 mg; 2.23 mmol; 95 %) as a yellow solid. LC-MS method J: [M+H]+344.2; Rt: 0.24 min Intermediate 40: 3-{3-methyl-2-oxo-5-[3-(piperazin-1-yl)azetidin-1-yl]-2,3- dihydro-1H-1,3-benzodiazol-1-yl}piperidine-2,6-dione; trifluoroacetic acid -118-Attorney Docket No. : P24-187-WO-PCTtert-butyl 4-{1-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3- benzodiazol-5-yl]azetidin-3-yl}piperazine-1-carboxylate To a solution of tert-butyl 4-(azetidin-3-yl)piperazine-1-carboxylate (200.0 mg; 0.80 mmol; 1.00 eq.) and 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1- yl)piperidine-2,6-dione (271.0 mg; 0.80 mmol; 1.00 eq.) in DMF (5.00 mL), 2- methylpyridine; {1,3-bis[2,6-bis(pentan-3-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H- imidazol-2-ylidene}dichloropalladium (67.54 mg; 0.08 mmol; 0.10 eq.) and Sodium tert-butylate for synthesis (154.5 mg; 1.61 mmol; 2.00 eq.) was added portionwise under argon atmosphere at RT. The mixture was stirred for 1 h at 100 °C. The reaction mixture was evaporated and purified by silica gel column chromatography, eluted with 0-15% Methanol in DCM, to afford tert-butyl 4-{1-[1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]azetidin- 3-yl}piperazine-1-carboxylate (170.0 mg; 0.31 mmol; 39 %). LC-MS method U: 499 [M+H]; Rt: 1.05 min 3-{3-methyl-2-oxo-5-[3-(piperazin-1-yl)azetidin-1-yl]-2,3-dihydro-1H-1,3- benzodiazol-1-yl}piperidine-2,6-dione; trifluoroacetic acid To a solution of tert-butyl 4-{1-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-1,3-benzodiazol-5-yl]azetidin-3-yl}piperazine-1-carboxylate (170.0 mg; 0.31 mmol; 1.00 eq.) in DCM (5.00 mL), TFA (1.00 mL) was added dropwise and the mixture stirred for 1 h at rt. The reaction mixture was evaporated with toluene and the -119-Attorney Docket No. : P24-187-WO-PCT residue was stirred with MTBE. The precipitate was filtered with suction to give 3-{3- methyl-2-oxo-5-[3-(piperazin-1-yl)azetidin-1-yl]-2,3-dihydro-1H-1,3-benzodiazol-1- yl}piperidine-2,6-dione; trifluoroacetic acid (225.0 mg; 0.32 mmol; Quant.) LC-MS method U: 399 [M+H]; Rt: 0.80 min Intermediate 41: tert-butyl 4-({2',6'-dioxo-2H-spiro[1-benzofuran-3,3'-piperidin]- 5-yl}methyl)piperidine-1-carboxylateethyl 5-bromo-2-hydroxy-2,3-dihydro-1-benzofuran-3-carboxylate To a stirred mixture of 5-bromo-2-hydroxybenzaldehyde (46.00 g; 224.26 mmol; 1.00 eq.) and tetrafluoroboric acid diethyl ether complex (7.30 g; 22.54 mmol; 0.10 eq.) in DCM (500.00 mL) at 20 °C were added ethyl 2-diazoacetate (43.10 g; 358.84 mmol; 1.60 eq.) at 20 °C. The resulting mixture was stirred for 2 h at room temperature and then concentrated under reduced pressure to provide ethyl 5-bromo-2-hydroxy-2,3- dihydro-1-benzofuran-3-carboxylate (64.50 g; 194.0 mmol; 86.5 %) without further purification. LC-MS method AE: Mass not observed; Rt: 0.68 min ethyl 5-bromo-1-benzofuran-3-carboxylate In a 2L round bottom flask were added ethyl 5-bromo-2-hydroxy-2,3-dihydro-1- benzofuran-3-carboxylate (90.00 g; 270.78 mmol; 1.00 eq.) and conc. H2SO4 (600.00 mL) at 0 °C.The resulting mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with EA (400 mL) and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography, eluted with DCM:MeOH (10:1) to afford ethyl 5-bromo-1-benzofuran-3-carboxylate (69.50 g; 258.3 mmol; 95.4 %). LC-MS method P: Mass not observed; Rt: 1.13 min 4-{[3-(ethoxycarbonyl)-1-benzofuran-5-yl]methylidene}piperidine-1-carboxylate -120-Attorney Docket No. : P24-187-WO-PCT To a stirred mixture of ethyl 5-bromo-1-benzofuran-3-carboxylate (15.00 g; 40.72 mmol; 1.00 eq.) and tert-butyl 4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)methylidene]piperidine-1-carboxylate (14.00 g; 42.5 mmol; 1.04 eq.) in 1,4- dioxane (250.00 mL) and H2O (50.00 mL) were added CsF (20.00 g; 125.08 mmol; 3.07 eq.) and Pd(dppf)Cl2.DCM (3.50 g; 4.07 mmol; 0.10 eq.). The resulting mixture was stirred for 2 h at 100 °C under N2atmosphere. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated under reduced pressure and the crude mixture was purified by silica gel column chromatography, eluted with PE:EA (10:1) to afford tert-butyl 4-{[3-(ethoxycarbonyl)-1-benzofuran-5- yl]methylidene}piperidine-1-carboxylate (11.50 g; 29.44 mmol; 72 %). LC-MS method I: [M-H]+329.0; Rt: 0.43 min 4-{[3-(ethoxycarbonyl)-1-benzofuran-5-yl]methyl}piperidine-1-carboxylate To a solution of tert-butyl 4-{[3-(ethoxycarbonyl)-1-benzofuran-5- yl]methylidene}piperidine-1-carboxylate (10.00 g; 25.60 mmol; 1.00 eq.) in MeOH (300.00 mL) was added Pd(OH)2 / C under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 1 h under hydrogen atmosphere using a hydrogen balloon. The resulting mixture was diluted with DCM (300 mL). The resulting mixture was filtered and the filtrated was concentrated under reduced pressure to give tert-butyl 4-{[3-(ethoxycarbonyl)-1-benzofuran-5- yl]methyl}piperidine-1-carboxylate (9.80 g; 25.29 mmol; 98.8 %) without further purification. LC-MS method P: Mass not observed; Rt: 1.42 min tert-butyl 4-{[3-(methoxycarbonyl)-2,3-dihydro-1-benzofuran-5- yl]methyl}piperidine-1-carboxylate To a stirred mixture of tert-butyl 4-{[3-(ethoxycarbonyl)-1-benzofuran-5- yl]methyl}piperidine-1-carboxylate (5.00 g; 12.90 mmol; 1.00 eq.) in MeOH (300.00 mL) were added Mg (1.65 g; 64.48 mmol; 5.00 eq.). The resulting mixture was stirred for 6 h at room temperature, diluted with DCM (300 mL). and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography, eluted with PE:EA (5:1) to afford tert-butyl 4-{[3- (methoxycarbonyl)-2,3-dihydro-1-benzofuran-5-yl]methyl}piperidine-1-carboxylate (2.50 g; 6.66 mmol; 51.6 %). -121-Attorney Docket No. : P24-187-WO-PCT LC-MS method C: [M+H]+376.0; Rt: 1.21 min tert-butyl 4-({2',6'-dioxo-2H-spiro[1-benzofuran-3,3'-piperidin]-5- yl}methyl)piperidine-1-carboxylate To a stirred mixture of tert-butyl 4-{[3-(methoxycarbonyl)-2,3-dihydro-1-benzofuran- 5-yl]methyl}piperidine-1-carboxylate (2.50 g; 6.66 mmol; 1.00 eq.) in THF (20.00 mL) were added t-BuOK (870.0 mg; 7.37 mmol; 1.11 eq.) at 0 °C under N2 atmosphere, followed by the addition of prop-2-enamide (480.0 mg; 6.62 mmol; 0.99 eq.) at 0°C. The resulting mixture was stirred for 30 min at room temperature. The reaction was quenched with NH4Cl (aq.) at room temperature and the resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 100 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 (4:1) to afford tert-butyl 4- ({2',6'-dioxo-2H-spiro[1-benzofuran-3,3'-piperidin]-5-yl}methyl)piperidine-1- carboxylate (1.64 g; 3.96 mmol; 59.4 %) LC-MS method C: [M-H]+413.0; Rt: 1.07 min Intermediate 42: 1-(2,3-dihydro-1H-isoindol-5-yl)-1,3-diazinane-2,4-dione hydrochloridetert-butyl 5-(2,4-dioxo-1,3-diazinan-1-yl)-2,3-dihydro-1H-isoindole-2-carboxylate To a stirred mixture of tert-butyl 5-bromo-2,3-dihydro-1H-isoindole-2-carboxylate (3.00 g; 9.56 mmol; 1.00 eq.) and 1,3-diazinane-2,4-dione (1.72 g; 14.34 mmol; 1.50 eq.) in 1,4-Dioxane (50.00 mL) were added Cs2CO3(9.83 g; 28.67 mmol; 3.00 eq.), EPhos Pd G4 (0.92 g; 0.96 mmol; 0.10 eq.) and Ephos (1.08 g; 1.91 mmol; 0.20 eq.) at room temperature. The mixture was stirred for 16 h at 100 °C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. And the crude material was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford tert-butyl 5-(2,4-dioxo-1,3-diazinan-1-yl)-2,3-dihydro- 1H-isoindole-2-carboxylate (2.95 g; 8.68 mmol; 90.8 %) LC-MS method AF: [M-tBu+2H]+276.0; Rt: 0.81 min -122-Attorney Docket No. : P24-187-WO-PCT 1-(2,3-dihydro-1H-isoindol-5-yl)-1,3-diazinane-2,4-dione hydrochloride Tert-butyl 5-(2,4-dioxo-1,3-diazinan-1-yl)-2,3-dihydro-1H-isoindole-2-carboxylate (2.90 g; 8.65 mmol; 1.00 eq.) was added in 4 M HCl solution in EtOAc (30.00 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The solid was collected by filtration and washed with EA, the filter cake was dried under reduced pressure to afford 1-(2,3-dihydro-1H-isoindol-5-yl)-1,3-diazinane-2,4-dione hydrochloride (2.20 g; 7.93 mmol; 91.7 %) without further purification. LC-MS method AF: [M+H]+232.0; Rt: 0.15 min Intermediate 43: 1-[(4-methoxyphenyl)methyl]-2,6-dioxopiperidin-3-yl trifluoromethanesulfonateTo a stirred solution of 3-hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (10.00 g; 38.11 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 was stirred 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 3 h 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 %) LC-MS method AD: [M+Na]+404.0; Rt: 0.93 min Intermediate 44: 3-(7-bromo-2-oxo-2,3-dihydro-1,3-benzoxazol-3-yl)-1-[(4- methoxyphenyl)methyl]piperidine-2,6-dione -123-Attorney Docket No. : P24-187-WO-PCTTo 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 0.5 h at 0 °C under nitrogen atmosphere and then Intermediate 43 (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 %). LC-MS method AF: [M+H]+445.0 ; Rt: 1.03 min Intermediate 45: 2,6-bis(benzyloxy)-3-[(4-chlorophenyl)methyl]pyridineA 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 (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 (5.00 mL) and 1,4-Dioxane (15.00 mL) was stirred for 3 h at 100 °C under argon atmosphere. The reaction mixture was cooled down and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 2,6-bis(benzyloxy)-3- [(4-chlorophenyl)methyl]pyridine (4.00 g; 8.90 mmol; 96 %) LC-MS method AF: [M+H]+416.0; Rt: 1.21 min -124-Attorney Docket No. : P24-187-WO-PCT Intermediate 46: 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1- yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dioneTo 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 0.5 h at 0 °C under nitrogen atmosphere and Intermediate 43 (7.10 g; 17.57 mmol; 1.40 eq.) at 0 °C was added. 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-(4-bromo-3-methyl-2- oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine- 2,6-dione (4.30 g; 8.52 mmol; 67 %) LC-MS method AD: [M+H]+458.0; Rt: 0.94 min Intermediate 47: 3-bromo-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dioneTo a stirred solution of 3-bromopiperidine-2,6-dione (1.00 g; 5.10 mmol; 1.00 eq.) in acetone (15.00 mL) were added K2CO3(2.23 g; 15.31 mmol; 3.00 eq.) and 1- (chloromethyl)-4-methoxybenzene (1.68 g; 10.21 mmol; 2.00 eq.) in portions at 0 °C. The rection mixture was stirred 16 h at room temperature, then diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na2SO4and filtered. The filtrate -125-Attorney Docket No. : P24-187-WO-PCT was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with PE / EA (4:1) to afford 3-bromo-1-[(4- methoxyphenyl)methyl]piperidine-2,6-dione (0.70 g; 1.99 mmol; 39.0 %) LC-MS method AD: 315 [M+H]+315.0; Rt: 0.84 min Intermediate 48: 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridineTo a stirred solution of Intermediate 30 (6.00 g; 13.16 mmol; 1.00 eq.) and 1-bromo- 4-iodobenzene (4.00 g; 13.43 mmol; 1.02 eq.) in 1,4-dioxane (35.00 mL) and H2O (7.00 mL) was added Pd(PPh3)4(3.20 g; 2.63 mmol; 0.20 eq.) and Na2CO3(3.00 g; 26.89 mmol; 2.04 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 reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA(10:1) to afford 2,6-bis(benzyloxy)-3-(4- bromophenyl)pyridine (3.50 g; 6.88 mmol; 52.3 % yield) as a white solid. LC MS Method I: [M+H]+446.0; Rt: 1.19 min Intermediate 49: 3-{4-[4-(azetidin-3-yloxy)piperidin-1-yl]phenyl}piperidine-2,6- dione; trifluoroacetic acid -126-Attorney Docket No. : P24-187-WO-PCTtert-butyl 3-(pyridin-4-yloxy)azetidine-1-carboxylate To a solution of pyridin-4-ol (2.00 g; 19.98 mmol; 1.00 eq.) in THF (30 mL) was added tert-butyl 3-hydroxyazetidine-1-carboxylate (4.40 g; 24.13 mmol; 1.21 eq.) and PPh3 (6.60 g; 23.91 mmol; 1.20 eq.) at room temperature. Then DIAD (4.43 mL; 23.96 mmol; 1.20 eq.) was added to the above solution and the mixture was heated at 55 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was quenched by the addition of H2O at room temperature and extracted by EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL) 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 (1:9) to afford tert-butyl 3-(pyridin-4- yloxy)azetidine-1-carboxylate (6.00 g; 19.81 mmol; 99.2 %) as a yellow oil. LC MS Method I: [M+H]+251.0; Rt: 0.65 min tert-butyl 3-(piperidin-4-yloxy)azetidine-1-carboxylate A solution of tert-butyl 3-(pyridin-4-yloxy)azetidine-1-carboxylate (5.90 g; 19.5 mmol; 1.00 eq.), dioxoplatinum (1.16 g; 4.85 mmol; 0.25 eq.) and TsOH (3.38 g; 19.43 mmol; 1.00 eq.) in EtOH (60 mL) was stirred for 16 h at room temperature under H2 atmosphere. The resulting mixture was quenched with water (150 mL) and extracted with DCM(3 x 100 mL). The combined organic layers were washed with -127-Attorney Docket No. : P24-187-WO-PCT brine (150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 3-(piperidin-4- yloxy)azetidine-1-carboxylate (5.00 g; 15.6 mmol; 80.1 %) as a colorless oil. LC MS Method I: [M+H]+257.0; Rt: 0.64 min tert-butyl 3-[(1-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}piperidin-4- yl)oxy]azetidine-1-carboxylate A solution of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (3.40 g; 7.51 mmol; 0.49 eq.) and Intermediate 48 tert-butyl 3-(piperidin-4-yloxy)azetidine-1-carboxylate (4.90 g; 15.29 mmol; 1.00 eq.) in 1,4-dioxane (50 mL) were added Ruphospallacycle Gen.4 (14.00 mg; 0.02 mmol; 0.01 eq.) and Cs2CO3(107.00 mg; 0.31 mmol; 0.02 eq.) at room temperature. The reaction mixture was stirred for 12 h 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 PE / EA (3:1) to afford tert-butyl 3-[(1-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}piperidin-4- yl)oxy]azetidine-1-carboxylate (1.00 g; 1.32 mmol; 8.6 %) as a yellow solid. LC MS Method: M [M+H]+622.0; Rt: 1.15 min tert-butyl 3-({1-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperidin-4-yl}oxy)azetidine-1- carboxylate A solution of tert-butyl 3-[(1-{4-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}piperidin-4- yl)oxy]azetidine-1-carboxylate (950.00 mg; 1.25 mmol; 1.00 eq.) in DMF (10 mL) was added Pd / C (133.00 mg; 0.12 mmol; 0.10 eq.). The mixture was stirred for 16 h at 25 °C under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with 50 mL of EA. The filtrate was quenched by the addition of H2O at room temperature and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 3-({1-[4-(2,6-dioxopiperidin-3- yl)phenyl]piperidin-4-yl}oxy)azetidine-1-carboxylate (600.00 mg; 1.11 mmol; 88.6 %) as a gray solid. LC MS Method AM: [M+H]+444.0; Rt: 0.62 min 3-{4-[4-(azetidin-3-yloxy)piperidin-1-yl]phenyl}piperidine-2,6-dione; trifluoroacetic acid To a stirred mixture of tert-butyl 3-({1-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperidin- 4-yl}oxy)azetidine-1-carboxylate (400.00 mg; 0.74 mmol; 1.00 eq.) in DCM (4.00 -128-Attorney Docket No. : P24-187-WO-PCT mL) was added TFA (1.00 mL) in portions at 25 °C under nitrogen atmosphere. The resulting mixture was stirred for 5h at 25 °C under nitrogen atmosphere. A slurry with TBME was formed. Then the solid was filtered, and the filter cake was washed with TBME (30 mL) and the filter cake was dried under reduced pressure to afford 3-{4- [4-(azetidin-3-yloxy)piperidin-1-yl]phenyl}piperidine-2,6-dione; trifluoroacetic acid (300.00 mg; 0.49 mmol; 66.5 %) as a yellow semi solid. LC MS Method AM: [M+H]+344.0; Rt: 0.34min Intermediate 50: 2-{4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}-1-[3-(piperazin-1- yl)azetidin-1-yl]ethan-1-onetert-butyl 4-[1-(2-{4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl)amino]phenyl}acetyl)azetidin-3-yl]piperazine-1-carboxylate Starting from Intermediate 2 (0.70 g; 1.28 mmol, 1.00 eq.) and 1-N-Boc-4-azetidin-3- yl-piperazine (319.31 mg; 1.28 mmol, 1.00 eq.) general procedure J for amide coupling was followed to afford tert-butyl 4-[1-(2-{4-[(7-{1-[(tert-butoxy)carbonyl]- 8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4- d]pyrimidin-2-yl)amino]phenyl}acetyl)azetidin-3-yl]piperazine-1-carboxylate (743.0 mg; 0.84 mmol; 73 %) as a light brown foamed oil. LC MS Method T: [M+H]+756.0; Rt: 1.43 min -129-Attorney Docket No. : P24-187-WO-PCT 2-{4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H- pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}-1-[3-(piperazin-1-yl)azetidin-1- yl]ethan-1-one Starting from tert-butyl 4-[1-(2-{4-[(7-{1-[(tert-butoxy)carbonyl]-8-methyl- 1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl)amino]phenyl}acetyl)azetidin-3-yl]piperazine-1-carboxylate (627.00 mg; 0.79 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 2- {4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H- pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}-1-[3-(piperazin-1-yl)azetidin-1-yl]ethan- 1-one (108.0 mg; 0.19 mmol; 24 %) as a light gray foamed oil. LC-MS Method T: [M+H]+556.0; Rt: 1.03 min. Intermediate 51: 1-(4-bromo-2-methylphenyl)-1,3-diazinane-2,4-dione O4-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 110 °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 °C 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 1-(4-bromo-2- methylphenyl)-1,3-diazinane-2,4-dione (32.00 g; 103.93 mmol; 78.1 %) as a light yellow solid. LC MS Method C: [M+H]+283.0; Rt: 0.64 min -130-Attorney Docket No. : P24-187-WO-PCT Intermediate 52: 1-(4-bromo-2-methylphenyl)-3-[(4-methoxyphenyl)methyl]-1,3- diazinane-2,4-dioneTo a stirred solution of Intermediate (10.00 g; 32.48 mmol; 1.00 eq.) and 1- (chloromethyl)-4-methoxybenzene (10.71 g; 64.95 mmol; 2.00 eq.) in DMF (150 mL) was added K2CO3(14.17 g; 97.43 mmol; 3.00 eq.) ain portions at room temperature. The reaction mixture was stirred at room temperature for 48h. The resulting mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 150mL). The combined organic layers were washed with brine (200 mL) 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 1-(4-bromo-2-methylphenyl)-3-[(4-methoxyphenyl)methyl]-1,3- diazinane-2,4-dione (8.00 g; 19.06 mmol; 58.7 %) as a colorless oil. LC MS Method AD: [M+H]+403.0; Rt: 0.94 min Intermediate 53: 3-[(4-methoxyphenyl)methyl]-1-[2-methyl-4-(4-{[1-(4- nitrophenyl)piperidin-4-yl]methyl}piperazin-1-yl)phenyl]-1,3-diazinane-2,4- -131-Attorney Docket No. : P24-187-WO-PCT 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 To a stirred mixture of Intermediate 52 (1.42 mg; 0.00 mmol; 0.00 eq.) and 1-(4- bromo-2-methylphenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (2.00 g; 4.76 mmol; 1.00 eq.) in Dioxane-1,4 (20 mL) were added Pd2(dba)3(460.00 mg; 0.48 mmol; 0.10 eq.) and Xphos (480.0 mg; 0.96 mmol; 0.20 eq.). Then Cs2CO3(3.14 g; 9.54 mmol; 2.00 eq.) was added and the reaction was stirred for 4 h 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 PE / EA (1:4) to afford 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 (3.00 g; 4.88 mmol; 102.4 %) as a yellow solid. LC MS Method AD: [M+H]+606.0; Rt: 0.83 min 3-[(4-methoxyphenyl)methyl]-1-(2-methyl-4-{4-[(piperidin-4- yl)methyl]piperazin-1-yl}phenyl)-1,3-diazinane-2,4-dione 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 (2.90 g; 4.72 mmol; 1.00 eq.) in DCM (29.00 mL) was added TFA (7.25 mL) in portions at room temperature under nitrogen atmosphere. The resulting mixture was -132-Attorney Docket No. : P24-187-WO-PCT stirred for 5h at room temperature under nitrogen atmosphere. The mixture was basified to pH 7 with saturated NaHCO3 (aq.). The resulting mixture was extracted with DCM. The combined organic layers were washed with NaCl (aq.) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-[(4-methoxyphenyl)methyl]-1-(2-methyl-4-{4-[(piperidin-4- yl)methyl]piperazin-1-yl}phenyl)-1,3-diazinane-2,4-dione (2.50 g; 4.58 mmol; 97.2 %) as a yellow solid. LC MS Method AD: [M+H]+506.0; Rt: 0.63 min 3-[(4-methoxyphenyl)methyl]-1-[2-methyl-4-(4-{[1-(4-nitrophenyl)piperidin-4- yl]methyl}piperazin-1-yl)phenyl]-1,3-diazinane-2,4-dione To a stirred solution of 3-[(4-methoxyphenyl)methyl]-1-(2-methyl-4-{4-[(piperidin-4- yl)methyl]piperazin-1-yl}phenyl)-1,3-diazinane-2,4-dione (2.40 g; 4.40 mmol; 1.00 eq.) and 1-fluoro-4-nitrobenzene (1.30 g; 8.75 mmol; 1.99 eq.) in ACN (25.00 mL) was added DIEA (3.00 g; 22.06 mmol; 5.01 eq.) in portion at room temperature. The resulting mixture was stirred for 3h at 90 °C. 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 3-[(4- methoxyphenyl)methyl]-1-[2-methyl-4-(4-{[1-(4-nitrophenyl)piperidin-4- yl]methyl}piperazin-1-yl)phenyl]-1,3-diazinane-2,4-dione (2.00 g; 2.86 mmol; 65.1 %) as a yellow solid. LC MS Method AD: [M+H]+627.0; Rt: 0.86 min 1-[4-(4-{[1-(4-aminophenyl)piperidin-4-yl]methyl}piperazin-1-yl)-2- methylphenyl]-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione 3-[(4-methoxyphenyl)methyl]-1-[2-methyl-4-(4-{[1-(4-nitrophenyl)piperidin-4- yl]methyl}piperazin-1-yl)phenyl]-1,3-diazinane-2,4-dione (1.90 g; 2.72 mmol; 1.00 eq.) was dissolved in in DMF (19 mL) and Pd / C (289.00 mg; 0.27 mmol; 0.10 eq.) was added . The reaction mixture was stirred for 16 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with 50 mL EA. The filtrate was quenched by the addition of H2O at room temperature and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 1-[4-(4-{[1-(4- aminophenyl)piperidin-4-yl]methyl}piperazin-1-yl)-2-methylphenyl]-3-[(4- -133-Attorney Docket No. : P24-187-WO-PCT methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (1.60 g; 2.56 mmol; 94.2 % yield) as a yellow solid. LC MS Method AD: [M+H]+597.0; Rt: 0.68 min Intermediate 54: 3,3-difluoro-4-(4-nitrophenyl)-1,4'-bipiperidinetert-butyl 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate To a stirred solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-1(2H)-carboxylate (100.00 g; 307.24 mmol; 1.00 eq.), 1-bromo-4- nitrobenzene (65.33 g; 307.24 mmol; 1.00 eq.) and Na2CO3 (51.42 g; 460.85 mmol; 1.50 eq.) in Dioxane-1,4 (1 L) / H2O (200 mL) was added Pd(PPh3)4(11.21 g; 9.22 mmol; 0.03 eq.) under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 90 °C under nitrogen atmosphere. The reaction mixture was diluted by H2O (500 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine-1- carboxylate (80.00 g; 261.28 mmol; 85.0 %) as a white solid. LC MS Method AD: [M+H-tBu]+249.2; Rt: 1.06 min tert-butyl 3-hydroxy-4-(4-nitrophenyl)piperidine-1-carboxylate To a stirred solution of tert-butyl 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine-1- carboxylate (80.00 g; 261.29 mmol; 1.00 eq.) in THF (700 mL) was added BH3•THF (287.41 mL; 287.41 mmol; 1.10 eq.) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 25 °C under nitrogen atmosphere.5N aq. NaOH (31.35 g; 783.86 mmol; 3.00 eq.) in H2O (140 mL) was added at 0 °C and the reaction mixture was stirred for 1 h at 0 °C. H2O2 (72.09 mL; 718.54 mmol; 2.75 eq.) was added dropwise and the resulting mixture was stirred for 5 h at 50 °C. The -134-Attorney Docket No. : P24-187-WO-PCT reaction was diluted by the addition of H2O (1000 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The organic phase was washed with brine. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with PE / EtOA (1 / 1) to afford tert-butyl 3- hydroxy-4-(4-nitrophenyl)piperidine-1-carboxylate (21.00 g; 64.64 mmol; 24.7 %) as a yellow solid. LC MS Method AD: [M+H-tBu]+267.2; Rt: 0.89 min tert-butyl 4-(4-nitrophenyl)-3-oxopiperidine-1-carboxylate To a stirred solution of tert-butyl 3-hydroxy-4-(4-nitrophenyl)piperidine-1- carboxylate (20.00 g; 61.57 mmol; 1.00 eq.) in DCM (500 mL) was added Dess- Martin periodinane (DMP) (54.97 g; 123.13 mmol; 2.00 eq.). The resulting mixture was stirred for 16 h at 25 °C. 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 4-(4-nitrophenyl)-3-oxopiperidine-1-carboxylate (12.00 g; 30.56 mmol; 49.6 %) as a yellow oil. LC MS Method Y: [M+H]+319.5; Rt: 1.28 min tert-butyl 3,3-difluoro-4-(4-nitrophenyl)piperidine-1-carboxylate To a stirred solution of tert-butyl 4-(4-nitrophenyl)-3-oxopiperidine-1-carboxylate (14.00 g; 25.55 mmol; 1.00 eq.) in DCM (200 mL) was added DAST (6.11 mL; 56.21 mmol; 2.20 eq.) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 25 °C under nitrogen atmosphere. The reaction mixture was quenched by the addition of sat. NaHCO3(aq.) (1000 mL). The resulting mixture was extracted with DCM (3 x 500 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 3) to afford tert-butyl 3,3-difluoro-4-(4-nitrophenyl)piperidine-1-carboxylate (5.60 g; 15.47 mmol; 60.5 % yield) as a yellow oil. LC MS Method G: [M+H]+343,25; Rt: 1.15 min 3,3-difluoro-4-(4-nitrophenyl)piperidine Starting from tert-butyl 3,3-difluoro-4-(4-nitrophenyl)piperidine-1-carboxylate (7.99 g; 22.07 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed in the presence of DCM (100 mL) and TFA (30 mL) to afford 3,3-difluoro-4-(4- nitrophenyl)piperidine (5.51 g; 21.34 mmol; 96.7 %) as a yellow oil. -135-Attorney Docket No. : P24-187-WO-PCT LC MS Method AD: [M+H]+243.2; Rt: 0.66 min tert-butyl 3,3-difluoro-4-(4-nitrophenyl)-[1,4'-bipiperidine]-1'-carboxylate To a stirred solution of 3,3-difluoro-4-(4-nitrophenyl)piperidine (5.20 g; 20.13 mmol; 1.00 eq.) and tert-butyl 4-oxopiperidine-1-carboxylate (4.22 g; 20.13 mmol; 1.00 eq.) in MeOH (150 mL) was added Ti(Oi-Pr)4 (12.55 mL; 40.27 mmol; 2.00 eq.) dropwise. The resulting mixture was stirred for 16 h at 25 °C. NaBH3CN (6.59 g; 100.67 mmol; 5.00 eq.) was added and the reaction was stirred for 16 h at 25 °C. The reaction was quenched by the addition of H2O (600 mL). The resulting mixture was extracted with DCM (3 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 2) to afford tert-butyl 3,3-difluoro-4-(4-nitrophenyl)-[1,4'-bipiperidine]-1'-carboxylate (6.20 g; 14.08 mmol; 69.9 %) as a yellow solid. LC MS Method AD: [M+H]+426.20; Rt: 0.82 min 3,3-difluoro-4-(4-nitrophenyl)-1,4'-bipiperidine Starting from tert-butyl 3,3-difluoro-4-(4-nitrophenyl)-[1,4'-bipiperidine]-1'- carboxylate (6.00 g; 13.63 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed in the presence of DCM (100 mL) and TFA (40 mL) to afford 3,3- difluoro-4-(4-nitrophenyl)-1,4'-bipiperidine (4.20 g; 12.50 mmol; 91.8 %) as a yellow solid. LC MS Method AD: [M+H]+326.1; Rt: 0.65 min Intermediate 55: 1-(4-{3,3-difluoro-4-[4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin- 2-yl}amino)phenyl]-[1,4'-bipiperidin]-1'-yl}-2-methylphenyl)-1,3-diazinane-2,4- dione -136-Attorney Docket No. : P24-187-WO-PCT1-{4-[3,3-difluoro-4-(4-nitrophenyl)-[1,4'-bipiperidin]-1'-yl]-2-methylphenyl}-3- [(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione Starting from Intermediate 54 (2.00 g; 5.95 mmol; 1.00 eq.) and Intermediate 52 (2.81 g; 5.95 mmol; 1.00 eq.) general procedure E for Buchwald coupling was followed with Cs2CO3(4.08 g; 11.91 mmol; 2.00 eq.), Dioxane-1,4 (100 mL), Pd2(dba)3(0.55 g; 0.60 mmol; 0.10 eq.) and Xphos (0.60 g; 1.19 mmol; 0.20 eq.) to afford 1-{4-[3,3- difluoro-4-(4-nitrophenyl)-[1,4'-bipiperidin]-1'-yl]-2-methylphenyl}-3-[(4- methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (2.00 g; 3.04 mmol; 51.1 % yield) as a yellow solid. LC MS Method C: [M+H]+648.30; Rt: 0.84 min 1-{4-[4-(4-aminophenyl)-3,3-difluoro-[1,4'-bipiperidin]-1'-yl]-2-methylphenyl}-3- [(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione To a stirred solution of 1-{4-[3,3-difluoro-4-(4-nitrophenyl)-[1,4'-bipiperidin]-1'-yl]- 2-methylphenyl}-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (2.00 g; 3.04 mmol; 1.00 eq.) and 4,4'-bipyridine (50.00 mg; 0.30 mmol; 0.10 eq.) in DMF (100 mL) was added Tetrahydroxydiboron (862.00 mg; 9.13 mmol; 3.00 eq.). The resulting mixture was stirred for 0,5 h at 25 °C. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with DCM / MeOH (10 / 1) to afford 1-{4-[4-(4-aminophenyl)-3,3-difluoro-[1,4'- bipiperidin]-1'-yl]-2-methylphenyl}-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4- dione (1.80 g; 2.87 mmol; 94.2 %) as a yellow solid. -137-Attorney Docket No. : P24-187-WO-PCT LC MS Method O: [M+H]+618.45; Rt: 0.72 min tert-butyl 2-({4-[3,3-difluoro-1'-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3- diazinan-1-yl}-3-methylphenyl)-[1,4'-bipiperidin]-4-yl]phenyl}amino)- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate Starting from 1-{4-[4-(4-aminophenyl)-3,3-difluoro-[1,4'-bipiperidin]-1'-yl]-2- methylphenyl}-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (3.0 g; 4,75 mmol; 1 eq.) and tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7- carboxylate (1.29 g; 4.75 mmol; 1.00 eq.) general procedure P for Buchwald coupling was followed with Cs2CO3(3.26 g; 9.50 mmol; 2.00 eq.), Dioxane-1,4 (50 mL) and EPhos Pd G4 (460.00 mg; 0.48 mmol; 0.10 eq.) to afford tert-butyl 2-({4-[3,3- difluoro-1'-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}-3- methylphenyl)-[1,4'-bipiperidin]-4-yl]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4- d]pyrimidine-7-carboxylate (2.80 g; 2.67 mmol; 56.1 %) as a yellow solid. LC MS Method O: [M+H]+851.4; Rt: 1.09 min 1-(4-{3,3-difluoro-4-[4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl}amino)phenyl]-[1,4'-bipiperidin]-1'-yl}-2-methylphenyl)-1,3-diazinane-2,4- dione To a stirred solution of tert-butyl 2-({4-[3,3-difluoro-1'-(4-{3-[(4- methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}-3-methylphenyl)-[1,4'- bipiperidin]-4-yl]phenyl}amino)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7- carboxylate (1.75 g; 1.67 mmol; 1.00 eq.) in TFA (20.00 mL) was added TfOH (5.00 mL; 53.81 mmol; 32.29 eq.) under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 25 °C under nitrogen atmosphere. The reaction mixture was evaporated and the residue was diluted with NaHCO3 solution (50 mL). The resulting mixture was extracted with DCM / MeOH (5 / 1) (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4and concentrated under reduced pressure to afford 1-(4-{3,3-difluoro-4-[4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl}amino)phenyl]-[1,4'-bipiperidin]-1'-yl}-2-methylphenyl)-1,3-diazinane-2,4-dione (1.02 g; 1.43 mmol; 85.7 %) as a yellow solid. LC MS Method X: [M+H]+651.3; Rt: 0.5 min Intermediate 56: methyl 2-[2-fluoro-4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl}amino)phenyl]acetate; trifluoroacetic acid -138-Attorney Docket No. : P24-187-WO-PCTtert-butyl 2-{[3-fluoro-4-(2-methoxy-2-oxoethyl)phenyl]amino}-5H,6H,7H,8H- pyrido[3,4-d]pyrimidine-7-carboxylate tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (5.79 g; 20.64 mmol; 1.00 eq.), methyl 2-(4-Amino-2-fluorophenyl)acetate (3.78 g; 20.64 mmol; 1.00 eq.) and Cesium carbonate (23.53 g; 72.22 mmol; 3.50 eq.) were suspended in 1,4-Dioxane (132 mL). Argon was then bubbled through the reaction mixture and Pd-PEPPSI-IPentCl 2-methylpyridine (547.47 mg; 0.62 mmol; 0.03 eq.) was added. The reaction mixture was stirred 24 h at 105°C. The brown suspension was filtered over Celite and rinsed with DCM. The solvent was evaporated. The residue was purified by flash chromatography Heptane / EtOAc to afford tert-butyl 2- {[3-fluoro-4-(2-methoxy-2-oxoethyl)phenyl]amino}-5H,6H,7H,8H-pyrido[3,4- d]pyrimidine-7-carboxylate (5.31 g; 12.76 mmol; 61.8 % yield) as an orange solid. LC MS Method T: [M+H]+417.2; Rt: 1.66 min Methyl 2-[2-fluoro-4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl}amino)phenyl]acetate; trifluoroacetic acid Starting from tert-butyl 2-{[3-fluoro-4-(2-methoxy-2-oxoethyl)phenyl]amino}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (5.31 g; 12.76 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford methyl 2-[2-fluoro- 4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)phenyl]acetate; trifluoroacetic acid (4.11 g; 9.43 mmol; 73.9 %) as a light yellow solid. LC MS Method T: [M+H]+317.2; Rt: 1.08 min Intermediate 57: 2-{2-fluoro-4-[(7-{8-methyl-2H,3H-[1,4]dioxino[2,3-b]pyridin-7- yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}acetic acid -139-Attorney Docket No. : P24-187-WO-PCTMethyl 2-{2-fluoro-4-[(7-{8-methyl-2H,3H-[1,4]dioxino[2,3-b]pyridin-7-yl}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}acetate Starting from 7-Chloro-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (1.00 g; 5.17 mmol; 1.00 eq.) and Intermediate 56 (1.71 g; 5.34 mmol; 1.03 eq.) general procedure F for Buchwald coupling was followed to afford methyl 2-{2-fluoro-4-[(7- {8-methyl-2H,3H-[1,4]dioxino[2,3-b]pyridin-7-yl}-5H,6H,7H,8H-pyrido[3,4- d]pyrimidin-2-yl)amino]phenyl}acetate (627.00 mg; 1.35 mmol, 26 %) as a pale orange solid. LC MS Method AJ: [M+H]+466.3; Rt: 0.79 min 2-{2-fluoro-4-[(7-{8-methyl-2H,3H-[1,4]dioxino[2,3-b]pyridin-7-yl}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}acetic acid Methyl 2-{2-fluoro-4-[(7-{8-methyl-2H,3H-[1,4]dioxino[2,3-b]pyridin-7-yl}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}acetate (627.00 mg; 1.35 mmol; 1.00 eq.) was filled into the vial and dissolved in THF (9.41 mL). Then, sodium hydroxide solution (2 N) (2.36 mL; 4.71 mmol; 3.50 eq.) was added to the mixture. Next, the reaction mixture was stirred at 50°C for 2h. THF was evaporated under reduced pressure, followed by acidification to pH = 2 with 2M aqueous HCl solution. The precipitate was filtered off, rinsed twice with deionized water (approx. 15 mL each time) 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}-5H,6H,7H,8H-pyrido[3,4- d]pyrimidin-2-yl)amino]phenyl}acetic acid (603.1 mg; 1.34 mmol, 99.2%) as a beige solid. LC MS Method AJ: [M+H]+452.3; Rt: 0.70 min Intermediate 58: Methyl 2-{2-fluoro-4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3- yl)amino]phenyl}acetate; trifluoroacetic acid -140-Attorney Docket No. : P24-187-WO-PCTtert-butyl 7-{[3-fluoro-4-(2-methoxy-2-oxoethyl)phenyl]amino}-1,2,3,4- tetrahydro-2,6-naphthyridine-2-carboxylate To a solution of tert-butyl 7-chloro-3,4-dihydro-1H-2,6-naphthyridine-2-carboxylate (400 mg; 1.49 mmol; 1.00 eq.) and Methyl 2-(4-Amino-2-fluorophenyl)acetate (272.65 mg; 1.49 mmol; 1.00 eq.) in 1,4-Dioxane (20 mL) were added 2- methylpyridine; {1,3-bis[2,6-bis(pentan-3-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H- imidazol-2-ylidene}dichloropalladium (0.09 mL; 0.15 mmol; 0.10 eq.) and Cesium carbonate (1.45 g; 4.465 mmol; 3.00 eq.) in portions at room temperature under argon artmosphere. The reaction mixture was stirred for 20 h at 100°C. The reaction mixture was evaporated and purified by Isco CombiFlash Rf® to afford tert-butyl 7-{[3- fluoro-4-(2-methoxy-2-oxoethyl)phenyl]amino}-1,2,3,4-tetrahydro-2,6- naphthyridine-2-carboxylate (720.00 mg; 1.73 mmol; 116,4 %). LC MS Method U: [M+H]+416.1; Rt: 1.53 min Methyl 2-{2-fluoro-4-[(5,6,7,8-tetrahydro-2,6-naphthyridin-3- yl)amino]phenyl}acetate; trifluoroacetic acid Tert-butyl 7-{[3-fluoro-4-(2-methoxy-2-oxoethyl)phenyl]amino}-1,2,3,4-tetrahydro- 2,6-naphthyridine-2-carboxylate (720.00 mg; 1.61 mmol; 1.00 eq.) was dissolved in DCM (10 mL) and TFA (2.00 mL; 10 eq.) was added and the reaction mixture was stirred for 2h at room temperature. The reaction mixture was evaporated with toluol under reduced pressure. The residue was stirred with MTBE and the precipitate was filtered with suction to afford methyl 2-{2-fluoro-4-[(5,6,7,8-tetrahydro-2,6- naphthyridin-3-yl)amino]phenyl}acetate; trifluoroacetic acid (800.00 mg; 106.4 %). LC MS Method U: [M+H]+316.0; Rt: 0.915 min -141-Attorney Docket No. : P24-187-WO-PCT Intermediate 59: 2-{4-[(6-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]- 2-fluorophenyl}acetic acidtert-butyl 7-(7-{[3-fluoro-4-(2-methoxy-2-oxoethyl)phenyl]amino}-1,2,3,4- tetrahydro-2,6-naphthyridin-2-yl)-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazine-1-carboxylate To a solution of Intermediate 1 (760.00 mg; 2.12 mmol; 1.00 eq.) and Intermediate 58 (793.02 mg; 1.69 mmol; 0.80 eq.) in 1,4-Dioxane (20 mL) were added 2- methylpyridine; {1,3-bis[2,6-bis(pentan-3-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H- imidazol-2-ylidene}dichloropalladium (0.13 mL; 0.21 mmol; 0.10 eq.) and Cesium carbonate (2.08 g; 6.37 mmol; 3.00 eq.) in portions at room temperature under argon atmosphere. The reaction mixture was stirred for 4 h at 100°C. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by Isco CombiFlash Rf® to afford tert-butyl 7-(7-{[3-fluoro-4- (2-methoxy-2-oxoethyl)phenyl]amino}-1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl)-8- methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (210.00 mg; 16.7 %). LC MS Method U: [M+H]+564.0; Rt: 1.58 min 2-{4-[(6-{1-[(tert-butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin- 7-yl}-5,6,7,8-tetrahydro-2,6-naphthyridin-3-yl)amino]-2-fluorophenyl}acetic acid To a solution of tert-butyl 7-(7-{[3-fluoro-4-(2-methoxy-2-oxoethyl)phenyl]amino}- 1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl)-8-methyl-1H,2H,3H-pyrido[2,3- -142-Attorney Docket No. : P24-187-WO-PCT b][1,4]oxazine-1-carboxylate (210.00 mg; 0.36 mmol; 1.00 eq.) in THF (5.00 mL) and H2O (5.00 mL) was added NaOH solution (0.02 mL; 1.08 mmol; 3.00 eq.) and the reaction mixture was stirred for 20 h at 50°C. The reaction mixture was acidified with 1 N HCl and extracted with DCM. The combined organic layers were washed with water, dried over sodium sulfate and filtered to afford 2-{4-[(6-{1-[(tert- butoxy)carbonyl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5,6,7,8- tetrahydro-2,6-naphthyridin-3-yl)amino]-2-fluorophenyl}acetic acid (222.0 mg; 101.9 %). LC MS Method U: [M+H]+550,0; Rt: 1,400 min Intermediate 60: 1-(4-bromo-3-fluorophenyl)-3-[(4-methoxyphenyl)methyl]-1,3- diazinane-2,4-dione3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione To a stirred solution of 1,3-diazinane-2,4-dione (3.00 g; 24.98 mmol; 1.00 eq.) and Cs2CO3 (42.00 g; 122.46 mmol; 4.90 eq.) in DMF (100 mL) was added 1- (chloromethyl)-4-methoxybenzene (13.00 g; 78.86 mmol; 3.16 eq.). The resulting mixture was stirred for 12 h at 25 °C under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL) and extracted with DCM (3 x 200mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by trituration with ACN (10 mL) to afford 3-[(4-methoxyphenyl)methyl]-1,3-diazinane- 2,4-dione (6.00 g; 24.97 mmol; 100.00 %) as a white solid. LC MS Method AK: [M+H]+235.2; Rt: 0.59 min. 1-(4-bromo-3-fluorophenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4- dione To a stirred solution of 3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (500.00 mg; 2.08 mmol; 1.00 eq.) and 1-bromo-2-fluoro-4-iodobenzene (660.00 mg; 2.08 mmol; 1.00 eq.) in DMF (10 mL) were added CuI (84.00 mg; 0.42 mmol; 0.20 -143-Attorney Docket No. : P24-187-WO-PCT eq.), K2CO (908.00 mg; 6.25 mmol; 3.00 eq.) and Glycine (32.00 mg; 0.42 mmol; 0.20 eq.) in portions at room temperature under N2 atmosphere. The resulting mixture was stirred overnight at 140°C under N2atmosphere. The resulting mixture was quenched with water (20 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (30 mL), filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: Xselect CSH Prep C18 OBD, 30*150mm, 5um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 44% B to 59% B in 10 min; RT1(min): 8.78) to afford 1-(4-bromo-3-fluorophenyl)-3-[(4-methoxyphenyl)methyl]- 1,3-diazinane-2,4-dione (320.00 mg; 0.78 mmol; 37.5 %s a yellow solid. LC MS Method AD: [M+H]+407.0; Rt: 1.03 min Intermediate 61: 1-{3-fluoro-4-[3-(piperazin-1-yl)azetidin-1-yl]phenyl}-3-[(4- methoxyphenyl)methyl]-1,3-diazinane-2,4-dione; trifluoroacetic acidtert-butyl 4-[1-(2-fluoro-4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan- 1-yl}phenyl)azetidin-3-yl]piperazine-1-carboxylate To a stirred mixture of Intermediate 60 (300.00 mg; 0.73 mmol; 1.00 eq.) and tert- butyl 4-(azetidin-3-yl)piperazine-1-carboxylate (186.00 mg; 0.73 mmol; 1.00 eq.) in Dioxane-1,4 (10 mL) were added Xphos (74.00 mg; 0.15 mmol; 0.20 eq.), Pd2(dba)3 (147.00 mg; 0.14 mmol; 0.20 eq.) and Cs2CO3(530.00 mg; 1.47 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 4-[1-(2-fluoro-4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo- -144-Attorney Docket No. : P24-187-WO-PCT 1,3-diazinan-1-yl}phenyl)azetidin-3-yl]piperazine-1-carboxylate (350.00 mg; 0.61 mmol; 83.4 %) as a yellow solid. LC MS Method AD: [M+H]+568.0; Rt: 0.81 min 1-{3-fluoro-4-[3-(piperazin-1-yl)azetidin-1-yl]phenyl}-3-[(4- methoxyphenyl)methyl]-1,3-diazinane-2,4-dione; trifluoroacetic acid To a stirred mixture of tert-butyl 4-[1-(2-fluoro-4-{3-[(4-methoxyphenyl)methyl]-2,4- dioxo-1,3-diazinan-1-yl}phenyl)azetidin-3-yl]piperazine-1-carboxylate (250.00 mg; 0.44 mmol; 1.00 eq.) in DCM (2.00 mL) was added TFA (0.50 mL) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 5h at room temperature under nitrogen atmosphere. The resulting mixture was treated with MTBE. The solid was filtered, washed with MTBE (30 mL) and concentrated under reduced pressure to afford 1-{3-fluoro-4-[3-(piperazin-1-yl)azetidin-1- yl]phenyl}-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione; trifluoroacetic acid (170.00 mg; 0.28 mmol; 65.1 %) as a grey solid. LC MS Method AF: [M+H]+468.0; Rt: 0.75 min Intermediate 62a and 62b: 1-{2-methyl-4-[3-(piperazin-1-yl)azetidin-1- yl]phenyl}-1,3-diazinane-2,4-dione; trifluoroacetic acidIntermediate 62b -145-Attorney Docket No. : P24-187-WO-PCT Intermediate 62a: tert-butyl 4-[1-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3- diazinan-1-yl}-3-methylphenyl)azetidin-3-yl]piperazine-1-carboxylate Starting from Intermediate 52 (2.00 g; 4.24 mmol; 1.00 eq.) and tert-butyl 4-(azetidin- 3-yl)piperazine-1-carboxylate (1.07 g; 4.21 mmol; 0.99 eq.) general procedure E for Buchwald coupling was followed to afford tert-butyl 4-[1-(4-{3-[(4- methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}-3-methylphenyl)azetidin-3- yl]piperazine-1-carboxylate (1.70 g; 2.93 mmol; 69.3 %) as a yellow solid. LC-MS method AF: [M+Na]+586.0; Rt: 0.80 min Intermediate 62b: 1-{2-methyl-4-[3-(piperazin-1-yl)azetidin-1-yl]phenyl}-1,3- diazinane-2,4-dione; trifluoroacetic acid Intermediate 62a (1.60 g; 2.76 mmol; 1.00 eq.) was suspended in TFA (16 mL) and TfOH (1.60 mL) was added at room temperature. The reaction mixture was stirred for 1 h at room temperature. The resulting mixture was treated with MTBE. The solid was filtered, washed with MTBE (30 mL) and dried under reduced pressure to afford 1-{2-methyl-4-[3-(piperazin-1-yl)azetidin-1-yl]phenyl}-1,3-diazinane-2,4-dione; trifluoroacetic acid (1.30 g; 2.70 mmol; 97.7 %) as a brown semi solid. LC MS Method AF: [M+H]+344.0; Rt: 0.56min Intermediate 63a and 63b: 3-(4-bromophenoxy)-1-[(4- methoxyphenyl)methyl]piperidine-2,6-dioneIntermediate 63a: 3-(4-bromophenoxy)piperidine-2,6-dione Molecular sieve (2.50 g) was added to the reaction flask.4-Bromophenol (2.50 g; 14.31 mmol; 1.00 eq.) was dissolved in DMF (30.00 mL) and inertised. The reaction was cooled down with a salt-ice bath for 10 minutes. Subsequently, NaH (1.43 g; 35.76 mmol; 2.50 eq.) was added portionwise over 10 minutes. The solution was stirred in the ice bath for 0.5 h. A solution of 3-bromopiperidine-2,6-dione (3.47 g; -146-Attorney Docket No. : P24-187-WO-PCT 17.17 mmol; 1.20 eq.) in DMF (10 mL) was added and the reaction mixture was stirred for 1 h in the ice bath under N2 atmosphere. The mixture was allowed to warm up to RT and heated up to 45°C and stirred for 1h. The reaction mixture was poured into a mixture (1:1) of saturated ammonium chloride solution and ice water (approx. 200 mL) and stirred for 0.25 h. The solid was filtered, washed three times with ice cold water, redissolved in EA and concentrated under reduced pressure. The crude product was treated with saturated ammonium chloride solution (approx.10 mL) and extracted three times with EA. Then, the combined organic phases were dried over sodium sulfate, filtered with suction and evaporated in vacuo to give 3-(4- bromophenoxy)piperidine-2,6-dione (2.97 g; 10.46 mmol; 73.1 %) as a white solid. LC MS Method AJ: [M+H]+282-284; Rt: 0.63 min Intermediate 63b: 3-(4-bromophenoxy)-1-[(4-methoxyphenyl)methyl]piperidine- 2,6-dione 3-(4-bromophenoxy)piperidine-2,6-dione (500.00 mg; 1.76 mmol; 1.00 eq.) and 4- Methoxybenzyl chloride (315,2 µl; 2.29 mmol; 1.30 eq.) were dissolved in DMF (10 mL). Cesium carbonate (688.1 mg; 2.11 mmol; 1120 eq.) was added and the reaction mixture was stirred at room temperature for 20h. The reaction mixture was diluted with deionized water (approx.100 mL) and extracted three times with DCM (3 x 120 mL), dried over sodium sulfate, filtered with suction and evaporated in vacuo. Next the crude product was purified by Isco CombiFlash Rf®to afford 3-(4- bromophenoxy)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (563.9 mg; 1.39 mmol; 79.3% yield) as a colorless oil. LC MS Method V: [M+H]+404-406; Rt: 1.53 min Intermediate 64: 3-{4-[3-(piperazin-1-yl)azetidin-1-yl]phenoxy}piperidine-2,6- dione; trifluoromethanesulfonic acid -147-Attorney Docket No. : P24-187-WO-PCTtert-butyl 4-{1-[4-({1-[(4-methoxyphenyl)methyl]-2,6-dioxopiperidin-3- yl}oxy)phenyl]azetidin-3-yl}piperazine-1-carboxylate Starting from 3-(4-bromophenoxy)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (338.9 mg; 0.84 mmol; 1.00 eq.) and 1-N-Boc-4-azetidin-3-yl-piperazine (250.3 mg; 1.01 mmol; 1.20 eq.) general procedure F for Buchwald coupling was followed to afford tert-butyl 4-{1-[4-({1-[(4-methoxyphenyl)methyl]-2,6-dioxopiperidin-3- yl}oxy)phenyl]azetidin-3-yl}piperazine-1-carboxylate (273.00 mg; 0.48 mmol; 57.7 %) as pink crystals. LC MS Method AJ: [M+H]+565.5; Rt: 0.63 min 3-{4-[3-(piperazin-1-yl)azetidin-1-yl]phenoxy}piperidine-2,6-dione; trifluoromethanesulfonic acid tert-butyl 4-{1-[4-({1-[(4-methoxyphenyl)methyl]-2,6-dioxopiperidin-3- yl}oxy)phenyl]azetidin-3-yl}piperazine-1-carboxylate (258.0 mg; 0.46 mmol; 1.00 eq.) was dissolved in TFA (4.22 mL; 54.83 mmol; 120.0 eq.). Trifluoromethanesulfonic acid (485.2 µl; 5.48 mmol; 12.00 eq.) was added and the reaction mixture was stirred at 70°C for 2h. The reaction mixture was concentrated under reduced pressure and purified by Isco CombiFlash Rf® to afford 3-{4-[3- (piperazin-1-yl)azetidin-1-yl]phenoxy}piperidine-2,6-dione; trifluoromethanesulfonic acid (218.0 mg; 0.44 mmol; 91.2 %) as a brown residue. LC MS Method AJ: [M+H]+345.2; Rt: 0.38 min Intermediate 65: 3-{1-methyl-7-[3-(piperazin-1-yl)azetidin-1-yl]-1H-indazol-3- yl}piperidine-2,6-dione; tris(trifluoroacetic acid) -148-Attorney Docket No. : P24-187-WO-PCTtert-butyl 4-(1-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyl-1H-indazol-7- yl}azetidin-3-yl)piperazine-1-carboxylate Starting from 3-[6-(benzyloxy)-2-(phenoxymethyl)pyridin-3-yl]-7- bromo-1-methyl- 1H-indazole (300.0 mg; 0.58 mmol; 1.00 eq.) and 1-N-Boc-4-azetidin-3-yl-piperazine (143.8 mg; 0.58 mmol; 1.00 eq.) general procedure F for Buchwald coupling was to afford tert-butyl 4-(1-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyl-1H-indazol-7- yl}azetidin-3-yl)piperazine-1-carboxylate (228.0 mg; 0.33 mmol; 57.3 %) as a beige foamed oil. LC MS Method T: [M+Na]+683.0 ; Rt: 1.83 min tert-butyl 4-{1-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl]azetidin-3- yl}piperazine-1-carboxylate Starting from tert-butyl 4-(1-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyl-1H- indazol-7-yl}azetidin-3-yl)piperazine-1-carboxylate (238.0 mg; 0.33 mmol; 1.00 eq.) general procedure G for reduction under hydrogen was followed to afford tert-butyl 4- {1-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl]azetidin-3-yl}piperazine-1- carboxylate (137.0 mg; 0.28 mmol; 85.7 %) as a light yellow oil. LC MS Method T: [M+Na]+505-506; Rt: 1.18 min 3-{1-methyl-7-[3-(piperazin-1-yl)azetidin-1-yl]-1H-indazol-3-yl}piperidine-2,6- dione; tris(trifluoroacetic acid) -149-Attorney Docket No. : P24-187-WO-PCT Starting from tert-butyl 4-{1-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7- yl]azetidin-3-yl}piperazine-1-carboxylate (137.00 mg; 0.28 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 3-{1-methyl-7-[3- (piperazin-1-yl)azetidin-1-yl]-1H-indazol-3-yl}piperidine-2,6-dione; tris(trifluoroacetic acid) (190.0 mg; 0.26 mmol; 92.1 %) as a beige semi-solid. LC MS Method T: [M+Na]+405.0; Rt: 0.93 min Intermediate 66: tert-butyl 7-[2-({4-[2-(4-{1-[3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-7-yl]azetidin-3-yl}piperazin-1-yl)-2-oxoethyl]phenyl}amino)- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl]-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazine-1-carboxylate OStarting from Intermediate 2 (75.05 mg; 0.14 mmol; 1.00 eq.) and Intermediate 65 (100.0 mg; 0.14 mmol: 1.00 eq.) general procedure J for amide coupling was followed to afford tert-butyl 7-[2-({4-[2-(4-{1-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H- indazol-7-yl]azetidin-3-yl}piperazin-1-yl)-2-oxoethyl]phenyl}amino)-5H,6H,7H,8H- pyrido[3,4-d]pyrimidin-7-yl]-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1- carboxylate ( 99.00 mg; 0.11 mmol; 80.2 %) as a light red-brown oil. LC MS Method T: [M+H]+897-898; Rt: 1.39 min Intermediate 67: 3-[4-(4-{[1-(4-aminophenyl)piperidin-4-yl]methyl}piperazin-1- yl)phenyl]piperidine-2,6-dione -150-Attorney Docket No. : P24-187-WO-PCT1-(4-nitrophenyl)piperidine-4-carbaldehyde 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 N2 atmosphere. 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:EA (3:1) to afford 1-(4-nitrophenyl)piperidine-4- carbaldehyde (1.00 g; 4.10 mmol; 48.5 %) as a yellow solid. LC MS Method P: [M+H]+235.2; Rt: 0.81 min 3-[4-(4-{[1-(4-nitrophenyl)piperidin-4-yl]methyl}piperazin-1- yl)phenyl]piperidine-2,6-dione To a stirred solution of Intermediate 60 (737.2 mg; 2.05 mmol; 1.00 eq.) and 1-(4- nitrophenyl)piperidine-4-carbaldehyde (500.0 mg; 2.05 mmol; 1.00 eq.) in DCM (2.50 mL) and MeOH (2.50 mL) were added sodium acetate trihydrate (845.4 mg; 6.15 mmol; 3.00 eq.) and sodium cyanoborohydride (542.5 mg; 8.20 mmol; 4.00 eq.) at room temperature under N2atmosphere. The reaction mixture was stirred for 2h at room temperature under N2 atmosphere. 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- yl]methyl}piperazin-1-yl)phenyl]piperidine-2,6-dione (620.0 mg; 1.26 mmol; 61.3 %) as a yellow solid. LC MS Method P: [M+H]+492.3; Rt: 0.84 min 3-[4-(4-{[1-(4-aminophenyl)piperidin-4-yl]methyl}piperazin-1- yl)phenyl]piperidine-2,6-dione -151-Attorney Docket No. : P24-187-WO-PCT 3-[4-(4-{[1-(4-nitrophenyl)piperidin-4-yl]methyl}piperazin-1-yl)phenyl]piperidine- 2,6-dione (150.0 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 H2 atmosphere. The resulting mixture was filtered and washed with DMF (10 mL). The filtrate was diluted with water (100 mL), 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)phenyl]piperidine-2,6-dione (90.00 mg; 0.19 mmol; 62.5 %) as a grey solid. LC MS Method P: [M+H]+462.3; Rt: 0.46 min Intermediate 68: 3-{4-[4-({1-[4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl}amino)phenyl]piperidin-4-yl}methyl)piperazin-1-yl]phenyl}piperidine-2,6- dioneTo a solution of Intermediate 67 (500.0 mg; 0.97 mmol; 1.00 eq.) and Intermediate 28 (184.00 mg; 0.98 mmol; 1.00 eq.) in Dioxane-1,4 (15.00 mL) were added EPhos Pd G4 (95.00 mg; 0.10 mmol; 0.10 eq.), Ephos (55.00 mg; 0.10 mmol; 0.10 eq.) and Cs2CO3(669.0 mg; 1.95 mmol; 2.00 eq). The reaction mixture was stirred for 16 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 / EA (3:1) to afford 3-{4-[4-({1-[4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl}amino)phenyl]piperidin-4-yl}methyl)piperazin-1-yl]phenyl}piperidine-2,6-dione (300.0 mg; 0.49 mmol; 50.4 %) as a brown solid. LC MS Method N: [M+H]+595.5; Rt: 0.53 min -152-Attorney Docket No. : P24-187-WO-PCT Intermediate 69: 1-(4-bromo-2-chlorophenyl)-3-[(4-methoxyphenyl)methyl]-1,3- diazinane-2,4-dione1-(4-bromo-2-chlorophenyl)-1,3-diazinane-2,4-dione A mixture of 4-bromo-2-chloroaniline (10.00 g; 47.66 mmol; 1.00 eq.) and prop-2- enoic acid (15.50 g; 204.3 mmol; 4.29 eq.) was stirred at 110 °C for 3 h. Then, urea (20.60 g; 325.87 mmol; 6.84 eq.) and AcOH (1000.00 mL) were added and the reaction mixture was stirred at 140 °C for 12h under N2 atmosphere. The resulting mixture was poured into water (1000 mL) at 0°C. The precipitated solid was filtered and dried under reduced pressure to afford 1-(4-bromo-2-chlorophenyl)-1,3- diazinane-2,4-dione (11.00 g; 21.34 mmol; 44.8 %) as a yellow solid. LC MS Method O: [M+H]+302.9; Rt: 0.76 min Intermediate 69: 1-(4-bromo-2-chlorophenyl)-3-[(4-methoxyphenyl)methyl]-1,3- diazinane-2,4-dione To a stirred solution of 1-(4-bromo-2-chlorophenyl)-1,3-diazinane-2,4-dione (10.00 g; 19.40 mmol; 1.00 eq.) and Cs2CO3(12.77 g; 38.80 mmol; 2.00 eq.) in DMF (200.0 mL) was added 1-(chloromethyl)-4-methoxybenzene (4.15 mL; 29.10 mmol; 1.50 eq.) under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 25°C under N2atmosphere. The reaction was extracted with EA (500 mL), washed with brine (3 x 200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with PE / EtOAc (1 / 1) and purified by reverse flash chromatography (column, C18 silica gel; mobile phase, MeCN in water, 30% to 50% gradient in 10 min; detector, UV 254 nm.) to afford 1-(4-bromo-2-chlorophenyl)-3-[(4-methoxyphenyl)methyl]- 1,3-diazinane-2,4-dione (7.50 g; 16.34 mmol; 84.2 %) as a yellow oil. LC MS Method AF: [M+H]+424.9; Rt: 0.98 min -153-Attorney Docket No. : P24-187-WO-PCT Intermediate 70a and 70b: 1-(2-chloro-4-{4-[(piperidin-4-yl)methyl]piperazin-1- yl}phenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dioneIntermediate 70a Intermediate 70bIntermediate 70a: tert-butyl 4-{[4-(3-chloro-4-{3-[(4-methoxyphenyl)methyl]-2,4- dioxo-1,3-diazinan-1-yl}phenyl)piperazin-1-yl]methyl}piperidine-1-carboxylate Starting from Intermediate 69 (2.00 g; 4.36 mmol; 1.00 eq.) and tert-butyl 4- [(piperazin-1-yl)methyl]piperidine-1-carboxylate (1.30 g; 4.36 mmol; 1.00 eq.) general procedure E for Buchwald coupling was followed to afford tert-butyl 4-{[4- (3-chloro-4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1- yl}phenyl)piperazin-1-yl]methyl}piperidine-1-carboxylate (1.80 g; 2.53 mmol; 58.1 %) as a yellow oil. LC MS Method AF: [M+H]+626.2; Rt: 0.84 min Intermediate 70b: 1-(2-chloro-4-{4-[(piperidin-4-yl)methyl]piperazin-1- yl}phenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione Starting from Intermediate 70a (1.70 g; 2.39 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 1-(2-chloro-4-{4-[(piperidin-4- yl)methyl]piperazin-1-yl}phenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4- dione (1.50 g; 2.20 mmol; 92.1 %) as a yellow oil. LC MS Method X: [M+H]+526.2; Rt: 0.65 min Intermediate 71: 1-[4-(4-{[1-(4-aminophenyl)piperidin-4-yl]methyl}piperazin-1- yl)-2-chlorophenyl]-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione -154-Attorney Docket No. : P24-187-WO-PCT1-[2-chloro-4-(4-{[1-(4-nitrophenyl)piperidin-4-yl]methyl}piperazin-1-yl)phenyl]- 3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione To a stirred solution of Intermediate 70b (1.40 g; 2.05 mmol; 1.00 eq.) and 1-fluoro-4- nitrobenzene (0.31 g; 2.05 mmol; 1.00 eq.) in DMF (30.00 mL) was added DIEA (0.75 mL; 4.11 mmol; 2.00 eq.). The reaction mixture was stirred for 16 h at 80°C. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with DCM / MeOH (15 / 1) to afford 1-[2-chloro-4- (4-{[1-(4-nitrophenyl)piperidin-4-yl]methyl}piperazin-1-yl)phenyl]-3-[(4- methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (1.20 g; 1.78 mmol; 86.4 %) as a yellow oil. LC MS Method AF: [M+H]+647.3; Rt: 0.86 min 1-[4-(4-{[1-(4-aminophenyl)piperidin-4-yl]methyl}piperazin-1-yl)-2- chlorophenyl]-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione Starting from 1-[2-chloro-4-(4-{[1-(4-nitrophenyl)piperidin-4-yl]methyl}piperazin-1- yl)phenyl]-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (1.10 g; 1.63 mmol; 1.00 eq.) general procedure N for nitro reduction was followed to afford 1-[4-(4-{[1- (4-aminophenyl)piperidin-4-yl]methyl}piperazin-1-yl)-2-chlorophenyl]-3-[(4- methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (1.05 g; 1.57 mmol; 96.7 %) as a brown solid. LC MS Method X: [M+H]+617.3; Rt: 0.66 min Intermediate 72: 1-{2-chloro-4-[4-({1-[4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin- 2-yl}amino)phenyl]piperidin-4-yl}methyl)piperazin-1-yl]phenyl}-3-[(4- -155-Attorney Docket No. : P24-187-WO-PCT methoxyphenyl)methyl]-1,3-diazinane-2,4-dionetert-butyl 2-{[4-(4-{[4-(3-chloro-4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3- diazinan-1-yl}phenyl)piperazin-1-yl]methyl}piperidin-1-yl)phenyl]amino}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate Starting from Intermediate 71 (1.00 g; 1.50 mmol; 1.00 eq.) and tert-butyl 2-chloro- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (0.41 g; 1.50 mmol; 1.00 eq.) general procedure P for Buchwald coupling was followed to afford tert-butyl 2-{[4- (4-{[4-(3-chloro-4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1- yl}phenyl)piperazin-1-yl]methyl}piperidin-1-yl)phenyl]amino}-5H,6H,7H,8H- pyrido[3,4-d]pyrimidine-7-carboxylate (1.30 g; 1.38 mmol; 92.2 %) as a yellow solid. LC MS Method AF: [M+H]+850.4; Rt: 0.85 min 1-{2-chloro-4-[4-({1-[4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl}amino)phenyl]piperidin-4-yl}methyl)piperazin-1-yl]phenyl}-3-[(4- methoxyphenyl)methyl]-1,3-diazinane-2,4-dione Starting from tert-butyl 2-{[4-(4-{[4-(3-chloro-4-{3-[(4-methoxyphenyl)methyl]-2,4- dioxo-1,3-diazinan-1-yl}phenyl)piperazin-1-yl]methyl}piperidin-1-yl)phenyl]amino}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (1.29 g; 1.37 mmol; 1.00 eq.) the general procedure B for Boc deprotection was followed to afford 1-{2-chloro-4- [4-({1-[4-({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)phenyl]piperidin-4- yl}methyl)piperazin-1-yl]phenyl}-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4- dione (1.00 g; 1.30 mmol; 95.0 %) as a yellow solid. LC MS Method AF: [M+H]+750.4; Rt: 0.74 min Intermediate 73a and 73b: 3-[1-methyl-7-(piperazin-1-yl)-1H-indazol-3- yl]piperidine-2,6-dione hydrochloride -156-Attorney Docket No. : P24-187-WO-PCTtert-butyl 4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyl-1H-indazol-7- yl}piperazine-1-carboxylate Starting from Intermediate 31 (1.00 g; 1.99 mmol; 1.00 eq.) and 1-Boc-piperazine (372.2 mg; 1.99 mmol; 1.00 eq.) general procedure F for Buchwald coupling was followed to afford tert-butyl 4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyl-1H- indazol-7-yl}piperazine-1-carboxylate (695.0 mg; 1.15 mmol; 57.4 %) as a brown solid. LC MS Method T: [M+H]+606-607; Rt: 2.37 min Intermediate 73a: tert-butyl 4-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol- 7-yl]piperazine-1-carboxylate Starting from tert-butyl 4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyl-1H-indazol- 7-yl}piperazine-1-carboxylate (690.0 mg; 1.14 mmol; 1.00 eq.) general procedure G for reduction under hydrogen was followed to afford tert-butyl 4-[3-(2,6- dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl]piperazine-1-carboxylate (405.0 mg; 0.95 mmol; 83.2 %) as a brown foam. LC MS Method T: [M+H]+428-429; Rt: 1.63 min Intermediate 73b: 3-[1-methyl-7-(piperazin-1-yl)-1H-indazol-3-yl]piperidine-2,6- dione hydrochloride Starting from Intermediate 73a (400.0 mg; 0.94 mmol; 1.00 eq.) general procedure C for Boc deprotection was followed to afford 3-[1-methyl-7-(piperazin-1-yl)-1H- indazol-3-yl]piperidine-2,6-dione hydrochloride ( 365.0 mg; 0.85 mmol; 90.6 %) as a brown solid. LC MS Method T: [M+H]+328-329; Rt: 0.953 min -157-Attorney Docket No. : P24-187-WO-PCT Intermediate 74: N-[(4-methoxyphenyl)methyl]-5H,6H,7H,8H-pyrido[3,4- d]pyrimidin-2-amine; bis(trifluoroacetic acid)tert-butyl 2-{[(4-methoxyphenyl)methyl]amino}-5H,6H,7H,8H-pyrido[3,4- d]pyrimidine-7-carboxylate N-[(4-methoxyphenyl)methyl]guanidine hydrochloride (18.7 g; 68.81 mmol: 1.00 eq.) was dissolved in 2-Propanol (203.0 mL). Potassium carbonate (14.28 g; 103.2 mmol;1.50 eq.) and tert-butyl (4E)-4-[(dimethylamino)methylidene]-3-oxopiperidine- 1-carboxylate (17.50 g; 68.81. mmol; 1.00 eq.) were added and the reaction mixture was stirred at 75°C for 22.5 h and at 80°C for 43 h. The reaction mixture was allowed to cool down to rt. The resulting precipitate was diluted with deionized water (approx. 250 mL) and stirred for 1 h, followed by filtration and drying (approx.2 mbar ; 60°C ; 18 h) to afford tert-butyl 2-{[(4-methoxyphenyl)methyl]amino}-5H,6H,7H,8H- pyrido[3,4-d]pyrimidine-7-carboxylate (18.03 g; 47.36 mmol; 68.8 %) as a beige solid. LC MS Method AJ: [M+H]+371.3; Rt: 0.78 min N-[(4-methoxyphenyl)methyl]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine; bis(trifluoroacetic acid) Starting from tert-butyl 2-{[(4-methoxyphenyl)methyl]amino}-5H,6H,7H,8H- pyrido[3,4-d]pyrimidine-7-carboxylate (10.00 g; 26.27 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford N-[(4- methoxyphenyl)methyl]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine; bis(trifluoroacetic acid) (12.46 g; 25.00 mmol; 95.2 %) as a beige-brown solid. LC MS Method AJ: [M+H]+271.2; Rt: 0.37 min Intermediate 75a and 75b: 7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine -158-Attorney Docket No. : P24-187-WO-PCTIntermediate 75a: tert-butyl 7-(2-{[(4-methoxyphenyl)methyl]amino}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazine-1-carboxylate Starting from Intermediate 1 (9.64 g; 26.76 mmol; 1.10 eq.) and Intermediate 74 (12.36 g; 24.33 mmol; 1.00 eq.) general procedure F for Buchwald coupling was to afford tert-butyl 7-(2-{[(4-methoxyphenyl)methyl]amino}-5H,6H,7H,8H-pyrido[3,4- d]pyrimidin-7-yl)-8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (12.25 g; 20.18 mmol; 82.9 %) as a beige foamed oil. LC MS Method T: [M+H]+519.2; Rt: 1.50 min Intermediate 75b: 7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine Intermediate 75a (12.25 g; 1.00 eq.; 20.177 mmol) was dissolved in TFA (112.0 mL) and cooled down to 0 - 5°C with an ice bath for 10 minutes. Next, Trifluoromethanesulfonic acid (11.20 mL) was added dropwise within 2 minutes and the reaction mixture was stirred for further 5 minutes at this temperature.2N NaOH (800 mL) was cooled down with an ice bath and the reaction mixture was added while stirring to this basic solution over 10 minutes. This precipitate was stirred for further 15 minutes, followed by filtration. The mother liquor was basified to pH 7, which caused another precipitation. The solid was filtered off, rinsed twice with deionized water (approx.100 mL each time) and dried to afford 7-{8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine (2.58 g; 8.43 mmol; 41.8 %) as a beige solid. The aqueous phase was extracted twice with ethyl acetate (approx.200 mL each time), once with MIBK (approx.100 mL) and once with a mixture of ethyl acetate and n-butanol (approx.200 / 20 mL). The combined organic phases were dried over -159-Attorney Docket No. : P24-187-WO-PCT sodium sulfate, filtered off and concentrated in vacuo. Next the crude product was purified by Isco CombiFlash Rf® to afford 7-{8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine; trifluoromethanesulfonic acid (5.14 g; 11.09 mmol; 55.0 % yield) as a dark grey solid. LC MS Method T: [M+H]+299.1; Rt: 0.86 min Intermediate 76: N-(4-bromophenyl)-7-{8-methyl-1H,2H,3H-pyrido[2,3- b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amineIntermediate 75b (500.00 mg; 1.68 mmol; 1.00 eq.), 1-Bromo-4-iodobenzene (580.6 mg; 2.01 mmol; 1.20 eq.) and Cesium carbonate (819.1 mg; 2.51 mmol; 1.50 eq.) were dissolved in 1,4-Dioxane (5,00 mL). The reaction was inserted with argon and XantPhos Pd G3 (83.65 mg; 0.08 mmol; 0,.5 eq.) was added. The reaction mixture was stirred at 100°C for 4.5h under argon atmosphere. The reaction mixture was filtered with suction, concentrated and purified by Isco CombiFlash Rf® to afford N- (4-bromophenyl)-7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine (734.8 mg; 1.49 mmol; 89.1 %) as a brown foam. LC MS Method T: [M+H]+453.1-455.1; Rt: 1.45 min Intermediate 77: 1-{4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}piperidine-4- carbaldehyde; pentakis(trifluoroacetic acid) -160-Attorney Docket No. : P24-187-WO-PCTN-{4-[4-(dimethoxymethyl)piperidin-1-yl]phenyl}-7-{8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-amine Starting from Intermediate 76 (100.00 mg; 0.20 mmol; 1.00 eq.) and 4- (dimethoxymethyl)piperidine (66.02 mg; 0.41 mmol; 2,00 eq.) general procedure P for Buchwald coupling was followed to afford N-{4-[4-(dimethoxymethyl)piperidin- 1-yl]phenyl}-7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H- pyrido[3,4-d]pyrimidin-2-amine (36.40 mg; 0.06 mmol; 31.5 % yield) as an orange residue. LC MS Method AL: [M+H]+532.3; Rt: 1.59 min 1-{4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H- pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}piperidine-4-carbaldehyde; pentakis(trifluoroacetic acid) Starting from N-{4-[4-(dimethoxymethyl)piperidin-1-yl]phenyl}-7-{8-methyl- 1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- amine (24.80 mg; 0.04 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 1-{4-[(7-{8-methyl-1H,2H,3H-pyrido[2,3-b][1,4]oxazin-7-yl}- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl)amino]phenyl}piperidine-4-carbaldehyde; pentakis(trifluoroacetic acid) (48.50 mg; 0.04 mmol; 94.2 % yield) as a red waxy oil. LC MS Method AL: [M / 2+H]+243.7-252.7; Rt: 0.39-0.43 min Intermediate 78: 1-(7-bromo-1-methyl-1H-indazol-3-yl)-3-[(4- methoxyphenyl)methyl]-1,3-diazinane-2,4-dione -161-Attorney Docket No. : P24-187-WO-PCT3-[(7-bromo-1-methyl-1H-indazol-3-yl)amino]propanoic acid 7-bromo-1-methyl-1H-indazol-3-amine (3.65 g; 1.14 mmol; 1.00 eq.) was suspended in 2N HCl (63.90 mL). Tetra-n-butylammonium bromide (484.7 mg; 1.49 mmol; 0.10 eq.) was added under stirring. Acrylic acid (2.06 ml; 29.77 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 stirring by adding NaOH (32 w%, 13 mL). The beige suspension was stirred at room temperature for 1h, filtered with suction, washed three times with deionized water (50 mL each) and dried under reduced pressure at 50°C and 10-20mbar for 71h to afford 3-[(7-bromo-1-methyl-1H-indazol-3-yl)amino]propanoic acid (4.36 g; 12.75 mmol; 85.65 % yield) as a beige solid. LC MS Method T: [M+H]+298-300; Rt: 1.34 min 1-(7-bromo-1-methyl-1H-indazol-3-yl)-1,3-diazinane-2,4-dione 3-[(7-bromo-1-methyl-1H-indazol-3-yl)amino]propanoic acid (4.36 g; 12.75 mmol; 1.00 eq.) was suspended in Acetic acid (glacial) (43.6 mL) and NaCN (1.48 g; 22.3 mmol; 1.75 eq.) was added. The reaction mixture was stirred at 75°C for 3.5 h. The reaction mixture was cooled to room temperature and HCl (25%, 13.2 mL) was added and the reaction mixture was stirred again at 75°C for 3.5 h. The beige suspension was cooled down to room temperature, diluted with 80 mL deionized water and stirred at room temperature for 2.25 h. Then, the suspension was filtered with suction, washed with deionized water (2 x 20 mL) and dried under reduced pressure at 50°C and 10-20mbar for 70 h and lyophilisated for 23 h to afford 1-(7-bromo-1-methyl-1H- indazol-3-yl)-1,3-diazinane-2,4-dione (2.93 g; 9.05 mmol; 71.0 %) as a pale beige solid. LC MS Method T: [M+H]+ 323-325; Rt: 1.34 min 1-(7-bromo-1-methyl-1H-indazol-3-yl)-3-[(4-methoxyphenyl)methyl]-1,3- diazinane-2,4-dione 1-(7-bromo-1-methyl-1H-indazol-3-yl)-1,3-diazinane-2,4-dione (1.00 g; 3.06 mmol; 1.00 eq.) was dissolved in DMF (10.00 mL). Cesium carbonate (1.20 g; 3.67 mmol; -162-Attorney Docket No. : P24-187-WO-PCT 1.20 eq.) and 4-Methoxybenzyl chloride (589 µl; 4.28 mmol; 1.40 eq.) were added and the reaction mixture was inertised with argon and stirred at rt for 16.5h. The reaction mixture was poured into deionized water (approx.250 mL) and saturated NH4Cl solution (approx.40 mL) was added and extraction carried out three times with EA (approx.60 mL each time). The combined organic layers 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 1-(7-bromo-1-methyl-1H- indazol-3-yl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (0.93 g; 2.03 mmol; 64.9 %) as a pale beige resin. LC MS Method T: [M+H]+ 443-445; Rt: 1.68 min Intermediate 79: 1-{1-methyl-7-[3-(piperazin-1-yl)azetidin-1-yl]-1H-indazol-3- yl}-1,3-diazinane-2,4-dione; trifluoroacetic acidtert-butyl 4-[1-(3-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}-1- methyl-1H-indazol-7-yl)azetidin-3-yl]piperazine-1-carboxylate Intermediate 78 (150.0 mg; 0.33 mmol; 1.00 eq.), tert-butyl 4-(Azetidin-3- yl)piperazine-1-carboxylate hydrochloride (105.7 mg; 0.36 mmol; 1.10 eq.) and Cs2CO3(321.1 mg; 0.99 mmol; 3.00 eq.) were suspended in 1,4-Dioxane (4.00 mL). The reaction was purged with nitrogen and Pd-PEPPSI-IPentCl 2-methylpyridine (27.60 mg; 0.03 mmol; 0.10 eq.) was added. The reaction mixture was stirred at 100 °C for 3h under nitrogen atmosphere. The brown-red suspension was filtered off, rinsed with DCM and the filtrate was evaporated. The residue was purified by flash chromatography DCM:MeOH (95:5) to afford tert-butyl 4-[1-(3-{3-[(4- methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}-1-methyl-1H-indazol-7- yl)azetidin-3-yl]piperazine-1-carboxylate (207.0 mg; 0.32 mmol; 97.9 %) as a light yellow foamed oil. LC MS Method T: [M-tBu]+548-549; Rt: 1.68 min -163-Attorney Docket No. : P24-187-WO-PCT 1-{1-methyl-7-[3-(piperazin-1-yl)azetidin-1-yl]-1H-indazol-3-yl}-1,3-diazinane- 2,4-dione; trifluoroacetic acid tert-butyl 4-[1-(3-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}-1- methyl-1H-indazol-7-yl)azetidin-3-yl]piperazine-1-carboxylate (207.0 mg; 0.32 mmol; 1.00 eq.) was dissolved in TFA (2.00 mL) and Trifluoromethanesulfonic acid (0.20 mL) was added. The reaction mixture was stirred for 1 h at room temperature and for 2 h at 60°C. The reaction solution was evaporated and purified by prep HPLC to afford 1-{1-methyl-7-[3-(piperazin-1-yl)azetidin-1-yl]-1H-indazol-3-yl}-1,3- diazinane-2,4-dione; trifluoroacetic acid (153.0 mg; 0.31 mmol; 95.6 %) as a white solid. LC MS Method T: [M+H]+384-385; Rt: 0.91 min Intermediate 80: Triethylazanium 2-{2-fluoro-4-[(7-{8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl)amino]phenyl}acetateIntermediate 12b (8.50 g; 18.47 mmol; 1.00 eq.) was dissolved in in 360 mL methanol +1% TEA , brought up to Isolute sorbent and purified by flash chromatography to afford triethylazanium 2-{2-fluoro-4-[(7-{8-methyl-1H,2H,3H- pyrido[2,3-b][1,4]oxazin-7-yl}-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2- yl)amino]phenyl}acetate (8.95 g; 15.95 mmol; 86.3 % yield) as a light brown foamed oil. LC MS Method T: [M+H]+451-452; Rt: 1.22 min Intermediate 81: 3-{5-[3-(piperazin-1-yl)azetidin-1-yl]pyridin-2-yl}piperidine- 2,6-dione; trifluoroacetic acid -164-Attorney Docket No. : P24-187-WO-PCT2',6'-bis(benzyloxy)-5-chloro-2,3'-bipyridine To a stirred solution of 5-chloro-2-iodopyridine (1.00 g; 3.97 mmol; 1.00 eq.) and Intermediate 30 (1.86 g; 4.36 mmol; 1.10 eq.) in DME (12.00 mL) and H2O (3.00 mL) were added Pd(PPh3)4 (0.48 g; 0.40 mmol; 0.10 eq.) and Na2CO3 (0.89 g; 7.94 mmol; 2.00 eq.) in portions at room temperature. The resulting mixture was stirred for 5 h at 80 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with PE / DCM (10:3) to afford 2',6'-bis(benzyloxy)-5-chloro-2,3'-bipyridine (1.80 g; 3.15 mmol; 79.5 %) as a yellow solid. LC MS Method O: [M+H]+403.2; Rt: 1.51 min tert-butyl 4-{1-[2',6'-bis(benzyloxy)-[2,3'-bipyridin]-5-yl]azetidin-3-yl}piperazine- 1-carboxylate To a stirred solution of tert-butyl 4-(azetidin-3-yl)piperazine-1-carboxylate (0.76 g; 3.10 mmol; 1.00 eq.) and 2',6'-bis(benzyloxy)-5-chloro-2,3'-bipyridine (1.77 g; 3.10 mmol; 1.00 eq.) in 1,4-Dioxane (10.00 mL) were added RuPhos Pd G4 (0.28 g; 0.31 mmol; 0.10 eq.), RuPhos (0.30 g; 0.62 mmol; 0.20 eq.) and Cs2CO3 (2.04 g; 6.20 mmol; 2.00 eq.) in portions at room temperature. The resulting mixture was stirred for 6 h at 100 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with EA / PE (8:1) to afford tert-butyl 4-{1-[2',6'-bis(benzyloxy)-[2,3'-bipyridin]-5- yl]azetidin-3-yl}piperazine-1-carboxylate (1.55 g; 2.50 mmol; 80.7 %) as a yellow solid. LC MS Method O: [M+H]+608.8; Rt: 0.97 min -165-Attorney Docket No. : P24-187-WO-PCT tert-butyl 4-{1-[6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl]azetidin-3-yl}piperazine- 1-carboxylate Tert-butyl 4-{1-[2',6'-bis(benzyloxy)-[2,3'-bipyridin]-5-yl]azetidin-3-yl}piperazine-1- carboxylate (1.50 g; 2.42 mmol; 1.00 eq.) was dissolved in DMF (20.00 mL) and Pd / C (1.03 g; 0.97 mmol; 0.40 eq.) was added. The reaction mixture was stirred for 16 h at room temperature under H2atmosphere. The resulting mixture was filtered and washed with DMF (20 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 4-{1-[6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl]azetidin-3- yl}piperazine-1-carboxylate (0.96 g; 2.16 mmol; 89.3 %) as a black solid. LC MS Method O: [M+H]+430.2; Rt: 0.64 min 3-{5-[3-(piperazin-1-yl)azetidin-1-yl]pyridin-2-yl}piperidine-2,6-dione; trifluoroacetic acid To a stirred mixture of tert-butyl 4-{1-[6-(2,6-dioxopiperidin-3-yl)pyridin-3- yl]azetidin-3-yl}piperazine-1-carboxylate (900.0 mg; 2.02 mmol; 1.00 eq.) in DCM (4.00 mL) was added TFA (1.00 mL) at room temperature. The reaction mixture was stirred for 2 h at room temperature. The mixture was concentrated under reduced pressure to afford 3-{5-[3-(piperazin-1-yl)azetidin-1-yl]pyridin-2-yl}piperidine-2,6- dione; trifluoroacetic acid (850.0 mg; 1.87 mmol; 92.2 %) as a black solid. LC MS Method AG: [M+H]+330.2; Rt: 0.13 min Intermediate 82: 2-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin-1-yl}acetic acid; trifluoroacetic acidtert-butyl 2-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin-1-yl}acetate To a stirred mixture of Intermediate 8 (2.30 g; 7.03 mmol; 1.00 eq.) and DIEA (5.86 mL) in DMF (20.00 mL) was added tert-butyl 2-bromoacetate (2.80 g; 14.07 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 resulting mixture was diluted with water (40 mL), extracted with EA (3 x 30 mL), washed with brine (20 mL), dried -166-Attorney Docket No. : P24-187-WO-PCT over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford tert-butyl 2-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin-1-yl}acetate (2.80 g; 6.88 mmol; 97.9 %) as a yellow solid. LC MS Method AF: [M+H]+388.0; Rt: 0.67 min 2-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin-1-yl}acetic acid; trifluoroacetic acid Starting from tert-butyl 2-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin-1- yl}acetate (2.70 g; 6.63 mmol; 1.00 eq.) general procedure B for Boc deprotection was to afford 2-{4-[4-(2,6-dioxopiperidin-3-yl)phenyl]piperazin-1-yl}acetic acid; trifluoroacetic acid (2.00 g; 4.02 mmol; 60.6 %) as a yellow solid. LC MS Method AF: [M+H]+332.0; Rt: 0.51 min Intermediate 83: 3-[4-(4-{2-[4-(4-aminophenyl)piperidin-1-yl]-2- oxoethyl}piperazin-1-yl)phenyl]piperidine-2,6-dione3-[4-(4-{2-[4-(4-nitrophenyl)piperidin-1-yl]-2-oxoethyl}piperazin-1- yl)phenyl]piperidine-2,6-dione Starting from 4-(4-nitrophenyl)piperidine (881.00 mg; 4.03 mmol; 1.00 eq.) and Intermediate 82 (2.00 g; 4.02 mmol; 1.00 eq.) general procedure J for amide coupling was followed to afford 3-[4-(4-{2-[4-(4-nitrophenyl)piperidin-1-yl]-2- oxoethyl}piperazin-1-yl)phenyl]piperidine-2,6-dione (2.00 g; 3.67 mmol; 91.3 %) as a yellow solid. LC MS Method AF: [M+H]+520.0; Rt: 0.76 min 3-[4-(4-{2-[4-(4-aminophenyl)piperidin-1-yl]-2-oxoethyl}piperazin-1- yl)phenyl]piperidine-2,6-dione Starting from 3-[4-(4-{2-[4-(4-nitrophenyl)piperidin-1-yl]-2-oxoethyl}piperazin-1- yl)phenyl]piperidine-2,6-dione (2.00 g; 3.67 mmol; 1.00 eq.) general procedure N for -167-Attorney Docket No. : P24-187-WO-PCT nitro reduction was followed to afford 3-[4-(4-{2-[4-(4-aminophenyl)piperidin-1-yl]- 2-oxoethyl}piperazin-1-yl)phenyl]piperidine-2,6-dione (1.00 g; 1.97 mmol; 53.8 %) as a yellow solid. LC MS Method AF: [M+H]+490.0; Rt: 0.62 min Intermediate 84: 1-(4-bromo-2-fluorophenyl)-3-[(4-methoxyphenyl)methyl]-1,3- diazinane-2,4-dioneTo a stirred solution of 3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (500.0 mg; 2.08 mmol; 1.00 eq.) and 4-bromo-2-fluoro-1-iodobenzene (660.0 mg; 2.08 mmol; 1.00 eq.) in DMF (10.00 mL) were added CuI (84.00 mg; 0.42 mmol; 0.20 eq.), Cs2CO3 (1.37 g; 4.16 mmol; 2.00 eq.) and N1,N2-dimethylcyclohexane-1,2- diamine (63.00 mg; 0.42 mmol; 0.20 eq.) in portions at room temperature under N2 atmosphere. The resulting mixture was stirred for overnight at 80 °C under N2 atmosphere. The reaction mixture was quenched with water (20 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (30 mL), filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: Xselect CSH Prep C18 OBD, 30*150mm, 5um; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 44% B to 55% B in 8 min; RT1(min): 8.67) to afford 1-(4-bromo-2-fluorophenyl)-3- [(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (350.0 mg; 0.85 mmol; 41.0 %) as a yellow oil. LC MS Method AD: [M+H]+407.0; Rt: 0.96 min Intermediate 85: 1-{2-fluoro-4-[3-(piperazin-1-yl)azetidin-1-yl]phenyl}-3-[(4- methoxyphenyl)methyl]-1,3-diazinane-2,4-dione; trifluoroacetic acid -168-Attorney Docket No. : P24-187-WO-PCTtert-butyl 4-[1-(3-fluoro-4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan- 1-yl}phenyl)azetidin-3-yl]piperazine-1-carboxylate Starting from Intermediate 84 (340.00 mg; 0.83 mmol; 1.00 eq.) and tert-butyl 4- (azetidin-3-yl)piperazine-1-carboxylate (211.0 mg; 0.83 mmol; 1.00 eq.) general procedure E for Buchwald coupling was followed to afford tert-butyl 4-[1-(3-fluoro- 4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}phenyl)azetidin-3- yl]piperazine-1-carboxylate (310.0 mg; 0.51 mmol; 61.1 %) as a yellow oil. LC MS Method AF: [M+H]+568.0; Rt: 0.87 min 1-{2-fluoro-4-[3-(piperazin-1-yl)azetidin-1-yl]phenyl}-3-[(4- methoxyphenyl)methyl]-1,3-diazinane-2,4-dione; trifluoroacetic acid Starting from tert-butyl 4-[1-(3-fluoro-4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo- 1,3-diazinan-1-yl}phenyl)azetidin-3-yl]piperazine-1-carboxylate (230.0 mg; 0.38 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 1- {2-fluoro-4-[3-(piperazin-1-yl)azetidin-1-yl]phenyl}-3-[(4-methoxyphenyl)methyl]- 1,3-diazinane-2,4-dione; trifluoroacetic acid (220.0 mg; 0.36 mmol; 96.3 %) as a yellow solid. LC MS Method AF: [M+H]+468.0; Rt: 0.74 min Intermediate 86: 3-[(4-methoxyphenyl)methyl]-1-{2-methyl-4-[4-(piperazin-1- yl)piperidin-1-yl]phenyl}-1,3-diazinane-2,4-dione; trifluoroacetic acid-169-Attorney Docket No. : P24-187-WO-PCT tert-butyl 4-[1-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}-3- methylphenyl)piperidin-4-yl]piperazine-1-carboxylate To a solution of 1-Boc-4-piperidin-4-yl-piperazine (300.0 mg; 1.06 mmol; 1.00 eq). and Intermediate 1 (426.7 mg; 1.06 mmol; 1.00 eq.) in 1,4-Dioxane (10.00 mL) were added 2-methylpyridine; {1,3-bis[2,6-bis(pentan-3-yl)phenyl]-4,5-dichloro-2,3- dihydro-1H-imidazol-2-ylidene}dichloropalladium (0.07 mL; 0.11 mmol; 0.10 eq.) and Cs2CO3(0.25 mL; 3.17 mmol; 3.00 eq.) in portions at rt under argon. The mixture was stirred for 20 h at 100 °C. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to afford tert-butyl 4-[1-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}-3- methylphenyl)piperidin-4-yl]piperazine-1-carboxylate (540.0 mg; 81.1 % yield). LC MS Method U: [M+H]+592.2; Rt: 1.36 min 3-[(4-methoxyphenyl)methyl]-1-{2-methyl-4-[4-(piperazin-1-yl)piperidin-1- yl]phenyl}-1,3-diazinane-2,4-dione; trifluoroacetic acid Starting from tert-butyl 4-[1-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3- diazinan-1-yl}-3-methylphenyl)piperidin-4-yl]piperazine-1-carboxylate (540.0 mg; 0.86 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 3-[(4-methoxyphenyl)methyl]-1-{2-methyl-4-[4-(piperazin-1-yl)piperidin-1- yl]phenyl}-1,3-diazinane-2,4-dione; trifluoroacetic acid (840.0 mg; 0.83 mmol; 97.0 %). LC MS Method U: [M+H]+492.1; Rt: 1.06 min Intermediate 87: 1-(4-{4-[4-(4-aminophenyl)piperazin-1-yl]piperidin-1-yl}-2- methylphenyl)-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione3-[(4-methoxyphenyl)methyl]-1-(2-methyl-4-{4-[4-(4-nitrophenyl)piperazin-1- yl]piperidin-1-yl}phenyl)-1,3-diazinane-2,4-dione -170-Attorney Docket No. : P24-187-WO-PCT To a solution of Intermediate 86 (600.0 mg; 0.59 mmol; 1.00 eq.; 60 %); and 1- Fluoro-4-nitrobenzene (92.26 mg; 0.65 mmol; 1.10 eq.) in DMF (10.00 mL) was added Cs2CO3(581.0 mg; 1.78 mmol; 3.00 eq.) under argon. The reaction mixture was stirred for 1 h at 80 °C. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to afford 3-[(4-methoxyphenyl)methyl]-1-(2-methyl-4-{4-[4-(4-nitrophenyl)piperazin-1- yl]piperidin-1-yl}phenyl)-1,3-diazinane-2,4-dione (380.0 mg; 0.60 mmol; quantitative). LC MS Method U: [M+H]+613.1; Rt: 1.33 min 1-(4-{4-[4-(4-aminophenyl)piperazin-1-yl]piperidin-1-yl}-2-methylphenyl)-3-[(4- methoxyphenyl)methyl]-1,3-diazinane-2,4-dione Starting from 3-[(4-methoxyphenyl)methyl]-1-(2-methyl-4-{4-[4-(4- nitrophenyl)piperazin-1-yl]piperidin-1-yl}phenyl)-1,3-diazinane-2,4-dione (830.0 mg; 1.21 mmol; 1.00 eq.) general procedure N for nitro reduction was followed to afford 1-(4-{4-[4-(4-aminophenyl)piperazin-1-yl]piperidin-1-yl}-2-methylphenyl)-3-[(4- methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (550.0 mg; 0.89 mmol; 73.6 %). LC MS Method U: [M+H]+583.2 Rt; 1.05 min Intermediate 88: 3-[(4-methoxyphenyl)methyl]-1-[2-methyl-4-(4-{4-[4- ({5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl}amino)phenyl]piperazin-1- yl}piperidin-1-yl)phenyl]-1,3-diazinane-2,4-dione; trifluoroacetic acidtert-butyl 2-[(4-{4-[1-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1- yl}-3-methylphenyl)piperidin-4-yl]piperazin-1-yl}phenyl)amino]-5H,6H,7H,8H- pyrido[3,4-d]pyrimidine-7-carboxylate -171-Attorney Docket No. : P24-187-WO-PCT Starting from tert-butyl 2-chloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7- carboxylate (362.6 mg; 1.33 mmol; 1.50 eq.) and Intermediate 90 (550.0 mg; 0.89 mmol; 1.00 eq.) general procedure F for Buchwald coupling was followed to afford tert-butyl 2-[(4-{4-[1-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1- yl}-3-methylphenyl)piperidin-4-yl]piperazin-1-yl}phenyl)amino]-5H,6H,7H,8H- pyrido[3,4-d]pyrimidine-7-carboxylate (610.0 mg; 0.65 mmol; 73.3 %). LC MS Method U: [M-boc]+714.3 Rt: 1.46 min 3-[(4-methoxyphenyl)methyl]-1-[2-methyl-4-(4-{4-[4-({5H,6H,7H,8H-pyrido[3,4- d]pyrimidin-2-yl}amino)phenyl]piperazin-1-yl}piperidin-1-yl)phenyl]-1,3- diazinane-2,4-dione; trifluoroacetic acid Starting from tert-butyl 2-[(4-{4-[1-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3- diazinan-1-yl}-3-methylphenyl)piperidin-4-yl]piperazin-1-yl}phenyl)amino]- 5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (610.0 mg; 0.65 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 3-[(4- methoxyphenyl)methyl]-1-[2-methyl-4-(4-{4-[4-({5H,6H,7H,8H-pyrido[3,4- d]pyrimidin-2-yl}amino)phenyl]piperazin-1-yl}piperidin-1-yl)phenyl]-1,3-diazinane- 2,4-dione; trifluoroacetic acid (600.0 mg; 0.69 mmol; 105.6 %). LC MS Method U: [M+H]+716.3 Rt: 1.06 min Intermediate 89: 1-[4-(4-{[4-(4-amino-1H-pyrazol-1-yl)piperidin-1- yl]methyl}piperidin-1-yl)-2-methylphenyl]-3-[(4-methoxyphenyl)methyl]-1,3- diazinane-2,4-dionetert-butyl 4-{[4-(4-nitro-1H-pyrazol-1-yl)piperidin-1-yl]methyl}piperidine-1- carboxylate -172-Attorney Docket No. : P24-187-WO-PCT To a stirred solution of 4-(4-nitro-1H-pyrazol-1-yl)piperidine hydrochloride (3.00 g; 12.83 mmol; 1.00 eq.) and tert-butyl 4-formylpiperidine-1-carboxylate (4.32 g; 19.24 mmol; 1.50 eq.) in DCM (10.00 mL) and MeOH (10.00 mL) were added NaOAc (5.51 g; 38.49 mmol; 3.00 eq.) and AcOH (0.81 g; 12.83 mmol; 1.00 eq.) in portion at room temperature. The resulting mixture was stirred for 3 h at 25 °C. Then NaBH3CN (1.68 g; 25.66 mmol; 2.00 eq.) was added in the mixture and the resulting mixture was stirred for 16 h at 25 °C. 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 tert-butyl 4-{[4-(4-nitro-1H-pyrazol-1-yl)piperidin-1- yl]methyl}piperidine-1-carboxylate (2.90 g; 7.28 mmol; 56.8 %) as a yellow solid. LC MS Method AD: [M+H]+394.2 Rt: 0.14 min 4-(4-nitro-1H-pyrazol-1-yl)-1-[(piperidin-4-yl)methyl]piperidine hydrochloride Starting from tert-butyl 4-{[4-(4-nitro-1H-pyrazol-1-yl)piperidin-1- yl]methyl}piperidine-1-carboxylate (2.90 g; 7.28 mmol; 1.00 eq.) general procedure C for Boc deprotection was followed to afford 4-(4-nitro-1H-pyrazol-1-yl)-1- [(piperidin-4-yl)methyl]piperidine hydrochloride (2.20 g; 6.61 mmol; 90.8 %) as a white solid. LC MS Method AD: [M+H]+294.2 Rt: 0.28 min 3-[(4-methoxyphenyl)methyl]-1-[2-methyl-4-(4-{[4-(4-nitro-1H-pyrazol-1- yl)piperidin-1-yl]methyl}piperidin-1-yl)phenyl]-1,3-diazinane-2,4-dione Starting from 4-(4-nitro-1H-pyrazol-1-yl)-1-[(piperidin-4-yl)methyl]piperidine hydrochloride (1.00 g; 3.00 mmol; 1.00 eq.) and Intermediate 52 (1.53 g; 3.61 mmol; 1.20 eq.) general procedure F for Buchwald coupling was followed to afford 3-[(4- methoxyphenyl)methyl]-1-[2-methyl-4-(4-{[4-(4-nitro-1H-pyrazol-1-yl)piperidin-1- yl]methyl}piperidin-1-yl)phenyl]-1,3-diazinane-2,4-dione (1.20 g; 1.88 mmol; 62.5 % yield) as a yellow solid. LC MS Method A: [M+H]+616.4 Rt: 0.53 min 1-[4-(4-{[4-(4-amino-1H-pyrazol-1-yl)piperidin-1-yl]methyl}piperidin-1-yl)-2- methylphenyl]-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione To a stirred solution of 3-[(4-methoxyphenyl)methyl]-1-[2-methyl-4-(4-{[4-(4-nitro- 1H-pyrazol-1-yl)piperidin-1-yl]methyl}piperidin-1-yl)phenyl]-1,3-diazinane-2,4- dione (1.00 g; 1.57 mmol; 1.00 eq.) in AcOEt (10.00 mL) and MeOH (10.00 mL) -173-Attorney Docket No. : P24-187-WO-PCT was added Raney-Ni (0.50 g; 5.54 mmol; 3.54 eq.) at room temperature under N2 atmosphere. The mixture was stirred for 2 h at room temperature under hydrogen atmosphere. The solids were filtered off, washed with MeOH and concentrated under reduced pressure to afford 1-[4-(4-{[4-(4-amino-1H-pyrazol-1-yl)piperidin-1- yl]methyl}piperidin-1-yl)-2-methylphenyl]-3-[(4-methoxyphenyl)methyl]-1,3- diazinane-2,4-dione (780.0 mg; 1.31 mmol; 83.9 % yield) as a yellow solid. LC MS Method O: [M+H]+586.4 Rt: 0.59 min Intermediate 90: 1-{6-[3-(piperazin-1-yl)azetidin-1-yl]pyridin-3-yl}-1,3- diazinane-2,4-dionetert-butyl 4-[1-(5-iodopyridin-2-yl)azetidin-3-yl]piperazine-1-carboxylate To a stirred solution of 2-fluoro-5-iodopyridine (800.0 mg; 3.41 mmol; 1.00 eq.) and tert-butyl 4-(azetidin-3-yl)piperazine-1-carboxylate hydrochloride (828.0 mg; 2.90 mmol; 0.85 eq.) in DMF (10.00 mL) was added K2CO3 (997.0 mg; 6.87 mmol; 2.02 eq.) in portions at room temperature under N2 atmosphere. The resulting mixture was stirred for 3 h at 90 °C under N2 atmosphere. The resulting mixture was diluted with water and extracted with EA. 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 to afford tert-butyl 4-[1-(5-iodopyridin-2- yl)azetidin-3-yl]piperazine-1-carboxylate (930.0 mg; 2.09 mmol; 61.4 % yield) as a yellow solid. LC MS Method AD: [M+H]+445.2; Rt: 0.65 min -174-Attorney Docket No. : P24-187-WO-PCT tert-butyl 4-[1-(5-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1- yl}pyridin-2-yl)azetidin-3-yl]piperazine-1-carboxylate To a stirred solution of tert-butyl 4-[1-(5-iodopyridin-2-yl)azetidin-3-yl]piperazine-1- carboxylate (920.0 mg; 2.07 mmol; 1.00 eq.) and 3-[(4-methoxyphenyl)methyl]-1,3- diazinane-2,4-dione (485.0 mg; 2.07 mmol; 1.00 eq.) in Dioxane-1,4 (15.00 mL) were added K2CO3(576.0 mg; 3.96 mmol; 1.91 eq.), CuI (76.00 mg; 0.38 mmol; 0.19 eq.) and Glycine (47.00 mg; 0.61 mmol; 0.30 eq.) in portions at room temperature under N2 atmosphere. The resulting mixture was stirred for overnight at 140 °C under N2 atmosphere. The resulting mixture was diluted with water and extracted with EA. 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 to afford tert-butyl 4-[1-(5-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3- diazinan-1-yl}pyridin-2-yl)azetidin-3-yl]piperazine-1-carboxylate (720.0 mg; 1.31 mmol; 63.2 % yield.) as a yellow solid. LC MS Method AD: [M+H]+551.30; Rt: 0.66 min 1-{6-[3-(piperazin-1-yl)azetidin-1-yl]pyridin-3-yl}-1,3-diazinane-2,4-dione Tert-butyl 4-[1-(5-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1- yl}pyridin-2-yl)azetidin-3-yl]piperazine-1-carboxylate (510.0 mg; 0.93 mmol; 1.00 eq.) was dissolved in TFA (10.00 mL) and TfOH (1.00 mL) was added at room temperature under N2 atmosphere. The resulting mixture was stirred for 1 h at 60 °C under N2 atmosphere. The resulting mixture was treated with MTBE. Then, the solid was filtered, washed with MTBE (50 mL) and concentrated under reduced pressure. The crude product was purified by Prep-HPLC to afford 1-{6-[3-(piperazin-1- yl)azetidin-1-yl]pyridin-3-yl}-1,3-diazinane-2,4-dione (300.0 mg; 0.89 mmol; 95.6 % yield) as a yellow solid. LC MS Method AD: [M+H]+331.20; Rt: 0.23 min Intermediate 91: 2-{4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-1,3-benzodiazol-4-yl]piperidin-1-yl}acetic acid; trifluoroacetic acid -175-Attorney Docket No. : P24-187-WO-PCTtert-butyl 4-(1-{1-[(4-methoxyphenyl)methyl]-2,6-dioxopiperidin-3-yl}-3-methyl- 2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl)-1,2,3,6-tetrahydropyridine-1- carboxylate To a stirred solution of Intermediate 46 (1.20 g; 2.51 mmol; 1.00 eq.) and tert-butyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1- carboxylate (0.98 g; 3.01 mmol; 1.20 eq.) in 1,4-dioxane (18.00 mL) and H2O (4.00 mL) were added Pd(PPh3)4(0.31 g; 0.25 mmol; 0.10 eq.) and Na2CO3(0.56 g; 5.02 mmol; 2.00 eq.) in portions at room temperature. The resulting mixture was stirred for 3 h at 40 °C under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to afford tert- butyl 4-(1-{1-[(4-methoxyphenyl)methyl]-2,6-dioxopiperidin-3-yl}-3-methyl-2-oxo- 2,3-dihydro-1H-1,3-benzodiazol-4-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (1.00 g; 1.71 mmol; 67.9 %) as a yellow solid. LC MS Method O: [M+H]+561.40; Rt: 1.08 min tert-butyl 4-(1-{1-[(4-methoxyphenyl)methyl]-2,6-dioxopiperidin-3-yl}-3-methyl- 2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl)piperidine-1-carboxylate To a stirred solution of tert-butyl 4-(1-{1-[(4-methoxyphenyl)methyl]-2,6- dioxopiperidin-3-yl}-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl)-1,2,3,6- tetrahydropyridine-1-carboxylate (1.00 g; 1.71 mmol; 1.00 eq.) in Dioxane-1,4 (20.00 -176-Attorney Docket No. : P24-187-WO-PCT mL) was added Pd / C (200.00 mg; 1.79 mmol; 1.05 eq.) at room temperature under N2 atmosphere. The mixture was stirred for 36 h at 80 °C under hydrogen atmosphere. The resulting mixture was filtered, washed with 60 mL of EA. The filtrate was concentrated under reduced pressure to afford tert-butyl 4-(1-{1-[(4- methoxyphenyl)methyl]-2,6-dioxopiperidin-3-yl}-3-methyl-2-oxo-2,3-dihydro-1H- 1,3-benzodiazol-4-yl)piperidine-1-carboxylate (680.0 mg; 1.13 mmol; 66.4 %) as a yellow solid. LC MS Method N: [M+H]+563.0; Rt: 0.98 min 3-[3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-1,3-benzodiazol-1- yl]piperidine-2,6-dione; trifluoroacetic acid To a stirred solution of tert-butyl 4-(1-{1-[(4-methoxyphenyl)methyl]-2,6- dioxopiperidin-3-yl}-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4- yl)piperidine-1-carboxylate (680.0 mg; 1.13 mmol; 1.00 eq.) in TFA (10.00 mL) was added TfOH (1.00 mL) at room temperature under N2 atmosphere. The mixture was stirred for 12 h at 60 °C under argon atmosphere. A slurry with TBME was formed. Then, the solid was filtered and the filter cake was washed with TBME (30 mL). The solid was dried under reduced pressure to afford 3-[3-methyl-2-oxo-4-(piperidin-4- yl)-2,3-dihydro-1H-1,3-benzodiazol-1-yl]piperidine-2,6-dione; trifluoroacetic acid (400.0 mg; 0.81 mmol; 71.2 %) as a yellow solid. LC MS Method AF: [M+H]+343.0; Rt: 0.57 min tert-butyl 2-{4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3- benzodiazol-4-yl]piperidin-1-yl}acetate To a stirred solution of 3-[3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-1,3- benzodiazol-1-yl]piperidine-2,6-dione; trifluoroacetic acid (380.0 mg; 0.77 mmol; 1.00 eq.) and DIEA (0.67 mL; 3.83 mmol; 5.00 eq.) in DMF (6.00 mL) was added tert-butyl 2-bromoacetate (314.0 mg; 1.53 mmol; 2.00 eq.) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of H2O at room temperature and extracted with EA. 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 2-{4-[1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]piperidin- 1-yl}acetate (350.0 mg; 0.65 mmol; 85.2 %) as a yellow solid. LC MS Method AF: [M+H]+457.0; Rt: 0.70 min -177-Attorney Docket No. : P24-187-WO-PCT 2-{4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3- benzodiazol-4-yl]piperidin-1-yl}acetic acid; trifluoroacetic acid Starting from tert-butyl 2-{4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-1,3-benzodiazol-4-yl]piperidin-1-yl}acetate (330.0 mg; 0.62 mmol; 1.00 eq.) the general procedure B for Boc deprotection was followed to afford 2-{4-[1- (2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4- yl]piperidin-1-yl}acetic acid; trifluoroacetic acid (250.0 mg; 0.37 mmol; 59.7 %) as a yellow solid. LC MS Method AF: [M+H]+401.0; Rt: 0.55 min Intermediate 92: 3-[2,6-bis(benzyloxy)pyridin-3-yl]-6-bromo-1-methyl-1H- indazoleTo a stirred solution of 6-bromo-3-iodo-1-methyl-1H-indazole (1.00 g; 2.96 mmol; 1.00 eq.) and Intermediate 30 (2.50 g; 5.14 mmol; 1.74 eq.) in THF (10.00 mL) and water (2.00 mL) were added Pd(dppf)Cl2•DCM (121.0 mg; 0.14 mmol; 0.05 eq.) and Cs2CO3 (3.00 g; 8.75 mmol; 2.95 eq.). The resulting mixture was stirred overnight at 70 °C under nitrogen atmosphere. The resulting mixture was treated with water and extracted with EA (3 x 100 mL). 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 to afford 3-[2,6-bis(benzyloxy)pyridin-3-yl]-6-bromo-1-methyl-1H- indazole (700.0 mg; 1.22 mmol; 41.2 %) as a yellow oil. LC MS Method P: [M+H]+500.1; Rt: 1.38 min Intermediate 93: 3-{1-methyl-6-[3-(piperazin-1-yl)azetidin-1-yl]-1H-indazol-3- yl}piperidine-2,6-dione; tris(trifluoroacetic acid) -178-Attorney Docket No. : P24-187-WO-PCTtert-butyl 4-(1-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyl-1H-indazol-6- yl}azetidin-3-yl)piperazine-1-carboxylate Starting from Intermediate 92 (300.0 mg; 0.58 mmol; 1.00 eq.) and 1-N-Boc-4- azetidin-3-yl-piperazine (143.6 mg; 0.58 mmol; 1.00 eq.) general procedure F for Buchwald coupling was followed to afford tert-butyl 4-(1-{3-[2,6- bis(benzyloxy)pyridin-3-yl]-1-methyl-1H-indazol-6-yl}azetidin-3-yl)piperazine-1- carboxylate (233.0 mg; 0.34 mmol; 58.1 %) as a yellow foamed oil. LC MS Method T: [M+H]+661-662; Rt: 1.78 min tert-butyl 4-{1-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]azetidin-3- yl}piperazine-1-carboxylate Starting from tert-butyl 4-(1-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyl-1H- indazol-6-yl}azetidin-3-yl)piperazine-1-carboxylate (233.0 mg; 0.34 mmol; 1.00 eq.) general procedure G for reduction under hydrogen was followed to afford tert-butyl 4- {1-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]azetidin-3-yl}piperazine-1- carboxylate (131.0 mg; 0.27 mmol; 79.3 %) as a light green solid. LC MS Method T: [M+H-tBu]+427-428; Rt: 1.14 min 3-{1-methyl-6-[3-(piperazin-1-yl)azetidin-1-yl]-1H-indazol-3-yl}piperidine-2,6- dione; tris(trifluoroacetic acid) Starting from tert-butyl 4-{1-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6- yl]azetidin-3-yl}piperazine-1-carboxylate (131.0 mg; 0.27 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 3-{1-methyl-6-[3- (piperazin-1-yl)azetidin-1-yl]-1H-indazol-3-yl}piperidine-2,6-dione; tris(trifluoroacetic acid) (200.0 mg; 0.27 mmol; quantitative). -179-Attorney Docket No. : P24-187-WO-PCT LC MS Method T: [M+H]+383-384; Rt: 0.89 min Intermediate 94a and 94b: 1-{4-[4-(azetidin-3-yl)piperazin-1-yl]-2- methylphenyl}-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione; trifluoroacetic acidIntermediate 94a: tert-butyl 3-[4-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3- diazinan-1-yl}-3-methylphenyl)piperazin-1-yl]azetidine-1-carboxylate Intermediate 52 (260.2 mg; 0.60 mmol; 1.00 eq.), 1-(Tert-butoxycarbonyl)-3-(1- piperazinyl)azetidine(149.3 mg; 0.60 mmol; 1.00 eq.), and Cs2CO3 (0.88 g; 2.70 mmol; 4.50 eq.) were suspended in 1,4-Dioxane (3.00 mL). The reaction vial was sonicated for 5 minutes and then purged with argon for 5 minutes. (SP-4-1)-[1,3- BIs[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2- ylidene]dichloro(2-methylpyridine)palladium (63.67 mg; 0.07 mmol; 0.12 eq.) was added. The reaction mixture was stirred at 100 °C for 24 hours and 2 days at room temperature. The reaction mixture was filtered over celite. The filtrate was evaporated under reduced pressure and purified by flash chromatography to afford tert-butyl 3- [4-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}-3- methylphenyl)piperazin-1-yl]azetidine-1-carboxylate (364.0 mg; 0.56 mmol; 93.5 %) as yellow oil. LC MS Method AB: [M+H-Boc]+464.2; Rt: 1.46 min Intermediate 94b: tert-butyl 3-[4-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3- diazinan-1-yl}-3-methylphenyl)piperazin-1-yl]azetidine-1-carboxylate Starting from Intermediate 94a (100.0 mg; 0.15 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 1-{4-[4-(azetidin-3-yl)piperazin-1-yl]-2- methylphenyl}-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione; trifluoroacetic acid (76.00 mg; 0.13 mmol; 81.1 %) as an off-white solid. -180-Attorney Docket No. : P24-187-WO-PCT LC MS Method AB: [M+H]+464.1; Rt: 1.12 min Intermediate 95: 2,6-bis(benzyloxy)-3-(4-bromo-2-methylphenyl)pyridineStarting from Intermediate (2.81 g; 6.60 mmol; 1.00 eq.) and 5-bromo—2-iodotoluene (2.00 g; 6.60 mmol; 1.00 eq.) general procedure O for Suzuki coupling was followed to afford 2,6-bis(benzyloxy)-3-(4-bromo-2-methylphenyl)pyridine (2.12 g; 4.42 mmol; 66,9 %) as a white solid. LC MS Method T: [M+H]+460.0; Rt: 2.28 min Intermediate 96: 3-{2-methyl-4-[3-(piperazin-1-yl)azetidin-1- yl]phenyl}piperidine-2,6-dione; tetrakis(trifluoroacetic acid)tert-butyl 4-(1-{4-[2,6-bis(benzyloxy)pyridin-3-yl]-3-methylphenyl}azetidin-3- yl)piperazine-1-carboxylate 2,6-bis(benzyloxy)-3-(4-bromo-2-methylphenyl)pyridine (2.12 g; 4.61 mmol; 1.00 eq.), tert-butyl 4-(azetidin-3-yl)piperazine-1-carboxylate hydrochloride (1.32 g; 4.61 mmol; 1.00 eq.) and Cs2CO3(4.50 g; 13.82 mmol; 3.00 eq.) were suspended in 1,4- Dioxane (42.40 mL). Next the solution was purged with argon for 5 minutes. After -181-Attorney Docket No. : P24-187-WO-PCT that (SP-4-1)-[1,3-BIs[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H- imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (0.20 g; 0.23 mmol; 0.05 eq.) was added and the reaction mixture was stirred at 100°C overnight under argon atmosphere. The reaction mixture was filtered through celite, washed with DCM and concentrated under reduced pressure. The residue was purified by flash chromatography to afford tert-butyl 4-(1-{4-[2,6-bis(benzyloxy)pyridin-3-yl]-3- methylphenyl}azetidin-3-yl)piperazine-1-carboxylate (2.26 g; 3.64 mmol; 78.9 %) as a yellow oil. LC MS Method T: [M+H]+621.0; Rt: 1.88 min tert-butyl 4-{1-[4-(2,6-dioxopiperidin-3-yl)-3-methylphenyl]azetidin-3- yl}piperazine-1-carboxylate Starting from tert-butyl 4-(1-{4-[2,6-bis(benzyloxy)pyridin-3-yl]-3- methylphenyl}azetidin-3-yl)piperazine-1-carboxylate (2.26 g; 3.64 mmol; 1.00 eq.) general procedure G for reduction under hydrogen was followed to afford tert-butyl 4- {1-[4-(2,6-dioxopiperidin-3-yl)-3-methylphenyl]azetidin-3-yl}piperazine-1- carboxylate (480.0 mg; 1.09 mmol; 29.8 %) as a blue solid. LC MS Method T: [M+H-tBu]+387.0; Rt: 1.18 min 3-{2-methyl-4-[3-(piperazin-1-yl)azetidin-1-yl]phenyl}piperidine-2,6-dione; tetrakis(trifluoroacetic acid) Starting from tert-butyl 4-{1-[4-(2,6-dioxopiperidin-3-yl)-3-methylphenyl]azetidin-3- yl}piperazine-1-carboxylate (480.0 mg; 1.08 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 3-{2-methyl-4-[3-(piperazin-1-yl)azetidin-1- yl]phenyl}piperidine-2,6-dione; tetrakis(trifluoroacetic acid) (730.0 mg; 0.89 mmol; 82.6 %) as a blue solid. LC MS Method T: [M+H]+343.0; Rt: 0.87 min Intermediate 97: 3-{7-[1'-(4-aminophenyl)-[1,4'-bipiperidin]-4-yl]-1-methyl-1H- indazol-3-yl}piperidine-2,6-dione -182-Attorney Docket No. : P24-187-WO-PCTtert-butyl 4-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl]-[1,4'- bipiperidine]-1'-carboxylate To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (2.35 g; 11.55 mmol; 4.00 eq.) and Intermediate 32 (1.30 g; 2.89 mmol; 1.00 eq.) in DCM (15.00 mL) and MeOH (20.00 mL) were added NaOAc (1.25 g; 14.44 mmol; 5.00 eq.) and NaBH3CN (0.57 g; 8.66 mmol; 3.00 eq.) at room temperature. The resulting mixture was stirred for 16 h at room temperature. The resulting mixture was quenched with water (50 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (50 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 EA / PE (1:1) to afford tert-butyl 4-[3-(2,6- dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl]-[1,4'-bipiperidine]-1'-carboxylate (1.36 g; 2.64 mmol; 91.5 %) as a white solid. LC MS Method AF: [M+H]+510.3; Rt: 0.79 min 3-(7-{[1,4'-bipiperidin]-4-yl}-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; trifluoroacetic acid Starting from tert-butyl 4-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl]- [1,4'-bipiperidine]-1'-carboxylate (1.30 g; 2.52 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 3-(7-{[1,4'-bipiperidin]-4-yl}-1-methyl- 1H-indazol-3-yl)piperidine-2,6-dione; trifluoroacetic acid (1.00 g; 1.88 mmol; 74.4 %) as a off-white solid. LC MS Method N: [M+H]+410.3; Rt: 0.44 min 3-{1-methyl-7-[1'-(4-nitrophenyl)-[1,4'-bipiperidin]-4-yl]-1H-indazol-3- yl}piperidine-2,6-dione To a stirred mixture of 1-fluoro-4-nitrobenzene (0.40 g; 2.68 mmol; 1.50 eq.) and 3- (7-{[1,4'-bipiperidin]-4-yl}-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione; -183-Attorney Docket No. : P24-187-WO-PCT trifluoroacetic acid (0.95 g; 1.78 mmol; 1.00 eq.) in DMF (10.00 mL) was added DIEA (0.89 mL; 5.35 mmol; 3.00 eq.) at room temperature. The mixture was stirred for 16 h at 90 °C. The resulting mixture was quenched by water (20 mL) and was extracted with EA (3 x 15 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. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:4) to afford 3-{1-methyl-7-[1'-(4-nitrophenyl)- [1,4'-bipiperidin]-4-yl]-1H-indazol-3-yl}piperidine-2,6-dione (0.90 g; 1.68 mmol; 94.2 %) as a light yellow solid. LC MS Method AH: [M+H]+531.5; Rt: 0.60 min 3-{7-[1'-(4-aminophenyl)-[1,4'-bipiperidin]-4-yl]-1-methyl-1H-indazol-3- yl}piperidine-2,6-dione To a stirred solution of 3-{1-methyl-7-[1'-(4-nitrophenyl)-[1,4'-bipiperidin]-4-yl]-1H- indazol-3-yl}piperidine-2,6-dione (850.0 mg; 1.59 mmol; 1.00 eq.) in DMF (10.00 mL) was added Pd / C (170.0 mg; 0.16 mmol; 0.10 eq.) at room temperature. The mixture was stirred for 5 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with DMF (15 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (15:1) to afford 3-{7-[1'-(4- aminophenyl)-[1,4'-bipiperidin]-4-yl]-1-methyl-1H-indazol-3-yl}piperidine-2,6-dione (800.0 mg; 1.57 mmol; 98.9 %) as a light yellow solid. LC MS Method AF: [M+H]+501.3; Rt: 0.67 min Intermediate 98: 1-(4-{2,6-diazaspiro[3.3]heptan-2-yl}-2-methylphenyl)-3-[(4- methoxyphenyl)methyl]-1,3-diazinane-2,4-dione; trifluoroacetic acidtert-butyl 6-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}-3- methylphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate -184-Attorney Docket No. : P24-187-WO-PCT To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hydrochloride (1.35 g; 5.46 mmol; 1.00 eq.) and Intermediate 52 (2.20 g; 5.46 mmol; 1.00 eq.) in 1,4-Dioxane, (30.00 mL) were added 2-methylpyridine; {1,3-bis[2,6-bis(pentan-3- yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazol-2-ylidene}dichloropalladium (459.0 mg; 0.55 mmol; 0.10 eq.) and Cs2CO3 (5.34 g; 16,39 mmol; 3.00 eq.) in portions at rt under Argon. Then the mixture was stirred for 3 h at 100 °C. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to afford tert-butyl 6-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo- 1,3-diazinan-1-yl}-3-methylphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (2.53 g; 4.76 mmol; 87.2 %). LC MS Method U: [M+H]+521.3; Rt: 1.81 min 1-(4-{2,6-diazaspiro[3.3]heptan-2-yl}-2-methylphenyl)-3-[(4- methoxyphenyl)methyl]-1,3-diazinane-2,4-dione; trifluoroacetic acid Starting from tert-butyl 6-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan- 1-yl}-3-methylphenyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (2.53 g; 4.76 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 1-(4-{2,6- diazaspiro[3.3]heptan-2-yl}-2-methylphenyl)-3-[(4-methoxyphenyl)methyl]-1,3- diazinane-2,4-dione; trifluoroacetic acid (3.10 g; 4.64 mmol: 97.4 %). LC MS Method U: [M+H]+421.1; Rt: 1.11 min Intermediate 99: 1-(4-{6-[1-(4-aminophenyl)piperidin-4-yl]-2,6- diazaspiro[3.3]heptan-2-yl}-2-methylphenyl)-1,3-diazinane-2,4-dione-185-Attorney Docket No. : P24-187-WO-PCT tert-butyl 4-[6-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}-3- methylphenyl)-2,6-diazaspiro[3.3]heptan-2-yl]piperidine-1-carboxylate To a solution of Intermediate 98 (3.10 g; 4.64 mmol; 1.00 eq.) and 1-Boc-4- piperidone (2.80 g; 13.92 mmol; 3.00 eq.) in MeOH (60.00 mL) and Acetic acid (glacial) (0.05 mL; 0.99 mmol; 20.00 eq.) was added NaBH3CN (920.7 mg; 13.92 mmol; 3.00 eq.) in portions at rt under Argon. Then the mixture was stirred for 20 h at rt. The reaction mixture was evaporated. The residue was diluted with water and extracted three times with DCM. The combined organic layers were washed with water, dried over sodium sulfate, filtered and purified by silica gel column chromatography to afford tert-butyl 4-[6-(4-{3-[(4-methoxyphenyl)methyl]-2,4- dioxo-1,3-diazinan-1-yl}-3-methylphenyl)-2,6-diazaspiro[3.3]heptan-2-yl]piperidine- 1-carboxylate (3.00 g; 4.72 mmol; qunatitative). LC MS Method U: [M+H]+604.2; Rt: 1.32 min 3-[(4-methoxyphenyl)methyl]-1-{2-methyl-4-[6-(piperidin-4-yl)-2,6- diazaspiro[3.3]heptan-2-yl]phenyl}-1,3-diazinane-2,4-dione; trifluoroacetic acid Starting from tert-butyl 4-[6-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3- diazinan-1-yl}-3-methylphenyl)-2,6-diazaspiro[3.3]heptan-2-yl]piperidine-1- carboxylate (3.00 g; 4.87 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 3-[(4-methoxyphenyl)methyl]-1-{2-methyl-4-[6-(piperidin-4- yl)-2,6-diazaspiro[3.3]heptan-2-yl]phenyl}-1,3-diazinane-2,4-dione; trifluoroacetic acid (3.00 g; 4.86 mmol; 99.7 %). LC MS Method U: [M+H]+504.1; Rt: 1.00 min 3-[(4-methoxyphenyl)methyl]-1-(2-methyl-4-{6-[1-(4-nitrophenyl)piperidin-4-yl]- 2,6-diazaspiro[3.3]heptan-2-yl}phenyl)-1,3-diazinane-2,4-dione To a solution of 3-[(4-methoxyphenyl)methyl]-1-{2-methyl-4-[6-(piperidin-4-yl)-2,6- diazaspiro[3.3]heptan-2-yl]phenyl}-1,3-diazinane-2,4-dione; trifluoroacetic acid (3.00 g; 4.86 mmol; 1.00 eq.) and 1-Fluoro-4-nitrobenzene (822.4 mg; 5.83 mmol; 1.20 eq.) in DMF (60.00 mL) was added Cs2CO3 (1.17 mL; 14.57 mmol; 3.00 eq.) under argon atmosphere. Then the mixture was stirred for 2 h at 80 °C. The reaction mixture was evaporated. The residue was diluted with water and extracted three times with DCM. The combined organic layers were washed with water, dried over sodium sulfate, filtered and purified by silica gel column chromatography to afford 3-[(4- methoxyphenyl)methyl]-1-(2-methyl-4-{6-[1-(4-nitrophenyl)piperidin-4-yl]-2,6- -186-Attorney Docket No. : P24-187-WO-PCT diazaspiro[3.3]heptan-2-yl}phenyl)-1,3-diazinane-2,4-dione (1.10 g; 1.69 mmol; 34.8 %). LC MS Method U: [M+H]+625.2; Rt: 1.36 min 1-(2-methyl-4-{6-[1-(4-nitrophenyl)piperidin-4-yl]-2,6-diazaspiro[3.3]heptan-2- yl}phenyl)-1,3-diazinane-2,4-dione; trifluoroacetic acid A solution of 3-[(4-methoxyphenyl)methyl]-1-(2-methyl-4-{6-[1-(4- nitrophenyl)piperidin-4-yl]-2,6-diazaspiro[3.3]heptan-2-yl}phenyl)-1,3-diazinane-2,4- dione (1.10 g; 1.69 mmol; 1.00 eq.) in Trifluoromethanesulfonic acid (1.00 mL) and TFA (10.00 mL) was stirred for 3 h at rt. The reaction mixture was evaporated under reduced pressure with toluene. The residue was stirred with MTB-Eter and the precipitate was filtered with suction to afford 1-(2-methyl-4-{6-[1-(4- nitrophenyl)piperidin-4-yl]-2,6-diazaspiro[3.3]heptan-2-yl}phenyl)-1,3-diazinane-2,4- dione; trifluoroacetic acid (1.10 g; 1.76 mmol; quantitative). LC MS Method U: [M+H]+505.2; Rt: 1.12 min 1-(4-{6-[1-(4-aminophenyl)piperidin-4-yl]-2,6-diazaspiro[3.3]heptan-2-yl}-2- methylphenyl)-1,3-diazinane-2,4-dione Starting from 1-(2-methyl-4-{6-[1-(4-nitrophenyl)piperidin-4-yl]-2,6- diazaspiro[3.3]heptan-2-yl}phenyl)-1,3-diazinane-2,4-dione; trifluoroacetic acid (1.10 g; 1.74 mmol; 1.00 eq.) the general procedure N for nitro reduction was to afford 1- (4-{6-[1-(4-aminophenyl)piperidin-4-yl]-2,6-diazaspiro[3.3]heptan-2-yl}-2- methylphenyl)-1,3-diazinane-2,4-dione (950.0 mg; 1.80 mmol; quantitative). LC MS Method U: [M+H]+475.1; Rt: 0.79 min Intermediate 100: 1-{1-methyl-6-[3-(piperazin-1-yl)azetidin-1-yl]-1H-indazol-3- yl}-1,3-diazinane-2,4-dione; bis(trifluoroacetic acid)tert-butyl 4-{1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6- yl]azetidin-3-yl}piperazine-1-carboxylate -187-Attorney Docket No. : P24-187-WO-PCT Starting from 1-(6-bromo-1-methyl-1H-indazol-3-yl)-1,3-diazinane-2,4-dione (150.0 mg; 0.44 mmol; 1.00 eq.) and 1-N-Boc-4-azetidin-3-yl-piperazine (110.6 mg; 0.44 mmol; 1.00 eq.) general procedure F for Buchwald coupling was followed to afford tert-butyl 4-{1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol-6-yl]azetidin-3- yl}piperazine-1-carboxylate (188.0 mg; 0.39 mmol; 87.4 %) as a light brown oil. LC MS Method T: [M+H]+484-485; Rt: 1.27 min 1-{1-methyl-6-[3-(piperazin-1-yl)azetidin-1-yl]-1H-indazol-3-yl}-1,3-diazinane- 2,4-dione; bis(trifluoroacetic acid) Starting from tert-butyl 4-{1-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methyl-1H-indazol- 6-yl]azetidin-3-yl}piperazine-1-carboxylate (188.0 mg; 0.39 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 1-{1-methyl-6-[3- (piperazin-1-yl)azetidin-1-yl]-1H-indazol-3-yl}-1,3-diazinane-2,4-dione; bis(trifluoroacetic acid) (230.0 mg; 94.4 %) as a beige solid. LC MS Method T: [M+H]+384-385; Rt: 0.85 min Intermediate 101: 3-{6-[4-(azetidin-3-yl)piperazin-1-yl]-1-methyl-1H-indazol-3- yl}piperidine-2,6-dione; bis(trifluoroacetic acid)tert-butyl 3-(4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyl-1H-indazol-6- yl}piperazin-1-yl)azetidine-1-carboxylate Starting from Intermediate 92 (300.0 mg; 0.58 mmol; 1.00 eq.) and 1-(Tert- butoxycarbonyl)-3-(1-piperazinyl)azetidine (143.6 mg; 0.58 mmol; 1.00 eq.) general procedure F for Buchwald coupling was followed to afford tert-butyl 3-(4-{3-[2,6- bis(benzyloxy)pyridin-3-yl]-1-methyl-1H-indazol-6-yl}piperazin-1-yl)azetidine-1- carboxylate (248.0 mg; 0.36 mmol; 62.2 %) as a yellow oil. LC MS Method T: [M+H]+661-662; Rt: 1.18 min tert-butyl 3-{4-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]piperazin-1- yl}azetidine-1-carboxylate -188-Attorney Docket No. : P24-187-WO-PCT Starting from tert-butyl 3-(4-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-1-methyl-1H- indazol-6-yl}piperazin-1-yl)azetidine-1-carboxylate (248.0 mg; 0.38 mmol; 1.00 eq.) general procedure G for reduction under hydrogen was followed to afford tert-butyl 3- {4-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl]piperazin-1-yl}azetidine-1- carboxylate (167.0 mg; 0.35 mmol; 92,2 %) as a light yellow oil. LC MS Method T: [M+H]+483-484; Rt: 1.13 min 3-{6-[4-(azetidin-3-yl)piperazin-1-yl]-1-methyl-1H-indazol-3-yl}piperidine-2,6- dione; bis(trifluoroacetic acid) Starting from tert-butyl 3-{4-[3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6- yl]piperazin-1-yl}azetidine-1-carboxylate (167.0 mg; 0.35 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 3-{6-[4-(azetidin-3- yl)piperazin-1-yl]-1-methyl-1H-indazol-3-yl}piperidine-2,6-dione; bis(trifluoroacetic acid) (186.0 mg; 0.30 mmol; 87.7 %) as a beige solid. LC MS Method T: [M+H]+383-384; Rt: 0.85 min Intermediate 102: 1-(2-methyl-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 Starting from Intermediate 52 (30.0 g; 73.65 mmol; 1.00 eq.) and tert-butyl 4- [(piperazin-1-yl)methyl]piperidine-1-carboxylate (22.0 g; 73.65 mmol; 1.00 eq.) general procedure F for Buchwald coupling was followed to afford 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 (44.0 g; 0.07 mol; 93,7 %) as a beige amorphous solid. LC MS Method AB: [M-Boc+H]+506.2; Rt: 1.49 min 1-(2-methyl-4-{4-[(piperidin-4-yl)methyl]piperazin-1-yl}phenyl)-1,3-diazinane- 2,4-dione -189-Attorney Docket No. : P24-187-WO-PCT 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; 59.43 mmol; 1.00 eq.) in DCM (400 mL) were added TFA (91.6 mL)) and TfOH (31.3 mL) in portions at 25 °C. The resulting mixture was stirred for 5h at room temperature. The reaction mixture was slowly poured into 2L MTBE and stirred overnight at room temperature. The solid was filtered, washed with MTBE and dried in vacuo at 50 °C to afford 1-(2-methyl-4-{4-[(piperidin-4-yl)methyl]piperazin-1- yl}phenyl)-1,3-diazinane-2,4-dione (65.00 g; 0.059 mol; 99.3%) as a light beige powder. LC MS Method N: [M+H]+ 386.25; Rt: 0.34min Intermediate 103: 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]methyl}piperazin-1- yl)phenyl]-1,3-diazinane-2,4-dione To a solution of Intermediate 102 (3.00 g; 7.78 mmol; 1.00 eq.) and 2-Fluoro-5- nitrotoluene (1.58 g; 10.2 mmol; 1.30 eq.) in DMF (30.00 mL) was added Cs2CO3(1.87 mL; 23.35 mmol; 3.00 eq.) under argon atmosphere. 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 DCM. The combined organic layers were washed with water, dried over sodium sulfate, filtered and purified by silica gel column chromatography to afford 1-[2-methyl-4-(4-{[1-(2-methyl-4-nitrophenyl)piperidin-4- yl]methyl}piperazin-1-yl)phenyl]-1,3-diazinane-2,4-dione (1.00 g; 1.75 mmol; 22.5 %). LC MS Method U: [M+H]+521.2-522.3; Rt: 1.28 min 1-[4-(4-{[1-(4-amino-2-methylphenyl)piperidin-4-yl]methyl}piperazin-1-yl)-2- methylphenyl]-1,3-diazinane-2,4-dione Starting from 1-[2-methyl-4-(4-{[1-(2-methyl-4-nitrophenyl)piperidin-4- yl]methyl}piperazin-1-yl)phenyl]-1,3-diazinane-2,4-dione (1.00 g; 1.75 mmol; 1.00 eq.) general procedure N for nitro reduction was followed to afford 1-[4-(4-{[1-(4- -190-Attorney Docket No. : P24-187-WO-PCT amino-2-methylphenyl)piperidin-4-yl]methyl}piperazin-1-yl)-2-methylphenyl]-1,3- diazinane-2,4-dione (745.0 mg; 1.38 mmol; 79.1 %) LC MS Method U: [M+H]+491.3-492.3; Rt: 0.82 min Intermediate 104: 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 To a stirred solution of 3-[4-(piperidin-4-yl)phenyl]piperidine-2,6-dione (400.0 mg; 1.40 mmol; 1.00 eq.) and 1-(4-nitrophenyl)piperidine-4-carbaldehyde (331.0 mg; 1.40 mmol; 1.00 eq.) in DCM (2.00 mL) and MeOH (2.00 mL) were added Sodium acetate trihydrate (578.0 mg; 4.21 mmol; 3.00 eq.) and NaBH3CN (278.0 mg; 4.20 mmol; 3.00 eq.) at room temperature under N2atmosphere. The resulting mixture was stirred for 2 h at room temperature under N2 atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM:MeOH (20:1) to afford 3-[4-(1-{[1-(4- nitrophenyl)piperidin-4-yl]methyl}piperidin-4-yl)phenyl]piperidine-2,6-dione (500.0 mg; 0.88 mmol; 62.9 %) as a yellow solid. LC MS Method M: [M+H]+491.2; Rt: 0.61 min 3-[4-(1-{[1-(4-aminophenyl)piperidin-4-yl]methyl}piperidin-4- yl)phenyl]piperidine-2,6-dione Starting from 3-[4-(1-{[1-(4-nitrophenyl)piperidin-4-yl]methyl}piperidin-4- yl)phenyl]piperidine-2,6-dione (480.0 mg; 0.85 mmol; 1.00 eq.) general procedure L for reduction was followed to afford 3-[4-(1-{[1-(4-aminophenyl)piperidin-4- yl]methyl}piperidin-4-yl)phenyl]piperidine-2,6-dione (400.0 mg; 0.82 mmol; 97.0 %) as a light yellow solid. -191-Attorney Docket No. : P24-187-WO-PCT LC MS Method M: [M+H]+461.2; Rt: 0.47 min Intermediate 105a and 105b: 3-(4-{4-[2-(piperazin-1-yl)acetyl]piperazin-1- yl}phenyl)piperidine-2,6-dione; trifluoroacetic acidIntermediate 105a Intermediate 105bIntermediate 105a: tert-butyl 4-(2-{4-[4-(2,6-dioxopiperidin-3- yl)phenyl]piperazin-1-yl}-2-oxoethyl)piperazine-1-carboxylate Starting from 2-{4-[(tert-butoxy)carbonyl]piperazin-1-yl}acetic acid (100.0 mg; 0.41 mmol; 1.00 eq.) and Intermediate 8 (190.3 mg; 0.49 mmol; 1.20 eq.) general procedure H for amide coupling was followed to afford tert-butyl 4-(2-{4-[4-(2,6- dioxopiperidin-3-yl)phenyl]piperazin-1-yl}-2-oxoethyl)piperazine-1-carboxylate (140.0 mg; 0.28 mmol; 67.1 %). LC MS Method U: [M+H]+500.3; Rt: 1.11 min Intermediate 105b: 3-(4-{4-[2-(piperazin-1-yl)acetyl]piperazin-1- yl}phenyl)piperidine-2,6-dione; trifluoroacetic acid Starting from Intermediate 105a (140.0 mg; 0.28 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 3-(4-{4-[2-(piperazin-1- yl)acetyl]piperazin-1-yl}phenyl)piperidine-2,6-dione; trifluoroacetic acid (160.0 mg; 0.31 mmol; 113.5 %). LC MS Method U: [M+H]+400.2; Rt: 0.84 min Intermediate 106: 4-(4-nitrophenyl)-1,4'-bipiperidine -192-Attorney Docket No. : P24-187-WO-PCTtert-butyl 4-(4-nitrophenyl)-[1,4'-bipiperidine]-1'-carboxylate To a stirred mixture of 4-(4-nitrophenyl)piperidine (1.00 g; 4.61 mmol; 1.00 eq.) and tert-butyl 4-oxopiperidine-1-carboxylate (1.06 g; 5.07 mmol; 1.10 eq.) in DCM (10.00 mL) and MeOH (10.00 mL) , was added NaOAc (1.99 g; 23.03 mmol; 5.00 eq.) at room temperature. The mixture was stirred for 1 h at room temperature. Then NaBH3CN (1.22 g; 18.43 mmol; 4.00 eq.) was added and the mixture was stirred for 12 h at room temperature. The resulting mixture was quenched by water and extracted with EA. 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 (1:1) to afford tert-butyl 4-(4-nitrophenyl)-[1,4'-bipiperidine]-1'-carboxylate (1.80 g; 4.46 mmol; 96.9 %) as a yellow oil. LC MS Method N: [M+H]+390.2; Rt: 0.63 min 4-(4-nitrophenyl)-1,4'-bipiperidine Starting from tert-butyl 4-(4-nitrophenyl)-[1,4'-bipiperidine]-1'-carboxylate (1.79 g; 4.44 mmol; 1.00 eq.) general procedure B for Boc deprotection was followed to afford 4-(4-nitrophenyl)-1,4'-bipiperidine (1.10 g; 3.65 mmol; 82.3 % yield) as a yellow solid. LC MS Method N: [M+H]+290.1; Rt: 0.36 min Intermediate 107: 1-{4-[4-(4-aminophenyl)-[1,4'-bipiperidin]-1'-yl]-2- methylphenyl}-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione -193-Attorney Docket No. : P24-187-WO-PCT3-[(4-methoxyphenyl)methyl]-1-{2-methyl-4-[4-(4-nitrophenyl)-[1,4'- bipiperidin]-1'-yl]phenyl}-1,3-diazinane-2,4-dione To a stirred mixture of Intermediate 1064-(4-nitrophenyl)-1,4'-bipiperidine (500.0 mg; 1.66 mmol; 1.00 eq.) and Intermediate 521-(4-bromo-2-methylphenyl)-3-[(4- methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (679.8 mg; 1.66 mmol; 1.00 eq.) in 1,4-dioxane (18.00 mL) and Cs2CO3 (1.14 g; 3.32 mmol; 2.00 eq.) were added Xphos (83.32 mg; 0.17 mmol; 0.10 eq.) and Pd2(dba)3 (320.1 mg; 0.33 mmol; 0.20 eq.) at room temperature. The mixture was stirred for 2 h at 100 °C. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with DCM / MeOH (1:1) to afford 3-[(4- methoxyphenyl)methyl]-1-{2-methyl-4-[4-(4-nitrophenyl)-[1,4'-bipiperidin]-1'- yl]phenyl}-1,3-diazinane-2,4-dione (820.0 mg; 0.98 mmol; 58.8 %) as a yellow oil. LC MS Method AD: [M+H]+612.2; Rt: 0.79 min 1-{4-[4-(4-aminophenyl)-[1,4'-bipiperidin]-1'-yl]-2-methylphenyl}-3-[(4- methoxyphenyl)methyl]-1,3-diazinane-2,4-dione Starting from 3-[(4-methoxyphenyl)methyl]-1-{2-methyl-4-[4-(4-nitrophenyl)-[1,4'- bipiperidin]-1'-yl]phenyl}-1,3-diazinane-2,4-dione (800.0 mg; 0.95 mmol; 1.00 eq.) the general procedure G for reduction under hydrogen was followed in the presence of EtOH (20.00 mL) and Pd / C (2.03 g; 1.90 mmol; 2.00 eq.) to afford 1-{4-[4-(4- aminophenyl)-[1,4'-bipiperidin]-1'-yl]-2-methylphenyl}-3-[(4- methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (510.0 mg; 0.86 mmol; 90.0 %) as a yellow solid. LC MS Method AD: [M+H]+612.2; Rt: 0.79 min Intermediate 108: 1-{4-[1'-(4-aminophenyl)-[1,4'-bipiperidin]-4-yl]-2- methylphenyl}-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione -194-Attorney Docket No. : P24-187-WO-PCTtert-butyl 4-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}-3- methylphenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate Starting from Intermediate 52 (2.00 g; 4.76 mmol; 1.00 eq.) and tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (1.75 g; 4.75 mmol; 1.00 eq.) general procedure O for Suzuki coupling was to afford tert- butyl 4-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}-3- methylphenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate (2.40 g; 4.58 mmol; 96.1 %) as a yellow oil. LC MS Method AD: [M+H]+506.0; Rt: 1.03 min 3-[(4-methoxyphenyl)methyl]-1-[2-methyl-4-(1,2,3,6-tetrahydropyridin-4- yl)phenyl]-1,3-diazinane-2,4-dione hydrochloride Starting from tert-butyl 4-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan- 1-yl}-3-methylphenyl)-1,2,3,6-tetrahydropyridine-1-carboxylate (2.40 g; 4.58 mmol; 1.00 eq.) general procedure C for Boc deprotection was followed in the presence of HCl (2.0 M Solution in EA) (24.00 mL) to afford 3-[(4-methoxyphenyl)methyl]-1-[2- methyl-4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-1,3-diazinane-2,4-dione hydrochloride (2.10 g; 4.57 mmol; 99.8 %) as a yellow oil. LC MS Method AD: [M+H]+406.0; Rt: 0.68 min tert-butyl 4-[4-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl}-3- methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl]piperidine-1-carboxylate To a stirred solution of 3-[(4-methoxyphenyl)methyl]-1-[2-methyl-4-(1,2,3,6- tetrahydropyridin-4-yl)phenyl]-1,3-diazinane-2,4-dione hydrochloride (2.00 g; 4.35 mmol; 1.00 eq.) and tert-butyl 4-oxopiperidine-1-carboxylate (4.56 g; 21.74 mmol; -195-Attorney Docket No. : P24-187-WO-PCT 5.00 eq.) in DCM (10.00 mL) and MeOH (10.00 mL) were added AcOH (261.0 mg; 4.35 mmol; 1.00 eq.) and NaBH3CN (1.14 g; 17.42 mmol; 4.00 eq.) at room temperature. The resulting mixture was stirred for 1 d at room temperature. The resulting mixture was quenched with water (150 mL) and 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. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (20:1) to afford tert-butyl 4-(4-{4-[(2,6-dioxopiperidin-3-yl)amino]-2- fluorophenyl}piperazin-1-yl)piperidine-1-carboxylate (1.20 g; 2.44 mmol; 84.2 %) as a light yellow solid. LC MS Method M: [M+H]+589.0; Rt: 0.58 min 3-[(4-methoxyphenyl)methyl]-1-{2-methyl-4-[1-(piperidin-4-yl)-1,2,3,6- tetrahydropyridin-4-yl]phenyl}-1,3-diazinane-2,4-dione Starting from tert-butyl 4-[4-(4-{3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3- diazinan-1-yl}-3-methylphenyl)-1,2,3,6-tetrahydropyridin-1-yl]piperidine-1- carboxylate (2.00 g; 3.36 mmol; 1.00 eq.) general procedure C for Boc deprotection was to afford 3-[(4-methoxyphenyl)methyl]-1-{2-methyl-4-[1-(piperidin-4-yl)- 1,2,3,6-tetrahydropyridin-4-yl]phenyl}-1,3-diazinane-2,4-dione (1.60 g; 3.17 mmol; 94.4 % yield) as a yellow solid. LC MS Method AD: [M+H]+489.0; Rt: 0.64 min 3-[(4-methoxyphenyl)methyl]-1-(2-methyl-4-{1-[1-(4-nitrophenyl)piperidin-4-yl]- 1,2,3,6-tetrahydropyridin-4-yl}phenyl)-1,3-diazinane-2,4-dione To a stirred solution of 3-[(4-methoxyphenyl)methyl]-1-{2-methyl-4-[1-(piperidin-4- yl)-1,2,3,6-tetrahydropyridin-4-yl]phenyl}-1,3-diazinane-2,4-dione (1.60 g; 3.17 mmol; 1.00 eq.) and 1-fluoro-4-nitrobenzene (942.0 mg; 6.34 mmol; 2.00 eq.) in ACN (16.00 mL) was added K2CO3(922.0 mg; 6.34 mmol; 2.00 eq.) in portion at room temperature. The resulting mixture was stirred for 3 h at 90 °C. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford 3-[(4- methoxyphenyl)methyl]-1-(2-methyl-4-{1-[1-(4-nitrophenyl)piperidin-4-yl]-1,2,3,6- tetrahydropyridin-4-yl}phenyl)-1,3-diazinane-2,4-dione (1.40 g; 2.25 mmol; 71.0 %) as a yellow solid. LC MS Method AD: [M+H]+610.0; Rt: 0.85 min -196-Attorney Docket No. : P24-187-WO-PCT 1-{4-[1'-(4-aminophenyl)-[1,4'-bipiperidin]-4-yl]-2-methylphenyl}-3-[(4- methoxyphenyl)methyl]-1,3-diazinane-2,4-dione To a solution of 3-[(4-methoxyphenyl)methyl]-1-(2-methyl-4-{1-[1-(4- nitrophenyl)piperidin-4-yl]-1,2,3,6-tetrahydropyridin-4-yl}phenyl)-1,3-diazinane-2,4- dione (1.40 g; 2.25 mmol; 1.00 eq.) in DMF (14.00 mL) was added Pd / C (240.0 mg; 0.23 mmol; 0.10 eq.). The mixture was stirred for 16 h at 25 °C under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with 50 mL of EA. The filtrate was diluted with H2O at room temperature and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 1-{4-[1'-(4-aminophenyl)-[1,4'-bipiperidin]-4-yl]-2- methylphenyl}-3-[(4-methoxyphenyl)methyl]-1,3-diazinane-2,4-dione (1.00 g; 1.62 mmol; 71.9 %) as a yellow solid. LC MS Method AD: [M+H]+582.0; Rt: 0.66 min Intermediate 109a and 109b: 6-[(piperidin-4-yl)methyl]-2H-spiro[1-benzofuran- 3,3'-piperidine]-2',6'-dione hydrochloridetert-butyl 4-{[3-(ethoxycarbonyl)-1-benzofuran-6-yl]methylidene}piperidine-1- carboxylate To a stirred mixture of ethyl 6-bromo-1-benzofuran-3-carboxylate (15.00 g; 52.96 mmol; 1.00 eq.) and tert-butyl 4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)methylidene]piperidine-1-carboxylate (18.00 g; 54.57 mmol; 1.03 eq.) in Dioxane- 1,4 (250.0 mL) and H2O (50.00 mL) were added Pd(dppf)Cl2•DCM (4.60 g; 5.46 mmol; 0.10 eq.) and CsF (25.00 g; 156.4 mmol; 2.95 eq.). The resulting mixture was stirred for 2h at 100 ºC under N2. The reaction mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced -197-Attorney Docket No. : P24-187-WO-PCT pressure and purified by silica gel column chromatography, eluted with PE / EtOAc (1:1) to afford tert-butyl 4-{[3-(ethoxycarbonyl)-1-benzofuran-6- yl]methylidene}piperidine-1-carboxylate (16.37 g; 38.21 mmol; 72.2 %) as an orange solid. LC MS Method AD: [M-Boc+H]+286.0; Rt: 1.44 min tert-butyl 4-{[3-(ethoxycarbonyl)-1-benzofuran-6-yl]methyl}piperidine-1- carboxylate To a stirred solution of tert-butyl 4-{[3-(ethoxycarbonyl)-1-benzofuran-6- yl]methylidene}piperidine-1-carboxylate (5.00 g; 11.67 mmol; 1.00 eq.) in MeOH (100.0 mL) was added Raney Ni (5.00 g; 80.93 mmol; 6.93 eq.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under hydrogen atmosphere. The reaction mixture was concentrated under reduced pressure to afford tert-butyl 4-{[3-(ethoxycarbonyl)-1-benzofuran-6- yl]methyl}piperidine-1-carboxylate (4.80 g; 11.47 mmol; 98.3 %)Ü as a yellow oil. LC MS Method O: [M+H-15]+373.1; Rt: 1.43 min tert-butyl 4-{[3-(methoxycarbonyl)-2,3-dihydro-1-benzofuran-6- yl]methyl}piperidine-1-carboxylate To a stirred solution of tert-butyl 4-{[3-(ethoxycarbonyl)-1-benzofuran-6- yl]methyl}piperidine-1-carboxylate (4.70 g; 11.23 mmol; 1.00 eq.) in MeOH (100.0 mL) was added Mg (4.00 g; 156.31 mmol; 13.9 eq.) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The reaction was filtered and the filter cake was washed with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 50 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with DCM / EtOAc (5:1) to afford tert-butyl 4-{[3- (methoxycarbonyl)-2,3-dihydro-1-benzofuran-6-yl]methyl}piperidine-1-carboxylate (2.70 g; 6.24 mmol; 55.6 %) as a yellow oil. LC MS Method AE: [M+H]+376.3; Rt: 1.25 min Intermediate 109a: tert-butyl 4-({2',6'-dioxo-2H-spiro[1-benzofuran-3,3'- piperidin]-6-yl}methyl)piperidine-1-carboxylate To a stirred solution of tert-butyl 4-{[3-(methoxycarbonyl)-2,3-dihydro-1- benzofuran-6-yl]methyl}piperidine-1-carboxylate (7.00 g; 16.19 mmol; 1.00 eq.) in THF (100.0 mL) was added t-BuOK (2.40 g; 20.32 mmol; 1.25 eq.). After 30 minutes -198-Attorney Docket No. : P24-187-WO-PCT prop-2-enamide (1.20 g; 16.55 mmol; 1.02 eq.) was added at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The reaction mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with DCM / EtOAc (5:1) to afford tert-butyl 4-({2',6'-dioxo-2H-spiro[1-benzofuran-3,3'- piperidin]-6-yl}methyl)piperidine-1-carboxylate (4.30 g; 9.73 mmol; 60.1 %) as a white solid. LC MS Method AD: [M+H-tBu]+359.1; Rt: 0.94 min Intermediate 109b: 6-[(piperidin-4-yl)methyl]-2H-spiro[1-benzofuran-3,3'- piperidine]-2',6'-dione hydrochloride Intermediate 109a (100.0 mg; 0.24 mmol; 1.00 eq.) was dissolved in 4M HCl in EA (5.00 mL; 20.00 mmol; 84.6 eq.) at room temperature. The mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 6-[(piperidin-4-yl)methyl]-2H-spiro[1-benzofuran-3,3'-piperidine]- 2',6'-dione hydrochloride (90.00 mg; 0.23 mmol; 98.8 %) as a yellow solid. LC MS Method AD: [M+H]+315.5; Rt: 0.58 min Intermediate 110: 6-({[1,4'-bipiperidin]-4-yl}methyl)-2H-spiro[1-benzofuran- 3,3'-piperidine]-2',6'-dione hydrochloridetert-butyl 4-({2',6'-dioxo-2H-spiro[1-benzofuran-3,3'-piperidin]-6-yl}methyl)- [1,4'-bipiperidine]-1'-carboxylate To a stirred mixture of Intermediate 109b 6-[(piperidin-4-yl)methyl]-2H-spiro[1- benzofuran-3,3'-piperidine]-2',6'-dione hydrochloride (130.0 mg; 0.35 mmol; 1.00 eq.) and tert-butyl 4-oxopiperidine-1-carboxylate (591.0 mg; 2.82 mmol; 8.05 eq.) in DCM (8.00 mL) and MeOH (8.00 mL) were added NaOAc (52.00 mg; 0.60 mmol; 1.72 eq.) and AcOH (94.00 mg; 1.49 mmol; 4.25 eq.) at room temperature. The mixture was stirred for 1 h at room temperature. Then NaBH3CN (21.00 mg; 0.32 -199-Attorney Docket No. : P24-187-WO-PCT mmol; 0.91 eq.) was added. The mixture was stirred for 12 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 tert-butyl 4- ({2',6'-dioxo-2H-spiro[1-benzofuran-3,3'-piperidin]-6-yl}methyl)-[1,4'-bipiperidine]- 1'-carboxylate (110.0 mg; 0.17 mmol; 49.5 % yield) as a yellow oil. LC MS Method N: [M+H]+498.3; Rt: 0.63 min 6-({[1,4'-bipiperidin]-4-yl}methyl)-2H-spiro[1-benzofuran-3,3'-piperidine]-2',6'- dione hydrochloride Tert-butyl 4-({2',6'-dioxo-2H-spiro[1-benzofuran-3,3'-piperidin]-6-yl}methyl)-[1,4'- bipiperidine]-1'-carboxylate (130.0 mg; 0.20 mmol; 1.00 eq.) was dissolved in 4M HCl in EA (5.00 mL; 20.00 mmol; 97.65 eq.) at room temperature. The mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 6-({[1,4'-bipiperidin]-4-yl}methyl)-2H-spiro[1-benzofuran- 3,3'-piperidine]-2',6'-dione hydrochloride (110.0 mg; 0.18 mmol; 90.1 %) as a white solid. LC MS Method AD: [M+H]+434.2; Rt: 0284 min Intermediate 111: 3-{2-fluoro-4-[3-(piperazin-1-yl)azetidin-1- yl]phenyl}piperidine-2,6-dione; trifluoroacetic acid2,6-bis(benzyloxy)-3-(4-bromo-2-fluorophenyl)pyridine To a stirred solution of 4-bromo-2-fluoro-1-iodobenzene (1.00 g; 3.16 mmol; 1.00 eq.) and Intermediate 30 (1.39 g; 3.16 mmol; 1.00 eq.) in 1,4-dioxane (10.00 mL) and H2O (3.30 mL) were added K2CO3 (919.0 mg; 6.32 mmol; 2.00 eq.) and Pd(PPh3)4 (384.0 mg; 0.32 mmol; 0.10 eq.) at 25 °C. The resulting mixture was stirred for 2 h at -200-Attorney Docket No. : P24-187-WO-PCT 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 2,6-bis(benzyloxy)-3-(4-bromo-2-fluorophenyl)pyridine (900.0 mg; 1.66 mmol; 52.6 %) as a yellow oil. LC MS Method AD: [M+H]+464.0; Rt: 1.27 min tert-butyl 4-(1-{4-[2,6-bis(benzyloxy)pyridin-3-yl]-3-fluorophenyl}azetidin-3- yl)piperazine-1-carboxylate To a stirred mixture of 2,6-bis(benzyloxy)-3-(4-bromo-2-fluorophenyl)pyridine (880.0 mg; 1.62 mmol; 1.00 eq.) and tert-butyl 4-(azetidin-3-yl)piperazine-1- carboxylate (412.0 mg; 1.62 mmol; 1.00 eq.) in Dioxane-1,4 (10.00 mL) were added Xphos (162.00 mg; 0.32 mmol; 0.20 eq.), Pd2(dba)3 (165.00 mg; 0.16 mmol; 0.10 eq.) and Cs2CO3 (1.17 g; 3.24 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 and purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 4-(1-{4-[2,6- bis(benzyloxy)pyridin-3-yl]-3-fluorophenyl}azetidin-3-yl)piperazine-1-carboxylate (670.0 mg; 1.04 mmol; 64.3 %) as a yellow solid. LC MS Method AD: [M+H]+625.0; Rt: 1.01 min tert-butyl 4-{1-[4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl]azetidin-3- yl}piperazine-1-carboxylate To a solution of tert-butyl 4-(1-{4-[2,6-bis(benzyloxy)pyridin-3-yl]-3- fluorophenyl}azetidin-3-yl)piperazine-1-carboxylate (630.0 mg; 0.98 mmol; 1.00 eq.) in Dioxane-1,4 (6.00 mL) was added Pd(OH)2 / C (15.00 mg; 0.10 mmol; 0.10 eq.). The mixture was stirred for 16 h at 25 °C under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with 50 mL of EA. The filtrate was diluted with H2O at room temperature and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 4-{1-[4-(2,6-dioxopiperidin-3-yl)-3- fluorophenyl]azetidin-3-yl}piperazine-1-carboxylate (450.0 mg; 0.97 mmol; 99.0 %) as a gray solid. LC MS Method AD: [M+H]+447.0; Rt: 0.67 min 3-{2-fluoro-4-[3-(piperazin-1-yl)azetidin-1-yl]phenyl}piperidine-2,6-dione; trifluoroacetic acid -201-Attorney Docket No. : P24-187-WO-PCT Starting from tert-butyl 4-{1-[4-(2,6-dioxopiperidin-3-yl)-3-fluorophenyl]azetidin-3- yl}piperazine-1-carboxylate (350.0 mg; 0.76 mmol; 1.00 eq.) the general procedure B for Boc deprotection was followed to afford 3-{2-fluoro-4-[3-(piperazin-1-yl)azetidin- 1-yl]phenyl}piperidine-2,6-dione; trifluoroacetic acid (240.0 mg; 0.51 mmol; 68.0 %) as a gray solid. LC MS Method AF: [M+H]+347.0; Rt: 0.60 min Intermediate 112: 3-{3-fluoro-4-[3-(piperazin-1-yl)azetidin-1- yl]phenyl}piperidine-2,6-dione; trifluoroacetic acid2,6-bis(benzyloxy)-3-(4-bromo-3-fluorophenyl)pyridine To a stirred solution of 1-bromo-2-fluoro-4-iodobenzene (1.00 g; 3.16 mmol; 1.00 eq.) and Intermediate 30 (1.39 g; 3.16 mmol; 1.00 eq.) in 1,4-dioxane (10.00 mL) and H2O (3.30 mL) were added K2CO3(919.0 mg; 6.32 mmol; 2.00 eq.) and Pd(PPh3)4(384.0 mg; 0.32 mmol; 0.10 eq.) at 25 °C. The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 2,6-bis(benzyloxy)-3-(4-bromo-3-fluorophenyl)pyridine (1.00 g; 1.85 mmol; 58.5 %) as a yellow oil. LC MS Method AD: [M+H]+464.0; Rt: 1.28 min tert-butyl 4-(1-{4-[2,6-bis(benzyloxy)pyridin-3-yl]-2-fluorophenyl}azetidin-3- yl)piperazine-1-carboxylate To a stirred mixture of 2,6-bis(benzyloxy)-3-(4-bromo-3-fluorophenyl)pyridine (500.0 mg; 0.92 mmol; 1.00 eq.) and tert-butyl 4-(azetidin-3-yl)piperazine-1- carboxylate (234.0 mg; 0.92 mmol; 1.00 eq.) in Dioxane-1,4 (10.00 mL) were added -202-Attorney Docket No. : P24-187-WO-PCT Xphos (93.00 mg; 0.19 mmol; 0.20 eq.), Pd2(dba)3 (94.00 mg; 0.09 mmol; 0.10 eq.) and Cs2CO3 (668.0 mg; 1.85 mmol; 2.00 eq.) at room temperature. The mixture was stirred for overnight at 100 °C under argon atmosphere. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford tert-butyl 4-(1-{4-[2,6- bis(benzyloxy)pyridin-3-yl]-2-fluorophenyl}azetidin-3-yl)piperazine-1-carboxylate (360.0 mg; 0.57 mmol; 62.0 %) as a yellow oil. LC MS Method AD: [M+H]+625.0; Rt: 1.02 min tert-butyl 4-{1-[4-(2,6-dioxopiperidin-3-yl)-2-fluorophenyl]azetidin-3- yl}piperazine-1-carboxylate To a solution of tert-butyl 4-(1-{4-[2,6-bis(benzyloxy)pyridin-3-yl]-2- fluorophenyl}azetidin-3-yl)piperazine-1-carboxylate (320.0 mg; 0.51 mmol; 1.00 eq.) in DMF (5.00 mL) was added Pd / C (54.00 mg; 0.05 mmol; 0.10 eq.). The mixture was stirred for 16 h at 25 °C under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with 50 mL of EA. The filtrate was diluted with H2O at room temperature and extracted with EA (3 x 30 mL). The combin...

Claims

Attorney Docket No. : P24-187-WO-PCT CLAIMS What is claimed:

1. A compound of formula I or a prodrug or pharmaceutically acceptable salt thereof,wherein: R1 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, hydrogen, OH, -O-C1-C6 alkyl, halogen, -NR’R’’ and -CN; R’ and R’’ are independently selected for each occurrence from the group consisting of hydrogen and C1-C6 alkyl; R2 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, 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, R9 and R10 are each independently selected from the group consisting of C1-C6 alkyl, hydrogen and halogen; or R8 and R9 maybe taken together with the carbons to which they are attached to form a 3, 4, 5 or 6 membered carbocycle; or R7 and R10 maybe taken together with the -819-Attorney Docket No. : P24-187-WO-PCT carbons to which they are attached to form a 3, 4, 5 or 6 membered carbocycle; W is selected from the group consisting of N and CH; Z is selected from the group consisting of CH, CR11 and 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 of -820-Attorney Docket No. : P24-187-WO-PCT-821-Attorney Docket No. : P24-187-WO-PCT-822-Attorney Docket No. : P24-187-WO-PCTR12is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6alkyl and C1-C6haloalkyl; R13 is hydrogen or C1-C6 alkyl; X is selected from the group consisting of -CH2-, -NR14- and -O-; R14 is hydrogen or C1-C6 alkyl; qq is 1, 2, 3 or 4; Ar is selected from the group consisting of-823-Attorney Docket No. : P24-187-WO-PCT R15 is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6 alkyl and C1-C6 haloalkyl; A is either absent or selected from the group consisting of (-CH2-)n, - O-,R16 is hydrogen or C1-C6 alkyl; R17 is hydrogen or C1-C6 alkyl; R18is selected independently for each position capable of substitution from the group consisting of hydrogen, halogen, C1-C6 alkyl and C1-C6 haloalkyl; 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; -824-Attorney Docket No. : P24-187-WO-PCT 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,-825-Attorney Docket No. : P24-187-WO-PCT-826-Attorney Docket No. : P24-187-WO-PCT-827-Attorney Docket No. : P24-187-WO-PCTR19is 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 or 4; nn is 0, 1, 2, 3 or 4; oo is 0, 1, 2, 3 or 4; 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.

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 R1 is -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 R2 is hydrogen.

9. The compound according to claim 1 wherein R3, R5, R6, R7, R9and R10are hydrogen and R4and R8are -CH3.

10. The compound according to claim 1 wherein R3, R4, R7, R8, R9 and R10 are hydrogen and R5and R6are -F.

11. The compound according to claim 1 wherein R3, R4, R5, R6, R9and R10are hydrogen and R7 and R8 are -F. -828-Attorney Docket No. : P24-187-WO-PCT 12. The compound according to claim 1 wherein R3, R4, R5, R6, R7, R8, R9 and R10 are 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 R13 is hydrogen or -CH3.

19. The compound according to claim 1 wherein R13 is -CH3.

20. The compound according to claim 1 wherein X is selected from the group consisting of. -CH2-, -NH-, -NCH3- and -O-.

21. The compound according to claim 1 wherein Ar is.

23. The compound according to claim 15 wherein Ar is.

24. The compound according to claim 23 wherein R15is hydrogen.

25. The compound according to claim 23 wherein R15 is halogen.

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

27. The compound according to claim 1 wherein A is absent. -829-Attorney Docket No. : P24-187-WO-PCT 28. The compound according to claim 1 wherein A is.

29. 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 is.

32. The compound according to claim 1 wherein A is.

33. 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 of -830-Attorney Docket No. : P24-187-WO-PCT-831-Attorney Docket No. : P24-187-WO-PCT-832-Attorney Docket No. : P24-187-WO-PCT.

37. 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 -833-Attorney Docket No. : P24-187-WO-PCT-834-Attorney Docket No. : P24-187-WO-PCT-835-Attorney Docket No. : P24-187-WO-PCT-836-Attorney Docket No. : P24-187-WO-PCT-837-Attorney Docket No. : P24-187-WO-PCT-838-Attorney Docket No. : P24-187-WO-PCT-839-Attorney Docket No. : P24-187-WO-PCT O N H N N N N O H N N N H N O N O N N N N N H N O N-840-Attorney Docket No. : P24-187-WO-PCT-841-Attorney Docket No. : P24-187-WO-PCT-842-Attorney Docket No. : P24-187-WO-PCTN N N N N O N O H N N N N N NH N O H N O N N -843-Attorney Docket No. : P24-187-WO-PCT-844-Attorney Docket No. : P24-187-WO-PCT-845-Attorney Docket No. : P24-187-WO-PCT O N H N N N N OH N N F N N F O N HOO O O OAttorney Docket No. : P24-187-WO-PCT O N-847-Attorney Docket No. : P24-187-WO-PCT-848-Attorney Docket No. : P24-187-WO-PCT O N H N N N N O H O O H H NOH N O O NH O NH O-849-Attorney Docket No. : P24-187-WO-PCT-850-Attorney Docket No. : P24-187-WO-PCT H-851-Attorney Docket No. : P24-187-WO-PCT O N N NH O O-852-Attorney Docket No. : P24-187-WO-PCT-853-Attorney Docket No. : P24-187-WO-PCT-854-Attorney Docket No. : P24-187-WO-PCTO N HOH N N H N N O N N F N H N O N O N N O NH O O O F OH HN F F O O O H HN F N N N O N N N N O N -855-Attorney Docket No. : P24-187-WO-PCTor a prodrug or pharmaceutically acceptable salt thereof. -856-Attorney Docket No. : P24-187-WO-PCT 40. A compound selected from Table 3 or a prodrug or pharmaceutically acceptable salt thereof.

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

42. A method, comprising: administering to a patient having an HPK1-mediated disorder a therapeutically effective amount of the compound of claim 1, 39 or 40 or a pharmaceutically acceptable salt thereof.

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

44. The method of claim 43, 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.

45. The method of claim 42, 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 / kg of 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.

46. The method of claim 42, 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.

47. The method of claim 42, wherein the compound is administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir.

48. The method of claim 42, wherein the compound is administered subcutaneously, intravenously, intramuscularly, intra-articularly, intra- synovially, intrasternally, intrathecally, intrahepaticly, intralesionally, and by intracranial injection or infusion technique. -857-

Images